Professional Documents
Culture Documents
Collaborators
S. Nassir Ghaemi, M.D., M.P.H.
Emory University
Professor of Psychiatry
and
Hagop S. Akiskal, M.D.
Professor of Psychiatry
University of California, San Diego
Professor of Psychiatry
University of New Mexico School of Medicine
Second Edition
Manic-Depressive Illness
Bipolar Disorders and Recurrent Depression
Professor of Psychiatry
The George Washington University Medical Center
Professor of Psychiatry
The Johns Hopkins University School of Medicine
1
2007
1
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In memory of
Richard Wyatt, M.D.,
husband and colleague
K.R.J.
Foreword
The original version of this book, published in 1990, was a
unique contribution to the literature on manic-depressive
illness. For a long time, certainly since Bleuler and Schneider developed broad criteria for schizophrenia, manicdepressive illness had been neglected both as a clinical
diagnosis and as a topic for research. The influence of psychoanalysis and Meyers psychobiology exacerbated this
neglect. Meaningful attention to the illness began to increase with the discovery of lithium as a surprisingly effective treatment for mania (this book is very appropriately
dedicated to John Cade and Mogens Schou). But it was
Goodwin and Jamisons work, coming at a time when
manic-depressive illness remained curiously marginalized
in the scientific literature, that gave the subject the treatment
it deserved. Remarkably, their text was lengthy enough to
allow detailed accounts and comprehensive summaries of
all the available literature while at the same time being accessible in style and presentation, with an authentic continuity in the voice of its two authors.
Kay Jamison and Fred Goodwin are, of course, giants
in this field, and their contribution seemed even then a remarkable one: Jamison for her profound clinical and psychological understanding, and Goodwin for his immense
pharmacological and biological knowledge. To attempt a
repeat of their efforts in a new edition was an enormous
challenge, especially since the rapid expansion of scientific and clinical information that has occurred in the last
20 years has made the single- or dual-author textbook an
increasingly endangered species. The authors solution for
this new edition of Manic-Depressive Illness is an innovative one that works exceedingly well: by enlisting the help of
close colleagues with various specialized interests and producing an interpretive synthesis of those views through the
filter of their own unparalleled expertise, they have avoided
creating a compilation of chapters written by individual authors and preserved the unity and structure of the original
work.
The book is divided into five parts covering the diagnosis,
clinical characteristics, psychology, pathophysiology, and
treatment of manic-depressive illness. It is an exceptional
record of the current state of the art, and we are confident
viii
Foreword
Emil Kraepelin, quoting Anton Mueller, in Hundert Jahre Psychiatrie (Berlin: Verlag von Julius Springer, 1918), p. 112.
Acknowledgments
Without the sustained commitment and clinical and scientific expertise of our collaborators, whose names appear opposite the title page, there would be no second edition of
Manic-Depressive Illness. We are immensely indebted to
them for their time and scholarship. The collaborators individual contributions ranged from a slight to substantial
updating of a first-edition chapter (retaining the original
organization and most of the original material) to, in a few
instances, the drafting of an entirely new chapter; most
contributions fell somewhere in between. They followed
general guidelines formulated by us, including our specifications about the conceptualization and usage of the terms
manic-depressive illness and bipolar disorder, the critical
need for rigorous and impartial review, and the shared goal
of contributing to a book that would maintain the unified
authorship voice of the first edition. There was extensive interaction between us and our collaborators throughout,
with many drafts of each chapter going back and forth.
In each case the last draft provided to us by a collaborator was revised and updated, usually extensively, by one or
both of us. When our judgment about a specific clinical or
scientific point differed from that of a collaborator, which
was not infrequently the case, we carefully considered the
collaborators point of view before making a final decision.
In the end, the two authors take responsibility for the contents of the book.
The collaborators would like to acknowledge the contributions of Po Wang and John Brooks (Dr. Ketter); Susan
Bachus, Lisa Catapano, Guang Chen, Jing Du, Holly A.
Giesen, Fatemi Hosein, Libby Jolkovsky, Celia Knobelsdorf,
Phillip Kronstein, Rodrigo Machado-Vieira, Andrew Newberg, Jennifer Payne, Jorge Quiroz, Giacomo Salvadore,
Peter J. Schmidt, Jaskaran Singh, and Carlos A. Zarate, Jr.
(Dr. Manji); Al Lewy, Joseph Soriano, John Stiller, Leonardo
Tonelli, and Thomas Wehr (Dr. Postolache); Gregory Fuller
(Dr. Potash); Rice Fuller (Dr. Sackeim); and Helena Verdeli
(Dr. Weissman). Drs. Goodwin and Jamison would like to
acknowledge additional colleagues who reviewed chapters
or otherwise provided input: Jules Angst, Ross Baldessarini,
Robert Belmaker, Charles Bowden, Joseph Calabrese, Kiki
Chang, Guy Goodwin, Heinz Grunze, Dean Jamison,
Acknowledgments
Contents
Introduction
Part I
1
Clinical Description
Manic States
Classic Clinical Descriptions
Subjective Experiences of Patients
Clinical Studies
Depressive States
Classic Clinical Descriptions
Subjective Experiences of Patients
Clinical Studies
Mixed States
Classic Clinical Descriptions
Subjective Experiences of Patients
Clinical Studies
Cyclothymia and Manic-Depressive Temperaments
Classic Clinical Descriptions
Clinical Studies
Conclusions
Diagnosis
Development of Contemporary Diagnostic Systems
ICD-6 through ICD-9 and DSM-I
and DSM-II
ix
3
3
3
5
7
8
8
9
13
14
15
15
18
19
24
29
32
32
37
40
65
65
68
71
72
72
77
78
82
82
84
86
89
89
90
Part II
4
91
92
93
93
96
96
98
99
100
100
100
101
102
102
102
104
106
107
107
108
108
109
112
Clinical Studies
Course and Outcome
Methodological Issues
Premorbid Functioning
Age at Onset
Number of Episodes
Frequency of Episodes (Cycle Length)
Decrease in Well Intervals with Increasing
Number of Episodes
Other Cycle-Length Patterns
Rapid Cycling
Onset and Duration of Episodes
Polarity
Pattern
Precipitants of Episodes
Long-Term Outcome
Modern Prospective Cohort Studies
Other Features of Long-Term Outcome
119
119
120
120
126
128
128
131
131
133
133
135
135
141
141
144
xii
Contents
Mortality
Bipolar-II Disorder
Mechanisms of Recurrence
Conclusions
Epidemiology
Application of Epidemiologic
Methods in Studies of Psychiatric
Disorders
Methodological Issues
Variable Diagnostic Criteria
Age-Specific Issues
Diagnostic Methods
Nonresponse or Refusal to Participate
in the Survey
Other Issues
Community Surveys among Adults
New Haven Survey
The Amish Study
Epidemiologic Catchment Area Study
National Comorbidity Survey
Cross-National Collaborative Group
Other International Studies
Bipolar Spectrum
Community Surveys with Children
and Adolescents
Global Burden of Disease Studies
World Mental Health Study, 2000
Associated Features
Temporal Variations
Gender
Social Class
Race/Ethnicity and Cultural Differences
Marital Status
Urban/Rural Comparisons
The Homeless and the Institutionalized
Pregnancy and Menopause
Smoking
Omega-3 Fatty Acids
Family History
Conclusions
146
146
149
149
155
7
155
157
157
158
160
206
Comorbidity
223
225
225
227
233
236
237
237
238
239
239
239
240
240
240
241
242
243
244
244
160
161
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162
162
163
165
165
171
175
176
178
180
181
181
181
181
182
183
183
183
184
184
184
185
185
Suicide
Diagnostic and Methodological Issues
Suicide Rates
Rates in the General Population
Rates in Manic-Depressive Illness
BipolarUnipolar Differences
Bipolar-I versus Bipolar-II Disorder
Differences by Gender
Seasonality
Causes of Suicide
Genetic and Family Transmission
Neurobiological Factors
Psychological Traits and Temperament
Social Factors
Clinical Correlates of Suicide
History of Suicide Attempts
Mixed States
Depression
Rapid Cycling
Anxiety and Agitation
Comorbidity and Axis II Disorders
Substance Abuse
Psychosis
Course of Illness
Conclusions
187
188
188
191
195
196
196
197
199
207
217
220
247
247
249
249
249
250
250
251
251
255
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259
261
262
262
262
263
263
264
265
266
266
267
267
269
204
Part III
205
205
206
Psychological Studies
Neuropsychology
Contributions of Neuropsychological Evaluation
Objectifying Clinical Constructs
273
273
273
Contents
10
Personality Disorders
Interpersonal Functioning
273
274
274
11
275
276
278
282
289
291
298
300
302
304
305
305
308
310
313
313
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315
318
320
321
321
321
323
323
324
324
325
326
326
329
330
332
333
334
337
337
343
350
352
352
Assessment
12
Creativity
Historical Background
Evidence for a Link between ManicDepressive Illness and Creativity
Methodological Issues
Biographical Studies
Studies of Living Writers and Artists
Family Studies
Hypothesized Relationships between
Manic-Depressive Illness and Creativity
Importance of Studying Positive Aspects of
Manic-Depressive Illness
Theoretical Considerations
Clinical Considerations
Social and Ethical Considerations
Conclusions
xiii
352
352
355
356
356
356
358
358
359
361
361
363
365
366
366
368
368
369
369
369
369
371
372
373
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373
374
374
376
376
376
378
379
379
381
381
383
389
394
397
402
402
403
405
406
xiv
Contents
Part IV
13
14
Pathophysiology
Genetics
History of the Study of Genetics
Early Observations
The Birth of Genetics
The German School of Psychiatric Genetics
Eugenics
PostWorld War II Era
Genetic Epidemiology of Manic-Depressive
Illness
Family Studies
Twin Studies
Adoption Studies
Advances in Understanding the Human Genome
The Linkage Method
The Method
LOD Score Approach
Affected Sibling Pair Method
Findings
Meta-analyses
Promising Linkage Regions
Complex Disorders
Alternative Phenotypic Definition
Clinical Subtypes of Major Depressive
Disorder
Clinical Subtypes of Bipolar Disorder
Endophenotypes
From the Book of Numbers to the Book
of Genesis: The Association Method
The Method
Promising Candidate Genes
Linkage Disequilibrium
Population Isolates
Consideration of Alternative Genetic Mechanisms
Anticipation and Trinucleotide Repeats
Parent-of-Origin Effect
Toward the Promised Land: Gene Expression
and Pathogenesis
Expression in the Brain
Expression in White Blood Cells
Testing Gene- and Allele-Specific Function
From Gene to Bedside: Pharmacogenetics
and Genetic Counseling
Pharmacogenetics
Genetic Counseling
Looking to the Future
Research Directions
Future Prospects for Patients
Conclusions
Genetic Epidemiology of Manic-Depressive
Illness
Advances in Understanding the Human
Genome
The Linkage Method
Alternative Phenotypic Definition
The Association Method
Alternative Genetic Mechanisms
Gene Expression and Pathogenesis
Pharmacogenetics and Genetic Counseling
Looking to the Future
413
414
419
421
422
423
423
425
426
426
426
427
430
430
430
431
435
436
436
443
445
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446
446
453
453
453
455
455
457
458
458
459
459
459
459
460
460
460
461
463
411
412
412
412
413
413
413
447
448
451
451
Neurobiology
15
609
611
611
612
617
621
625
627
627
629
637
637
Contents
638
639
652
652
653
653
Part V
17
16
659
659
660
660
664
665
665
666
667
667
667
668
669
670
671
672
673
673
673
674
678
678
678
679
680
682
682
18
683
684
688
Treatment
Fundamentals of Treatment
The Human and Economic Costs
of Manic-Depressive Illness
Real-World Pharmacotherapy and Its
Effectiveness
Structure and Rationale of the Treatment Chapters
Stages of Treatment
General Clinical Considerations
The Role of Lifestyle Changes in Optimizing
Treatment
Summary
Understanding and Interpreting the Treatment Research Literature
Observational (Naturalistic) Studies
Levels of Evidence and the Evidence-Based
Medicine Movement
The Bias against OffOn, OnOff (MirrorImage) and Crossover Designs, Even When
Placebo Controlled
Challenges in Interpreting Level I Studies
Treatment Guidelines and Algorithms
for Bipolar Disorder
Medications Used to Treat Manic-Depressive
Illness
Lithium
Anticonvulsants
Antidepressants
Typical Antipsychotics
Atypical Antipsychotics
Benzodiazepines
661
662
662
663
664
664
664
664
xv
699
699
701
702
702
703
705
705
706
706
706
707
707
712
715
715
716
717
719
719
719
721
721
722
722
723
725
726
727
728
729
729
733
736
737
742
742
xvi
Contents
19
20
21
Medication Adherence
Clinical Management
Clinician Attitudes
Suggestions for Facilitating Adherence
to Medication
Adjunctive Psychotherapy and Self-Help
Alliances
Review of the Literature
Definitional and Measurement Issues
Rates of Nonadherence among Bipolar
Patients
Reasons for Nonadherence
743
743
744
22
23
839
841
843
851
852
852
854
855
857
Psychotherapy
869
871
871
871
881
882
885
887
888
889
899
900
902
797
798
798
800
801
814
815
817
818
819
819
829
830
831
835
836
849
850
850
863
865
865
Clinical Management
Historical Context
Psychotherapeutic Issues
Mood Charting
Patient Education
Family Education and Family Therapy
National and Local Support Associations
Review of the Literature
Psychoeducation
Cognitive-Behavioral Therapy
Interpersonal and Social Rhythm Therapy
Family/Couples Therapy
Psychotherapy for Children and
Adolescents
Ongoing Effectiveness Studies
Meta-analyses of Psychological
Treatments
Conclusions
747
748
748
749
749
751
759
759
762
765
781
782
783
784
785
785
788
789
790
792
24
Treatment of Comorbidity
Substance Abuse
Pharmacological Treatment
Psychosocial Treatment
Anxiety Disorders
Panic Disorder
Social Anxiety Disorder
Obsessive-Compulsive Disorder
Post-traumatic Stress Disorder
902
903
904
904
907
907
907
908
909
909
912
912
915
915
916
917
917
917
929
929
929
930
930
932
933
933
933
934
937
937
939
945
946
946
947
947
948
Contents
25
948
949
949
949
950
951
953
953
953
954
956
957
958
Clinical Management
Management of Acute Risk Factors
Management of Chronic Risk Factors
Psychological Aspects of Treatment
Other Aspects of Treatment
Review of the Literature
Acute Clinical Management
Long-Term Suicide Prevention
Conclusions
xvii
958
959
960
961
964
966
966
967
975
977
981
1239
Introduction
Melancholia is the beginning and a part of mania . . . . The development of a mania is really a
worsening of the disease (melancholia) rather than a change into another disease.
Aretaeus of Cappadocia, ca. 100 AD 1
xx
Introduction
Introduction
xxi
xxii
Introduction
Clinical Studies
The second part covers various clinical aspects of manicdepressive illness. Appropriately, we begin in Chapter 4
with a discussion of course and outcome, fundamental
characteristics of the illness that provide the basis for differentiating it from schizophrenia. In addition to its obvi-
Introduction
Psychological Studies
Manic-depressive illness has been a rich source of theory
and data for investigators interested in psychological mechanisms. The third part of the book considers these developments. Manic-depressive illness has contributed to the
general study of psychology by serving as a paradigm for
explorations of state and trait differences. It also has been a
model for the general psychological assessment of cognition and for the more specific differentiation of cognition
in manic and depressive states from that in schizophrenia.
We begin with a survey of what is known about neuropsychological deficits in mood disorders, including recent
research documenting significant impairments in intellec-
xxiii
tual functioning, attention, learning and memory, and executive functioning (Chapter 9).
The psychological manifestations of manic-depressive
illness, observable in personality and behavior as well as
cognitive patterns, can result in profound discord in family
life and other social relationships; this is especially true for
those with the bipolar form of the illness. In Chapter 10 we
review studies of personality functioning in manic and depressed states and how it compares with that in normal
states in patients themselves and in the general population.
We also discuss personality disorders that commonly coexist with manic-depressive illness, as well as the effects of
medication on personality. The chapter then addresses interpersonal aspects of the illness, with emphasis on the
bipolar subgroup.
Chapter 11 is devoted to the wide array of methods that
now exists for assessing manic, mixed, and depressive
states; these assessment measures add the perspective of
formal psychological evaluation to the discussion of differential diagnosis in Chapter 3.
Widespread interest in creativity, the subject of Chapter
12, has lent visibility to this aspect of the study of manicdepressive illness. The age-old link between madness and
creativity has been studied with increasingly sophisticated
methods in recent years. Research has demonstrated that it
is not schizophrenia but manic-depressive illness, especially its bipolar forms, that is more often associated with
creative accomplishment. Among the most interesting developments in this field is the hypothesis that the genetic
predisposition for manic-depressive illness also confers
a creative edge on affected individuals and their close relatives. Explorations of the characteristics that help make
some individuals more creative than others should have
implications for the general population. Among the positive features of the bipolar form of the illness being examined in relation to creativity are the heightened energy level
and speed of cognition of hypomania, linked to a global, inclusive associative process, and certain temperamental factors; positive (and painful) experiences derived from having
affective illness are salient as well. In addition to raising
important psychological, social, and ethical issues, these
and related positive features of the bipolar form of the illness can play a key role in reducing the burden of stigma
borne by patients. Understanding these features is, of course,
necessary in dealing with one of the most sensitive and
difficult issues in treatmentmedication adherence.
Pathophysiology
The size of the fourth part of the book, the largest, testifies to the wealth of biological knowledge that has accrued through research on manic-depressive illness. The
illness has come to represent an extraordinarily rich
xxiv
Introduction
source of information about the interrelationships between behavioral and biological phenomena; certainly it
has stimulated fascinating and productive theories about
brainbehavior relationships.
We begin with a survey of the salient literature on genetics (Chapter 13). In this chapter we review genetic epidemiology, results of studies using the linkage method, alternative phenotypic definition, association methods, gene
expression and pathogenesis, pharmacogenetics, and genetic counseling. We then look at the future of the field, including new technologies and what we can expect to learn
from each.
Chapter 14, on neurobiology, provides the conceptual
base necessary for an appreciation of the biochemical and
pharmacological studies whose review follows. Much of
modern neurobiology and neuropharmacology has been
driven by efforts to understand the effects of moodaltering drugs. Indeed, attempts to understand why certain
drugs affect mood have inspired major hypotheses about
the neurobiology of behavior. The chapter also describes
animal models designed to simulate affective illness and
reviews the formidable literature on the major neurotransmitter, neuroendocrine, and neuropeptide systems involved
in manic-depressive illness, along with extensive new findings related to postsynaptic signal transduction networks
and gene expression.
With the emergence of highly sophisticated brainimaging technologies, it has become important to review
the anatomical correlates of mania and depression critically, if only to help guide the application of imaging approaches; we do so in Chapter 15. Functional neuroimaging work has advanced rapidly in recent years. We review
research findings on cerebral activity in normal, depressed,
and manic states, as well as summarize what is known
about baseline cerebral activity markers of treatment response.
Chapter 16 covers sleep and biological rhythms, reflecting our judgment that these two fields, which developed
independently of one another, have found a natural point
of convergence in the pathophysiology of manic-depressive
illness. It is increasingly clear that sleep physiology is important to circadian physiology and that sleep disturbances
seen in affective illness reflect disturbances in circadian
rhythms. This area of study has, in our estimation, yielded
some of the most interesting developments in understanding manic-depressive illness. The identification of seasonal
affective disorder, for example, represents a systematic,
quantitative rediscovery of ancient observations of seasonality in mood disorders and suicide. The speed with which
the initial observation of seasonal mood disorder was
incorporated into the DSM nosology testifies to the
responsiveness of our current diagnostic system. Research
Treatment
The final part of the book covers all aspects of the treatment of manic-depressive illness. It is traditional in its organization, separating acute from prophylactic treatment
and medical from psychological treatment. Despite this
division, we wish to emphasize the profound importance
of integrating medical and psychological approaches. Although the structure of this part of the book is traditional,
the organization of each chapter is not. Each begins with
practical recommendations for clinical management and
then reviews the treatment literature, highlighting areas inadequately explored in existing reviews, including the efficacy of lithium in treating depression as well as mania
and the quality of the prophylactic response. We discuss
treatment controversies such as antidepressant-induced mania, mixed states, and rapid cycling; the use of adjunctive
treatments for breakthrough episodes during prophylactic
treatment with mood stabilizers; the important but often
overlooked distinction between prevention of relapse and
prevention of recurrence (new episodes); the relative efficacy and side-effect profiles of the mood stabilizers and
the antipsychotics; and the use of alternative or adjunctive
approaches for patients who do not respond to initial treatment. It has been of great, often life-saving clinical importance to now have anticonvulsant and antipsychotic medications that provide an alternative for those patients who
do not respond to or will not take lithium. We make clear
our belief that lithium remains the gold standard of treatment, however, despite an increasing tendency to use lessproven medications.
The two chapters on adherence and psychotherapy
(Chapters 21 and 22, respectively) should be read together.
Our purpose here is not to provide a general psychotherapy primer but to focus on issues of special importance to
the psychotherapy of manic-depressive illness, especially the
bipolar form. These issues include fears of recurrence, the
psychological scars left by the illness, and concerns about
genetic vulnerability. The central issue in the psychological
management of bipolar patients is medication adherence.
Recent studies suggest that outcomes of medical treatment
Introduction
xxv
tempt to impose order on a rich but vast and disparate literature. We were convinced that this goal could be accomplished only by seeing the subject through from beginning
to endin other words, by writing a book rather than editing a collection. We were able to accomplish this by jointly
authoring the first edition. As indicated in our acknowledgments and in the list of collaborators for this edition, however, we found it imperative to seek the help of colleagues;
we could not have completed this book without them. Our
intent was to go beyond a review of the literatureto assess
the nodal points in knowledge of the illness, to integrate
them in a way that would enhance the quality of clinical
care available, and to suggest opportunities for future research. In the early twenty-first century, manic-depressive
illness continues to present new challenges and questions
that extend from the realm of basic neurobiological science
to those of clinical practice and social ethics. The skill the
field brings to identifying these questions will determine
the strategies formulated to answer them, and in turn
will bear directly on future advances in treatment and prevention.
Throughout the writing of this edition of the book, as
during the first, we have been impressed time and again by
the excellent science, imaginative clinical research, and
profoundly important treatment advances generated by
our colleagues. We are delighted to acknowledge our debt
to them, both for their science and for the lives they have
saved. As before, our debt to our students and patients is
immeasurable.
NOTES
1.
REFERENCES
Blehar, M.C., and Oren, D.A. (1997). Gender differences in depression. Medscape Womens Health, 2(2), 3.
Blehar, M.C., and Rudorfer, M.V. (1998). Womens mental health
researchwhat is the need? Psychopharmacol Bull, 34(3),
237238.
xxvi
Introduction
Part I
Clinical Description
and Diagnosis
Manic-depressive insanity . . . includes on the one hand the whole domain of the so-called
periodic and circular insanity, on the other hand simple mania, the greater part of the morbid
states termed melancholia and also a not inconsiderable number of cases of amentia
[confusional insanity].
Emil Kraepelin1 (1921, p. 1)
It was the work of Angst and Perris that helped spread my theory that unipolar and bipolar diseases . . . have different clinical pictures. The bipolar form displays a considerably more colorful appearance; it varies not only between the two poles, but in each phase offers different pictures. The unipolar forms . . . return, in a periodic course, with the same symptomatology.
Karl Leonhard (1979, pp. 34)
HISTORICAL ROOTS
PreNineteenth-Century Ideas
The medical writers of ancient Greece conceived of mental
disorders in terms that sound remarkably modern.2 They
believed that melancholia was a psychological manifestation of an underlying biological disturbance, specifically, a
perturbation in brain function. In documents dating back
to the fifth and fourth centuries BC, Hippocrates and his
school3 described melancholia as a condition associated
with aversion to food, despondency, sleeplessness, irritability, restlessness, and they stated that fear or depression
that is prolonged means melancholia (Jackson, 1986, p.
30). Early conceptions of melancholia and mania were,
however, broader than those of today. The two terms, together with phrenitis, which corresponds roughly to an acute
organic delirium, made up all mental illness throughout
3
Aretaeus of Cappadocia, who lived in the second century AD, appears to have been the first (whose work has
survived to modern times) to bring together the syndromes described in Greek medicine and propose that
mania was an end stage of melancholia, a view that was to
prevail for centuries to come. Roccatagliata (1986, p. 229),
who referred to Aretaeus as the clinician of mania,
noted that he isolated . . . a form of mental disease presenting phases of depression alternating with phases of
mania, and reported Aretaeuss characterization of the
illness:
Some patients after being melancholic have fits of
mania . . . so that mania is like a variety of being
segments by Nassir Ghaemi) Piquer went on to quote Hippocrates and Arateus in support of his view.
As noted previously, the subsequent literature of the
seventeenth and eighteenth centuries is replete with clinical observations of manic and depressive symptomatology.
As pointed out by Pichot (1995), the disciples of Esquirol
played a critical role as they paved the way for recognition
of the mental disease that ultimately came to be known as
manic-depressive insanity through the work of Kraepelin
(1899). For instance, Jules Baillarger7 wrote in 1854:
There exists a special type of insanity characterized by
two regular periods, the one of depression and the other
of excitement. . . . This type of insanity presents itself in
the form of isolated attacks; or, it recurs in an intermittent manner; or, the attacks might follow one another
without interruption.
Nineteenth-Century Ideas
The explicit conception of manic-depressive illness as a
single disease entity dates from the mid-nineteenth century. As noted above, the French alienists, Falret and Baillarger, independently and almost simultaneously formulated the idea that mania9 and depression could represent
different manifestations of a single illness. Students of
Esquirol and, therefore, intellectual descendants of Pinel,
they had been strongly influenced by Pinels sharp disdain
for the classification epidemic, as well as by contemporary arguments for a unitary concept of general paresis.
ca. 1735
ca. 1759
ca. 1806
ca. 1845
a
Although the idea for this time line was ours, locating the quotations would have been next to impossible without the excellent historical sources
cited for each. We are especially indebted to Whitwell (1936), Jackson (1986), and Roccatagliata (1986).The quotations, particularly those from the Middle
Ages, do not always represent prevailing thought, but they do illustrate the thread of this theme throughout history. Also, when the conditions we
would characterize as manic-depressive illness were interpreted as medical rather than philosophical or religious problems, a relationship between
mania and depression was almost always suggested, explicitly or implicitly.
b
Cited by Whitwell (1936, pp. 163164). From De acut, et diut, morborum, causis, signis, et curatione (Paris), 1554.Transl. R. Moffatt.
c
Quoted by Whitwell (1936, p. 175), who gave Trallianuss birth and death dates as 525605, from Trallianus Alexander: Medici libri duodecim, interpret,
Guintherius (Basil), 1556.
d
Quoted by Whitwell (1936, p. 181), who gave Avicennas birth and death dates as 9801037. Whitwell cited as a source Opera, ed.: Alpagus et Benedictus (Venet.), 1582, and Morb. Ment. (Paris) 1659. Italics in original.
e
Quoted by Whitwell (1936, p. 196), who gave Gaddesdens birth and death dates as 12801361. Source cited is Gaddesden Joh.: Practica Johanni
AnglicaRosa medicina nuncupata (Papiae), 1492.Transl. Wolffe.
f
Cited by Whitwell (1936, p. 205), who gave Manarduss birth and death dates as 14621536. Citation given is Manardus Joh: Epist. Med. (Venet.), 1542.
Italics in original.
g
Quoted by Whitwell (1936, p. 98), who gave Platters birth and death dates as 15361614. Although it is not clear which of Platters works is the
source of this quotation, Whitwell later quoted from Praxeos medicae Tomi tres (Basil), 1656, and Histories and Observations (London: Culpeper and Cole),
1664.
h
Quoted by Jackson (1986, p. 255) from Willis, T.: Two Discourses Concerning the Soul of Brutes.Transl. S. Pordage (London: Thomas Dring), Ch. Harper
and John Leigh,A 1683, pp. 201, 205.
i
Quoted by Jackson (1986, p. 256) from Boerhaave, H.: Boerhaaves Aphorisms: Concerning the Knowledge and Cure of Diseases,Which Is That of a Vital and
Sensitive Man.The First Is Physiological Shewing the Nature, Parts, Powers, and Affections of the Same.The Other Is Pathological,Which Unfolds the Diseases
Which Affect It and Its Primary Seat; to Wit, the Brain and Nervous Stock, and Treats of Their Cures: with Copper Cuts (London:W and J Innys), 1735, pp. 323324.
j
Quoted by Jackson (1986, p. 259) from Cullen, W.: First Lines of the Practice of Physic. 2 vols., in 1. ed. J. Rotheram (New York: E. Duyckinck), 1806, p. 497.
k
Quoted by Jackson (1986, p. 262) from Esquirol, E.: Mental Maladies: A Treatise on Insanity.Transl. E. K. Hunt (Philadelphia: Lea and Blanchard), 1845,
pp. 381382.
In 1854, Falret described a circular disorder (la folie circulaire), which for the first time expressly defined an illness
in which this succession of mania and melancholia manifests itself with continuity and in a manner almost regular (perhaps a foreshadowing of the modern concept of
rapid cycling). In the same year, Baillarger (1854) described
double insanity (la folie double forme), emphasizing
that the manic and depressive episodes were not two different attacks but rather two different stages of the same attack. Thus, cyclicity with or without clear-cut remission
was already being described in these pioneering French
contributions. Although clearly anticipating Kraepelins
later synthesis, these descriptions nonetheless focused on
chronic illness with poor prognosis; the relationship of these
forms to other varieties of mania or melancholia was
not delineated. Other valuable contributions were made by
Griesinger (1867), who provided rich clinical descriptions
of melancholia and mania, although he described primarily chronic states with poor prognosis. As Aretaeus had
centuries before, Griesinger conceived of mania as an
end stage of a gradually worsening melancholia and of
both as different stages of a single, unitary disease (Jackson, 1986).
Although mild cases of mania had been described by
the ancients, as well as by Falret, Esquirol, and other observers, Mendel (1881) was the first to define hypomania as
that form of mania which typically shows itself only in
the mild stages abortively, so to speak. Kahlbaum (1882)
described circular disorders (cyclothymia), which were
characterized by episodes of both depression and excitement but did not end in dementia, as chronic mania or
melancholia could. Despite these contributions, most clinical observers continued to regard mania and melancholia
as separate entities, chronic in nature, and following a deteriorating course. Nonetheless, some German authors
during this period, such as Hecker (see the translation by
Koukopoulos, 2003), reserved cyclothymia for the milder,
nondeteriorating, forms observed in private clinical practice. Heckers work is actually quite consistent with what today we have come to recognize as bipolar-II disorder:
Virtually all of the [patients with cyclothymia] presented
with a depressive state. The state of excitationand I
should like to emphasize thishad escaped the attention, in the majority of milder cases, of the patients
doctor, his family and friends, and the patient himself.
The patients only became aware of it when I described
the characteristics of this state to them. Even more
often, however, it was the patients themselves who, having up until that moment considered them as their
healthiest periods, were forced to recognize that they
were ill in these periods also.
Post-Kraepelinian Developments
After Kraepelin, the evolution of the concept of manicdepressive illness proceeded differently in Europe and the
United States (Pichot, 1988). Europeans continued to place
primary emphasis on the traditional medical disease model
of mental illness, whereas psychiatrists in the United States
were profoundly influenced by the new perspectives of
psychoanalysis and other theories emphasizing psychological and social factors. During the first half of the twentieth
century, the views of Meyer (18661950) gradually assumed
a dominant position in American psychiatry, a position
maintained for several decades. Meyer believed that psychopathology emerged from interactions between an individuals biological and psychological characteristics and
his social environment.12
The disease model, by contrast, is based on the premise
that clinical phenomena in a given patient are understandable (and therefore potentially predictable) in terms of a
given disease with a specific natural history and pathophysiology. European psychiatry in the nineteenth and
early twentieth centuries had successfully employed this
traditional medical disease model in the definition and
treatment of general paresis secondary to syphilis of the
central nervous system and organic syndromes associated
with vitamin deficiencies (especially pellagra).13 Failure to
identify mechanisms of pathophysiology in the major socalled functional psychoses, including manic-depressive
illness, stimulated doubts about the continued usefulness
of the model, particularly since the prevailing biological
hypotheses emphasized infectious agents and neuropathological lesions. Consistent with this pessimism was the failure of the biologically based treatments of the time. In this
climate, it is not surprising that American psychiatrists,
manifesting the national penchant for pragmatism, were
drawn to treatment approaches that emphasized psychological and social factors. When the Meyerian focus, considerably influenced by psychoanalysis, turned to manicdepressive illness, the individual and his environment were
the natural focus, and clinical descriptions of symptoms
and the longitudinal course of the illness were given less
emphasis.14
Until the latter part of the twentieth century, the
American nosological systems for affective disorders reflected these competing sets of etiological assumptions.
Depression was divided into several dichotomies: reactiveendogenous, neuroticpsychotic, and, more recently,
system that went beyond clinical description alone. Leonhard observed that, within the broad category of manicdepressive illness (i.e., recurrent affective illness), some patients had histories of both depression and mania, whereas
others had depressions only. He then noted that patients
with a history of mania (whom he termed bipolar) had
a higher incidence of mania in their families as compared
with those with recurrent depressions only (whom he
termed monopolar). In 1966, Angst and Perris independently provided the first systematic family history data to
support Leonhards distinction, validating it by an independent criterionfamily history. As discussed in Chapter 13,
some of the subsequent family history studies are consistent with a model in which bipolar and the more highly recurrent forms of unipolar depression are variants of the
same fundamental disorder (Kraepelins manic-depressive
illness), with bipolar illness representing the more severe
end of the spectrum.
The bipolarunipolar distinction was formally incorporated into the American diagnostic system, DSM, the
third edition (DSM-III), in 1980; was subsequently carried
forward into DSM, the fourth edition (DSM-IV); and
became explicit in the international classification system
in ICD-10. Unfortunately the structure of DSM-IV (see
Fig. 31 in Chapter 3), which breaks out bipolar disorder as
a separate illness distinct from all other mood disorders
(i.e., from the depressive disorders) obscures the fact that
originally, the bipolarunipolar distinction was conceived
of as a way to distinguish two forms of a recurrent illness.
In other words, the DSM structure gives precedence to polarity over cyclicity, obscuring the reality that one rather
common variant of unipolar illness is as recurrent or cyclic
as bipolar illness. Further, DSM-IV really has no language
for the unipolar patient with frequent recurrences, since its
recurrent category is so broad as to include patients with
only two depressions in a lifetime (see Chapter 3 for a
more extensive discussion of this point).
Before the mid-1970s, the scientific literature on manicdepressive illness typically did not include information
on the number of patients with or without a history of
mania. During the past three decades, however, the bipolarunipolar distinction has been examined in numerous
studies encompassing family history, natural course, clinical symptoms, personality factors, biological measures,
and response to various pharmacological treatments. The
question of bipolarunipolar differences in clinical features of depression is reviewed in this chapter; these as well
as other reported bipolarunipolar differences (e.g., biological, pharmacological, psychological) are summarized
in Table 11 and further detailed in the relevant chapters
(including this onesee also Table 13 on clinical differences later in the chapter). Our purpose in outlining these
Unipolar
Depressive Symptoms
See Table 13
See Table 13
Younger
Narrower range
More
Shorter
Shorter
More important at
illness onset than
for later episodes
More
Older
Broader range
Fewer
Longer
Longer
Relation to illness
onset not clear
Single status
a risk factor
1.21.5%
2050%
F=M
More frequent
Unclear
510%
5080%
F >M
Less frequent
Unclear
Less
Less
More
More normal
More
More
More
More
Less
Less normal
Less
Less
Higher
More
Lower
Less
Natural Course
Age at onset
Number of episodes
Length of depressive episodea
Cycle length
Precipitants of episodes
Marital Status
Fewer
Epidemiology
Lifetime risk
Proportion of major affective illness
Gender ratio
Substance abuse
Suicide
Personality
Depression/introversion
Impulse control
Stimulus seeking
Personality profile
Hyperthymic temperament
Cyclothymia
Family History/Genetics
Monozygotic twin concordance rates
Mania among first-degree relatives
Biological/Physiological
Monoaminergic function
(metabolites, receptors,
neuroendocrine response,
electrolytes, etc.)
Pain sensitivity
Hemispheric
function dysfunction
Brain imaging parameters
More
?
?
(continued)
11
Unipolar
Longer
Less frequent (?)
Fall/winter depression
Spring/summer
mania
Shorter
More frequent (?)
Spring depression
(?)
Less (?)
More rapid (?)
More frequent
More frequent
More (?)
Less rapid (?)
Less frequent
Less frequent
More frequent
Less frequent
Good
Sleep/Rhythms
Sleep duration
Phase advance
Seasonal patterns
Pharmacological Response
Response to antidepressants
Speed of response to antidepressants
Tolerance to antidepressants
Antidepressant response to
mood stabilizers
Manic/hypomanic response
to antidepressants
Prophylactic response
to lithium
Prophylactic response to
antidepressants
a
Studies demonstrating longer duration of episodes with unipolar versus bipolar depression are generally not corrected for number of episodes. See text.
Note: See individual chapters for details. Some of the bipolarunipolar comparisons included both
bipolar-I and -II, while others focused on either one or the other, an obvious source of heterogeneity. Not
all of the reported differences have been replicated uniformly, which is not surprising given the heterogeneity of both the bipolar and unipolar groups (for example, early-onset, highly recurrent unipolar depression will be closer to bipolar depression in clinical characteristics). The sequence of the table follows
that of the chapters in this volume.
F = female; M = male; UPBP = unipolarbipolar.
their long-term follow-up study, emerged from observations of hospitalized depressed patients without other psychiatric diagnoses, many of the more recent studies were
conducted in patients in whom neither the depressed nor
the hypomanic phase was severe enough to require hospitalization and in whom concomitant diagnoses (principally
borderline personality disorder and substance abuse disorder) were not uncommon (Coryell et al., 1985, 1995; Endicott et al., 1985). Such definitional broadening is not universally accepted (Ghaemi et al., 2002). Thus, Baldessarini
(2000) pointed out that mood fluctuations can be found in
many if not most psychiatric disorders and expressed concern that the continued broadening of the bipolar diagnosis
risks weakening the core concept of bipolar disorder. Similar
concerns were expressed by van Praag (1993), and we agree.
Angst (1978), having earlier recognized the problem of
the range of meanings that could confuse application of
12
involved in making a DSM diagnosis of hypomania include the not-always-warranted primacy accorded to elated
mood over dysphoric mood and the durational requirement of 4 or more consecutive days, both of which have
been widely criticized by clinical researchers (see the discussion in Chapter 3).
Most significant, contemporary data necessitate revision of the more traditional view of bipolar as substantially less common than unipolar illness. In Egeland and
Hotstetters (1983) study, using sensitive methods of ascertainment and considering cyclothymia, bipolar-II, and
bipolar-I together, the incidence of bipolar disorder was approximately equal to that of unipolar illnessthat is, it
accounted for 50 percent of major affective illness.23 Angst
and colleagues (1978) also found that the ratio of bipolar
to unipolar illness was about 1:1 in patients followed for
up to 16 years, a ratio very close to that noted in the subsequent follow-up of that cohort, in which only 46 percent
of the patients were still unipolar (Angst et al., 2002,
2004). Other recent studies using this broader definition
of bipolar have found a similarly high bipolar/unipolar
ratio.24
Unfortunately, many studies of recurrent affective illness employ relatively insensitive methods of ascertainment
and correspondingly rigid criteria for an episode. Although
such inflexible criteria are useful for certain research purposes, they exclude many patients from consideration.
Egeland and Hotstetter (1983) referred to the bipolar illness typically cited in the literature (i.e., bipolar-I) as the
tip of the iceberg of bipolarity. Current data indicate that
manic-depressive spectrum conditions (see below), many
of them below the threshold of mania, may be found in 58
percent of the population (Angst, 1978) (see Chapter 5).
However, the validity of the diagnoses in most of these surveys (obtained by trained lay interviewers) has been questioned, primarily because estimates based on diagnoses by
experienced clinicians tend to be substantially lower (see
Chapters 4 and 5).
A broad range of bipolarunipolar differences have
been reported (see Table 11). They include four separate
spheres of datagenetic, clinical, biological, and pharmacological. Considerable caution is warranted in interpreting these differences, however, given the heterogeneity in
both groups. While most of these studies have focused on
bipolar-I patients (reducing heterogeneity on that side),25
the unipolar groups have been highly heterogeneous with
respect to the critical variable of recurrence or cycle
length; clearly the unipolar groups represented in Table 11
have generally not been selected for frequent recurrences
(Cassano et al., 1992; Winokur et al., 1993, 1994, 1995; Judd
et al., 2003a). Indeed, to our knowledge, there have been no
studies comparing bipolar and unipolar illness in which
the groups have actually been matched for episode frequency. This is a serious limitation in light of the increasing evidence that more highly recurrent unipolar patients
appear to be quite similar to bipolar patients in some important respects (e.g., early age at onset, family history of
mania, atypical features, and prophylactic response to
lithium).
Implicit in the foregoing discussion of bipolarunipolar
distinctions is the need for a more explicit focus on the relationship between cyclicity and polarity. To what extent
do differences in cyclicity contribute to or obscure reported
bipolarunipolar differences? In other words, how are we
to know whether a given bipolarunipolar difference is
a function of the presence or absence of a history of
mania/hypomania, or occurs because the bipolar group is
more cyclic or recurrent than the unipolar group? These
important questions are discussed later in the chapter. The
relationship between polarity per se and other dimensions
of affective illnessfamily history, age at onset, severity,
psychotic features, response to treatment, and biological
markersgenerally has been studied one dimension at a
time. A more comprehensive understanding of these interrelationships awaits studies that employ simultaneous
weighing of multiple dimensions.
Unipolar Mania
The classic studies of Leonhard (1957), Perris (1966), Angst
(1966), and Winokur and colleagues (1969) noted the relatively rare occurrence of manic patients with no apparent
history of depression. In Leonhards series, pure mania
represented 9 percent of the bipolar group, whereas in the
other studies it made up less than 5 percent. Although Leonhard initially considered patients with pure mania a separate group, subsequent studies indicated that they could
not be distinguished from bipolar patients by either family
history, course, treatment, or clinical features of mania.
Thus, pure mania has generally been considered a variant
of bipolar illness. Present knowledge suggests the likelihood that patients so identified either have had unreported
depressions or have not been followed long enough to rule
out future depressions. For some unipolar manic patients,
depressive episodes are subsyndromal: they fail to be diagnosed because they lack a prominent or reported mood
component; that is, the depressions manifest themselves
primarily as episodes of increased sleep, decreased energy,
and slowed thinking.
Abrams and colleagues26 (Abrams and Taylor, 1974;
Abrams et al., 1979) prompted a reevaluation of this question by reporting a 28 percent and an 18 percent incidence
of unipolar mania among two relatively large independent
samples of manic patients (N = 127 for the two samples).
Among the problems with these two studies, however, is
13
14
with respect to recurrence, increasing the chances that bipolarunipolar comparisons will really be about polarity, as
noted above. Perriss (1966) bipolarunipolar studies come
closest to this in that his unipolar patients had all experienced at least three depressions. But the median number of
episodes experienced by his unipolar patients was still substantially below that of his bipolar group.
A number of important studies of the unipolar-tobipolar conversion conducted since 1990 are not included
in Table 12 because they do not provide this type of
analysis. They generally found rates of conversion from an
initial unipolar to a subsequent bipolar diagnosis that
range up to 50 percent;28 the highest rate was found in the
study of the Angst group, which had the longest follow-up
period. Generally, the younger the age at onset of depression, the higher was the rate of subsequent conversion to
bipolar (see, for example, Rao et al., 1995; Geller et al.,
2001). These issues are detailed in Chapter 4.
We have already noted that some unipolar patients have
bipolar-like coursesnamely early age at onset and frequent recurrences. Akiskal and Mallya (1987) pursued this
observation by examining unipolar patients for depressive
symptoms that might be considered analogous to mania/
hypomania. Koukopoulos and Koukopoulos (1999) described these agitated depressions as depressive mixed
states, a concept that overlaps considerably with agitated
depression (see Chapter 2). Depressive mixed states were
studied more systematically in the RavennaSan Diego
Collaborative Study.29 In that research, only three manichypomanic symptoms were required, the most frequent
being psychomotor agitation (which was not goal directed), distractibility, and racingcrowded (predominantly
Table 12. Estimates of Percent False Unipolar Using Different Cutoff Points
for Unipolar Depression
FALSE UNIPOLAR %
Grof
(Unpublished)
Perris
(1968)
Angst et al.a
(1978)
18.5
28.4
15.3
13.1
26.2
11.9
11.4
22.5
13.2
12.5
22.9
7.8
10.7
25.0
Required Number of
Depressive Episodes
a
The larger percentages from the Angst et al. data may reflect a sampling bias toward more recurrent
forms of the illness.
15
Table 13. Clinical Differences between Bipolar (Primarily Bipolar-I) and Unipolar Depressions
Symptom
Clinical Comparisons
Studies
Anxiety
UP >BP
Tension/fearfulness
BP >UP
Somatic complaints
UP >BP
Psychomotor retardation
BP >UP
UP >BP
Psychomotor agitation
UP >BP
Atypical features
BP-II >UP
BP-II = UP
Appetite loss
UP >BP
BP >UP
BP-I/-II >UP
BP >UP
Irritability
BP-II >UP
Insomnia (initial)
UP >BP
Insomnia (late)
BP >UP
Hypersomnia
BP >UP
Postpartum episodes
BP >UP
Pain sensitivity
UP >BP
BP >UP
17
Table 13. Clinical Differences between Bipolar (Primarily Bipolar-I) and Unipolar Depressions (continued)
Symptoms
Clinical Comparisons
Studies
Weight loss
UP >BP
Psychotic features
BP >UP
BP >UP
BP = bipolar; UP = unipolar.
range of clinical features. We have already noted the heterogeneity in both the bipolar and unipolar groups (especially
the latter), which makes any generalizations difficult to say
the least. In addition to the unknown variability in extent of
recurrence (cycle lengths), most of these studies did not control for differences in severity of depression or age at onset.30
It is worth noting that the comparisons in Table 13 are
predominantly between unipolar and bipolar-I patients
(although several of the studies refer only to bipolar
without specifying subtype). Indeed, it has been suggested
that bipolarunipolar differences become clearer when
the bipolar-II group is excluded. The most widely replicated studies point to a picture of the bipolar-I depressed
patient as having more mood lability, psychotic features,
psychomotor retardation, and comorbid substance abuse.
In contrast, the typical unipolar patient in these studies
had more anxiety, agitation, insomnia, physical complaints, anorexia, and weight loss. As noted in the table,
there are a number of other features for which there is only
one study or conflicting studies; certainly some of the apparent disagreement may be related simply to inadequate
description of the bipolar or unipolar samples.
There is a much smaller body of data on unipolar
bipolar-II comparisons, and most of these data focus on depressive mixed states (more frequent in bipolar-II, as discussed above and in Chapter 2) and on so-called atypical
features. Atypical depression was originally described in
unipolar patients on the basis of a group of symptoms including hypersomnia, increased weight and appetite, leaden
paralysis, interpersonal rejection sensitivity, and preferential
response to monoamine oxidase inhibitors (MAOIs) (reviewed by Raskin and Crook, 1976). Given the suggestion of
earlier studies that MAOIs are preferentially effective in
bipolar depression (Himmelhoch et al., 1991), an interest in
the relationship between atypical features and bipolar illness has developed. Following up on studies of atypical features reviewed in the first edition, a number of more recent
18
19
Clinical Comparisons
Studies
Anxiety
BP-II >BP-I
BP-II >BP-I
BP-II <BP-I
BP-II >BP-I
Rapid cycling
BP-II >BP-I
Psychotic features
Suicide/suicide attempt
BP-II = BP-I
BP-I >BP-II
BP-II >BP-I
Premenstrual dysphoria
Hospitalizations
Agitation; irritability
BP-I = BP-II
BP-II >BP-I
BP-I >BP-II
BP-I >BP-II
BP-II >BP-I
Percent female
Severity of depressive episodes
Length of depressive episode
Percent medicated
BP-II >BP-I
BP-I >BP-II
BP-I >BP-II
BP-I >BP-II
BP = bipolar.
20
all the above-mentioned states only represent manifestations of a single morbid process.
demonstrable, a useful category can still be defined by establishing a minimum (or maximum) threshold of symptoms for inclusion in the category; consider, for example,
hypertension and hypothyroidism. And the pattern of illness characteristicssymptoms, course, family history, and
treatment response, for examplereflects a convergence of
several dimensional variables. Such a model should be acceptable to those who are comfortable with large, internally
variable categoriesthe lumpersas well as to those who
want to create a new category for every variantthe splitters. This conception is simply for the sake of narrative convenience, not to reflect a conviction that any particular
group has discrete, discontinuous boundaries. On the contrary, and as we emphasized in the first edition of this book,
we are impressed with the subtlety of the shadings.39 How
these issues bear on diagnosis is discussed in Chapter 3.
Exploration of spectrum models is important for several reasons. The reliable characterization and validation
of subsyndromal states similar to bipolar illness would enhance research on genetic markers and modes of genetic
transmission, as discussed in Chapter 13, as well as provide
an approach for identifying individuals at risk for the development of full-blown bipolar illness (Alda, 2004). Additionally, a spectrum model would permit the evaluation
of treatments for attenuated variants, including the question of whether early intervention could lessen the chance
21
22
continuum from normal happiness or joy through cyclothymic personality, nonpsychotic hypomania, and psychotic mania. It is clear, however, that this string of states
does not reflect a spectrum of ever-increasing happiness
and joy, since these pleasant emotions are replaced by qualitatively very different moods and sensations as one crosses
the line from hypomania into mania. Klermans recommendation that the term elations be used to encompass
the spectrum of mania emphasizes mood over other important features, such as energy level, activity, behavior, and
cognition. As noted earlier, the terminology can be confusing. In Klermans spectrum, cyclothymic personality falls
between normal happiness and hypomania. In DSM-IV, a
diagnosis of cyclothymia requires hypomanic episodes. In
this diagnostic system, cyclothymia is differentiated from
bipolar-II major affective disorder on the basis of its less
severe depressions, which do not meet criteria for major
depressive disorder. Using elation as the criterion for the
manic spectrum also is reminiscent of older formulations
in which depression and mania were at opposite ends of a
continuum, with normal in the middle. Such a continuum
is quite limited as a model, primarily because it cannot account for mixed states, which, as discussed in Chapter 2,
are quite common. Some believe it preferable to consider
the depressive and manic spectra as independent and
capable of interacting in a variety of combinations and
permutations.42 It is interesting that in both the Endicott
(1989) and the Angst and Gamma (2002) schema, the manicdepressive spectrum is dominated by depressive recurrences, with very mild and short hypomanias. This conception is in line with our view that recurrence and cyclicity
are more fundamental than polarity, which in turn accords
with Kraepelins nosologic position. We remain concerned,
however, that relatively little research has been conducted
on the continuum of manic states (Jamison, 2004), a concern we expressed in the first edition of this text.
As reviewed in Chapter 2, severe psychotic features, including mood incongruence, are extensively documented
for bipolar patients in both the classical and the recent literature. The boundary between severe mania and schizobipolar disorder is not clear (see Chapter 3). Suffice it to
say that new data appear to be consistent with the view that
schizobipolar patients lie on a continuum with severe mania, whether one examines family history (Van Eerdewegh
et al., 1987; Toni et al., 2001) or course (Cutting, 1990).
If we integrate the depressive and manic spectra, we can
construct an overall spectrum of bipolar illness. At one
end is cyclothymic personality; then cyclothymic disorder
(bipolar, other in Dunners terms or md in Angsts terms43);
followed by bipolar-II disorder (mD or bipolar disorder,
not otherwise specified, in DSM-IV); then Md (often
misdiagnosed as unipolar mania); and finally MD (i.e.,
Mania
Depression
MD
Dm Md
23
D dm
d m
Normals
24
dominated by depressive symptomotology.48 In this respect, bipolar-I and -II appear to be quite similar (Judd
et al., 2003a). This is where a great deal of the disability
associated with the illness appears to residein the subdepressive symptomotology between episodes (Altshuler et al.,
2002). Given that the depressive dominance is found in epidemiologic samples and in pedigree and family studies, one
cannot criticize the foregoing clinical studies on the basis of
tertiary referral bias, by which the more depression-prone
bipolar patients are retained in follow-up studies. As detailed in Chapter 2, the depressive phase of bipolar disorder
and depressive presentations in clinical practice represent a
highly important aspect of bipolarity.
The spectrum concept is not just a recent peculiarity of
the clinical and research focus on soft bipolarity. As reviewed here and in Chapter 2, these concepts are ancient.
Indeed, it has been suggested that all major mental disorders can perhaps best be characterized in spectrum models
(Maser and Akiskal, 2002). As noted earlier, Baldessarini
(2000) criticized the concept of a broad bipolar spectrum
on methodological grounds, arguing that it risks diluting
the concept of bipolar disorder, thereby reducing the rigor
of contemporary research. We agree. It is true that most
authors cited by Baldessarini as having made major contributions to the field (from Aretaeus on) endorsed a
broad conceptualization of manic-depressive illness; as
we noted earlier, however, manic-depressive spectrum
denotes something different from bipolar spectrum.
While the more recently proposed soft forms of bipolarity make some clinical and intuitive sense to us, they still
require considerably more research from a wider range of
independent research groups focused on external validators, especially family history, treatment response, and
long-term outcome. For the clinician dealing with individuals, deciding whether one is encountering one end of a
normal range of behavior, a personality disorder, or manicdepressive illness requiring treatment remains a challenge.
CONCLUSIONS
The existence of the softer phenotypes on the fringes of
classic or hard bipolar phenotypes that encroach into the
territory of unipolar depression indicates the need for at
least a partial return to the unitary Kraepelinian concept
of manic-depressive illness. While some view the bipolar
spectrum as the modern heir of this classic broader position, subsuming all conditions under the rubric of bipolar is a less than totally satisfactory way to emphasize the
close relationship between bipolar illness and highly recurrent unipolar depression (many patients with the latter
condition, after all, remain nonbipolar in the usual sense).
If our diagnostic systems were to return to the Kraepelinian position of taking recurrence as the first principle for
organizing the affective disorders (as we propose in Chapter 3), one would not have to posit that all early-onset recurrent depressions are part of the bipolar spectrum.
On the other hand, contemporary studies49 of depressive
mixed states appear to provide some empirical support
for Kraepelins descriptions of excited depression and
depression with flight of ideas, apparently representing
those highly recurrent unipolar patients who, despite not
having a history of manic or hypomanic episodes, may
have enough manic-like features when depressed, as well
as sufficient bipolarity in their family histories, to be considered part of the bipolar spectrum in the sense of having
some bipolar diathesis. For conceptualizing the relationship
between bipolar disorder per se and recurrent depressive
disorders, however, we still prefer the Kraepelinian concept of manic-depressive illness because it is unitary; all
recurrent affective illness is encompassed, although Kraepelin anticipated the later bipolarunipolar subdivision.
Indeed, while much future research needs to be conducted
to fully validate the concept of a manic-depressive spectrum, the pendulum appears to have shifted distinctly in
favor of the Kraepelinian position, which includes much of
the domain of frequently recurrent depression under the
broad manic-depressive rubric.
Finally, we should reiterate why the exploration of spectrum models of manic-depressive illness is so important.
First, for the bipolar subgroup, validation of subsyndromal
states will enhance research on genetic markers and modes
of genetic transmission. Second, it will allow the identification of individuals potentially at risk for the development
of full bipolar illness, opening up the possibility of trials of
early interventions that could reduce the likelihood of progression. Lastly, the model of a manic-depressive spectrum
increases clinicians awareness of the close relationship between bipolar illness and some forms of unipolar depression (an understanding that has been undermined by the
structure of DSM-IV). It is only this awareness that can
help the clinician avoid the all-too-common misdiagnosis
of bipolar patients as unipolar, a mistake that can lead to
the almost always ill-advised treatment decision, discussed
in Chapter 19, of administering an antidepressant in the
absence of a mood stabilizer.
NOTES
1. The authors acknowledge a deep intellectual debt to the great
German psychiatrist Emil Kraepelin. Kraepelin, the son of an
actor, was born in 1856 in Neustrelitz, near the Baltic Sea. His
older brother Karl, a biology teacher, influenced Emils decision to become a doctor and an academician. Interested in
psychiatry while still at the Wrzburg Medical School, Kraepelin, upon graduation in 1878, studied with the neuroanatomists Bernard von Gudden and P. E. Flechsig. He then
turned to experimental psychophysiological research, under
the tutelage of Wilhelm Wundt. He held psychiatric hospital
appointments in Munich, Leubus, and Dresden. In 1886, he
became professor of psychiatry in Dorpat, then moved to the
same position in Heidelberg in 1890 and to Munich in 1904
[or 1903?]. In 1922, he retired from teaching and became head
of the Research Institute of Psychiatry in Munich.
According to Alexander and Selesnick (1966), Kraepelins
training, personality, and dedication were well suited to the
task of classifying and generalizing the myriad clinical observations made during the nineteenth century: He learned
early to respect authority, order, and organization. . . .
Imperial German psychiatry was said to have gained its
prominence under the chancellorship of Kraepelin, one of
Bismarcks admirers (pp. 162163). As Bismarck unified
Germany, Kraepelin brought order to the balkanized psychiatry of the turn of the century. The first edition of his textbook, which he continued to revise throughout his life, was
published in 1883. In succeeding editions, he refined and expanded the textbook from the brief outline of the first edition to the 2,425 pages of the ninth edition, published in 1927,
a year after his death. The textbook was notable for its division of major psychiatric illness into two categories and for
its emphasis on prognosis. The third and fourth parts of
the eighth edition, covering manic-depressive insanity and
paranoia, were published separately in 1921, and it is that
monograph that is cited throughout this book.
Zilboorg (1941), from his psychoanalytical perspective,
summarized the personal observations of Kraepelin from
those who knew him personally:
[They] tell of his rather pleasant, responsive personality, of his tactful ability in bringing people together to
work as an organized group, and of his great gifts as a
teacher; yet it is curious that his scientific personality
was so very detached, almost distant from the inner life
of the patient. To Kraepelin a mentally sick person
seems to have been a collection of symptoms. He was
a true son of the great, energetic, and creative age that
was interested greatly in humanity but comparatively
little in man. Perhaps this trait in Kraepelin as a psychiatrist, which today would be considered a defect, was
the very characteristic which helped rather than hindered him in the creation of his great system and school.
He was able to collect and to study thousands of case
histories, covering not only the story of each illness, but
the history of each patients life before the illness and
a follow-up history of his life after he left the hospital.
Dealing with such large masses of data, Kraepelin was
able to sort out everything these many individuals had
in common, leaving out of consideration the purely individual data. He thus arrived at an excellent general
picture, at a unique perspective of a mental illness as a
whole. But he seems to have been almost unaware that
in his careful study he lost the individual. (p. 452)
Berrios and Hauser (1988) took issue with this assessment, noting the great depth and beauty of Kraepelins late
25
26
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
extreme in the form of an episode. Thus, depressive temperaments are vulnerable to a swing into hypomania or mania, whereas those with hyperthymic temperaments are
likely to swing into depressions. According to Akiskal and
colleagues (1998b), such propensities may serve as the basis
for mixed states (see Chapter 2).
The very existence of depressive mixed states (isolated intradepressive manic symptoms) argued for a continuum,
which is consistent with the contemporary work of Benazzi
and Akiskal (2001) and Sato and colleagues (2003).
Although not incompatible with Kraepelins descriptions of
manic-depressive illness, Meyers approach implied a different conceptual framework. The Meyerians, although allowing for the operation of biological and genetic factors, understood them as part of an individuals vulnerability to specific
psychological and social influences. This perspective was
symbolized by the rubric manic-depressive reaction in the
first official diagnostic manual of the American Psychiatric
Association, published in 1952.
This would apply most clearly to German and British psychiatry, perhaps less so to French psychiatry (Leff, 1977).
This emphasis on presenting episode rather than course was
somewhat ironic, because Meyers own writings emphasized
a longitudinal perspective.
Primary is defined as depression in the absence of any preexisting or antecedent psychiatric or medical disorder.
At any rate, from a clinical and epidemiologic standpoint,
current data indicate that the foregoing depressive dichotomies
are best regarded as part of a depressive spectrum (Judd and
Akiskal, 2000).
To Bleuler, a patient was predominantly schizophrenic or
predominantly manic-depressive. Patients were distributed
all along this spectrum, and an individual patient could be at
different points on the spectrum at different times.
Compared with unipolar patients, bipolar depressed patients
were reported to have lower ratings of anxiety, anger, and
physical complaints (Beigel and Murphy, 1971b); more psychomotor retardation (Beigel and Murphy, 1971b; Himmelhoch et al., 1972; Kotin and Goodwin, 1972; Dunner et al.,
1976a; Katz et al., 1982); lower levels of measured physical activity (Kupfer et al., 1974); and more total sleep time (Hartmann, 1968; Kupfer et al., 1972; Duncan et al., 1979).
Winokur divided his primary unipolar patients (none of
whom had a family history of mania) into familial pure depressive disease (FPDD), sporadic pure depressive disease
(SPDD), and depression spectrum disease (DSD). (Primary
was defined as depression in the absence of any preexisting
or antecedent psychiatric or medical disorder.) The two pure
types had no other preceding psychiatric diagnoses and no
alcoholism among first-degree relatives. The distinction between them was that FPDD patients had a first-degree relative with primary depression, whereas SPDD patients did
not. DSD patients were those with alcoholism or antisocial
personality among first-degree (male) relatives; they were
predominantly female patients with early onset. Winokur
(1980) suggested that genetically, the FPDD subtype was
closely related to bipolar illness.
Akiskal, 1981, 1983a, 1998; Benazzi, 1997, 2001, 2003; Akiskal
and Pinto, 1999; Angst and Marneros, 2001; Benazzi and
Akiskal, 2001, 2003; Marneros, 2001; Hantouche et al.,
2003b.
31.
32.
33.
34.
35.
36.
37.
38.
39.
27
40. With appropriate cut-off scores, the GBI can be used for case
identification in either nonclinical or clinical populations. It
may be particularly useful in family studies. For example,
evaluated against clinically determined DSM-III diagnoses,
the GBI was found to have a sensitivity of 90 percent and a
specificity of 98 percent when used with adolescent offspring
of bipolar-I parents and parents with nonaffective major psychiatric diagnoses (Klein et al., 1986b). Originally structured
to identify only bipolar affective states, the GBI has been
broadened to apply to the separation of bipolar from unipolar subjects with considerable success (Depue et al., 1989).
41. TEMPS exists in an interview format (TEMPS-I) (Akiskal
et al., 1998a; Placidi et al., 1998) and a self-rated autoquestionnaire version (TEMPS-A) (Akiskal and Akiskal, 2005). The
cutoffs, determined by extreme distributions based on z-scores
(corresponding to +2 standard deviations), represent individuals at putative risk for clinical bipolar disorder. Akiskal (1995)
actually proposes that temperaments can both provoke and
react to life events, thereby leading to complex life situations,
emotional arousal, and, eventually, affective episodes. This
viewpoint is supported by data on juvenile subjects indicating
that cyclothymic reactivity is associated with stress, anxiety,
and behavioral disturbances (Signoretta et al., 2005). Only
new research will reveal the extent to which the promise of
TEMPS-A will be justified. Such research is in progress.
42. Joffe et al., 1999; Angst and Marneros, 2001; Angst et al., 2003.
43. The DSM-III-R category bipolar disordernot otherwise
specified, was originally meant to apply to bipolar-II patients; however, many such patients meet DSM-III-R criteria
for bipolar major affective disorder, given that the criteria
for major depression are broad enough to encompass a
wide range of severity. On the other hand, cyclothymia in
DSM-III-R reflects a milder state, referred to by Dunner as
cyclothymic personality, that is also milder than the
cyclothymia described by Akiskal.
44. More recently, using nonclinical community samples, Angst
(1991) identified recurrent brief depression (RBD) or recurrent brief hypomania (RBM), each with a minimum of 12
episodes a year. He suggested that these are part of the bipolar spectrum.
45. Akiskal and Mallya, 1987; Cassano et al., 1992; Simpson et al.,
1993; Benazzi, 1997; Manning et al., 1997; Hantouche et al.,
1998; Angst and Gamma, 2002; Mainia et al., 2002.
46. Akiskal et al., 1977, 1978, 1979a, 1983: Depue et al., 1978;
Waters, 1979; Akiskal, 1981, 1983a,b.
47. As detailed in Chapter 21, nonadherence is a major problem
for both bipolar-I and bipolar-II patients, although the factors that contribute to it may be different in each group.
48. This predominance of depression in bipolar disorder might
be reconciled with the proposal of Koukopoulos and others
that mania represents the underlying state in bipolar disorder by noting that many depressions in the bipolar spectrum
involve activation and other manic-like symptoms.
49. The widespread use of effective pharmacological treatments,
along with earlier recognition, probably accounts for the fact
that contemporary studies of manic-depressive illness are
more dependent on outpatient samples, whereas earlier studies were predominantly of inpatients.
Clinical Description
Griesinger, Weygandt, Falret, Jaspers, Baillarger, Campbell, or Henderson and Gillespie. We believe the clinical
writings of these classic authors provide both historical
perspective and a singular understanding of the nature of
manic-depressive illness.
The accounts of manic-depressive (predominantly bipolar) patients presented in this chapter provide the personal
dimension missing from clinicians and researchers reports,
however astute their observations. These descriptions, which
vary widely, reflect both the nature of the illness and the
nature of the people suffering from it. In the scientific literature, relatively scant attention is paid to firsthand accounts of manic-depressive illness; rather, the emphasis is
on the use of objective observer ratings as a basis for studying and describing major affective disorders, including
their psychotic variants. One reason for this virtual exclusion of experiential information is that firsthand accounts
are subjective and necessarily biased. Thus, patients may
remember with clarity some aspects of their disorder and
forget or ignore others; they may verbalize what is easiest
to describe and say little about aspects less readily articulated. They may relate only those experiences most novel
to them, thus giving disproportionate weight to out-of-theordinary events, or they may describe what they think the
observer wishes to hear. In addition, moods can radically
alter memory and perception, resulting in state-dependent
distortions. Finally, those individuals most capable of discussing their experiences in an articulate manner may belong, by virtue of this fact, to a more introspective and less
representative group.
These are legitimate concerns for anyone desiring
systematic, clear-cut, and reducible data. Clinicians have
long been aware, however, that experiential accounts are
vital to an understanding of individuals and their illnesses.
29
30
Clinical Description
have included the findings of many of these pre-1990 studies because of their historical as well as clinical and scientific interest.
With greater attention to clinical research on bipolar
disorder since 1990, the limitations of the older literature have to some extent been addressed. For instance, the
twin French collaborative studies of the clinical epidemiology of mania (EPIMAN) and bipolar depression
(EPIDEP) have focused on carefully measured clinical
nuances of manic, mixed, and bipolar-II disorders, as
well as their temperamental foundations (e.g., Hantouche
et al., 1998). Bipolarity beyond Classic Mania, an extensive
examination of soft bipolar variants (Akiskal, 1999), and
a European monograph entitled Bipolar Disorder One
Hundred Years after Manic Depressive Illness (Marneros
and Angst, 2000) were published to pay tribute toand
extendKraepelins clinical vision and methodology.
Another trans-Atlantic monograph, Bipolar Disorders,
focuses on mixed, atypical, and rapid-cycling bipolar disorder (Marneros and Goodwin, 2003). Finally, an entire
issue of the Journal of Affective Disorders devoted to
soft and hard phenotypes within the bipolar spectrum was published in 2003. The data-based contributions of this monograph came from the United States,
France, Italy, Switzerland, and Germany, countries where
clinical research is currently being conducted on the phenomenology of the broadly conceived manic-depressive
spectrum.
In this chapter we address only those aspects of symptom presentation relevant to clinical description. These
include the observable patterns of mood, energy, sleep,
thought, and behavior typically used in clinical diagnosis.
(Detailed discussion of related topics is found in Chapters
1, 3, 9, 10, and 15.) Before proceeding, we emphasize that
while many generalizations can be drawn from clinical
descriptions of manic-depressive illness, individuals are
bound to differ widely with regard to an illness that is at
once genetically based, environmentally influenced, and
psychologically expressed. Kraepelin (1921), although committed to the idea and practice of classification, also was
sensitive to the infinite capacity for individual expression
in the illness. Referring to the subclassifications proposed
by earlier writers, he concluded (p. 139): I am convinced
that that kind of effort . . . must of necessity wreck on the
irregularity of the disease. The clinical differences seen
across individuals can be striking (as are, more often, the
similarities), but it remains unclear to what extent one
episode resembles another in a given individual. Anecdotal
accounts, along with several studies discussed later, support some constancy of clinical presentation, including the
presence or absence of melancholic and psychotic features,
in the same patient across time.1
31
Finally, although much of the clinical description presented here emphasizes differences among clinical states,
we stress from the outset that the coexistence of affective
states is fundamental to bipolar disorder and that oscillation into, out of, and within the various forms and states of
manic-depressive illness is, in its own right, a hallmark of
the disease. As we shall see, pure affective states are rare:
mania is often complicated by depressive symptoms, and
conversely, depression, especially the bipolar form, usually
is accompanied by at least one or more symptoms of mania. Bauer and colleagues (2005), for example, found in
their study of 441 bipolar patients that clinically significant
depressive symptoms occurred in 94 percent of those with
mania or hypomania, while 70 percent of patients in a depressive episode had clinically significant manic symptomatology. Thus, far from being a bipolar disorder, with
the assumption of clinically opposite states, the illness is
characterized by co-occurrence of manic and depressive
symptoms more often than not. Bauer and colleagues
(2005) also found that depressive and manic symptoms
were positively, not inversely, correlated, suggesting that a
dimensional conceptualization of mood state in this disorder is more valid than the categorical conceptualization
presumed by both the DSM [Diagnostic and Statistical
Manual] and ICD [International Classification of Diseases] (p. 88).
Patterns of manic and depressive symptoms clearly have
a cyclic quality, but their overlapping, transitional, and fluctuating aspects are enormously important in describing and
understanding the illness overall. Thus, Kraepelin (1921,
p. 54) wrote:
The delimitation of the individual clinical forms of the
malady is in many respects wholly artificial and arbitrary.
Observation not only reveals the occurrence of gradual
transitions between all the various states, but it also shows
that within the shortest space of time the same morbid
case may pass through most manifold transformations.
Campbell (1953, pp. 112113) emphasized this fundamentally dynamic nature of bipolar illness by comparing
the illness to a film:
The fluidity, change, and movement of the emotions, as
they occur in the ever-changing cyclothymic process, may
be compared to the pictures of a cinema, as contrasted
with a still photograph. Indeed, the psychiatrist, observing a manic-depressive patient for the first time, or as he
undergoes one of the many undulations in mood, from
melancholia to euphoria or from hypomania to a depression, is reminded of the experience of entering a movie
during the middle of the story. No matter where one takes
up the plot, the story tends to swing around again to the
32
MANIC STATES
Classic Clinical Descriptions
Manic states are typically characterized by heightened
mood, more and faster speech, quicker thought, brisker
physical and mental activity levels, greater energy (with a
corresponding decreased need for sleep), irritability, perceptual acuity, paranoia, heightened sexuality, and impulsivity. The degree, type, and chronicity of these cognitive,
perceptual, and behavioral changes determine the major
subclassification of mania, namely hypomania or mania.
In hypomania, the above changes are generally moderate
and may or may not result in serious problems for the
individual experiencing them. In more intense episodes,
however, they profoundly disrupt the lives of patients, their
families, and society.
Mood
Mood in hypomania is usually ebullient, self-confident,
and exalted, but with an irritable underpinning. Most early
clinical descriptions emphasized the elevated, volatile, and
fluctuating nature of hypomanic mood. Campbell (1953,
pp. 151, 153) described its euphoric aspect:
Associated with the euphoria there is a genuine feeling of
well-being, mentally and physically, a feeling of happiness
and exhilaration which transports the individual into a
new world of unlimited ideas and possibilities. . . . When
a 19-year-old [hypo]manic was advised that he was indeed ill, he replied, if Im ill, this is the most wonderful
illness I ever had.
Clinical Description
a point, associational fluency is furthered by mild hypomania. Bleuler (1924, pp. 466, 468), for example, commented that thought remains relatively intact in the less severe forms of mania:
The thinking of the manic is flighty. He jumps by by-paths
from one subject to another, and cannot adhere to anything. With this the ideas run along very easily and involuntarily, even so freely that it may be felt as unpleasant by the
patient. . . . Because of the more rapid flow of ideas, and
especially because of the falling off of inhibitions, artistic
activities are facilitated even though something worth while
is produced only in very mild cases and when the patient is
otherwise talented in this direction. The heightened sensibilities naturally have the effect of furthering this.
Kraepelin (pp. 6869) went on to describe the progressively worsening clinical state of delusional mania:
The Delusions and Hallucinations, which in the morbid
states hitherto described are fugitive or merely indicated,
acquire in a series of cases an elaboration which calls to
33
34
Figure 21. Specimen of handwriting produced during mania. (Source: Kraepelin, 1921, p. 35. Reproduced with permission.)
Clinical Description
The handwriting of the patients may at first be quite regular and correct. In consequence of the excitability, however, it usually becomes gradually always larger, more pretentious and more irregular. There is no more
consideration for the reader; the letters run through one
another, are scribbled; more words are underlined; there
are more marks of exclamation; the flourishes become
bolder. . . . The number of documents produced by
manic patients is sometimes astonishing, though certainly
they themselves do not count on their being read; the
pleasure of writing itself is the only motive.
Sexual or erotic excitement is common in mania. Aretaeus of Cappadocia (150 AD) (quoted in Jelliffe, 1931,
p. 20), for example, wrote that a period of lewdness and
shamelessness exists in mania. Likewise, Kraepelin (1921,
p. 22) noted that sexual excitability is increased and
leads to hasty engagements, marriages by the newspaper,
improper love-adventures, conspicuous behaviour, fondness for dress, on the other hand to jealousy and matrimonial discord. Tuke (1892, pp. 764765) described this
as well:
A very common symptom in maniacal conditions is
erotic excitement. This varies from a mere coquetry, a
somewhat extended application of the command love
one another, an undue attention to the opposite sex, and
so forth, up to the extreme of salacity, when the mind is
wholly occupied by the urgent sexual appetite, and all
restraint is abandoned.
35
The patient cannot sit or lie still for long, jumps out of
bed, runs about, hops, dances, mounts on tables and
benches, takes down pictures. He forces his way out, takes
off his clothes, teases his fellow patients, dives, splashes,
spits, chirps and clicks. . . . [There are] discharges of inner
restlessness, shaking of the upper part of the body, waltzing about, waving and flourishing the arms, distorting the
limbs, rubbing the head, bouncing up and down,
stroking, wiping, twitching, clapping and drumming. . . .
[Death may be caused] by simple exhaustion with heart
failure (collapse) in long continuing, violent excitement
with disturbance of sleep and insufficient nourishment,
by injuries with subsequent blood-poisoning.
36
Clinical Description
37
38
tingling of the spinal chord [sic] and warm sense of wellbeing in the solar plexus, long before any reaction in the
mental sphere occurred. The same thing happens with the
sinking feeling of fear and horror which accompanies
extreme depression.
Clinical Description
39
nearest minute, was recorded in the margin. It was all vitally important. The major work which would be based
on this material would be accurate, original, provocative,
and of profound significance. All that had ever happened
to me was now worthwhile.
40
class: champagne tastes bubble to the surface, are the surface, in mania), and totally inappropriate siren-like
clothes. During one spree in London I spent several hundred pounds on books having titles or covers that somehow caught my fancy: books on the natural history of the
mole, twenty sundry Penguin books because I thought it
could be nice if the penguins could form a colony, five
Puffin books for a similar reason, on and on and on it
went. Once, I think, I shoplifted a blouse because I could
not wait a minute longer for the woman-with-molasses
feet in front of me in line. Or maybe I just thought about
shoplifting, I dont remember, I was totally confused. I
imagine I must have spent far more than $30,000 during
my two major manic episodes, and God only knows how
much more during my frequent milder manias.
But then back on lithium and rotating on the planet at
the same pace as everyone else, you find your credit is
decimated, your mortification complete: mania is not a
luxury one can easily afford. It is devastating to have the
illness and aggravating to have to pay for medications,
blood tests, and psychotherapy. They, at least, are partially
[tax] deductible. But money spent while manic doesnt fit
into the Internal Revenue Service concept of medical
expense or business loss. So, after mania, when most
depressed, youre given excellent reason to be even more
so. (Jamison, 1995, pp. 7475)
Clinical Studies
Mania is a complex, volatile, and fluctuating cauldron of
symptoms. The form and ways which mania manifests are
manifold, said Aretaeus (translated by Jelliffe, 1931, p. 20)
nearly 2000 years ago. Some are cheerful and like to
play . . . others passionate and of destructive type, who seek
to kill others as well as themselves. Although classically described as a state of extraordinary energy and activity, mania can also present clinically as manic stupor and catatonia. Manic mood, frequently characterized as elated and
grandiose, as often as not is riddled with depression, panic,
and extreme irritability; mania without significant mixed
features is what is known as classic mania. For years, mania
was differentiated mistakenly from schizophrenia because it
reputedly lacked a thought disorder. It now is recognized as
an often floridly psychotic condition, as we shall see below.
Manic episodes differ from person to person and in the
same individual from time to time, although Falret (1854,
cited in Sedler, 1983) and Kraepelin (1921) noted a tendency for constancy in symptom patterns across episodes
in the same individual. While few systematic data are available on this latter point, Wellner and Marstal (1964, p. 176),
reporting on a study of 279 manic episodes in 221 patients,
concluded that atypical attacks are followed by atypical,
and typical by typical significantly more often than not
(p = 0.002), indicating the patients inclination to reproduce the type of their psychoses. Beigel and Murphy
(1971a) found that patients with multiple manic attacks
tended to exhibit similar behavior and mood patterns during subsequent episodes. Two more recent studies (Cassidy
et al., 2001a; Woods et al., 2001) demonstrated that manic
and mixed episodes show diagnostic stability over time;
the interepisode stability of depressive mixed states, while
significant, is considerately less pronounced than is the case
for manic states (Sato et al., 2004). Francis and colleagues
(1997) found that the symptom profile of catatonia is highly
consistent across episodes, while Cassidy and colleagues
(2002), who evaluated 77 bipolar patients during two distinct manic episodes separated, on average, by 2 years, concluded that manic symptomatology remains generally consistent from episode to episode. Specifically, they found
that severity of mania, dysphoria, hedonic activation, psychosis, and irritable aggression tends to correlate across
episodes; psychomotor symptoms do not.
Regardless of the degree of constancy of the clinical picture across attacks, it is clear that symptoms vary widely
during any given manic episode as it progresses through
various stages. These stages, characterized by Carlson and
Goodwin (1973) and discussed more fully below, begin
with elation or irritability, evolve into a more severe form
as arousal and hyperactivity escalate, and culminate in
floridly psychotic disorganization.
Mood
Research on mood symptoms in mania, summarized in
Table 21, demonstrates that most patients, on average, are
depressed (46 percent) or labile (49 percent) nearly as often as they are euphoric (63 percent) or expansive (60 percent); they are irritable (71 percent) even more often. The
depression, irritability, and mood lability are generally
seen less often in early stages of an episode, although few
studies have specified the stage, level, or severity of mania
at the time of observation.
Winokur and colleagues (1969) observed depressed
mood in 68 percent of their manic patients, as well as more
severe depressive symptoms (including depressive delusions and psychomotor retardation) in a significant subgroup. They found that short depressive contaminations
in the manic episode were significantly more common in
women (79 percent) than in men (49 percent) (p. 64). Like
many investigators, they were particularly impressed by
the volatility of mood during manic episodes:
In our series of patients, the degree of mood elevation
varied from patient to patient and from time to time during the same episode. The changes in mood were capricious, responding to internal as well as external stimuli
Clinical Description
41
Patients
(N)
31
100a
Irritability
(%)
Euphoria
(%)
85
98
68b
67
92
12
20
20
100
90
52
81
31
30
94
70
92c
78
76
44
63
16
75
81d
119
81
39
9f
100
89
95
55
90
66
90
59
97
63e
56
44
52
60
67g
103
316
51
158
91
Weighted Meanj
Expansiveness
(%)
100
Total nj
Lability
(%)
97
Depression
(%)
59
29i
42
63
46
49
1121
71
60
Mood
Cognition
Behavior
Stage I
Stage II
Stage III
Figure 22. Relationship between states of a manic episode and daily behavior ratings. (Source: Carlson and Goodwin, 1973.)
15
Nurses Ratings
12
9
Dysphoria
6
Mania
3
1
Hospital
Days
Psychosis
93
95
100
Stage I
Stage II
A little
pressured
speech,
somewhat
tangential,
hyperactive,
happy
Brought too
many clothes
from home,
paranoid,
hyper-religious,
hyperverbal,
pacing,
numerous
telephone
calls,
grandiose
105
Stage III
110
Stage II
Hyperverbal,
Still paranoid
delusional,
but more cooperative,
has x-ray
restless,
vision,
hypersexual,
talking with
manipulative,
dead father,
still angry,
panicked
makes telephone
afraid he
calls
might
blow
up, labile,
suspicious,
sexually preoccupied,
occasionally disoriented,
unable to complete a
thought, very angry
Stage I
Quieter,
more organized,
overtalkative,
seductive,
still
depressed
115
Normal
Appropriate,
realistic,
showing concern
for others
Clinical Description
43
44
Study
Patients
(N)
Grandiosity
(%)
Flight of Ideas/
Racing Thoughts
(%)
Distractibility/
Poor Concentration
(%)
Confusiona
(%)
Lundquist, 1945
95
31
79
100
97
58
100b
86
93
100
20
100
75
70
35
52
78
63
16
71
50
77
33
41
26
49
16
58c
75
119
9
27
67
11
316
158
Total ne
968
Weighted meane
23
72
73
56
67
91d
55
78
95
97
76
75
29
latter separately below). Although difficult, this distinction is important, since it is possible to have either disorder without the other (Holzman et al., 1985). Much of
thought is nonverbal, and individuals often say one thing
while thinking another. Here we use as a working definition of thought disorder one provided by Solovay and
colleagues (1987, p. 13): thought disorder is not intended
to denote a unitary dimension or process; rather, it refers
to any disruption, deficit, or slippage in various aspects of
thinking, such as concentration, attention, reasoning, or
abstraction.
Certain psychotic features of mania and bipolar
depressiondelusions and hallucinationsare relevant
but not central to the concept of thought disorder. The
Clinical Description
45
Table 24. Thought Pathology in Mania and Schizophrenia: Similarities and Differences
Study
Similarities
Differences
46
Andreasen, 1984
47
Table 24. Thought Pathology in Mania and Schizophrenia: Similarities and Differences (continued)
Study
Similarities
Differences
and communication
Schizophrenic patients: poverty of
speech
Clinical Description
Figure 23. Standardized Thought Disorder Index scores on factors derived from principal components analysis for five groups of subjects. (Source: Shenton et al., 1987.)
"1
Combinatory
Thinking
Idiosyncratic
Thinking
Autistic
Thinking
49
Fluid
Thinking
Absurdity
Schizophrenic (N ! 43)
Manic (N ! 20)
Schizoaffective, manic (N ! 12)
Schizoaffective, depressed (N ! 10)
Normal (N ! 22)
Confusion
50
in levels of thought disorder between medicated and unmedicated manic patients. Manic patients were at least as
thought disordered as, if not more so than, schizophrenic
patients (Harrow et al., 1986).
In the short-term follow-up phase (7 weeks), manic
thought disorder in medicated patients improved, although
some patients continued to show severe thought disorder.
Manic patients did not show a more rapid reduction in
thought pathology relative to the schizophrenic patients
(Harrow et al., 1982).
One year after hospital discharge, a surprisingly large
number of manic patients showed relatively severe
bizarreidiosyncratic thinking or positive thought disorder (Fig. 24). There was also a significant reduction in
severity of thought pathology for both manic and schizophrenic patients at follow-up. Manic patients showed a
greater reduction in pathology (from 73 to 27 percent rated
as severe or very severe) relative to the schizophrenic patients (from 50 to 27 percent) (Harrow et al., 1986).
Two- to 4-year follow-up data revealed that of the manic
patients, 30 percent had severe or very severe thought disorder, and another 30 percent had definite signs of abnormal
thinking. Of the 14 formerly hospitalized manic patients
who showed severe or very severe thought disorder, only 4
were rehospitalized at the time of the follow-up assessment.
Figure 24. Composite level of thought disorder during and after hospitalization in manic,
schizophrenic, and nonpsychotic psychiatric patients and normal subjects. (Source: Grossman
et al., 1986; Harrow et al., 1982, 1986.)
100
80
60
40
20
Acute
1
24
Year Years
(N!34) (N!34) (N!47)
Manics
Level of thought
disorder:
Acute
1
Year
(N!48) (N!30)
Schizophrenics
Severe or
very severe
Moderate
Acute
1
Year
(N!31) (N!30)
Nonpsychotic
Psychiatric
Patients
(N!34)
Normals
None, minimal
or mild
Clinical Description
51
Table 25. Relationship of Manic Behavior and Psychosis to Thought Disorder in 47 Formerly
Hospitalized Manic Patients at 2- to 4-Year Follow-Up
No or Mild
Thought Disorder
(%)
(n = 19)
Signs of Abnormal
Thought Disorder
(%)
(n = 14)
Severe or Very
Severe Thought Disorder
(%)
(n = 14)
None
58
71
29
Equivocal
42
36
21
36
None
74
29
43
Equivocal
26
36
29
36
29
Definite
Ratings of Psychosis
Definite
Source: Grossman et al., 1986. Reprinted with permission from the American Journal of Psychiatry, Copyright 1986, American Psychiatric
Association.
Positive thought disorder was associated with manic behavior; that is, those patients who showed more manic behaviors had more severe thought disorder (see Table 25). There
was a significant correlation between thought disorder and
psychosis, but psychotic symptoms alone did not account
for all of the variance associated with thought disorder at
follow-up. Manic patients with more than one previous
hospitalization or with a more chronic manic course had
significantly more thought disorder than patients with only
one or no previous hospitalizations (Grossman et al., 1986).
These findings of Harrows group are indicative of the
fact that manic thought disorder can prevail long past an
acute episode, a point suggesting the need for caution in
accepting assumptions of a relatively benign course of illness or of a return to normality for all patients with bipolar illness (see Chapter 4 for further discussion of the
problematic course of bipolar disorder). The findings must
be tempered, however, by certain methodological constraints, especially one relevant to recent investigations. In
the current era, manic-depressive patients seen and treated
in university teaching hospitals represent a disproportionately ill and treatment-refractory group. Bipolar patients
with a more typical (i.e., salutary) course are now treated,
for the most part, by the general psychiatric community.
Those patients less responsive to standard medical interventions are more frequently referred to research centers
for evaluation and treatment. Further confounding interpretation of the above findings are issues of patient
nonadherence to medication regimens (see Chapter 21),
medication side effects, and seasonal biases (e.g., annual
assessments, if completed 1, 2, or 4 years after an acute
episode, may increase the likelihood of testing during a
periodic recurrence rather than a remission). The continuance of significant thought pathology in many manic patients is of both clinical and theoretical relevance and is an
important area for further research (see Perugi et al., 1998a,
for a discussion of cognitive decline in chronic mania).
Linguistic and Communication Patterns. Investigators
have found differences in linguistic patterns between manic
and schizophrenic patients (Kagan and Oltmanns, 1981;
Harvey, 1983; Ragin and Oltmanns, 1987). Hoffman and colleagues (1986) found that total speech deviance and utterance length were greater in manic than in schizophrenic
patients. The authors concluded that manic speech difficulties were due to shifts from one discourse structure to
another, while schizophrenic speech difficulties reflected a
basic deficiency in elaborating any discourse structure (p.
836). In a related study, Fraser and colleagues (1986) found
that schizophrenic patients had less syntactically complex
speech than manic patients. This finding is consistent with
those of the more recent work of Thomas and colleagues
52
Normal Persons
1
Schizophrenics
3
Manics
6
4
7
Figure 25. Sample of discourse structures taken from three groups. Note: Nodes correspond to
statements generated by text. Linkages are formed from dependency relations. Substructures
identified by open circles correspond to largest subtree embedded in segment. Jagged line indicates nontransitive dependency; broken lines represent nondependent associations. Upward
branching nodes can be seen to receive more than one chain of superordinate statements. Two
manic patients have larger subtrees compared with three schizophrenic patients. 1, 2, and 5 are
well-formed trees. (Source: Hoffman et al., 1986.)
(1996) and Lott and colleagues (2002), who also found that
manic speech was more complex. The structural differences
in language are schematized in Figure 25. Hoffman and
colleagues (1986) speculated that the shift from one discourse structure to another is related to the manic patients
increased distractibility and general level of overactivation,
each of which involves both verbal and nonverbal behavior.
Distractibility in bipolar illness, which is pervasive and often severe, is discussed in detail in Chapter 9.
Predictability of verbal communication has been studied
through close analysis, a measure of the ability of normal
subjects to guess words deleted from transcripts of speech
samples. Using this technique, Ragin and Oltmanns (1983)
found that depressed speech was the most predictable,
Clinical Description
53
Manic >Depressed
Depressed >Manic
Lexical diversity
Colorfulness
Action verbs
Adjectives
Concreteness
Words reflecting power
and achievement
Vagueness
Qualifying adverbs
First-person pronouns
Overstatement
Delusions and Hallucinations. Problems in the assessment of delusions and hallucinations are many and troublesome. Orvaschel and colleagues (1982) found that family reports of affective delusions identified only 18 percent
of probands who admitted such symptoms on direct interview with the Schedule for Affective Disorders-Lifetime
(SADS-L). In a study of psychosis in 89 bipolar patients,
Rosen and colleagues (1983a) found that 49 (55 percent)
emerged as psychotic on the basis of interviews (SADS)
alone. After a review of all interviews and prior records,
however, 63 were identified as psychotic. Price and colleagues (1984), like Orvaschel and colleagues (1982), found
a lack of reliability in reports from family members. Yet as
Pope and Lipinski (1978) observed in their early review of
the literature, the general findings of all these studies,
despite wide differences in time, setting, and sample selection, are reasonably consistent.
Table 27 summarizes findings from 33 studies of psychotic features in mania. Approximately two-thirds of the
bipolar patients in these studies were found to have a lifetime history of at least one psychotic symptom (phase of
illness usually unspecified, but when specified, more often
manic). The range of rates was 47 to 90 percent. These
results are consistent with Carlson and Goodwins (1973)
finding that 30 percent of their bipolar-I patients (i.e.,
those with a history of mania) did not progress to stage III
mania. Rosenthal and colleagues (1979) also observed that
33 percent of their bipolar-I patients never became formally psychotic during mania. The high prevalence of psychotic features in these studies is consistent with the presence of a psychosis factor in most factorial studies of
mania and with Koukopouloss (2005) assertion that the
manic syndrome is basically a psychotic condition.
Some evidence suggests that early age at onset of bipolar illness is likely to be associated with an increased rate
Study
Lange, 1922
Bowman and Raymond,
19311932a,b
Patients Any
N
(%)
Grandiose
(%)
Persecutory/
Paranoid
(%)
HALLUCINATIONS
Passivity
(%)
Any
(%)
700
Auditory
(%)
Visual Olfactory
(%)
(%)
Presence or History
of Psychotic
Symptomsa
(%)
1009
20
Rennie, 1942
66
Lundquist, 1945
95
96
31
73
100b
48
17
24
First-Rank
Thought Schneiderian
Disorder Symptoms
(%)
%
8
22
13
18
24
47
54
12
Carlson and
Goodwin, 1973
20
66
52
30
19
78
63
16
19
22
21
33
75
65
20
40
23
60
42
48
27
15
12
23
53b
55
67
43
25
44
119
52
65
56
35c
47
84
33
44
35c
30c
53
34
30
30
21c
67c
66
32
71
89
55 (71)e, f
71
75c
Winokur, 1984
122
298d
467
55
41
54
14
9
74c
25
44
14
13
34g
90
7890h
139
65
214g
67
863g
61
352c
42
Weighted meansj
(individual episode
dataa)
34
47c
316
Total n
34
64c
11
31
17
34
25
196(48)i
50
25
22
18
14
68
11 (23)i
5973
53
31
39
12
23
15
61
19
17
(continued)
Study
Patients Any
N
(%)
HALLUCINATIONS
Grandiose
(%)
Persecutory/
Paranoid
(%)
Passivity
(%)
Any
(%)
Auditory
(%)
Visual Olfactory
(%)
(%)
Presence or History
of Psychotic
Symptomsa
(%)
Thought First-Rank
Disorder Schneiderian
(%)
Symptoms %
Weighted meansj
lifetime dataa
35
22
18
10
60
34
53
31
29
12
23
18
12
15
61
19
18
Clinical Description
The relationship between the presence or a history of psychotic features and the long-term course of illness is unclear.
While several studies have not found a correlation between
psychosis and poorer outcome,10 many more have.11 There
is even more agreement that mood-incongruent psychotic
features predict a less positive course.12 Only one early investigation (Abrams and Taylor, 1983) and a single recent
study (Keck et al., 2003) found otherwise. Keck and colleagues hypothesized that their findings, which are at variance with most others, may reflect the high morbidity and
poor functional outcome in the great majority of the patients they studied. There does not appear to be a significant correlation between psychosis and an increased likelihood of attempting suicide (Grunebaum et al., 2001; Black
et al., 2003; Keck et al., 2003; see Chapter 8).
Young and colleagues (1983) examined the relationship
between psychotic features and other manic symptoms.
They found no association of psychotic features with insight,
disruptiveaggressive behavior, appearance, and rate and
amount of speech, or with demographic variables, such as
age, gender, and race. They did find, however, that psychotic patients were significantly more likely than nonpsychotic patients to have grandiose and expansive mood, increased psychomotor activity and energy, and increased
sexual interest, and were also more likely to report sleepdisturbance symptoms. Baethge and colleagues (2005),
who studied hospitalized bipolar patients, found that those
who reported hallucinations were less well educated and
had higher anxiety scores, longer hospitalizations, and less
insight into their illness. Comparisons of bipolar-I and -II
patients have found, as one would expect, a greatly elevated
rate (nearly three-fold) of psychotic symptoms in those
with bipolar-I (Vieta et al., 1997; Suppes et al., 2001; Serretti et al., 2002).
Finally, Endicott and colleagues (1986) studied 1,084
first-degree relatives of 298 probands with schizoaffective,
psychotic, and nonpsychotic unipolar and bipolar major
depressive disorders. They found that over the course of a
lifetime, bipolar disorder and psychosis were positively
associated in both probands and relatives. Bipolar illness
in a proband did not predict psychosis in relatives, however, whereas psychosis in a proband was related to
increased risk of psychosis (but not to bipolarity) in relatives. According to Endicott and colleagues, these findings suggest that, although bipolarity and psychosis often
occur in the same individuals, they may not reflect the
same genetic influence. The authors speculated that the
risk for the expression of psychotic symptoms is increased in individuals who also have had a bipolar disorder (p. 11). Interestingly, Winokur and colleagues (1986;
Winokur and Kadrmas, 1989) showed that the risk
for psychosis, as well as polyepisodic course in bipolar
57
Kraepelin (1921, pp. 6869) also emphasized the changing nature of manic delusions (especially when contrasted
with those expressed during the depressive phase, which he
thought were for the most part uniformly adhered to):
manic delusions change frequently, emerge as creations of
the moment and again disappear; they move very frequently on religious territory, tending to be grandiose; and
patients often narrate all sorts of journeys and adventures,
secret experiences. He also reported that the same delusional ideas often appeared again in subsequent attacks.
Winokur and colleagues (1969, p. 72), like Kraepelin, suggested that delusions of mania are not well systematized
and, apart from grandiose optimism, tend not to be acted
upon. They attributed the fact that manic patients seldom
act on their delusions (a point perhaps worth disputing) to
58
the brief duration of the delusions and the patients inability to make any sort of concerted action. They noted further that both manic and depressive delusions, which occur
primarily in the most disturbed patients, tend to be appropriate to the patients mood and not to be systematized. The
same investigators found that religious themes were the
most common manic delusions in both men (27.0 percent)
and women (30.1 percent). Political themes were more common in men (18.9 percent) than in women (3.2 percent),
and sexual and financial themes were about equally common (13.5 and 9.5 percent, respectively, in men; 5.4 and 7.9
percent, respectively, in women).
Hallucinations, or perceptions of sensory impressions
without the existence of external physical stimuli, represent a fascinating, not uncommon, and yet relatively
unstudied part of the clinical phenomenology of affective illness. They occupy a portion of the continuum of
dream-stateillusoryhallucinatory phenomena, which
ranges from distortions and misperceptions on the one
hand to the total conjuring of fully developed images on
the other. Hallucinations can vary in a wide range of aspects, such as their extent (frequency and duration), location, constancy, intensity, effect on overt behavior, affect
produced, content, and causal attributions (Lowe, 1973).
Yet despite these complexities, hallucinations are most
commonly presented in the psychiatric research literature
as simply present or absent in a given sensory modality
(e.g., auditory or visual).
Hallucinations generally occur less frequently than
delusions in both the manic and depressed phases of bipolar illness, although Carlson and Strober (1979) reported a
significantly higher rate of hallucinations in bipolar depression. Baethge and colleagues (2005) found comparable
rates of hallucinations in mania and depression, but twice
as high a rate in bipolar mixed patients (see Table 28).
The lifetime history data presented earlier in Table 2-7
suggest that at least half of all patients report a history of
delusions, but only about a fifth report the experience of
hallucinating while depressed or manic. Auditory hallucinations, averaged across the data-based studies, are more
common than visual ones.
Kraepelin (1921, pp. 56) found that in mania, the perception of external impressions was invariably encroached
upon and that defective perceptions often were related to
extraordinary distractibility of attention. He described
not only the blurring of illusions, hypnagogic phenomena,
and hallucinations, but also their overlap with mood and
thinking in the bipolar form of manic-depressive illness
(pp. 8, 11):
Isolated hallucinations are observed frequently and in the
most different states, although they do not very often
Clinical Description
59
Table 28. Comparison of Psychotic Features during Mania and Bipolar Depression
PERCENTAGE OF PATIENTS
Category of
Symptoms
Winokur
et al., 1969a
Carlson and
Strober, 1979
Rosenthal
et al., 1980
Black and
Nasrallah, 1989
Mania
48
56
96c
44
Depression
33
66
28
12
21b
33
66
14
6b
50
24
Mantere
et al., 2004
Baethge
et al., 2005
Delusions
Hallucinations
Mania
Depression
11 (23d)
11
Psychotic
Symptomse
Mania
Depression
Mixed
44
9
40
60
protocol in at least four regions of France. The main findings of this study are generally consistent with those of
earlier research in indicating that further phenomenological understanding of mania requires a multidimensional perspective. The authors of this study went beyond
the euphoricdysphoric dichotomy and proposed the existence of independent euphoric, depressive, hostile, psychotic, and deficit factors, each of which was correlated
with a core activation (disinhibitioninstability) factor of
mania.
Like Bauer and colleagues (1994), Akiskal and colleagues (2001) concluded that, rather than euphoria/irritability, the central definitional focus of mania should be
psychomotor activation. This conclusion is consistent with
the emphasis of Heinroth (1818) and Koukopoulos (2005),
which posits that excitement is the fundamental state of
the bipolar subgroup of manic-depressive illness. By incorporating new features of mania derived from the EPIMAN
study (e.g., pathological gregariousness and overfamiliarity) and using clinical expertise, different groups of investigators have developed a factorial structure of mania that
incorporates psychomotor activation as the major criterion, along with mood disturbance, other signs and symptoms, and a lack of insight and judgment; this work, in
conjunction with that of other investigators, has led to proposed changes in the DSM-IV criteria for mania. Ghaemi
and colleagues (1995) also underscored the cognitive dysfunction in the areas of insight and judgment in mania;
similar findings were reported by DellOsso and colleagues
(2000). Interestingly, insight appears to be less impaired
during mixed mania (Cassidy et al., 2001a; see Chapters 21
and 22).
Table 210 summarizes the findings of factorial studies
of the structure of mania. It is clear that current diagnostic
systems fail to reflect the actual complexity of the state.
Nor do most diagnostic formulations adequately capture
the essential relationship, indeed the often total overlap,
between major subtypes of mania and mixed states. Virtually all investigations of the structure of mania have noted
common underlying dimensions: a mood component, characterized by either predominantly euphoric or dysphoric
qualities; psychomotor activation; psychotic features; and
irritability and/or aggression.
There are fewer data on the structure of hypomania,
but as with mania, cardinal manifestations are irritability,
coupled with heightened activation and behavioral excess.
Serretti and Olgiati (2005) compared patterns of manic
symptoms in 158 bipolar-I and 122 bipolar-II patients (see
Table 211). The bipolar-I patients had a higher prevalence
of reckless activity, distractibility, psychomotor agitation,
irritable mood, and increased self-esteem. Juruena and
colleagues (2006) compared 27 bipolar-I patients with
Rapid/
Hyper-
Decreased
Assaultive
Pressured
Hyper-
Nudity/
Sexual
Hyper-
Extrav-
Inconti-
Patients
activity
Sleepa
Behavior
Speech
verbosity
Exposure
sexuality
agance
Study
(N)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
Lange, 1922
700
Head
Regression
Religiosity
Decoration
(Pronounced)
Catatonia
Smearing
nence/
(%)
(%)
(%)
(%)
(%)
14
19
27
24
70
Clayton et al.,
1965
31
94
100
74
90
99
65
Winokur et al.,
100b
76
20
100
75
100
52
100
48
100
23
33
78
100
46
100
33
38
63
81
63
16
56
69
1969
69
Carlson and
Goodwin, 1973
100
80
50
45
86
27
75
25
14
32
25
123
46
29
32
28
10
100
78
89
78
56
(continued)
Study
Violent/
Rapid/
Nudity/
Inconti-
Hyper-
Decreased
Assaultive
Pressured
Hyper-
Sexual
Hyper-
Extrav-
Head
Regression
Patients
activity
Sleepa
Behavior
Speech
verbosity
Exposure
sexuality
agance
Religiosity
Decoration
(Pronounced)
Catatonia
Smearing
nence/
(N)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
(%)
62
111
19
61
31
316d
99
85
79
46
80
27c
158
Total nf
1857
Weighted meanf
a
98
99
90
83
93
47
88
89
29
51
32
39
34
28
24
13
Sample Size
Assessment Tool
Murphy and
Beigel, 1974
30
MSRS
Double, 1991
81
RDC
MRS
Primary Factors
10 nondelineated
factors
CPRS
237
DSM-III-R
MSRS
Clinical assessment
105
Core Dimensions/
Clusters
I. Euphoriagrandiosity
II. Paranoia
destructiveness
I. (Mild) excitation
II. Elationpressured
speechflight of ideas
III. Psychosisseverity
IV. Psychomotor activation
aggressive overactivity
1. Dysphoric mood
2. Psychomotor
pressure
3. Psychosis
4. Euphoric mood
5. Irritability, aggression
RDC
1. Manic activation
DSM-III-R
2. Depressed state
3. Sleep disturbance
4. Irritability/paranoia
Cassidy et al., 2001a
327
DSM-III-R
SMS
1. Hypomania; low
psychosis; mild,
classic mania
2. Severe, classic pure
mania; devoid of
dysphoric features
3. Grandiosity and psychosis,
but without marked
psychomotor pressure,
sleep disturbance,
hypersexuality, humor,
and irritable paranoia
4. Dysphoria; complete
absence of euphoric mood
or humor; little grandiosity
or hypersexuality
5. Dysphoria, but less than
factor 4. Higher levels
of grandiosity, humor,
psychomotor activation,
hypersexuality
Hypomania
Acute mania
Delusional mania
Depressive or
anxious mania
Mixed state
(continued)
63
64
Study
Sample Size
Assessment Tool
Primary Factors
162
DSM-III-R
SADS
ADRS
1.
2.
3.
4.
5.
6.
Impulsivity
Hyperactivity
Anxious pessimism
Distressed appearance
Hostility
Psychosis
I.
II.
III.
IV.
Depressive
Delusional
Classic
Irritable
576
DSM-IV
GAF
AMDPS
1.
2.
3.
4.
Depressive mood
Irritable aggression
Insomnia
Depressive inhibition
I.
II.
III.
IV.
Pure mania
Aggressive mania
Psychotic mania
Depressive (mixed)
mania
5. Pure mania
6. Emotional liability/agitation
7. Psychosis
Akiskal et al., 2003a
104
DSM-IV
MSRS
GAF
HDRS
1.
2.
3.
4.
5.
6.
7.
Disinhibition
Hostility
Deficit
Psychosis
Elation
Depression
Sexuality
Gonzlez-Pinto
et al., 2003
103
DSM-IV
MRS
HDRS
1.
2.
3.
4.
5.
Depression
Dysphoria
Hedonism
Psychosis
Activation
I. Hedonism
II. Dysphoria
III. Activation
ADRS = Affective Disorders Rating Scale; AMDPS = Association for Methodology in Psychiatry System; CPRS = Comprehensive Psychopathology Rating Scale; DSM-III-R = Diagnostic and Statistical Manual, 3rd edition, revised; DSM-IV = Diagnostic and Statistical Manual,
4th edition; GAF = Global Assessment of Functioning; HDRS = Hamilton Depression Rating Scale; MRS = Mania Rating Scale (Young);
MSRS = Manic State Rating Scale; MVAS-BP = Multiple Visual Analogue Scales of Bipolarity; RDC = Research Diagnostic Criteria;
SADS = Schedule for Affective Disorders; SMS = Scale for Manic States.
Clinical Description
65
BP-II (n = 122)
(%)
Excessive activity
98.1
96.7
Reckless activity
72.1
Distractibility
Risk Ratio
95% Confidence
Interval
0.47
1.32
0.563.13
41.8
<0.01
1.81
1.402.33
96.8
79.5
<0.01
3.67
1.648.22
98.7
96.7
0.41
1.71
0.555.32
Agitated activity
87.9
52.4
<0.01
3.13
2.084.71
Pressured speech
93.0
86.0
0.07
1.48
0.932.38
Racing thoughts
94.9
89.3
0.11
1.52
0.872.67
Elevated mood
90.5
94.2
0.27
0.82
0.601.10
Irritable mood
91.1
68.8
<0.01
2.34
1.483.71
Increased self-esteem
86.7
63.9
<0.01
1.97
1.372.84
Symptom
Probability
DEPRESSIVE STATES
Classic Clinical Descriptions
The bipolar depressive states, in sharp contrast to the manias, are usually characterized by a slowing or decrease in
almost all aspects of emotion and behavior: rate of thought
and speech, energy, sexuality, and the ability to experience
pleasure. As with the manic states, severity varies widely.
Symptoms can range from mild physical and mental slowing, with very little distortion in cognition and perception,
to profound depressive stupors, delusions, hallucinations,
and clouding of consciousness. Of the three major symptomatic groups we have been examiningmood, cognition
and perception, and activity and behaviormood is perhaps the least variable across the continuum of depressive
states, although, as we shall see, irritability and anger often
accompany the more usual melancholic picture. Cognition and perception, on the other hand, change profoundly, as do activity and behavior. We begin with extensive classic descriptions of depressive mood, then discuss
66
Mood
Mood in all of the depressive states is bleak, pessimistic,
and despairing. A deep sense of futility is often accompanied, if not preceded, by the belief that the ability to
experience pleasure is permanently gone. The physical
and mental worlds are experienced as monochromatic, as
shades of gray and black. Heightened irritability, anger,
paranoia, emotional turbulence, and anxiety are common.
The frightening lack of color and the inability to experience meaningful emotional responses were described by
Campbell (1953, p. 106):
General impairment in emotional feeling is another
symptom often described by the manic-depressive patient
in a depressive episode. In addition to distortions in sensing impressions, such as a queer, odd or unreal feeling,
the patient may complain of a universal dulling of the
emotional tone. This symptom, like the feeling of unreality, frightens the patient because it tends to alienate him
from his environment. Indeed, it is an important constituent of the patients fear of insanity. It is bad enough
not to speak the same language as other peopleit is
worse not to feel the same emotions.
Clinical Description
the volition of will, and profoundly altered sleep and eating patterns are hallmarks of this type of depression (see
Chapter 16 for detailed discussion of altered sleep and
activity patterns). Campbell (1953, p. 85) described the
fatigued, psychomotorically retarded appearance of depressed patients:
Depressed mood is often suggested by the bearing, gait or
general appearance of the patient. The depressed individual usually walks slowly and reacts sluggishly. He appears
to push himself along, as if he were being held back, rather
than propelling himself with normal agility. There are no
unnecessary movements with the hands or feet, the patient
sitting in a languorous but not restful posture. The shoulders sag, the head is lowered and the entire body seems to
droop; loosely hanging clothes sometimes suggest the
weight loss often present in the melancholic individual.
Everyone is acquainted with the tendency of the angles of
the mouth to turn down in the saddened person; a smile,
when it occurs, must be forced, and even then there is
something sickly or distorted in its expression. The facial
musculature of the depressed individual lacks tone, giving
the face an inert, myasthenic appearance. The upper eyelids also manifest this careworn expression. . . .
The eyes, which normally portray the spark, vitality
and curiosity of the personality, are dull and lustreless. In
some individuals the eyes have a faraway, unnatural stare,
which even the layman recognizes as a mark of extreme
pre-occupation or mental illness.
67
68
Clinical Description
69
70
Preoccupation with sin and perceived religious transgressions are not uncommon in severe depression, and
many deeply depressed patients would empathize with
Cowpers strong sense of Gods wrath, and a deep despair
of escaping it. William James wrote definitively of this
preoccupation, as well as of religious ecstasies, in The Varieties of Religious Experience (1902).
Finally, as noted above, thoughts of suicide often accompany the despair, apathy, guilt, and feelings of inadequacy
associated with depression. Extensive discussion of suicidal thoughts and behaviors is given in Chapter 8; here
we present one womans description of the depression
leading up to a nearly lethal suicide attempt (Jamison, 1995;
pp. 110111, 113):
A floridly psychotic mania was followed, inevitably, by a
long and lacerating, black, suicidal depression; it lasted
more than a year and a half. From the time I woke up
in the morning until the time I went to bed at night, I was
unbearably miserable and seemingly incapable of any
kind of joy or enthusiasm. Everythingevery thought,
word, movementwas an effort. Everything that once
was sparkling now was flat. I seemed to myself to be dull,
boring, inadequate, thick brained, unlit, unresponsive,
chill skinned, bloodless, and sparrow drab. I doubted,
completely, my ability to do anything well. It seemed as
though my mind had slowed down and burned out to the
point of being virtually useless. The wretched, convoluted,
and pathetically confused mass of gray worked only well
enough to torment me with a dreary litany of my inadequacies and shortcomings in character, and to taunt me
with the total, the desperate, hopelessness of it all. What is
the point in going on like this? I would ask myself. Others
would say to me, It is only temporary, it will pass, you
will get over it, but of course they had no idea how I felt,
although they were certain that they did. Over and over
and over I would say to myself, If I cant feel, if I cant
move, if I cant think, and I cant care, then what conceivable point is there in living?
The morbidity of my mind was astonishing: Death
and its kin were constant companions. I saw death everywhere, and I saw winding sheets and toe tags and body
Likewise for Scott Fitzgerald (1956, pp. 7273; first published in 1936), sleep and hating to face the night became
sources of terror:
[E]very act of life from the morning toothbrush to the
friend at dinner had become an effort . . . hating the night
Clinical Description
Clinical Studies
There has been much less quantitative study of the clinical
features of bipolar depression than is the case for either
mania or nonbipolar depression. In fact, the substantial
literature on depression seldom differentiates bipolar from
unipolar depression,16 and until recently, bipolar depression was usually excluded from study and discussion.
Further complicating matters, bipolar depression has frequently been misdiagnosed as unipolar depression, or not
discussed in the context of its often mixed forms. For our
data-based clinical description of bipolar depression, we
have relied primarily upon the early monograph of
Winokur and colleagues (1969), Benazzis series of outpatient studies,17 and the work of several other researchers
(Perugi et al., 1998a; Koukopoulos and Koukopoulos, 1999;
Mitchell et al., 2001). Specific comparisons of bipolar and
unipolar depression are presented in Chapter 1.18 In this
section we present the findings of data-based studies with
regard to symptom presentation in bipolar depression,
psychotic features, depressive mixed states, and bipolar
unipolar differences in depressive symptomatology.
Mood
Winokur and colleagues (1969) studied the symptomatology and clinical course of 21 treated bipolar depressed
patients (5 men and 16 women, with a combined total of 33
separate depressive episodes). They described the onset of
depression as abrupt in 5 episodes (15 percent) and gradual
in 28 (85 percent). Mood was observed to be melancholic
or tearful in virtually all patients (100 and 94 percent,
respectfully), with approximately half (52 percent) displaying hopelessness. Fully three-fourths of bipolar depressed
patients were described as irritable, almost as high a percentage (85) as was found by the same authors in manic
patients (see Table 21). Irritability, which is pervasive during bipolar depression (Deckersbach et al., 2004; Benazzi
and Akiskal, 2005), is considered more extensively later
in this section, as well as in the subsequent discussion of
mixed depressive states.
71
72
MIXED STATES
Mixed states, in which symptoms of depression and mania
combine, represent a complex and often confusing aspect
of the clinical presentation of bipolar illness. They can be
conceived of as transitional states from one phase of illness
to another or as independent clinical states combining various mixes of mood, thought, and activity components. To
a considerable extent, mixed states are even more vulnerable to the inadequacies of modern diagnostic systems than
other types or stages of affective illness. Indeed, systematic
diagnostic criteria, impressively standardized for most
other types and phases of affective disorders, are least validated for mixed states. Differential diagnosisespecially
among mixed states, agitated depressions, and borderline pathologiescan be a difficult clinical problem (see
Chapter 3).
Mixed states are broadly defined as the simultaneous
presence of depressive and manic symptoms. Yet we know,
for example, as noted earlier, that mania frequently is
accompanied by moderate to severe depression. Should
depression during mania be conceptualized as a mixed
state, a typical mania, an atypical mania, or a severe (stagerelated) form of mania? Should a mixed depressive
episode be defined by the presence of four manic symptoms or only two? Are the diagnostic criteria of DSM-IV
prohibitively strict, as most researchers think? (According
to DSM-IV, a diagnosis of mixed states requires that all of
the criteria, except duration, for both a manic and a depressive episode be met nearly every day during at least a
1-week period, and that the symptoms be severe enough to
cause marked impairment or necessitate hospitalization,
or that there be psychotic features.) Until more systematic
and discriminating definitions and criteria are developed,
the pragmatism of the immediate clinical or research issue
will determine the answers to such questions.
Clinical Description
73
Sleep Disorder
Insomnia
100
85
58
Early-morning awakening
27
Hypersomnia
23
77
Activity
Fatigue
76
Psychomotor retardation
76
Social withdrawal
83
100
97
50
45
Increase in appetite
23
Loss of weight
26
Libido
Loss of sexual interest
73
Somatic Complaints
67
64
77
72
Heinroth (1818) delineated, in detail, mixed states of exaltation and depression (see Marneros, 2001). Later in the
mid-nineteenth century, Falret (cited in Sedler, 1983) noted
the strong depressive quality often observed before, during, and after manic episodes, as well as melancolie anxieuse. The latter state, he wrote, is characterized by constant
pacing and inner turmoil, which incapacitates these patients
74
Kraepelin conceptualized mixed states as primarily transitional phenomena, but recognized their existence as individual attacks that frequently occur in later stages of the
illness, often associated with poor outcome. Table 213 summarizes Kraepelins classification and description of mixed
states, which he conceptualized as different combinations of
the manic and depressive symptoms of mood, activity, and
thought. Below is Kraepelins (1921, pp. 103104) description
of two of the most important kinds of these mixed states,
depressive or anxious mania and excited depression:
Depressive or Anxious ManiaIf in the picture depression takes the place of cheerful mood, a morbid state
arises, which is composed of flight of ideas, excitement,
and anxiety. The patients are distractible, absent-minded,
enter into whatever goes on round them, take themselves
up with everything, catch up words and continue spinning out the ideas stirred up by these; they do not acquire
a clear picture of their position, because they are incapable of systematic observation, and their attention is
claimed by every new impression. They complain that
they must think so much, their thoughts come of themselves, they have a great need of communicating their
thoughts, but easily lose the thread, they can be brought
out of the connection by every interpolated question, suddenly break off and pass to quite other trains of thought.
Many patients display a veritable passion for writing, and
scrawl over sheets and sheets of paper with disorderly
effusions. At the same time ideas of sin and persecution
are usually present, frequently also hypochondriacal delusions, as we have formerly described them.
Mood is anxiously despairing; it gives itself vent in
great restlessness, which partly assumes the form of
movements of expression and practical activity, but partly
also passes over into a wholly senseless pressure of activity. The patients run about, hide away, force their way out,
make movements of defense or attack; they lament,
scream, screech, wring or fold their hands, beat them
together above their head, tear out their hair, cross themselves, slide about kneeling on the floor. With these are
associated rhythmical, rubbing, flourishing, snatching,
Jaspers, while noting occasional ambiguity in Kraepelins nosology of mixed states, acknowledged its clinical
utility. The many possible combinations of components
euphoria, flight of ideas, and pressure of movement on the
one hand, and sadness and retardation of thought and of
movement on the othermade possible a better understanding of the wide variety of affective states seen in clinical
practice. Thus, Jaspers (1997, p. 598; first published in 1913)
described a mixed melancholia, one that he suggested might
be characterized as a querulant mania or nagging depression in some, and as a wailing melancholia in others:
In this state the over-valued or compulsive depressive
ideas become delusionlike. They are fantastically elaborated (the patients are the cause of all the misfortune in
the world; they are thought to be beheaded by the devil,
etc.). The ideas are believed even though the patient
seems relatively sensible. Underlying the experiences there
are a host of body sensations (which soon lead to
hypochondriacal delusions: the patients are filled up to
the neck with excreta; the food falls through the empty
body right to the bottom); then there are the most severe
Mood
Activity
Thought
Anxiety
Anxiety
Elation
Anxiously despairing.
Overactivity
Overactivity
Overactivity
Flight of Ideas
Inhibition of Thought
Inhibition of Thought
Depressed
Manic
Manic
Depressed
Manic
Depressed
Manic
Manic
Depressed
Summary
Mood
Activity
Thought
(continued)
Mood
Activity
Thought
Elation
Depression
Elation
Motor Retardation
Motor Retardation
Inhibition of Thought
Flight of Ideas
Flight of Ideas
Manic
Depressed
Depressed
Depressed
Depressed
Manic
Manic
Depressed
Manic
Summary
Mood
Activity
Thought
Clinical Description
Manic stupor, according to Kraepelins student and colleague Weygandt (1899, translated into English in the Harvard Review, 2002, p. 276), is the most important of the
mixed states:
Manic stupor as a phase of manic-depressive insanity is
characterized by psychomotor inhibition and manic, elevated mood, with inhibition of thought (which usually
occurs in a depressive state) instead of flight-of-ideas.
This condition can occur transiently during a manic or
depressive episode, particularly during switching from the
manic phase to the depressive, when a shift has already
taken place in psychomotor activity but not in affect . . . .
The psychopathological condition is usually characterized by psychomotor manifestations (specifically stupor)
as the prominent feature: some patients lie [in bed] showing very severe inhibition for a long time. Their limbs are
cold; they refuse food, and every attempt to feed them is
vain due to their opposition; for months they are mute.
Only the facial expression, which shows no trace of
depression and often shows a slight smile, reveals that a
case is not typical circular [manic-depressive] stupor
with depressed mood. In other cases, the [psychomotor]
block is less intense: such patients may answer if asked
questions, but they speak in a soft voice and hesitate before replying. They prefer not to speak spontaneously at
all. Furthermore, these patients want to stay in bed all the
time and refuse to work. Considerable retardation in their
movements can be observed immediately: the gait is
heavy and leaden; they hesitate to shake hands; and their
writing is clearly slowed down. In less severe cases, the
[psychomotor] block is occasionally interrupted by a fast,
goal-directed movement.
77
78
I am so biliousthat I nearly lose my headand so nervous that I cry for nothingat least today I burst into tears
all alone by myself over a cistern of Gold fisheswhich
are not pathetic animals. . . . I have been excitedand
agitated and exhausted mentally and bodily all this
summertill I really sometimes begin to think not only
that I shall die at top firstbut that the moment is not
very remoteI have had no particular cause of grief
except the usual accompaniments of all unlawful passions.
In a letter to a friend (written in December 1793), Scottish poet Robert Burns, who was also afflicted with a vexacious melancholia on and off throughout his life, provided
a particularly graphic description of the terrible agitation
that can accompany depression (The Letters of Robert
Burns, ed. G.R. Roy, 1985):
Here I sit, altogether Novemberish, a damnd mlange of
Fretfulness & melancholy; not enough of the one to rouse
me to passion; nor of the other to repose me in torpor;
my soul flouncing & fluttering round her tenement, like a
wild Finch caught amid the horrors of winter newly
thrust into a cage.
Clinical Studies
To date, the best historical discussions of mixed states are
those of Weygandt (1899), Kraepelin (1921), Campbell
(1953), Winokur and colleagues (1969), Himmelhoch (1979),
and Koukopoulos (Koukopoulos et al., 1992; Koukopoulos
and Koukopoulos, 1999). These authors described the clinical course, presentation, and correlates of mixed states, as
well as hypotheses regarding their etiology and nature
(including their relationship to the continuum hypothesis
of affective illness, kindling and rapid cycling, and mixedheredity hypotheses).
Reported rates of mixed states vary as a function of the
inclusion criteriathat is, whether the diagnostic criteria
are narrow or broadand the nature of the rating scales
employed,22 as reflected in the wide range of rates reported
by the 18 studies summarized in Table 214. An average of
28 percent of affectively ill patients experienced mixed
states across these studies. By any standard, mixed states
are not as rare as they once were reputed to be. (Kraepelin
and Weygandt, of course, were fully aware of how common mixed states are. In a study of 150 manic-depressive
patients at the Heidelberg Psychiatric Clinic, 36 percent
were diagnosed with a form of mixed states: 15 percent
with sustained mixed episodes, 8 percent with agitated
depression, 7 percent with manic stupor, and 6 percent
with unproductive mania [Weygandt, 1899].)
Symptomatic presentations of mixed states range from
a single opposite-state symptom found in the midst of an
Clinical Description
Patients (N)
61
16
20
65
84
31
60
25
Nunn, 1979
112
36
103
67
18
44
48
46
108
45
71
40
261
>50a
104
37
237
14
105
54
327
13
576
10
103
24
99
39
2,497
28b
a
Because of the sampling methods, the use of enriched criteria from
European concepts of mixed states (Berner et al., 1992) and various
thresholds for diagnosing mixed states beyond the strict DSM-IV
guidelines, the rate of mixed states in this study cannot be given as a
single round figure. If excluded, weighted mean becomes 26%.
b
Assuming the minimum 50% for Perugi et al.
79
tigated the relationship of depression to mania in 20 hospitalized patients. Through an analysis of nurses and
physicians behavioral ratings and notes, they found a statistically significant positive association between mania
and depression in the majority of cases.
Racing thoughts during depression can be considered
another type of mixed state, one observed by earlier clinicians (Kraepelin, 1921; Lewis, 1934). More recently, this
state was examined by Ianzito and colleagues (1974) and
Braden and Qualls (1979). Ianzitos group found a relatively low rate of racing thoughts in their 89 depressed inpatients (5 percent), but they used the Present State Exam,
which emphasizes the pleasurable and exciting quality
as well as the rapidity of thought. Braden and Qualls, by
contrast, found that one-third to one-half of their depressed inpatients reported racing thoughts, with a definite diurnal variation (worsening in the evening, greatest
severity at bedtime). They drew the following conclusion
(pp. 1718):
In bipolar patients and cyclothymics, the racing thoughts
may occur in both high and low states. The symptom
may thus be related more to the underlying pathology of
the affective illness than to the characteristics of either
pole.
80
Percentage of Patients
Mood
Depressed
100
Euphoric
100
Irritable
100
Labile
100
Hostile
79
100
Grandiosity
57
Flight of ideas
43
Delusions (depressive)
36
Delusions (nondepressive)
21
Auditory hallucinations
14
Visual hallucinations
Disorientation
100
Insomnia
93
Pressure of speech
93
63
43
43
Anxiety attacks
43
Extravagance
14
Clinical Description
81
pole in depressive mixed states are psychomotor activation and/or agitation, irritability and mood lability, racing
or crowded thoughts, and sexual arousal, as well as severe
insomnia, panic attacks, and suicidal crises in severely
complicated variants.23 Indeed, increased suicidality and
the risk of suicide are particularly associated with mixed
states (Hantouche et al., 2003; Strakowski et al., 1996;
Marneros et al., 2004; see Chapter 8). A recent study of
bipolar adolescents found that mixed states contributed
independently to the risk of suicidal behavior, but the
increased risk was among the girls only (Dilsaver et al.,
2005). In a meta-analysis of risk factors for suicide and attempted suicide, Hawton and colleagues (2005) at the
University of Oxford also found mixed states to be a significant risk factor.
Consistent with Aretaeus, who had observed that melancholics could be angry without reason, Mammen and
colleagues (2004) found that 39 percent of their bipolar
patients reported anger attacks during depression. Such
attacks may well represent a form of depressive mixed
state.
As discussed in Chapter 1, Benazzi and Akiskal (2005)
compared the relationship between irritability and other
clinical features in a large number of bipolar-II and unipolar major depressive subjects. Major depressive episodes
with irritability were present in 60 percent of their bipolarII patients and in 37 percent of their depressive patients. In
the bipolar-II patients, those who presented with irritability had a significantly younger age at index episode, higher
rates of atypical depressive features, and more significant
Axis I comorbidity relative to those who did not. They also
were more likely to meet the study criteria for depressive
mixed states, defined by the investigators as a major
depressive episode plus three or more concurrent intradepressive hypomanic symptoms (whether occurring in
the bipolar-II or major depressive patients). In the unipolar patients, those who presented with irritability had a significantly younger age at onset and higher rates of atypical
depression; they were also more likely to meet criteria for
a depressive mixed state and to have a family history of
bipolar illness. According to the authors, their data
demonstrate that irritability may be a good marker of depressive mixed states, a view consistent with that of others who have found high rates of irritability and anger
attacks associated with these states (e.g., Fava and Rosenbaum, 1999; Deckersbach et al., 2004; Perlis et al., 2004).
The relationship between age at onset and mixed states is
unclear. Some investigators have found that earlier age
at onset is associated with mixed states (Nunn, 1979; Post
et al., 1989; McElroy et al., 1997), but others have not
(Marneros et al., 1991a,b; Strakowski et al., 1996; Perugi
et al., 1997).
82
that the manic reaction, melancholia, hypomanic reaction, cyclothymic personality, cycloid personality, depressive personality and periodic insanity, are all a part of the
same disease process, and that any one of these may
change into any other.
Clinical Description
Kraepelin also discussed a milder form of manic temperament within the domain of the normal, but still a
link in the long chain of manic-depressive dispositions, a
form that progresses to what he termed the irritable temperament. In Kraepelins (1921, pp. 129131) words:
It concerns here brilliant, but unevenly gifted personalities with artistic inclinations. They charm us by their
intellectual mobility, their versatility, their wealth of ideas,
their ready accessibility and their delight in adventure,
their artistic capability, their good nature, their cheery,
sunny mood. But at the same time they put us in an
uncomfortable state of surprise by a certain restlessness,
talkativeness, desultoriness in conversation, excessive need
for social life, capricious temper and suggestibility, lack of
reliability, steadiness, and perseverance in work, a tendency to building castles in the air . . . periods of causeless depression or anxiety. . . .
The irritable temperament, a further form of manicdepressive disposition, is perhaps best conceived as a mixture of the fundamental states . . . in as much as in it
manic and depressive features are associated. . . . The
patients display from youth up extraordinarily great fluctuations in emotional equilibrium and are greatly moved
by all experiences, frequently in an unpleasant way. While
on the one hand they appear sensitive and inclined to
sentimentality and exuberance, they display on the other
hand great irritability and sensitiveness. They are easily
offended and hot-tempered; they flare up, and on the
most trivial occasions fall into outbursts of boundless
fury. She had states in which she was nearly delirious,
was said of one patient; Her rage is beyond all bounds,
of another. It then comes to violent scenes with abuse,
83
84
Clinical Studies
Compelling evidence argues for including cyclothymia as
an integral part of the spectrum of manic-depressive illness. The data presented here describe several aspects of
Clinical Description
patient as high-strung,explosive,moody,hyperactive,
or sensitive.
Mood, cognitive, and behavioral patterns in 46 patients
with cyclothymia were studied by Akiskal and colleagues
(1977); although based on a small sample, their findings
are useful in providing an overall view of cyclothymic
states. As might be expected, the mood and cognitive aspects parallel, in milder form, those for mania and depression. Three-fourths of Akiskal and colleagues patients
met criteria for alternating patterns of sleep disorder, fluctuating levels in the quality and quantity of work or
school productivity, and financial disinhibition. One-half
of the patients reported periods of irritability or aggressiveness, patterns of frequent shifts in interests or plans,
drug or alcohol abuse, or fluctuating levels of social interaction. Episodic promiscuity or extramarital affairs were
reported by 40 percent of the sample, and joining new
movements with zeal, followed by disillusionment, by 25
percent. Although frequencies of specific behavior patterns are of interest, replicated and comparison population figures are necessary. Thus we await more detailed
studies of cognitive and perceptual changes across mood
states, much larger sample sizes, and replications utilizing
more standardized measures.
Cyclothymia is a common temperamental variant,
occurring in 0.4 to 6.3 percent of the population (Depue
et al., 1981; Placidi et al., 1998; Chiaroni et al., 2005).
According to Akiskal (1998), the most frequent subtypes
of cyclothymia are pure cyclothymia (equal proportion of
depressive and hypomanic swings, alternating in an
irregular fashion), predominantly depressed cyclothymia
(depressive periods dominating the clinical picture,
85
interspersed with even, irritable, and occasional hypomanic periods), and hyperthymia (hypomanic traits
decreased need for sleep, expansive behavior, wild
lifestyledominating, with occasional depressive and
irritable episodes). Systematic qualitative data to verify
this taxonomy do not exist, however.
Discriminatory criteria for the irritable temperament
have remained elusive (Akiskal, 1992a; Akiskal et al.,
1998b). The hyperthymic type, by contrast, is probably distinct from the cyclothymic (Akiskal, 1992a). Indeed, in a
factor analytic study of temperaments in an Italian student population, the cyclothymic and hyperthymic types
emerged as separate superfactors (Akiskal et al., 1998b).
The hyperthymic type is best described as adaptivetrait hypomania (which distinguishes it from hypomanic
episodes), consisting of the triad of high energy, overconfidence, and cheerfulness, with virtually no depressive dips
(which distinguishes this type from the cyclothymic type
proper). Again, while such speculations are interesting,
they need greater validation and replication.
The validated criteria for the cyclothymic type summarized in Box 21 portray a temperament with greater instability than the hyperthymic type, and for that reason
one perhaps more proximal to bipolar disorder; indeed,
cyclothymia often precedes or underlies bipolar-II disorder
(Hantouche et al., 1998; Perugi and Akiskal, 2002). Of the
affective temperaments, cyclothymia is the most correlated
with emotional and behavioral problems (Signoretta et al.,
2005).
On the other hand, the hyperthymic type represents
a more adaptive set of traits. The criteria for hyperthymic temperament, as validated by Akiskal and colleagues (1998a), require that four of the following traits
(which constitute the habitual long-term functioning of
the individual) be present: (1) warm, people seeking, or
extraverted; (2) cheerful, overoptimistic, or exuberant;
(3) uninhibited, stimulus seeking, or risk taking; (4)
overinvolved and meddlesome; (5) vigorous, overenergetic, and full of plans; (6) self-assured, overconfident,
or boastful; and (7) overtalkative or articulate. Researchers in Italy (Maremmani et al., 2005) compared responses from 1,010 students aged 14 to 26 on Cloningers
revised Tridimensional Personality Questionnaire (TPQ)
(Cloninger, 1987) and on the semi-structured affective
temperament interview (TEMPS-I) (Placidi et al., 1998).
The TPQ constructs of gregariousness, exploratory
excitability, uninhibited optimism, attachment, confidence, extravagance, independence, vigor, and impulsiveness correlated highly with the temperamental construct of hyperthymia. Jamison (2004) has discussed at
length the relationship among exuberant, hyperthymic,
and extraverted temperaments, as well as the relationship
86
CONCLUSIONS
This chapter has presented a clinical description of manicdepressive illness (with emphasis on the bipolar form) that
combines three methods of observation: descriptions of
both ancient and modern clinical observers, first-person
accounts from patients with manic-depressive illness, and
results obtained from clinical studies. Each method is
unique, invaluable, but incomplete. Good clinical description is beholden to all three perspectives.
Pathognomonic cycles of mood and activity serve as a
background for ongoing fluctuations in thinking, perception, and behavior. The bipolar form of manic-depressive
illness encompasses the extremes of human experience.
Moods swing between euphoria and despair, irritability
and panic. Cognition can range from psychosis or delirium to a pattern of fast, clear, and sometimes creative associations; it can also manifest as retardation so profound
that consciousness is clouded. Behavior can be seductive,
hyperactiveexpansive, and dangerous; or it can be reclusive, sluggish, and suicidal.
The rapid undulations and combinations of such
extremes result in an intricately textured clinical picture. It
is important to note that the designation mixed states is
often arbitrary. Indeed, manic patients are depressed and
irritable at least as often as they are elated, and bipolar
depressed patients are frequently agitated and may have
racing thoughts.
NOTES
1. Falret, 1854 (translated by Sedler, 1983); Kraepelin, 1921;
Campbell, 1953; Wellner and Marstal, 1964; Beigel and Murphy, 1971a; Cassidy et al., 2001a, 2002; Woods et al., 2001; Sato
et al., 2004.
2. Kraepelin continued:
Statues salute him by nodding; the moon falls down
from the sky; the trumpets of the Day of Judgment are
sounding. He hears the voice of Jesus, speaks with God
and the poor souls, is called by God dear son. There are
voices in his ears; the creaking of the floor, the sound of
the bells take on the form of words. The patient has
telepathic connection with an aristocratic fiance, feels
the electric current in the walls, feels himself hypnotized; transference of thought takes place.
3. As discussed later in this chapter, Carlson and Goodwin
(1973), in their systematic study of the stages of mania, found
that mania usually evolves gradually. In their hospitalized
patients, the early stages of mania could be discerned in
nurses recordings of mood and behavior reviewed after the
apparently sudden onset of manic episodes.
4. Harrow et al., 1972a,b, 1982, 1983, 1986; Harrow and Quinlan,
1977; Harrow and Prosen, 1978.
5. Harrow et al., 1972a,b, 1986; Himmelhoch et al., 1973; Adler
and Harrow, 1974; Harrow and Quinlan, 1977; Grossman
et al., 1981.
6. Breakey and Goodell, 1972; Grossman et al., 1981; Andreasen,
1984; Shenton et al., 1987; Solovay et al., 1987.
7. The discrepancy between the results of these two groups may
be due in part to differences in the assessment of thought
disorder. Resnick and Oltmanns (1984) used a global rating,
whereas Harrow and colleagues (1982) used specific tests.
8. Andreasen, 1984; Resnick and Oltmanns, 1984; Simpson and
Davis, 1985; Ragin and Oltmanns, 1987.
9. Morice and Ingram, 1983; Morice and McNicol, 1986;
Docherty et al., 1996; Thomas et al., 1996; Lott et al., 2002.
10. Pease, 1912; Rosenthal et al., 1979; Harrow et al., 1990; Goldberg et al., 1995; Keck et al., 2003.
11. Beigel and Murphy, 1971b; Murphy and Beigel, 1974; Taylor
and Abrams, 1975; Rosen et al., 1983b; Young et al., 1983,
Winokur et al., 1985; Coryell et al., 1990, 2001; Tohen et al.,
1990; Young and Klerman, 1992; Toni et al., 2001.
12. Brockington et al., 1983; Winokur, 1984; Coryell et al., 1990;
Miklowitz, 1992; Tohen et al., 1992; Fennig et al., 1996; Perugi
et al., 1999; Strakowski et al., 2000.
13. Double, 1990; Bauer et al., 1994; Cassidy et al., 1998; Dilsaver
et al., 1999; Perugi et al., 2001b; Swann et al., 2001; Sato et al.,
2002.
14. Suicidal behavior, discussed in the next section, is covered
more fully in Chapter 8.
15. All quotations from this source are from F. Scott Fitzgerald,
The Crack-up, copyright 1945 by New Directions Publishing Corp. Reprinted by permission of New Directions Publishing Corp.
16. It is even more rare for a clinical study of unipolar depression to differentiate the highly recurrent form (part of Kraepelins manic-depressive illness) from the nonrecurrent
form.
17. Benazzi, 1999b, 2000a,b, 2001, 2003, 2004.
18. More specialized reviews of related clinical topics can be
found in Chapters 1, 8, 9, 10, 11, and 16.
19. Kraepelin, 1921; Bowman and Raymond, 19311932a; Schneider, 1959; Beck, 1967; Winokur et al., 1969.
Clinical Description
20. Charney and Nelson, 1981; Frangos et al., 1983; Helms and
Smith, 1983; Winokur, 1984. Baethge et al., 2005.
21. Charney and Nelson, 1981; Frances et al., 1981; Glassman and
Roose, 1981; Coryell and Tsuang, 1982; Nelson et al., 1984;
Spiker et al., 1985; Roose and Glassman, 1988.
22. McElroy et al., 1992, 1995; Cassidy and Carroll, 1998; Cassidy
et al., 1998; Sato et al., 2002.
23. Akiskal and Mallya, 1987; Koukopoulos and Koukopoulos,
1999; Benazzi, 2000b; Benazzi and Akiskal, 2001; Sato et al.,
87
Diagnosis
DEVELOPMENT OF CONTEMPORARY
DIAGNOSTIC SYSTEMS
Successive versions of the International Classification of
Diseases (ICD), now in its tenth revision (Sato et al., 2002),
represent the official diagnostic system used by clinicians
throughout most of the world. The major exception, of
course, is the United States, where clinicians use the American Psychiatric Associations (APA) Diagnostic and Statistical Manual, the fourth edition of which (DSM-IV) was
published in 1994. The different diagnostic systems are illustrated in Boxes 31a and 31b. Two European systems of
classification are also importantthe Present State Examination (PSE)-Catego (Wing and Nixon, 1975) and the system developed by the Association for Methodology and
Documentation in Psychiatry (Guy and Ban, 1982).
89
90
300.4
311
Bipolar Disorders
296
296.89
301.13
296.8
293.83
292.84
296.90
295.70
295.40
298.8
298.9
Bipolar I disorder
.0x single manic episode
specify if mixed
.40 most recent episode hypomanic
.4x most recent episode manic
.6x most recent episode mixed
.5x most recent episode depressed
.7 most recent episode unspecified
Bipolar II disorder
specify (current or most recent episode) hypomanic/depressed
Cyclothymic disorder
Bipolar disorder not otherwise specified
Mood disorder due to (indicate the general medical
condition)
specify type: with depressive/manic/mixed features
specify if: with onset during intoxication/withdrawal
see substance-related disorders for codes
for specific drugs of abuse
for other agents (including antidepressants)
Code as other substanceinduced mood disorder
Mood disorder not otherwise specified
Schizoaffective disorder
specify: bipolar type/depressive type
Schizophreniform disorder
specify: with or without good prognostic features
Brief psychotic disorder
specify: with or without marked stressor, with postpartum onset
Psychotic disorder not otherwise specified
F 31.0
F 31.1, 31.2
F 31.6
F 31.3, 31.4, 31.5
F31.8
F 34.0
F 31.9
F 10-19
F 25.0
F 25.1
F 25.2
F 25.9
F 23
F 23.2
Depressive episode
Recurrent depressive disorder
Persistent mood (affective) disorders
Dysthymia
Other persistent mood (affective) disorders
Persistent mood (affective) disorders,
unspecified
Other mood (affective) disorders
Single mixed affective episode
Recurrent brief depressive episode
Bipolar affective disorder (BAD)
Manic episode
specify if hypomania, mania with or without psychosis
BAD, current episode hypomania
BAD, current episode manic with or without
psychosis
BAD, current episode mixed
BAD, current episode depressed with or
without psychotic symptoms
Other bipolar affective disorders
specify if bipolar-II disorder or recurrent
manic episodes
Cyclothymia
BAD, unspecified
Mental and behavioral disorders due to psychoactive substance abuse
Schizoaffective disorder, manic type
Schizoaffective disorder, depressive type
Schizoaffective disorder, mixed type
Schizoaffective disorder, unspecified
Acute and transient psychotic disorder
Acute schizophrenic-like psychotic disorder
Diagnosis
Figure 31. DSM-IV classification of mood disorders. NOS = not otherwise specified.
Mood Disorders
Bipolar Disorders
Bipolar-I
Disorder
Bipolar-II
Disorder
Cyclothymic
Disorder
Depressive Disorders
Bipolar
DisorderNOS
91
Major
Depressive
Disorder
Single
Episode
Dysthymic
Disorder
Recurrent
Depressive
DisorderNOS
92
ICD-10 became official in 1993. Heavily influenced by the development of DSM-IV, it groups all mood disorders together
by replacing manic-depressive psychosis with bipolar affective disorder and recurrent depressive disorders. ICD-10
does stay more true to the original Kraepelinian vision
by linking the two recurrent forms of major affective disorder.5 Neurotic depression, reactive depressive psychosis, and
affective (cyclothymic) personality disorder are relocated to
the major groups of affective disorders. The classification
scheme for ICD-10 is reviewed in Box 31b, presented earlier.
Diagnosis
Of the above changes, perhaps the most important clinically are the introduction of bipolar-II disorder, the definition of rapid cycling, the definition of mixed episodes,
and the exclusion of antidepressant-induced mood states
from the diagnosis of bipolar disorder. In general, it would
appear that the DSM-IV task force attempted to balance
the expansion of the bipolar diagnosis to include type II
and a clearly defined rapid-cycling course with more restrictive definitions of mixed states and antidepressantinduced mania.
On the latter point, there is indeed significant evidence
that antidepressant-induced mania is a predictive marker
for bipolar disorder (Akiskal and Benazzi, 2003; Akiskal
et al., 2003). The exclusion of this diagnostic group is not
supported clinically or empirically by most of the available
evidence. To quote Dunner (1998) (a member of the DSMIV task force):
There was a sense from the Task Force that bipolar conditions should not be overdiagnosed in the community; if
they are, lithium might be too broadly applied to patients
with mood disorders. . . . The criteria for bipolar II were
defined in a way that is somewhat restrictive. . . . Hypomanic episodes occurring in response to treatment with
antidepressant pharmacotherapy would not count toward
the diagnosis of bipolar II but would instead be termed
substance-induced hypomania. Frankly, this latter option
makes little sense to me and is inconsistent with the natural course of bipolar disorder. . . . It is difficult to induce
mania or hypomania in a true unipolar patient; there is a
likelihood that patients who develop hypomania in
response to treatment are actually bipolar.
93
Thus, while DSM-IV incorporates some useful new features, it leaves considerable room for improvement. It may
be hoped that this will be accomplished. The APA and the
National Institute of Mental Health (NIMH) have commissioned a series of white papers on various diagnostic
issues as a way to launch the process of the development of
DSM-V. Also, the APA and WHO are jointly sponsoring a
series of conferences to stimulate and coordinate the empirical research necessary to fill key information gaps relevant to improving current diagnostic systems; the promotion of international collaborations is a key goal of the
APAWHO effort (American Psychiatric Association, 2005).
Figure 32 presents our proposal for the organization of
mood disorders in DSM-V.
We now turn to the specific diagnostic criteria set forth
in DSM-IV. For mania, depression, and mixed states, the
criteria define episodes; for bipolar-II disorder, cyclothymia,
and schizoaffective disorder, they include a definition of
the disorder. The role of biological correlates of diagnosis
is reviewed in Chapters 9, 13, 14, and 15.
DIAGNOSTIC CRITERIA
When making a diagnosis, the clinician should assess presenting signs and symptoms, and weigh them together
with the patients history and prior response to treatment,
as well as the familys history. Individual symptomseven
clusters of symptomsexamined at one point in time often
lack diagnostic specificity, although such cross-sectional
views are sometimes the only ones available. In the following sections, we use the relevant DSM-IV categories as a
framework for discussing diagnostic criteria for mania
and hypomania, depression, mixed states, cyclothymia,
and schizoaffective disorder. We also review problems involved in applying the DSM-IV criteria.
94
Figure 32. Mood disorders in DSM-V: a proposal. BP = bipolar; NOS = not otherwise specified.
Mood/Affective Disorders
Bipolar
BP-I
BP-II
BPNOS
Unipolar
Cyclothymia
Psychotic
Nonpsychotic
Depressive Disorders
Major Depression
Psychotic
Nonpsychotic
Dysthymia
Depressive
Disorder-NOS
Diagnosis
95
Another important difference between the DSM-IV definitions of mania and hypomania has to do with the duration
of the syndrome, defined as 1 week for the former and a
minimum of 4 days for the latter. Clinical and research experience suggests that 2 to 3 days of hypomania appears to
identify a cohort of patients with a variant of bipolar illness
that is milder in manic symptomatology than the classic
form (Angst, 1998). Duration of 1 day or less of hypomania
is more controversial, often making it difficult to distinguish the state from the rapid mood alternations of borderline personality disorder or normal variants in temperament. The following is Dunners (1992, p. 13) account of
how the 4-day minimum criterion came to be set:
The initial definition proposed by Dunner et al. had
posited a 3-day or longer duration of hypomania. This definition was based on a study of normal women who were
being assessed for a premenstrual mood disturbance and
who on interview were sometimes found to have 12 days
96
cyclothymia (discussed below), which is not easily distinguishable from bipolar-not otherwise specified (NOS).
Additional discussion relevant to the bipolar-II diagnosis is included in Chapters 1 and 2. For example, Benazzi
and Akiskal (2005) have offered a definition of trait mood
lability and suggested that it can be used as a screening
tool for bipolar-II.
Depression
DSM-IV criteria for a major depressive episode are presented in Box 35. As with the criteria for mania, the
boundaries of major depressive disorder were considerably
broadened in DSM-III-R through the incorporation of additional psychotic features, including mood-incongruent
delusions, and this broadened definition carries over into
DSM-IV. We return to this issue later in the section on differential diagnosis. The required minimum 2 weeks duration is regarded as too short by many clinicians, who prefer the 1 month originally given in the criteria of Feighner
and colleagues (1972).
As noted earlier in this chapter and in Chapter 1, one
of the major, and in our opinion unfortunate, changes in
the transition to ICD-10 and DSM-IV is that both of these
nosologies, as a first principle, separate bipolar disorder
from major depression (single or recurrent), thereby reinforcing the bipolarunipolar dichotomy. Within the DSMIV framework, there is no attempt to differentiate bipolar
from unipolar depression on any grounds other than the
presence or absence of a history of mania. Clinical features
reported to differentiate bipolar from unipolar depression
as described in Chapter 1 are not incorporated into the
DSM-IV system. In contrast, ICD-9, under the rubric of
manic-depressive psychosesdepressed type, properly emphasized the recurrent nature of endogenous forms of
depression, implying that such depressions are closely related to bipolar illness (i.e., Kraepelins manic-depressive
illness).
Mixed States
The factor analytic studies referred to earlier (and reviewed
in Chapter 2) reported two types of mixed states with
marked lability of mood: one displayed depression with labile periods of pressured, irritable hostility and paranoia;
the other displayed an incongruous mix of elated mood
and psychosis, which would switch frequently to anxiety,
depression, and irritability.
Kraepelin originally viewed mixed states as the most
common form of manic-depressive illness. In fact, in the
1899 edition of his textbook, he placed a great deal of emphasis on six types of mixed states, including forms that
clinicians today may label as mania (dysphoric mania) or
depression (agitated depression, depression with racing
Diagnosis
97
98
Cyclothymia
Consistent with our discussion of cyclothymia in Chapter
2, DSM-IV notes that the boundaries between this disorder, bipolar disorder, and bipolar-NOS are not well de-
Diagnosis
Schizoaffective Disorder
In DSM-I and -II, schizoaffective illness was included as a
subtype of schizophrenia, reflecting the broad Bleulerian
concept of schizophrenia as discussed later in this chapter.
Subsequent research (reviewed in Chapter 2) documented
the frequent occurrence of Schneiderian first-rank11 and
related schizophrenic symptoms (e.g., catatonic features,
paranoia, bizarre behavior, formal thought disorder) in
individuals whose family history, natural course, other
symptoms, and treatment outcome clearly placed them in
the manic spectrum. American psychiatry departed significantly from the Bleulerian tradition when, in DSM-III,
the scope of affective illnesses was substantially broadened
to include nonaffective psychotic symptoms. Schizoaffective illness was moved from schizophrenia to an intermediate category labeled psychotic disorders not elsewhere
classified. With DSM-III-R and ICD-9, schizoaffective disorder was given its own criteria. Those criteria essentially restated the acute symptoms required for a diagnosis of
schizophrenia, but without continuous signs of illness for 6
months or more. The schizoaffective category was thus reserved for patients who met the acute symptomatic criteria
for mania (or depression) and for schizophrenia and who
had delusions or hallucinations in the absence of prominent
mood symptoms for more than 2 weeks. (If the delusions or
hallucinations were present for less than 2 weeks, the patient
met criteria for a primary affective disorder.)
99
In DSM-IV, the main change is in criterion C. This criterion had previously been worded as follows: Schizophrenia has been ruled out, [when] the duration of all
episodes of a mood syndrome has not been brief relative to
the total duration of the psychotic disturbance. In DSMIV, this wording is somewhat clearer: Symptoms that meet
criteria for a mood episode are present for a substantial
portion of the total duration of the active and residual periods of the illness. By still using the somewhat deliberately vague phrase substantial portion, the DSM-IV definition seeks to increase the relevance of mood symptoms
to the definition of schizoaffective disorder. In other words,
one might diagnose DSM-IV schizoaffective disorder in a
person with prominent mood syndromes and only a relative excess of psychotic symptoms (e.g., 2 weeks of psychosis outside of a mood syndrome). Yet one would not diagnose the disorder in a person with prominent chronic
psychosis and only brief mood episodes (e.g., 2 weeks of a
major depressive episode). Mood episodes must be relatively frequent and lengthy in the DSM-IV definition of
schizoaffective disorder. Otherwise, the appropriate diagnosis would appear to be schizophrenia with comorbid
major depressive episodes (in the case of depression). This
tendency of the DSM-IV definition of schizoaffective disorder to be weighted toward the presence of mood symptoms is intended to focus this diagnosis on persons whose
illness is closely related to mood disorders.
Some controversy persists over whether this newly delineated category is closer to affective illness or to schizophrenia, or whether it is a valid diagnosis in its own right.
There are at least five major schools of thought on the matter, among them that schizoaffective illness represents
A separate illness.
An intermediate form on the continuum of psychosis.
Comorbidity of schizophrenia and affective disorders.
A more severe variant of bipolar disorder.
A less severe variant of schizophrenia.
Some investigators believe that since patients with moodincongruent symptoms are now included under mood disorders in DSM-IV, the remaining individuals with a mix of
schizophrenic and affective symptoms (particularly depressive symptoms) are closer to the schizophrenic end of
the schizoaffective spectrum (Kendler et al., 1986). As
outlined in Chapter 13, family history studies support an
association between DSM-III-R (or RDC) schizoaffective
disorder and manic-depressive illness, as well as schizophrenia. Yet most studies have not found that schizoaffective disorder runs in families, as would be expected if it
were a separate disease entity (Kendler et al., 1993). The genetic finding of co-occurrence of schizophrenia and bipolar disorder in at least some genealogies of schizoaffective
100
Clinical Summary
The nosological systems that evolved during the latter
part of the 20th century are in many respects superior to
those used earlier. They are, for the most part, etiologically neutral, allowing for independent assessment of the
types and severity of symptoms, the presence of precipitating events, the extent of functional impairment, personality characteristics, and the presence of other psychiatric diagnoses. Problems remain in the classification of
manic-depressive illness, however. For example, DSM-IV
implies that bipolar disorder is a separate illness and fundamentally different from all forms of unipolar depression; this supposition goes beyond the data, especially
with respect to the more recurrent forms of unipolar depression. Also troubling is the absence from all categories
of affective illness of criteria concerning long-term course
and family history and the failure to provide for a mild
form of depression in bipolar illness. These and other features of the system are problematic for clinical as well as
conceptual reasons.
Diagnosis
101
Schizophrenia
Manic-Depressive Illness
Kraepelin, 1896
Bleuler, 1911
Characterized by an episodic
course with intermittent
recovery.
Symptoms are nonspecific;
diagnosis is made only after
schizophrenia is excluded.
Kraepelin, 1919
Findings
Kasanin, 1933
Langfeldt, 1937
102
construct may be best when evaluating relationships between biological or other variables and symptoms such as
psychosis in bipolar disorder or schizophrenia, while a
categorical construct allows evaluation of diagnostic reliability.
Findings of a carefully conducted nosological study by
Kendler and colleagues (1998) argue against the concept of
a nosologic continuum. That study assessed diagnostic
groupings based on family data, as well as symptom groupings. It found that most patients appeared to fall into different diagnostic categories rather than one (as suggested
by Crow). Similarily, based on a factor analysis of a group
of 191 psychotic patients whose diagnoses included schizophrenia and mood disorders with psychosis, Dikeos and
colleagues (2006) concluded that diagnosis by itself explained the large majority of the clinical characteristics
examined, although dimensional measures were more
useful than diagnosis as predictors of clinical course. Others who have explored the predictive value of diagnostic
versus dimensional measures in psychotic patients across
both schizophrenic and affective disorder patients include
van Os and colleagues (1996, 1998), Toomey and colleagues
(1998), Ventura and colleagues (2000) and Serretti and
colleagues (2001). Finally, another view, closer to that of
Crow, is expressed by Craddock and Owen (2005, p. 364)
who pointed to the emerging evidence for shared and
overlapping susceptibility genes as the beginning of the
end for the Kraepelinian dichotomy, a topic that is explored in Chapter 13.
DIFFERENTIAL DIAGNOSIS
Until the 1980s, the most commonly encountered problems in making differential diagnoses of bipolar illness
involved its overlapping boundaries with schizophrenia and
schizoaffective illness, as well as with personality disorders,
especially borderline disorders. These two major differential
diagnoses remain highly important, but to them must be
added the most clinically significant problemthe differential diagnosis of bipolar disorder and unipolar depression.
Bipolar illness also must be distinguished from schizophreniform disorder, brief reactive psychosis, cycloid psychosis, atypical psychosis, organic brain disorders, and
epilepsy. The overlap between primary affective diagnoses
and substance abuse is of such importance that we address
it in a separate chapter (see Chapter 7).
Diagnosis
disorder can sometimes be excluded by considering previous episodes; a history of either clear affective illness or
clear schizophrenia cautions against diagnosing a present
episode as schizoaffective.
103
illness should be considered. Schizophrenia would be diagnosed if, in addition, the patient continuously manifested
overt signs of a psychotic illness for at least 6 months, and
the manic symptoms were brief relative to the duration of
the schizophrenic symptoms. On the other hand, schizoaffective illness, manic type, would be diagnosed if the criterion of 6 months of continuous psychotic illness were not
met, but there had been more than 2 weeks of quiet delusions or hallucinations.
It is now well recognized that strict application of the
Bleulerian concept of thought disorder as pathognomonic
of schizophrenia can result in misdiagnosis of manicdepressive patients (see Chapters 1 and 10). More than a
quarter of patients with mania have classic Bleulerian
symptoms of schizophrenia (Pope and Lipinski, 1978).13
See Chapter 2 for further discussion of psychosis and
thought disorder in mania and schizophrenia.
104
Clinical Summary
The clinician can distinguish manic-depressive illness from
schizophrenia or schizoaffective disorder in most cases by
careful attention to the patients personal and family history, premorbid functioning, age at onset, and sequence
and patterning of symptoms. In manic-depressive illness,
delusions or hallucinations generally follow a period of either manic or depressive symptoms, and affective symptoms are prominent almost continuously.
Unipolar Depression
As noted in Chapter 1, evidence has begun to accumulate
over the last decade that the misdiagnosis of bipolar disorder as unipolar depression is a major clinical problem.
There are likely five primary causes for this development:
(1) patients lack of insight with regard to manic as
opposed to depressive symptoms; (2) clinicians neglect of
information available from family members or other third
parties; (3) clinicians relative focus on euphoric rather
than dysphoric or irritable mood as a criterion for hypomania; (4) the structure of DSM-IV, which by separating
out bipolar from all depressive disorders has obscured the
close relationship between early-onset recurrent depression and bipolar disorder; and (5) widespread interest in
and use of second-generation antidepressants.
In some clinical studies, between 40 and 60 percent of
patients with bipolar disorder appear to have been misdiagnosed with unipolar depression in both inpatient and
outpatient psychiatric settings (Benazzi, 1999; Ghaemi et al.,
1999, 2000). Data that are not widely known because they
were collected as part of a family history study (Tsuang
et al., 1980) illustrate the extent of the problem. When patients who had previously been hospitalized for mania
were evaluated by an extensive research diagnostic interview several years later (but without input from a family
member), about 60 percent had forgotten or denied that
they had ever been manic. These findings, reported in the
United States, appear to hold true in other countries as
well; similar results were found in Spain, for example, although the latter study also noted a high rate of misdiagnosis as schizophrenia and personality disorder (Vieta and
Salva, 1997). In another study, careful evaluation of the history of 108 patients in primary care revealed that 48 (44
percent) had hypomanic symptoms, thus indicating an apparent misdiagnosis rate of about 40 percent in the primary care setting as well (Manning et al., 1997). Hence
careful attention to the differential diagnosis of bipolar
disorder and unipolar depression is essential.
As we note throughout this text, much of the problem of
the misdiagnosis of bipolar disorder as unipolar depression has to do with the structure of DSM-IV itself (recall
Diagnosis
105
106
occurred simultaneously, and whether they led to significant social and occupational dysfunction. The sensitivity
or true positive rate (the proportion of those actually ill
thus identified) and specificity or true negative rate (the
proportion of those not ill thus identified) of this selfreport questionnaire depend on the population it is used
to evaluate. Thus, as discussed more thoroughly in Chapter 11, relatively high sensitivity was achieved among patients from a university affective disorders clinic with a
high proportion of bipolar-I patients who, moreover, were
likely to have been educated about their illness. By contrast, in a community-based sample (where a screening instrument is presumably most useful), sensitivity was only
28 percent; that is, the MDQ missed more than 70 percent
of those diagnosed as bipolar by a clinician using the
Structured Clinical Interview for DSM (SCID) (Zimmerman et al., 2004). Similarly, in an independent validation
study with a clinical sample, the MDQ was found to be
more diagnostically sensitive for 26 patients with bipolar-I
disorder (69 percent) than for 8 patients with bipolar-II
disorder (30 percent) (Miller et al., 2002). Further, patients
with impaired insight would be expected to deny their
symptoms on the MDQ.16 These studies suggest that the
MDQ may be more useful in a clinical than in a community setting (Hirschfeld et al., 2003). Modifications to the
MDQ that might increase its utility as a screening tool in
community samples have been discussed by Miller and
colleagues (2004) (see Chapter 11).
Besides the issue of differential sensitivity in community versus clinical settings, the larger question is whether
it is appropriate to use the MDQ as a diagnostic tool
without further clinical assessment. Here the concept of
predictive value is relevant (Phelps and Ghaemi, 2006).
Sensitivity and specificity are characteristics of a scale; predictive values are characteristics of a sample to which the
scaled is applied. If the underlying prevalence of an illness
is low, then even a highly sensitive scale can have a low
positive predictive value, just as a highly specific scale can
have a weak negative predictive value. For instance, if the
MDQ, based on its two main validation studies, is applied
in a community setting where the baseline rate of bipolar
illness is 10 percent, a positive predictive value of less than
4551 percent is obtained. In other words, only about half
of the MDQ-positive subjects actually have bipolar disorder. In contrast, the negative predictive value of the MDQ
in such settings would be quite high, over 9297 percent.
Thus in the community setting, the MDQ can help rule
out but not rule in bipolar disorder. This limitation again
highlights the importance of combining the MDQ or any
self-report diagnostic scale with clinician-based interview
evaluations. Further, this limitation should be taken into
Diagnosis
Finally, further research is required to establish the validity of adult ADHD. This is especially urgent now, given
that adult ADHD is becoming an increasingly common diagnosis (some of this increase in diagnosis is, no doubt, in
response to a new agent being marketed with this condition as an indication).
In the National Comorbidity Survey, adult ADHD was
diagnosable in about 4.4 percent of the adult population
(Kessler et al., 2006). However, 86 percent of these individuals were also diagnosable with mood or anxiety disorders.
The authors, and many ADHD experts view these data as
simply representing comorbidity; thus the importance of
diagnosing and treating adult ADHD is emphasized. An
equally possible if not more logical conclusion would be
that since adult ADHD is hardly diagnosable without concomitant other mood or anxiety disorder diagnoses, those
other diagnoses may account for most if not all of the cognitive symptoms that are labeled ADHD. This perspective
flows from an appreciation of the concept of diagnostic hierarchy, whereby mood disorders in particular can cause
other kinds of symptoms (whether psychotic, anxiety, or
cognitive); thus those other diagnoses should not be made
in the presence of an active mood disorder (Surtees and
Kendell, 1979). In other words, if those mood or anxiety
disorders are adequately treated, the cognitive symptoms
will improve, suggesting that no separate ADHD diagnosis
is necessary. Such extensive overlap between diagnoses
should raise the possibility of a single diagnosis with multiple manifestations, not simply the concept of multiple diagnoses. Further, advocates for the diagnosis of adult
ADHD often point to retrospective data in adults with
bipolar disorder, in which 9.5 percent of such patients are
retrospectively diagnosable with ADHD in childhood
(Nierenberg et al., 2005). Yet such data do not necessarily
support the common presence of ADHD in adulthood, but
rather are compatible with the alternative view that many
children with purported ADHD develop bipolar disorder
in adulthood, raising the possibility that the ADHD-like
presentation in childhood may have represented an early
manifestation of the bipolar illness. In other words, instead
of thinking that such persons had one illness in childhood
and have another in adulthood, it may be more plausible
that the same illness manifested itself differentially at different ages, with ADHD-like symptoms in childhood and
more classic bipolar symptoms in adulthood.
In sum, given these possibilities, we would urge caution
in the diagnosis and treatment of adult ADHD, always giving preference to initially diagnosing and treating mood
disorders until euthymia is achieved before making the
ADHD diagnosis or seeking to treat it with stimulants.
Most experts would agree (given the abuse potential of
107
Cycloid Psychosis
The concept of cycloid psychosis, first described by Leonhard (1957), like that of schizoaffective disorder, a hybrid
rooted in the overlapping symptoms of schizophrenia and
recurrent (predominantly bipolar) affective illness, was discussed in more detail in the first edition of this volume.
The condition occurs predominantly among females and
108
Diagnosis
109
Delirium
The DSM-IV diagnostic criteria for delirium are given in
Box 312. Severe (stage III) mania (Carlson and Goodwin,
1973) can involve clouding of consciousness, occasionally rendering it difficult to differentiate from delirium
110
in delirium than in stage III mania. The sustained euphoria (or irritability) characteristic of mania, by contrast, is
not likely in delirium.
As with all diagnoses of organic brain disorders, indications (from the patients history, physical examination,
or laboratory data) of a specific organic etiological factor
are important to the diagnosis. As noted in Chapter 7,
manic episodes are commonly associated with substance
abuse, particularly in young patients, and here the challenge is to differentiate a pure organic delirium from a
manic episode precipitated and colored by alcohol or
drugs.
Dementia
The DSM-IV criteria for dementia, given in Box 313, overlap somewhat with those for delirium. The considerable
attention that has been paid to differentiating between true
dementia and depressive pseudodementia is often justified
since the pseudodementia associated with depression is
highly treatable. Recent data suggest, however, that depression in the elderly can often herald dementia, making the
distinction less exclusive than may earlier have been assumed (Jorm, 2000). As discussed in Chapter 9, bipolar
patients in particular often experience profound deficits in
Diagnosis
111
112
Epilepsy
Given the possibility that the pathophysiology of manicdepressive illness may overlap with that of some identifiable brain disorders, differential diagnosis cannot easily be
reduced to simple formulas. For practical purposes, however,
a differential diagnosis is critical to making an accurate
treatment selection and prognosis. Thus, the clinicians
first task when presented with manic or depressive symptoms is to consider other (possibly correctable) factors that
might explain the symptoms. The absence of a personal or
family history of affective illness and poor response to
traditional treatments for manic-depressive illness are important clues suggesting the possibility of an organic etiology (McElroy et al., 1992). Although no single medical
screening test is definitive, certainly a neurological examination, formal neuropsychiatric testing, an MRI, an EEG, a
CT scan, and a chemical screen for metabolic and toxic
disturbances should supplement the careful taking of the
patients history. Where the evidence points to a possible
commingling of manic-depressive illness and a seizure disorder diathesis, anticonvulsants with a primary effect on
temporal lobe disorders (e.g., carbamazepine, valproate, or
lamotrigine) should be the treatment of choice.
Epilepsy comprises a group of disorders of the central nervous system that, like other organic disorders, must be differentiated from bipolar illness. The condition is commonly associated with psychiatric symptoms, which can
be divided into those occurring during actual seizure activity and those manifested only during interictal periods.
Findings of epidemiologic surveys of large numbers of
patients with epilepsy (see, e.g., Gibbs and Gibbs, 1952) indicate that psychotic symptoms are about 10 times more
likely to occur in association with temporal lobe than with
generalized epilepsy (reviewed by McKenna et al., 1985;
Kanner, 2004). The psychoses associated with temporal
lobe epilepsy were initially described at a time when the
broad Bleulerian concept of schizophrenia was prevalent.
It is thus not surprising that patients with these psychoses
tended to be described as schizophrenic, and less frequently
as affectively ill. Clinically, these psychoses are generally
mixed syndromes with a prominence of visual and olfactory hallucinations, rapid fluctuations of mood, catatonic
features, and dreamlike statesall of which occur in an
episodic course.
In his studies of patients with temporal lobe epilepsy,
Flor-Henry (1969) found that 40 percent had either manicdepressive or schizoaffective features, and 42 percent had
predominantly schizophrenic symptoms. Further frustrating attempts to understand the association between psychosis and temporal lobe epilepsy is the fact that patients
can at times manifest predominantly affective symptoms
and at other times predominantly schizophrenic symptoms.
Flor-Henry also found an association between ictal laterality
and type of mood syndrome: left-side epileptic foci in temporal lobe epilepsy were associated with depressive syndromes, whereas right-side epileptic foci were associated
Clinical Summary
CONCLUSIONS
To make an accurate diagnosis of bipolar disorder, the patients history should be reviewed carefully with the
patient and a family member; this focus on history is at
least as important as a full description of the presenting
episode. Whenever possible, the onset, duration, and treatment response of all past episodes should be recorded on a
life chart, along with important life events. Much of this
information can be obtained before the initial appointment by having the patient and family members fill out a
Diagnosis
113
114
more likely to be associated with the bipolar form. Differentiating the bipolar form of manic-depressive illness
from personality disorders or post-traumatic stress disorder (PTSD) is complex. Frequently, the conditions can cooccur. If any acute episodes meet the criteria for mania or
hypomania, bipolar disorder should be diagnosed, regardless of the extent of concomitant PTSD or personality disorder features. If the course is almost completely characterized
by physical or sexual trauma, along with the typical features of borderline personality (interpersonal conflict and
rage, repeated self-injury, manipulative relationships),
then the occurrence of mood lability by itself likely will not
justify the bipolar diagnosis. Again, attention should be
paid to family history, and more emphasis placed on course
of illness rather than acute presentation.
10.
11.
NOTES
1. Andreasen et al., 1981; Tsuang et al., 1981; Andreasen and
Grove, 1982; Keller and Baker, 1991; Blacker and Tsuang, 1992;
Dunner, 1992; DeBattista et al., 1998; Goodwin and Ghaemi,
1998.
2. The RDC, together with the Schedule for Affective Disorders
and Schizophrenia, proved to be reliable diagnostic instruments when used by interviewers from different centers
around the country to rate past psychiatric symptoms and
lifetime diagnoses in patients who were mentally ill at the
time of assessment. However, the lifetime diagnoses of hypomania and recurrent unipolar depression were not as reliable
as other categories (Keller et al., 1981).
3. Angst, 1980; Marneros et al., 1988, 1989, 1991, 2000; Maj et al.,
1989.
4. Akiskal et al., 1995; Goldberg et al., 1995, 2001, Kessing, 2005.
5. Outside the United States, most of the rest of the world is
characterized by geographically stable populations, making
it easier to recognize the recurrent nature of the affective disorders.
6. Not all studies are consistent. For instance, one study found
that bipolar-II disorder was much less stable (33 percent unchanged diagnostically 6 years later) than bipolar-I disorder
(60 percent unchanged); it also found that decreased need
for sleep was the best predictor among diagnostic criteria for
bipolar-II disorder (Rice et al., 1992). Dunner also found that
the reliability of the bipolar-II diagnosis was much greater
when made by clinicians with expertise in mood disorders
than when based solely on research diagnostic instruments
such as the Structured Clinical Interview for DSM (SCID)
(Dunner and Tay, 1993).
7. Testing the DSM-IV definition, Benazzi (2001) reported that
almost all patients who met the DSM-IV definition of bipolarII disorder also experienced 2 to 3 days of hypomania.
8. A recent excellent historical review demonstrated that Kraepelins original conception of mixed states was derived largely
from Weygandt, and that Kraepelin and Weygandt viewed
mixed states not as uncommon, but as being the most common form of manic-depressive illness (Salvatore et al., 2002).
9. Along with major depression and inner agitation, at least
three of the following symptoms must be present: (1) racing
12.
13.
Diagnosis
16.
17.
18.
19.
115
Part II
Clinical Studies
The universal experience is striking, that the attacks of manic-depressive insanity . . . never lead
to profound dementia, not even when they continue throughout life almost without interruption. . . . As a rule the disease runs its course in isolated attacks more or less sharply defined
from each other or from health, which are either like or unlike, or even very frequently are
[the] perfect antithesis.
Emil Kraepelin (1921, p. 3)
The first relates to patient selection. The index hospitalization required in many older outcome studies can produce either underestimates or overestimates of recurrence.
Underestimates can result when, during a single hospitalization, a patient has multiple rapid cycles that are counted
as a single episode. On the other hand, overestimates can
result from basing recurrence rates on hospital admission
data, because those data exclude patients who experience a
single episode, recover without hospitalization, and never
have a recurrence. While some recent studies (virtually all
of which focused on the bipolar subgroup) have avoided
these problems by recruiting patients from the general
community, other samples (e.g., those of the Stanley Foundation Bipolar Network) have been drawn from clinics in
which sicker, treatment-resistant patients tend to be overrepresented. Indeed, clinical samples are, by definition, not
representative, because a substantial portion of the bipolar
population is not receiving treatment at any given time.
The second issue has to do with diagnosis. Many of
the classic studies of natural course do not distinguish
between the bipolar and recurrent unipolar subgroups.
Numerous interpretive problems result, particularly in
studies from the United States, where diagnostic criteria
for unipolar illness (i.e., depressions that are not bipolar)
allow for considerable heterogeneity (see the discussions of
this issue in Chapters 1 and 3). For this reason, we emphasize the literature on bipolar patients, although some conclusions may be relevant to the more recurrent forms of
unipolar illness as well. Furthermore, most classic studies
of bipolar patients have involved patients hospitalized for
mania and thus have not included the bipolar-II subgroup.
The extent to which patients with schizoaffective features
are included in the sample is another diagnostic issue (see
the later discussion).
METHODOLOGICAL ISSUES
As with most fields of inquiry, studies of the course and outcome of manic-depressive illness involve methodological
complexities that should be kept in mind when interpreting
the study results. Two issues are especially important.
119
120
Clinical Studies
PREMORBID FUNCTIONING
The distinction between premorbid functioning in children and childhood manifestations of full-blown manicdepressive illness can be somewhat arbitrary, because the
disorder may present a different clinical picture in childhood than in adolescence or adulthood. We discuss clinical
manifestations of possible childhood variants of the illness,
as well as premorbid functioning in its early-onset forms,
in Chapter 6, issues of premorbid/underlying personality in
Chapter 10, and issues of neurocognitive development in
Chapter 9. Here we focus on other measures of premorbid
functioning (e.g., social, academic) in samples that do not
include childhood-onset recurrent mood disorder.
In the original Kraepelinian definition, patients with
manic-depressive illness were free of any morbid symptoms before the onset of their illness. Some modern data are
consistent with this impression. In an elegant prospective
study, Reichenberg and colleagues (2002) examined results
from an extensive array of tests designed to measure level of
functioning in persons who later developed schizoaffective,
AGE AT ONSET
The age when manic-depressive illness most often begins
(in both its bipolar and recurrent unipolar forms) is
intrinsically important to genetically vulnerable individuals and their clinicians and may offer clues to future course.
In this section, we examine the literature on this issue in
general; Chapter 6 focuses on studies of early onset in prepuberty and adolescence, and Chapter 13 examines how
differences in age at onset relate to estimates of the degree
of genetic vulnerability.
121
Purpose/Design
Other Findings
Stephens and
McHugh, 1991
235 bipolar
26.7
116 bipolar
23.3
22 bipolar
Benazzi, 1999
186: 45 bipolar-I,
141 bipolar-II
Meeks, 1999
86 bipolar
24.9
37 bipolar-II
122
Study
190 bipolar
211 bipolar-I
123
152 bipolar
232 bipolar
22.2
2,308 bipolar
19.8
Note: Weighted means; 15 studies since 1990 (N = 4,494) = 22.2; studies before 1990 (N = 4,210) = 28.1; studies 1907present (N = 8,704) = 25.1.
124
Clinical Studies
Figure 41. Distribution of age at onset (years) in bipolar-I and -II patients across seven studies.
600
500
! men
! women
No. of Patients
400
300
200
100
0
Under
10
1014
1519
2024
2529
Age
3034
3539
4044
45 +
experience neurological abnormalities.10 These observations highlight the importance of differential diagnosis of
primary mood disorders and mood disorders that occur
secondary to specific neuropathology (see Chapter 3).
It is not yet clear to what extent grouping patients by
age at onset really identifies distinct subgroups with differential phenomenology, pathophysiology, family history,
outcome, and/or treatment response. Studies examining
family history in early- versus late-onset groups have generally shown more genetic loading for recurrent mood disorder associated with early onset (see below).11 But age at
onset did not differ significantly in several studies comparing patients with mixed and pure mania (McElroy et al.,
199512; Akiskal et al., 1998; Brieger et al., 2003), and it does
not appear to be a distinguishing feature of bipolar-I versus bipolar-II disorder (Benazzi, 1999). On the other hand,
early onset has shown rather consistent correlations with
certain clinical features, including rapid cycling, presence
of comorbid anxiety disorder, suicidal behavior, psychotic
features, and treatment resistance.
Carlson and colleagues (2002) reported that patients
with an early onset (before age 19) had significantly worse
outcomes on a variety of measures than those with later
onset (after age 19).13 Likewise, a French study of 58 earlyonset (before age 18) versus 39 late-onset (after age 40)
bipolar patients found that the former group experienced
more psychosis (in agreement with the data of McGlashan
[1988] and Schulze et al. [2002]), mixed episodes, panic
disorder comorbidity, and lithium resistance and were
more likely to have first-degree relatives with bipolar disorder (Schurhoff et al., 2000).14 Among 320 bipolar-I and -II
patients, those with onset younger than age 18 had more
comorbid anxiety, rapid cycling, suicidality, and substance
abuse compared with those with an onset above age 18
(Carter et al., 2003). An examination of a large cohort of
Stanley Foundation Bipolar Network patients showed significant correlations between early onset (up to age 17) and
greater incidence of learning disabilities, rapid-cycling
course, and family history of bipolar disorder (Suppes
et al., 2001),15 while Ernst and Goldberg (2004) found that
onset below age 19 was associated with more rapid cycling
and comorbid substance abuse.16 Engstrom and colleagues
(2003) reported lower levels of treatment response and significantly greater numbers of suicide attempts in earlyversus late-onset patients in a Swedish population.
Although the evidence for a connection between early
onset and the complicating illness features described is
compelling, one must exercise caution when using crosssectional studies to distinguish damaging effects of the illness from so-called clinical subtype features. That is, worse
outcomes in early-onset patients could be a factor of longer
duration of illness rather than a phenotypic characteristic.
125
126
Clinical Studies
NUMBER OF EPISODES
In his classic 1921 monograph, Kraepelin noted that of 459
manic-depressive patients he had studied (which included
unipolar patients), only 55 percent had experienced more
than one episode and only 28 percent more than three. A
careful reading of Kraepelins clinical descriptions suggests, however, that many of his ostensibly single-episode
patients were in fact severely and chronically ill and had
experienced multiple episodes, which at that time required
continuous hospitalization (the single hospitalization being counted as single episode).
Considered together, findings of longitudinal studies
of manic-depressive patients not taking prophylactic medication (Table 42), which included those with both bipolar and unipolar forms of the illness, indicate that most
patientsparticularly those studied in the past 35 years
had more than one episode.17 Table 42 also indicates that
most patients with major affective disorder (i.e., Kraepelinian manic-depressive illness) have a recurrent course.
Many textbooks, apparently relying on older data, fail to
emphasize this point sufficiently.
The near-total likelihood of recurrence is supported by
recent research. In a 4-year naturalistic follow-up study of
75 bipolar patients, only 28 percent remained in remission
(Tohen et al., 1990). If relapse were to continue at this rate
over the long term (18 percent per year), fewer than 1 percent
of patients would remain in remission at about 10 years
follow-up. In the National Institute of Mental Healths
(NIMH) Collaborative Program on the Psychobiology of
Depression-Clinical Studies (CDS), relapse into a new
episode within 5 years was observed in 81 to 91 percent of
patients, the variability in percentage being related to the
polarity of the index episode (i.e., depressive, mixed, or
manic states) (Keller et al., 1993).
In contrast, relapse in unipolar depression is not as frequent and is more dependent on the number of previous
episodes, with a much higher risk of relapse after the third
major depressive episode. In a separate analysis of the data
from the NIMH Collaborative Program on the Psychobiology of Depression-Clinical Studies, the 5-year recurrence
rate was 64 percent among 380 patients with unipolar depression, rising to 80 percent at 10 years and 85 percent at
15 years (Mueller et al., 1999). In a Japanese collaborative
study (Kanai et al., 2003), 95 previously untreated unipolar
depressed subjects (70.5 percent first episode, 29.5 percent
recurrent; mean age 44.3) were followed for 6 years. In this
cohort, lower rates of relapse were seen, with only 45 percent experiencing a new episode at 6 years. This lower
relapse rate may reflect the fact that, unlike the CDS cohort,
most of these patients had not already experienced recurrent major depressive episodes. The lower rate of episode
Study
Kraepelin, 1921
Sample
Size
459
Years of
Observation
23
46
7+
Comments
Variable, up to
a lifetime R
45
27
28
Pollock, 1931
5,739
11 R
55
35
Rennie, 1942
66
26 R
29
26
37
20% <10 R
38%, 1020 R
42%, 2030 R
50
25
25
Lundquist, 1945
103
Stenstedt, 1952
62
1.220+ R
26
42
32
42
112 P
13
42
45
131
19.6 R
17
40
43
Perris, 1968
53
10 P
17
32
47
95
26 P, R
22
69
P, R
13
33
48
15
40
20
25
055
1342
840
269
Total
105
96
6,951
1828 R
Note: Studies reported here included both bipolar and unipolar patients.
P = prospective; R = retrospective.
a
These studies included some patients treated prophylactically; most of the other studies included patients treated acutely.
Source: Update of Goodwin and Jamison (1984).
Clinical Studies
studies have been identified, and not all of the study findings have been consistent.
Figure 42 illustrates the relationship between average
cycle length and episode number. This graph is based on six
studies involving a total of 20,660 patients. Despite substantial individual variability, the averages show a remarkably consistent pattern across the studies. For example, note
the pattern in the 105 bipolar patients of Zis and colleagues
(1979): the average cycle length between the first and second
episodes was 36 months, diminishing to about 24 months,
then to 12 months. In 46 bipolar patients studied by RoyByrne and colleagues (1985a), the mean cycle lengths for the
first seven episodes were 53, 28, 25, 20, 12, 15, and 9 months.
In 95 bipolar patients from Angsts Zurich clinic, the median first cycle length was 48 months, compared with 22
months for the second cycle, 24 for the third, 14 for the
fourth, and 12 for the fifth (Angst, 1981b). The longer average cycle length in the Kraepelin data reflects the inclusion
of unipolar patients, whose cycles are longer than those of
bipolar patients (Angst, 1981b; Fukuda et al., 1983).
The findings of the six studies illustrated in Figure 42
are consistent with the retrospective data of Taschev (1974),
who found the average second cycle to be as long as the
first, but the fourth cycle to be half as long as the second.
A prospective study of patients in the 1980s (Keller et al.,
1982) also documented the increasing probability of an
60
50
40
Cycle Length (Months)
128
30
20
10
0
1
Number of Episodes
10
11
129
130
Clinical Studies
Is there any evidence that episodes increase in frequency over time? Kessing and Andersen (1999) reported
that such was the case for both unipolar depression (15
percent increased risk of recurrence with each episode)
patients who failed to respond to lithium and who appeared to respond to anticonvulsant agents.
Taken as a whole, the findings reviewed here, although
not decisively confirming the validity or generalizability of
the kindling model, appear to suggest its relevance to at
least some patients with manic-depressive illness, including both bipolar and recurrent unipolar forms.28
Rapid Cycling
The inclusion of rapid cycling in DSM-IV was based to a
large extent on a study by Bauer and colleagues (1994),
who compared 120 patients with rapid-cycling bipolar disorder and 119 nonrapid-cycling patients. They found that
45 percent of the rapid cyclers had bipolar-II disorder,
compared with 38 percent of the nonrapid cyclers, a difference that did not achieve statistical significance. Those
with rapid cycling, not surprisingly, had more episodes in
a 12-month prospective follow-up period; there were also
more females in the rapid-cycling group. Based on these
131
132
Clinical Studies
Genetic
Predisposition (1)
Experimental Predispositions
Conditioned
Compensatory
Response
Hypomania
(5)
MANIA
EUTHYMIC
DEPRESSION
Minor Dysphorias
(2)
Full-Blown
Depression
(3)
Similar
Recurrences
(4)
Faster Onsets
(6)
and Cycling
(7)
Spontaneous
Episodes
(8)
STRESS
Figure 43. Behavioral sensitization paradigm of progressive course of illness leading to rapid cycles.
(Source: Post et al., 1986a.)
ically and phenotypically to non-rapid-cycling patients (Nurnberger et al., 1988b; Wehr et al., 1988; Coryell et al., 1992).
Illness in rapid-cycling patients can include a non-rapid-cycling
course.
Rapid cycling may be viewed as an extreme development
of tendencies inherent in a non-rapid-cycling course:
Increasing frequency of episodes* (Grof et al., 1974)
Switches into new episodes with no normal interval
between* (Winokur et al., 1969)
Circularity of episodes (Koukopoulos and Reginaldi, 1973)
Rapid cycling may exhibit a somewhat different pharmacological response profile.
Relative frequency in bipolar-I versus -II is unsettled.
with no affective symptoms (only 10 percent of rapid cyclers, versus 49.5 percent of nonrapid cyclers; p = .09).
Although the CDS has the major advantage of being the
kind of careful prospective, naturalistic study needed by the
field, it is limited by those same study methods. Patients who
remained in the study after having been recruited into one
of the five tertiary-care centers in which it was conducted
may not have been representative of the larger population
of patients with rapid-cycling bipolar disorderindividuals
whose chaotic lives often do not allow for long-term prospective follow-up in a systematic research study. Nonetheless,
one cannot ignore the findings of this study, especially given
the fact that, in a separate cohort, Maj and colleagues (1994)
also found that only 18.9 percent of 37 individuals with rapid
cycling continued to experience four or more episodes per
year during 5-year follow-up. Future prospective research
on more community-based samples may clarify these questions that are so important to the estimation of prognosis in
individual patients.
Rapid cycling appears to represent a generally treatmentrefractory state compared with nonrapid cycling. Most of
the studies on this issue have involved lithium, which has
led to the common belief that rapid-cycling patients do
not respond well to lithium and respond better to anticonvulsants. In fact, as discussed in Chapters 18, 19, and 20, it
appears that most rapid-cycling patients do not respond
particularly well to any medicationlithium or anticonvulsants. Alternatively, as suggested by a number of investigators (Koukopoulos et al., 1983; Wehr et al., 1988; Baldessarini
et al., 2000), the responsiveness of rapid-cycling patients to
mood stabilizers may be greatly enhanced when concomitant antidepressant use is avoided.
Recent genetic studies on rapid cycling have yielded
instructive, if inconclusive, results. Associations have been
reported with the serotonin transporter gene polymorphism (Rousseva et al., 2003) and with a low-activity allele
for the catechol-O-methyltransferase (COMT) gene (Kirov
et al., 1998; Papolos et al., 1998), although the COMT allele
association was not seen in a study of 52 children (mean
age 10.9 years) (Geller and Cook, 2000). A family history
study in 165 patients with rapid-cycling bipolar disorder
did not identify major differences in familial mental illness
compared with non-rapid-cycling bipolar disorder, with
the exception of a suggestion of more substance abuse
among relatives of rapid-cycling bipolar probands (Lish
et al., 1993).
Taken together, the data tend to favor the concept that
rapid cycling represents one extreme of a bipolar spectrum
of cyclicity, but it is generally not a stable characteristic in
an individual patient.
133
POLARITY
Estimates of the proportion of bipolar patients who begin
the illness with a manic episode range from 34 to 79 percent, averaging just over 50 percent. It is important to recognize that the other half of patients with the bipolar form
of manic-depressive illness will go undiagnosed as bipolar
at the onset of their condition, because they initially experience only major depressive episodes33; this condition is
sometimes called false unipolar depression. This dilemma
arises from the current DSM nosology (see Chapters 1 and 3),
which places primary emphasis on polarity at the expense
of cyclicity or recurrence. This approach guarantees an
initial misdiagnosis in many patients who have bipolar
disorder but have not yet experienced their first manic
episode. The problem was less acute with the classic construct of manic-depressive illness, which took into account
other course factors, such as recurrence of episodes, as well
as family history.
One study of false unipolar depression examined 17,447
patients with mood disorders who were hospitalized in
Denmark over a 22-year period (19711993) (Kessing, 1999).
Among those whose first episodes were depressive, if
a manic episode was to develop, it usually did so within
5 years. Patients with false unipolar depression experienced more recurrent depressive episodes than did patients with true unipolar depression.34
It is also important to recognize that there is a relationship between false unipolar depression and age at onset
(see Chapter 1). An often-cited figure is that 1 to 2 percent
of patients with depression may experience a hypomanic/
manic episode in every year of follow-up. This figure is
based on the CDS cohort (Coryell et al., 1995), in which 10.2
percent of a depressed subgroup (mean age 36.8 years)
had a manic or hypomanic episode during 10 years of
follow-up. A younger age at onset within this cohort was
associated with increased risk of manic/hypomanic switch,
however. Other younger cohorts have confirmed higher
natural switch rates to mania (see Chapter 6). For example,
in a group of 72 depressed children (mean age 10.3 years),
Geller and colleagues (2001) found that 49 percent had experienced a manic or hypomanic episode at 10-year followup. In a group of 74 depressed young adults (mean age
23.0 years), Goldberg and colleagues (2001) observed
that 46 percent had experienced a manic or hypomanic
episode at 15-year follow-up. Thus the risk of switching
from false unipolar depression to bipolar disorder is highest in childhood and young adulthood, occurring at a rate
of about 3 to 5 percent per year; it then decreases by the
late 30s, at which point it flattens out to about 1 percent
per year.
134
Clinical Studies
PATTERN
The topic of episode pattern is of historical importance.
Early investigators demonstrated that three basic patterns
were apparent: mania followed by depression and then a
well interval (MDI), depression followed by mania and then
a well interval (DMI), and continuous cycling (MDMD).38
There is some evidence from these studies that the MDI
pattern may have the best outcome (Koukopoulos et al.,
1980) and the MDMD pattern the worst. As we suggested
in the first edition, the DMI pattern appears to be associated with mania occurring after treatment of the depressive phase with antidepressants (Maj et al., 1989).
Contemporary studies of episode pattern are not entirely consistent with this older literature. In a study of all
hospitalized cases of bipolar and unipolar disorders in
Denmark over a 22-year period (19711993; N = 17,447), the
DMI and MDI courses were associated with a similar
number of recurrences (Kessing, 1999). On the other hand,
in a recent reanalysis of data from the CDS in which 165
bipolar-I patients were followed for 15 years, Turvey and
colleagues (1999) reported that mood episodes beginning
with depression (depression only or depression followed by
mania) were associated with worse 15-year outcomes than
those beginning with mania. Also, polarity sequences
tended to remain stable over time: 75 to 80 percent of individuals whose first observed mood episode began with
mania continued to have mood episodes beginning with
mania, and 55 to 60 percent of those whose mood episodes
began with depression also maintained that pattern. This
study is the longest outcome study assessing polarity. Its
findings suggest that patterns of mood episodes are sustained over time and that the poorer prognosis of depressive as opposed to manic episodes persists in the long run.
Finally, it should be noted that some confusion regarding the patterning of episodes has been introduced by recent treatment guidelines asserting that the polarity of the
index episode predicts the polarity of a relapse following
the episode. As discussed in detail in Chapters 17 and 20,
this conclusion should apply only to those relapses that occur shortly after remission is achieved, and these generally
occur as a result of an effective treatments being withdrawn before the continuation phase of treatment is completed. In an analysis of the course of patients on placebo
participating in an 18-month study of maintenance treat-
135
ment with lithium or lamotrigine when the time frame beyond the continuation phase of treatment was examined
the next new episode was almost always (85 percent of the
time) of opposite polarity confirming classic observations
(F. Goodwin and Calebrese [in preparation]).
PRECIPITANTS OF EPISODES
Findings of most studies of diagnostically heterogeneous
groups of depressed patients suggest that stressful life
events, such as losing a loved one, changing jobs, or moving, are more frequent during the 3 to 12 months preceding
the onset of a depressive episode. Although the literature
on events precipitating depression is extensive, that pertaining specifically to bipolar patients is more modest. It
comprises primarily interesting but ultimately inconclusive case reports (reviewed by Ellicott, 1988), an intriguing
report on increased relapses among bipolar patients after a
hurricane,39 and 14 systematic studies, all but 3 of which
were retrospective. These studies are outlined in Table 43;
their conclusions are summarized in Box 42. Taken together, they provide considerable support for the importance of stressful events in the onset of episodes in bipolar
patients.
Although some theories assign primary causal importance to psychosocial environmental forces, it is now generally accepted that environmental conditionspsychosocial
or physicalcontribute more to the timing of an episode
than to underlying vulnerability, which is largely genetic
(see Chapter 13). Thus modern biological theory reaffirms
the classic position of Kraepelin (1921, pp. 180181):
We must regard all alleged injuries as possibly sparks for
the discharge of individual attacks, but that the real cause
of the malady must be sought in permanent internal
changes, which at least very often, perhaps always, are innate. . . . Unfortunately, the powerlessness of our efforts
to cure must only too often convince us that the attacks of
manic-depressive insanity may be to an astonishing degree independent of external influences.
Table 43. Life Events, Kindling, and Mood Episodes in Bipolar Disorder
Sample
Size
Ambelas, 1979
67
Paykel LE scale
79
Own LE questionnaire
Glassner and
Haldipur, 1983
53
149
Bidzinska, 1984
36
Study
136
Own LE interview
Puzynski LE questionnaire
Findings
First-episode patients were
overrepresented in
LE-associated mania.
52% reported LEs before first
episode, compared with 15%
before subsequent episodes.
23% of early-onset bipolar
patients (age <20) had LEs
before episodes, compared
with 63% of late-onset bipolar
patients (age >20). However,
early-onset patients had the
same percentage LEs before first
and subsequent episodes (23%),
as did late-onset patients
(64% and 61%, respectively).
More patients with later episodes
than first episode of depression
reported no preceding negative
LEs (50% vs. 38%; p < .02) or
conflict events (81% vs. 57%;
p < .001).
LEs preceded more of first three
episodes (2.6) than fourth
through sixth episodes
(1.9; p < .05).
Supports
Kindling
Comments
Yes
Yes
Indeterminate
Yes
Yes
66
148
137
26
64
Scale of Assessment of
LE and Social Support
of the California
Department of Mental
Health
SADS-Lifetime (SADS-L)
or Structured Clinical
Interview for DSM (SCID)
Note: Total sample = 688 (limited to patients identified as having bipolar disorder, with exception of Perris et al., 1984).
Yes
Indeterminate
No
No
Prospective
138
Clinical Studies
Specific Factor
Study
Endocrine States or
Substances
Drugs
Isoniazida
Procarbazine
Levodopa
Methyldopa withdrawal
Hallucinogens (e.g., LSD, PCP and
mescaline)
Cocaineb
Alcoholb
Bromide
Sympathomimetic amines
Cimetidine; amantadine
Alprazolam
Lorazepam
Guanfacined
Lisinoprild
Sayed, 1976
Waters and Lapierre, 1981
Hubain et al., 1982; Lazare, 1979;
Rego and Giller, 1989
Sotsky and Tossell, 1984
Crane, 1956
Koehler-Troy et al., 1986
Weilburg et al., 1987
Maxwell et al., 1988; ODowd and
McKegney, 1988; Schaerf et al., 1988;
Wright et al., 1989; Liegghio and Yeragani,
1988; Price and Bielefeld, 1989
France and Krishnan, 1984
Rigby et al., 1989
Horrigan and Barnhill, 1999
Skop and Masterson, 1995
Metabolic Conditions
Postoperative state
Hemodialysis
Muncie, 1934
Cooper, 1967
Infections
Influenza
Q Fever
PostSt. Louis type A encephalitis
Cryptococcal meningitis
Tolmetin
Iproniazid
Methylphenidate
Triazolam
Zidovudinec
Busipirone
Head trauma
(continued)
140
Clinical Studies
Table 44. Conditions and Drugs Reported to Precipitate Manic Episodes (continued)
General Category
Specific Factor
Study
Parasagittal meningioma
Benign pheno-occipital tumor
AIDS
Oppler, 1950
Bourgeois and Campagne, 1967
Dauncey, 1988; Gabel et al., 1986; Kermani
et al., 1985; Mijch et al., 1999
Lendvai et al., 1999
Black and Perlmutter, 1997
Casanova et al., 1996; Heila et al., 1995
Salazar-Calderon et al., 1993
Creutzfeld-Jakob Disease
Syndenhams chorea
Multiple sclerosis
Chondroma
Vascular Lesionse
Aneurysm
Infarction
Other
Note: This table is based on the definition of secondary mania provided by Krauthammer and Klerman (1978); the data have been updated by
our own review and those of Lazare (1979), Yassa and colleagues (1988a), and Sultzer and Cummings (1989).
a
Mania induced by antidepressants (tricyclic monoamine oxidase inhibitors [MAOIs] and selective serotonin reuptake inhibitors [SSRIs]) is
thoroughly discussed in Chapter 20. Reports of antipsychotic-induced mania are discussed in Chapter 18.
b
The impact of alcohol and illicit drug abuse on manic-depressive illness is detailed in Chapters 7 and 21.
c
Used for treatment of acquired immunodeficiency syndrome (AIDS).
d
Antihypertensive medications.
e
A comprehensive review of secondary mania in association with central nervous system (CNS) pathology can be found in Chapter 17.
these latter reports are retrospective, rather than prospective like the CDS, the inability to replicate the findings of
the CDS in other samples raises questions about the generalizability of the CDS sample.
Wehr and colleagues (1987a) proposed that sleep reduction may be the common denominator of several disparate
events and stressors that reportedly precipitate mania. Indeed, this suggestion is well supported by our clinical experience. Sleep loss is common to reports of manic episodes
following (1) various stressful events, such as bereavement
(e.g., Krishnan et al., 1984); (2) the postpartum state; and
(3) jet lag associated with flying across time zones. Selective serotonin reuptake inhibitor (SSRI) antidepressants
are capable of destabilizing sleep patterns. Because of the
importance of this issue, we outline in Chapter 19 specific
approaches designed to minimize sleep loss in bipolar
patients.
Another important potential trigger for mood episodes
is the season of the year. Issues regarding light and seasonality were addressed extensively in the first edition and are
further discussed in Chapter 16 of this volume. In the context of course of illness, patients with bipolar and recurrent
unipolar conditions often experience seasonal patterns. In
one study published since the first edition of this text, 49
percent of 146 patients who met DSM-III-R criteria for seasonal affective disorder (Faedda et al., 1993) were diagnosable with bipolar disorder, mainly type I (30 percent of the
total sample; 19 percent were type II), meaning that these
patients tended to experience full manic episodes in spring
or summer. While winter depression is often the focus in the
diagnosis and treatment of seasonal affective disorder, the
high likelihood of summer mania should also be noted.43
LONG-TERM OUTCOME
The literature on long-term outcome in bipolar disorder
can be quite confusing. We have already noted some
problems that can contribute to this confusion, such as effects of treatment in studies done in the modern era, selection bias in studies from academic health centers, and
lack of adjustment through appropriate statistical techniques (e.g., multivariate regression) for other potential
predictors of outcome (such as socioeconomic status and
antidepressant use). Another problem is multiple publications over time based on the same dataset, which can appear to readers to represent different datasets. For this
reason, we have grouped studies of long-term outcome by
their initial recruitment location, rather than by specific
publications.
The literature from the 1970s and 1980s on long-term
outcome in bipolar illness tended to find somewhat better
outcomes than have more recent studies. For instance, in a
report on a 35-year follow-up of the original 100 patients
admitted for mania in the Iowa 500 study, Tsuang and colleagues (1979) found that when marital, residential, occupational, and psychiatric (symptomatic) status were combined, outcome was good in approximately 64 percent of
patients, fair in 14 percent, and poor (i.e., chronic) in 22
percent. This study, while more than 25 years old, still encompasses the modern era in which pharmacological
treatments were available.
141
142
Clinical Studies
Table 45. Prospective Cohort Natural-History Studies in Manic-Depressive Illness Since 1990
Study
Follow-up Period
Findings
139
Up to 4 years
75
Up to 4 years
428
Up to 20 years
82
Up to 5 years
134
Up to 1 year
50
Up to 1 year
McLean/Harvard cohort II
(Tohen et al., 2000, 2003)
173
Up to 4 years
648
Up to 1 year
1000
Up to 5 years
191
N/A
406
Up to 40 years
Sample Size
symptomatic recovery. Incidentally, only 47 percent of patients were fully adherent to treatment at follow-up, which
is consistent with the literature reviewed in Chapter 21.
A second Cincinnati cohort project, initiated in 1996, recruited bipolar patients hospitalized with their first manic
30 percent of the time in subsyndromal mood states. Initial mood-incongruent psychosis predicted worse outcome
than initial mood-congruent psychosis (after adjusting for
some clinical factors with analysis of covariance).
The CDS and McLean-Harvard cohorts can be seen as
complementary, because they represent different types of
patients. Data on the CDS cohort were collected at five U.S.
academic health centers. The cohort consisted of patients
in their 30s and 40s initially, whose illness usually had begun a decade or more earlier with depression as its primary presenting feature (for which the patients had been
treated primarily with antidepressants), and who tended
to have comorbid diagnoses. This represents a modern
manic-depressive illness cohort, with nonclassical features
of illness. The McLean-Harvard cohort consisted completely of hospitalized bipolar patients, most of whom
were psychotic and experiencing their first manic episode.
Most were insured, of middle to high socioeconomic status, and with few psychiatric comorbidities. This cohort
is close to a modern analogue of the classic patients of
the pretreatment era, similar to those Kraepelin described
from among psychotic patients hospitalized at the Munich
asylum. As Grof and colleagues (1995) suggested, it could
be that the natural history of the bipolar variant of classic
Kraepelinian manic-depressive illness is quite different
from that of the bipolar disorder identified in many cohorts today. At any rate, differences in findings among
contemporary cohorts need to be assessed in light of the
different samples they represent. Each cohort is discussed
below in turn.45
The CDS has produced the most published data in recent years on the course of manic-depressive illness. The
sample in that study consisted of roughly one-third outpatients and two-thirds inpatients initially recruited during
the years 19781981 at five U.S. academic health centers.
This cohort has now been followed for up to 25 years, with
a retention rate in follow-up of more than 80 percent. As
of 2003, about 80 percent of this cohort was reportedly in
continued treatment with pharmacotherapy (R. Keller,
personal communication, 2003). At 5-year follow-up, more
previous episodes predicted more relapses but also quicker
recovery (recovery at 6 months was 55 percent for a first
episode, 73 percent for one or two previous episodes, and
90 percent for more than three previous episodes). Psychosis predicted only 37 percent recovery at 6 months, versus 65 percent in nonpsychotic patients. At 5-year followup, all of the patients initially treated for pure mania had
recovered, compared with 89 percent of those with pure
depression and 83 percent of those with mixed states. Despite ongoing high-intensity somatotherapy in the majority of subjects (75 percent), early relapse rates were relatively high: at 6 months, 20 percent of patients with pure
143
144
Clinical Studies
145
episodes and dysthymia (24 percent; n = 104). In a followup of up to 20 years (mean 8.7 years), patients were symptomatic 59 percent of the time. During these symptomatic
periods, depressive symptoms were again almost three
times more likely to be associated with subsyndromal states
(43 percent of total follow-up period) than with major depressive states (15 percent of total period).
As a result of these studies, Judd and colleagues (2002)
and others (Kupka et al., 2005) have urged a shift in longterm studies to focus on chronicity and subsyndromal
morbidity. One example of such work is a study that found
subsyndromal depressive morbidity in bipolar disorder
(N = 25) to be associated with increased functional impairment (Altshuler et al., 2002).
It is also notable that subsyndromal manic morbidity
was found to be most prominent in a 4-year follow up of
children (N = 86; mean age at baseline 10.8 years) (Geller
et al., 2004). In this cohort, patients spent 57 percent of the
follow-up time in manic or hypomanic states, versus 47
percent in depressive states and 37 percent in mixed states.
(The total exceeds 100 percent because mixed states were
included in all three categories.) These findings suggest that
the chronic subsyndromal depressive course is a feature of
adult bipolar disorder, whereas in children a more chronic
manic/mixed course predominates (see Chapter 6).
A number of considerations arise in interpreting the results of outcome studies. The first is the extent to which
these outcomes reflect natural history as opposed to being
either attenuated or exacerbated by treatment effects.
Most of the investigators cited earlier noted that their patients were treated primarily according to current standards, although information on specific treatments was
not provided. When treatment effects were addressed, it
was generally in the context of the assumption that continuing morbidity had to be occurring despite these effective
treatments. Another possibility exists, however: that in
some cases, treatment is only minimally beneficial or neutral, but capable of exacerbating the course of bipolar illness. As noted earlier and discussed in detail in Chapter 19,
this possibility is especially salient for antidepressants,
which may lead to subsyndromal cycling states that could
in turn account for the outcomes described by Geller and
colleagues (2004). The issue of how to treat subsyndromal chronic bipolar depression is a vexing problem for
clinicians and an important unanswered question for
researchers. If antidepressants are related to cycling, one
option would be to decrease their use. On the other hand,
if antidepressants were not being used, their possible benefits in some patients would be missed. The use of
cognitive-behavioral and other psychotherapies would appear to be appropriate in this situation (see Chapter 22),
although this approach has not been well studied. Other
146
Clinical Studies
MORTALITY
Suicide is a frequent outcome of manic-depressive illness;
in bipolar patients, it occurs more frequently early in the
course of the illness (see Chapter 8). Although suicide is
the single most important factor contributing to increased
mortality in manic-depressive patients,47 other causes,
such as the increased risk of cardiovascular disease, contribute as well. Indirect consequences of psychotic behavior during untreated episodesincluding malnutrition,
exposure, and exhaustionall compromise general health
and presumably contribute to a higher mortality rate. So,
too, do smoking and alcohol and drug abuse. As reviewed
in Chapters 14 and 15, some of the biological dysfunction
noted in manic-depressive patients involves systems other
than the brain. These dysfunctions could also contribute
to higher-than-normal mortality rates.
Recent studies of mortality in bipolar disorder are
listed in Table 46, along with the weighted mean standardized mortality ratio (SMR) from studies reviewed in
the first edition of this text.47 Early studies of mortality
rates in manic-depressive illness, which did not separate
bipolar from unipolar forms, claimed substantially increased mortalityup to six times the rate expected for
the same age group in a normal population. More recent
studies have found a less striking but still considerable increase in mortality, averaging approximately 2.3 times the
expected rate in the general population. This difference in
results probably reflects improvements in psychiatric care,
particularly the availability of specific treatments for the
depressive and manic phases. Thus in Derbys (1933) study,
22 percent of hospitalized manic patients died, and 40
percent of these deaths were from exhaustion, whereas
in the Iowa 500 follow-up, Tsuang and colleagues (1980)
found a significant increase only in circulatory deaths
and only among women. Corroborating the earlier Iowa
findings in a follow-up of 1,593 affective patients, Black
and colleagues (1987a) noted that non-suicide-related
deaths were excessive only among those patients with
a concurrent medical disorder.
The largest recent prospective study of mortality in
bipolar disorder involved up to 38 years of follow-up of
depressed hospitalized patients in Zurich. Angst and colleagues (1999) reported that, overall, these patients demonstrated increased mortality compared with the general
population, with a 61 percent higher risk of death (SMR =
1.6). The greatest risk was associated with suicide (SMR =
18), but statistically significant risks were also associated
BIPOLAR-II DISORDER
The course of bipolar-II disorder has not been as well
studied as that of bipolar-I illness; moreover, one of the issues in research on bipolar-II disorder is the relative lack of
reliability for this diagnosis (see Chapter 3). The CDS in
particular, however, has begun to shed light on the course
of this condition. In 5-year follow-up, while bipolar-II
subjects were less likely than bipolar-I subjects to be hospitalized, no other clinical differences in outcome (cycle
length, number of mood episodes, suicide attempts) were
found (Coryell et al., 1989b). Depressive episodes and
symptom severity did not differ between the two groups,
nor did frequency or duration of hypomanic versus manic
episodes (in the bipolar-I group). Differences in psychosocial outcome between the two groups also were not evident. Manic episodes, by definition, occurred exclusively
in the bipolar-I group. In a follow-up period of up to 10
years, only 7.5 percent (N = 64) of individuals with bipolarII illness switched to type I. However, if one includes
dropouts from follow-up in that study, which may reflect
the disinclination of more severely ill patients to continue to
participate in the biennial interviews, rates of switch from
type II to type I approach 15 percent. In a follow-up of up to
20 years, the primary morbidity over time was chronic subsyndromal depression, and the prominence of depression
was even more pronounced than in the bipolar-I cohort
(Judd et al., 2003). During the follow-up period (mean 13.4
years; N = 86), patients were symptomatic 54 percent of the
time. During these symptomatic periods, patients were predominantly depressed (93 percent of symptomatic period,
Duration of
Observation
(Years)
Deceased
(%)
Standard
Mortality
Ratioa
Suicide %
of all
Deaths
Cardiovascular
Disease % of
all Deaths
472
1217
12.1
15.7
42.1
473 F
354 M
6.75 (avg.)
4.9
5.9
1.23
1.07
21.7
9.5
30.4
33.3
133
16
30.1
2.50
27.5
17.5
34,465 F
19,638 M
120
26.8
32.4
1.8
2.2
17.9
23.1
26.5
28.5
299 F
198 M
130
15.1
18.7
1.3
25.6
20.7
8808 F
6578 M
11.5 (mean)
10.5 (mean)
19.8
26.1
27
2.5
18.7
20.1
29.9
32.1
Study
Sharma and
Markar, 1994
Comments
(continued)
Study
Angst et al., 2002
Sample
Size
291 F
115 M
Duration of
Observation
(Years)
3438
Deceased
(%)
Standard
Mortality
Ratioa
Suicide %
of all
Deaths
Cardiovascular
Disease % of
all Deaths
72.2
82.6
1.59
1.64
13.8
15.8
35.2
26.3
2.28
BP = bipolar; CVD = cardiovascular disease; Dx = diagnosis; UP = unipolar; SMR = standard mortality ratio; SZA = schizoaffective.
a
Ratio of observed mortality to expected mortality based on a normal demographically matched comparison population.
b
Based on a total of 7,584 subjects from 11 pre-1990 studies in which excess mortality was determined.
Comments
186 UP and 220 BP; BP patients had
SMR for CVD = 1.84 vs. UP SMR
for CVD = 1.36; treated BP
patients had lower SMR for CVD
than untreated (1.68 vs. 2.23)
149
50 percent of total follow-up period), and minimally hypomanic (2.4 and 1.3 percent, respectively) or mixed (4.3 and
2.3 percent, respectively). Depressive symptoms were almost
three times more likely to be subsyndromal (37 percent of
total follow-up period) compared with major depression (13
percent); again, then, these data reflect primarily subsyndromal or interepisode chronicity.
Vieta and colleagues (1997) reported that bipolar-II
(n = 22) compared with bipolar-I patients (n = 38), had more
past depressive episodes (5.6 versus 2.6), more hypomanic
episodes (7.0 versus 3.2), and, of course, more total lifetime
episodes (12.6 versus 6.3). Again, bipolar-I disorder was associated with more hospitalizations (3.0 versus 1.0).
The phenomenon of double-depression refers to the
persistence of milder depressive states (dysthymia) following recovery from an episode of major depression (Keller
et al., 1983). Klein and colleagues (1988) noted that, compared with other unipolar patients, those with doubledepression had a higher incidence of hypomanic episodes
during follow-up.
MECHANISMS OF RECURRENCE
CONCLUSIONS
The natural course and outcome of manic-depressive illness contribute to its definition and its differentiation
from schizophrenia. For the clinician, understanding natural course can help answer a patients questions about the
most important estimate of all, the prognosis: Will it return, and when? Here we summarize the key points of this
chapter that can help answer these questions.
Despite substantial methodological problems of both
earlier and recent studies and limited data from prospective follow-up studies, the literature on the course and outcome of manic-depressive illness supports the following
conclusions:
The bipolar subtype has the earliest age at onset, followed
by the more recurrent forms of unipolar depression, followed by the less recurrent forms. For the bipolar subgroup, the representative value varies with the definition
of onset, ranging from the appearance of first symptoms
(such as mood lability) before age 20 to the first hospitalization (in the 2530 age range).
Almost all bipolar patients experience relapse, given adequate observation time. Results of contemporary studies
indicate higher relapse rates than those found in earlier
studies; extended use of antidepressants may have contributed to this increase. Highly recurrent unipolar depression is a risk factor for developing bipolar illness.
Cycle length does not change predictably with time, although it may shorten progressively in the initial stages
of illness in a subgroup of individuals.
150
Clinical Studies
NOTES
1. Behavioral, intellectual, and language tests were part of the
standard examination battery administered by the Israeli Draft
Board Registry. Anyone previously diagnosed with the aforementioned disorders by the time of the draft examinations or
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
directly thereafter was excluded from the study. The experimental group was culled from those who developed the disorders at least 1 year after examination. To control for instability
of diagnosis, the authors included only patients whose diagnosis after a 4-year follow-up was the same as the entry diagnosis.
Psychotic bipolar patients were excluded from this study because part of the cohort had been assessed using International Classification of Diseases (ICD)-9 criteria, before the
bipolar definition had been broadened to include more psychotic features.
van Os et al., 1995; Bromet et al., 1996; Vocisano et al., 1996;
McClellan et al., 2003.
While some of these data were taken from subanalyses of
large epidemiological samples, most were gathered from
clinical populations. We discuss age-at-onset results from
epidemiological samples in Chapter 6. Although it is impossible to eliminate selection bias completely, we took care here
to select only those patient samples that appeared to represent the general bipolar population.
Reliability measures were based on age-at-onset assessments
made by two independent physician raters. Reliability coefficients for first treatment and first hospitalization were 0.94
and 0.97, respectively.
One must also consider the possible contributions of changes
in maternal behavior (smoking and drinking during pregnancy), as well as changes in dietary factors, such as decreased intake of omega-3 fatty acids (since World War II)
due to changes in infant formulas (see Chapter 5).
It is likely that the lower age at onset seen in more recent birth
cohorts results from a confluence of these multiple factors.
Additional information about this survey was obtained from
the study authors for the present review. Although subject to
recall bias and not administered by a trained clinician, the
survey used to determine age at onset did adhere to DSM-IV
episodic criteria. Furthermore, to control for underreporting
of later ages at onset, the authors did not include the youngest cohort of participants (born after 1959) in their analyses.
For example, Mick and colleagues (2003) compared measures of cognitive and global functioning, comorbidity, and
clinical features across three groups arbitrarily designated as
childhood, adolescent, and adult onset. They found significantly more comorbid anxiety disorders in the child and
adolescent groups compared with the adult group, but no
difference among groups in cognitive or global functioning.
However, there was a trend for more rapid cycling and mixed
episodes in the earlier-onset group, although the sample size
lacked the power to permit evaluation of statistical significance for some of these measures.
Neurological abnormalities were descriptive and based on
medical records. Among 14 patients in the elderly-onset mania
group, 10 had neurological problems such as seizures, gait disturbance, recurrent cerebral contusions, and cerebral infarcts.
Winokur and colleagues (1993) found no association between a family history of bipolar disorder and age at onset.
Lish (1994) and colleagues, however, found a significant correlation between childhood/adolescent onset and a family
history of the disorder. This finding was replicated by Engstrom and colleagues (2003). Johnson and colleagues (2000)
reported that patients with a family history of bipolar disorder had a significantly lower age at onset than those with no
such family history.
12. However, a recent study from this group did find that mixed
episodes were more common in a bipolar group with an early
age at first hospitalization (younger than 18) compared with
those first hospitalized in their twenties (Patel et al., 2006).
13. Although this study included patients with adolescent onset
(minimum age = 15), the authors confirmed the diagnosis at
intake and at follow-up with clinician-administered Structured Clinical Interview for DSM (SCID) results and corroborating evidence from family reports, as well as school and
medical records.
14. Here again, both early- and late-onset groups were adults at
the time of assessment (mean age 33.6 and 60.2, respectively).
Diagnosis was verified with DSM-IV criteria and corroborating medical records, as well as family interviews.
15. At the time of assessment, the sample included all adults
(mean age 43.1) diagnosed with DSM-IV bipolar disorder. Age
at onset was determined by clinician-administered questionnaire, medical records, and family interviews in some cases.
Confirming other reports, Suppes and colleagues (2001) also
found a highly significant relationship between incidence of
childhood sexual abuse and early onset (p .001), a possible
triggering phenomenon discussed in Chapter 7.
16. As in most studies of this kind, Ernst and Goldberg ascertained age at onset retrospectively, in this instance using life
charts.
17. Perris (1968) found 83 percent with four or more episodes
and 43 percent with seven or more. In a 1978 paper, Angst
(1978) updated a careful longitudinal study of 95 bipolar patients who at that time had been followed for an average of
26 years (standard deviation 11.9). The study included both
retrospective and prospective phases, the latter involving direct patient and family contact at least every 5 years. Patients
by and large did not receive prophylactic treatment, although
most had individual episodes treated with medications. The
number of episodes ranged from 2 to 54, with a median of 9;
84 percent had 5 or more episodes, 69 percent had 7 or more,
and 42 percent had 11 or more. A naturalistic study of 51
bipolar patients who received unsystematic acute and prophylactic treatment showed that all but 2 of the patients had
experienced 3 or more episodes, with a median of 15 (RoyByrne et al., 1985a). Although this finding is consistent with
earlier data, it is important to remember that the patient
groups are not comparable, because the research setting of
the Roy-Byrne study tended to select treatment-resistant
patients. In a chart review study of 236 bipolar patients
from the prepharmacotherapy era (between 1920 and 1950),
Winokur and Kadrmas (1989) found that, during a follow-up
period averaging 2.4 years, 28 percent had 1 episode, 22 percent had 2, 14 percent had 3, 11 percent had 4, 4 percent had 5,
2 percent had 6, 0.8 percent had 7, 0.4 percent had 8, and 11
percent had 9 or more.
18. Angsts Dm group is roughly analogous to the bipolar-II subgroup in DSM-III-R, although hospitalization is not necessary for the diagnosis of either major depression or mania in
DSM-III-R.
19. Today, given modern treatment, relatively few patients would
actually meet this criterion (i.e., hospitalization).
20. In their 1979 review of the literature on the natural course of
manic-depressive illness (both unipolar and bipolar, with
the index episode usually a hospitalization), Zis and Goodwin (1979) divided studies that showed low rates of relapse
151
from those that showed high rates. They found that those with
low relapse rates were marred by methodological limitations,
including short duration of observation, focus on episodes
involving hospitalization, exclusion of episodes preceding index admission, inclusion of nonrecovered patients, combined
episodes treated as single episodes, and high unipolar/bipolar
patient ratio. For example, studies with low relapse rates
tended to include only episodes requiring hospitalization,
introducing a bias toward patients with longer and more severe episodes. Thus in Perriss 1968 study, only 40 percent of
patients had had four or more episodes involving hospitalization, but when all episodes were included, more than 80
percent had had four or more. Obviously, excluding episodes
preceding the index hospital admission also leads to underestimation. When, for instance, Bratfos and Haug (1968) included preadmission episodes, the proportion of patients
with single episodes dropped to 13 percent.
As noted previously, early studies often found a high proportion of single-episode patients because they included in
that single-episode count the many chronic patients who in
fact had had multiple (but uncounted) episodes while hospitalized. Cutler and Post (1982a) traced the long-term course
of illness in a group of bipolar patients who were chronically
hospitalized in a state institution. Their detailed analysis indicated that each of these patients displayed a pattern similar
to what Kraepelin had observed more than half a century
earlier: multiple, discrete episodes embedded in a single
long-term hospitalization. Estimates of relapse rates probably were lower than justified in the older studies, even when
based on patients who were not chronically hospitalized.
In those cases, combined episodes (e.g., a mania followed by
a depression, perhaps interspersed with a brief well interval)
may have been counted as a single episode. The presence of a
continuously circular course (Koukopoulos et al., 1980) or
rapid cycles (Dunner et al., 1976b) makes it more likely that
multiple episodes will be counted as one.
21. It may also be that recurrence is related to other features of
bipolar illness, such as age at onset and genetic risk. This interesting possibility has not been adequately explored since
the time of a chart review conducted during the prepharmacology era (Winokur and Kadrmas, 1989), which suggested
that certain clinical features may be associated with the illnesss natural tendency to recur. Winokur and Kadrmas
found that, compared with patients who had only one or two
episodes during a follow-up period averaging 2.4 years, patients with a polyepisodic course (more than three episodes)
were more likely to have had an early age at onset, a finding
that replicates an earlier report by Okuma and Shimoyama
(1972). Winokur and Kadrmas also found that a polyepisodic
course was associated with a more insidious onset of the index episode and a greater frequency of bipolar illness in firstdegree relatives. They speculated that this last finding could
indicate that cyclicity more than polarity is genetically transmitted: the more total episodes, the greater the likelihood of
manic episodes.
22. In 1938, Eliot Slater of the Maudsley Hospital in London
published a paper (On the Periodicity of Manic Depressive
Insanity) (Slater, 1938a) in which he reexamined cases of patients who had been the source for Kraepelins data regarding
the shortening of cycle length. Unfortunately perhaps for later
generations, Slaters paper, published in a German psychiatric
152
Clinical Studies
journal that was prominent before World War II, lapsed into
obscurity in succeeding decades, especially in the nonGerman-speaking world. (This lack of attention in the AngloAmerican setting is particularly ironic given that Slater was
an Englishman.) In our review, we found the initial peer review and the most extensive discussion of Slaters fallacy in
English in a 1996 paper by Haghighat (1996), who also noted
earlier citations in book chapters by Angst (1988). In 2000,
Angst and Sellaro (2000) again referred to Slaters report in
English, and we recently obtained an English translation of
the original paper.
In that study, Slater reviewed 116 charts of patients diagnosed by Kraepelin in Munich with manic-depressive illness.
Among the features he assessed, Slater highlighted his reexamination of Kraepelins report of decreasing intervals of
wellness with an increase in the number of episodes, which
became a central feature of what would later be called the
kindling model. Slater confirmed that the duration of mood
episodes appeared to increase to a small degree over time.
However, his key finding was that the apparent decrease in
euthymic intervals between episodes was a statistical artifact.
Slater pointed out that people who have longer intervals between episodes will not fall ill as often as those in whom the
intervals are shorter. In other words, if all patients are included in the analysis, some will experience only two
episodes and others six, for example. It may be that those
with six episodes have short periods of wellness between
episodes, whereas those with two episodes experience long
periods of wellness. If those two types of patients are added
together, as was done by Kraepelin, there will appear to be
a progressive decrease in euthymic intervals. The actual state
of affairs will not necessarily be so. One would have to
demonstrate that intervals of wellness shortened over time in
the same patients, whether they had two episodes or six. In
sum, interepisode intervals of wellness need to be corrected
for the number of episodes. When Slater made this correction, Kraepelins finding vanished (except to a small degree
for earlier episodes). In a recent outcome study of firstepisode manic patients at McLean Hospital, Baldessarini and
colleagues (2000) found the same effect. Taken as a group,
the sample appeared to demonstrate progressive shortening
of intervals of wellness, but when the data were corrected for
number of episodes, there was no apparent shortening of
well intervals.
We would like to acknowledge and thank Dr. Ross
Baldessarini for bringing this long-neglected paper to our attention. We would also like to acknowledge and thank our
colleague, Dr. Godehard Oepen, for assistance in translating
and interpreting Slaters study.
23. Bratfos, 1968; Bratfos and Haug., 1968; Angst et al., 1973; RoyByrne et al., 1985a; Goldberg, 1993; Goldberg and Harrow,
1994; Kessing, 1998; Kessing et al., 1998a; Cusin et al., 2000.
24. Another study found that number of episodes did not predict recurrence at 1-year prospective follow-up (Staner et al.,
1997). Such short-term studies are less useful in refuting kindling hypotheses, however, because the kindling model is a
long-term model. The studies of the groups led by Coryell
and colleagues (2001) and Baldessarini and colleagues (1999)
were longer-term (up to 10 years).
25. Kendler and Karkowski-Shuman (1997) also assessed this finding within individuals by stratifying their dataset by individual
26.
27.
28.
29.
30.
31.
32.
33.
and assuming a separate hazard function for their Cox proportional hazards model for each person in the study.
In a study with the methodological limitation of including
only hospitalized patients, there was no evidence of a difference in episode severity in individuals experiencing their
first manic episode as opposed to one of multiple episodes
(Keck et al., 1995). However, because all patients were hospitalized, differential severity may have been difficult to detect.
The sample was from the Mediterranean island of Sardinia.
Independent confirmation or refutation of the kindling
model based on other lines of evidence may gradually develop. For instance, Huber and colleagues (2001) presented a
mathematical nonlinear model of sensitization. This model
has two components: a positive feedback loop (more episodes
lead to more episodes) and a long time interval. The authors
showed that this mathematical model can support autonomous disease progression as well as irregular rapid cycling as an end stage of disease, as predicted by the kindling
hypothesis.
Swift, 1907; MacDonald, 1918; Pollock, 1931; Angst and Weis,
1967; Zis et al., 1979.
The 1989 study of Winokur and Kadrmas (1989), although
limited by its chart review methodology, is nevertheless of
interest because it is based on the prepharmacology era. The
authors reported that patients with a polyepisodic course
(more than three episodes per average follow-up of 2.4
years) were significantly more likely to have an early age at
onset (before age 20) than those with one or two episodes.
Another question is whether episodes come in bursts or clusters, as originally described by Kraepelin in his studies of
predominantly chronic patients with frequent relapses. As
discussed in Chapter 20, this issue is important in assessing
prophylactic treatment, and indeed in making treatment decisions. If episodes of manic-depressive illness characteristically occur in clusters, it may be difficult to interpret prophylactic trials in individual patients. The evidence on this issue
is somewhat conflicting. Saran (1970) compared episode frequencies in six untreated bipolar patients for 2 years before
and 3 years after an arbitrary point in time. Even in such a
small number of patients, there was some suggestion of
episode clustering. In a 2- to 20-year follow-up (mean 5.6
years) of patients admitted for manic episodes, Winokur
(1975) found that 91 percent of first-episode patients had
experienced another episode during follow-up, compared
with only 53 percent of those with a history of previous
episodesa result interpreted as evidence of episode clustering. Angst and colleagues (1970) did not find different relapse rates before and after lithium treatment. It is also worth
noting that there may be some methodological issues with
extrapolating from such group findings to clustering in individual patients.
For example, Kupka and colleagues (2005) found more
bipolar-I than bipolar-II patients among 539 outpatients in
the Stanley Network.
In a study of 320 hospitalized patients with bipolar-I disorder, the polarity of the first episode was determined to be
major depressive in 52 percent, mixed in 26 percent, and pure
manic in 22 percent. Patients whose illness began with depression were more likely to develop a rapid-cycling course
and experienced more suicide attempts but less psychosis
than the other groups. The mixed group tended to be more
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
153
Hopkins cohort (Stephens and McHugh, 1991), an Indian cohort (Khanna et al., 1992), a Danish cohort (Kessing, 1998,
1999), an Italian cohort (Cusin, 2000), and a Taiwanese cohort (Tsai, 2001).
The Cologne cohort consisted of 106 patients with DSMIII mood disorders, a subgroup of a total cohort of 402 patients (the rest with psychotic disorders). With a mean of 27.9
years of outcome data, 64 percent of the mood disorder sample
was fully remitted (Marneros et al., 1990). Subclassification of
bipolar and unipolar conditions was not performed. In multivariate analysis, male gender was a major predictor of poor
functional outcome (Diester et al., 1993). Other apparent predictors were an asthenic low self-confident premorbid personality and a higher number of mood episodes.
The Johns Hopkins cohort, also mentioned in this chapter
in the discussion of polarity, consisted of patients hospitalized between 1913 and 1940, and therefore represents a true
pretreatment natural-history sample. The study group consisted of 914 patients with at least 5 years of medical record
follow-up data. With a mean follow-up of 13.5 years, only 11
percent of the bipolar group (n = 297) and 22 percent of the
unipolar group (n = 945) did not experience future mood
episodes. About one third of the total sample had a chronic
outcome, somewhat worse in the bipolar subgroup (43 percent), and 13 percent committed suicide.
The Indian cohort consisted of 95 patients with bipolar
disorder hospitalized in an academic psychiatric hospital
over a period of 3 months in 1989. Medical records were assessed for course of illness. The main findings were more
manic than depressive episodes and worse outcomes in those
with initial manic episodes (unadjusted for other clinical
factors statistically). The sample was predominantly male
(84 percent) and predominantly manic (83 percent of first
episodes reported). Interestingly, not a single case of a rapidcycling course or of polyphasic episodes was documented,
a finding that one might speculate is related to lack of antidepressant exposure in a setting in which many patients remain untreated.
The Denmark cohort is described further in this chapter
in the discussion of kindling.
The Italian cohort consisted of 244 patients with bipolar
disorder with 14-year outcome data. The main finding was
that an initial manic as opposed to depressive episode predicted a higher frequency of episodes in the outcome period.
In the Taiwanese cohort, 101 patients with bipolar disorder were identified by hospital records and agreed to followup after 15 years. The main predictor of poor psychosocial
outcome was medication nonadherence, which was observed
in 33 percent of the sample.
45. Although the second McLean-Harvard cohort is a proxy for
a first-episode study, it is notable that 24.7 percent had experienced previous nonhospitalized major depressive episodes.
Therefore, this subgroup did not really consist of firstepisode bipolar subjects.
46. In Chapter 9, we review the evidence that some neurocognitive impairment may exist even prior to the onset of the illness.
47. In a postmortem study of 122 bipolar patients, for example,
Taschev (1974) found that 27 percent had died by suicide.
Among manic patients from the Iowa 500 series, Winokur
and Tsuang (1975b) found that 8.5 percent of the deaths were
154
Clinical Studies
Epidemiology
Seek the points of contact which may reveal the underlying law. Some things can be learned
only by statistical comparison.
Sir William Osler (in Thayer, 1920, p. 52)
156
Clinical Studies
Epidemiology
METHODOLOGICAL ISSUES
The chapter on epidemiology in the first edition of this
text focused on methodological problems because at the
time there were more problems than data. Although these
problems cannot be ignored in interpreting the growing
body of data now emerging, we need not dwell on them
because they have been addressed in many of the more
recent studies. Therefore, this section reviews only those
methodological issues that are particularly relevant to
current understanding of the epidemiology of bipolar disorder.
Survey
Bipolar-I disorder
Before CS
After CS
4.9 (0.3)
4.0 (0.3)
8.9 (0.6)
5.4 (0.5)
0.9 (0.1)
0.5 (0.1)
1.3 (0.2)
1.3 (0.2)
157
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Clinical Studies
can markedly alter rates (Narrow et al., 2002) (see the later
discussion).
Age-Specific Issues
The criteria for diagnosing bipolar disorder in children are
even less clear than those used for adults (for example, see
the discussion of problems in defining age at onset in children and adolescents later in this chapter and in Chapter 6).
Indeed, since 1980 (DSM-III, DSM-III-R, and DSM-IV),
adult criteria have been applied to diagnose mania and depression in children without taking into account differences
in age and developmental stage (Sanchez et al., 1999). Bipolar disorder in young people may therefore be misdiagnosed or underdiagnosed. Moreover, although mania in
youth can be a severe illness frequently associated with
mixed features, psychosis, rapid cycling, and comorbid disruptive disorders, there is often a clinical bias against making a diagnosis of mania in children. And the relationship
between bipolar disorder and other, more prevalent childhood psychiatric illnesses, such as attention-deficit hyperactivity disorder (ADHD), is problematic (see the later discussion of surveys of children and adolescents). Estimates
of the age at onset of bipolar disorder must take into account this lack of clarity regarding first presentation of the
disorder in youth. Eventually, longitudinal studies of children from families with a high risk of bipolar disorder may
clarify issues of first presentation (see Chapter 6).
The effects of duration and severity on prevalence must
also be considered when reviewing the literature on prevalence of childhood bipolar disorder (Sanchez et al., 1999).
DSM-III-R removed the 7-day minimum duration criterion for mania required by DSM-III. Consequently, reports
based on DSM-III-R criteria may overdiagnose mania, especially in childhood. In DSM-IV, the duration criterion
was reinstated, and the severity requirement was added.
In April 2000, NIMH convened a group of experts for
a Bipolar Child Roundtable to discuss possible approaches
for addressing outstanding issues related to research on prepubertal bipolar disorder. The major issues of relevance to
epidemiology addressed at the roundtable were the earliest
age at which bipolar disorder can be diagnosed and the predictive value of the early manifestations of bipolar illness in
children and adolescents. The experts generally agreed that a
diagnosis of bipolar disorder using DSM criteria is possible
in prepubertal children.
Discussion among the expert group resulted in agreement
on two basic definitions: (1) a narrow phenotype that adheres strictly to bipolar-I and bipolar-II criteria, and (2) a
broader phenotype that encompasses more heterogeneity
basically bipolar-not otherwise specified (NOS)and includes children who do not quite meet the criteria (especially
Epidemiology
159
Validation studies also need to take developmental manifestations into account. The expert group suggested that
studies could encompass children as young as 4 years of
age. Reconstruction of the history of adults with earlyonset bipolar illness may be useful as well. For example, in
studies of the offspring of bipolar parents, which should
include all of their children, parents should be asked about
their own age at onset. The group deemed it important
also that children with possible bipolar disorder, as well as
their parents, be interviewed with developmentally appropriate measures.
Information about instruments currently employed in
NIMH-funded studies of childhood-onset bipolar disorder was assembled for use at the roundtable. The most
commonly used diagnostic instrument is KSADSin
most cases, the Washington University (St. Louis) version
(WASH-U-KSADS) or KSADS with the WASH-U-KSADS
sections on mood disorders and rapid cycling added. Ancillary instruments being used include the Child Behavior
Checklist (CBCL) (Achenbach, 1991a,b).
Efforts that might be undertaken to resolve the diagnostic issues raised above include the following: describing the
course of bipolar-I, bipolar-II, cyclothymia, and bipolarNOS, with attention to the impact of development on
changing patterns of symptoms; establishing the predictive
validity of bipolar disorder in prepubertal children; defining thresholds for and boundaries between bipolar-I,
bipolar-II, and cyclothymia in prepubertal children; and
identifying occasions on which combining versus separating bipolar-I and -II would be appropriate (in treatment
studies of mania, for example, where severity is an issue,
combining manic with hypomanic patients may be inappropriate). Although future epidemiologic studies will
need to incorporate the clinical findings of studies conducted to date, the unresolved issues of diagnosis in children described here make the accuracy of estimates of
rates of childhood bipolar disorder and determinants of
age at onset uncertain. See Chapter 6 for a comprehensive
discussion of these issues.
Epidemiologic findings for the elderly are also ambiguous. In geriatric inpatient units, the prevalence of treated
bipolar disorder has been described as reaching 10 percent
(Yassa et al., 1988). Yet there is a disparity between the
prevalence of bipolar disorder among elderly patients in
hospitals and elderly individuals living in the community.
Moreover, the rates of bipolar disorder are dramatically
lower among community-dwelling elderly people than
among younger persons (Shulman and Hermann, 1999).
One reason for this is the increased early mortality from
medical causes, such as cardiovascular disease and suicide
among those with the disorder (Snowdon, 1991).
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Clinical Studies
Diagnostic Methods
Over the years, we have seen the development of a number
of structured interview instruments that have improved
the precision with which psychiatric disorders can be
identified and their rates estimated (see Chapters 3 and 11).
Yet different diagnostic criteria or revised versions of the
same criteria can affect rates and their comparisons. Thus
differences among diagnostic instruments used in community studies may explain some of the variation in the
rates obtained.
The DIS (Robins et al., 1981a), mentioned earlier, is
a highly structured interview designed for large-scale epidemiologic studies. It generates DSM-IV diagnoses in
computer algorithm form for the major psychiatric disorders. The CIDI (WHO, 1990; Wittchen et al., 1998a), also
noted previously, consists of state-of-the-art structured diagnostic interviews based on the DIS and generates DSMIV and ICD diagnoses. Trained lay interviewers administer
both the DIS and the CIDI. The two instruments differ in
that the DIS includes impairment criteria when generating
diagnoses, whereas the CIDI does not. Moreover, after an
initial round of questions about symptoms, the CIDI returns to reassess those symptoms, while the DIS asks about
symptoms only once. A modification of the CIDI made by
the University of Michigan Institute for Social Research
(UM-CIDI) (Kessler, 1995) simplified that instruments
complex questions. Qualifiers such as a lot (as in the
question, Did the symptom interfere with your life and
activities a lot?) were clarified (as in the question, How
much did the symptom interfere with your life or
activitiesa lot, some, a little, not at all?).
Another semistructured interview instrument is the
Schedule for Affective Disorders and Schizophrenia (SADS)
(Endicott and Spitzer, 1978), which is tied to the Research
Diagnostic Criteria (RDC) (Spitzer et al., 1978) and the
DSM. This instrument has been used less often than the DIS
or the CIDI in community surveys because it must be administered by trained mental health professionals.
The Structured Psychopathological Interview and Rating of the Social Consequences of Psychiatric Disturbances for Epidemiology (SPIKE for the original German)
(Angst et al., 1984) is yet another semistructured clinical
interview. It allows the assessment of 29 separate syndromes, including hypomania, in terms of symptoms, their
length, their frequency of occurrence, subjective suffering,
social consequences, treatment, and family history, and
generates DSM-III diagnoses.
The Structured Clinical Interview for DSM (SCID) is a
semistructured clinical interview used for making a major
Axis I DSM-III-R or DSM-IV diagnosis. Through a
decision-tree approach, the SCID guides the clinician in
Epidemiology
Other Issues
Sample Size
The relatively short duration of many manic and depressive episodes and the presence of mixed states cause difficulties in assessment. Short episodes are counted in some
studies but overlooked in others that use diagnostic instruments with long-duration criteria. Short episodes also are
responsible for large differences in rates of point and annual prevalence. Gagrat and Spiro (1980) explained this
difficulty and underscored the problems created by studying a phenomenon with a low baseline rate. As they noted,
point prevalence studies for a short-duration disorder
with a yearly prevalence of 0.7 percent would require the
screening of very large numbers of people. Even allowing
for a mean duration of manic episodes of 2 months (a mean
duration of 2 months assumes that many of the manic
episodes in the community are shortened by treatment),
the point prevalence rate would be on the order of 0.2 percent if the annual prevalence in the population at large
were 1.0 percent. This means it would be necessary to
screen 1,000 people to find 2 active cases. Epidemiologic
studies of several hundred thousand people at a time would
be required to determine the point prevalence in the population at large. Moreover, it is questionable whether current epidemiologic research instruments would be reliable
in such studies.
Except for demographic characteristics such as age and
gender, the relatively low prevalence of bipolar disorder
makes estimates of variations in rates by risk factor difficult even in reasonably sized epidemiologic surveys. For
example, in a sample of 5,000, which would be considered
a reasonably sized community survey, a lifetime prevalence
of 2 percent for a disorder would yield at most 100 cases.
Few epidemiologic studies have 5,000 subjects. When the
population is segmented by age, gender, and race, moreover, the sample size in each group dwindles rapidly. Finally, as discussed later, time constraints prevent any one
study from including all the relevant risk factors, and multiple instruments are required.
161
Functional Impairment
The assessments used in recent epidemiologic studies require some evidence of functional impairment to determine the clinical significance of the case. Questions about
impairment of major roles or treatment seeking are designed
to elicit this information. Variations in these questions can
seriously alter rates among studies, as revealed by the comparison of the rates in the ECA and the NCS, described
later.
Age at Onset
Different methods may be used for computing the age at
onset of bipolar disorder. One method is to use two measures of central tendency: the mean or average age at onset
and the median, or the age that corresponds to the 50th
percentile of the distribution. An advantage of using this
method is that age at onset can be summarized as one estimate. The disadvantage is that both the mean and the median can be biased by extreme values at either the lower or
higher end of the distribution of ages.
Another method for analyzing age at onset is to compute the incidence (or hazard) rate of bipolar disorder for
each age of life. This is done by taking the number of new
cases that appear at each age and dividing it by the population at risk for that age. The major advantage of this
method is that trends in incidence rates can be compared
across all ages, although the population at risk becomes
162
Clinical Studies
Epidemiology
163
latter two sets of diagnostic criteria are now used infrequently.) Subjects were first asked whether they had ever
experienced a symptom at any time during their lives and
whether they had experienced impairment in life activities from that symptom. For each symptom, the interviewer ascertained whether alcohol, drugs, medication, or
physical illness was the underlying cause. Subjects were
then asked whether they had experienced the symptom
during the last 2 weeks, the last month, the last 6 months,
and the last year, and this information was used to generate a diagnosis for period prevalence. The DIS determined
the severity of a disorder in addition to its presence and
duration.
The DIS appears to have relatively high reliability for diagnosing major depression but considerably less reliability
for manic episodes. In comparing the agreement between
the DIS administered to the same subjects by a lay interviewer and a physician, the kappa statistic for major depression was found to be 0.50 and for mania 0.21 (Helzer
et al., 1985). Some questions remain about the continued
use of the DIS and interpretation of the data it yields (see,
e.g., Anthony et al., 1985). The accuracy of lifetime recall has
been questioned, as has the lack of comparability of diagnoses made by lay interviewers and by experienced clinicians, whose pattern recognition and access to family
history are likely to produce a more accurate diagnosis.
Robbins and colleagues (1982) compared 1-month prevalence rates of depression and mania at two ECA sites (St.
Louis and Baltimore) based on diagnoses by lay interviewers and psychiatrists using the DIS. Although the rates were
not significantly different in Baltimore, both disorders were
diagnosed three times more often by psychiatrists than by
lay interviewers in St. Louis. A recent study of 41,838 individuals in the Swedish Twin Registry underscores the considerable problem in interpreting findings obtained by lay
interviewers (Soldani et al., 2005). Telephone screening for
mania, when compared with actual hospitalization and
other medical records, resulted in spuriously high falsepositive rates for mania in particular and for bipolar disorder in general. The investigators concluded that instead of
the reported rate of 1.6 percent, a more accurate estimate
would be 0.9 percent. These discrepancies suggest that some
caution should be applied in interpreting ECA data, although the study is methodologically superior overall to
past attempts at estimating the prevalence and incidence of
bipolar illness.
The lifetime and annual prevalence and annual incidence for bipolar-I disorder for the total noninstitutionalized ECA sample and each of the five sites are presented
in Table 52. The total sample size was 18,571 respondents aged 18 and older, 59 percent of whom were female.
The overall response rate was 76 percent. The lifetime
164
Clinical Studies
Table 52. Lifetime and Annual Prevalence/100 (Standard Error) and Incidence Rate/100
of Bipolar-I Disorder in Five Epidemiologic Catchment Area Sites
New Haven,
CT
Baltimore,
MD
St. Louis,
MO
Durham,
NC
Los Angeles,
CA
Number in sample
5,034
3,481
3,004
3,921
3,131
77
78
79
79
68
% Female
59
62
60
60
53
Total
1.2 (0.21)
0.6 (0.20)
1.0 (0.20)
0.3 (0.14)
0.6 (0.16)
Males
1.0 (0.27)
0.7 (0.22)
1.1 (0.30)
0.1 (0.11)
0.6 (0.23)
Females
1.3 (0.30)
0.5 (0.24)
1.0 (0.27)
0.6 (0.25)
0.5 (0.21)
0.8
1.4
1.1
0.2
1.2
Total
1.0 (0.16)
0.5 (0.14)
1.0 (0.20)
0.2 (0.08)
0.4 (0.13)
Males
0.9 (0.22)
0.5 (0.21)
1.0 (0.30)
0.0
0.3 (0.15)
Females
1.1 (0.23)
0.5 (0.18)
1.0 (0.27)
0.4 (0.16)
0.5 (0.20)
0.8
1.0
1.0
0.0
0.1
Total
0.6 (0.12)
0.2 (0.09)
0.1 (0.07)
0.3 (0.10)
0.5 (0.15)
Males
0.4 (0.15)
0.0
0.0
0.1 (0.09)
0.5 (0.21)
Females
0.7 (0.19)
0.4 (1.6)
0.2 (0.13)
0.5 (0.18)
0.5 (0.20)
Parameter
Lifetime prevalence/100
M/F Ratio
Annual prevalence/100
M/F Ratio
Annual Incidence/100
Epidemiology
165
166
Clinical Studies
NCS (1994)
NCS-R (2005)
Number in sample
8,098
9,282
84
71
Interview measure
UM-CIDI
CIDI
Diagnostic outcome
DSM-III-R
DSM-IV
Interviewers
Lay
Lay
% Female
52
52
1.7 (0.20)
1.0 (0.1)
Males
1.6 (0.28)
0.8 (0.1)
Females
1.7 (0.28)
1.1 (0.2)
Total
1.3 (0.18)
0.6 (0.1)
Males
1.4 (0.25)
0.6 (0.1)
Females
1.3 (0.24)
0.7 (0.1)
23.3 (0.9)
21.4 (1.2)
Median
21.0
19.0
CIDI = Composite International Diagnostic Interview; DSM = Diagnostic and Statistical Manual; UMCIDI = University of Michigan Institute for Social Researchs modification of the CIDI.
Sources: Kessler et al., 1994; National Comorbidity Study Replication (2005).
Epidemiology
Table 54. Comparison of the Epidemiologic Catchment Area Study (ECA) and the National
Comorbidity Survey (NCS)
Parameter
Date conducted
Sample size
Site
Age range (years)
Instrument
Diagnosis
Interviewers
ECA
NCS
19801984
19901992
18,571
8,089
5 U.S. sites
48 U.S. states
1865
1554
DIS
CIDI
DSM-III
DSM-III-R
Lay
Lay
CIDI = Composite International Diagnostic Interview; DIS = Diagnostic Interview Schedule; DSM = Diagnostic and Statistical Manual.
167
ECA (1980)
NCS (1990)
Male
1.0 (0.16)
1.6 (0.29)
Female
1.1 (0.17)
1.8 (0.30)
Gender
p Value
.43
.77
18.7 (6.1)
24.0 (7.5)
Median
18
22
Educational level
Less than high school
1.3 (0.25)
2.2 (0.61)
1.1 (0.21)
2.0 (0.36)
College or higher
0.9 (0.16)
1.2 (0.27)
p Value
.33
.12
1.2 (0.22)
2.7 (0.53)
$20,000$34,999
0.7 (0.21)
1.4 (0.38)
$35,000$69,999
1.2 (0.33)
1.6 (0.34)
$70,000 +
N/A
p Value
.34
0.8 (0.39)
.04
Marital status
Married
0.8 (0.13)
1.3 (0.22)
Separated/divorced
1.6 (0.40)
3.8 (0.93)
Never married
1.3 (0.23)
1.8 (0.48)
p Value
.02
.002
Domicile
Rural
0.9 (0.26)
1.3 (0.39)
Urban
1.1 (0.13)
1.8 (0.24)
p Value
.63
168
.31
Table 56. Target Population, Sample Size, Response Rate, and Gender and Age Distributions for the Cross-National Sites
Characteristic
Size of target population
Total number in study, age 18+ years
ECAa
NCSb
Alberta,
Edmonton
Puerto
Rico
West
Germany
Taiwan
Korea
New
Zealand
1,198,000c
247,005,000d
397,965e
1,792,127c
29,240,900f
1,681,118c
13,520,908c
181,000g
18,571
8,098
3,258
1,513
481
11,004
5,100
1,498
76
84
72
91
76
90
83
70
% Female
59
52
59
57
52
48
52
66
1825
14
19
22
22
N/A
25
20
20
2645
33
59
46
50
55
43
49
55
4664
21
16
21
28
45
24
30
24
65+
31
N/A
11
N/A
N/A
0.5
N/A
Note: Figures shown are in raw percentages; percentages may not add to exactly 100 at certain sites because of missing values
N/A = not assessed.
a
U.S. Epidemiologic Catchment Area Study, 1980.
b
U.S. National Comorbidity Survey, 1990.
c
Population figures according to 1980 census.
d
Population figures drawn from 1990 U.S. Census of 48 conterminous states.
e
Population figures according to 1981 census.
f
Population figures according to 1974 census of West Germany, former Federal Republic of Germany.
g
Population figures according to 1986 census.
Age at
Onset (years)
Median Age
at Onset (years)
Overall
Males
Females
M/F Ratio
ECA, 1980
0.9 (0.10)
0.8 (0.14)
1.0 (0.15)
0.7
18.1 (0.68)
18
NCS, 1990a
1.7 (0.21)
1.6 (0.29)
1.8 (0.30)
0.9
24.0 (0.92)
23
Edmonton
0.6 (0.16)
0.7 (0.25)
0.5 (0.21)
1.4
17.1 (1.12)
22
Puerto Rico
0.6 (0.23)
0.8 (0.38)
0.5 (0.27)
1.6
27.2 (3.40)
18
Munichb
0.5 (0.37)
N/A
1.0 (0.71)
N/A
29.0
25
Taiwan
0.3 (0.06)
0.3 (0.09)
0.3 (0.07)
1.0
22.5 (1.90)
22
Korea
0.4 (0.09)
0.6 (0.16)
0.2 (0.09)
3.0
23.0 (2.54)
18
Christchurch
1.5 (0.36)
1.7 (0.56)
1.2 (0.45)
1.4
18.2 (5.90)
N/A
United States
Persons without
Bipolar Disorder
ECA, 1980
23.9 (4.70)
2.9 (0.18)
9.6 (5.616.6)
.0001
NCS, 1990c,d
40.5 (6.08)
4.2 (0.33)
15.8 (9.326.9)
.0001
Edmonton
44.5 (12.72)
3.6 (0.38)
25.7 (8.676.6)
.0001
Puerto Rico
24.5 (25.50)e
5.8 (0.67)
5.6 (1.029.8)
Taiwan
11.8 ( 5.84)e
0.7 (0.08)
18.1 (5.857.0)
Korea
15.1 ( 8.40)e
3.1 (0.25)
5.5 (1.520.2)
Christchurch
32.7 (11.69)
4.0 (0.59)
13.1 (4.241.1)
Survey Site
Odds Ratio
(95% CI)b
p Value
United States
170
.04
.0001
.01
.0001
Epidemiology
171
Persons with
Bipolar Disorder
Persons without
Bipolar Disorder
Odds Ratio
(95% CI)b
p Value
United States
ECA, 1980
16.2 (4.09)
1.5 (0.13)
12.8 (6.824.1)
.0001
NCS, 1990c,d
27.0 (5.49)
3.1 (0.28)
12.5 (6.922.6)
.0001
Edmonton
16.7 (9.55)
1.3 (0.68)
16.5 (4.067.6)
.0001
Puerto Rico
49.6 (18.00)e
1.3 (0.33)
79.2 (17.3323)
.0001
Taiwan
14.5 (6.36)e
0.3 (0.06)
53.5 (17.9160)
.0001
Korea
9.0 (6.70)e
1.7 (0.19)
14.1 (2.677.3)
.002
20.6 (10.09)e
1.8 (0.40)
17.2 (4.369.1)
.0001
Christchurch
has also been noted in genetic studies showing an increased familial aggregation of panic disorder in probands
with bipolar disorder (MacKinnon et al., 1998). The meaning of these results and whether they represent a specific
genetic subtype are unclear (see Chapter 13).
Table 510 shows the significant association between
substance abuse or dependence and bipolar disorder in all
countries except Puerto Rico and New Zealand. These results suggest that cultural differences in substance abuse
may explain some of the association (see Chapter 7).
Iceland
172
Clinical Studies
Persons without
Bipolar Disorder
Odds Ratio
(95% CI)b
ECA, 1980
57.2 (5.51)
17.5 (0.41)
7.6 (4.712.1)
.0001
NCS, 1990c,d
58.2 (6.11)
23.4 (0.69)
5.0 (3.08.4)
.0001
60.0 (12.53)
20.1 (0.82)
6.4 (2.119.5)
.001
12.8 (1.00)
Survey Site
p Value
United States
Edmonton
Puerto Rico
0.0
Taiwan
19.3 (7.13)
6.7 (0.25)
3.3 (1.29.0)
.02
Korea
54.8 (11.68)
22.8 (0.61)
4.6 (1.312.5)
.02
Christchurch
23.7 (10.60)
20.9 (1.23)
0.8 (0.92.8)
.77
Hungary
A national community study was conducted in Hungary to
estimate the prevalence of affective disorders in the adult
population aged 18 to 64, sampled from the registries of 15
general practitioners in five different geographic areas
Florence, Italy
This study included a community sample of 1,000 people
in Florence, Italy, drawn from the registries of general
physicians (Faravelli et al., 1990). In contrast to the majority of the other epidemiological surveys, the interviews
were carried out by qualified psychiatrists or third-year
trainees. The annual prevalence for bipolar-I was 1.9/100
for females and 0.6/100 for males, for an overall prevalence
of 1.3/100. These rates are again in the same range as the
U.S. rates, except for higher rates in females. For bipolar-II
disorder, the overall prevalence was 0.2/100. The high annual rates of bipolar disorder are similar to lifetime rates
Table 511. Prevalence/100 of Bipolar Disorder from Other Cross-National Community Surveys
Study
Country/Year
Diagnostic Method
Diagnosis
Time Period
Prevalence/100
Zurich,
Switzerland, 19781982
Florence, Italy, 1987
1920
1589
SPIKE
DIS
Cohort born
in 1931
DIS
BP-I
BP-I
BP-II
BP-I
BP-II
Annual
Annual
Annual
Lifetime
Lifetime
0.7
1.3
0.2
0.2
0.5
Iceland, 1987
Shantin, Hong
Kong, 19841986
7,229
1864
DIS
BP I or II
Lifetime
2,741
2433
SADS
BP-I
BP-II
6 months
Males, 0.15;
females, 0.16
0.7
0.9
Israel, 1987
Nottingham,
England, 19921994
Hungary, 1998
397, 048a
2,953
1664
1864
SCAN, SANS
DIS
Not stated
SCID-III-R
BP
BP-I
BP-II
BP
2-year incidence
Lifetime
Lifetime
Annual incidence
0.005
1.5
2.0
0.0022:
males, 0.00037;
females,
0.00060
Ireland, 19952000
29,542
Oslo,
Norway, 19941997
2,066
1865
CIDI
BP
Lifetime
Annual
1.6
0.9
Sao Paulo,
Brazil, 19941996
1,464
18+
CIDI
BP
Netherlands, 19961999
7,067
1864
CIDI
1.0
0.5
0.3
2.0
Australia
Butajira, Ethiopia
10,641
68,378
18+
1549
CIDI
CIDI
BP-I
BP-NOS
BPb
BP-I
Lifetime
Annual
Annual incidence
Lifetime
Annual
Lifetime
Chile
15+
CIDI
BP-I
0.5
0.5: males, 0.6;
females, 0.3
1.9: males, 1.5;
females, 2.2
Sample Size
4,547
1,000
862
2,978
Lifetime
BP = bipolar; BP-NOS = bipolar disordernot otherwise specified; CIDI = Composite International Diagnostic Interview; DIS = Diagnostic Interview Schedule; SANS = Schedule for Assessment
of Negative Symptoms; SCAN = Schedules for Clinical Assessment in Neuropsychiatry; SCID = Structured Clinical Interview for DSM; SPIKE = Structured Psychopathological Interview and Rating
of the Social Consequences of Psychiatric Disturbances for Epidemiology.
a
Population at risk from 1991 Nottingham population census.
b
Euphoric type.
174
Clinical Studies
Israel
In an epidemiologic study of mental disorders among
young adults in Israel, a 10-year birth cohort (19491958)
was interviewed by psychiatrists using the Israeli version of
SADS, based on RDC criteria. A two-stage screening process was used. Subjects scoring positive on the screen
(about a fifth of the sample) received the full diagnostic interview by a psychiatrist. The screened positive sample included 2,741 Israeli-born offspring of Jewish immigrants.
The 6-month prevalence was 0.7 percent for bipolar-I disorder and 0.9 percent for bipolar-II disorder. Annual or
lifetime prevalence rates were not reported. The rates did
not vary significantly by gender. The 6-month prevalence
of definite bipolar-I disorder was higher among Israelis of
European ethnicity (0.61) compared with Israelis of North
African ethnicity (0.15, p < .05) (Levav et al., 1993). There
were no significant differences by education.
Zurich, Switzerland
Subjects for the Zurich Cohort Study were drawn from the
total population of the canton of Zurich. The sample was
the result of a two-stage design that selected subjects at
high risk for psychiatric disorders and applied random
controls for 4,547 subjects at the ages of about 19 (males)
and 20 (females). Reassessments were conducted when the
subjects were about 22, 27, 29, and 34 years of age. Screening took place in 1978, the first and second interviews were
conducted in 1979 and 1981, and the last (fifth) interview
was conducted in 1993. Each interview covered the previous 12 months. Symptomatology was assessed using SPIKE
(Angst et al., 1984), administered by trained clinical psychologists in the subjects homes. SPIKE is a semistructured clinical interview, which, as noted earlier, allows the
assessment of 29 separate syndromes, including hypomania, in terms of symptoms, their length, their frequency of
occurrence, subjective suffering, social consequence, treatment, and family history.
The 1-year prevalence of bipolar-I disorder was 0.7 percent (Angst et al., 1984). The study identified brief hypomania (recurrent and sporadic), a condition characterized
by short episodes of 1 to 3 days duration and high recurrence, as a new diagnostic group with a 1-year prevalence
rate (cumulative) of 2.8 percent (see later discussion).
The lifetime prevalence of bipolar spectrum disorder, which included a full range of manic symptoms (see
the later discussion of bipolar spectrum) was 5.5 percent
(Angst, 1995). Overall, the study demonstrated the high
prevalence rates of DSM-IV hypomania and brief hypomania among the general population and the clinical and
social relevance of these diagnoses. Because this was a
prospective study with five waves of interviews focusing on
rates from the previous year, it may have been more successful than other studies at identifying fluctuating hypomanic episodes. There have been no other epidemiologic
studies of comparable design.
Ireland
A prospective study in rural Ireland of 29,542 subjects
from 39 electoral districts was initiated in 19952000 to
assess all first episodes of bipolar disorder. The SCID-III-R
(Spitzer et al., 1992) and DSM-III-R were used. As of 2002,
the annual incidence of bipolar-I for women was 0.0006
and for men was 0.00037; the overall incidence was
0.0022.5
Nottingham, England
This study estimated the incidence rate of ICD manic psychosis in first referrals to general adult psychiatric clinics
over the 2-year period 19921994. It differs from the others
reviewed here in that it was not community based. Therefore, patients who did not present for treatmentmost
likely milder caseswere not included (Brewin et al.,
1997). New patients were evaluated with the Schedule for
Clinical Assessment in Neuropsychiatry (SCAN) (WHO,
1994) and the Schedule for Assessment of Negative Symptoms (SANS) (Andreasen, 1982). Using the 1991 Nottingham
population census as the population at risk (denominator)
and new referrals meeting the ICD criteria for manic psychosis as the case (numerator), the incidence rate was
0.005, with a slightly higher rate among females (Brewin
et al., 1997).
Norway
A sample of 2,066 subjects aged 18 to 65, randomly selected
from the Norwegian National Population Registry, was interviewed with the CIDI between 1994 and 1997 (Kringlen
et al., 2001). The overall annual prevalence of bipolar disorder was 0.9 percent (0.8 percent for males and 1.0 percent for
females). The overall lifetime prevalence for bipolar disorder
was 1.6 percent, with little difference by gender (1.7 percent
for males and 1.4 percent for females). These rates are close to
those found in the NCS, which also used the CIDI.
Epidemiology
The Netherlands
A prospective survey of 7,067 subjects aged 18 to 64 years
from the Dutch general population was conducted at three
points in time between 1996 and 1999, using the CIDI (de
Graaf et al., 2002; Regeer et al., 2002). Summing of the responses at the three points yielded a lifetime prevalence for
bipolar-I or bipolar-NOS of 2.4 percent. A clinical reappraisal, blind to the original diagnosis, was conducted by
trained clinicians using the SCID. The results led to a reduction of the rate to 2.0 percent. The annual incidence
was 0.3 and was higher in females than in males, but these
rates are based on small numbers (Bijl et al., 2002).
So Paulo, Brazil
A community survey of a sample of 1,464 adults living in
one catchment area of a large hospital complex in So Paulo
was conducted using the CIDI (Andrade et al., 2002). The
lifetime and annual rates of bipolar disorder were 1.0 and
0.5, respectively. The rates among men and women were
similar. Data on the association with other demographic
characteristics were not presented for bipolar disorder separately from other mood disorders.
Chile
The CIDI was administered to a stratified random sample
of 2,978 individuals from four provinces representative of
Chiles population aged 15 and above (Vicente et al., 2006).
The lifetime and annual rates of manic disorder were 1.9
and 1.4, respectively. Lifetime rates were higher in women
(2.2) than in men (1.5).
Bipolar Spectrum
The rates of bipolar disorder reported above may be underestimates because many subjects who have brief recurrent hypomanic episodes may not be captured in surveys
(see Chapters 2 and 3). Moreover, there is controversy about
what symptoms should be included in the full spectrum of
bipolar disorder. Some epidemiologic data on the spectrum that include hypomanic episodes are now available.
The relatively low reported rates of hypomania noted in
previous surveys may be due to the fact that hypomania is
frequently unrecognized by subjects themselves as a pathological condition. However, there may be a wide bipolar
spectrum in clinical samples (Angst, 1998). The bipolar
spectrum includes mania, hypomania, recurrent brief hypomania, sporadic brief hypomania, and cyclothymia.
Modern concepts of bipolar disorder are still developing
and can include bipolar-I and -II, hypomania, cyclothymia,
mania with depression, and depression with hypomania,
as well as highly recurrently major depression.6 Six subtypes
of bipolar disorder were described by Klerman (1981): (1)
175
mania, (2) hypomania, (3) hypomania or mania precipitated by drugs, (4) cyclothymic personality, (5) depression
with a familial history of bipolar disorder, and (6) mania
without depression. The concept of soft bipolar spectrum
(Akiskal, 1996) includes Klermans subtypes 3 through 6,
as well as recurrent depression without spontaneous hypomania but with hyperthymic temperament (Angst, 1998).
Epidemiologic studies have found lifetime prevalence
rates for certain segments of the bipolar spectrum that
range from 3.0 to 8.3 percent (Table 512). The further the
spectrum is extended, however, the lower is the diagnostic
reliability.
In this context, longitudinal epidemiologic studies of
young adults to determine instances of subtle onset of
symptoms could provide data for use in testing the hypothesis of a bipolar spectrum. However, almost all epidemiologic studies are cross-sectional. One attempt to
study the spectrum was the longitudinal study of Angst
(1998), discussed previously. In that study, the cumulative
prevalence (based on four interviews over 12 years) for
DSM-IV hypomania/mania was 5.5 percent. Brief (recurrent or sporadic) hypomania had a prevalence of 2.8 percent. Therefore, the inclusion of brief hypomania raised
the Zurich rate for bipolar spectrum to 8.3 percent
(Akiskal 2000). All of the subgroups in this studythose
that met the DSM-IV criteria for hypomania and those with
sporadic or brief recurrent hypomaniahad similar symptom profiles and a family history of depression (Angst,
1998). Angst recommended that the bipolar spectrum be
broadened to include brief hypomania in light of its high
prevalence and clinical relevance.
The largest study of bipolar spectrum disorder included
more than 85,000 adults in the United States and used the
Mood Disorder Questionnaire (MDQ), a screening instrument of uncertain reliability. This study found a rate of
bipolar spectrum of 3.7 percent. The relationship between
data on bipolar spectrum obtained from a screening questionnaire and from a full diagnostic interview is unclear,
however (Hirschfeld et al., 2001, 2003a,b; see Chapter 11).
The recent NCS-R found a lifetime prevalence of bipolar spectrum of 4.4 percent: 1.4 percent for bipolar-I, 1.6
percent for bipolar-II, and 1.4 percent for bipolar subthreshold (defined as those individuals who have euphoria
or irritability plus two other symptoms for 4 days or longer
with at least mild impairment and a history of major depression). Males were more likely to be diagnosed with
subthreshold bipolar disorder than were females (1.7 and
1.0 percent, respectively) (Kessler et al., 2006).
Bipolar spectrum is an ambiguous classification and
includes subtypes that are subtle and difficult to diagnose. There is general agreement, however, that bipolar
disorder encompasses a broad spectrum and that clinically
176
Clinical Studies
Country
United States
Italy
Hungary
United States
Germany
Israel
Switzerland
United States
United States
Brazil
United States
Italy
Age Range
(Years)
15+
1589
1864
1864
2060
2433
1935
18+
18+
18+
18+
14+
Diagnostic
Method
Time Period
DIS
DIS
CIDI
SADS-L
SADS-L
SADS-L
SPIKE
MDQ
DIS
CIDI
CIDI
MINI
Lifetime
Annual
Lifetime
Lifetime
Lifetime
6-month
Lifetime
Lifetime
Lifetime
Lifetime
Lifetime
Lifetime
Prevalence/100
3.3
3.4
5.1
3.0
6.5
2.6
5.5a
3.7
6.4
8.3
4.4
5.5
CIDI = Composite International Diagnostic Interview; DIS = Diagnostic Interview Schedule; MDQ = Mood Disorder Questionnaire; MINI = Mini
International Neuropsychiatric Interview; SADS-L = Schedule for Affective Disorders and Schizophrenia-Lifetime; SPIKE = Structured Psychopathological Interview and Rating of the Social Consequences of Psychiatric Disturbances for Epidemiology.
a
8.3 if brief hypomania is included.
177
Epidemiology
Country
(Year)
NCS,
unpublished
MECA,
unpublished
United States
(1992)
United States
(1992)
Lewinsohn
et al., 1995
Wittchen
et al., 1998
Western Oregon
(1987)
Bavaria, Germany
(1988)
Sample
Size
Age Range
(Years)
Diagnostic
Method
Diagnosis
Time
Period
1517
CIDI
BP-I
Lifetime
1.4
1,285
917
DISC
Mania
Hypomania
6-month
6-month
1.2
0.6
1,709
1418
KSADS/LIFE
BP
Lifetime
1.0
3,021
1424
CIDI
BP-I
Annual
Lifetime
Annual
Lifetime
1.4
0.4
0.4
0.4
1-month
1-month
1-month
0.2
0.5
0.2
468
BP-II
Aalto-Setl
et al., 2001
Helsinki, Finland
(2000)
647
Follow-up of high
school students, 2024
SCAN
BP-I
BP-II
BP-NOS
Prevalence/
100
178
Clinical Studies
Table 514. The 10 Leading Causes of Death in Adults Ages 1559, by Broad Income Group, 2001
LOW- AND MIDDLE-INCOME COUNTRIES
Cause
HIGH-INCOME COUNTRIES
Deaths
(millions)
Percentage of
total deaths
Cause
Deaths
(millions)
Percentage of
total deaths
HIV/AIDS
2.05
14.1
0.13
10.8
1.18
8.1
Self-inflicted injuries
0.09
7.2
Tuberculosis
1.03
7.1
0.08
6.9
0.73
5.0
Trachea, bronchus,
and lung cancers
0.08
6.8
Cerebrovascular disease
0.71
4.9
Cerebrovascular disease
0.05
4.4
Self-inflicted injuries
0.58
4.0
0.05
4.4
Violence
0.45
3.1
Breast cancer
0.05
4.0
0.33
2.3
0.04
3.1
0.32
2.2
Diabetes mellitus
0.03
2.1
10
Chronic obstructive
pulmonary disease
0.32
2.2
10
Stomach cancer
0.02
2.0
180
Clinical Studies
Table 515. The 10 Leading Causes of Disability (Years Lived with Disability) by Broad Income Group, 2001
LOW- AND MIDDLE-INCOME COUNTRIES
Cause
HIGH-INCOME COUNTRIES
YLD
(millions
of years)
Percentage of
total
YLD
Cause
YLD
(millions
of years)
Percentage of
total
YLD
8.39
11.8
Unipolar depressive
disorders
43.22
9.1
Unipolar depressive
disorders
Cataracts
28.15
5.9
6.33
8.9
24.61
5.2
5.39
7.6
15.36
3.2
3.77
5.3
Osteoarthritis
13.65
2.9
Osteoarthritis
3.77
5.3
Perinatal conditions
13.52
2.8
Cerebrovascular disease
3.46
4.9
Cerebrovascular disease
11.10
2.3
Chronic obstructive
pulmonary disease
2.86
4.0
Schizophrenia
9
10
10.15
2.1
Diabetes mellitus
2.25
3.2
9.81
2.1
Endocrine disorders
1.68
2.4
Protein-energy
malnutrition
9.34
2.0
10
Vision disorders,
age-related
1.53
2.1
In a study from Victoria, Australia, rates of bipolar disorder were estimated from published studies by applying
the Dutch disability weights (Vos and Mathers, 2000). The
DALYs rates for depression were 7.7 for females and 5.3 for
males, and those for bipolar disorder were 1.3 for females
and 1.4 for males. These rates were lower than those for
the established market economies in the WHO studyfor
depression, 10.7 for females and 6.0 for males, and for
bipolar disorder, 2.1 for females and 2.2 for males. The
burden of major depression was found to be higher for females than for males, but that of bipolar disorder did not
differ by gender (Vos and Mathers, 2000), as determined
from the gender ratios in the tables presented earlier.
Psychiatric disorders are expected to represent a greater
global share of the disability burden than cardiovascular
disease by 2020 (Murray and Lopez, 2000). Indeed, the results of the World Bank Development Study and the Murray and Lopez report caught the attention of the administration of WHO and helped spur the initiation of the World
Mental Health Study, 2000, which is described next.
Epidemiology
ASSOCIATED FEATURES
In this section, we summarize what is known about the
correlates of bipolar disorder. These variables are often
called risk factors, but to avoid possible causal implications, we use instead the term associated features. Some
of this information has been presented earlier (e.g., in our
review of cross-national studies or variation in rates by
marital status or age), and some is discussed in detail in
other chapters. Here we summarize that material, along
with other information available from analytical epidemiologic studies. Analysis of data on associated features from
community surveys is problematic except for such broad
factors as age and gender because large samples are necessary for a disorder of relatively low prevalence. Therefore,
few community-based epidemiologic studies of bipolar
disorder are able to examine associated features beyond
age, age at onset, and gender.
Temporal Variations
Gershon and colleagues (1987) observed birth cohort
changes in mania among relatives of bipolar and schizoaffective patients. Using life table analysis, they found higher
rates of bipolar disorder among those cohorts born after
the 1940s, suggesting that the cumulative hazard for the
disorder in a given age group is greater in those born after
that decade. Gershon and colleagues (1987) concluded that
cohorts with the highest rates of affective illness appear to
have been born in the decades after World War II (these
findings are the same for bipolar and major depressive disorders).
Somewhat similar findings were derived independently
in the ECA (Lasch et al., 1990). Respondents were divided
into eight birth cohorts, each spanning a 10-year interval.
Actuarial life table analysis showed variations in the risk of
mania by birth cohort, with the greatest risk seen among
the post-1935 cohorts.
Various explanations have been proposed to account for
these results (Klerman and Weissman, 1989). The temporal
variations noted could be due to differential mortality
181
Gender
Mood disorders as a group are consistently more prevalent
among women than men, but the difference is due to the
higher prevalence of unipolar major depression in women.
When only subjects with bipolar disorder are considered,
nearly equal gender ratios have been found across most but
not all national and cross-national studies, as reported earlier. Variations in one direction or another are likely due to
the instability of small samples.
Social Class
In the first edition of this text, we reviewed more than 30
early studies of the association between social class and
manic-depressive illness published between 1913 and 1989.
We discussed in detail the considerable methodological
problems involved in virtually every one of the studies but
were impressed, nonetheless, by the overall association between bipolar illness and one or more measures reflecting
upper social class.10 The complexities are many, of course.
We discuss in Chapter 12 the possible links among creativity, educational and occupational achievement, and certain
behavioral, temperamental, cognitive, and behavioral characteristics associated with bipolar illness. Education and
occupational achievement are, of course, associated with
higher social class. It is also possible that characteristics associated with mild manic states, such as increased energy,
risk-taking sexual drive, productivity, and social outgoingness, make some individuals more attractive and therefore,
on occasion, more likely to marry into a higher social class.
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Clinical Studies
More recent epidemiologic data show an equal distribution of the disorder among all social classes and educational levels. While bipolar illness in a small minority of
patients may facilitate achievement and may aid the creative process (see Chapter 12), it is likely that most of the
earlier association between bipolar disorder and higher social class had to do with diagnostic practices and inaccuracies in the concept. Upper- and middle-class people were
more likely to be diagnosed as bipolar, whereas lower-class
individuals, especially the urban poor, were (and still are)
more likely to be diagnosed as schizophrenic (often mistakenly so) and consequently treated as such. Criteria for
social class also varied widely across studies. Nonetheless,
these investigations remain interesting for their span over
many decades, their historical significance, and their great
range across countries and cultures.
Most newer studies have failed to find a significantly
lower than expected rate of bipolar disorder associated with
indices of upper social class (educational status, occupation,
economic status, or parental social class). In both the ECA
and the NCS, lower educational level was not found to be
associated with an increased risk of bipolar disorder. The
NCS found an association between rates of bipolar illness
and lower family income; it is unclear, however, whether the
latter is a direct consequence of the illness or a trigger for its
onset. Abood and colleagues (2002) examined 90 patients
with bipolar-I disorder from a publicly financed service in
Dublin to assess the association of the disorder with social
advantage. Although not a representative sample, when compared with other psychiatric patients, excluding those with
schizophrenia, the bipolar patients had similar demographic
and socioeconomic characteristics (including more frequent
residential moves).
On the other hand, a sample of 130 patients meeting
DSM-III-R criteria for bipolar disorder and depression
were compared on their and their relatives occupational
levels (Verdoux and Bourgeois, 1995). Occupational level
did not differ significantly between unipolar and bipolar
probands, although higher levels predominated among
bipolar probands brothers and children. A comparison of
entire groups including probands and all their relatives
revealed a social advantage for the relatives of bipolar patients. These results are consistent with the downwarddrift hypothesis of bipolar disorder, which suggests that if
there is any social advantage among bipolar patients, it
may be reflected in the higher social class of their relatives.
The devastation of the illness may erase these advantages
and result in the association between the disorder and lower
income seen in the NCS or the increased rates among the
homeless discussed later. Consistent with this hypothesis is
a recent study (Tsuchiya et al., 2004) finding that higher
Epidemiology
Marital Status
Epidemiologic studies investigating marital status among
bipolar patients have revealed that the disorder is slightly
more common among single and divorced persons. The
ECA revealed that individuals who are separated or divorced
are more likely to suffer from bipolar disorder as compared
with married or never-married individuals (see Table 57).
In a Hungarian national survey (Szadoczky et al., 1998), bipolar disorder was found to be more frequent among those who
were separated and divorced. The rate among those never
married was high as well. Early onset of the illness may contribute to the latter phenomenon, negatively influencing personality development and thus causing difficulties in establishing and maintaining interpersonal connections.
As Krauthammer and Klerman (1979) pointed out,
marital status may change as a result of the disorder, rather
than leading to its onset. On the other hand, it is plausible
that being single or divorced constitutes a risk for bipolar
illness in some populations; it is also plausible, indeed likely,
that stressful marriages may precipitate affective episodes
and, conversely, that supportive marriages may have a protective effect.
While persons with bipolar disorder are more likely
than those in the general population to be single, divorced,
or in a disrupted marriage, we know of no evidence to
support a causal relationship between the disorder and
marital status. The establishment of such a link is hampered by small sample sizes and a lack of clarity as to the
direction of causality in studies addressing the question.
Therefore, although it is likely that symptoms of untreated
mania are disruptive to forming or sustaining intimate relationships, this hypothesis is not supported empirically.
(See Chapter 10 for further discussion of the effect of bipolar disorder on interpersonal relationships.)
Urban/Rural Comparisons
No urban/rural differences in rates of bipolar disorder
were found in the ECA or the NCS. In Taiwan, the lifetime
prevalence was higher in metropolitan Taipei (1.6 percent)
than in small towns (0.7 percent) and rural villages (1.0
183
184
Clinical Studies
other note regarding prevalence rates within this population is that substance abuse can easily coexist with or mask
other underlying mental disorders, especially affective disorders. Therefore, these already high rates of bipolar disorder may be underestimates.
A more recent study of 1,022 homeless men living in shelters or on the street in Munich, Germany, using the SCID,
also revealed high rates of mood disorders (lifetime prevalence of 32.8 percent for any mood disorder and of 5.2 percent for bipolar disorder). The highest rate was found for
substance abuse (79.6 percent), particularly alcohol dependence (72.7 percent) (Fichter et al., 2001). A lifetime rate of
bipolar disorder (3.6 percent), based on the CIDI, was found
among 838 homeless men and women in a study conducted
in Paris in 1996 (Kovess and Lazarus, 1999). Comparable
studies in other European countries did not report bipolar
disorder separately from other mood disorders (Vzquez
et al., 1997; Muoz et al., 1998; Babidge et al., 2002).
Some studies have oversampled the incarcerated
(Buhrich et al., 2000) and the institutionalized (Robins
and Regier, 1991). These groups were found to have higher
rates of bipolar disorder than the general population. For
example, Blazer (1985) found a lifetime prevalence of 5.4
percent for those living in prisons and 9.7 percent for those
living in nursing homes. Yet the studies showed that the inclusion of these populations added only a small fraction
(1.0 percent) to the estimated percentage of the general
population having a mental disorder. Therefore, their inclusion or exclusion has little effect on community rates.
Smoking
Bipolar disorder is associated with increased risk of smoking. A case-control study carried out in Alava, Spain, in-
Epidemiology
Family History
There is strong agreement that bipolar disorder is heritable. While family studies cannot determine heritability,
one of the strongest predictors of first onset of bipolar illness is a family history of the disorder. Unfortunately, family history is excluded from epidemiologic studies, mainly
because collecting accurate information on family history
is time-consuming.
As detailed in Chapter 13, the morbid risk for bipolar
disorder among first-degree relatives of bipolar probands
is elevated substantially over the risk in the general population. Furthermore, adoption studies have shown that the
monozygotic-to-dizygotic concordance ratio is higher for
bipolar disorder than for unipolar depression, indicating
greater genetic involvement in the former condition. A number of genetic linkage and association studies are under way
to determine the genes involved.
CONCLUSIONS
In its calculations of rates of disability, WHO has ranked
bipolar disorder among the top 10 disabling disorders in
both developed and developing countries. It is not easy to
summarize the results of epidemiologic studies of bipolar
disorder from around the world, especially in light of a
number of methodological problems. Nonetheless, it is
possible to derive reasonable estimates of the prevalence
and incidence of the disorder.
Findings of recent studies generally indicate an overall
lifetime prevalence of bipolar-I disorder of about 1 percent.
The range of rates is not great, even from diverse countries.
In the United States, Europe, Scandinavia, the South Pacific, South America, and the United Kingdom, the lifetime
prevalence of bipolar-I disorder ranges from 0.2 percent
(Iceland) to 2.0 percent (the Netherlands and Hungary).
Most rates are around 1 to 1.5 percent. The exceptions are
Iceland (0.2 percent) and three Asian countries with lifetime rates of 0.015 to 0.3 percent. The reasons for the
markedly low Asian rates, which are also low for a number
of other mental disorders, are unclear. Studies of Asians
living outside the continent are needed to determine
whether these low rates are related to genetic differences, to
living in Asian countries, or to ascertainment factors.
Studies that include a broad bipolar spectrum produce much higher lifetime prevalence rates of 3.0 to 8.3
percent. While there have been efforts to determine the
rates of bipolar-II and milder forms of bipolar disorder
185
in community surveys, it is difficult to distinguish between normal moods and mild hypomania in nonpatient
populations, making the validity of these findings questionable. Moreover, all of these rates for bipolar spectrum
may be underestimates because they do not include patients
with highly recurrent major depression, some of whom
may fall within the bipolar spectrum (see Chapter 1).11
Several features associated with bipolar disorder have
been studied. Most studies with large sample sizes have
not shown strong differences in rates of bipolar disorder
by gender. Persons who are separated or divorced have
higher rates of the disorder than their married counterparts. Differences by social class and racial group have
been less well studied. Smoking is more prevalent among
those with bipolar disorder than among the general population. And pregnancy and menopause represent vulnerable periods for women in the development of manic
episodes.
A family history of bipolar disorder in first-degree relatives remains the strongest predictor of risk of onset of
bipolar disorder. However, it is also a risk factor not usually included in epidemiologic surveys.
NOTES
1. Cowley and Wyatt, 1993; World Bank, 1993a,b; Murray and
Lopez, 1996.
2. In the ECA and the NCS, the diagnostic interviews (the DIS
and the UM-CIDI, respectively) contained questions designed to determine the clinical significance of each symptom involved in the disorder (Narrow et al., 2002). Questions
in the two surveys were similar, and information was obtained as to whether the symptom was severe enough to require telling a doctor or any professional about it, to take
medicine for it, and/or to interfere with usual activities.
Symptoms failing to meet any of these criteria were not identified as clinically significant and did not count toward making
the diagnosis. The ECA used this approach for most disorders.
However, neither the ECA nor the NCS applied these criteria
at the symptom level for major depression or bipolar disorder. In both cases, questions about clinical significance were
asked only after all symptoms had been obtained and diagnostic criteria met. Applying clinical significance criteria at
the symptom level and not at the end of the diagnostic stage
reduced the overall rates of mental disorders in both surveys.
The impact was greater in the NCS, and the disparity in rates
between the ECA and the NCS was reduced, with an estimated 18.5 percent annual rate of any disorder.
Applying the clinical significance criteria in the ECA reduced the annual rate of unipolar depression by about 18
percent and that of bipolar disorder by 44 percent (see Table
51) (Narrow et al., 2002). The rate of unipolar major depression was reduced to 4.0 percent, compared with 4.9 percent
without the clinical significance criteria. The clinical significance criteria had a greater effect on major depression prevalence rates in the NCS than on those in the ECA, drawing the
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Clinical Studies
3.
4.
5.
6.
7.
8.
9.
10.
11.
ECA and the NCS. The annual rate of bipolar-I for the first
wave of the ECA using these conventions was 0.9 percent;
adding cases from the second wave produced a rate of 1.0
percent. The annual rate in the NCS was 1.1 percent with
these conventions.
That such modifications can reduce or increase disparate
rates concerns health policy planners and insurers, who base
the direct costs of service delivery for a disorder on its prevalence rate. The WHO initiative to revise the CIDI by including impairment criteria for each disorder is addressing this
issue (Regier and Burke, 2000). However, there is still no
fully satisfactory method of calculating the actual rates.
Simpson et al., 1993; Benazzi, 1997; Koukopoulos and
Koukopoulos, 1999; Dilsaver and Akiskal, 2005; Rybakowski
et al, 2005; Sharma et al., 2005.
Dilling and Weyerer, 1984; Henderson et al., 2000; Murphy
et al., 2000; World Health Organization International Consortium of Psychiatric Epidemiology, 2000.
Scully et al., 2000, 2002a,b; Baldwin et al., 2002.
Angst, 1978; Dunner et al., 1982; Akiskal et al., 2000; Cassano
et al., 2000; Angst et al., 2002.
Research on minors often makes a distinction by pubertal
status. Puberty has been shown to differentiate the onset and
clinical course of mood disorders in longitudinal and epidemiologic studies (Angold et al., 1998, 1999; Weissman
et al., 1999a,b). The rates and gender ratios of depression
change dramatically at puberty, with a marked increase occurring in overall rates, especially among females. Some
studies separate prepubertal children from adolescents, others focus on one or the other, and still others merge the two.
Most studies use chronological age to designate pubertal status; a few use Tanner staging (see Angold et al., 1998, 1999).
We recognize the importance of these age distinctions and
make them where the necessary data are available. In the absence of such data or the need to make an age-specific point,
however, we use the term children to describe minors.
Strober et al., 1993; Lewinsohn et al., 1995; Rao et al., 1995;
Geller et al., 1998.
More information on the ICPE can be obtained from http://
www.hcp.med.harvard.edu/icpe/.
For example, Hollingshead and Redlich, 1958; Parker et al.,
1959; Rao, 1966; Hare, 1968; Rowitz and Levy, 1968; Bagley,
1973; Gershon and Liebowitz, 1975; Petterson, 1977; Coryell
et al., 1989.
Indeed, Kraepelins manic-depressive illness included both
bipolar and highly recurrent unipolar subgroups.
In rare cases the first beginnings can be traced back even to before the tenth year. . . . The greatest frequency of first attacks falls, however, in the period of development with its increased emotional excitability between the fifteenth and the twentieth year.
Emil Kraepelin (1921, p. 167)
high-risk subjects that have attempted to identify characteristics of children of bipolar parents, with particular emphasis on early markers of potential bipolar illness. Unfortunately, many unresolved issues remain. The interest in
manifestations of bipolar disorder among children and
young adolescents is far greater than the yield from research addressing the key questions involved.
Throughout the discussion, we attempt to identify problems with the methods used in existing studies, as well as research needed to address important issues. One of the
most pervasive difficulties stems from the failure of many
studies to distinguish between childhood- and adolescentonset bipolar disorder; this occurs, for example, when
vague terms such as juvenile-onset bipolar disorder and
pediatric bipolar disorder are used or when child and adolescent samples are combined in the same study. This is a
widespread problem in the study of adolescent bipolar disorder, where distinctions are seldom made between childhood and adolescent onset. Some studies of adolescents with
bipolar disorder include patients whose symptoms actually
first occurred before age 12 or before puberty. As detailed in
chapter 4, age at onset is also defined differently in various
studiesfor example, as age at first diagnosable symptoms
of mania or at first symptoms of any affective disorder, or as
age at first actual diagnosis of mania or depression by a
mental health professional. Studies have employed different
diagnostic criteria as well, and many have included clinical
populations with a mix of bipolar-I and other bipolar spectrum disorders, despite the fact that there is very little information specifically on bipolar-II disorder in children or
adolescents (see Chapter 3). Finally, one of the greatest
methodological gaps is the paucity of longitudinal studies of
either childhood or adolescent bipolar disorder. Such studies are essential to clarify diagnostic controversies and to
187
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Clinical Studies
with prepubertal and early-adolescent onset of bipolar disorder (mean age at onset 7.3 years), Geller and colleagues
(1998b, 2002c) found that five mania-specific symptoms
were especially likely to discriminate bipolar children from
children with ADHD or normal comparison groups: elation, grandiosity, flight of ideas/racing thoughts, decreased
need for sleep, and hypersexuality. Table 61 presents examples of manic symptoms in children compared with
normal characteristics of youngsters of similar age (Geller
et al., 2002b).
Geller and colleagues (2002c) also found that 60 percent of their sample had symptoms of psychosis, including 50 percent who had grandiose delusions. In a later
follow-up study, they found that psychosis predicted
more weeks ill with mania or hypomania (Geller et al.,
2004). In their review of psychotic symptoms in pediatric
bipolar disorder, Pavuluri and colleagues (2004) found
that the prevalence of psychotic features ranged from 16
to 88 percent; most common were mood-congruent delusions, especially of the grandiose type. Biederman and
colleagues (2004c) found that nearly 1 in 4 of the 298
bipolar patients they studied were psychotic or had a history of psychosis. Likewise, in their study of 263 bipolar
children and adolescents, Birmaher and colleagues (2005b)
found that one-third (33.1 percent) of their subjects had a
history of psychosis.
Geller and colleagues required elation and/or
grandiosity for the diagnosis of mania in children, as did
Leibenluft and colleagues (2003a). This is an important, if
still preliminary, consensus of clinical researchers, although,
as Carlson (2005) pointed out, uncertainty remains about
what actually constitutes these two symptoms. Methods of
assessment vary widely, as do cultural expectations and
developmental factors, and all are likely to influence the
ascertainment of both euphoria and grandiosity (Breslau,
1987; Shaffer, 2002; Harrington and Myatt, 2003). Some
studies have defined mania by the presence of highly labile moods with intense irritability, rage, explosiveness,
and destructiveness; extreme agitation; and behavioral
dysregulation (e.g., Biederman et al., 2000a). Irritability,
and indeed rage, are noted as prominent features in many
bipolar children (e.g., Faraone et al., 1997b; Carlson and
Kelly, 1998; Geller et al., 2002c). The children are often aggressive and frequently are described by their parents as
out of control. Not surprisingly, they are often seen in
hospital settings, and overall their functioning is marked
by severe impairment in social and academic as well as
family roles (Geller et al., 2000a). Box 61 presents a
mothers diary of the behaviors of her 9-year-old bipolar
son, conveying a sense of the severe but characteristic features of the disorder. Suicidal thoughts and behaviors are
not uncommon.
Elated Mood
Child was extremely happy on days family
went to Disneyland, on Christmas
morning, during grandparents visits
( joy appropriate to context, not
impairing).
Grandiosity
After school hours, 7-year-old boy played
at being a firefighter, directing other
firefighters and rescuing victims. Child
did not call fire station and tell
firefighters what to do.
Racing Thoughts
Normal children do not report racing
thoughts.
Source: Adapted from Geller et al., 2002a. Reprinted with permission from Mary Ann Liebert, Inc.
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Clinical Studies
BOX 61. Twelve Days in May: Diary of a Mother of a Nine-Year-Old Bipolar Child
5/11
5/12
5/13
5/14
5/15
5/16
5/17
5/18
5/19
5/20
5/21
5/22
Mixed, very irritable to hypomanicincrease in goaldirected activities, very easily frustrated and angered.
Good and uneventful day.
Very irritable in A.M.threatened fathersaid: Im going to kill you someday. Manic after schoolvery goaldirectedtaking all the tools out of the basement to
use up in his room (hammer, sander, drill, staple gun).
Very angry when I intervenedvery loud, shouting,
laughing, singing, dancing,I dont feel good today. I
want to kill myself. When I grow up, I am going to kill
myself because being bipolar is bad. Hallucinating in
afternoonauditory and visual; goblin, clown, queen. I
hear the devil, I hear penises in your brain, Mom. Very
hyperactive, and not rational. Gave him Risperdal and
he went to sleep.
Hypomanic, happy in the afternoon.
Woke up laughingfound some needlepoint yarn and
needles under the bed.Im giving myself a lab test
trying to stick needles into his arm. Giddy, shouting
hubba, hubba, hubba, howdy, howdy over and over
again, very wound up. Settled down and watched some
TV. Pleasant and more normal, but talkative in the afternoon. Easier to please. More irritable after dinner. Fascinated with knives, demonstrated how he would stab a
wolf. Very quiet in my lap. He said: I love you, Mom.You
dont love me, you want me to die. I will if you want
me to.
Source: Papolos and Papolos, 2002, pp. 2223. 2002 by Demitri Papolos and Janice Papolos. Used with permission of Broadway Books, a division
of Random House, Inc.
Depressive Features
For many individuals, bipolar disorder first emerges in the
form of depressive episodes in childhood (e.g., Geller et al.,
1994; Lish et al., 1994). Although depression in children
may be readily diagnosed using adult criteria, the majority
of such cases probably go undetected and untreated. Even
if they are detected, however, there is presently no certain
way of knowing the extent to which early-onset depression
presages childhood-onset bipolar disorder; the issue is
an important question not only clinically but for research
as well.
As noted previously, studies of bipolar illness have often
combined childhood- and adolescent-onset populations,
and longitudinal studies of the outcomes of depression
in children have been rare. Given that unipolar depression
in children is substantially more prevalent than mania
and is characterized by marked clinical and etiological
heterogeneity, it is difficult to identify predictors specific
Diagnostic Controversies
Despite general agreement that bipolar disorder can emerge
in childhood, several problems make it difficult to validate
some of the assertions made about diagnosis of bipolar
children. Three related issues are discussed here: comorbidity and indistinct diagnostic boundaries, the validity
and meaning of a diagnosis of mania, and the lack of developmental guidelines.
191
defiant disorder.2 Findings of the major studies of comorbidity in childhood-onset bipolar disorder are presented
in Table 62. As can be seen in the table, many clinical investigations have documented a high rate of comorbid
anxiety disorders as well.3 (There is some indication that
bipolar-II children and adolescents, like adults, are more
likely to have comorbid anxiety disorders than those with
bipolar-I disorder [Axelson et al., 2006].) Perhaps nothing
has fueled the controversy as much as the potentially confusing overlap of symptoms between mania and disruptive
behavioral disorders.
Many studies have shown that children with a bipolar
diagnosis have a high probability of being diagnosed with
ADHD. Geller and colleagues (2000a), for example, found
this to be the case in 98 percent of their sample (see also
Biederman et al., 2000a; Sachs et al., 2000; Spencer et al.,
2001). Considerably lower rates have been found by other
researchers, however (Masi et al., 2003; Faedda et al., 2004;
Jaideep et al., 2006). Some investigators have argued that
many children diagnosed with ADHD also have bipolar
disorder. Biederman and colleagues (1996) identified psychiatrically referred children with ADHD, who were then
assessed for the presence of mania at baseline and at 1 and
4 years later. Bipolar disorder was diagnosed in 11 percent
of the ADHD children at baseline and in an additional 12
percent at the 4-year follow-up. Arguing that a substantial
number of children diagnosed with ADHD may actually
have unrecognized bipolar disorder, Biederman fueled
a controversy that is still active (Wozniak et al., 1995;
Faraone et al., 1997b; Biederman, 1998). Many investigators
have also observed high rates of conduct disorder and oppositional defiant disorder (e.g., Biederman et al., 2000a;
Geller et al., 2000b; Wozniak et al., 2001), as well as substance abuse and anxiety disorders (e.g., Birmaher et al.,
2002), among bipolar children (see also reviews in Biederman et al., 2000a, and Papolos, 2003).
What is the meaning of the overlap between mania and
ADHD (or other disruptive behavior disorders)? There are
several different perspectives on this question. One general
argument is that the comorbidity is simply an artifact of
overlapping symptomatology. Three more specific arguments are that the ADHDmania overlap is (1) true comorbidity (coexistence of separate disorders), potentially
marking a genetically mediated subtype; (2) artifactual, reflecting severe psychopathology that is not specifically
bipolar; and (3) artifactual, possibly reflecting a developmental manifestation of bipolar disorder in children.
The general argument that bipolar comorbidity may be
a result of overlap of symptoms suggests that diagnostic
inaccuracies are caused by indistinct symptom boundaries, clinician bias, or biased diagnostic expectations due
to ascertainment source. Biederman and his colleagues at
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Clinical Studies
Assessment used
Mean age (yrs)
% Male
68
Outpatient
psychopharmacology
clinic
KSADS
7.9
78
60
Childrens inpatient
unit
93
Research study,
outpatient
KSADS
8.7
91
WASH-U KSADS
10.9
61
93
91/38
10
56
31
Not stated
Probably high
66
75/54
87
79
14
None
10
0
Average: 3 diagnoses
23 syndromal
Not stated
Not stated
Not stated
98 (4 diagnoses: 20.4)
Comorbidities
% ADHD
% ODD/CD
% OCD
Anxiety disorders
% substance abuse disorders
% psychosis
% no comorbidity
% With >1 diagnosis
ADHD = attention-deficit hyperactivity disorder; KSADS = Kiddie Schedule for Affective Disorders and Schizophrenia; OCD = obsessivecompulsive disorder; ODD/CD = oppositional defiant disorder/conduct disorder; WASH-U KSADS = Washington University at St. Louis
modification of KSADS.
Source: Updated from Geller et al., 1999. Reprinted with permission.
193
Percentage
70
Bipolar
ADHD
60
50
40
30
20
Distractibility
Hyperenergetic
Accelerated speech
Irritable mood
Increased productivity
Increased goal-directed
activity
Sharpened thinking
Hypersexuality
Racing thoughts
Flight of ideas
Silliness, laughing
Daredevil acts
Elated mood
Grandiosity
10
Mania items
Figure 61. Baseline percentage of mania items in bipolar versus ADHD groups. (Source: Geller et al., 1998a. Reprinted with permission
from Elsevier.)
although such symptoms may occur in children with bipolar disorder, each is also nonspecific. Precise diagnostic
definitions that can help separate truly bipolar manifestations from overlapping conditions are needed to avoid
misdiagnosis, as well as to facilitate recognition of bipolar
illness.
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Clinical Studies
pervasive developmental disorder, or other medical conditions. In the past, some of these children were labeled as
minimally brain damaged or hyperkinetic. Many of
these historical syndromes have been described in terms
that bear a marked resemblance to contemporary descriptions of childhood mania.
A related issue raised by Carlson and others is the possibility that mania or manic-like symptoms may occur as a
dimension of disorder or serve as a marker of severe psychopathology without necessarily indicating the presence
of a bipolar syndrome. Carlson and colleagues (1998) recruited a sample of boys aged 6 to 10 who had heterogeneous disruptive and/or depressive symptoms. The boys
mothers were asked about the presence of manic symptoms, and their responses led the researchers to distinguish
three groups: those boys with at least two manic symptoms, and two matched comparison groupsthose seen
immediately next in the series of interviews but without
manic symptoms, and those matched on the first groups
comorbid disruptive symptoms (conduct disorder, ADHD,
or oppositional defiant disorder) but without manic symptoms. The authors found that although the boys with
symptoms of mania differed significantly from the nonmanic next control group, most of those differences disappeared in a comparison with the group with comorbid
conditions. The presence of manic symptoms uniquely
predicted significant emotionality and generally predicted
more severe psychopathology (Carlson and Youngstrom,
2003). The investigators are continuing to study these children over time, attempting to determine whether some are
truly bipolar, while in others the manic-like symptoms
may serve mainly as markers for behavioral and emotional multimorbidity. Similarly, Hazell and colleagues
(2003) followed up boys aged 9 to 13 who met criteria
for ADHD plus mania. When the boys were reevaluated after 6 years, there were no clear cases of bipolar disorder
among those with prior manic symptoms; however, the
boys with earlier manic symptoms had lower overall global
functioning.
Geller and colleagues (2002) have reoperationalized
several of the DSM criteria (most notably euphoria and
grandiosity) to make them what the authors believe to be
developmentally appropriate for children. Not everyone
agrees with this reformulation, however (Harrington and
Myatt, 2003). In a recent cross-national (United States and
United Kingdom) study of five cases of children with
mood symptoms in whom bipolar disorder might have
been a diagnostic consideration, disagreement on diagnosis occurred in three of the five cases. The reason for this
appears to be differing interpretations of specific symptoms. DSMs reliance on symptom counts (used in the
United States) may result in a conceptualization that dif-
195
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Clinical Studies
Course of Disorder
Children diagnosed with bipolar disorder typically do not
display course features commonly associated with classic
bipolar disorder in adults, such as distinct mood episodes
that endure for days or weeks (often clearly manic or depressive) separated by periods of being relatively well. Instead, bipolar children frequently display mixed mood
states, extremely rapid cycling, and chronic psychopathology. The controversy over diagnostic criteria, including
duration of episodes in children with purported bipolar
disorder, is discussed further below.
Faraone and colleagues (1997b) found mixed states in 59
percent of children diagnosed with bipolar disorder, while
Geller and colleagues (2002a) reported a rate of 55 percent.
Gellers group (2002b) found that 87 percent of their sample had ultradian cycles (variation within a 24-hour period). Moreover, these children were chronically ill and
bipolar disorder is clinically similar to adult bipolar disorder. Until recently, however, relatively little research had
been conducted in adolescent populations.
Despite current awareness, adolescent bipolarity often
was not recognized as such in the past. Diagnostic errors
were common, reflecting biases of the time. These biases
included the above-noted reluctance to accept the existence of youthful onset of bipolar disorder and a common tendency to assume that psychotic symptoms such as
thought disorder, grandiosity, and bizarre delusional and
hallucinatory phenomena are pathognomonic of schizophrenia (Carlson and Goodwin, 1973). Additionally, morbid preoccupations, frenzied behavior, moodiness or rapid
mood swings, irritability, defiance, and a host of other disturbances were often regarded as exaggerations, if not typical manifestations, of adolescence. As discussed earlier,
moreover, even when recognized as clearly pathological,
disturbed behaviors in youths have been difficult to distinguish from alcohol and drug abuse disorders, conduct and
other disruptive behavior disorders, and personality disorders. These diagnostic challenges remain today.
In recent years, however, several factors have contributed to the increased recognition and accurate diagnosis of adolescent bipolar disorder. These factors include
greater awareness of the existence of severe mood pathology in adolescents, improved diagnostic criteria and interview methods for identifying depression and mania in
younger populations, and increased availability of effective pharmacological and psychotherapeutic treatments
for mood disorders. Increasingly, adult diagnostic criteria
are being applied reliably and effectively to the diagnosis of
bipolar disorder in adolescents. There is a general consensus that adolescent-onset bipolar disorder is a relatively
common presentation and that, as noted, it essentially resembles the disorder in adults.
197
Manic Features
Although the phenomenology of adolescent-onset mania
has been studied incompletely, existing research clearly
indicates a heterogeneity that may reflect different subgroups. Pooled data from several investigations of mania
in adolescents have revealed pressured speech, euphoria,
and hyperactivity to be the most common symptoms, similar to what has been found for adults (Faedda et al., 1995).
Lewinsohn and colleagues (1995) noted a much higher frequency of elevatedexpansive mood than irritability in
their community sample (which, however, consisted primarily of those with bipolar spectrum rather than bipolar-I
disorder). Faraone and colleagues (1997b), on the other
hand, found relatively high rates of irritability and low
rates of euphoria in their clinical sample of young manic
patients. Both the Lewinsohn and Faraone subjects reported high rates of increased activity, grandiosity, and
distractibility.
In an analysis of the symptoms of mania in 115 adolescents with manic or subsyndromal manic episodes, Lewinsohn and colleagues (1995) identified two factors: (1)
behavioral disorganization, consisting of decreased need
for sleep, flight of ideas, distractibility, and poor judgment;
and (2) inflated self-esteem and increased activity. The
198
Clinical Studies
Depressive Features
For a substantial number if not the majority of individuals
with adolescent-onset bipolar disorder, the illness starts
with depression, thereby delaying recognition and diagnosis of the bipolar course. Kutcher and colleagues (1998)
found that depressions were the first affective episodes in
75 percent of their sample of adolescents with bipolar-I
disorder. Likewise, a community sample of adolescents
with bipolar spectrum disorders revealed that 61 percent
had experienced an initial depressive episode before mania or hypomania occurred (Lewinsohn et al., 1995). And
among those who responded to a volunteer survey of members of the National Depressive and Manic-Depressive Association (now called the Depression and Bipolar Support
Alliance), both early age at onset (childhood or adolescence) and female gender were associated with higher rates
of initial depressive symptoms or both depressive and
manic symptoms (Lish et al., 1994). The studies of Kutcher
and colleagues (1998) and Lewinsohn and colleagues (1995)
did not evaluate initial symptom presentation by gender
status.
The switch rate of adolescent major depression to eventual mania or hypomania is quite variable across studies.
Interpretation of this variation is complicated by the
above-noted common practice of mixing children and
adolescents in the same study samples. For instance, in a
review of seven studies of more than 250 depressed children and adolescents followed for 2 to 4 years, Faedda and
colleagues (1995) found a mean rate of switch from depression to eventual mania of about 25 percent. A review by
Kovacs (1996) yielded a switch range of 8 to 37 percent; her
own longitudinal study of 92 depressed children followed
for 5 to 10 years yielded a rate of 21 percent. More recently, Birmaher and colleagues (2006) conducted a 2-year
prospective study of 263 children and adolescents (mean
199
Depressive symptoms in adolescents with bipolar disorder tend to be quite similar to those seen in adults, although
psychotic features are more common in the younger age
group (Carlson and Strober, 1979; Chambers et al., 1982;
Friedman et al., 1983). Preoccupation with death and
thoughts of suicide are common, and suicide attempts are
frequent (see Box 62 for one 15-year-old bipolar girls
account of her experience during a suicidal depression).
Lewinsohn and colleagues (2003), for example, found that
44 percent of the bipolar adolescents in their sample had attempted suicide; in comparison, 22 percent of the adolescents with major depression had attempted suicide, as had
18 percent of those with subsyndromal bipolar disorder
syndrome (defined by the investigators as abnormally and
persistently elevated, expansive, or irritable mood plus one
other DSM-III-R manic symptom, but never having met
criteria for full bipolar disorder).
Course of Disorder
Longitudinal studies of youths with bipolar-I disorder are
rare; therefore, most data on the course of the illness come
from retrospective accounts or short-term treatment outcome studies (e.g., Kafantaris et al., 1998; Kutcher et al.,
1998). The latter studies certainly document the likelihood
of further episodes and hospitalizations, but more information is needed to clarify the predictors of relatively better or worse outcomes and responsiveness to treatment
in patients with adolescent onset.
Strober and colleagues (1995) conducted one of the few
longitudinal studies, a 5-year naturalistic follow-up of 54
adolescents (mean age 16.0) who had been inpatients diagnosed with bipolar-I disorder (although age at first diagnosable episode was not reported). The rate of recovery from
the index episode was high (96 percent), with only 2 of the
patients failing to achieve recovery during the 5-year period.
However, time to recovery was affected by the polarity of
the index episode: median time to recovery was significantly longer for those who had pure depressive episodes
(26 weeks) compared with those who had pure manic (9
weeks) or mixed (11 weeks) episodes. The majority (56 percent) of those who recovered remained free of major relapses
during the follow-up period, and the probability of relapse
did not vary by polarity of the index episode (although
among those who had multiple relapses, most had mixed or
cycling index episodes). Suicide attempts sufficient to require
medical attention occurred in 20 percent of the adolescents
during the 5-year follow-up (Strober et al., 1995). None of the
clinical or demographic factors that were evaluated in the
study significantly predicted relapse, and all participants
were treated aggressively. Thus it is important to note that
the information on course derived from this study cannot be
generalized to untreated bipolar disorder in adolescents.
200
Clinical Studies
A 2-year prospective study of adolescent-onset psychotic disorders by McClellan and colleagues (1999) included a comparison of a small group of bipolar youths
with patients who had schizophrenia. The results indicated
that 50 percent of the bipolar youths had an episodic
course, and 40 percent were chronically impaired (but
fared significantly better than the schizophrenic youths).
Rajeev and colleagues (2003) observed adolescent-onset
patients with bipolar mania for 6 months; like Strober and
colleagues (1995), but unlike McClellan and colleagues
(1999), they found 96 percent recovery and very little
chronicity. Recently, researchers at the University of Pittsburgh, Brown University, and the University of CaliforniaLos Angeles conducted a longitudinal study of 263 bipolar children and adolescents (13.0 3.1 years old); they
interviewed their subjects on average every 35 weeks for
94.8 51.5 weeks using the Longitudinal Interval Follow-up
Evaluation. Although two thirds of the subjects recovered
from the index episode, 50 percent had at least one syndromal recurrence (Birmaher et al., 2005b). Subjects were
symptomatic for the majority (60 percent) of the follow-up
period; almost one quarter (22 percent) of the time was
spent in full syndromal episodes.
Additional research is needed on predictors of treatment responsiveness in bipolar adolescents (see Chapter
23). Moreover, given the potential for misdiagnosis of
bipolar disorder in youths, further studies of the potentially adverse effects of antidepressant medications and
stimulants used to treat ADHD are warranted (e.g., Soutullo
et al., 2002).
201
202
Clinical Studies
Comorbidity
Comorbidity complicates the diagnostic and clinical picture of adolescent-onset bipolar disorder, as it does for
childhood-onset illness. Tables 63 and 64, respectively,
display the results of the major studies of comorbidity
among adolescent-onset and combined samples of adolescent- and child-onset bipolar subjects. Nowhere is the
question of the meaning of comorbidity more complex than
with adolescent-onset bipolar disorder, because the cooccurrence of psychiatric syndromes can be due to several
factors. There are, for example, indistinct diagnostic boundaries and overlapping symptoms. Irritability, impulsivity, and
excessive activity, for instance, are symptoms shared by bipolar and other syndromes. Moreover, there is a causal relationship between bipolar illness and other disorders, in that
symptoms of mania or depression may lead to substance or
alcohol abuse. (Likewise, substance abuse can precipitate
mood disorders.) Too, there are shared genetic or other risk
factors, such as parental assortative mating, and similar or related genes may be implicated in both ADHD and bipolar
disorder. Considerable research, including carefully designed longitudinal studies, is needed to help clarify the
meaning of comorbid conditions in those with childhoodand adolescent-onset bipolar disorder.
Comorbid conditions that commonly complicate differential diagnosis include drug or alcohol abuse, conduct
disorder, and ADHD, all of which may involve manic-like
symptoms of irritability, disruptiveness, hostility, impulsiveness, distractibility, antisocial behaviors, and the like.
Psychotic symptoms may be mistaken for schizophrenia,
and drug and alcohol abuse may obscure and complicate
the diagnosis of mania, depression, or mixed states.
Comorbidity with personality disorders may also complicate the diagnosis of bipolar disorder in adolescents.
Although relatively few studies of Axis II disorders in
bipolar youths have been conducted, this important topic
should be pursued because personality pathology not
only makes differential diagnosis potentially difficult; it
also affects the interpretation of studies of course and
treatment outcome. A small study by Kutcher and colleagues (1990), for example, revealed a rate of 15 percent
for borderline personality disorder among euthymic bipolar adolescents, and the presence of that disorder predicted worse responsiveness to lithium. Mood instability,
impulsiveness, an inclination to suicide, irritability, and
other characteristics of borderline personality disorder represent a conceptual challenge in determining the boundary
between severe mood disorder and personality pathology.
Such issues are pursued in greater detail in Chapter 10. It
Assessment used
Mean age (yrs)
% male
17
Outpatient
psychopharmacology
clinic
KSADS
15.8
65
28
Adolescent inpatient
treatment
59
71/35
38
59
35
35
Not stated
Probably high
21
KSADS
15.8
44
Comorbidities
% ADHD
% ODD/CD
% OCD
% anxiety disorders
% substance abuse disorders
% psychosis
% no comorbidity
% With >1 diagnosis
33
Specifically excluded
48
31
Not stated
ADHD = attention-deficit hyperactivity disorder; KSADS = Kiddie Schedule for Affective Disorders
and Schizophrenia; OCD = obsessive-compulsive disorder; ODD/CD = oppositional defiant disorder/
conduct disorder.
Source: Updated from Geller et al., 1999. Reprinted with permission.
203
Sample size
Source of sample
Assessment used
Mean age (yrs)
% Male
42
Outpatient treatment study
KSADS
11
62
23
Outpatient olanzapine trial
KSADS
10.2
57
71
38/7
Not stated
17
2
Not stated
Not stated
78
100/35
35
57
Not stated
44
Not stated
Comorbidities
% ADHD
% ODD/CD
% OCD
% anxiety disorders
% substance abuse disorders
% psychosis
% no comorbidity
ADHD = attention-deficit hyperactivity disorder; KSADS = Kiddie Schedule for Affective Disorders and Schizophrenia; OCD = obsessivecompulsive disorder; ODD/CD = oppositional defiant disorder/conduct disorder.
is likely that mood instability and cognitive and behavioral dysfunction due to bipolar disorder in childhood
and adolescence contribute to the development of personality pathology.
Studies vary in the rates of comorbid diagnosis reported among individuals with adolescent-onset bipolar
disorder. Lewinsohn and colleagues (1995, 2003) found high
rates of comorbid anxiety disorders (33 percent), substance
abuse, and disruptive behavior disorders (22 percent each),
as well as ADHD (11 percent), in their community sample
of youths with bipolar spectrum disorders. Kutcher and
colleagues (1998) found that 61 percent of their adolescentonset sample had no psychiatric diagnoses other than
mood disorders; among those who did, generalized anxiety disorder (21 percent), ADHD (11 percent), and conduct
disorder (11 percent) were observed most frequently. Findling and colleagues (2001) also observed high levels of comorbidity (76 percent overall, including 62 percent with
ADHD) among adolescents with bipolar-I disorder (many
of whom, however, probably had had childhood onset).
ADHD as a comorbid condition is of particular interest, as
discussed earlier, because of the problem of differential diagnosis, markedly different treatment strategies, and the
possibility that comorbid ADHD may identify a genetic
subtype and predict a worse course and poorer response to
lithium (e.g., Strober et al., 1998).
A recent European study of 98 consecutively referred
bipolar children and adolescents found that 38 percent
204
Clinical Studies
the frequent onset of bipolar disorder in adolescence, apparently after pubertal changes.
A neurodevelopmental emphasis has emerged in the
field of schizophrenia (e.g., Lenzenweger and Dworkin,
1998), helping to identify early markers of neurocognitive
impairment that are predictive of eventual schizophrenia,
as well as to generate etiological models pertinent to abnormal brain development. Benes (1999) and others have
noted the significance of puberty for the development of
neural circuits that are relevant to mental disorders.
Walker (2002), for example, explored the role played by
hormones in neuromaturation, speculating that vulnerability to mental disorders such as schizophrenia, severe depression, and bipolar illness is mediated in part by the effects of hormones on gene expression. Further research on
the development of the brain and on the role of pubertal
changes in neurodevelopmental processes might help clarify whether pubertal effects are indeed significant in triggering underlying vulnerabilities to bipolar disorder.
A small body of research has begun to emerge on the
neurocognitive, neuroanatomic, and neurochemical correlates of bipolar disorder in adolescents (e.g., Davanzo
et al., 2003; DelBello et al., 2004; see also Chapters 9, 14,
and 15). Sigurdsson and colleagues (1999), for example, reviewed chart notes for a sample of bipolar adolescents and
found significantly greater evidence of delays in linguistic,
social, and motor development among bipolar youths
compared with those with early-onset unipolar depression, and especially among those who developed psychotic
symptoms. Although the neurodevelopmental differences
were relatively general and nonspecific, these findings are
compatible with the hypothesis that such impairments
are indicators of neurocognitive vulnerability factors for
bipolar disorder. A growing literature suggests that bipolar
youths are more likely than controls to demonstrate impairment on a wide variety of neuropsychological measures, including executive functioning, sustained attention,
and working memory (Dickstein et al., 2004; Meyer et al.,
2004; Doyle et al., 2005). These deficits, in turn, contribute
to substantial academic difficulties (Pavuluri et al., 2006).
There is accumulating evidence that comorbid ADHD significantly contributes to the cognitive deficits (McClure
et al., 2005; Rucklidge, 2006).
In related work, Friedman and colleagues (1999) conducted a magnetic resonance imaging (MRI) study of adolescent bipolar and schizophrenic patients compared with
non-ill youths. They found few differences among the patient groups, but the schizophrenic and bipolar youths differed significantly from normal controls on various measures, including reduced intracranial volume and increased
frontal sulcal prominence, among others. These results are
consistent with neurodevelopmental abnormalities and
matters, such as age-related changes in awareness and memory, temporal changes in morbidity and sample availability, and diagnostic practices (see Chapter 5).
At the same time, it has been argued that changes in
health practices and environmental factors may induce
earlier expression of bipolar disorderor actual increased
rates of bipolarity. Such factors may include widespread
and increased use of stimulant and antidepressant medications (e.g., Zito et al., 2002) that could trigger bipolar
rapid-cycling patterns in susceptible children or decrease
the age at onset (DelBello et al., 2001); alcohol and drug
use at younger ages, possibly inducing earlier onset of
bipolar symptomatology; earlier onset of puberty; and exposure to maternal health risks during pregnancy (e.g.,
smoking, drug and alcohol intake, dietary reductions in
omega-3 fatty acids, social stressors). Also, as noted in
Chapter 13, genetic anticipation effects may promote earlier onset. These issues are clearly important, with critical
implications for etiology and treatment, and require further study.
IMPLICATIONS OF CHILDHOOD
AND ADOLESCENT ONSET
OF BIPOLAR DISORDER
Other chapters in this volume address some of the implications of the onset of bipolar disorder in childhood and early
adolescence, including effects of age at onset on course
(Chapter 4), epidemiology and the possibility of cohort
changes in age at onset (Chapter 5), genetic implications
of early onset (Chapter 13), and treatment considerations
(Chapter 23). A few important issues merit emphasis here,
however, including the implications of childhood and adolescent onset for treatment and prevention.
Clinical Implications
Even apart from the goal of validating the diagnostic features of childhood bipolar disorder, it is important to
study whether the outcomes and features of childhoodonset cases of the disorder differ from those of adolescentand adult-onset cases. If, as discussed earlier, childhood
onset reflects a particularly virulent form of the disorder,
then relatively chronic symptomatology, mixed-state
episodes, and rapid cycling might be expected to continue.
It is possible, however, that such atypical features reflect
developmental manifestations of nonspecific severe dysregulation, with maturity revealing a more recognizable
episodic course with relatively better interepisode functioning. To answer this question, relevant longitudinal
studies would need to separate out the effects on course
and functioning that are due to comorbid childhood
psychopathologyand indeed, to determine whether such
205
206
Clinical Studies
for example, Post, 2006, and Chapter 4). If this were in fact
the case, vigorous early intervention with mood-stabilizing
drugs to prevent episodes would have critical and positive
implications for long-term outcome. The successful use of
such interventions would then depend on research aimed
at identifying the earliest valid markers of bipolar disorder.
At the very least, early recognition and diagnosis of established cases could have important consequences for treatment and eventual course. These are not easy tasks, however.
Underrecognition of childhood disorders and underutilization of treatment are rampant problems in public health,
not limited to mood disorders.
207
208
Table 65. High-Risk Studies with Comparison Groups and Direct Assessment of Children: Clinical Findings
HIGH RISK
COMPARISON
ASSESSMENT
209
Study
Parents
Children
Parents
Children
Method
Findings
11 BP-I, 7 BP-II
(7 fathers,
11 mothers)
14 M, 17 F
(ages 714)
14 with no
disorder
10 M, 8 F
(ages 714)
Direct interview
of child and parent;
semistructured
interview with some
KSADS items.
24 BP
(11 fathers,
13 mothers)
19 M, 18 F
(ages 1521)
14 with
psychiatric
disorders
(outpatient)
(10 fathers,
4 mothers)
13 M, 9 F
(ages 1521)
Direct interview of
child; structured
interview (KSADS)
modified to
include cyclothymia.
19 BP-I (sex
unspecified) and
spouses; (12 had
unspecified
diagnoses)
12 M, 17 F
(ages 617)
22 with no
disorder
(sex
unspecified)
16 M, 21 F
(ages 617)
Direct interview of
child and parent;
structured interview
(KSADS-E); used
NIMH criteria,
similar to RDC.
Significantly higher
rates of mood
disorders in bipolar
offspring than in
offspring of non-ill
parents; 50% of
bipolar offspring
had some psychiatric diagnosis. Presence
of subclinical affective
symptoms suggestive
of depressive or
hyperthymic personality.
Significantly higher rates of
mood disorders (38%)
in offspring sample
compared with psychiatric sample (5%). High
rate of cyclothymia (9 of
16 youths). Higher risk
of mood disorders if
mother bipolar.
3 (10%) of 29 offspring of
bipolar parents had
mania/hypomania vs.
none for controls. Overall,
66% of offspring of bipolar
parents vs. 43% of controls
had some diagnosis. No
significant effect of two ill
parents.
(continued)
Table 65. High-Risk Studies with Comparison Groups and Direct Assessment of Children: Clinical Findings (continued)
HIGH RISK
Study
Parents
Nurnberger
et al., 1988
210
GrigoroiuSerbanescu
et al., 1989
Hammen
et al., 1990
Children
COMPARISON
ASSESSMENT
Parents
Children
Method
Findings
39 with no
disorder (sex
unspecified)
18 M, 21 F
(ages 1525)
Direct interview of
child; structured
interview (SADS-L
adapted for children).
61 couples with
no disorder
34 M, 38 F
(ages 1017)
Direct interview of
child and parent;
structured interview
(KSADS-E); reported
point prevalence.
7 (10%) of 72 offspring
had affective disorder (1
bipolar); there were also
significantly higher rates
of anxiety disorders,
ADHD, and personality
disorders than in control
offspring. Severity of
illness in offspring was
related to severity of
illness in parent and
psychopathology in
spouse of bipolar parent.
14 BP mothersa
and spouses
(7 fathers with
no disorder,
others with
varied disorders)
(1) 16 unipolar
mothers and
spouses (5
fathers no
disorder, others
with varied
disorder); (2)
14 medically ill
(1) 10 M, 12 F;
(2) 9 M, 9 F;
(3) 19 M, 19 F
(all groups
ages 816)
Direct interview of
child and parent;
structured interview
(KSADS-E).
8 M, 10 F
(ages 816)
Radke-Yarrow
et al., 1992
211
Carlson and
Weintraub, 1993
(follow-up of
Weintraub and
Neale, 1984)
22 BP mothersb
(5 BP-I, 17
BP-II) and
spouses (14
unipolar fathers,
8 fathers with no
disorder)
Sibling pairs:
22 ages
112312c,
22 ages 58b
(gender not
specified,
stated as
approximately
equal in each
group)
134 children of BP
parents originally
studied at ages
716; follow-up
of 125 after age 18
mothers and
spouses (5
fathers no
disorder, others
varied disorders);
(3) 24 non-ill
mothers and
spouses (15 fathers
with no disorder,
others varied
disorders)
(1) 41 unipolar
mothersd and
spouses (22
fathers with
depression or
anxiety disorder,
19 fathers with
no disorder);
(2) 37 mothers
with no disorder
and spouses (37
fathers with
no disorder)c
211 of 240 in
original group
of children of
parents with
unipolar
depression,
schizophrenia,
substance abuse;
98 of 108 in
original group
of children of
normal controls
Results reported
on adult
follow-up based
on SCID
interviews,
DSM-III criteria.
Table 65. High-Risk Studies with Comparison Groups and Direct Assessment of Children: Clinical Findings (continued)
HIGH RISK
COMPARISON
ASSESSMENT
212
Study
Parents
Children
Parents
Children
Method
Findings
30 families selected
because adult
bipolar proband
or probands
adult sibling was
in bipolar pedigree
study (NIMH
Genetic Initiative
Study); 12 parents
affected: 8 BP-I,
1 BP-II, 3
unipolar
depressed
132 BP: 56% BP-I,
36% BP-II, 8%
BP-NOS or
cyclothymia
(79% mothers)
Total sample
across 30
families: 24 M,
26 F (ages 617);
23 offspring of
affected families
18 sets of parents
with no disorder
27 offspring of
nonaffected
families
Direct interview of
child and parent,
structured interview
(Diagnostic Interview
for Children and
Adolescents-Revised)
with revised mania
sections.
9 offspring of 23 affected
parents had affective
disorder (including 5
bipolar), compared with
3 of 27 with unaffected
parents.
210: 49% F
(average
age = 12.0 yr)
138: 57% F
(average
age = 11.5 yr)
19 BP-I, 1 BP-II
(5 fathers,
15 mothers)
6 M, 19 F
(ages 1319)
19 with no disorder
6 M, 16 F
(ages 1319)
Parental interview.
Children assessed by
KSADS-PL, K-MRS,
KSADS-P. Family
history obtained via
FHRDC, DSM-IV
diagnosis.
SADS-L, Self-report
measures, actigraph,
Social Rhythm
Metric, diaries
Offspring of BP parents
showed 7.7-fold higher
risk for any BP disorder,
4.0-fold risk for any
mood disorder, and
2.2-fold risk for anxiety
disorders.
Significantly higher rates of
mood disorders in children
of bipolar parents (CBP)
(14/19) than in offspring
of non-ill parents (CC)
(2/19), p < .001. CBP had
stronger ruminative coping
styles and significantly
greater self-esteem variation, but did not differ in
positive affect. CBP exhibited shorter and less variable sleep latency.
Birmaher
et al., 2005
Klimas-Dougan
et al., 2006
25 BP mothers
37 MDD mothers
26 psychiatrically
well mothers
Administered a battery
Lifetime MDD diagnosis:
of neuropsychological
children of bipolar mother,
tests, including
12%; MDD mother, 17%;
Wisconsin Card
well mother, 8%. Children
Sorting Test, Trail
of BP mothers exhibited
Making Test, California deficits in executive
Verbal Learning
functioning, perceptual
Task, Continuous
memory, and sustained
Performance Task,
attention, but not in verbal
and WISC-R/WAIS
memory. These deficits were
not found in children of
MDD mothers or in healthy
control mothers.
213
3-year follow-up data reported here, with reduced sample numbers due to attrition (see Hammen et al., 1987, for initial results). Father data based on mothers FHRDC reports; high rates
of divorce in unipolar and bipolar families.
b
n = 26 BP mothers reported later in study (Radke-Yarrow, 1998).
c
3-year follow-up also.
d
n = 42 unipolar mothers reported later in study (Radke-Yarrow, 1998).
ADHD = attention-deficit hyperactivity disorder; BP = bipolar; BP-NOS = bipolar-not otherwise specified; CBCL = Child Behavior Checklist (Achenbach, 1991); F = female; FHRDC = Family
History Research Diagnostic Criteria; K-MRS = Kiddie Mania Rating Scale; KSADS = Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children; KSADS-E = KSADSEpidemiological Version; KSADS-P = KSADS-Present State; KSADS-PL = KSADS-Present and Lifetime version; M = male; MDD = major depressive disorder; NIMH = National Institute of Mental
Health; RDC = Research Diagnostic Criteria; SADS = Schedule for Affective Disorders and Schizophrenia; SADS-L = SADS-Lifetime; SCID = Structured Clinical Interview for DSM. WAIS = Wechsler
Adult Intelligence Scale; WISC-R = Wechsler Intelligence Scale for Children-Revised.
Source: Updated from Geller et al., 1998a.
214
Clinical Studies
of the marital relationship, as well as the gender and mental health of the spouse, as psychosocial contributors to
outcomes among offspring (see Chapter 10).
The results of these case-control studies, along with
those of other designs that did not include comparison
groups but did report childrens diagnoses, were summarized in a meta-analysis by Lapalme and colleagues (1997).
They concluded that 52 percent of the offspring of bipolar
parents met criteria for a diagnosis of at least one psychiatric disorder, compared with 29 percent of children of
parents with no disordersa highly statistically significant
difference. (Note that these figures should be viewed as approximations because some of the samples overlapped, potentially causing cases to be counted more than once.) Aggregating across various samples makes it easier to see the
specific concentration of mood disorders in the offspring.
In total, 26.5 percent of the offspring of bipolar parents had
an affective disorder (including major, minor, and intermittent depression and dysthymia, as well as mania, hypomania, cyclothymia, and hyperthymic states), compared
with 8.3 percent of children of non-ill parents. Bipolar disorder occurred in 5.4 percent of the offspring of bipolar
parents but in none of the children of non-ill parents. Obviously, this figure cannot be taken as a final estimate of
risk for bipolarity because most of the children had not
passedor even enteredthe age of risk. However, the
figure does suggest that the majority of offspring of a bipolar parent fail to manifest diagnosable bipolar disorder at
an early age.
Despite the overall consistency of the findings of these
studies, there remain significant gaps in our knowledge of
childrens risk. Few of the studies included young children,
while most included both older children and adolescents.
The developmental manifestations of bipolar disorder,
therefore, have not been fully tested in adequately large
samples. The general lack of longitudinal studies means
that the continuity or changes in symptom expression over
time remain obscure. Although several studies attempted
to evaluate subsyndromal symptoms of mood disorders or
personality characteristics,6 there is currently little consensus on the best and most valid instruments for this purpose. Additionally, future researchers will need to articulate theoretical models with specific variablesincluding
both neurobiological and psychological factorsthat
might be measured as markers or mechanisms of risk. To
date, little information exists about the predictive value of
the bipolar parents clinical historyincluding not only
course subtypes, but also the role of the history of manic
and depressive features of the illness, age at onset, and response to treatment. Moreover, virtually no studies have
considered the potential impact on children of parental
comorbidity, such as substance abuse or ADHD.
215
Most of the early studies and the case-control investigations discussed previously reported clinical diagnostic
outcomes but did not include measures of childrens personality, adaptive behaviors, and functioning in typical
roles. Such variables are important to characterize potential markers of bipolar disorderunique attributes that
define both positive aspects of bipolar heritage and predictors of later adjustment, including coping capabilities that
may affect mental health status. A brief review of relevant
findings is presented in Box 65.
217
218
Clinical Studies
Proportion relapsed
0.7
Intact Family
0.6
0.5
0.4
No Intact Family
0.3
0.2
0.1
0.0
0
12
15
18
21
24
Follow-up (months)
Figure 62. Two-year rate of recovery by living situation in subjects with a prepubertal and early adolescent bipolar disorder phenotype. Fifty-eight of the 89 subjects had recovered by 24 months.
There was a significant difference between the 39 recovered subjects
who lived with their intact biological families and the 19 who resided
in other living situations (Cox model 2 = 7.40, degrees of freedom
[df] = 1, p = .007). The Kiddie Mania (K-M) estimate for recovery in
intact families was 76.5% (95% confidence interval [CI] = 64.888.1),
and for recovery in other living situations it was 50.0% (95%
CI = 34.165.9). (Source: Geller et al., 2002. Reprinted with permission
from the American Journal of Psychiatry, Copyright 2002, American
Psychiatric Association.)
unipolar or well women; marital stress tended to be associated with other forms of family stress and maladaptive
functioning as well, however, which made the effects difficult to disentangle (Radke-Yarrow, 1998). The combination of low maternal scores on global functioning and
high indices of family stress (including marital conflict)
was a strong predictor of depression in offspring, especially older children. In a more recent analysis, Meyer and
colleagues (2004) reported that frequent maternal expressions of anger and irritability (perhaps themselves manifestations of mixed mania and therefore of genetic importance) during childrens early years were associated with
the development of mania in adulthood, even after controlling for maternal psychiatric features. Although based
on a small sample, the results of this study hint that highly
stressful family environments may contribute to the
timingor even the expressionof bipolar features in
those at genetic risk (see also Miklowitz et al., 1988). In a
4-year prospective study of 86 prepubertal and earlyadolescent bipolar patients, Geller and colleagues (2004)
found that low maternal warmth predicted faster relapse
after recovery from mania. In an earlier study, the same investigators had found that patients with prepubertal and
early-onset adolescent bipolar disorder who were exposed
to low levels of maternal warmth were four times more
likely to relapse after recovery than those exposed to high
levels of maternal warmth (Geller et al., 2002b). This effect
0.8
0.7
Low maternal warmth
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
12
15
Follow-up (months)
18
21
24
219
220
Clinical Studies
CONCLUSIONS
Increasing interest in mood disorders of children and
adolescents has stimulated research and careful clinical
221
NOTES
1. See excellent reviews by Faedda et al., 1995; Geller and Luby,
1997; Coyle et al., 2003; Carlson, 2005.
2. See Biederman et al., 2000a, 2004c; Geller et al., 2000b;
Masai et al., 2003.
3. Masi et al., 2001; Wozniak, 2002; Faedda et al., 2004; Harpold
et al., 2005.
4. This statement appeared on the Web site of the Child and
Adolescent Bipolar Foundation, http://www.bpkids.org (accessed August 31, 2006).
5. See Strober et al., 1995; Faraone et al., 1997a; McElroy et al.,
1997; Kafantaris et al., 1998.
6. Decina et al., 1982; Gershon et al., 1985; Klein et al., 1985;
Nurnberger et al., 1988; Grigoroiu-Serbanescu et al., 1989,
1991; Birmaher et al., 2005a,b.
7. See Gershon et al., 1985; LaRoche et al., 1987; GrigoroiuSerbanescu et al., 1989; Radke-Yarrow et al., 1992; Todd et al.,
1996.
Comorbidity
The patient who has for years before his illness shown morbid traits, who has been anxious, or
quarrelsome, or suspicious, or odd, or solitary, or obsessional, or in some other way has shown
that he is constantly at odds with himself, as well as with his surroundingssuch a patient is
not going to be cured of his maladjustment by having an affective flare-up. A sortie does not
end a siege.
Sir Aubrey Lewis (1936, p. 997)
224
Clinical Studies
Anorexia Nervosa
Bulimia Nervosa
Eating Disorders
Generalized Anxiety Disorder
Post-traumatic Stress Disorder
Obsessive-Compulsive Disorder
Simple Phobia
Social Phobia
Panic Disorder/Agoraphobia
Anxiety Disorders
Opiate Abuse
Sedative Abuse
Cocaine Abuse
Stimulant Abuse
Marijuana Abuse
Alcohol Abuse
Substance Abuse Disorders
10
15
20
25
30
35
40
45
Percent comorbidity
Figure 71. Axis I psychiatric comorbidities. Percent comorbidity in bipolar patients enrolled in the
Stanley Bipolar Treatment Network. (Source: Adapted from McElroy et al., 2001. Reprinted with permission from the American Journal of Psychiatry, Copyright 2001. American Psychiatric Association.)
Comorbidity
225
Alcohol Abuse/Dependence
In a letter to a friend, the poet Edgar Allan Poe wrote about
alcohol and mental illness from a deeply personal perspective:
I became insane, with long periods of horrible sanity.
During these fits of absolute unconsciousness I drank,
God only knows how much or how long. As a matter of
226
Clinical Studies
Differing views about whether alcohol abuse disorder precedes or follows the onset of manic-depressive illness persist today, and there is a growing appreciation of the importance of recognizing this comorbidity (dual diagnosis).
Table 71. Lifetime Prevalence Rates for Alcohol and Drug Abuse/Dependence in Persons with Mood Disorders
and in the General Population
Type of Abuse/Dependence
Bipolar-I (%)
Bipolar-II (%)
46
39
17
13.5
Abuse only
15
18
Dependence
31
21
12
41
21
18
Abuse only
13
Dependence
28
12
11
Alcohol
Drug
Note: Data are from the Epidemiological Catchment Area (ECA) study and are based on DSM-III diagnosis.
ECA = Epidemiological Catchment Area.
Source: Regier et al., 1990.
6.2
Comorbidity
227
50
45
40
35
Percent
30
25
20
15
10
5
0
BP-I
BP-II
SZ
PD
OCD
DYS
MD
GP
Diagnosis
Figure 72. Lifetime prevalence of alcohol abuse disorder. BP-I = bipolar-I; BP-II = bipolar-II;
DYS = dysthymia; GP = general population; MD = major depression; OCD = obsessive-compulsive disorder; PD = panic disorder; SZ = schizophrenia. (Source: Regier et al., 1990.)
Drug Abuse/Dependence
The data on rates of comorbid bipolar illness and drug
abuse/dependence are much less extensive and consistent
than those on comorbid alcohol-related disorders, in no
small part because of the illegal nature of drug-related disorders. The ECA data for drug abuse/dependence in patients with mood disorders show strikingly high lifetime
228
Clinical Studies
prevalence rates of 18 percent in unipolar depressed patients and 41 percent in bipolar-I patients (Regier et al.,
1990), nearly identical to the rates for alcohol-related disorders (see Table 71). In the general population, drug
abuse/dependence is significantly less common than
alcohol-related disorders (see also Table 72).
Determining the sequence of comorbid mood disorders
and drug abuse/dependence presents the same methodological problems as those encountered in the case of alcohol-related diagnoses. The ECA data show that the affective disorder is 1.3 times more likely to occur before the
drug abuse disorder (see the later discussion).
Cocaine
An interview study of patients voluntarily enrolled in a
bipolar disorder case registry found that 3.4 percent met
the diagnostic criteria for cocaine abuse, and 6.7 percent
met the criteria for cocaine dependence (Chengappa et al.,
2000). Consistent with other findings on drug abuse problems, more patients with bipolar-I than with bipolar-II
abused cocaine.
Data of this sort cannot address the nature of the relationship between the mood and drug disorders. Clearly
there are features of bipolar illness that can increase the
likelihood of cocaine abuse, such as a desire to relieve the
psychomotor retardation of bipolar depression and a desire to reinduce, prolong, or accelerate elevated mood and
energy states. Weiss and Mirin (1986), for example, found
Drug dependence
Male (%)
Female (%)
Prevalence
5.9
Lifetime
2.0
6-month
4.4
5.4
3.5
Lifetime
0.8
1.3
0.3
12-month
7.5
9.4
5.9
Lifetime
2.8
3.8
1.9
12-month
1.3
1.8
0.7
1-month
1.7
12-month
229
Comorbidity
Overall, the rates of bipolar illness in opiate abusers, although not as dramatically high as in cocaine abusers, are
greater than those found in the general population, but not
as high as the rates of unipolar depression among those
with opiate dependence.
Marijuana
Although it is perhaps more intuitive to link increased alcohol consumption with the depressed phase of bipolar
illness, evidence suggests that the link is as or more common with hypomania, mania, and mixed or transitional
states. Indeed, bipolar patients who increase their alcohol
consumption generally do so during the manic phase
(Zisook and Schuckit, 1987). Table 73 summarizes six studies of the relationship between alcohol intake and phase of
illness. Alcohol, to a point, does appear to provide some relief for the irritability, restlessness, and agitation associated
with mania. In this sense, although its use is damaging
overall, it is not surprising that alcohol consumption increases during mania.
There is some evidence that bipolar patients (38 percent)
are more likely than unipolar patients (15 percent) to increase their drinking when in a depressive episode (Bernadt
and Murray, 1986). The tendency for bipolar patients to
drink more heavily when depressed may reflect the increased agitation and perturbation associated with coexisting transitional or mixed states. In an early study, Winokur
and colleagues (1969) found that the percentage of bipolar
patients increasing their alcohol consumption was higher
during mixed and manic states (43 and 42 percent, respectively) than during bipolar depression (27 percent). Himmelhoch and colleagues (1976a) noted that the major differ-
Table 73. Relationship between Alcohol Consumption and Phase of Bipolar Illness
DEPRESSED PHASE (%)
Study
Increase
Decrease
No Change
Increase
Decrease
No change
100
29
71
26
43
31
83
17
27
73
42
47
97a
50
50a
21
22
57
14
79
38
25
36
20
23
57
Minski, 1938
230
Clinical Studies
Self-Medication Hypothesis
The hypothesis that alcohol and drug abuse/dependence
occurs in an effort to self-medicate mood disorders has
been suggested in various ways for more than a thousand
years. In 1884, Freud recognized that cocaine, with its
mood-elevating properties, could be used as a potent antidepressant. Later, Milkman and Frosch (1973; quoted in
Khantzian, 1985, p. 1260) wrote:
[H]eroin addicts preferred the calming and dampening effects of opiates and seemed to use them to shore up tenuous defenses and reinforce a tendency toward withdrawal
and isolation, while amphetamine addicts used the stimulating action of amphetamines to support an inflated
sense of self-worth and a defensive style involving active
confrontation with their environment.
Comorbidity
Precipitation of Illness
An underlying bipolar illness may be precipitated by alcohol or drug abuse. For example, the first manic episode in
a biologically vulnerable individual may be triggered by
hallucinogen or stimulant abuse. Interactions among predisposed individuals, their substance abuse patterns, and
the onset of abnormal mood episodes have been observed
by many clinicians and investigators.
The most demonstrable drug-induced psychoses in
manic-depressive patients are those resulting from hallucinogenic drugs such as LSD and PCP. The psychotic
symptoms associated with the abuse of these drugs have
been well documented by several authors (e.g., El-Guebaly,
1975; Bowers, 1977; Erard et al., 1980). Amphetamine abuse
was noted by Ellinwood and Petrie (1979) to be a precipitant
of psychosis. Many of the presenting symptoms (e.g., delu-
231
232
Clinical Studies
Modification of Course
Alcohol and drug abuse may modify the course and expression of manic-depressive illness. Substance abuse
problems can lead to more severe psychopathology and
less favorable outcomes in a number of ways, including
higher rates of mixed states, rapid cycling, impulsivity, aggression, and destabilization of sleep patterns. They may also
slow the time to recovery, increase the probability of treatment nonadherence, and decrease the effectiveness of prescribed medications. As reviewed in Chapter 8, the mortality associated with substance abuse and depressive disorders
is cause for particular concern. More than 90 percent of
suicides are associated with a psychiatric disorder (Institute
of Medicine, 2002), but the association is stronger for some
conditions than others. Two of the highest-risk conditions
are bipolar disorder and substance abuse, and there appears
to be an often dangerous interaction between the two. Harris and Barraclough (1997) examined the effect of comorbid substance abuse on suicide rates in 7,819 patients with
bipolar disorder, unipolar depression, or schizophrenia. Substance abuse problems increased the lifetime risk of suicide
in all of the patients, but the increase was greatest among
those with bipolar disorder (recurrent unipolar patients
were not identified separately).
Rapid-cycling bipolar disorder, defined by four or more
mood episodes per year, tends to have a more treatmentresistant course, and a link between the risk of rapid cycling
Comorbidity
233
ANXIETY DISORDERS
While comorbidity implies the presence of two separate
disorders, individual symptoms of anxietyagitation, accelerated thought processes, restlessness, social anxiety,
irritability, and dysphoric moodare common features of
234
Clinical Studies
Table 74. Percent of 288 Bipolar Patients Who Also Met Criteria
for Various Anxiety Disorders
Disorder
Lifetime %
Current %
Anxiety disorders
42
30
Panic disorder/agoraphobia
20
Social phobia
16
13
Simple phobia
10
Obsessive-compulsive disorder
Population
Sample Size
Comorbidity Findings
Patients with PD
Patients with PD
108
130
168
Patients with BP
71
Patients with BP
37
263
Patients with BP
129
315
Hungarian National
Epidemiologic Survey,
subgroup with BP
108
81
24
149
236
Clinical Studies
Table 75. Overview of Studies of Comorbidity of Bipolar and Anxiety Disorders (continued)
Study
Population
Patients with BP
Sample Size
288
Comorbidity Findings
42% had a comorbid Axis I
anxiety disorder; 20% had
PD with agoraphobia; 16%
had social phobia; 10% had
simple phobia; 6% had
GAD; 7% had PTSD; 9%
had OCD
BP = Bipolar disorder; ECA = Epidemiologic Catchment Area; GAD = generalized anxiety disorder; NCS = National Comorbidity Survey;
OCD = obsessive-compulsive disorder; PD = panic disorder; PTSD = post-traumatic stress disorder.
Source: Adapted from Freeman et al., 2002.
Panic Disorder
Panic disorder is one of the most common comorbid anxiety disorders seen in bipolar patients (McElroy et al.,
2001). Data from the ECA study found that the lifetime
prevalence of panic disorder among individuals with
Comorbidity
237
Obsessive-Compulsive Disorder
Analysis of data from the ECA study showed a lifetime
prevalence of OCD of 21.0 percent in patients with bipolar
disorder; this was significantly higher than the rates of 12.2
percent in unipolar depression and 2.5 percent in the
238
Clinical Studies
Sample Characteristics
BP = bipolar disorder.
Source: Otto et al., 2004. Reprinted with permission from Blackwell Publishing.
Sample Size
71
29
17
39
50
77
40
21
288
102
122
11
19
Comorbidity
239
Eating Disorders
Only a few studies have assessed the co-occurrence of
bipolar disorder and eating disorders in community sam-
240
Clinical Studies
Axis II Disorders
Affective instability is a common feature of certain personality disorders, especially those found in cluster B. Because
of the frequency with which these disorders are seen in
MEDICAL ILLNESSES
In addition to psychiatric disorders, bipolar patients experience certain general medical conditions at a higher rate
than the general public. Some of this excess morbidity is
associated with adverse effects of medications used to treat
bipolar disorder and some with lifestyle. In other cases, the
etiology of the comorbidity is not fully understood. Because many patients with serious mental illnesses have difficulty obtaining adequate medical care, the treating psychiatrist may be the only physician caring for these
patients on a regular basis, and therefore should screen
them for common medical problems.
Cardiovascular Disease
Cardiovascular disease accounts for the majority of the
mortality seen with metabolic syndrome (discussed later).
Obesity, glucose dysregulation, and dyslipidemia are all
risk factors for cardiovascular disease, and consequently
patients with bipolar disorder experience cardiovascular
mortality at elevated rates compared with the general population (Weeke, 1979; Sharma and Markar, 1994). The
mortality ratio of bipolar patients versus the general population for cardiovascular disease is 3.0. Additionally, when
all the symptoms of the metabolic syndrome are controlled
for, bipolar disorder continues to be an independent risk
factor for cardiovascular mortality (Norton and Whalley,
1984). Before the modern era of psychopharmacology,
death from manic exhaustion was not uncommon; many
such deaths were attributable to cardiac events (Derby,
1933; Cade, 1979). In a long-term study that followed a
group of 406 patients for more than 30 years, mortality
due to circulatory disorders was second only to suicide as a
cause of death among patients with bipolar disorder
(Angst et al., 2002). A large study of 15,386 patients hospitalized in Sweden for bipolar disorder between 1973 and
1995 found that the most frequent cause of death was cardiovascular disease, followed by suicide and cancer. The
observed number of cardiovascular deaths among male
patients was 1.9 times the expected number. Among females, the mortality rate was 2.6 times the expected number (Osby, 2001).
Increased platelet aggregation and low-grade systemic
inflammation seen in depressed patients may be mechanisms by which a mood disorder is a significant and independent risk factor for ischemic heart disease (Musselman
et al., 1996). Patients with bipolar disorder also are more
likely to smoke and to have a history of hypertension
(Yates and Wallace, 1987; Johannessen et al., 2006).
Comorbidity
241
Study Population
Assessment Instrument;
Diagnostic Criteria
Strakowski et al.,
1992
Strakowski et al.,
1993
McElroy et al., 1995
SCID; DSM-III-R
SCID; DSM-III-R
SCID; DSM-III-R
8.5% had AN or BN
Semistructured Clinical
Interview; DSM-IV
SAGA; DSM-III-R
SCID; DSM-III-R
DIGS; DSM-IV
SCID; DSM-III-R
SCID; DSM-IV
5.9% had AN or BN
SCID; DSM-IV
2.3% had BN
SCID; DSM-IV
15% had an ED
AN = anorexia nervosa; BED = binge eating disorder; BN = bulimia nervosa; BP = bipolar disorder; DIGS = Diagnostic Interview
for Genetic Studies; ED = eating disorder; SAGA = Semi-Structured Assessment for the Genetics of Alcoholism; SCID = Structured
Clinical Interview for DSM.
a
Subjects were participants in the Collaborative Study of the Genetics of Alcoholism.
Source: Reprinted from McElroy et al., 2005 with permission from Elsevier.
Thyroid Dysfunction
Thyroid dysfunction associated with bipolar disorder is a
significant problem. In addition to the medical morbidity
associated with thyroid problems, mood states and affective stability are intimately connected to proper functioning of the hypothalamicpituitarythyroid axis (see Chapter 14). Patients with thyroid disease have higher rates of
panic disorder, simple phobia, OCD, major depressive disorder, bipolar disorder, and cyclothymia than the general
population (Placidi et al., 1998). Bipolar women have
higher rates of comorbid thyroid disease than men; analysis of the first 500 STEP-BD participants, for example,
found rates of 26.9 percent in females and 5.7 percent in
males (Baldassano et al., 2005). Hypothyroidism is the
242
Clinical Studies
the association between bipolar disorder and thyroid dysfunction. In a sample of bipolar patients who had never
been treated with either lithium or carbamazepine, the rate
of thyroid hypofunction was 9 percent (Valle et al., 1999).
Hypofunction was determined on the basis of serum levels
for total thyroxine (T4), total triiodothyronine (T3), and
thyroid-stimulating hormone (TSH) levels. Bipolar-II patients showed significantly lower levels of thyroid functioning than those with bipolar-I disorder, as measured by
higher TSH levels. Primary hypothyroidism was diagnosed
in 3 percent of a general population sample (Flynn et al.,
2004).
The relationship between thyroid hypofunctioning and
rapid cycling is unclear. In the sample just described, no
difference in thyroid parameters was observed between
rapid-cycling and non-rapid-cycling bipolar patients.
Other studies, however, have found hypothyroidism to be
a risk factor for rapid cycling. For example, in a sample of
30 patients with rapid-cycling bipolar disorder, 60 percent
also had hypothyroidism (Bauer et al., 1990). Subclinical
hypothyroidism, in which thyroid hormone levels are low
compared with controls but still fall within the broad normal range, has been found to be associated with rapid cycling (Kusalic, 1992), although more recently, doubt has
been cast on this association (Post et al., 1997). Identifying
subclinical hypothyroidism in bipolar patients may be almost as important as identifying overt dysfunction. In
1974, Wenzel and colleagues introduced a system for grading hypothyroidism. In this classification, grade 1 represents overt hypothyroidism, as defined by decreased serum
T4. Grades 2 and 3 define subclinical hypothyroidism.
Grade 2 is characterized by increased TSH with normal T4,
and grade 3 by the presence of an isolated exaggeration of
the TSH response to stimulation by thyroid-releasing hormone (TRH) (Wenzel et al., 1974).
Subclinical hypothyroidism can influence the outcome
of mood disorders even in samples of patients with otherwise normal thyroid indices. Frye and colleagues (1999)
assessed thyroid function prospectively in 52 outpatients
with bipolar disorder. Even though their free thyroxine index (FTI) values were within the normal range, patients
with lower mean FTI values had more affective episodes
and more severe depressive symptoms. Cole and colleagues
(2002) found less favorable treatment response in bipolar
patients with low-normal FTI and high-normal TSH. Others have found subclinical hypothyroidism to be associated
with an elevated lifetime prevalence of depression (Haggerty et al., 1993). The rate of subclinical hypothyroidism is
particularly high (30 percent) in patients with refractory,
treatment-resistant depression (Howland, 1993). The relationship between subclinical hypothyroidism and treatment response is discussed further in Chapter 19.
Hyperthyroidism has also been linked to depressive disorders in some studies (Kathol et al., 1986; Placidi et al.,
1998), but not all (Fava et al., 1995; Engum et al., 2002;
Thomsen and Kessing, 2005); it has also been linked to mania in a case series (Brownlie et al., 2000), but this finding
was not confirmed in a controlled study (Cassidy et al.,
2002). In a recent large historical cohort study of 133,570 patients with a clinical diagnosis of osteoarthritis, depressive
disorder, or bipolar disorder (610 of whom had hyperthyroidism), patients with bipolar disorder had a hazard ratio
for hyperthyroidism of 1.59 (p < .052) compared with the
arthritis controls, and 1.86 ( p < .014) compared with those
with depression (Thomsen and Kessing, 2005).
Although the evidence for a link between mood disorders and decreased thyroid function is more consistent
than that for a link to increased thyroid function, the hypothesis that some mood disorders may be linked to dysregulation of thyroid function is consistent with most of
the data. Clearly, all patients with a mood disorder should
be tested routinely for thyroid abnormalities, including abnormal levels of TSH and free T4. Even in the context of
normal T4, elevated TSH should prompt a further workup
and consideration of thyroid supplementation. The absence of abnormal TSH should not rule out hypothyroidism in a patient with clinical manifestations of the disease because many patients with both major depression
and bipolar disorder fail to mount a TSH response to a
TRH challenge (Gold et al., 1977). Evaluation of thyroid
abnormalities is particularly appropriate in rapid-cycling
and treatment-resistant patients.
Comorbidity
243
among overweight individuals. Overweight and obese individuals may also be targets of discrimination. The socioeconomic effects of excess weight were studied in a group
of 10,039 randomly selected young people, who were evaluated for weight and BMI and then followed-up 7 years later.
Women who had been overweight had completed fewer
years of school, were less likely to be married, and had
lower household incomes than those who had not been
overweight; these findings were independent of baseline socioeconomic status. Men who had been overweight also
were less likely to be married. In contrast, people with other
chronic health conditions did not differ in these ways from
the nonoverweight subjects (Gortmaker et al., 1993).
Among individuals seeking weight loss treatments, rates
of mood disorders have ranged from a low of 8 percent
(Wise and Fernandez, 1979) to a high of 60 percent (Hudson et al., 1988). Although there can be an overrepresentation of psychopathology among treatment-seeking patients, studies using community samples have yielded
similar results. A national survey of 40,086 adults examined the relationship between body weight and clinical depression, suicidal ideation, and suicide attempts. Among
women, increased body weight was associated with major
depression and suicidal ideation; in men, there was also an
association with suicide attempts (Carpenter et al., 2000).
Diabetes
Because overweight and obesity are associated with diabetes, many of the risk factors that have been linked to
weight gain apply also to the development of diabetes. The
prevalence of reported diabetes mellitus was found to be
approximately three times higher in a sample of 345 hospitalized bipolar patients (9.9 percent) than in the general
population (3.4 percent) (Cassidy et al., 1999). Patients in
this sample also had a more severe course of their mood
disorder and significantly more lifetime psychiatric hospitalizations than the nondiabetic subjects. Age at first hospitalization and duration of psychiatric disorder were similar in the two groups. Patients with bipolar disorder and
comorbid diabetes have also been reported to be more
likely to experience rapid cycling and to have a chronic
rather than an episodic course of illness (Ruzickova et al.,
2003). A comparison of 26 diabetic and 196 nondiabetic
subjects from a community-based project carried out in
Canada found that the disability rates for bipolar disorder
were significantly different (Ruzickova et al., 2003); 81 percent of comorbid patients were receiving disability compensation payments for bipolar disorder, compared with
only 30 percent of bipolar patients without diabetes.
When patients with diabetes are being treated, lithium
should be used with care. Patients with juvenile-onset
insulin-dependent diabetes are susceptible to diabetic
244
Clinical Studies
nephropathy, and the risk is increased by the presence of hypertension. On the other hand, there is evidence that when
lithium is combined with an oral hypoglycemic medication
or insulin, it has an assisting hypoglycemic effect in diabetic
patients (Hu et al., 1997). Fasting blood glucose levels were
found to be decreased in patients taking lithium combined
with other therapy, but not in those being treated with a hypoglycemic agent alone. A possible explanation for this finding is that lithium increases the sensitivity of glucose transport to insulin in skeletal muscle and adipocytes (Tabata et
al., 1994). The authors of this study noted that the effects of
lithium on glucose transport and metabolism in skeletal
muscle were strikingly similar to the effects of exercise.
Dysregulation of the hypothalamicpituitaryadrenocortical axis occurs frequently in patients with mood disorders. Hypercortisolemia, associated with depressive
states, can lead to insulin resistance. Conversely, diabetic
vascular CNS lesions may contribute to mania. WeberHamann and colleagues (2002) found that postmenopausal women who had depression also had significantly higher levels of free cortisol than age-matched
controls. Elevated levels of cortisol can lead to decreased
insulin receptor sensitivity through currently unknown
mechanisms (Perry et al., 2003).
A more hypothetical link between bipolar disorder and
diabetes relates to intracellular signal transduction involving the enzyme glycogen synthase kinase-3- (GSK-3).
Alterations in GSK-3 functioning play a role in insulin
resistance. Insulin inhibits GSK-3, which results in enhanced glucose transport into skeletal muscle. Insulinmediated inhibition of GSK-3 leads as well to increased
glucose utilization and the production of glycogen (Orena
et al., 2000). GSK-3 is also one of the targets for lithium
action. Lithium significantly inhibits brain GSK-3 at concentrations relevant for the treatment of bipolar disorder
(Gould et al., 2004). In addition to its role in glucose regulation, active GSK-3 facilitates apoptosis in neurons,
while inhibition of GSK-3 attenuates cellular apoptosis,
resulting in a neuroprotective effect (Hetman et al., 2000).
Disturbances in the GSK-3 signal transduction pathway
associated with diabetes may affect the viability of neurons
that play a role in mood stabilization. Diminished insulinmediated inhibition of GSK-3 may have an effect opposite to that of lithium and may ultimately lead to an accentuation of psychiatric symptoms related to bipolar
disorder. For a more detailed discussion of the neuroprotective role of lithium and its putative significance for
lithiums mood-stabilizing effects, see Chapter 14.
Migraine Headaches
The lifetime prevalence of migraine is markedly higher
among individuals with mood disorders (Swartz et al.,
CONCLUSIONS
The scientific principle of parsimony holds that one should
not increase, beyond what is necessary, the number of entities required to explain an observed phenomenon. In
many cases, attributing all of a patients symptoms to a single diagnostic entity is an appealing strategy. Symptoms
that might be caused by a comorbid illnesssuch as excessive worry (generalized anxiety disorder), social avoidance
(social anxiety disorder), distractibility (ADHD), and low
energy and fatigue (diabetes)are consistent with a diagnosis of affective disorder. Nevertheless, a large body of evidence derived from rigorously conducted studies unambiguously supports the presence of extensive comorbidity
in bipolar illness, although with what frequency and which
diagnosis subtype is open to debate (while substance abuse
is more common in bipolar-I than in bipolar-II patients,
the opposite is true for anxiety and eating disorders). It is
Comorbidity
245
treating such problems as substance abuse, thyroid dysfunction, and anxiety. Patients who fail to respond adequately to
multiple trials of medication should not be considered treatment resistant until a comprehensive assessment for untreated comorbidities has been undertaken. (See Chapter 24
for a discussion of the treatment of comorbid conditions.)
NOTES
1. These percentages are substantially higher than noted in the
bipolar case registry (Chengappa et al., 2000), because in the
Estroff et al. (1985) study, cocaine abuse was observed during
an active episode of either mania or depression.
2. Estroff et al., 1985; Winokur et al., 1998; Goldberg et al., 1999;
Cassidy et al., 2001.
3. Nearly 70 percent of all of the patients included in the analysis
were participants in a study in which the concomitant mood
stabilizer was olanzapine, which was considered placebo for
purposes of the analysis. A smaller, well-designed study of
lithium with antidepressants versus placebo did find a higher
switch rate in the antidepressant plus lithium group, but in
the meta-analysis this study was overwhelmed by the huge
olanzapine study. See Chapter 19 for additional discussion of
this study.
4. As noted in the introduction to this chapter, however, there
are biases that operate in the other direction, namely the tendency of nonclinician interviewers to overdiagnose when using symptom checklists.
Suicide
The patients . . . often try to starve themselves, to hang themselves, to cut their arteries; they
beg that they may be burned, buried alive, driven out into the woods and there allowed to
die . . . . One of my patients struck his neck so often on the edge of a chisel fixed on the ground
that all the soft parts were cut through to the vertebrae.
Emil Kraepelin (1921, p. 25)
years, researchers have recognized that these end points reflect a wide range of thoughts and behaviors. Today, the
focus is on the use of more nuanced measures, such as the
type (e.g., violent versus nonviolent) and the severity (e.g.,
Beck Scale of Suicidal Ideation, Schedule for Affective Disorders and Schizophrenia [SADS] suicide subscale) of the
attempt. Suicidal ideation without particular information
about plans or means is common in manic-depressive illness. Yet it is neither a sensitive nor a specific predictor of
suicide, at least over the long term (see Chapter 25), and
scales for rating suicidal ideation and intent therefore lead to
high false-positive and false-negative rates (Jacobs et al.,
2003). This chapter thus places greater emphasis on actual
suicide attempts, especially those of high lethality (although,
unfortunately, most studies of suicide attempts do not rate
lethality), and completed suicide.
The approaches taken in research on suicide have generally ignored the presence of two distinct populations. The
first comprises those individuals who commit suicide who
have never been diagnosed with a psychiatric disorder. This
group accounts for approximately 50 percent of all suicides,
even though retrospective studies have found that a psychiatric diagnosis could be established in more than 90 percent of such cases (Henriksson et al., 1993; Cheng et al.,
2000). This finding was the basis for The Surgeon Generals
Call to Action to Prevent Suicide (U.S. Public Health Service,
1999), which cited stigma, lack of public education about
psychiatric disorders, and insufficient financial resources as
barriers to diagnosis and treatment for those at risk of committing suicide. It also addressed the need to train physicians to recognize and treat conditions, such as depression
or bipolar disorder, that can lead to increased suicide risk.
The other group of concern encompasses the remaining
50 percent of individuals who commit suicide despite
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Clinical Studies
Cancer
Multiple Sclerosis
Huntingtons Disease
AIDS
Anxiety Disordersa
Personality Disorders
Schizophrenia
Alcohol Dependence and Abuse
Opioid Dependence
Bipolar Disorder
Depression
Suicide Risk: Number of Times the Expected Rate in the General Population
Figure 81. Suicide risk in psychiatric or medical illness: number of times the expected rate in the
general population. aObsessive-compulsive disorder and panic disorder. (Source: Adapted from Harris
and Barraclough, 1997. Reprinted with permission from the American Journal of Psychiatry, copyright
2001, American Psychiatric Association.)
of bipolar disorder. Prior to this, a diagnosis of manicdepressive disorder had required a history or presence
of recurrent depression or an episode of mania, thus encompassing the broader group of patients that is the focus of this volume (see Chapter 1). The narrower bipolar
diagnosis required the presence or history of an episode
of mania or hypomania; patients with recurrent depression were subsumed under the unipolar depression diagnosis, and recurrent unipolar was broadened to include
anyone with more than one episode. This shift in diagnostic practice has made it more difficult to interpret
secular trends. In this chapter, we employ the diagnostic terms relevant to particular studies, but otherwise (as
throughout the volume) use manic-depressive illness to
refer to the broader concept of recurrent major affective
disorder; we use bipolar disorder to refer to the bipolar
spectrum.
Particularly critical is the enormous range across studies in the length of follow-up periods; this broad range
necessarily results in variable periods of risk for suicide.
Moreover, when studies include only patients who have
been hospitalized, suicide rates are likely to be higher, reflecting a greater severity of illness. Most early studies of
suicide in manic-depressive illness were of hospitalized
patients; many more recent studies are of outpatients or
combinations of outpatients and inpatients. Because suicide risk is one of the most decisive criteria for admission
to a psychiatric hospital, studies of hospitalized patients
are necessarily skewed toward a greater likelihood of
suicide.
Suicide
SUICIDE RATES
In this section, we begin by reviewing suicide rates among
the general population and among bipolar and unipolar
depressed patients. We then present specific rates according to diagnosis (bipolar versus unipolar; bipolar-I versus
bipolar-II), gender, and seasonality.
249
250
Clinical Studies
BipolarUnipolar Differences
Most studies have tended to find somewhat higher suicide
rates in unipolar depression than in bipolar disorder
(e.g., Harris and Barraclough, 1997; Osby et al., 2001;
Angst et al., 2002). Others, however, have found either no
bipolarunipolar difference2 or higher rates among patients with bipolar disorder (e.g., Rihmer and Pestality,
1999; Bottlender et al., 2000). The reason for these disparate findings, in our view, lies largely in the heterogeneity of the unipolar population and the underdiagnosis of
mixed states and other forms of bipolarity.
The broad definition of unipolar depression in todays
nomenclature simply means that the diagnosis is not bipolar; that is, a unipolar diagnosis encompasses patients with
all degrees of recurrence, ranging from single-episode depression to highly recurrent or cyclic depression (see
Chapter 2). Yet the research literature rarely has distinguished among unipolar patients on the basis of differences in their patterns of recurrence, which may in turn reflect different suicide risks depending on comorbidities,
course of illness, and other clinical factors noted throughout this chapter. We believe that patients with recurrent
unipolar depression may be likely to have suicide rates as
high as or higher than those with bipolar disorder, whereas
patients with less recurrent forms of unipolar depression
are likely to have lower rates. Because the majority of unipolar patients have at least some recurrence, their inclusion
could be expected to skew the unipolar category to higher
rates. This might explain why Harris and Barracloughs
meta-analysis (see Fig. 81) and other studies have found
somewhat higher rates in unipolar depression than in
bipolar disorder. A compounding problem is that, as we
have seen (see Chapter 19), a substantial percentage of patients with major depression eventually convert to bipolar
Suicide
251
Table 81. History of Prior Suicide Attempts in Patients with Unipolar Major Depression
and Bipolar-I and Bipolar-II Disorder
Study
2/23 (9)
11/29 (38)
9/16 (56)
26/204 (13)
30/122 (25)
15/56 (27)
31/303 (10)
7/29 (24)
7/40 (18)
60/558 (11)
9/35 (26)
17/94 (18)
12/38 (32)
6/22 (27)
24/126 (19)
34/353 (10)
7/25 (28)
143/1234 (12)
103/606 (17)
68/253 (24)
TOTAL
Note: Bipolar-I + bipolar-II versus unipolar: X2 = 21.32, degrees of freedom (df ) = 1, p < .001; bipolar-I versus unipolar: X2 = 9.41, df = 1, p < .01;
bipolar-II versus unipolar: X2 = 26.59, df = 1, p < 0.001; bipolar-II versus bipolar-I: X2 = 5.85, df = 1, p < .02.
Source: Rihmer and Kiss, 2002. Reprinted with permission from Blackwell Publishing.
Differences by Gender
In the general population of the United States, approximately three times as many women as men attempt suicide; however, four times as many men actually kill themselves (NCIPC, 2005). The patterns of suicidal behavior
among women and men with manic-depressive illness
show both similarities to and differences from this pattern.
Like the general female population, bipolar women attempt suicide more often than bipolar men. In contrast to
the general population, however, there is no clear predominance of males among bipolar patients who actually
commit suicide; the completed suicide rate for males is
generally equivalent to or lower than that for females.
Seasonality
Seasonality affects the timing of manic and depressive affective episodes (see Chapter 16). It also has a profound
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Clinical Studies
Figure 82. Seasonal patterns of suicide. (Source: Jamison, 1999, Night Falls Fast. Reprinted with permission.)
15
England
1485-1715
14
Europe
1840-1876
13
England
1865-1884
12
11
15 World Health
Organization countries
1951-1959
10
United States
1980-1995
9
8
7
6
5
Jan
Feb
Mar
Oct
Nov
Dec
Suicide
for depression and mania (a spring peak); no such correlation was found in women. It may be that women were admitted earlier in the course of their depressive episode and
that the peak severity occurred later; men may have been
more severely depressed at the time of their admission.
This issue has not been studied systematically.
Maes and colleagues (1993a) found significant spring
seasonality for violent suicides but not for nonviolent suicides in Belgium. They also noted seasonality in the severity of depressive symptomatology as measured by the Zung
self-rating scale, with greater severity reported in the spring
months. Preti and colleagues (1998, 2000), examining violent suicide attempts in Italy, found a peak in the spring
months, but only for violent suicide attempts in males. No
seasonal trend was observed in nonviolent suicides among
males or females during 19841995.
Findings reported by Maes and colleagues (1994) and
Linkowski and colleagues (1992) suggest that violent suicides and perhaps violent attempts may be more common
in sunny weather or higher temperatures. It is known that
violent suicides and attempts are much more common in
males than in females, a fact that is consistent with the
greater occurrence of seasonality patterns in males.
Rasanen and colleagues (2002) investigated the seasonal
distribution of the specific suicide method for both genders (N = 20,234) in Finland for the years 19801995. In
summer, significant peaks occurred in suicides by drowning, jumping, and gassing among males. In autumn, there
were peaks in female suicides by poisoning and drowning.
Traffic suicides showed substantial winter troughs for both
genders. The results demonstrated that specific violent and
nonviolent methods for suicide formed their traditional
clusters on the basis of seasonality, except for suicides by
gassing and shooting.
Gender differences in seasonal patterns of suicide in
Italy were examined by Micciolo and colleagues (1989).
They found cyclic fluctuations in the number of suicides in
both sexes, but only one significant peak per year for men
and two for women. The most significant peak for both
men and women was in May; women had a second peak
in October and November. Hakko and colleagues (1998)
studied seasonal patterns of suicide in Finland using a
database of 21,279 suicides and found a peak for males
from April to July; the distribution for females was bimodal, with peaks in May and October. In the elderly, they
found a significant excess of suicides in autumn. Violent
suicides showed a single spring peak, whereas nonviolent
suicides displayed a bimodal distribution. Marion and colleagues (1999) found that in British Columbia, suicides
among the young were associated with a springsummer
peak, whereas those among the elderly appeared to be related to deviations from expected temperatures for the
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Clinical Studies
time. A recent study of suicides and seasonality in the Austrian prison system (N = 412), conducted over a 53-year period by Fruehwald and colleagues (2001), found no seasonal fluctuation in suicide rates. Parker and colleagues
(2001) found no seasonal variation in 2,013 male and 1,382
female suicides in the equatorial region of Singapore.
Given the strength and breadth of the early findings of
a strong seasonal component to suicide, an obvious question is why the seasonal effect has abated. In a review of the
international literature on the seasonal incidence of suicide, Aschoff (1981) proposed that environmental factors
play a role in the seasonal patterns observed. He found that
during the nineteenth century, seasonal variation in suicide rates was greatest in the least industrialized nations
and declined with greater industrialization. It is likely that
certain aspects of industrialization (e.g., artificial light,
central heating) may partially insulate patients from environmental risk factors for affective episodes. Seasonal variation in suicide rates, as we have seen, is greatest in the
temperate latitudes as opposed to the north, with its extremes of light and temperature. Seasonal variation also is
most correlated with hours of clear sunshine (not day
length per se). Petridou and colleagues (2002), evaluating
the traditional peak occurrence of suicide in June in the
northern hemisphere and in December in the southern
hemisphere, found an association between the seasonal
amplitude of suicide and total sunshine. They suggested
that suicide may be triggered by sunlight, perhaps through
seasonally determined hormones such as melatonin (see
later discussion). Papadopoulos and colleagues (2005)
studied Greek suicide patterns and solar radiance data for
a 10-year period and found that the solar radiance on the
day preceding suicide was positively correlated with suicide risk, as was average solar radiance during the 4 days
preceding that. They hypothesized that sunshine acts as a
natural antidepressant, which first improves motivation,
then only later improves mood, thereby creating a potential short-term increased risk of suicide initially upon its
application (pp. 287288).
Another likely explanation for the trend toward diminishing amplitude of the spring-to-summer peak in suicide
rates is the greater use of mood-stabilizing medications.
Rihmer and colleagues (1998) hypothesized that the link
between seasonality and suicide has been weakened by the
widespread use of lithium and antidepressants. Likewise,
Oraveez and colleagues (2006) attributed the decrease in
the seasonality of suicides in Slovenia to improvements in
access to and effectiveness of psychiatric treatment following the 1991 war. Because major depression has such a
strong seasonal component, the investigators argued that
the decrease in the seasonality of suicide occurred as a result of improved treatment.
Suicide
fall. Admissions for mixed mania had a significantly different pattern, with a peak in late summer and a nadir in late
November. Whitney and colleagues (1999) likewise found
that mixed-state admissions in Canada peaked in the summer, but they did not find a seasonal pattern for mania and
depression. DMello and colleagues (1995), studying the admissions of 377 bipolar patients in Michigan over a 6-year
period, observed that women had a bimodal seasonal distribution, with peak admission rates in the spring and fall.
They found that aggressive behavior peaked in the spring for
both men and women. Several other investigators (Parker
and Walter, 1982, in New South Wales; Mulder et al., 1990, in
New Zealand; and Takei et al., 1992, in London) found a
peak in admissions for mania in spring and summer.
These findings suggest a seasonal pattern in activation
levels in bipolar disorder. Wehr (1992) observed that the risk
for depression peaked at two opposite times of the year
spring/early summer and fall/early winter. These two periods are associated with opposite vegetative symptoms: sleep
and appetite increases in winter depressions and decreases
in spring/summer depressions. Maes and colleagues (1993b)
observed that the severity of depression as measured by the
Zung Self-Rating Depression (ZD) and Anxiety (ZA) scales
showed a significant increase in the spring (AprilMay),
with lows occurring in AugustSeptember; up to 31 percent
of the variance in the weekly average of ZA scores could be
explained by a circannual rhythm. In a subsequent study,
Maes and colleagues (1995) noted a correlation between seasonal variations in serum l-tryptophan and suicide. Taken
together, the studies reviewed here suggest an activation
of manic-depressive illness (including mixed states, as well
as unipolar recurrent depression) in the spring/summer
months that roughly parallels the seasonal increase in suicides reported in the temperate zones, especially in males.
The second suicide peak in October may reflect an increase not only in unipolar depressive episodes, but also in
suicidal depressions following the pronounced increase in
manic episodes among bipolar patients during the summer
months. That is, this second peak may represent suicidal
postmanic depressions. It also may reflect the impact of
mixed, transitional mood states. As patients recover from
summer or autumn hypomania or mania, or as they switch
from hypomania or mania into depression, mixed states are
not uncommon. A recent study of depressed patients with
mixed states found that the depressive episodes peaked in
autumn (Sato et al., 2006). In vulnerable individuals, this
may lead to periods of an acute, agitated suicidal state.
CAUSES OF SUICIDE
In this section, we review what is known about the biological, psychological, and social factors associated with suicide
255
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Clinical Studies
16
19
Tsuang 1983 19
Linkowski et al. 1985 20
Shafil et al. 1985 21
Wender et al. 1986 22
Mitterauer 1990 23
Pfeffer et al. 1994 24
Malone et al. 1995
25
Pooled
0
5 6 7 8 9 10 11 12 13 14 15
Risk Ratio (95% Cl)
Figure 83. Meta-analysis of 22 studies of familial risk of suicide behavior based on random
effects of modeling of relative risk (size of shaded squares reflects approximate weighting by
sample size and variance measures) among families of suicidal probands versus controls and
their 95% confidence intervals (CI; horizontal bars), with a pooled risk ratio and its CI (diamond). All 22 studies found increased familial risk associated with suicidal probands. The
pooled risk ratio (vertical line with diamond) is 2.86 (CI, 2.323.53), which is highly significantly
(p < .0001) greater than the null of 1.0 (vertical line). (Source: Baldessarini and Hennen, 2004.)
concordance rates in twins and adoptees, biological markers, and genetic polymorphisms, as well as linkage analysis.
Twin studies are designed to separate genetic from environmental contributions by comparing risks in MZ and
DZ twins. Roy and colleagues (1999) compared concordance rates in 176 twin pairs with a suicide and found a
greatly elevated rate among MZ (13.2 percent) versus DZ
(0.7 percent) twins. His review examined only completed
suicides, not attempts. In an analysis pooling seven twin
studies, the rate of suicide or suicide attempts in MZ twin
pairs (23 percent) was found to be much higher than that
in DZ (0.1 percent) twin pairs (Table 82) (Baldessarini
and Hennen, 2004). These rates yielded a relative risk of
175, but the investigators considered this figure to be unreliably high because the 0.1 percent rate in DZ pairs was cal-
Suicide
257
Identical (MZ)
Fraternal (DZ)
Risk Ratio
0/11
0/8
Not estimable
Haberlandt, 1967b
14/51
0/98
>27
4/15
0/58
>15
Zair, 1981a
1/1
Not reported
Not estimable
7/62
2/114
365/1,538
0/1,199
>285
10/26
0/9
>133
Total (7 studies)
401/1,704
2/1,486
Twin rates
23.5%
0.135%
175d
Family risk
Not applicable
8.98%e
2.62
Notes: The estimated risk (concordance) among DZ co-twins (0.135%) is 67 times lower than the average rate (8.98%) among the combined
pool of first- and second-degree relatives in family studies summarized in Table 1 of Baldessarini and Hennen (2004), suggesting a more-plausible
estimate of the MZ/DZ risk ratio of 2.62 (23.5%/8.98%; X8 [1 df ] = 276; p < .0001). Even with DZ and family rates pooled, the MZ/DZ risk ratio
would be 23.5%/7.40%, or 3.18. For most studies, CIs are not provided because zero values appear in several numerators.
a
Based on rate of suicides.
b
Based on rate of suicides plus attempts.
c
Based on rate of attempts only.
d
Overall, Fishers exact p < .0001 for the 7 studies.
e
Based on raw data pooled from Table 1, column 3 (612/6811, or 8.98%), in Baldessarini and Hennen (2004).
CI = confidence interval; DZ = dizygotic; MZ = monozygotic.
Source: Baldessarini and Hennen, 2004. Reprinted from Genetics of Suicide: An Overview by Baldessarini and Hennen. Copyright 2004. Reproduced by permission of Taylor & Francis Group, LLC, http://www.taylorandfrancis.com.
258
Clinical Studies
Biological
Adoptive
5/156 (3.20%)
1/83 (1.20%)
2.67 (0.3222.4)b
12/269 (4.46%)
0/148 (0.00%)
4.46d
28/387 (7.24%)
8/180 (4.44%)
1.63 (0.763.50)
Suicides
15/387 (3.88%)
1/180 (0.56%)
6.93 (0.9352.4)
Attempts
13/387 (3.36%)
7/180 (3.89%)
0.86 (0.322.13)
20/543 (3.68%)
2/263 (0.76%)
4.84 (1.1420.6)
Notes: All three studies are based on a single Danish database. Study A data are for rates of suicides or attempts in biological or adoptive firstdegree relatives of early-adopted probands who were diagnosed with schizophrenia-like disorders (n = 33), committed suicide (n = 57), or were diagnosed with an affective disorder (definite or probable DSM-III major depression or bipolar disorder; n = 71), compared with early-adopted controls
matched for number, gender, socioeconomic class of adoptive parents, age at adoption, current age compared with proband age at suicide, and time
living with biological mother. Study B data (involving suicidal adopted probands), although complementary to other analyses, are probably not independent and are therefore not included in D (pooled data from studies A and C).
a
Schizophrenia-like probands.
b
Fishers exact p = 0.0056.
c
Suicidal probands.
d
CI is indeterminate because of zero numerator.
e
Mood-disordered probands.
CI = Confidence interval.
Source: Baldessarini and Hennen, 2004. Reprinted from Genetics of Suicide: An Overview by Baldessarini and Hennen. Copyright 2004. Reproduced by permission of Taylor & Francis Group, LLC, http://www.taylorandfrancis.com.
association with psychiatric disorders or major life stressors. Psychiatric disorders and major life stressors, in other
words, may trigger the genetic susceptibility to suicidal behavior.
Kety (1987) was among the first to hypothesize that a genetically influenced inability to control impulsive behavior
might be a specific and independent susceptibility factor.
Several family studies have lent support to the hypothesis
that impulsive aggression, independently of psychiatric illness, increases suicide risk.7 Impulsive aggression has been
linked to low serotonin function (see reviews by Linnoila
and Virkkunen, 1992; Oquendo and Mann, 2000), which is
a biological marker of suicidal behavior (see later discussion).
Aggressiveness/impulsivity was one of a number of potential suicide risk factors studied by Oquendo and colleagues (2004). They tested the stressdiathesis model for
suicidal behavior in a prospective investigation of 308 patients with major depressive or bipolar disorder. They
found that the three strongest predictors of future suicidal
Suicide
Neurobiological Factors
Serotonin Hypofunction
Many studies conducted over several decades have found
an association between suicide and serotonin hypofunction. The first investigators to observe the association were
Asberg and colleagues (1972), who found, in particularly
violent suicide cases, low levels of 5-hydroxyindolacetic
acid (5-HIAA)the principal serotonin metabolitein
cerebrospinal fluid (CSF). A meta-analysis of 20 studies
involving 1,002 psychiatric patients found that those with
a history of attempted suicide, particularly violent attempts,
had lower levels of 5-HIAA in CSF than did psychiatric
controls (Lester, 1995). Lower serotonergic activity has
259
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Clinical Studies
Low Cholesterol
A number of studies have suggested a possible relationship
between low cholesterol and impulsive aggression, including higher death rates from suicide. The link is hypothesized to occur through cholesterols effect on serotonin activity (Mann, 1998). The findings of these studies, however,
which include both large epidemiologic surveys and studies of suicidal individuals, have been mixed.9 In some
cases, an association was found only in violent suicide attempters (Alvarez et al., 2000). (See reviews by Boston
et al., 1996; Hillbrand and Spitz, 1997.)
In those studies looking specifically at bipolar patients,
the findings have again been mixed. Bocchetta and colleagues (2001) studied 783 consecutive patients admitted to
a lithium clinic. They found that the proportion of men
with a lifetime history of suicide attempts or a history of a
suicide by a first-degree relative was significantly higher in
the group with low cholesterol levels (in the lowest 25th
percentile) than in those with higher levels. Cassidy and
Carroll (2002a) found low fasting cholesterol in manic patients, particularly during mixed manic episodes, and hypothesized that this condition is secondary to immune activation. On the other hand, Tsai and colleagues (2002),
studying 43 bipolar patients who died by suicide in Taiwan
between 1985 and 1996, found no difference in cholesterol
levels compared with controls, who were bipolar patients
still living.
In summary, if there is a relationship between low cholesterol and suicide, it is likely to apply to violent suicide
attempts and completed suicides. However, lowering cho-
Suicide
lesterol with statin medications does not appear to have increased suicide risk in the large samples studied (Manfredini et al., 2000; Muldoon et al., 2001), and it is unclear
whether the association between low cholesterol and suicide risk will hold true in bipolar patients.
261
suicide attempters and nonattempters. Likewise, a metaanalysis found that DST nonsuppression was predictive of
completed suicide (Lester, 1992).
Findings of a more recent study strengthened the relationship between nonsuppression and completed suicide.
Coryell and Schlesser (2001) found that nearly half of 78
inpatients with affective disorders were DST nonsuppressors at admission. After being followed for 15 years, 26.8
percent of nonsuppressors eventually died by suicide,
compared with only 2.9 percent of DST suppressors.
Within this sample, a comparatively small number of bipolar patients had received a DST because most had been admitted in a manic state, which made cooperation in taking
the DST more difficult. Data from studies of abused children and patients with post-traumatic stress disorder also
suggest that these overwhelming stressors can persistently
alter the responses of the HPA axis (Heim and Nemeroff,
1999, 2002).
Norepinephrine Function
Several studies have identified alterations in norepinephrine transmission in relation to suicide. Ordway (1997)
and others (Arango et al., 1997; Gonzalez-Maeso et al.,
2002) found reductions in norepinephrine levels in the
locus caeruleus (LC) of suicide victims, as well as increased levels of tyrosine hydroxylase and supersensitivity of alpha-2 adrenoceptors. Ordway characterized the
changes he found in suicide victims as being similar to
those found in rats after LC activation. He hypothesized
that suicide victims experience chronic activation of
the LC, leading to depletion of norepinephrine and other
compensatory changes. Recently, Ono and colleagues
(2004) found evidence suggesting that a Val/Val polymorphism for the catecholamine-metabolizing enzyme,
catechol-O-methyltransferase, may be protective against
suicide.
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Clinical Studies
Social Factors
The impact of social factors, such as losing an important
relationship or a job or facing legal or criminal proceed-
Suicide
Mixed States
Mixed states are a significant risk factor for suicide.
Among the first to study the relationship between agitated,
dysphoric states and suicide was Jameison (1936), who
concluded that mixed states were the most dangerous clinical phase of illness for suicide risk.11 In his investigation of
100 suicides (half with manic-depressive psychosis), he
noted that the combination of depressive symptoms, mental alertness, and tense, apprehensive, and restless behavior
was particularly lethal. Mixed states represent a potentially
deadly combination of depressive affect and cognition,
linked to dysphoric state, heightened energy level, and increased impulsiveness. Jameisons clinical account of
mixed states and their association with suicide remains
apt, as does his observation that those patients who were
both tense and restless were at the greatest risk for suicide:
Finally there are the patients with mixed manicdepressive states. The majority of these show the usual depression, numerous self-accusations, ideas of guilt and
punishment and a varying degree of hypochondriasis. At
the same time there is a mental alertness, associated with
tense, apprehensive and restless behavior. The retardation
of thought and action that paralyzes the acting out of the
wish for death in the average depressed patient is entirely
absent in these persons. They are, therefore, the most
dangerous types of patients with mental disease, so far as
suicide is concerned. The records of the fifteen patients
in the group emphasize this strikingly. Three of these
patients committed suicide twenty-four hours after leaving the hospital, two within forty-eight hours, another
263
Depression
It has long been known that depression is strongly correlated with suicide and suicide attempts (Jameison and
Wall, 1933; Barraclough et al., 1974; Weeke, 1979). More recent findings strengthen the early clinical observations.
Isometsa and colleagues (1994) studied a sample of 31
bipolar patients who committed suicide in Finland within
a 12-month period, 74 percent of whom had been receiving psychiatric care at the time of their suicide. Among
these patients, 79 percent were depressed at the time of
death, 11 percent were in a mixed state, and 11 percent died
during or immediately after remission of psychotic mania.
Dilsaver and colleagues (1997) found bipolar depression
to have been associated with suicidality somewhat more
frequently than were mixed states, although both conditions were associated with greater suicidality than was
pure mania. Grunebaum and colleagues (2004) compared
suicide attempts among 347 patients with melancholic
versus nonmelancholic major depression. They found
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Clinical Studies
that melancholic features during depression were correlated with more serious past attempts and the probability
of suicide at follow-up.
The severity of depression is a factor as well (Arato et
al., 1988; Henriksson et al., 1993; Isomets et al., 1994).
Swedish researchers psychiatrically assessed an entire rural
population and then kept track of its mental health for the
next 15 to 25 years (Hagnell et al., 1981). Virtually all of the
men who committed suicide during the follow-up period
had been diagnosed during their initial evaluations as having depressive illness. The suicide rate for men with no
psychiatric diagnosis at all was 8.3 per 100,000, but for
those with depression it escalated to 650. No one with mild
depression committed suicide, but the rate rose to 220 per
100,000 for those who had been diagnosed with moderate
depression and to 3,900 per 100,000 for those with severe
depressive illnesses.
Weeke (1979) found that at the time of death, 58 percent
of manic-depressive patients who committed suicide had
been in a constant or worsening depressive state. Fully 30
percent of the patients, however, had been classified as depressive state, recovering. Keith-Spiegel and Spiegel (1967)
compared the clinician-rated mood states of 61 psychiatric
patients immediately preceding their suicides with those of
51 matched control patients of comparable age and diagnoses who had not committed suicide or had no history of
a suicide attempt. Those who killed themselves had histories of more frequent and more severe depressions, as well
as more suicide attempts, threats, and suicidal ideation. Of
particular significance, however, was that just before
death, those who committed suicide had been assessed by
their clinician as being calmer and in better spirits than
members of the control group. An apparently unwarranted
mood shift had been observed in those who killed themselves.
These findings add weight to the clinical observation,
dating back hundreds of years, that improvement in depression is associated with an increased risk for suicide.12
Several factors may account for this counterintuitive observation. The improvement may reflect a sense of calm
once the decision has been made to die, a genuine calm before the storm brought about by biological changes, or a
transition from one phase of the illness to another (e.g.,
from depression to hypomania, mania, or a mixed state). It
also may reflect true clinical improvement, with a concomitant level of frustration when symptoms recur. In
some instances, an improved clinical state enables a previously indecisive and lethargic patient to become more able
to make an unambivalently lethal decision and to act on
that decision. Finally, improvement may in fact be a patients deliberate deception of physicians, hospital staff,
and family so a suicide plan can be carried out. Problems
Rapid Cycling
Rapid cycling increases the risk of suicide and suicidal behavior. One of the first large studies to examine the relationship between suicide and rapid cycling was NIMHs
Collaborative Study on the Psychobiology of DepressionClinical Studies (Fawcett et al., 1987). Of the studys 954 patients, 569 had unipolar depression,13 185 had bipolar-I, 114
had bipolar-II, and the remaining 80 had schizoaffective
disorder. The incidence of suicide over the 4-year study period was 3 percent. The rate did not differ by diagnosis.
What did distinguish patients who died by suicide from
those who did not was mood cycling during the index
episode (p <.002). Mood cycling in this study meant that
the patient had been admitted in one mood state, such as
mania, and cycled into the other before recovery. While this
is not synonymous with the classic definition of rapid cycling (i.e., four or more affective episodes in 1 year), there is
overlap between the two groups. The authors of the study
concluded that mood cycling, which is a feature of bipolar
or schizoaffective disorder, is associated with suicide, particularly in men.
In a 5-year prospective study of 345 patients with
bipolar-I or -II disorder, 89 patients were identified, using
DSM-IV criteria, as having a pattern of rapid cycling for
1 year or more (Table 84; Coryell et al., 2003). The rapidcycling patients were significantly more likely than the rest
of the patients to have had onset of illness before age 17 and
were twice as likely to attempt, but not to complete, suicide.14 The differences between the groups were most pronounced for attempts rated as being of high lethality.
Brodersen and colleagues (2000) conducted a 16-year
follow-up study of 133 patients with major affective disorders (defined as having two to three affective episodes in
a 5-year period) treated with lithium. Most of the 11 suicides occurred among the atypical patients (those with
schizoaffective disorder, bipolar-II disorder, mixed episodes,
and/or rapid cycling). MacKinnon and colleagues (2005),
in a study of 1,574 family members with bipolar disorder,
also found that a history of rapid mood switching was
Suicide
265
Table 84. Relationship between Rapid Cycling, Suicide, and Suicide Attempts
before Intake and during Follow-Up
Any Rapid Cycling
(n = 89)
No Rapid Cycling
(n = 256)
Any attempt
51 (57.3)a
85 (33.2)
31 (34.8)a
38 (14.8)
36 (40.4)a
35 (13.7)
3 (3.4)
11 (4.3)
Any attempt
46 (51.7)a
70 (27.3)
27 (30.3)a
33 (12.9)
30 (33.7)a
36 (14.1)
a
Significant differences by chi square, p <.001.
Source: Adapted from Coryell et al., 2003. Copyright American Medical Association. All rights
reserved.
266
Clinical Studies
suicidal bipolar patients. Likewise, MacKinnon and colleagues (2005) found that comorbid panic disorder increased the risk of suicidality in individuals with bipolar
disorder. Among patients with major depression, Reich
(1998) found that suicide attempts were correlated with
higher levels of comorbid anxiety. Hall and colleagues (1999)
found that severe anxiety was present in 90 percent and
panic attacks in 80 percent of suicide attempters. Schnyder
and colleagues (1999) reported similar findings showing the
presence of severe anxiety in a study of 30 consecutive emergency room suicide attempters who were later admitted to a
psychiatric inpatient unit (diagnoses not specified in the
study). Likewise, Angst and colleagues (1998) found the
presence of anxiety to be a suicide risk factor in a 5-year
follow-up sample of 186 patients with unipolar and 220 patients with bipolar depression. And in an analysis of 76 inpatient suicides, Busch and colleagues (2003) found that 79
percent of patients had chart notes indicating severe anxiety/
agitation within 1 week of their suicide.
One study attempted to ascertain what features of bipolar illness, including panic disorder, are related to suicidality. Dilsaver and colleagues (1997) divided their sample of
125 bipolar patients into three groupsthose with bipolar
depression, those with depressive mania, and those with
pure mania. They examined the incidence of suicidality
(rated using the SADS), psychosis, and intra-episode panic
disorder (IEPD). IEPD was highly prevalent in the bipolar
depression (79 percent) and depressive mania groups (56
percent) but rare (2.3 percent) in the pure mania group.
Overall, the findings suggest a high degree of overlap
among suicidality, IEPD, and bipolar depression or depressive mania, as opposed to pure mania.
Taken together, these studies argue for the assessment of
severe anxiety or agitation and for aggressive anxiolytic
treatment in the management of suicide risk in affective
disorders (see Chapter 25).
Insomnia and excessive concern about sleep disturbances have been noted as correlates of increased potential
for suicide,15 as has pervasive hopelessness (see earlier discussion). The body of evidence has led to widespread acceptance that insomnia and hopelessness are risk factors
for suicide. Global insomnia is considered an acute risk
factor because it was found, in a prospective study, to be
associated with suicide within the first year of study entry
(Fawcett et al., 1990).
Substance Abuse
Comorbid substance abuse is another risk factor for suicide in both bipolar and unipolar patients, particularly in
the young (Fawcett et al., 1987; Murphy, 1988). In their
large, prospective study, Fawcett and colleagues (1987)
found a significant increase in long-term risk with socalled double abuse (alcohol plus any other abused substance). They also found recent, moderate alcohol abuse to
be a short-term (acute) risk factor (see Chapter 25).
Like Fawcett and colleagues, others have noted an association between alcohol abuse and suicide. Barraclough
and colleagues (1974) found that as the number of suicide
attempts increased, so did the chances that the attempter
was alcohol dependent. In a study of 204 suicides, Rich and
colleagues (1988) noted substance abuse and affective disorders to be the most frequent diagnoses for men and
women. Morrison (1975) found that bipolar patients who
were also alcohol dependent had a higher rate of suicide in
their family histories than did nondependent bipolar patients. In a study of suicide among adolescents and young
Suicide
adults, Runeson (1989) observed a 47 percent rate of comorbid substance abuse with any Axis I or II diagnoses.
Depressive disorders were diagnosed in 64 percent of those
who committed suicide (major depressive disorder = 41
percent).
Tondo and colleagues (1999) found an association between substance abuse disorders and suicide attempts in
hospitalized patients, with substance abuse raising the suicide risk more than two-fold regardless of the disorder. In
a study of 307 male veterans, Waller and colleagues (1999)
noted that comorbidity of alcohol abuse and bipolar-I or
unipolar depressive disorder was always associated with an
increased risk of suicidality.
Pini and colleagues (1999) found that among 125 bipolar
patients with psychotic features, the subgroup having substance abuse associated with other Axis I comorbidities
had an earlier age at onset of their bipolar disorder, more
frequent onset with a mixed state, and a higher risk of suicide. Oquendo and Mann (2001) observed that bipolar patients who attempted suicide had higher levels of aggression and comorbid substance abuse than nonattempters.
Vieta and colleagues (2000) noted that among 40 patients
with bipolar-II disorder, 21 percent had substance abuse
comorbidity, and this group had significantly higher rates
of suicidal ideation and attempts. Vieta and colleagues
(2001) studied 129 bipolar outpatients in remission, finding
comorbidity in 31 percent; these patients also had higher
rates of mixed states, depressive episodes, and suicide attempts. Cornelius and colleagues (1995) found that suicidality was disproportionately higher among patients with
comorbid depression and substance abuse than among
those with either disorder alone.
The connection between suicide and substance abuse
may be attributable to increased impulsivity or aggressiveness, impaired sleep, or destabilization of illness. As we
have seen, low levels of the serotonin metabolite 5-HIAA
are correlated with aggression and impulsivity, and it has
been shown that patients making the most violent and impulsive suicide attempts have low 5-HIAA levels (see also
Chapter 14). It is of interest that Rosenthal and colleagues
(1980) found significantly lower levels of 5-HIAA among
depressed patients with a family history of alcoholism
than among those without such a family history. Low 5HIAA levels also have been found in alcoholics after recovery (Ballenger et al., 1979; Linnoila and Virkkunen, 1992;
Virkkunen and Linnoila, 1993). Therefore, not only do
substance abusers have impaired judgment and decreased
inhibition from the drugs themselves, but they may also
bear a biological risk for suicide. Bipolar patients who are
impulsive or more temperamentally prone to agitated
states may be more inclined to use alcohol and other drugs
than those who are not. Swann and colleagues (2004)
267
Psychosis
The relationship between psychosis and suicide in mood
disorders is unclear. An early, often-cited retrospective
analysis of patients with unipolar depression hospitalized
at the New York State Psychiatric Institute between 1955
and 1980 found an unusually high rate of delusions among
those who committed suicide (Roose et al., 1983). Bipolar
patients were not considered separately in this study, but
the findings were suggestive of symptom patterns associated with a high risk of suicide. The authors noted that depressed inpatients who were delusional were five times
more likely than those who were nondelusional to commit
suicide, and that delusional males were particularly vulnerable. Two recent studies found that bipolar children
and adolescents with a history of psychotic features were
more likely to be suicidal than those who did not have
such a history (Papolos et al., 2005; Caetano et al., 2006).
The recent study from the Juvenile Bipolar Research Foundation (Papolos et al., 2005) also found that bipolar children and adolescents who threatened to commit suicide
were far more likely to report having hallucinations than
those who did not threaten suicide.
On the other hand, several studies suggest no such relationship. A study of 1,593 affectively ill patients revealed no
increased risk of suicide among the 27.8 percent who had
been psychotic at the time of their index hospitalization
(Black et al., 1988). Likewise, Fawcett and colleagues (1987)
found that psychotic patients diagnosed with affective illness did not have higher prospective rates of suicide over a
10-year follow-up. Dilsaver and colleagues (1997) found no
association between the presence of psychosis and mild
suicidality; a subsequent study found no association between psychotic features and suicidality in adolescents
(Dilsaver et al., 2005). Similarly, Coryell and Tsuang (1982)
and Frangos and colleagues (1983) found no increased risk
of suicide in patients with delusional depression.
Course of Illness
There is consistent evidence of an increased risk of suicide
and suicide attempts early in or just after the first episode
of affective illness,17 as well as in bipolar disorder more
specifically. Among the first to study the time course of suicide attempts in bipolar patients were Johnson and Hunt
(1979). They found in their very small sample that 30 percent of suicide attempts (90 percent of which warranted
hospitalization) occurred at the onset of the illness or
268
Clinical Studies
Males
Females
All ages
15.0
22.4
<30 yra
81.6
71.7
a
Age at first admission and in the first year of follow-up.
Source: Reprinted with permission from Osby et al., 2001. Copyright, American Medical Association. All rights reserved.
Table 86. Comorbid Conditions and Suicide Attempts in Bipolar Disorder by Age at Onset (percent)
Onset Age <13 yr
(n = 272)
Wald X2
(2 df )
p Value
Suicide attemptsa
49.8
37.0
24.6
32.58
<.0001b,c,d
69.2
53.9
38.3
48.87
<.0001b,c,d
Alcohol abuse/dependence
47.3
46.6
31.9
15.89
.0004b,c
34.2
33.4
15.1
40.86
<.0001b,c
Suicide
CONCLUSIONS
Suicide is still far too common in manic-depressive illness.
Patients diagnosed today face a lifetime suicide risk of at
least 5 percent. While this figure is lower than in previous
erasa result in part of better treatments and in part of
the inclusion of less severely ill patients in outcome
studiesseveral groups of patients continue to bear a disproportionately high risk burden, including those who are
hospitalized or recently discharged and those who are untreated, inadequately treated, or treatment resistant. Further, the suicide rate remains strikingly high early in the
course of illness.
The precise causes of suicide remain elusive, although
they most certainly entail an interaction between the underlying affective illness and additional biological and psychosocial risk factors. But research has not yet found any
particular combination of risk factors to be sensitive or
sufficient enough to predict a suicide. Salient risk factors
include rapid cycling, mixed states, and severe depressive
episodes. A significant advance has come with the identification of which of many risk factors operate in the short
term (e.g., agitation, severe hopelessness, global insomnia)
versus the long term (e.g., past suicide attempt, various
comorbidities). Risk factors and their identification,
269
NOTES
1. National statistics tend to underestimate suicide deaths because of the difficulty of establishing suicidal intent in singlecar accidents and other accidental deaths and because of
cultural, financial, and religious disincentives to label a death
as a suicide.
2. For example, Fawcett et al., 1987, 1990; Black et al., 1988;
Angst et al., 1999.
3. Wetterberg et al., 1978; Carlsson et al., 1979; Oddie et al., 1979;
Perez et al., 1980; Aschoff, 1981; Behall et al., 1984; Losonczy et
al., 1984; Gordon et al., 1987; Lacoste and Wirz-Justice, 1989;
Sarrias et al., 1989; Soutre et al., 1989; Modai et al., 1992;
Maes et al., 1995; Pine et al., 1995; Verkes et al., 1996; Zajicek et
al., 2000.
4. Mann et al., 1992; DHondt et al., 1994; Maes et al., 1995; Pine
et al., 1995.
5. Pokorny, 1983, 1991; Goldstein et al., 1991; IOM, 2002.
6. For example, Egeland and Sussex, 1985; Brent et al., 1996;
Johnson et al., 1998; Statham et al., 1998; Johnson and
Cameron, 2001; Fu et al., 2002.
7. Pfeffer et al., 1994; Brent et al., 1996, 2003; Johnson et al.,
1998.
8. Mann et al., 1999; Keilp et al., 2001; Oquendo and Mann,
2001; Oquendo et al., 2004.
9. Fawcett et al., 1997; Partonen et al., 1999; Tanskanen et al.,
2000; Ellison and Morrison, 2001; Golomb et al., 2002;
Lester, 2002; Lalovic et al., 2004.
10. Bunney and Fawcett, 1965; Fawcett and Bunney, 1967; Bunney
et al., 1969; Krieger, 1970.
11. Koukopoulos and Koukopoulos (1999) traced the history of
the conceptualization of mixed states back to Kraepelin, who
conceived them as a form of manic-depressive insanity; before that to the state of melancholia agitata described by
Richarz (1858); and still further back to Hippocrates, who described the anxiety seen in agitated melancholia in Diseases
II. This state, characterized by anxiety and agitation as primary symptoms, has gradually been separated from manicdepressive illness, appearing today as a subtype of major
depression-agitated type.
12. Rush, 1812; Kraepelin, 1921; Clouston, 1915; Henderson and
Gillespie, 1927; Jameison and Wall, 1933; Stengel, 1955; Copes
et al., 1971; Copas and Fryer, 1980; Barner-Rasmussen, 1986;
Schweizer et al., 1988.
13. Of the 569 with unipolar major depression, 210 were in first
episodes, and 359 were in recurrent episodes.
14. There were too few completed suicides to permit meaningful
comparisons.
15. Jameison and Wall, 1933; Slater and Roth, 1969; Barraclough
et al., 1974; Motto, 1975; Fawcett et al., 1987, 1990.
16. Cluster B disorders are antisocial personality disorder, borderline personality disorder, histrionic personality disorder,
and narcissistic personality disorder.
17. Guze and Robins, 1970; Tsuang and Woolson, 1977, Weeke,
1979; Inskip et al., 1998.
Part III
Psychological
Studies
Neuropsychology
I seem to be in perpetual fog and darkness. I cannot get my mind to work; instead of associations clicking into place everything is an inextricable jumble; instead of seeming to grasp
a whole, it seems to remain tied to the actual consciousness of the moment. . . . I could not feel
more ignorant, undecided or inefficient. It is appallingly difficult to concentrate.
John Custance (1952, p. 62)
First, neuropsychological investigation can identify the constituent processes impaired in some of the classic symptoms
of the disorder. For example, psychomotor disturbance is
common in major depression and bipolar disorder, and depressed bipolar patients may be especially likely to manifest
psychomotor retardation (Sobin and Sackeim, 1997). In
turn, this motor disturbance is viewed by some as having
special prognostic significance with respect to treatment
outcome (Hickie et al., 1990a, 1996; Parker and HadziPavlovic, 1993). However, the term psychomotor retardation is itself an amalgam, and the slowness of movement
seen in depressed patients may reflect slowing in any of a variety of cognitive or motor processes. Indeed, some success
has been achieved in using objective measures to dissect the
constituent processes of such retardation and to identify
those disturbed in affective disorders (Sobin and Sackeim,
1997). Thus in principle, neuropsychological evaluation can
determine just what is slowed in psychomotor retardation
and quantify the extent of abnormality.
Similarly, disturbances in attention are rife in mood disorders, yet they can pertain to distinct cognitive processes
such as vigilance or sustained attention, freedom from distraction, divided attention, and capacity to shift set.1 Neuropsychological investigation can clarify the nature of what
is typically referred to as impaired concentration.
CONTRIBUTIONS OF NEUROPSYCHOLOGICAL
EVALUATION
The contributions of traditional neuropsychological
testing to our understanding of manic-depressive illness
pertain to four issues. Such investigation can (1) provide
an empirical basis for and clarification of clinical phenomenological concepts; (2) determine which abnormalities are state dependent and which are state independent;
(3) characterize the neuropsychological functions that appear to be most persistently impaired, providing a clue to
pathophysiology; and (4) determine the burden of the illness and its treatments with respect to cognitive functioning in terms of both cross-sectional and longitudinal outcomes.
273
274
Psychological Studies
evaluation also yields information on strengths and weaknesses that go beyond clinical phenomenology. For the past
40 years, there has been an unresolved debate about whether
the bipolar subgroup of manic-depressive illness is overrepresented in individuals with higher levels of intelligence
and/or creativity (Richards et al., 1983; Andreasen, 1987;
Jamison, 1993) (see Chapter 12). This issue can be addressed
by determining whether premorbid intelligence in individuals with bipolar disorder exceeds population norms, and
whether such individuals exceed normative values on indicators of creativity, such as those assessed by measures of
cognitive flexibility and idiosyncratic thought. In turn, findings in this area may be helpful in considering sociobiological questions, such as why the genes for bipolar disorder
have been preserved.
More generally, through comparison of individuals in remission and in the depressed or manic state of bipolar disorder, neuropsychological investigation can provide new information on the sensorimotor and cognitive abnormalities
that fluctuate with affective state or are invariant across the
disorder. As noted above, the state of depression or mania
can introduce serious confounds in neuropsychological
evaluation. Therefore, a number of recent investigations
have placed special emphasis on detailing the deficits characteristic of bipolar patients in remission,2 of children at risk
for the disorder (Decina et al., 1983; Dickstein et al., 2004;
Meyer et al., 2004), and of other first-degree relatives
(Sobczak et al., 2002; Ferrier et al., 2004; Zalla et al., 2004),
including discordant monozygotic twins (Gourovitch et al.,
1999). Indeed, the identification of abnormalities that persist
across the phases of the illness or that precede its first expression as a mood disorder may provide markers of disease
vulnerability and suggest neurobiological abnormalities responsible for disease expression.
Neuropsychology
Neuropsychological burden not only results from disease expression and progression, but may also be an inadvertent outcome of treatment (as may neuroprotection).
An especially frequent complaint of patients treated with
lithium is that, in concert with a dampening of the peaks
and valleys of mood fluctuation, creative processes are inhibited. Some individuals report that they are not as original or forward thinking when treated with lithium, or are
less quick to see connections and less spontaneous (see
Chapter 12). These claims have been tested in neuropsychological investigations, whose results have revealed adverse cognitive effects of lithium that are dose dependent
and appear to reverse shortly after discontinuation of the
drug (Shaw et al., 1986, 1987).
META-ANALYSIS OF FINDINGS
ON NEUROPSYCHOLOGICAL DEFICITS
IN MOOD DISORDERS
In the following sections, we present a critical evaluation of
what has been learned from neuropsychological evaluations
of samples of manic-depressive patients. Much of the literature on neuropsychological function in mood disorders, especially in the depressed phase, has failed to distinguish between bipolar and unipolar subgroups. Necessarily, some of
the discussion of neuropsychological deficits in depression
Figure 91. Findings obtained with Complex Figure Test. Unmedicated unipolar (UP) and bipolar
(BP) patients in an episode of major depression were divided into young and elderly groups. Across
multiple measures of memory, the elderly BP patients were greatly impaired, while the young BP patients tended to have the best performance. Shown are scores for copying a complex figure and also
for later reproduction of the figure from memory. The delayed reproduction scores show the special
deficit in the bipolar elderly. (Source: Burt et al., 2000. Reprinted with permission from Lippincott
Williams & Wilkins.)
35
Copy
Delayed Reproduction
30
25
20
15
10
0
UP: Young
BP: Young
275
UP: Elderly
BP: Elderly
276
Psychological Studies
levels of intelligence, or surrogate measures such as occupational achievement, differ from population norms.
Figure 92 presents a meta-analysis of recent studies
contrasting the full-scale intelligence quotient (IQ) scores
of bipolar patients and healthy volunteers obtained with
the WAIS-R. Despite the relatively small number of studies, significant deficits were observed in the remitted, manic,
and mixed samples relative to controls. (Only one study
[Deptula et al., 1991] was classified as exclusively examining bipolar depressed patients.) Thus, preliminary evidence
indicates that intelligence, as assessed by a well-validated
measure, is reduced in bipolar illness in both the remitted
and manic states. This conclusion is supported by a variety
of early studies that found evidence for general intellectual
impairment in symptomatic bipolar patients.
The above findings do not imply that variations in state
have no impact on intelligence scores. Cross-sectional comparison with control samples can establish whether each
state manifests abnormality, but can give only a rough indication of the magnitude of changes that may occur within
the same individuals in different states. Indeed, there is evidence that some patients have higher intellectual functioning
when hypomanic than when depressed (Donnelly et al.,
1982). Furthermore, a variety of longitudinal studies have
found the remitted state to be associated with higher IQ than
the depressed state.5 While such findings have been interpreted as indicating a state-dependent deterioration in IQ
(Miller, 1975), much of this work was subject to the same
confound: repeat IQ testing generally results in a modest increase in scores attributable to practice effects (Matarazzo et
al., 1980). Most studies tested patients in a depressed or
manic state, with later retesting during euthymia. Such an
invariant order would bias results toward higher scores in the
euthymic or remitted state relative to depression or mania.
The firmest conclusion that can be drawn from this literature is that samples of bipolar patients, whether remitted or
not, show modest global cognitive impairment as reflected
by diminished IQ scores. This conclusion is strengthened
by findings obtained using broad-based clinical neuropsychological batteries, such as the Halstead-Reitan or LuriaNebraska. Summary impairment scores on these batteries
correlate highly with IQ scores. Several studies have found
gross impairment, on a level comparable to that in schizophrenia, in manic samples, and moderate-to-severe impairment in unipolar and/or bipolar depressed samples.6
Interpretation of a global intellectual deficit in bipolar
disorder is highly contingent on beliefs about the level of
premorbid functioning. For example, an IQ deficit in the remitted state may reflect an impairment that preceded the expression of bipolar disorder, or may represent a form of deterioration resulting from the disorder or its treatments. On
the other hand, it has been suggested that bipolar patients
Neuropsychology
277
All Studies
All Mania
Souza et al. (1995)
Gourovitch et al. (1999)
All Mixed
Dalby and Williams (1986)
All Depression
Deptula et al. (1991)
All Remitted
Zubieta et al. (2001)
Zalla et al. (2004)
van Gorp et al. (1999)
van Gorp et al. (1998)
Morice (1990)
Ali et al. (2000)
"2
"1.5
"1
"0.5
0.5
1.5
Figure 92. Meta-analysis of full-scale intelligence quotient (IQ) scores obtained with the Wechsler
Adult Intelligence Scale-Revised (WAIS-R). Effect sizes (Hedges G) are presented for individual study
comparisons of a bipolar sample with healthy controls, as well as for samples of bipolar patients in
remission, depression, mixed state, or mania and across all studies. Squares = confidence interval;
circles = mean.
may be premorbidly advantaged; that is, their level of intelligence prior to disease expression tends to be above average.
Were this the case, it would indicate that the deficits observed in comparisons with healthy volunteers underestimate the deterioration from premorbid values.
Unfortunately, while often discussed, this issue has received limited research attention. Mason (1956) contrasted
the prerecruitment IQs of Army veterans hospitalized for
schizophrenia and what was termed manic-depressive illness, which no doubt included some patients with recurrent
unipolar depression. The schizophrenia sample had premorbid IQs below control values, whereas the IQs of mood disorder patients were significantly better than those of healthy
subjects. Woodruff and colleagues (1968, 1971) found that
bipolar patients and their brothers had higher levels of occupational and educational achievement than unipolar patients
and their brothers, with the latter group not differing from
healthy volunteers. Other work has similarly indicated that
the families of individuals with bipolar disorder have an advantage relative to population norms for educational and occupational achievement (Petterson, 1977; Waters et al., 1981),
as well as creativity (see Chapter 12). Indeed, limited research
with children of bipolar probands before the first manifestation of frank mood disorder supports the possibility of an IQ
elevation in the premorbid state (Decina et al., 1983).
This possibility of an elevation in premorbid intellectual abilities relative to population norms is reinforced by
the literature on the relationship between social class and
bipolar disorder. A number of studies, starting at the beginning of the twentieth century, have generally found that
bipolar disorder is overrepresented in individuals with
middle and high income levels and among business and
other professionals. It is possible that these associations reflect an ascertainment bias. Individuals of a higher socioeconomic level may be especially likely to be diagnosed
with a mood disorder instead of schizophrenia or schizoaffective disorder, with the reverse pertaining to those of
lower socioeconomic levels. However, the fact that these associations are also observed among the family members of
bipolar probands undercuts this hypothesis (Woodruff
et al., 1971; Monelly et al., 1974; Eisemann, 1986; Coryell
et al., 1989).
Thus there is reason to suspect that as a group, individuals with bipolar disorder are endowed with general intellectual abilities superior to the distribution in the general
population and may be more likely to have backgrounds of
middle and upper socioeconomic levels. Yet it also appears
that bipolar disorder is characterized by poorer general intelligence across all phases of illness. If both of these views
are correct, it would suggest that the disorder is associated
278
Psychological Studies
with significant deterioration in general intellectual abilities or that there are compensatory cognitive advantages in
a subgroup of individuals with bipolar illness (see Chapter
12). Studies contrasting patient samples with healthy volunteers likely underestimate the extent of deterioration because they do not account for the premorbid baseline.
Contexts in which a group differs in premorbid intellectual abilities present significant problems in interpreting
comparisons with patients with other disorders or healthy
volunteers. Neuropsychological tests differ in their sensitivity
to the generalized effects of brain insult. For example, vocabulary and comprehension subtests of the WAIS-R are traditionally viewed as hold scales because of their relative immutability in providing an indication of premorbid ability in
the face of brain damage. However, samples of patients with
bipolar disorder have usually been matched to comparison
groups on the basis of current demographic and neuropsychological features (e.g., age, sex, current IQ). This design
may entail, therefore, that the two groups are mismatched
with respect to premorbid levels. Thus patterns of apparently
specific deficits seen in remitted or symptomatic states may
be reflecting only the varying sensitivity of tests to a generalized destructive process.
Neuropsychology
279
All Studies
All Mania
Robertson and Taylor (1985)
All Mixed
Dalby and Williams (1986)
All Depression
Deptula et al. (1991)
All Remitted
Park (1997)
Morice (1990)
Coffman et al. (1990)
Ali et al. (2000)
"2.5
"2
"1.5
"1
"0.5
0.5
1.5
2.5
1.5
2.5
All Mixed
Dalby and Williams (1986)
All Depression
Deptula et al. (1991)
All Remitted
Morice (1990)
Coffman et al. (1990)
Ali et al. (2000)
"2.5
"2
"1.5
"1
"0.5
0.5
280
Psychological Studies
Depressed Patients
110
Healthy Volunteers
IQ Score
100
90
80
10
0
Pre-Morbid
FSIQ
Pre-Morbid
VIQ
Pre-Morbid
PIQ
WAIS-R
FSIQ
WAIS-R
VIQ
WAIS-R
PIQ
Figure 94. Premorbid intelligence quotient (IQ) estimates and IQ scores obtained with the
Wechsler Adult Intelligence Scale-Revised (WAIS-R) in unmedicated patients with major depression and healthy controls. Premorbid estimates were identical in the patient (n = 100) and
control (n = 50) groups. The patient group showed a marked discrepancy between verbal and
performance IQ (VIQ > PIQ). FSIQ = full-scale IQ; PIQ = performance IQ; VIQ = verbal IQ.
(Source: Sackeim et al., 1992. Reproduced with permission of Psychology Press.)
Neuropsychology
281
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Healthy Control
0.2
Bipolar
Unipolar
0.1
0
"30
"20
"10
10
20
30
40
50
VIQ-PIQ Discrepancy
Figure 95. Cumulative distribution of verbal and performance IQ discrepancy scores for
healthy controls and bipolar and unipolar depressed patients. Both patient groups are shifted to
the right of healthy controls and have an average discrepancy favoring a verbal IQ approximately
10 points higher across the distribution in controls. (Source: Sackeim et al., 1992. Reproduced
with permission of Psychology Press.)
between the groups. Structure coefficients were determined for this linear function. These coefficients are more
stable than the original weighting of subtests in the discriminant function (Huberty, 1984), and reflect the association between scores on a subtest and total scores on the
composite discriminant function. The median structure
coefficient for the five PIQ subtests was 0.53, with a range
of 0.43 to 0.70. In contrast, the median structure coefficient for the six VIQ subtests was 0.13, with a range of 0.03
to 0.38. All five PIQ subtests made strong contributions to
the differentiation between patients and controls. The
comprehension (0.29) and digit span (0.38) VIQ subtests
also contributed, but more weakly. Therefore, the results of
this analysis suggest that the PIQ deficit in mood disorders
is not specific to a particular PIQ subtest, but is expressed
uniformly across all five PIQ subtests.
Thus the relative deficit in PIQ is uniform across the
various subtests assessing this form of intelligence. The
magnitude of this discrepancy appears to be independent
of the phase of affective disorder, and may be a marker of
a bipolar diathesis. Early work on children at risk indicated
282
Psychological Studies
Psychomotor Functioning
The domain of psychomotor functioning reflects the integrity of processes determining the speed of information
processing and the speed and organization of motor behavior. Individuals may appear to be slowed because of
dysfunction in motor output and/or in the speed of thought.
Alternatively, individuals may appear to be dull or slow
because of poverty of mental content, in essence a lack of
thought. This domain pertains to functions as diverse as
manual dexterity, reaction time, and levels of spontaneous
activity. As reviewed by Sobin and Sackeim (1997), a variety of experimental techniques have been developed to
assess the component processes that may underlie psychomotor disturbance in mood disorders.
Disturbances of motility and speed of processing have
long been considered central to the phenomenology of mood
disorders. Psychomotor disturbance has generally been regarded as a cardinal feature of endogenous or melancholic
depression, and some have contended that careful assessment of psychomotor disturbances has predictive value
with respect to treatment outcome. The racing thoughts of
the manic state suggest dysregulation in speed of processing
that is opposite to that often seen in the depressed state.
Thus psychomotor function, like mood and sleep, may be
one of the few domains to show opposite symptom manifestations depending on phase of illness.
Some theorists have taken this overlap between the mood
and motor output systems to suggest that mood disorders
are essentially disorders of motility (Flor-Henry, 1983).
While this is clearly an overstatement, it is noteworthy that
mood disturbance occurs at especially high rates in patients
with movement disorder. This observation is especially well
documented for Parkinsons and Huntingtons diseases. As
indicated earlier, Huntingtons disease is of special note as
perhaps the only neurological illness to produce both depression and mania at some frequency. In contrast, imaging
research has yet to relate psychomotor disturbance in mood
Neuropsychology
disorders to basal ganglia dysfunction. Instead, the Hammersmith group found that psychomotor symptoms covary
with the magnitude of regional cerebral blood flow deficits
in prefrontal regions (Dolan et al., 1993). Indeed, they suggested that the prefrontal deficits commonly seen in both
major depression and schizophrenia reflect a common psychomotor disturbance. Presumably, this disturbance pertains to executive functions that regulate the flow and speed
of information processing.
283
284
Psychological Studies
Neuropsychology
Motor Skills
Traditional neuropsychological evaluations have placed
little emphasis on assessment of reaction time per se. This
Figure 96. Meta-analysis of psychomotor measures. Effect sizes (Hedges G) are presented for
individual study comparisons of a bipolar sample with healthy controls, as well as for samples of
bipolar patients in remission, depression, mixed state, or mania and across all studies.
Squares = confidence interval; circles = mean.
All Studies
All Mania
Park and Holzman (1992)
Jones et al. (1994)
All Mixed
Seidman et al. (2002)
All Remission
Zubieta et al. (2001)
van Gorp et al. (1999)
Hawkins et al. (1997)
Coffman et al. (1990)
Ali et al. (2000)
"2.5
"2
"1.5
"1
285
"0.5
0.5
1.5
2.5
286
Psychological Studies
Spontaneous Activity
Routine clinical evaluations of psychomotor disturbance
and those conducted using formal rating instruments typically address a different level of behavior from that assessed with neuropsychological or information processing
measures. For example, the CORE is a well-studied instrument that quantifies the extent of psychomotor disturbance.
Box 91 lists the 18 behavioral manifestations assessed by
terview)
Facial apprehension (rate any episode or fixed expression)
Delay in responding verbally (average across the interview)
Length of verbal responses
Inattentiveness
Facial agitation (movement; rate any episodeintensity rather
than duration)
Body immobility (amount, not speed; average across the interview)
Motor agitation (rate any episode; intensity rather than persistence)
Poverty of associations (ability to elaborate)
Slowed movement (speed, not amount; average across the interview)
Verbal stereotypy (rate any episode)
Delay in motor activity (average across the interview)
Impaired spontaneity of talk (ability to initiate conversation)
Slowing of speech rate (average across the interview)
Stereotyped movements (rate any episode)
Neuropsychology
symptoms accounting for a smaller portion of the variance.8 Parker and colleagues claimed that the fundamental symptomalogical characteristic of the melancholic patient is psychomotor disturbance. They also found that
the severity of psychomotor disturbance has predictive
value with regard to treatment outcome with ECT and
medications (Hickie et al., 1990b, 1996; Parker and HadziPavlovic, 1993), and that the psychomotor disturbance in
melancholic unipolar patients shares features with the
bradykinesia of Parkinsons disease in demonstrating difficulties with the initiation of movement in the absence of
external cues (Austin et al., 2000; Rogers et al., 2000). The
theoretical importance of some of these findings is challenged by the notion that the broad definition of psychomotor disturbance incorporates assessment of cardinal
features of melancholia (such as lack of mood reactivity)
that may not reflect psychomotor abnormalities. Thus the
associations between the CORE and melancholic diagnosis may be partly tautological, and the linkage to treatment
outcome could conceivably be associated with items influenced by melancholic manifestations that do not reflect
psychomotor disturbance (e.g., inattentiveness).
A recent study contrasted the CORE ratings of bipolar
and unipolar depressed patients. Parker and colleagues
(2000) compared 904 unipolar and 83 bipolar patients using three methods for subtyping melancholia (DSM, clinical classification, and CORE). With all three methods, bipolar patients were considerably more likely to be diagnosed
with melancholia and psychotic depression. Prevalence of
psychomotor disturbance and pathological guilt were the
signs or symptoms that distinguished the groups.
While it can be argued that studies of reaction time and
other aspects of information processing may provide too
narrow a view of psychomotor disturbance, it is also true
that the use of rating scales such as the CORE is limited in
that ratings may be contaminated by patient behavior reflective of domains other than psychomotor disturbance.
Patient reports of lack of interest, loss of pleasure, or marked
psychic anxiety may affect ratings of psychomotor disturbance. An alternative approach is to examine objective
measures that reflect broader aspects of psychomotor function. Two such measures examine spontaneous activity and
speech rate.
Various devices are available for continuous recording of
the amount of motor activity. For example, activity monitors, worn like a wrist watch, can provide 24-hour data on
fluctuation in movements of the wrist or arm. The potential
utility of this approach is illustrated by findings in movement disorders. Although Huntingtons disease is characterized by chorea, patients with this disorder have shown
less daytime spontaneous movement than healthy controls.
Further, this hypokinesia correlates cross-sectionally with
287
impairment in voluntary movement, with disturbed posture and gait, and most robustly with reduced functional
capacity (van Vugt et al., 2001). Over a 2-year follow-up period, van Vugt and colleagues (2001) also found that spontaneous activity remained unchanged in clinically stable
patients, but worsened in those who deteriorated in functional capacity. Thus in this context, hypokinesia, as assessed by activity monitoring, showed a strong relationship
with functional impairment.
A set of small-group comparisons reported by Kupfer
and colleagues led to a number of explicit hypotheses about
the patterns of gross motor activity in depression and
mania.9 These investigators suggested that (1) manic patients have higher activity levels than severely agitated depressed patients; (2) unipolar depressed patients have higher
activity levels than bipolar depressed patients; (3) clinical
remission in depression is accompanied by an increase in
activity levels; and (4) manic patients manifest their highest activity levels in the late evening and early nighttime,
whereas hypomanic patients peak during the daytime (see
Chapter 2 for a discussion of the overlap between agitated
depressive and mixed hypomanic states). These observations were based on small subgroups; lacked comparison
with a normal control group; and were derived from work
on a specialized inpatient unit at the National Institutes of
Health (NIH), where hospital routine and regimentation
may have affected activity levels. While there has been surprisingly limited further research in this area since the mid1970s, the additional studies that have been done have substantially clarified the nature of the deficit in spontaneous
activity during episodes of major depression.
In a study by Wolff and colleagues (1985), a group of 18
normal controls was housed on the same ward and shared
in the same activities as a group of 30 euthymic patients (25
bipolar, 5 unipolar). In addition, 27 patients were studied
through at least two phases of illness (depression, euthymia,
or mania); the depressed state was consistently associated
with lower 24-hour levels of activity than euthymia. This
difference was significant for the within-subject comparison
during daytime but not nighttime periods. Mania was associated with higher activity levels than depression, with the
difference seen mainly in the late evening and nighttime
hours (7:00 PM to 4:00 AM). Although mania tended to be
associated with higher levels than euthymia, none of these
comparisons were significant; however, the sample size for
comparisons with euthymia was substantially smaller for
mania (n = 11) than for depression (n = 23). Of special note is
that, in comparison with controls, euthymic patients still
manifested lower 24-hour activity levels, attributable mainly
to the daytime period (2:00 PM to 12:00 AM).
Royant-Parola and colleagues (1986) followed a group of
12 patients with major depression, monitoring their activity
288
Psychological Studies
Speech Rate
Speech is a motor act. Clinically, it is common to observe
severely depressed patients speaking in a halting, slow manner with frequent pauses, and often with a weak or raspy
voice. It is also clear that manic patients often have racing
speech along with racing ideas. Thus it is an empirical matter whether objective analysis of speech and voice characteristics will reveal abnormalities associated with mood
disorders and/or provide information of prognostic significance.
The small literature in this area has presented consistent
findings. The most common paradigm has been to examine automatic speech, as in counting from 1 to 10, where
cognitive load is minimal,10 although there have also been
studies that involved taking samples of natural speech, as
might occur during a diagnostic interview (Bouhuys and
Mulder-Hajonides van der Meulen, 1984; Alpert et al.,
Neuropsychology
2001; Cannizzaro et al., 2004). The most common dependent measure has been speech pause time (SPT), the duration of the silent interval between phonations. Szabadi and
colleagues (1976) and later Greden and colleagues (Greden
and Carroll, 1980; Greden et al., 1981; Greden, 1982) first
claimed that SPT was elongated in major depression without
a change in phonation time, and that SPT shortened with
clinical remission. These claims have received substantial
support and have been extended to bipolar depressed patients. SPT has shown significant associations with depression severity, the Widlocher scale (Widlocher, 1983) for
assessing psychomotor retardation, and reaction time.11
Other aspects of speech, including total speaking time,
various quantitative features of fundamental frequency
and pitch, and speed of voice change, have shown less consistent associations with mood disorders. There is surprisingly little information on the impact of manic states on
these measures, and comparisons of unipolar and bipolar
depressed patients have shown limited power.
Attention
Impaired attention and insufficient motivation are the two
most common reasons given for the pattern of widespread
neuropsychological deficit in mood disorders (Miller, 1975;
Bearden et al., 2001). To the extent that motivational impairments resolve with remission of depression or mania,
persistent neuropsychological impairments are unlikely to
be due to motivational factors. Attentional processes are in
many respects the gateway to learning, memory, and other
higher cognitive processes. While some forms of learning
(e.g., procedural learning) undoubtedly occur outside of
awareness and do not depend on the integrity of attentional processes, such is not the case for much of our knowledge of ourselves and the world.
Attention is a complex concept that encompasses multiple distinct processes. The concept of working memory denotes the capacity to hold in awareness for a limited time a
limited number of visual or auditory representations. This
type of attentional process, as in keeping in mind a telephone number, can be assessed with various span tasks,
in which patients recall or recognize a serial list of digits,
letters, or shapes just presented. In contrast, the capacity to
detect a rarely occurring target is the form of attention
commonly referred to as vigilance. The classic example
here is the air traffic controller who monitors a screen for
representations of two aircraft on a collision course. Although this event is infrequent, detecting its occurrence is
of obvious importance. In psychiatric research, vigilance is
commonly assessed with the Continuous Performance Test
(CPT), originally developed by Beck and colleagues (1956)
to detect lapses in attention among epilepsy patients. Another form of attention concerns freedom from distraction
289
290
Psychological Studies
All Studies
All Mania
Umbricht et al. (2003)
Souza et al. (1995)
Robertson and Taylor (1985)
Park and Holzman (1992)
Martnez-Arn (2004b)
Jones et al. (1994)
Gourovitch et al. (1999)
Ferrier et al. (1999)
Agarwal et al. (2002)
All Mixed
Wielgus and Harvey (1988)
Thomas et al. (1996)
Sweeney et al. (2000)
Swann et al. (2003)
Seidman et al. (2002)
Sax et al. (1999)
Oltmanns (1978)
Kaprinis et al. (1995)
Harvey and Serper (1990)
Gruzelier et al. (1988)
Green and Walker (1986)
Green and Walker (1986)
Gildengers et al. (2004)
Dupont et al. (1990)
Clark et al. (2001)
All Depression
Sweeney et al. (2000)
Martnez-Arn (2004b)
All Remitted
Zubieta et al. (2001)
Zalla et al. (2004)
van Gorp et al. (1998)
Swann et al. (2003)
Sapin et al. (1987)
Rubinsztein et al. (2000)
Park (1997)
Paradiso et al. (1997)
Morice (1990)
Martnez-Arn (2004b)
Krabbendam et al. (2000)
Kaprinis et al. (1995)
Hawkins et al. (1997)
Ferrier et al. (1999)
Docherty et al. (1996)
Coffman et al. (1990)
Cavanagh et al. (2002)
Asarnow and MacCrimmon (1981)
Ali et al. (2000)
Addington and Addington (1998)
"2
"1.5
"1
"0.5
0.5
1.5
Figure 97. Meta-analysis of attention measures. Effect sizes (Hedges G) are presented for individual study
comparisons of a bipolar sample with healthy controls, as well as for samples of bipolar patients in remission, depression, mixed state, or mania and across all studies. Squares = confidence interval; circles = mean.
in their cognitive demands, averaging across distinct attentional measures could obscure more discrete patterns of
deficit. Therefore, the analyses were predated for studies of
patients in remission and for all studies as a function of the
specific neuropsychological procedure used to evaluate attention. As seen in Figure 98, although the number of studies contributing to results for individual tests is often small,
a consistent pattern is evident. Except for working-memory
Neuropsychology
1.8
Remitted
Total
1.6
1.4
1.2
1
Effect Size
0.8
0.6
0.4
0.2
0
"0.2
Miscellaneous (2/9)
Trails B (8/14)
Trails A (8/13)
Symbol (7/11)
Stroop (8/12)
Span (9/22)
Dichotic (1/6)
CPT (4/10)
"0.4
Cancellation (2/6)
291
Figure 98. Effect sizes for various measures of attention. Effect sizes (Hedges G) are
shown for comparisons of bipolar patients in remission with healthy controls and for the
total set of comparisons of bipolar patients across phases of illness with healthy controls.
The numbers in parentheses indicate for each attentional measure the number of comparisons of remitted bipolar patients, followed by the total number of comparisons.
CPT = Continuous Performance Test.
292
Psychological Studies
Declarative Memory
Semantic
Memory
Episodic
Memory
Impersonal
Memory
Autobiographical
Memory
Non-Declarative Memory
Classical
Conditioning
Priming
Procedural
Memory
Working Memory
Phonological
Loop
Visuospatial
Scratchpad
Neuropsychology
Short-Term Memory
The distinction between short-term and long-term memory is arbitrary, and is usually taken as representing the
methodological distinction between memory for new information tested after a very short delay (usually less than
10 seconds) and after longer delays (tens of seconds to years)
(Wickelgren, 1973). This distinction is consequential because
holding information in short-term memory is thought
to be mediated by prefrontal working-memory processes,
while the consolidation and retention of this information
are determined by the integrity of the medial temporal
lobe and other structures. The distinction is reflected in
the common experience of not being able to reproduce a
phone number when attention is directed away. In the absence of continual rehearsal, some information is lost, and
in the case of bilateral hippocampal damage, retention of
new declarative information may be limited to the period of
rehearsal. Retention of new information over delays greater
than tens of seconds depends on the integrity of consolidation and retrieval processes that are thought to involve initially the hippocampus and other structures.
By far the most common method for assessing shortterm memory has involved forward and backward auditory digit span procedures, although word, letter, block, and
shape span tasks are also available (Lezak, 1995; Spreen and
Strauss, 1998). The early literature is not consistent in addressing the elemental question of whether auditory digit
span performance is abnormal in mood disorders.13 However, as seen in Figure 98, more recent studies comparing
patients with bipolar disorder and healthy controls have
revealed a consistent deficit in the performance of span
tasks, auditory or visual, and pertaining to digits, words, or
shapes. Across 22 studies and all phases of bipolar disorder,
the pooled effect size for this comparison was moderate:
0.58 (SE = 0.12, p < .001). In the 9 studies contrasting patients
in remission, the effect size was 0.50 (SE = 0.11, p < .001).
293
It is conceivable that the impairment of span performance is specific to procedures not involving auditory
presentation of digits. Baddeley (1986) proposed that the
phonological loop challenged by digit span tasks is distinct
from a visuospatial scratch pad, with both being key aspects
of working or short-term memory (see Fig. 99). However,
no differences are seen in a comparison of effect sizes in
studies using digit span and those using other span procedures. Thus the conclusion is justified that bipolar patients,
whether in remission or not, have a deficit in short-term
memory, as reflected in span performance. This deficit is
interpreted as reflecting impaired attention.
Verbal learning tasks present another context for assessing the integrity of short-term memory. However, recall or
recognition after a single presentation of a list relies on
both short- and long-term processes. This point is supported by the serial position effect, in which recall is best
for the early (primacy effect) and late (recency effect) items
in a list and poorest for the middle ones (Bayley et al., 2000).
The recency effect reflects the integrity of short-term memory given the minimal interval between presentation of the
last items on the list and recall. The primacy effect reflects
the contribution of transfer to long-term memory and the
consolidation process. Since many of the reports on learning in bipolar illness concern cumulative performance in recalling a list during repeated testing over several trials, such
procedures, while involving minimal retention intervals
since the last presentation of a list, nonetheless rely heavily
on long-term memory.
Figure 910 illustrates the effect sizes obtained in comparisons of patients with bipolar disorder and healthy controls on learning tasks, both verbal and nonverbal. Across
all studies, the effect size is 0.91 (SE = 0.11, p < .001). In
comparisons restricted to remitted patients, the effect size
is 0.81 (SE = 0.15, p < .001).
Without question, bipolar disorder is associated with a
marked deficit in the acquisition of new information. This
deficit is seen in all phases of the illness, and its magnitude
does not appear to be lessened among patients in remission. However, cross-sectional comparison should be used
only to establish the existence of deficits in specific phases
of the disorder. Whether the deficits are truly comparable
in mania, depression, or remission requires within-subject
longitudinal investigation. For example, the reduced noise
of measurement involved in neuropsychological assessment of remitted as opposed to acutely ill patients can
inflate effect sizes indicating deficits in remission. Furthermore, it is common to evaluate clinical samples in a
medication-free state when acutely ill at baseline, but to
evaluate patients in remission who are medicated. Such
a confound could also intensify the deficits observed in
remitted patients.
294
Psychological Studies
All Studies
All Mania
Gourovitch et al. (1999)
Ferrier et al. (1999)
All Mixed
Sweeney et al. (2000)
Fleck et al. (2003)
Dupont et al. (1990)
Clark et al. (2001)
All Depression
Wolfe et al. (1987)
All Remission
Zubieta et al. (2001)
van Gorp et al. (1999)
van Gorp et al. (1998)
Paradiso et al. (1997)
Krabbendam et al. (2000)
Fleck et al. (2003)
Ferrier et al. (1999)
Cavanagh et al. (2002)
Ali et al. (2000)
"3
"2
"1
Figure 910. Meta-analysis of learning measures. Effect sizes (Hedges G) are presented for individual study comparisons of a bipolar sample with healthy controls, as well as for samples of bipolar patients in remission, depression, mixed state, or mania and across all studies. Squares = confidence
interval; circles = mean.
Long-Term Memory
In recent years, it has been claimed that memory is the domain demonstrating the greatest impairment in mood disorders. Literature reviews and meta-analyses have indicated
that relative to healthy controls, patients in an episode of
major depression (bipolar or unipolar) manifest markedly
inferior performance on tests involving the recall or recognition of information over a substantial delay or after
Neuropsychology
Figure 911. Dissociation in the effects of electroconvulsive therapy (ECT) on learning and retention of new information. Patients
were randomly assigned to low- or high-dosage bilateral (BL) or right
unilateral (RUL) ECT. Before and immediately after the course, they
were administered a test of verbal list learning and retention using
the selective reminding procedure (Buschke, 1973). Little change in
immediate learning was seen when post-ECT values were compared
with baseline values, with the exception of possible improvement in
the low-dose RUL ECT group. In contrast, both low- and high-dose
BL ECT resulted in clear-cut deficits in free recall of the list after a delay. The results illustrate the selective effect of ECT on the retention
of newly learned information, which is thought to be due to a deficit
in consolidation. (Source: Sackeim et al., 1993.)
15
Learning
Retention
10
5
0
"5
"10
"15
"20
"25
Low RUL
High RUL
Low BL
Treatment Group
High BL
295
Mediational Processes
Many processes determine whether a particular memory
will be retrieved. Some of these processes relate to the infrastructure of memory, so that there is a contrast, for example, between deficits in the storage of information as
assessed by recognition tasks and in the active retrieval of
information as assessed by recall performance. Other processes, such as the organization imposed on newly presented
information and the resultant depth of encoding, may determine whether information is learned and/or stored. Still
other factors affect not so much whether new information
will be retained, but how the choice is made whether to recall events from the past. For example, the issue is hotly debated as to whether being in the depressed or manic state
biases retrieval toward memories that share the same affective valence. This form of mood-congruence effect addresses the question of whether depressed patients have
preferential access to or are biased to retrieve negatively
evaluated information.
Storage Versus Retrieval. Assuming that information is
acquired, failure to recall can be due to a breakdown either
in consolidation or storage or in retrieval. Because recognition of information is far less demanding of retrieval
processes but is dependent on the adequacy of storage, an
296
Psychological Studies
All Studies
All Mania
Souza et al. (1995)
Park and Holzman (1992)
Martnez-Arn et al. (2004)
Jones et al. (1994)
Gourovitch et al. (1999)
Ferrier et al. (1999)
All Mixed
Wielgus and Harvey (1988)
Seidman et al. (2003)
Seidman et al. (2002)
Harvey et al. (1986)
Gruzelier et al. (1988)
Gildengers et al. (2004)
Fleck et al. (2003)
Dupont et al. (1990)
Dalby and Williams (1986)
Clark et al. (2001)
All Depression
Wolfe et al. (1987)
Martnez-Arn et al. (2004)
Deptula et al. (1991)
All Remission
Zubieta et al. (2001)
van Gorp et al. (1999)
van Gorp et al. (1998)
Martnez-Arn et al. (2004)
Krabbendam et al. (2000)
Fleck et al. (2003)
Ferrier et al. (1999)
Coffman et al. (1990)
Cavanagh et al. (2002)
Ali et al. (2000)
Addington and Addington (1998)
"3
"2
"1
Figure 912. Meta-analysis of memory measures. Effect sizes (Hedges G) are presented for individual study
comparisons of a bipolar sample with healthy controls, as well as for samples of bipolar patients in remission,
depression, mixed state, or mania and across all studies. Squares = confidence interval; circles = mean.
Neuropsychology
ongoing cognitive operations and do not benefit from rehearsal. For example, remembering where one put ones keys
is typically an instance of automatic or incidental learning.
Typically, one does not consciously attempt to remember
this information, and one is usually unaware of learning it.
Skill or procedural learning and other nondeclarative forms
of memory do not involve explicit, consciously mediated
cognitive rehearsal. In contrast, effortful processes require
the use of limited attentional capacities and interfere with
other cognitive activities. The cognitive operations are initiated voluntarily and benefit from practice.
Similarly, a levels-of-processing approach emphasizes
that the amount of attentional capacity allocated to the initial steps of information processing (e.g., encoding) influences the later retrievability of the information. The
deeper the level of processing, the greater is the attentional
allocation and the better the retrieval. For example, if ones
task in listening to a set of words is to determine which
words rhyme with a target (acoustic or shallow processing),
later memory of the list will be poorer than if the task is to
determine whether each word has the same meaning as a
target (semantic or deep processing). The two models are
convergent in that engaging in greater depth of processing
is often an effortful, attention-demanding process.
The notion that individuals in episodes of major depression have a deficit in engaging spontaneously in effortful or deeper levels of processing has received substantial,
although not unequivocal (Christensen et al., 1997), support. In a now-classic study, Weingartner and colleagues
(1981) found that depressed patients did not differ from
healthy controls in recalling words that had been acoustically (shallowly) processed, but were inferior in remembering semantically (deeply) processed words. The control
group showed the typical advantage of better recall of the
deeply processed words. In contrast, the patient group had
equivalent scores on the two tasks, suggesting that despite
the difference in task requirements, the patients encoding
on both tasks was shallow.
A second study reported by Weingartner and colleagues
(1981) demonstrated that when deep encoding was provided externally on a verbal memory task, depressed patients performed similarly to healthy controls. Essentially,
when given a list of random words, a depressed sample was
shown to have markedly impaired recall. When presented
a word list drawn from discrete semantic categories in
which the word order was clustered, however, patients were
not distinguishable in recall from healthy controls. Both
the extent of categorization of words and the overt clustering within categories determined the magnitude of the difference in recall between patients and controls.
The implication of this work is that depressed patients,
when exposed to new material, are less likely than healthy
297
298
Psychological Studies
Summary
Deficits in learning and memory characterize unipolar depression and bipolar disorder through all its phases. The
effect sizes for these deficits are the largest among neuropsychological domains. While it has been common in
recent years to assert that episodes of major depression are
associated with a memory deficit, there is little evidence
that the deficits seen in learning and/or memory processes
extend beyond attentional disturbance. This attentional
disturbance may be structural in the sense of dysfunction
in a limited-capacity store, or perhaps more likely, a disturbance in the allocation of attentional resources. The
substantial literature on bipolar patients in remission indicates that the deficits in learning and memory persist during euthymia. There are compelling findings that mood disorder patients in episodes of major depression are more
likely to engage in shallow processing and to fail to impose
the organization on incoming information that assists in acquisition and retention. This cognitive laziness results
from a failure of executive functionin this case, the utilization of strategies that facilitate learning and memory.
Thus it becomes especially germane to inquire whether
there is a more general impairment of executive functions.
Executive Functions
Neuropsychology
Figure 913. Meta-analysis of executive function measures. Effect sizes (Hedges G) are presented for individual study comparisons of a bipolar sample with healthy controls, as well as for samples of bipolar patients in remission, depression, mixed state, or mania and across all studies. Squares = confidence interval;
circles = mean.
All Studies
All Mania
Martnez-Arn (2004a)
Gourovitch et al. (1999)
Ferrier et al. (1999)
All Mixed
Sweeney et al. (2000)
Seidman et al. (2003)
Seidman et al. (2002)
Gildengers et al. (2004)
Clark et al. (2001)
All Depression
Sweeney et al. (2000)
Savard et al. (1980)
Martnez-Arn (2004a)
All Remitted
Zubieta et al. (2001)
Zalla et al. (2004)
van Gorp et al. (1998)
Savard et al. (1980)
Rubinsztein et al. (2000)
Rossi et al. (2000)
Park (1997)
Morice (1990)
Martnez-Arn (2004a)
Krabbendam et al. (2000)
Ferrier et al. (1999)
Coffman et al. (1990)
Cavanagh et al. (2002)
Ali et al. (2000)
"2.5
"2
"1.5
"1
299
"0.5
0.5
1.5
2.5
300
Psychological Studies
All Studies
All Mania
Robertson and Taylor (1985)
All Mixed
Seidman et al. (2002)
Gildengers et al. (2004)
Dalby and Williams (1986)
All Remitted
Zubieta et al. (2001)
Morice (1990)
Hawkins et al. (1997)
Docherty et al. (1996)
Coffman et al. (1990)
Ali et al. (2000)
"1
"0.5
0.5
1.5
Figure 914. Meta-analysis of reasoning measures. Effect sizes (Hedges G) are presented for individual study comparisons of a bipolar sample with healthy controls, as well as for samples of bipolar
patients in remission, depression, mixed state, or mania and across all studies. Squares = confidence
interval; circles = mean.
Neuropsychology
oral word association (COWA). Such tests assess the spontaneous production of words beginning with a given letter,
usually F, A, or S (FAS test), within a stipulated period of
time. Alternatively, the tests may assess production of
words as instances of a concept, such as animal naming.
Verbal fluency, especially letter fluency, has often been
taken as another type of executive function. Indeed, there
is evidence that COWA is one of the last measures of prefrontal function to mature, with developmental improvement extending beyond age 12, whereas adult levels are
achieved considerably earlier for many other measures
(Lewis, 1983). There is some evidence from both imaging
and lesion studies that temporal lobe regions may make
more of a contribution to category than to letter fluency.
However, this distinction and the stronger claim that letter fluency is subserved largely by prefrontal regions are
supported only partially by lesion analysis and imaging
Figure 915. Meta-analysis of verbal skill measures. Effect sizes (Hedges G) are presented for individual
study comparisons of a bipolar sample with healthy controls, as well as for samples of bipolar patients in
remission, depression, mixed state, or mania and across all studies. Squares = confidence interval;
circles = mean.
All Studies
All Mania
Souza et al. (1995)
Martnez-Arn (2004b)
Jones et al. (1994)
Gourovitch et al. (1999)
Ferrier et al. (1999)
All Mixed
Thomas et al. (1996)
Seidman et al. (2002)
Kremen et al. (2003)
Kaprinis et al. (1995)
Dupont et al. (1990)
Dalby and Williams (1986)
Coffman et al. (1990)
Clark et al. (2001)
All Depression
Wolfe et al. (1987)
Martnez-Arn (2004b)
All Remission
Zubieta et al. (2001)
Zalla et al. (2004)
van Gorp et al. (1999)
van Gorp et al. (1998)
Morice (1990)
Martnez-Arn (2004b)
Krabbendam et al. (2000)
Hawkins et al. (1997)
Ferrier et al. (1999)
Docherty et al. (1996)
Cavanagh et al. (2002)
Ali et al. (2000)
"2.5
"2
"1.5
"1
301
"0.5
0.5
1.5
2.5
302
Psychological Studies
All Studies
All Mania
Souza et al. (1995)
Jones et al. (1994)
Gourovitch et al. (1999)
Ferrier et al. (1999)
All Mixed
Seidman et al. (2003)
Seidman et al. (2002)
Getz et al. (2003)
Dupont et al. (1990)
Clark et al. (2001)
All Remitted
van Gorp et al. (1998)
Sapin et al. (1987)
Morice (1990)
Ferrier et al. (1999)
Ali et al. (2000)
Addington and Addington (1998)
"2.5
"2
"1.5
"1 "0.5
0.5
1.5
2.5
Figure 916. Meta-analysis of visual skill measures. Effect sizes (Hedges G) are presented for individual study comparisons of a bipolar sample with healthy controls, as well as for samples of bipolar patients
in remission, depression, mixed state, or mania and across all studies. Squares = confidence interval;
circles = mean.
(see Fig. 915). The effect size (Hedges G) for the comparison of bipolar and healthy control groups across all studies
(n = 26) is 0.35 (SE = 0.09, p < .001). However, the effect is
not significant across 12 studies of remitted bipolar samples
(effect size = 0.22, SE = 0.12, p = .064) or 5 studies in mania
(effect size = 0.495, SE = 0.31, p = .11). Relative to the pattern
of widespread impairment across symptomatic and remitted states, verbal skills appear to have been preserved. In the
few cases in which bipolar samples had inferior verbal fluency performance relative to healthy controls, the patient
groups tended to make more incorrect responses (e.g., repeating the same word) and did not differ in number of responses (Wolfe et al., 1987; Coffman et al., 1990).
A different level of deficit is manifest in Figure 916,
which summarizes our meta-analysis of visuospatial performance measures. One study (Sapin et al., 1987) was excluded because of an outlying value that only accentuated
the deficit in remitted patients. Across all studies, the effect size is 0.65 (SE = 0.18, p < .001), and in remitted bipolar
patients it is 0.57 (0.28, p < .01).
deficit profiles for the comparisons of depressed, mixedstate manic, and remitted samples with healthy controls, as
well as the comparisons across all phases of illness. The
profile is relatively invariant across the phases of illness.
Three central points can be made.
First, the same pattern of strengths and weaknesses is
seen in remission and during episodes of affective disturbance. This invariance suggests that the core disturbance is
state independent. Second, it is often claimed that the magnitude of deficit is generally greatest during mania, still
marked during major depression, and least evident in remission. The deficit noted by investigators as residual
during remission varied considerably among the studies
included in our meta-analysis. Indeed, limited power, differences in the reliability of measurement, and other factors make it likely that different tasks would achieve statistical significance in separating remitted patients from
controls. By combining these findings in a meta-analysis, it
became evident that the remitted samples generally had
the same level of deficit as the acutely ill groups in the areas
most disturbed, and perhaps somewhat less marked deficits
in the areas most disturbed in the acutely ill groups (e.g.,
learning and memory). The larger point is that the cognitive deficits observed in remitted patients were not a pale
shadow of the deficits seen during affective disturbance,
Neuropsychology
1.4
1.2
Effect Size
1.0
0.8
0.6
0.4
0.2
0
Remission
FSIQ
VIQ
PIQ
Motor
Attention
Learning
Depression
303
Mixed
Mania
All
Memory
Executive Function
Reasoning
Verbal Skills
Visual Skills
Figure 917. Profile of neuropsychological impairment in bipolar disorder. Effect sizes are shown for comparisons of a bipolar group
(in remission or in a phase of depression, mixed state, or mania) with healthy controls for 11 cognitive domains. All bipolar subgroups,
including remission, show deficits relative to controls. These impairments are most accentuated for the learning, memory, and executive function domains and are pronounced for all domains except those heavily involving verbal skills (verbal IQ, reasoning, and verbal
skills). The preservation of verbal skills against a background of generalized impairment may be the salient dissociation. FSIQ = fullscale IQ; PIQ = performance IQ; VIQ = verbal IQ.
304
Psychological Studies
of brain damage (Lezak, 1995). These subtests assess semantic memory, or knowledge of facts, which has not
been found to be impaired in bipolar disorder. Specifically,
these subtests, by posing specific questions, may place few
demands on attention or any form of new learning. This
view posits, therefore, that the relative preservation of verbal skills is due to their escaping the deleterious and otherwise generalized impact of the core cognitive disturbance,
presumably in the area of attention. However, the findings
regarding verbal fluency and reasoning may belie this view
since it is difficult to argue that attentional processes do
not contribute to their performance.
A second alternative is to view this preservation of verbal processes as indicating a disassociation in the cognitive neural systems dysregulated in bipolar disorder. At the
grossest level, this view would suggest preservation of lefthemisphere subsystems involved in verbal processing. How
this could come about and the neurochemical and/or neurodevelopmental processes responsible for such a dissociation are a matter of speculation.
Finally, this asymmetry may be an endophenotype of
bipolar disorder. We should not assume that the topography of cognitive function is a flat playing field in this patient population. As discussed at the outset, there is good
reason to suspect that intellectual endowment is distributed differently in the families of bipolar probands than in
the general population. Indeed, one of the earliest studies of
children at risk found that the VIQPIQ discrepancy was
robust before the onset of the first affective episode and
was most common in children with prodromal symptoms
(Decina et al., 1983; Sackeim and Decina, 1983). Thus the
genetic transmission of bipolar disorder may confer a relative advantage for verbal processes. The insult that results
in manifestation of the disorder may have a rather generalized effect, leading to impairments in multiple domains.
This decrease in function is shared relatively equally, and
verbal functions appear to be preserved only because their
baseline was elevated. Research on the neuropsychological
profiles of first-degree relatives of bipolar probands (Keri
et al., 2001a) and of monozygotic twins discordant for
bipolar disorder (Gourovitch et al., 1999) is in its infancy,
but has indicated that impairments are evident in tests of
learning and memory but not in verbal skills.
Neuropsychology
305
Psychological Studies
60
50
Tapping Rate (per 10 s trial)
306
40
30
20
10
0
On Wk. 1
Off Wk. 2
Off Wk. 3
On Wk. 4
On Wk. 5
Figure 918. Tapping rate with lithium discontinuation and reinstatement. Twenty-two patients were retested for tapping speed
weekly for 5 weeks. Lithium was discontinued after the first week and
reinstated by the fourth week. Tapping speed improved in weeks 2
and 3 off lithium and slowed with lithium reinstatement. (Source:
Shaw et al., 1987.)
discontinuation of lithium and deteriorating with its reintroduction. The magnitude of this effect, while consistent,
was small. For example, the deterioration between weeks 3
and 5 (p < .02) averaged a 4.2 percent reduction in tapping
rate.
The study by Shaw and colleagues (1987) constituted the
first report of reversible lithium-induced motor speed impairment. Several previous studies of patients and healthy
participants had suggested that lithium had a negative effect on performance of the WAIS-R digit symbol test and
possibly on perceptual-motor tasks (Demers and Heninger,
1971; Judd, 1979; Squire et al., 1980). The digit symbol subtest is usually regarded as an attentional measure. Given its
timed nature, however, motoric slowing would have a negative impact. Thus the findings of the Shaw et al. (1987)
study raise the possibility that lithium resulted in a subtle
slowing of basic motor movement, which could affect any
timed procedure.
The findings obtained with the Buschke Selective Reminding Test are illustrated in Figure 919. This test produces a variety of indices of the adequacy of short- and
long-term memory, and a representative index of each is
plotted in the figure. Short-term recall is heavily influenced by attention and reflects the recall of items just recently presented, as in the reminding procedure. Long-term
recall concerns the number of words recalled at some interval since original presentation or reminding. No impact of
Neuropsychology
14
Short-term Recall
Long-term Recall
12
Memory Score
10
8
6
4
2
0
On Wk. 1
Off Wk. 2
Off Wk. 3
On Wk. 4
On Wk. 5
307
308
Psychological Studies
Clinical Features
A good deal of medical research involves searching for
clinicalpathological correlations in an effort to identify
individuals at heightened risk or to further our understanding of disease processes. Once it has been accepted
that manic-depressive illness, especially its bipolar form, is
associated with a profile of cognitive deficits, a host of
questions arise regarding the factors that influence the expression of such neuropsychological disturbances. For example, do all individuals manifest the cognitive deficits
characteristic of bipolar illness, or do subgroups manifest
these effects more intensely? Alternatively, does the manifestation of cognitive deficits change with development? In
particular, does chronicity of illness affect the expression
of such deficits? Is the adult pattern of cognitive deficit
seen in pediatric bipolar disorder or in children at risk for
the disorder? If so, does this obviate the potential confound of medication effects? And to what extent does the
severity of cognitive deficits covary with structural abnormalities of the brain, especially the burden of hyperintensities as revealed by f MRI?
Psychotic Features
A number of studies have found a link between the presence of psychotic features and a more chronic and severe
course of bipolar illness with respect to both symptomatic
and functional outcomes.23 Especially since cognitive impairment is linked to poorer functional outcomes in bipolar disorder (Zarate et al., 2000), one might surmise that
psychotic features are predictive of poorer neuropsychological outcome. This conjecture has received some empirical support. Albus and colleagues (1996) failed to find differences in cognitive performance between first-episode
nonpsychotic patients with mood disorders and healthy
controls. In contrast, mood disorder patients with psychotic
features performed as poorly as patients with first-episode
schizophrenia. Thus in this study, the presence of psychosis
Neuropsychology
was found to be a greater determinant of neuropsychological profile than the diagnosis of mood disorder or schizophrenia. In light of the neuropsychological deterioration
often seen early after the onset of psychosis in first-episode
schizophrenia and the hypothesis that psychotic states are
intrinsically toxic (Wyatt, 1991, 1995), it is especially important to examine the validity of this association and to determine whether early intervention can improve cognitive
and other long-term outcomes in patients with bipolar disorder with psychotic features. The duration of untreated
psychosis in patients with first-episode schizophrenia is associated with both the quality of symptomatic outcomes
and the extent of cognitive deterioration (Norman and
Malla, 2001; Amminger et al., 2002).
309
310
Psychological Studies
are not restricted to white matter and their etiology has not
been established, we use the term encephalomalacia.
Figure 920 illustrates a moderate-to-severe case of encephalomalacia. FLAIR images are presented for a patient
with late-onset, first-episode major depression. The image
on the left illustrates PVH, with thick bands of high signal
intensity (white) adjacent to the lateral ventricles. Note
that on the left side of this image, the HI are extending into
the deep white matter. The image on the right is of a higher
MRI slice from the same patient and shows multiple confluent HI through the DWMH. In patients presenting with
these MRI findings, clinicians typically receive radiological
reports that emphasize ischemic small-vessel disease.
In one of the largest prospective MRI series in major
depression, all 51 elderly patients (aged >60) referred for
ECT presented with HI, more than half rated moderate to
severe, and 51 percent had lesions of subcortical gray nuclei
(Coffey et al., 1990). These rates of abnormality greatly exceeded those found in a healthy control sample, with basal
ganglia abnormalities being most discriminative (Fig. 921).
The depressed samples studied to date have often included
patients with comorbid medical illnesses, without adequate controls for risk factors for cerebrovascular disease
(CVD), medications being taken, or drug abuse. Nonetheless, in the work of Coffey and colleagues (1990), when
depressed patients with preexisting neurological conditions were excluded, the rate of encephalomalacia greatly
exceeded that found in normal controls. In a replication
study, patients with major depression showed marked increases in the frequency of PVH, DWMH, and basal ganglia and thalamic HI relative to controls matched for CVD
risk factors (Coffey et al., 1993). The age-adjusted odds ratio for PVH was 5.32. In other, often large population studies of elderly healthy controls, when the halos or caps commonly seen at the top and bottom of the lateral ventricles
were excluded, approximately 10 to 30 percent presented
with MRI white matter abnormalities, with typically mild
severity and low rates of subcortical gray matter abnormalities (Breteler et al., 1994).
The rate or severity of encephalomalacia in geriatric depression may equal or exceed that in Alzheimers disease
(Erkinjuntti et al., 1994) and may be comparable to that in
multi-infarct dementia (Zubenko et al., 1990; see Sackeim
et al., 2000a, for a review). Meta-analyses have supported
the excess of HI in geriatric unipolar depression (Videbech,
1997). These abnormalities tend to be overrepresented in
frontal lobe white matter and in the basal ganglia, perhaps
with a left-sided predominance (Greenwald et al., 1998).
For instance, Greenwald and colleagues (1998) found that
left frontal DWHI and left putamen HI discriminated between an elderly unipolar sample and a matched healthy
comparison group.
Neuropsychology
311
Figure 920. Fluid-attenuated inversion recovery (FLAIR) images of a patient with late-onset major depression. White or bright areas show
magnetic resonance imaging (MRI) hyperintensities. The image on the left demonstrates periventricular hyperintensities, with a broad band of
increased signal adjacent to the lateral ventricles and invading the deep white matter. The image on the right, from the same patient at a higher
level, shows multiple, confluent foci of hyperintensities in the deep white matter (centrum semiovale).
312
Psychological Studies
70
Depressed
Control
60
Percent of Subjects
50
40
30
20
10
0
PVH
DWMH
Subcortical Gray
Figure 921. Representation of the findings of Coffey and colleagues (1990). The percentages of patients with major depression
and control subjects are contrasted in rates of periventricular hyperintensities (PVH), deep white matter hyperintensities (DWMH), and
hyperintensities in subcortical gray matter structures.
Neuropsychology
The striking thing is that the correlates of these abnormalities appear to differ in bipolar and unipolar disorder.
There is a dramatic difference in age at manifestation. In
all populations studied to date, HI burden increases with
advancing age. This may also be true in bipolar disorder.
What is exceptional, however, that adolescents with bipolar
disorder show the abnormality (Botteron et al., 1995; Lyoo
et al., 2002; Pillai et al., 2002). In unipolar patients and
neurological samples, the presence and severity of HI are
linked to CVD. Indeed, the predominant view is that encephalomalacia is an outcome of ischemic changes in
white matter watershed areas that are fed by tiny arterioles
and have limited collateral vascular supply. Rigidification
of these small vessels or blockage through arteriosclerosis
will result in ischemic damage. Not surprisingly, then, age
and cerebrovascular risk factors would be key determinants. Further, given this hypothesized vascular etiology,
it is not surprising that encephalomalacia is especially
prevalent in late-onset depression in patients without a
family history of mood disorder. It is CVD that is the primary agent, and not a genetic liability to depression. Indeed, the invasion of fibers in the white matter by HI must
be a random process. If the right fibers are damaged, major depression may result as disconnection syndrome
(Geschwind, 1965). Further, it makes sense that encephalomalacia, by reflecting ischemic brain changes, is associated
with specific forms of cognitive impairment and predicts
future course.
The young age at which many bipolar patients show this
abnormality makes it unlikely that these HI are the outcome of an ischemic disease process. Indeed, the notion
that the severity of the MRI abnormalities covaries with
cerebrovascular risk factors has not been established in
bipolar samples. Excluding patients or controlling for CVD
risk factors still results in an excess of HI in bipolar samples relative to controls (Altshuler et al., 1995; Hickie et al.,
1995). Thus while a vascular, age-related etiology for encephalomalacia is most likely in unipolar disorder, a different etiology may be at play in bipolar disorder. In turn, it
cannot be assumed that HI burden is associated with neuropsychological impairment in bipolar disorder.
Limited investigation has been done in this area. In a
small sample, Dupont and colleagues (1990) found that
bipolar patients with HI were more impaired than bipolar
patients without HI or healthy controls on tests of attention,
letter fluency, visuospatial skills, and memory. In contrast,
Krabbendam and colleagues (2000) compared matched
groups of remitted patients with bipolar disorder, patients
with schizophrenia, and healthy controls. The groups did not
differ in the presence or severity of HI. More surprisingly, no
differences in cognitive performance were found between
patients with and without white matter lesions. Clearly, this
313
area needs further attention, and the pathoetiology of encephalomalacia in bipolar disorder remains a mystery.
314
Psychological Studies
of depression, accompanied by crying, beliefs of worthlessness or hopelessness, and other classic phenomena associated with the depressed state.29 Turning the stimulation off
turns off the emotional display. The importance of such
demonstrations lies not so much in the hints about localization, but more in the fact that the immediacy of the depressive mood and of the changes in emotional expression
and worldview indicate the triggering of an integrated depressive system that alters the content of both mood and
thought. Thus the brain, at least in this context, behaves in
a way envisaged neither by James (1890) nor by Schachter
(Schachter and Singer, 1962). We do not come to have a feeling because we are expressing the emotion (e.g., we know
we are afraid because we are running), as suggested by
James. Nor do we come to have a feeling because of an appraisal we have made about our surroundings that explains
why we are aroused, as suggested by Schachter. In the case of
deep-brain stimulation, mood, expression, and thought
present simultaneously as integrated psychic phenomena
triggered by a manipulation of brain tissue. None has primacy, as would be demanded by these earlier theories.
Depressive-catastrophic reactions during the Wada
procedure are another example of provoked and transient
mood disorder. This procedure involves injecting a barbiturate into the internal carotid artery to temporarily barbiturate the ipsilateral hemisphere (Snyder and Harris,
1997; Wada, 1997). Contralateral flaccid hemiplegia or hemiparesis and homonymous hemianopsia soon result. The
procedure is used to establish laterality of language and
verbal memory in individuals scheduled for neurosurgery
(Branch et al., 1964; Cohen-Gadol et al., 2004; Takayama et
al., 2004). At a point when sensorimotor function and cognition return toward baseline, some patients report depressed mood and catastrophic beliefs (e.g., their lives are
ruined, the world is coming to an end). Since the 1950s,
some investigators have claimed that left-side injections
are more likely to produce this outcome, whereas rightside injections are more likely to result in a euphoric reaction.30 While this idea is subject to controversy (Kolb and
Milner, 1981; Kurthen et al., 1991), results of a recent study
using masked ratings of facial expression during the Wada
procedure support the notion that depressive reactions are
more common with left-side injection.
Normal functioning is characterized by its own mood
swings. Profound sadness, as during mourning or other
losses, is a normal variant and shares virtually all the symptoms of the clinical disorder. What distinguishes major depressive episodes from the normal experience of intense
dysphoric states is not so much the phenomenology of these
presentations as the fact that major depression does not resolve as quickly. Viewing these phenomena in normal individuals as a deficit state strains credibility. Furthermore,
states of euphoria and mania also involve integrated manifestations in mood, motor function, cognition, and conation, with many of these functions appearing to be in
overdrive.
Another argument regarding the status of depression
and mania as release phenomena concerns the fact that the
disorders most clearly reflecting deficits in emotional processes are distinct from depression and mania. Individuals
may have agnosias for emotional communications. In
other words, they may be incapable of identifying affective
intonation or emotional facial expressions. For example,
prosopoaffective agnosia refers to the inability to discern facial emotional expression without an accompanying deficit
in processing of facial identity (Vuilleumier et al., 1998).
Other neurological disorders can result in an incapacity
to display emotions, either voluntarily or spontaneously
(Borod et al., 1988; Ghacibeh and Heilman, 2003). And
alexithymia is a disorder involving the capacity to feel or
process affectively laden information (Becerra et al., 2002;
Kano et al., 2003; Larsen et al., 2003); some refer to this
condition as emotional blunting or emotion blindness. If
affective disorders have a form of negative symptoms reflecting a fundamental defect or incapacity, these conditions would be exemplars.
Neuropsychology
11
Bipolar
Unipolar
Number of Treatments
10
9
8
7
6
2
1
0
Low RUL
Med. RUL
High RUL
Low BL
High BL
Figure 922. Number of electroconvulsive therapy (ECT) treatments for bipolar and unipolar depressed patients. Based on data
pooled across four studies at the New York State Psychiatric
Institute/Columbia University, 78 bipolar patients required on average
about 1.5 fewer treatments than 185 unipolar depressed patients.
Patients were randomly assigned to forms of ECT that differed in electrical dosage (low, medium, and high) and electrode placement (right
unilateral [RUL] versus bilateral [BL]). An analysis of variation
(ANOVA) was conducted on the number of treatments administered,
with diagnosis (bipolar versus unipolar), treatment condition (five levels), and the interaction of those two factors as between-subject terms,
and age and pre-ECT Hamilton Rating Scale for Depression (HAM-D)
score as covariates. The main effects of diagnosis (p = .0008) and preECT HAM-D score (p = .0002) were significant. (Source: Adapted from
Sackeim et al., 1987, 1993, 2000b, and Sackeim, 2004.)
315
properties. In a variety of animal models, including kindling, electroconvulsive shock (ECS) exerts more powerful
anticonvulsant properties than drugs such as carbamazepine or valproate. In this light, it is not surprising that
ECT has been of value in the treatment of resistant seizure
disorders, including status epilepticus (Sackeim et al., 1983b;
Lisanby et al., 2001).
The therapeutic properties of ECT have been linked to
its anticonvulsant effects. Forms of ECT that result in the
most marked increases in seizure threshold tend to be the
most effective (Sackeim, 1999). The strength of the inhibitory process immediately after the seizure can be indexed by the presence or absence of postictal suppression
of the electroencephalogram (EEG). Postictal suppression
(bioelectric silence) is predictive of a favorable outcome
(Nobler et al., 1993; Suppes et al., 1996; Perera et al., 2004).
Most critically, since Ketys work initiated the field of brain
imaging (Kety et al., 1948), it has been clear that ECT results in marked reductions in CBF (and CMRglu).32 Recent
work has revealed powerful relationships between the extent of this suppression in prefrontal regions and clinical
outcome in both major depression and mania (Nobler
et al., 1994, 2000b, 2001). Consonant with this perspective,
ECT results in a marked increase in slow-wave (delta) activity. The efficacy of the procedure has been linked to a
topography dominated by increased slow-wave activity in
prefrontal regions (Sackeim et al., 1996a). Thus depressed
and manic patients may have bad brakes, resulting in
a failure to diminish activation in the released mood circuitry. ECT, at least temporarily, enhances inhibitory tone,
reducing expression of the released mood circuitry.
The large imaging literature on antidepressant effects
is mainly in keeping with this view (Mayberg et al., 1999;
Drevets et al., 2002; Seminowicz et al., 2004). Although there
are disagreements about the sites of inhibition that are most
critical, the antidepressant effects of ECT, sleep deprivation, and antidepressant medications have commonly been
tied to reductions of regional cerebral blood flow (rCBF)
or CMRglu in specific brain regions. Frontal pole, medial
orbital prefrontal cortex, anterior cingulate, and amygdala
have been identified as primary in reflecting the covariation
between reduced CBF or CMRglu and clinical outcome.33
Of course, this view readily accommodates the fact that
several anticonvulsant agents have mood-stabilizing properties. Thus to the extent that depressed or manic patients
can be said to have bad brakes, treatments with prophylactic properties may exert tonic inhibition.
316
Psychological Studies
Neuropsychology
317
Laughing
Laughing and Crying
Crying
25
Number of Patients
20
15
10
0
Left
Bilateral
Right
Indeterminate
Figure 923. Distribution of primarily left-sided, right-sided, bilateral, and indeterminate nonirritative lesions in patients with pathological laughing only, laughing and crying, and crying only. Leftsided and right-sided lesions are associated with pathological crying and laughing, respectively,
whereas bilateral lesions are associated with presentation of both uncontrollable laughing and crying.
(Source: Sackeim et al., 1982b.)
regions in the contralateral hemisphere. Likewise, the affective changes seen after barbituration of the left or right
hemisphere suggest that contralateral disinhibition may be
at play.
Figure 924 presents findings regarding the lateralization of epileptic foci in cases of gelastic epilepsy. There was
an overwhelming excess of left-sided foci, as predicted
the opposite of what was seen with pathological laughing
in the context of silent lesions. Thus, the model offered by
Sackeim and colleagues (1982b) stipulated that depressed
and euphoric states are under reciprocal inhibitory control. Depressive phenomena are released mainly by disinhibitory mechanisms, while euphoric mood changes and
laughter are released by disinhibition or direct excitation.
The model did not require that the inhibitory control mechanisms be reciprocal. Including this element implied a partial seesaw effect. Reciprocal regulation would mean that
depression and euphoria cannot be experienced simultaneously, an issue that is key to the conceptualization of mixed
states.
Our conceptions of how emotional processes are represented in the brain are rudimentary. Undoubtedly the
model of Sackeim and colleagues is overly broad and, at
best, an echo of the true state of affairs. Nonetheless, the
evidence that led to this model was consistent and illustrated the power of using experimental invasive techniques
(e.g., deep brain stimulation, Wada test, hemispherectomy), along with experiments in nature (lateralization of
epileptic foci and silent lesions), to constrain theorizing
Figure 924. Distribution of left-sided, right-sided, and indeterminate epileptic foci in patients with gelastic (laughing) epilepsy. Foci
were more than twice as likely to be left-sided than right-sided.
(Source: Sackeim et al., 1982b.)
Indeterminate
Left
Bilateral
Right
318
Psychological Studies
Neuropsychology
1993), the larger point is that left and right unilateral ECT
both show considerable efficacy in the treatment of mania
and depression, and that any difference in therapeutic effects is relatively minor compared with the shared variance. Given the asymmetrical physiological and cognitive
effects of unilateral ECT, the efficacy data largely contradict a prominent role for functional brain asymmetry in
treatment mechanisms and, by extension, in the pathophysiology of depression and mania.
A key observation that promoted interest in lateralization effects was the association between localization of
stroke and other forms of brain damage and manifestation
of mood disturbance. Clinically, as mentioned earlier, it
has long been noted that unipolar mania (i.e., manifestation of mania without prior or subsequent episodes of
major depression) occurs almost exclusively in the context
of coarse brain injury (Jorge et al., 1993; Fujikawa et al.,
1995; Robinson, 1997). Further, it is generally agreed that
such lesions are predominantly right-sided (Cummings
and Mendez, 1984; Starkstein et al., 1988a).
In contrast, the relationships between location of brain
lesion and manifestation of depression have become less
certain with additional research. Interest in the laterality of
emotion was sparked by findings relating side of brain injury to affective state (Gainotti, 1972) and to uncontrollable emotional expressions (Sackeim et al., 1982a), by the
demonstration of asymmetry in the emotional expressions
of the human face (Sackeim et al., 1978), and by the linkage
of disturbances in the processing of affectively laden information to right-sided brain damage (Heilman et al., 1975).
However, the relevance of a laterality dimension to mood
disorders was contingent on reliable associations between
side of brain damage and manifestations of mood disturbance.
Gainotti (1969, 1972) was the first to examine systematically the distinct differences in emotional reactions of patients with left- and right-hemisphere stroke. Right-sided
damage was associated with anosognosia (denial of illness) or anosdisaphorie (lack of concern about illness, i.e.,
a carefree attitude) and a euphoric-indifference reaction.
Robinsons research, however, catalyzed interest in this
area. In a seminal paper, Robinson and colleagues (1984)
linked the severity of depressive symptoms shortly after
stroke to damage to left-sided prefrontal regions. The
closer the lesions were to the left frontal pole, the more severe was the depressive syndrome. Right parietal lesions
were also linked to depression, but at lower incidence and
with lesser intensity of depressive manifestations. This work
had important methodological limitations, such as the exclusion of patients with significant aphasia, which possibly
distorted the sample of patients with left-sided injury, and
problems in the blinding of assessment given the motor,
319
sensory, and cognitive deficits that reveal the side of lateralized brain damage. Most of the subsequent studies failed
to replicate Robinsons core findings, and some metaanalyses of this literature contested the existence of an
association between lesion location and depressive manifestations (Carson et al., 2000; Narushima et al., 2003;
Yu et al., 2004).
Missing from this perspective were the results of longterm follow-up of individuals with penetrating head wounds
after World War II. Mood disturbance was common in such
patients. In particularly careful work, Lishman (1968) noted
that right posterior head wounds were far more likely to be
associated with depressive and manic manifestations than
were injuries to any of the remaining three quadrants. It
hardly appeared likely that different forms of nonirritative
brain insultstroke versus head woundcould fundamentally alter the linkage between side of brain insult and
depressive symptoms.
One possibility accounting for the discrepancies in this
literature concerns the issue of time since stroke. Robinsons early work involved patients who were examined very
soon after stroke, recruited at emergency room presentation. Later studies often examined patients months to years
after their cerebrovascular accident. There has been little
longitudinal work addressing whether localization of damage is related to the persistence (chronicity) and/or late
emergence of depressive symptoms. Nelson and colleagues
(1994) evaluated affective symptoms in patients with lateralized stroke at 2-week, 2-month, and 6-month time points.
Initially, the group with left-hemisphere stroke experienced
a slower rate of recovery from depressive symptoms. At the
6-month time point, however, the emotional functioning
of the right-hemisphere group worsened. The evidence regarding temporal interval as a moderator of the relationship between lesion location and affective disturbance is not
consistent, and considerably more work is necessary (Carson et al., 2000). Nonetheless, the positive findings in this
area introduce a dynamic element to the relationships between brain injury and altered affective states.
One interpretation of this literature would be to argue
that in the acute poststroke period, depressive symptoms
are most severe when the lesion is closest to the left frontal
pole. The most recent meta-analysis (Narushima et al.,
2003) supports this association. However, manifestation of
this syndrome is time-limited, and depressive symptoms
spontaneously remit within a few months. In contrast, right
parietal lesions result in milder depressive symptoms in
the acute period. Yet this disturbance is more likely to be
chronic, and these lesions may also result in late-emerging
affective disturbance. Following the disinhibition model
for nonirritative lesions, both left anterior and right posterior stroke may disinhibit right prefrontal areas critical to
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Psychological Studies
2001; Burt et al., 2002). The active rTMS conditions compared with sham have been fast-frequency left DLPFC stimulation and slow-frequency right DLPFC stimulation. Both
interventions yield moderate to large effect sizes for antidepressant properties; in other words, both are consistently superior to sham. However, these findings are of greater theoretical than practical importance. In absolute magnitude,
the therapeutic effects in the active conditions, although superior to those in sham, have commonly been modest, and
the durability of the benefit derived has rarely been tested.
For rTMS to have a role in routine practice, these issues must
be addressed (Sackeim, 2000b).
From a theoretical perspective, however, it is extraordinary that a highly lateralized intervention can display these
antidepressant properties, and moreover, that antidepressant effects can be achieved with opposite physiological alterations (inhibition versus excitation) that are dependent
on the laterality of the brain region stimulated. Taken at
face value, for example, these effects could indicate that the
key to exerting antidepressant properties is the state of the
seesaw: any intervention that tips the seesaw toward
greater left prefrontal or reduced right prefrontal expression in the DLPFC will have antidepressant properties. This
formulation could mean that mood states are not attributable to the physiological status of a specific brain region, but
are an emergent property reflecting the balance of activity
among regions in a distributed network. Another possibility is that different individuals benefit from slow right or
fast left rTMS, and that left-sided hypofunction and rightsided hyperfunction are alternative routes to major depression (Kimbrell et al., 1999; Speer et al., 2000).
Focal brain stimulation offers an experimental means of
testing key concepts about the neuroanatomy and neurophysiology of mood disorders and their treatment. Two
caveats are in order about the state of knowledge in this
area. First, while it is established that slow right and fast
left rTMS have antidepressant properties, however modest, it is assumed that fast right and slow left rTMS are ineffective, something that has never been adequately tested.
For example, were slow left DLPFC to exert equal antidepressant properties, a fundamental role for laterality in generating therapeutic effects would be seriously questioned.
The key experiment, in which depressed patients are randomly assigned in a 2 2 design to slow- or fast-frequency
stimulation and left or right DLPFC, has not been conducted, and is essential to further understanding of the effects of this intervention on mood.
The second caveat is more general. It is often assumed
that knowledge of the mode of action of a therapeutic
agent (e.g., serotonin reuptake blockade) dictates conceptualization about the underlying pathophysiology (or vice
versa). However, there are many examples in medicine in
Neuropsychology
CONCLUSIONS
Normal Findings in Bipolar Patients
Bipolar patients have normal VIQ, a finding that challenges
the idea that bipolar disorder is associated with pervasive
intellectual impairment. One possible explanation is that
the cognitive systems underlying language are spared from
the otherwise generalized bipolar disease process; or they
may be constitutionally endowed at higher capacity. Likewise, preliminary evidence indicates that procedural learning and memory are not significantly affected by bipolar
illness, while limited data suggest that the ability to recall
past events, or details of past events, is not significantly impaired in bipolar patients.
Alone among the executive functions, reasoning remains relatively preserved in bipolar illness. Because the
results of tests of reasoning correlate substantially with the
321
NOTES
1. Corwin et al., 1990; Rubinsztein et al., 2000; Sweeney et al.,
2000; Murphy and Sahakian, 2001; Quraishi and Frangou,
2002; Martinez-Arn et al., 2004b; Marvel and Paradiso,
2004.
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Psychological Studies
15. Craik and Tulving, 1975; Craik and Jennings, 1992; Mandzia
et al., 2004; Newell and Andrews, 2004.
16. Roy-Byrne et al., 1986; el Massioui and Lesevre, 1988; Hartlage et al., 1993; Christensen et al., 1997; Thomas et al., 1999;
Den Hartog et al., 2003; Hammar, 2003; Hammar et al.,
2003a,b; Politis et al., 2004.
17. Nelson and Craighead, 1977; Breslow et al., 1981; Gotlib, 1981;
Clark and Teasdale, 1982; Coyne and Gotlib, 1983; Gotlib and
Olson, 1983; Yang and Rehm, 1993; Murray et al., 1999; Winter
et al., 2000.
18. Sackeim and Prohovnik, 1993; Soares and Mann, 1997;
Haldane and Frangou, 2004; Rogers et al., 2004.
19. Joanette and Goulet, 1986; Bayles et al., 1993; Schlosser et al.,
1998; Spreen and Strauss, 1998; Spence et al., 2000.
20. Mann et al., 1999; Keilp et al., 2001; Oquendo and Mann,
2001; Oquendo et al., 2004.
21. Phillips et al., 2003a,b; Schaefer et al., 2003; Tavares et al.,
2003; Chamberlain and Sahakian, 2004.
22. One study (Joffe et al., 1988) found no difference among
bipolar patients treated with lithium, carbamazepine, or no
medication on tests of attention, visuomotor function, and
memory. However, this study also failed to find differences
between the bipolar groups and healthy controls on the cognitive measures, raising doubt about the sensitivity or reliability of the neuropsychological assessment. Other studies
yielding negative findings on the cognitive effects of lithium
include Telford and Worrall, 1978; Kjellman et al., 1980; and
Ghadirian et al., 1983.
23. Tohen et al., 1990a,b, 2000; Albus et al., 1996; Atre-Vaidya
et al., 1998.
24. McKay et al., 1995; Tham et al., 1997; Kessing, 1998; van Gorp
et al., 1998; Denicoff et al., 1999.
25. Lesser et al., 1993; Salloway et al., 1996; Dahabra et al., 1998;
Kumar et al., 1998.
26. Hickie et al., 1995, 1997; Simpson et al., 1997a, 1998; Baldwin
et al., 2000.
27. Steingart et al., 1987; Junqu et al., 1990; Cadelo et al., 1991;
Baloh et al., 1995.
28. Dupont et al., 1987, 1990, 1995; Swayze et al., 1990.
29. Bejjani et al., 1999; Berney et al., 2002; Stefurak et al., 2003;
Okun et al., 2004.
30. Terzian and Cecotto, 1959; Alema and Donini, 1960; Terzian,
1964; Rosadini and Rossi, 1967; Rossi and Rosadini, 1967.
31. Sackeim et al., 1983a, 1987b; Sackeim, 1999, 2004.
32. Engel et al., 1982; Rosenberg et al., 1988; Volkow et al., 1988;
Silfverskild and Risberg, 1989; Nobler et al., 1994, 2001;
Henry et al., 2001.
33. Wu et al., 1992, 1999; Mayberg et al., 1999; Teneback et al.,
1999; Nobler et al., 2000a; Drevets et al., 2002.
34. Andersen et al., 1993; Benedek and Peterson, 1995; Jeret, 1997;
McCullagh and Feinstein, 2000; Kaschka et al., 2001; Smith
et al., 2003; House et al., 2004.
35. Hommes, 1965; Gainotti, 1970, 1972; Robinson and Szetela,
1981; Robinson et al., 1984; Narushima et al., 2003.
10
Those only, who lived for some time with [Lord Byron], could believe that a mans temper,
Proteus like, was capable of assuming so many shapes. It may literally be said, that at different
hours of the day he metamorphosed himself into four or more individuals, each possessed of
the most opposite qualities; for, in every change, his natural impetuosity made him fly into the
furthermost extremes. In the course of the day he might become the most morose, and the
most gay; the most melancholy, and the most frolicsome . . . the most gentle being in existence,
and the most irascible.
Julius Millingen (Byrons physician), 1831
The intense emotions and troubling thoughts and behaviors of manic and depressive states often confound the person who has bipolar disorder and family members alike:
What is due to the illness? What is due to personality? Where
does one end and the other begin? Will treatment alter not
only the disorder, but also personality? Do pathological
mood states reflect the real self, or is there a coherent self despite the mood swings that characterize the disorder? Scientists and clinicians ask related questions: Are there unique
and characteristic personality styles associated with bipolar
disorder, and are they present when the person is not affectively ill? Are there predisposing or precursor traits? Do
personality characteristics affect the course of the disorder?
(Related questions concerning the mild forms of bipolar
disorder that may be continuous with personality patterns
are discussed separately in Chapter 2.)
Questions about personality are both personally meaningful and clinically and theoretically important because
they may help shed light on the enormous variability among
individuals with bipolar disorder and aid in achieving
a fuller understanding of the disorders development. Issues
of personality have been addressed in various ways by psychologists and psychiatrists, and in the first section of this
chapter we review both the complexities of the questions
examined and the research results.
We next address the issue of personality disorders, the
enduring and dysfunctional patterns of behaviors and traits
defined by Axis II of the Diagnostic and Statistical Manual
(DSM), that may accompany Axis I diagnoses of any kind.
Personality disorders may profoundly color the experience
of the coexisting psychological disorder, as well as affect
both the clinical and social adjustment of the individual
and the success of treatment. They have been the focus of
many recent studies in the field of bipolar research, and the
results of these studies may help inform patients and clinicians about how individuals with a diagnosis of bipolar illness can be so different from one another in presentation
and prognosis.
Finally, we discuss the interpersonal functioning of individuals with bipolar disorder in major role areas, such
as intimate relationships, social behavior, and family relations. There is increasing interest not only in the clinical
manifestations of bipolar disorder, but also in the ways in
which individuals with the disorder live their lives and
cope with their condition. What are the unique interpersonal patterns and challenges for the bipolar patient, and
what does the social milieu itself contribute to the understanding of the course of the disorder? Of particular importance is growing awareness of the discrepancies that
sometimes exist between social functioning and clinical
status.
Prior to DSM-III the term manic-depressive illness
could either mean what we now call bipolar disorder or include all recurrent affective disorders. When the context of
the older literature makes clear that it is referring to bipolar disorder, we use that term. Because the literature relevant to this chapter rarely distinguishes recurrent from
nonrecurrent forms of unipolar depression, we focus on
the bipolar subgroup of manic-depressive illness.
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Psychological Studies
ality types), the response to psychotherapy and medication, the tendency to become dependent on alcohol or
other drugs, and adherence to prescribed treatment regimens. They have also identified personality as an important determinant of the nature and extent of interpersonal relationships. These relationships, in turn, can affect
both precipitating events and the likelihood of emotional
support during and after affective episodes. The ability
to handle the enormous stress and complications of affective illness is assumed to be strongly influenced by premorbid personality and character structure.
Personality is altered by affective illness. In this model, personality is assumed to be altered by the experience of affective illness. Various consequences of the illnessincluding
changes in self-esteem and social interaction patterns;
difficulties in sustaining meaningful relationships and employment; and frequent fluctuations in mood, energy, perception, and thinkingare all thought to both cause and
reflect short- or long-term personality changes that may
be reversible or irreversible. The obvious importance and
impact on personality of such illness variables as frequency, duration, severity, and nature of episodes have
not been well studied.
These models of the association between affective illness
and personality are not mutually exclusive, and they may be
difficult to disentangle in practice. Moreover, research has
not tested all of the models with respect to bipolar disorder,
leaving many questions unanswered. Recent research has
generally addressed several largely descriptive issues. One
such issue concerns the stability of personality traits and
whether they vary by manic or depressed state. A related issue is whether there are unique personality characteristics
of bipolar patients that differ from those of unipolar depressed or well individuals. Still another set of issues has
to do with the predictive association between personality
features and clinical course. Before turning to a review of
studies that address these matters, however, a further caution concerning methodological issues is in order.
Methodological Issues
In addition to the conceptual issues raised above, many
specific methodological problems are intrinsic to the study
of personality and bipolar disorder. The most central of
these is the problem of trait and state, or disentangling
manifestations of illness from the more stable and lasting
structures of personality. Specific problems include the
substantial difficulties of separating the current clinical
state from measured personality traits, of assessing the
effects of medications on personality (independently of
their effects on the underlying affective illness), of sorting
through the personality effects of previous manic and
325
depressive episodes, and of delineating the effects of subclinical episodes on personality. Fundamental issues of measurement and philosophy emerge when two pivotal questions are posed. First, what aspects of personality are being
studied when one is assessing the successfully treated person
with bipolar illnesstrue premorbid ones or affectively
changed and attenuated ones? Second, to what extent is personality a function of medication level or of the cumulative
effects of disease?
Another set of problems concerns issues of diagnostic and
illness heterogeneity. Heterogeneity is well recognized in the
unipolar depressive disorders (in symptom patterns, etiology, severity, episodic patterning, and frequency). Although
bipolar illness is more homogeneous, it, too, can be confusingly varied. Few investigations of personality distinguish
between bipolar-I and bipolar-II, and fewer still consider
other issues related to the full spectrum of bipolarity, such
as the stage or severity of manic and depressive illness at the
time of testing, the ratio of manic to depressive episodes, the
age at illness onset, the frequency and nature of mixed states,
the duration and patterning of episodes, and the characteristic nature of the manic episodes (euphoric and expansive, for
example, rather than paranoid and dysphoric). All of these
variables are likely to have both long- and short-term effects on the expression of personality. Other variables generally not controlled for in personality studies of affective
illness include seasonal factors of importance to studies
done during both remission and illness (see Chapter 4); the
competence and sophistication of clinical care, including
such common problems as prescribing incorrect medications or dosages; and selection factors intrinsic to the nature of remission studiesthat is, a selection bias favoring
healthier, more normal bipolar patients.
Measurement and design also are problematic. Until recently, comparison groups were inadequate. Early studies
compared manic-depressive (predominantly bipolar) with
schizophrenic patients; more recent studies have used
unipolar depressed patients as controls. Studies using subjects from the general population as controls, although a
clear improvement, too often have not controlled for family history of affective illness or for important demographic variables, such as age, IQ, socioeconomic status,
and gender. Standard problems of measurement, such as
the reliability and validity of the psychometric tests used,
are well reviewed elsewhere. We note here, however, that
much of the earlier research employed assessment methods based on questionable assumptions and validity (e.g.,
Rorschach), or on instruments that may no longer be widely
used now that newer and more empirically and conceptually based approaches are available. In the sections to follow,
older work is noted briefly, with greater emphasis on more
contemporary methods.
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Psychological Studies
Several study designs have been used to investigate personality and bipolar illness, including studies of patients
across different mood states. In addition, comparisons
have been made between affectively ill bipolar and unipolar patients, remitted bipolar and unipolar patients, and
remitted bipolar patients and members of the general population. These design strategies are generally appropriate
to address simple, descriptive questions, but more complex
designs, including longitudinal studies, are greatly needed
to pursue questions relating personality characteristics to
the clinical and course features of bipolar disorder and social adjustment. Heterogeneity of comparison groups (for
example, the tendency not to distinguish melancholic
from nonmelancholic unipolar depression) is a significant
problem (Parker et al., 2004).
Psychoanalytic Perspectives
Prior to the psychoanalytic era, most early clinical investigators assumed that personality structure in bipolar disorder reflected the underlying disease process.2 Psychoanalytic
theorists considered two major issues in their writings on
manic-depressive illness: the etiology of mania and depression and the underlying personality structure of patients
with bipolar illness. Most psychoanalysts focused primarily on the origins and nature of depression rather than
mania. Their findings on this subject are well known and
are not presented here. Instead, we briefly outline psychoanalytic concepts of mania and the manic-depressive personality. Although neither time nor research has supported
the psychoanalytic perspective on bipolar illness, it is historically important, especially in the United States, because
it deeply influenced generations of psychiatrists, psychologists, and social workers.
From a psychoanalytic perspective, mania can best be
understood as a defense against underlying depressive affect. This fundamental concept has been stated in different
ways by many authors.3 Although interesting, the psychoanalytic perspective suffers from the usual difficulties involved in analyzing open-ended, clinical observations: such
observations are retrospective, interpretative, and highly
speculative. Comparison groups are lacking, and there are
few, if any, ways of subjecting the theory to test. Finally, as
(Kotin and Goodwin, 1972, p. 684) concluded from their
data-based studies of mania:
Our data suggest that if mania is a defense against depression, it is often an inadequate defense, since depressive
symptoms remain prominent during the manic phase.
80
70
T Scores
worthlessness or excessive or inappropriate guilt, respectively). In an attempt to study alternating views of the self
in depression and mania, Platman and colleagues (1969)
administered the Emotions Profile Index weekly to 11 bipolar patients. This psychological measure was designed to
assess eight primary emotions: fear, anger, acceptance, rejection, surprise, exploration, joy, and deprivation. Twelve
staff members were asked to provide their conceptions of
mania and depression. This collective profile was then compared with the profiles produced by patients while manic or
depressed.
The staff s and patients conceptions of depression were
strikingly similar on all eight dimensions. For both groups,
depression was characterized by decreases in sociability, in
interest in new experiences, and in feelings of acceptance,
as well as by increases in feelings of deprivation, in aggression, and in rejection of others. Mania, on the other hand,
was perceived in very different ways by staff and patients,
with seven of eight mean scores showing highly significant
differences (at the p < .01 level). Patients while manic saw
themselves as sociable, trusting, moderately impulsive, and
cautious and not at all stubborn or aggressive. Staff members, however, saw them as only moderately sociable, somewhat distrustful, extremely impulsive and aggressive, quite
rejecting of others, and completely incautious and unafraid.
Response patterns from patients were far more variable than
those from staff members, suggesting a more stereotypical
(or accurate) view from the latter group.
Patients were asked, when normal, to recall their previous
manic and depressive episodes. Their recalled depressive
profiles were similar to those produced while actually depressed, and both resembled the staff-generated depressive
profile. By contrast, profiles of recalled manic episodes did
not resemble those actually obtained during mania. The patients recall of mania was far more highly correlated with
staff perceptions of mania (r = .95) than with their own ratings produced while manic (r = .35). The authors concluded:
These facts imply that the self-critical judgmental process
is severely impaired in the manic state but not in the depressed state. This is consistent with the well-known fact
that manic patients do not usually admit to any illness, or
that they deny the maladaptive nature of their behavior.
This is also why it is difficult to detect the presence of
manic states by means of self-description type inventories; these usually show that the manic patient is normal.
90
60
50
40
0
327
Hs
Hy Pd Mf Pa
MMPI Scales
Pt
Sc Ma Si
One interesting theoretical question posed by these findings is whether the manic patient is deliberately misrepresenting his feelings and behavior, or whether he is simply
unable to discriminate the specific feelings and behaviors
which are judged by an outside observer as pathognomonic
of mania (Platman et al., 1969, p. 213).
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Psychological Studies
Jamison and colleagues (unpublished data) examined selfperceptions across affective states in 69 euthymic bipolar
patients using the Semantic Differential, a combination of associational and scaling procedures. Patients were tested with
22 pairs of opposite adjectives (e.g., goodbad, strongweak,
complexsimple), shown as the polar ends of a seven-point
continuum. Patients indicated their perceptions of themselves when manic, hypomanic, depressed, and normal by
marking the most descriptive point between each polar pair.
Analyses of variance by gender, with repeated measures of
mood phase, were performed on the adjective pairs. The
phase of illness affected virtually all pairs, indicating that
changes in self-perception across the affective states of bipolar illness were consistent and widespread (Fig. 102). Statistical comparisons, conducted to identify significant differences between each pair of different mood phases, revealed
a number of consistent patterns, particularly for the adjective
pairs reflecting a positivenegative, or valuative, dimension.
Rash
Serious
Humorous
Sociable
Unsociable
Fair
Sensitive
Unfair
Insensitive
Enthusiastic
Bored
Exciting
Boring
Competent
Cooperative
Gentle
Confident
Incompetent
Uncooperative
Wild
Insecure
Neuroticism
Measures of neuroticism, typically using the MPI (or its later
version, the Eysenck Personality Inventory [EPI]), identify
significant differences between each pair of different mood
phases (e.g., Clark et al., 1994). The neuroticism scale of the
MPI/EPI is more likely to reflect changes in clinical state
than is the extraversion scale. Several investigators have
shown that neuroticism scores decrease following recovery
in patients with endogenous depression (Crookes and Hutt,
1963; Coppen and Metcalfe, 1965; Ingham, 1966). In normal
populations, neuroticism and extraversion are independent
factors, but in psychiatric patients, the correlation between
the two is usually quite high.
Eysenck and colleagues (Eysenck and Eysenck, 1963a,b)
have defined neuroticism as a largely inherited lability of
the autonomic nervous system and as a general measure
of emotionality. Its principal components include mood
swings, a sense of inferiority, poor emotional adjustment,
lack of social responsibility, suspiciousness, lack of persistence, social shyness and hypochondriasis, and lack of relaxed composure. Moodiness, which has the single highest loading on the neuroticism factor in the EPI, is
illustrated by positive answers to the following sample
items: Do you sometimes feel happy, sometimes depressed, without any apparent reason? Are you inclined
to be moody? and Do you have frequent ups and downs
329
ExtraversionIntroversion
As with neuroticism, the primary psychological measure
of the extraversionintroversion dimension used in research on affective illness is the MPI/EPI. Extraversion was
originally characterized in the MPI/EPI by impulsivity
(typical item: Are you inclined to be quick and sure in
your actions?) and sociability (typical item: Would you
be very unhappy if you were prevented from making numerous social contacts?). In normal populations, impulsivity and sociability correlate at 0.5, producing a secondorder factor of extraversion. More recently, impulsivity has
been recognized as a separate factor, and it is not included
in contemporary assessments of extraversion. Thus there
may be some discrepancy between results of older and
newer studies (Watson et al., 1994). Introversion can be
further subdivided into social introversion (characteristic
of those who prefer not to have much social contact with
others) and neurotic introversion (characteristic of those
who are afraid to have contact with others and are basically unsure of themselves and their interpersonal competence) (Eysenck, 1956). Just as neuroticism has been
conceptualized as negative affectivity (as discussed earlier), extraversion has been conceptualized as positive
affectivitya stable, heritable, temperamental trait (Clark
et al., 1994).
Based on the typical conceptualization of extraversion,
many researchers have expected to find greater levels of
this trait among bipolar patients. The authors of the MPI/
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Psychological Studies
EPI (Eysenck, 1959; Eysenck and Eysenck, 1963a,b) described a typical extravert as one who:
shown to occur in pediatric bipolar patients and in the offspring of bipolar patients (Chang et al., 2003).
In summary, there are few significant differences between remitted bipolar patients and normal individuals on
the two most frequently assessed personality dimensions,
neuroticism and extraversionintroversion. Other studies
that have included different measures of personality traits
have also failed to find significant differences (e.g., Lepkifker
et al., 1988). However, Solomon and colleagues (1996) found
that the bipolar-I group scored significantly lower than
never-ill controls on measures of emotional stability, ego resiliency, and ego control. They cautioned that their comparison group had been screened for absence of psychopathology, whereas prior disorders may not have been ruled out
for control groups in other studies. They also noted that
nearly 50 percent of their bipolar group had a history of
substance abuse. The results of early studies require caution
as well because their samples were small, and probably differed as to the extent of their predominance of mania and
depression, as well as their social role functioning. Thus
some samples of bipolar patients may indeed differ from
normal controls during remission, perhaps depending on
the composition and clinical features of the sample. In particular, it is likely that elevated neuroticism and introversion characterize those with prominent depressive episodes.
(See Savitz and Ramesar, 2006, for an excellent review of
personality research in bipolar disorder.)
Significant differences are found between bipolar patients and controls on measures of temperament. Several
studies have found that cyclothymia and novelty seeking
are more elevated in bipolar samples.
Several investigators have found that an underlying cyclothymic temperament is particularly associated with
bipolar-II disorder (Hartouche et al., 1998; Benazzi and
Akiskal, 2005), as well as being elevated in healthy relatives
of bipolar probands (Mendlowicz et al., 2005). Other investigators have confirmed Kraepelins observation of a high
rate of hyperthymic temperament in both bipolar-I and
bipolar-II patients (Cassano et al., 1992; Perugi et al., 1998),
although the interpretation of this observation is confounded by the fact that elevated rates of hyperthymic temperament have been demonstrated in control subjects as
well (Evans et al., 2005; Matsumoto et al., 2005; Mendlowicz et al., 2005). Other researchers have found that individuals with bipolar disorder score significantly higher than
controls on measures of novelty seeking (a tendency to seek
out new situations, to be curious and impulsive, a trait discussed further in the next section) (Cronin and Zuckerman, 1992; Young et al., 1995; Nowakowska et al., 2005). A
similar elevation in novelty-seeking behavior has been
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Psychological Studies
various traits are increasingly the focus of research, as discussed in the next section.
333
In three researchers taking lithium at higher levels, however, effects were more pronounced. They noted occasional hypersensitivity but also decreased responsivity to
their environment, increased indifference and malaise,
greater passivity, and cognitive changes (discussed further
in Chapters 12 and 21). Judd and colleagues (1977a), studying lithiums effects on normal male volunteers, found
that in addition to reporting a mood-lowering effect, their
subjects cited less inclination and desire to deal with the
demands of the environment. Normal men studied by
Kropf and Mller-Oerlinghausen (1979) showed, while on
lithium, decreased social involvement, activity, and concentration, as well as increased boredom and lethargy.
When White and colleagues (1979) administered the Profile of Mood States (POMS) to 10 normal volunteers treated
with lithium, the subjects reported a reduced sense of wellbeing and fewer social interactions; they also complained
of fatigue, anxiety, lack of initiative, and decreased efficiency.
In an indirect measure of lithiums ability to attenuate emotional responsiveness, Belmaker and colleagues (1979) found
that, while taking lithium, neither normal subjects nor patients experienced the predicted increased heart rate generally caused by participation in cognitive tasks. Both of these
studies, although intriguing, were relatively short-term trials (13 weeks and 2 weeks, respectively), and there is some
indication that longer periods of time on lithium result in
at least partial accommodation to some of these effects.
The most clear-cut influences of lithium on bipolar
personality were evident in personality studies done on
euthymic, lithium-stabilized patients. Additionally, a few
studies have examined personality and mood stabilization
over time in lithium-treated, affectively ill patients. Bonetti
and colleagues (1977) administered the EPI and the MarkeNyman Temperament Scale to 33 recurrent (minimally
three episodes) unipolar and 28 bipolar patients at the end
of the index episode and at least 3 months later. They found
that personality changes were more pronounced in the
bipolar patients, especially on measures of sociability, initiative, and impulsiveness. Neuroticism scores decreased
most dramatically within the unipolar group (testretest
differences, p < .001). The authors speculated that lithium
both reduced symptoms and altered habitual patterns of
personality, such as high activity levels and impulsiveness
in bipolar patients and anxiousneurotic traits in unipolar
patients.
In an interesting and important study of the relationship
between lithium blood level and personality change, Kropf
and Mller-Oerlinghausen (1985) conducted a double-blind
study of lithium dose reduction (20 percent) in 14 long-term
lithium-treated patients (5 unipolar, 9 bipolar), all of whom
were euthymic when tested. Eleven patients (3 unipolar,
8 bipolar) maintained at their regular lithium levels served as
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Psychological Studies
PERSONALITY DISORDERS
Axis II (personality) disorders occur relatively frequently
in clinical populations (with a range of about 5 to 40 percent, varying by personality disorder type) (Widiger and
Rogers, 1989). Although epidemiologic studies of personality pathology in community samples have been infrequent
and limited in scope, Weissmans (1993) review of such
studies suggests that the population prevalence is 10 to 23
percent. Researchers have raised the question of the rates
of personality disorders in bipolar samples and explored
the correlates of Axis II pathology.
Early studies of the comorbidity of personality disorder
with bipolar illness were hampered by methodological
shortcomings, such as shifting diagnostic criteria for assessing Axis II disorders, assessment methods of uncertain
validity, unclear or mixed samples of bipolar patients (e.g.,
Sample
Method
Clinical State
20 adolescents/
outpatientsb
Euthymic
26 inpatients
(16 bipolar-I,
10 bipolar
schizoaffective)
50 outpatients
Personality Disorders
Examination (PDE)
(interview)
Structured Interview for
DSM-III Personality
Disorders (SIDP-III)
23 oupatients
(married or
cohabiting)
66 patients
33 first-episode,
26 multipleepisode
inpatients
42 outpatients
Comparison Group
Borderline, narcissistic
62
Histrionic, antisocial,
borderline
58
Borderline, histrionic
22
Dependent, borderline,
obsessive-compulsive
53 manic
or hypomanic,
45 euthymic
Borderline, schizoid,
histrionic
48
Avoidant, Cluster
B (mixed)c
45
Histrionic, borderline,
avoidant, compulsive
48 bipolar
patients,
16 controls
38d
Histrionic, compulsive,
paranoid
Cluster A, Cluster Cc
38 bipolar,
51 unipolar
29
Compulsive, narcissistic,
borderline
Histrionic, compulsive
Personality Diagnosis
Questionnaire-Revised
(PDQ-R)
PDE
Current symptoms
not controlled
33 patients with
schizophrenia
Current symptoms
not controlled but
stable
Few or no current
symptoms
90 outpatients
61 Veterans Affairs
(VA) outpatients
SCID-II PDQ-R
60 inpatients
52 outpatients
Euthymic
58 normal controls
Compared patients
with and without
history of alcohol
abuse disorder
117 unipolar
depressed
inpatients
a
Estimates of personality disorders in general clinical populations range from 5 to 40 percent (Widiger and Rogers, 1989), and in community samples from 10 to 23 percent (Weissman,
1993).
b
There were no differences in rates of Axis II disorders between bipolar-I and schizoaffective patients, so the authors combined the groups in their analysis.
c
Cluster A: paranoid, schizoid, schizotypal; Cluster B: antisocial, borderline, histrionic, narcissistic; Cluster C: avoidant, dependent, obsessive-compulsive.
d
Highest in patients with history of alcohol abuse.
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Psychological Studies
and impair the ability to form solid and sustaining relationships, thereby contributing to diffuse Axis II symptomatology. Thus the maladaptive behaviors reflected in personality disorders may in some cases be dysfunctional
coping methods or adaptations to the illness.
A third conceptual consideration concerns sampling: patients included in the studies reported in Table 101 may reflect those who are most disturbed, and who are seen in
research-oriented settings that may draw more difficult patients not readily managed in community or private care. As
noted, clinical samples in general (compared with epidemiologic samples), and especially those in tertiary care settings, may not be representative in terms of comorbidity because they are likely to be sicker.
Finally, as discussed in Chapter 3, some would argue
against conceptualizing Axis II disorders as conditions
comorbid with bipolar disorder. Instead, it is argued,
they may represent forms of disorder in the bipolar spectrum (e.g., Akiskal et al., 1985, 2000; Deltito et al., 2001).
Gunderson and colleagues (2006) recently reported the
results of a 4-year prospective investigation of 196 patients with bipolar disorder and 433 patients with personality disorders. They found that bipolar-I and bipolar-II
disorders were significantly more common in patients
with borderline personality disorder (19.4 percent) than
in patients with other types of personality disorder (7.9
percent). The presence of co-occurring bipolar disorder
had no significant effect on the course of the borderline
personality disorder, as measured by remission rates, functional adjustment, or treatment utilization rates (hospitalization and medication usage). The investigators concluded that there was only a modest association between
bipolar disorder and borderline personality disorder,
thereby making a strong spectrum relationship with
bipolar disorder extremely unlikely (p. 1177). We do not
know enough at the present time to draw firm conclusions on this question.
Despite uncertainty about the conceptualization of personality disorder comorbidity, one meaning of comorbid
Axis II pathology is not ambiguous: bipolar (or any psychiatric) patients who have personality pathology typically
have worse outcomes. Kay and colleagues (2002) found significantly lower rates of employment, more complex medication regimens, and greater likelihood of substance and
alcohol abuse among bipolar-I male veterans who had diagnosed personality disorders (but no differences between
the groups in age at onset or duration of disorder). Over
time, Carpenter and colleagues (1995) found that patients
with personality disorder had significantly more symptoms and worse social adjustment scores than those without such disorder. Others have also found this to be the
case (Bieling et al., 2003). Kutcher and colleagues (1990)
INTERPERSONAL FUNCTIONING
No one has the slightest idea of what Ive been through
with Cal [Robert Lowell]. In 4 12 years, counting this present
breakup, he has had four collapses! Three manic, and one
depression. These things take time to come and long after
he is out of the hospital there is a period which can only be
called nursing. The long, difficult pull backwhich does
not show always to others. I knew the possibility of this
when I married him, and I have always felt that the joy of
his normal periods, the lovely time we had, all Ive
learned from him, the immeasurable things Ive derived
from our marriage made up for the bad periods. I consider
it all a gain of the most precious kind. But he has torn
down this time everything weve built up . . . how difficult
these break-ups are for both of us. (Elizabeth Hardwick13)
Moods are by nature compelling, contagious, and profoundly interpersonal. Mania and depression alter the perceptions and behaviors not only of those who have them,
337
Social Functioning
Impairment during Mania and Depression
The complex, subtle, and potentially infuriating aspects of
manic interpersonal behavior were observed by most early
clinical investigators (see Chapter 1). Hypomanic behavior,
especially, was noted for its powerful and confusing influence on others. The positive, engaging, and occasionally
charismatic qualities of many individuals with bipolar illness are discussed at length in Chapters 2 and 12. Here we
describe some of the more detrimental interpersonal features of bipolar illness.
Kraepelin (1921, p. 61) wrote of the skill of hypomanic
patients in manipulating fellow patients:
It is just the peculiar mixture of sense and maniacal activity, frequently also an extensive experience of institutions,
which makes them extremely ingenious in finding out
means to satisfy their numerous desires, to deceive their
surroundings, to procure for themselves all kinds of advantages, to secure the property of others for themselves.
They usually soon domineer completely over their fellowpatients, use them for profit, report about them to the
physician in technical terms, act as guardian to them,
and hold them in check.
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Psychological Studies
patients as manifesting a particular kind of narcissistic dependency on their love objects, Jacobson (1953, p. 66) provided a perspective at variance with that of the earlier psychoanalytic writers:
We are also surprised to see that as long as they are not
sick, they may be delightful companions or marital partners, a feature that Bleuler mentioned especially. In their
sexual life they may show a full . . . response, and emotionally, in contradistinction to schizoid persons, a touching warmth and unusual, affectionate clinging to people
they like . . . [they] are potentially able to function
extraordinarily well.
Cohen and colleagues (1954, p. 119), however, commented on what they viewed as the illusion of normal relationships in manic-depressive patients:
The appearance of closeness is provided by the hypomanics liveliness, talkativeness, wittiness, and social aggressiveness. Actually, there is little or no communicative
exchange between the hypomanic and any one of his socalled friends. . . . The concept of reciprocity is missing;
the needs of the other for similar experiences are not recognized.
The playful, high-energy, and extraverted behaviors associated with mania are often irritating. So, too, are the interpersonal qualities usually present during depression. Interviews with roommates of college students identified by
clinical assessments as falling in the bipolar spectrum (cyclothymia as well as bipolar-I or -II) found that bipolar students were perceived as excessively excitable, showed poor
judgment, were argumentative when hypomanic, and were
irritable and socially withdrawn when depressed (Depue
et al., 1981). It is not surprising, given the number of negative social behaviors exhibited by the bipolar students, that
58 percent of the roommates reported that they avoided the
subject, finding him or her noxious.
Fluctuations in levels of sociability almost define bipolar
illness. Energetic seeking out of other people and uninhibited social behavior are common features of mania.
Winokur and colleagues (1969, p. 63) described this in their
monograph:
A most characteristic sight when the patient is brought to
the hospital is a frightened and exhausted family, which
has frequently been awake for 1 or more nights being lectured to by a bright-eyed and excited patient.
In their study of 30 bipolar patients, Murphy and colleagues (1974) found two distinctive behavioral characteristics of mania: noticeably increased psychomotor activity
and, of relevance here, a need for increased interpersonal
contact (people seeking). Akiskal and colleagues (1977)
reported that half of their cyclothymic patients alternated
periods of uninhibited people seeking with periods of introverted self-absorption.
During depressive episodes, maladaptive patterns of relating to others are common, including social withdrawal,
loss of enjoyment and pleasure, irritability, increased criticism of and negativism toward others, and sensitivity to
criticism or rejection by others (see Chapter 2; Benazzi,
2000). Depressed people are often highly dependent on
others for reassurance and support, yet appear paradoxically to reject the support or view it as untrustworthy and
insufficient. Friends and family may be frustrated by the
exaggerated dependence of the depressed patient, especially when they seem unable to relieve his or her despondency. Moreover, the depressed person may be particularly
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Psychological Studies
episode frequency, and poorer social/leisure activity was associated with more episodes and hospitalizations. Scores on
depression symptomatology were also associated with lower
levels of social/leisure activity.
Several studies have found that depression is more linked
to difficulties in functioning than is mania. In a study aimed
at exploring the mutual influence of social and clinical functioning, Gitlin and colleagues (1995) evaluated the impact of
both past episode history and subclinical symptoms on indicators of social functioning in a sample of 82 bipolar patients
followed for at least 2 years. Social (close relationships) and
family functioning were significantly related to number of
past and recent depressive episodes but not to manic or hypomanic episodes. In all the analyses, subclinical symptoms
were more strongly predictive of poorer social functioning
than was number of clinical episodes. The researchers also
determined that depressive episodes were significantly more
(negatively) predictive of the quality of relationships with
family members than were manic episodes, with a similar
trend toward a greater association of depression with social
(close) relationships. In contrast, occupational functioning
was negatively associated with both depressive and manic
episodes.
A recent review and investigation of functional outcomes in bipolar patients revealed depression to be one of
the few fairly consistent predictors of social, family, and
marital (as well as occupational) functioning (Bauer et al.,
2001). This study is noteworthy for its careful assessment
of symptoms and functioning over 48 weeks in a sample of
43 male Veterans Affairs outpatients. The amount of time
depressed and average depression symptom scoresbut
not mania scoreswere significantly correlated with social and work functioning. Other researchers (Cooke et al.,
1996) also found that bipolar patients low scores on social
functioning were associated with subclinical depressive
symptoms (subclinical mania/hypomania was not assessed),
and social functioning was lower in bipolar-II than in
bipolar-I patients. Different investigators (Romans and
McPherson, 1992), in contrast, found that a subgroup of
patients with a predominantly manic course reported less
adequate close relationships and less available social contacts than did those with depressive episodes, although the
effect was not statistically significant. Perhaps consistent
with the previously cited studies, Romans and McPherson
found that patients with a longer history of illness reported
fewer close and general social contacts.
A study of 40 bipolar-I patients social functioning
(Lam and Wong, 1997) included ratings of relationships
with intimate partners and friends and social presentation. The investigators evaluated recognition of prodromes
of mania and depression and scored the patients reports of
how they coped with prodromal symptoms of depression
and mania. Generally, those with good awareness of prodromal symptoms and good coping methods had better
overall social functioning. A multiple-regression analysis
to predict overall social functioning indicated that lower
current subclinical depression scores and good reported
coping with prodromes of mania and depression significantly predicted good functioning, whereas number of
past hospitalizations and current subsyndromal manic
symptoms did not.
341
Sample
OConnell
et al., 1985
60 bipolar-I
outpatients
Miklowitz et al.,
1988
23 bipolar
inpatients
52 bipolar-I
outpatients
14 bipolar-I and
7 bipolar-II
patients
Coryell et al.,
1998
113 bipolar
(with mania)
inpatients and
outpatients
Kulhara et al.,
1999
118 bipolar-I
outpatients
Johnson et al.,
2000
59 bipolar-I
patients
Johnson et al.,
2003
94 bipolar
patients
Cohen et al.,
2004
52 bipolar-I
outpatients
343
Sample
125 bipolar
outpatients
(116 bipolar-I,
9 bipolar-II)
47 bipolar-I
outpatients
(as reported retrospectively by their mothers) was significantly worse than that of normal comparison subjects of
similar age. Appropriate social behavior, quality of peer relations, and pursuit of interests appeared to be impaired
in the prebipolar lives of patients. It is unclear, however,
whether these individuals were actually symptomatic at
young ages. Moreover, variability in reported adjustment
suggests differing subgroups, including some with exceptionally good functioning. Such patterns warrant further
studyas does clarification of the role of childhood disorders (see Chapter 7) in later social adjustment.
In view of the apparent impact of depressive symptoms
on social adjustment, it may be noted that research on
unipolar depression is focused increasingly on interpersonal
functioning. Social variables are seen as playing a role in
vulnerability to onset of the disorder and in the prediction
of relapse, recurrence, and chronicity, and also as resulting
from the impact of depression on the relationships of the
depressed person with others. A large body of research has
begun to document the role of social factors in depression,
presumably operating both as cause and consequence of the
disorder (e.g., reviews in Hammen and Brennan, 2002; see
also Joiner and Coyne, 1999). This research may provide
guidelines for further studies of bipolar samples.
There is a related need for further study of the specific
effects of depression and mania on interpersonal relationships. Are there conditions under which manic and hypomanic symptoms portend decrements in social connections, as appears to be the case with depression? Or can
they under some circumstances facilitate social contacts
and friendships? Can the optimism and positive affectivity
often associated with bipolar patients who have an underlying hyperthymic temperament lead to more opportunity
for relationships that may prove to be sustaining and
meaningful?
Marriage
I am tired of papering over the cracks and pretending to
friends and relatives that life is wonderful. It is the nearest
and dearest who come in for the bulk of the barrage. . . .
It is the Jekyll and Hyde syndrome. I never know which is
going to walk in through the door, and the unpredictability is most unnerving. It is like living on a knife-edge. You
can never relax or take anything for granted and any
thought of lapsing into placid serenity is completely out
of the question. (Anonymous18)
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345
346
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347
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Psychological Studies
Sexual Behavior
Again judging from my own experience, the sexual symptoms of the manic state seem to be the most powerful and
important of all. . . . The normal inhibitions disappear,
and sexual activity, instead of being placed, as in our
Western Christian civilization, in opposition to religion,
becomes associated with it. This release of the underlying
sexual tension . . . seems to me to be the primary and
governing factor of all the ecstasies and many other experiences of the manic state. (John Custance, 1952)
increased sexual intensity was a lasting characteristic attributable to their mood disorder.
As noted, bipolar illness also can be associated with decreased sexual drive. For example, Winokur and colleagues
(1969) reported that 63 percent of patients with bipolar
mixed states reported decreased sexual interest. Indeed,
approximately three-fourths of bipolar depressed patients
have been found to experience a loss of sexual interest: 73
percent reported by Winokur and colleagues (1969) and 77
percent by Casper and colleagues (1985).
Sexual responsiveness can also be dampened in patients
taking lithium.20 Sheard (1971, 1975) and Lion (1975) attributed this phenomenon to a common effect on aggressive
and sexual behaviors, both often occurring together in
bipolar patients. Lorimy and colleagues (1977) reported
that half of their patients taking prophylactic lithium experienced troublesome side effects affecting their sexual activities, including decreases in sexual intensity, frequency of
sexual drive, and frequency of sexual intercourse. However,
patients reported that once intercourse began, there was no
decrement in enjoyment or orgasmic ability.
What accounts for these lithium-induced changes is
unclear. Among the possible explanations are lithiuminduced hypothyroidism, decreased frequency or intensity
of hypomanic episodes, or the direct effect of lithium on
the central mechanisms underlying sexual drive and behavior. Yet another possible reason for these changes is
vacillation in interpersonal relationships brought about by
lithium, with secondary manifestation in the sexual domain.
349
350
Psychological Studies
attributes (p < .01) after lithium treatment. Spouses particularly noted decreases in nervousness; bizarre, threatening,
and violent behavior; withdrawn or demanding behavior;
guilt; sadness; and undue exaggeration of abilities. But they
also reported missing the enthusiasm and heightened sexuality associated with hypomanic phases:
Hypomanic joviality, enthusiasm, and spontaneity are often regarded as social pluses; and manic-depressives and
their spouses complain about the loss of these valued attributes. When pressed to discuss the sexual compatibility
of the marriage, frequently they will say it is worse since
lithium treatment started, as the lithium-treated spouse
has less libidinal strivings. (Demers and Davis, 1971,
p. 352)
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Psychological Studies
CONCLUSIONS
Personality
Contemporary research generally dispels the idea that the
personalities of bipolar patients are fundamentally different from those of people without mood disorders. Descriptive studies comparing bipolar patients with other groups
have yielded few consistent results and clearly suggest enormous variability, depending in part on the instruments used
and individuals current mood status. The major drawback
of such studies is their limited utility. Nevertheless, the close
and likely bidirectional association between personality and
mood disorders suggests that many behaviors and attitudes
we regard as personality may in fact be somewhat unstable
and highly colored by affective experiences. The field now
appears ready to proceed to more conceptually and practically challenging questions and prospective methods concerning the predictive utility of personality constructs:
Do they tell us something important about the course of
disorder, treatment responsiveness, and functional outcome
beyond that attributable to symptoms or psychosocial context? Are there premorbid signs of eventual bipolar disorder
that might help in both understanding the risk for illness
and altering its course? What are the underlying neurobiological processes of normal mood and temperament that
may help us understand mood disorders?
Personality Disorders
Research on personality disordersthe enduring, pervasive, and dysfunctional styles measured on Axis II of the
DSMhas increased in sophistication in the bipolar field.
As with most Axis I disorders, studies of bipolar patients
evaluated during remission indicate relatively high rates of
personality disorders, and such disorders generally predict
a relatively worse course of illness and functional adjustment. However, the overlap among bipolar symptoms,
mood states, and personality pathology may obscure the
question of whether a bipolar patient truly has an Axis II
disorder.
Interpersonal Functioning
Interpersonal functioning is commonly a casualty of bipolar disorder, although there is tremendous variability in
individuals abilities to sustain close friendships and family relationships. It is unclear whether the effects of bipolar
disorder on interpersonal functioning are the result of
episodes or of underlying impairment of social skills.
There is, however, ample evidence that poor social functioning may negatively affect clinical outcomes. Thus interventions targeting social and family relationships may potentiate the effects of psychopharmacology and, of course,
benefit the loved ones greatly affected by their relatives disorder.
NOTES
1. These differences were well summarized by Hall and Lindzey
(1970): the relative importance of the uniqueness of the individual (the idiographic-nomothetic controversy), whether
man should be viewed as possessing purposive or teleological qualities, the importance of group membership, the relative importance of conscious and unconscious determinants
of behavior, the number of motivational concepts, the importance of the principles of reward and association, the relative emphasis on stable structures or the process of change
in personality, the functional independence of personality
structure at any particular point in time, the relative importance of genetic factors in determining behavior, and the relative importance of early developmental experiences.
2. Thus Kraepelin (1921) delineated four fundamental types
of temperament: depressive, manic, irritable, and cyclothymic.
Kretschmer (1936) stressed the overlap among these personality types in the prepsychotic, cycloid personality of manicdepressive patients: they form layers or patterns in individual
cases, arranged in the most varied combinations. Campbell
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Psychological Studies
17. Johnson et al., 2000; Cohen et al., 2004; Kim and Miklowitz,
2004; Yan et al., 2004.
18. Published in The Times (London), January 24, 1986.
19. Stoddard and colleagues (1977) studied eight affective episodes
in a 39-year-old rapid-cycling woman. They collected systematic behavioral data twice a day and observed that she became sexually provocative during mania. Conversely, a significant predictor of her switch into depression was a
decrease in sexual preoccupation (p < .05).
20. In addition to the references in this paragraph, see Demers
and Davis (1971).
21. Demers and Davis, 1971; Ruestow et al., 1978; Frank et al.,
1981; OConnell and Mayo, 1981.
22. Downey and Coyne, 1990; Gelfand and Teti, 1990; Hammen,
1991; Goodman and Gotlib, 1999; NICHD Early Child Care
Research Network, 1999.
11
Assessment
Our customary grouping into manic and melancholic attacks does not fit the facts, but requires
substantial enlargement, if it is to reproduce nature.
Emil Kraepelin (1921, p. 191)
preclinical states lies in their ability to predict who will develop bipolar disorder over time. Because those with the
disorder may be untreated and underdiagnosed, it would
be useful to have screening measures to identify such individuals in general psychological, psychiatric, or medical settings. Also discussed in this chapter are measures of functional outcomes in work and social relationships; we note
the paucity of such approaches relative to those with a
clinical focus. Gaining a fuller understanding of bipolar
disorderas well as helping patients improve in key areas
that affect the quality of their livesrequires attention to
the development and application of such measures.
Several general types of measures have been developed to
classify and quantify changes in affective states. The major
categories, delineated by von Zerssen and Cording (1978), are
(1) self-ratings, made by patients; (2) observer ratings, usually made by clinicians; (3) analyses of behavior (including
linguistic analyses of speech or written productions); and (4)
objective measurements, either of spontaneous activities
(physical activity) or of reactions within a standardized situation (objective psychometric tests). This chapter necessarily
is limited to an overview of self-rating and observer rating
scales constructed to measure manic, depressive, mixed, and
cyclothymic states. Measurement issues specific to particular
topics are covered in the relevant chapters of this volume. For
example, diagnostic evaluation is covered in Chapter 3, assessment of course and outcome in Chapter 4, assessment of
neuropsychological functioning in Chapter 9, and measures
of personality in Chapter 10. This chapter includes those
generic rating scales that have been used or replicated most
widely, as well as several instruments with potential utility
for specific goals, such as screening for bipolar disorder.
We begin by describing conceptual and methodological
issues involved in the assessment of manic and depressive
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Psychological Studies
states. We then review in turn instruments used for assessment of the two states, and analyze and compare the scales
used for both purposes. The following sections describe instruments used for combined assessment of manic and depressive states, assessment of bipolar risk and screening for
bipolar disorder, charting of the course of bipolar disorder,
assessment of psychosocial adjustment, and assessment of
bipolar symptoms in children and adolescents.
Methodological Issues
Added to these conceptually challenging issues are numerous psychometric hurdles that must be overcome by any
good measure, including establishment of various forms of
reliability and validity. As discussed later, clinical activity
and research in the field of bipolar disorder have brought
Assessment
Mood ScorePatient
Most Depressed
75
50
25
Most Happy
Most Depressed
Mood ScoreStaff
357
75
50
25
Most Happy
10
ECT
20
30
40
50
Lithium
1 g/day
Admission
Discharge
Morning
Evening
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Psychological Studies
At the same time, however, observer ratings have significant potential drawbacks, as discussed at length by both
Lorr (1974) and Bech (1981). Lorr noted that variability in
the degree of the patients disturbance from one interview
to another affects both self- and observer ratings. Furthermore, observers may differ in efficiency and their manner
in relating to the patient, and rating scales may be worded
ambiguously or require too much inference. Bech (1981)
stressed sources of variance in observer ratings, including
differences that occur because information is not gathered
from the same sources, differences in multiple observers
perceptions of the same phenomena, and variations in the
terminology used to report results of observations of the
same phenomena. Variations in the mood of the observer
also affect ratings for some items (Bunney and Hamburg,
1963); this is the case especially for anger and anxiety ratings, which may be distorted if the observer confuses his
own feelings with those of the patient.
Assessment
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Psychological Studies
Part BIntensity
(How intense is it?)
The Patient
0 to 5
0 to 5
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
Looks depressed
Is talkinga
Moves from one place to anothera
Makes threats
Has poor judgmenta
Dresses inappropriately
Looks happy and cheerful
Seeks out others
Is distractiblea
Has grandiose ideas
Is irritablea
Is combative or destructive
Is delusional
Verbalizes depressive feelings
Is activea
Is argumentative
Talks about sex
Is angrya
Is careless about dress and grooming
Has diminished impulse controla
Verbalizes feelings of well-being
Is suspicious
Makes unrealistic plans
Demands contact with othersa
Is sexually preoccupied
Jumps from one subject to another
small samples, the scale is a reliable, valid, and sensitive measure of mania. More recent data showed that interrater reliability averaged .68 across items (Altman et al., 1994). The
YMRS is increasingly being employed in bipolar clinical trials and treatment outcome studies because of its ease of use
(e.g., Tohen et al., 2000; Leverich et al., 2001). The following
is a sample from the YMRS developed to assess elevated
mood:
Elevated Mood
0 = absent
1 = mildly or possibly increased on questioning
2 = definite subjective elevation; optimistic, self confident; cheerful; appropriate to content
3 = elevated, inappropriate to content; humorous
4 = euphoric; inappropriate laughter; singing
Assessment
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Psychological Studies
Both the original and revised scales were based on Carrolls observation that neither existing self-report nor
clinician-based scales were adequate for diagnosis of depressive symptoms (Carroll et al., 1981).
Most empirical evaluation of the Carroll scales has been
based on the original version, but the author has indicated
that the evaluation results are also applicable to the CDS-R.
The scales appear to have excellent convergent validity with
both self-report and clinician-based measures (e.g., correlation with the BDI, r = .86; correlation with the observerrated HAM-D, r = .71 [Carroll, 1998]). Because it is similar in
structure and content to the HAM-D and is less timeconsuming and less expensive to administer, it may be a
good alternative (see Smouse et al., 1981; Tandon et al., 1986).
Correlations with other depression scales suggest that it is as
sensitive to bipolar as to unipolar depression. Carroll and
colleagues (1981) suggested that a cutoff of 10 can serve as a
screen for the presence of significant depression.
Assessment
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Psychological Studies
1986). This last point may be an especially important limitation in the assessment of bipolar depression. As noted
earlier, Rush and colleagues (1996a) developed a clinicianadministered version of what they believe is an improved
HAM-D addressing several of the shortcomings noted.
The IDS-C is currently being used in the multisite
NIMHStanley Foundation Bipolar Network study (Leverich et al., 2001), and its scores correlate highly with
those on the HAM-D. A study of depressed inpatients reported by Corruble and colleagues (1999) confirmed the
IDS-Cs strong psychometric properties and suggested that
it is more sensitive to treatment-related changes than the
Montgomery-Asberg Depression Rating Scale (MADRS)
(discussed later). The brief, 16-item clinician version of
the QIDS was also found to have excellent psychometric
properties in a large-scale study of unipolar depressed
and bipolar outpatients (Trivedi et al., 2004). Finally, there
is a Revised HAM-D (Warren, 1994). It remains to be seen
whether alternatives to the HAM-D will flourish in clinical research over time.
The interobserver reliability of the Bech-Rafaelsen Melancholia Rating Scale has been found to be as high as that of
Assessment
365
reviewed in Chapters 1 and 2, bipolar and unipolar depressed patients show different patterns of response to
some of the same standard rating instruments (Paykel and
Prusoff, 1973). In this light, it is unfortunate that there have
been no systematic studies of the differential sensitivity of
rating scales to bipolar depression. To our knowledge, the
only scale designed specifically with bipolar patients in
mind is the ADRS (Murphy et al., 1982), described later.
Instruments for assessment of depression are being
refined and developed with increasing frequency and
psychometric sophistication. The tension between having
well-developed and empirically sound measures on the one
hand and the capacity for widespread use and communicability on the other will doubtless grow. Most of todays instruments continue to be validated by comparison with
older instruments (e.g., the HAM-D) without sufficient
consideration of sources of invalidity of the latter. A further
significant problem is the heterogeneity of the scales contents, with some being far more focused on somatic or cognitive symptoms than others (see the later discussion). This
variation leads to discrepancies in the results of treatment
and clinical studies. Moreover, given the heterogeneity
among clinical presentations of depressive syndromes,
there have been calls for the development of more narrowband instruments that can be used to assess individual or
clusters of symptoms, such as energy and fatigability, sleep
difficulties, and hopelessness. Such more narrowly focused
assessments could potentially facilitate advances in treatment or in understanding of depressive subtypes.
Perhaps the greatest limitation of most well-established
self-report and observer rating scales for depression is
their failure to capture potentially unique aspects of bipolar depression. This shortcoming, discussed at length in
Chapter 2, is of obvious concern to most researchers in the
field (see Berk et al., 2004, for a review of the subject). Further research on the clinical features of bipolar depression
is needed to help identify factors that should be developed
or refined in assessment instruments.
366
Psychological Studies
50
Observer Ratings
40
30
20
10
0
Mood
Cognition
Sleep
Psychomotor
Activity
Speech
Behavior
Figure 112. Relative weighting of item content: Observer rating measures of mania.
Observer Ratings
15
10
0
Aggression/
Hostilities
Hypersexuality
Impaired
Judgment
Seeking
Out
Others
Impulsivity
Appearance
Figure 113. Relative weighting of item content for behavior items: Observer rating measures of mania.
Self-ratings
30
20
10
0
Mood
Cognition
Sleep
Psychomotor
Activity
Energy
Weight
Somatic
368
Psychological Studies
Observer Ratings
30
20
10
0
Mood
Cognition
Sleep
Psychomotor
Activity
Energy
&
Libido
Weight
&
Appetite
Somatic
Symptoms
or observer rating scales with the exception of work activities and interests, which together make up 7 percent of
the total self-rating and 6 percent of the total observer rating items (all of the latter are on the HAM-D). As in the
assessment of mania, the choice of instruments for assessment of depression depends on the patient population being evaluated, the level of interviewer training required,
and the nature of the clinical or research issue being addressed. It is often useful to combine a self-rating with an
observer rating measure.
Assessment
369
370
Psychological Studies
Stimulus-seeking/excitement
(receptivity toward and
stimulation by the world)
Flight of ideas/thought
retardation (thought
processes)
Decisiveness/doubt
Assessment
371
372
Psychological Studies
Response
1. Has there ever been a period of time when you were not
your usual self and . . .
you felt so good or so hyper that other people thought
you were not your normal self or you were so hyper that
you got into trouble?
you were so irritable that you shouted at people or
started fights or arguments?
you felt much more self-confident than usual?
you got much less sleep than usual and found you didnt
really miss it?
you were much more talkative or spoke much faster
than usual?
thoughts raced through your mind or you couldnt slow
your mind down?
you were so easily distracted by things around you that
you had trouble concentrating or staying on track?
you had much more energy than usual?
you were much more active or did many more things
than usual?
you were much more social or outgoing than usual; for
example, you telephoned friends in the middle of the
night?
you were much more interested in sex than usual?
you did things that were unusual for you or that other
people might have thought were excessive, foolish, or
risky?
spending money got you or your family into trouble?
2. If you checked YES to more than one of the above, have
several of these ever happened during the same period
of time?
3. How much of a problem did any of these cause youlike
being unable to work; having family, money, or legal
troubles; getting into arguments or fights?
No problem
Minor problem
Moderate problem
Serious problem
yes
O no
yes
no
yes
yes
no
no
yes
no
yes
no
yes
no
yes
yes
no
no
yes
no
yes
yes
no
no
yes
yes
no
no
Source: Adapted from Hirschfeld et al., 2000. Reprinted with permission from the American Journal
of Psychiatry, Copyright 2005, American Psychiatric Association.
Assessment
Figure 116. Relapsing mania with isolated periods of depression. Light blue = depression; dark
blue = manic excitement. (Source: Kraepelin, 1921, p. 143) Reprinted with permission.
Alter
1840
Januar
Febr
Marz
April
Mai
373
Juni
Juli
August
Sept
Okt
Nov
Dez
374
Psychological Studies
Assessment
375
M4
M3
M2
M1
0
D1
D2
D3
D4
Jan.
Feb.
Mar.
Apr.
May
Jun.
Figure 117. Example of time line for characterizing the timing and features of changes in
symptoms of unipolar depression and bipolar disorder (see text for explanation).
their quality and utility to be relatively poor. Thus although many such scales exist, few have provided the utility and psychometric qualities necessary for their survival
(see Williams, 2000).
Currently, three patient-report scales are used relatively
widely in research on quality-of-life issues for those with
mood disorders. The Social Adjustment Scale-Self Report
(SAS-SR) (Weissman and Bothwell, 1976; Weissman et al.,
1978) assesses instrumental and emotional role functioning
in six areas: work, social and leisure, maritalsexual, relationships with extended family, parenting, and family unit.
It includes a total of 54 items and yields both subscale and
overall adjustment scores. An example is the following:
How have you been getting along with the children during the last 2 weeks?
1. I had no arguments and got along very well.
2. I usually got along well but had minor arguments.
3. I had more than one argument.
4. I had many arguments.
5. I was constantly in arguments.
376
Psychological Studies
Measurement of Depression
The assessment of depressive symptoms and syndromes in
children and adolescents has been well described elsewhere (e.g., Nezu et al., 2000). In general, self-report questionnaires about symptoms and diagnostic interviews can
be administered reliably and yield valid conclusions about
symptom severity and the presence of depressive disorders.
For example, a Childrens Depression Inventory (CDI) was
developed by Kovacs (1981); it has a three-response options
format with content appropriate for those aged 7 to 17. The
BDI, discussed earlier, is suitable for most patients aged 13
and older.
377
Assessment
Table 114. Scores on Items of the Conners Abbreviated Parent Questionnaire for Subjects with a Prepubertal and
Early Adolescent Bipolar Disorder (BP) Phenotype, Subjects with Attention-Deficit Hyperactivity
Disorder (ADHD), and Healthy Comparison Subjects
Questionnaire Item
SUBJECTS WITH A BP
PHENOTYPE (n = 92)
HEALTHY COMPARISON
SUBJECTS (n = 92)
Mean
Mean
Std. Dev.
Mean
Std. Dev.
Std. Dev.
1. Restless or overactive
2.9a
0.9
3.0a
0.8
1.2
0.5
2. Excitable, impulsive
3.2a
0.8
3.1a
0.8
1.3
0.5
2.7a
1.0
2.5a
0.8
1.1
0.3
2.9a
1.0
2.9a
0.9
1.2
0.4
5. Constantly fidgeting
2.7a
1.0
3.1a
0.8
1.2
0.4
3.2a
0.9
3.3a
0.7
1.2
0.4
3.3a,b
0.9
2.9a
1.0
1.2
0.4
2.5a,c
1.0
1.9a
0.9
1.2
0.5
3.2a,c
0.9
2.3a
1.0
1.2
0.4
3.1a,c
1.0
2.3a
1.0
1.2
0.4
Note: See Tillman and Geller (2005) for a scoring algorithm and age-specific cutoffs for use of the Conners Abbreviated Parent Questionnaire
as a screening tool. Std. Dev. = standard deviation.
a
Significant difference compared with the healthy comparison group (p < .0001).
b
Significant difference compared with the ADHD group (p < .003).
c
Significant difference compared with the ADHD group (p < .0001).
Source: Tillman and Geller, 2005. Reprinted with permission from the American Journal of Psychiatry, Copyright 2005, American Psychiatric Association.
Two major issues are associated with assessment of depression in children. First, most diagnostic interview procedures assume that childrens reports of their symptoms should be supplemented by information collected
from caretakers. Most diagnostic methods for assessing depression, such as the clinician-administered KSADS (Ambrosini, 2000) or the Diagnostic Interview Schedule for
Children (DISC), which is administered by trained laypersons (Shaffer et al., 2000), prescribe separate interviews for
children and parents. KSADS commonly uses a best clinical estimate method, combining information from the
child and the parent weighted by the type of information
given, according to the clinicians judgment. For example,
internal symptoms, such as depressed feelings and negative
thoughts, cannot readily be detected by parents, and there-
378
Psychological Studies
claims were based largely on inadequate designs, including simple associations between mothers and childrens
symptoms that could be accurate given the common finding
of disorders in offspring of depressed women. Subsequent
studies using sophisticated methods, such as covariance
structure analysis with latent variables formed from different
informants, have supported the hypothesis that depressed
mothers may report more negative behaviors. As these studies have shown, the fact that maternal depression truly is associated with more child disorder makes the conclusion of
bias unclear (Fergusson et al., 1993; Boyle and Pickles,
1997). Other researchers who have evaluated parentchild
concordance over time (Renouf and Kovacs, 1994; Boyle and
Pickles, 1997) have suggested that maternal bias, if any, may
be more pronounced for younger than for older children.
CONCLUSIONS
NOTES
1. Many of these studies were reported in a special issue of the
Journal of Affective Disorders in 2005: Akiskal et al., 2005a,b,c;
Akiyama et al., 2005; Erfurth et al., 2005a,b; Matsumoto
et al., 2005; Mendlowicz et al., 2005.
2. Paykel and Weissman, 1973; Harrow et al., 1990; Mintz et al.,
1992; Gitlin et al., 1995.
12
Creativity
[Edgar Allan Poes alcoholism] was one of the methods by which he fought the intolerable
morbidity of his manic-depressive state of mind . . . Had this been his only weapon to relieve
the depressions that overtook him, he would, like thousands of others similarly affected, have
lived his life unknown and gone unsung by posterity. But he had a second weaponhis pen.
W. R. Bett (1952, pp. 7475)
HISTORICAL BACKGROUND
The notion of a relationship between creativity and extremes in mood states is an ancient one, described in preGrecian myths and later by Plato and Socrates. Divine
madness and inspiration were thought to be obtainable
only during particular states of mind, such as loss of consciousness, affliction with illness, or fits of possession. In
his speech on divine madness in Phaedrus, Socrates said:
Madness, provided it comes as the gift of heaven, is the
channel by which we receive the greatest blessings . . .
[T]he men of old who gave things their names saw no
disgrace or reproach in madness; otherwise they would
not have connected it with the name of the noblest of all
arts, the art of discerning the future, and called it the
manic art. (Plato, 1974, pp. 4647)
380
Psychological Studies
William James, like his brother Henry and other members of their family, was subject to profound, debilitating
depressions. Nonetheless, he wrote about the potentially
valuable combination of an ardent, excitable temperament
with talent (James, 1902):
The psychopathic temperament [by which James meant
border-line insanity, insane temperament, loss of mental
balance], whatever be the intellect with which it finds itself paired, often brings with it ardor and excitability of
character. . . . His conceptions tend to pass immediately
into belief and action . . . [W]hen a superior intellect and
a psychopathic temperament coalesceas in the endless
permutations and combinations of human faculty, they are
bound to coalesce often enoughin the same individual,
we have the best possible condition for the kind of effective
genius that gets into the biographical dictionaries. Such
men do not remain mere critics and understanders with
their intellect. Their ideas possess them, they inflict them,
for better or worse, upon their companions or their age.
Myerson and Boyle, writing from Bostons McLean Hospital in the 1940s, reiterated the basic position of William
James; as Kraepelin and Rush had done, they focused on
manic-depressive illness. In discussing affective psychosis
in socially prominent families, they concluded (Myerson
and Boyle, 1941):
It does not necessarily follow that the individuals who appear in these records were great because they had mental
disease, although that proposition might be maintained
with considerable cogency and relevance. It may be that
the situation is more aptly expressed as follows. The
manic drive in its controlled form and phase is of value
only if joined to ability. A feebleminded person of hypomanic temperament would simply be one who carried on
Creativity
381
circumstances, creativity can be facilitated by such disorders. Indeed, great creative accomplishment is by definition a rare merging of temperament, intellect, imagination, happenstance, energy, and discipline.
While we focus here on mood, cognitive, and temperamental aspects of great achievement, the role of hard work
and discipline cannot be overemphasized. Lord Byron is
a good example of this point. There can be little question
that his poetry was strongly affected by his extreme moods
and indisputable mental anguish, but his personal discipline was extraordinary. Byrons extensive reworking of
a single stanza from Don Juan, for example, is illustrated in
Figure 121 and Box 121. His reason was punctuated,
even disturbed, by passion, wrote another poet, but whatever he was in person he was not, as an artist, passions
slave. In the poetry Byron masks his passion and makes it
into endurable art (Bold, 1983, p. 13). Byron himself wrote:
Yet, see, he mastereth himself, and makes / His torture tributary to his will.1
Methodological Issues
There are several ways to examine the relationship between manic-depressive illness and creativity, but until recently, apocryphal speculation far outweighed systematic
study. Criticism of work purporting to find a link has been
justified. Biographical studieswhile intrinsically fascinating, irreplaceable, and deeply instructive sources of information about moods, their extremes, and their roles in
the lives of artistsare fraught with difficulties (Jamison,
1993).2 This criticism has been discussed at length elsewhere (see, e.g., Jamison, 1993; Post, 1994; Ludwig, 1995).
Writers and artists, for example, however brutally honest they may be in some of their self-assessments, are of
necessity subjective and biased as well. The reliability of
letters, journals, and memoirs can be limited because they
are written from a single perspective or because the writer
was fully mindful of future biographers and posterity. Biographers, too, write with biases and under the influence
of prevailing or idiosyncratic viewpoints. Historical context and existing social customs also determine which
behaviors are culled or emphasized for comment. Certain
lifestyles provide cover for deviant and bizarre behavior,
and the arts, especially, have long given latitude to extremes
in behavior and mood. The assumption is prevalent that
within artistic circles, madness, melancholy, and suicide are
somehow normal, making it difficult at times to distinguish
truth from expectation.
Biographical or posthumous research poses other problems as well. Any historical perspective dictates that a listing of highly accomplished, affectively ill individuals will
be illustrative, but by no means definitive. Always in the
analysis of individual lives, problems arise. It is fairly easy
382
Psychological Studies
Figure 121. Autograph page from stanza 9, canto III, of Byrons Don Juan (reduced by one-third).
(Source: Reproduced by permission of the Pierpont Morgan Library, New York. MA56-57.)
Creativity
383
Biographical Studies
Many case-history studies of psychopathology in eminent
writers and artists were conducted during the late nineteenth and early twentieth centuries. Lombroso (1891)
found an overrepresentation of manic-depressive illness in
his study of geniuses and attributed it to his belief that
those who suffered from the illness feel and notice more
things and with greater vivacity and tenacity than other
men, their recollections are richer, and their mental combinations more fruitful (p. 27). Babcock (1895), writing a few
years later, observed that the geniuses he had studied were
more likely to be emotionally unstable and given to extremes in moods. Jacobson (1912), White (1930), and LangeEichbaum (1932) found high general rates of insanity in
their biographical studies of genius. The latter concluded
that within the group defined as geniuses, artists and poets
tended more to insanity than scientists and statesmen. Reid
(1912) and Onuf (1918) found that manic-depressive illness
was strongly overrepresented in their eminent subjects.
In a more quantitative analysis, Juda (1949) studied 113
German artists, writers, architects, and composers; she was
one of the first to undertake an extensive, in-depth investigation of not only artists and writers but also their relatives.
Subjects
Findings
Juda, 1949
Martindale, 1972
Trethowan, 1977
60 eminent composers
Jamison, 1993
36 eminent/most
anthologized British
and Irish poets (born
17051805)
15 abstract expressionist
artists (New York
School)
Post, 1994
Creativity
385
Subjects
Findings
Ludwig, 1995
1,004 eminent
individuals across
all fields of
accomplishment
Post, 1996
45 scientists,
52 composers,
48 artists, 50 writers
21 eminent Hungarian
poets (born
15541925)
40 eminent American
modern jazz
musicians
Czeizel, 2001
Wills, 2003
Table 122. Mood Disorders and Suicide in Eminent British and Irish Poets
Born 17051805
Poets
Comments
Samuel Johnson
17091784
Thomas Gray
17161771
Williams Collins
17211759
Christopher Smart
17221771
Joseph Warton
17221800
Oliver Goldsmith
17301774
William Cowper
17311800
James Macpherson
17361796
Robert Fergusson
17501774
Thomas Chatterton
17521770
John Bampfylde
17541796
386
Table 122. Mood Disorders and Suicide in Eminent British and Irish Poets
Born 17051805 (continued)
Poets
Comments
George Crabbe
17541832
William Blake
17571827
Robert Burns
17591796
Joanna Baillie
17621851
William Lisle Bowles
17621850
Samuel Rogers
17631855
William Wordsworth
17701850
387
Table 122. Mood Disorders and Suicide in Eminent British and Irish Poets Born
17051805 (continued)
Poets
Comments
Thomas Campbell
17771844
Leigh Hunt
17841859
Thomas Love
Peacock 17851866
George Gordon, Lord
Byron 17881824
John Clare
17931864
John Keats
17951821
George Darley
17951846
Hartley Coleridge
17961849
Creativity
389
Table 122. Mood Disorders and Suicide in Eminent British and Irish Poets Born
17051805 (continued)
Poets
Comments
Thomas Hood
17991845
Thomas Lovell
Beddoes
18031849
Robert Stephen
Hawker
18031875
James Clarence
Mangan
18031849
Note: Poets selected for inclusion were the most frequently represented in 15 anthologies of
eighteenth- and nineteenth-century British and Irish verse.
Source: Adapted from Jamison, 1993.
There have been fewer studies of psychopathology in living writers and artists. Andreasen and colleagues undertook the first such inquiries into the relationship between
creativity and mental disorders (Andreasen and Canter,
1974; Andreasen and Powers, 1975; Andreasen, 1987).
These studies, using structured interviews, the Research
Diagnostic Criteria (RDC), and matched control groups,
Depression
Mania
Psychosis
Suicide
53
77
13
17
20
180
59
Nonfiction writers
64
47
11
Artists
70
50
Composers
48
46
10
Poets
Fiction writers
390
Psychological Studies
25
Percentage
20
15
10
0
Expected
Rate in
General
Population
Artists
Writers
(Andreasen, (Schildkraut
a
& Hirschfeld,
1987)
1990)b
Poets
(Ludwig,
1992)
Artists
(Ludwig,
1992)
Novelists
(Ludwig,
1992)
Poets
Writers
(British,
(Post,
17081805) 1994)
(Jamison,
1993)
Poets
(Hungarian,
15541978)
(Czeizel,
2001)
Figure 122. Suicide rates in writers and artists. aSuicide rate at the time of study completion. bTwo
other artists died in single car accidents.
Creativity
391
Table 124. Lifetime Prevalence of Mental Illness in Writers and Control Subjects
Diagnosis (Research
Diagnostic Criteria)
Writers
(n = 30)
(%)
Controls
(n = 30)
(%)
80
30
.001
43
10
.01
Bipolar-I
13
NS
Bipolar-II
30
10
NS
Major depression
37
17
NS
NS
Alcoholism
30
.05
Drug abuse
NS
Suicide
NS
Schizophrenia
NS = not significant.
Source: Adapted from Andreasen, 1987. Reprinted with permission from the American Journal of Psychiatry, American Psychiatric Association.
had been hospitalized. Poets were most likely to have received medication for depression (33 percent) and were the
only ones to have received medical intervention (hospitalization, electroconvulsive therapy, and/or lithium) for mania
(17 percent). Thus, one-half of the poets had been treated
with drugs or hospitalized for mood disorders. This rate is
strikingly high when compared with rates in the general
population (see Chapter 5). It is even higher when one
considers the fact that the proportion of those in the general population so seriously ill as to actually seek and receive
treatment is much lower, perhaps one-third to one-half the
rates reported in prevalence studies using diagnostic criteria
alone (Andreasen and Canter, 1974; Robins et al., 1984). A
further probable underestimate of the total rate of affective
illness in the study sample derives from the samples being
comprised largely of men, who, as noted, are less likely than
women to suffer from depression, as well as less likely to
seek treatment. The playwrights had the highest total rate
of treatment for mood disorders (63 percent), but a very
high percentage (38 percent) had been treated with psychotherapy alone; it is unclear whether this was due to a
difference in illness severity or in treatment preference. Visual artists and biographers had relatively lower rates of
treatment (13 and 20 percent, respectively); all treatment
was with antidepressants.
392
Psychological Studies
100
80
60
40
20
Artists (n ! 8)
Biographers (n ! 5)
Novelists (n ! 8)
Playwrights (n ! 8)
Poets (n ! 18)
Total
General
Sample Populationa
(N ! 47)
Figure 123. Rates of treatment for affective illness in a sample of British writers and
artists. The percentages for the general population are based on Epidemiological Catchment
Area data. They indicate that less than one-third of those individuals with bipolar or unipolar
disorder receive treatment in any 6-month period. (Source: Jamison, 1989.)
393
Creativity
3.0
2.5
2.0
1.5
1.0
J
J
J
Month
Mood Scores
Productivity Scores
3.0
Mood and Productivity Ratings
2.5
2.0
1.5
1.0
J
J
J
Month
Mood Scores
Productivity Scores
states. Cognitive and mood changes showed far more overlap than behavioral ones, indicating that the milder forms
of hypomania may represent the more productive phase.
The affective continuum that ranges from normal states
through hypomania and then mania is very important,
but poorly understood (Jamison, 2004). It remains unclear
whether the overlap in cognitive and mood changes represents etiologically related syndromes or phenomenologically similar but causally unrelated patterns of expression.
It also remains unclear to what extent writers and artists
are simply more sensitive than the general population to
their own mood states and are therefore more able, and
perhaps also more willing, to articulate and report them.
In the no-treatment group, the periods of intensified
mood and increased productivity may represent a milder
form of hypomania, with cognitive and mood changes
only. These milder forms of hypomania or intensified normal functioning may result in simultaneous peaks for
mood and productivity. In the treatment group, the execution of work may have preceded and lagged behind the
mood component.
In another study of psychiatric disorders in living writers,
Ludwig (1994), using the Diagnostic and Statistical Manual
(DSM)-III-R and the Lifetime Creativity Scales developed
by Richards and colleagues (1988, discussed below), compared 59 female writers with 59 female nonwriters matched
for age, educational level, and fathers occupational status.
The writers were far more likely to meet the diagnostic criteria for depression and mania, and five times more likely
to have made a suicide attempt (see Fig. 126). They were
also more likely to have had a history of panic attacks, drug
abuse, or an eating disorder.
394
Psychological Studies
60
50
Writers (n ! 59)
Nonwriters (n ! 59)
Percent
40
30
20
10
0
Mania
(p < .01)
Suicide
Attempts
(p < .01)
Depression
(p < .00000)
Family Studies
A familial association between psychopathology and creativity has been found in several studies. Early biographical
work by Lombrosa (1891), Galton (1892), and LangeEichbaum (1932) suggested that both psychopathology and
creative accomplishment ran in the families of eminent
writers, artists, and composers. Juda (1949), as we have noted,
found that first-degree relatives of artists and writers were
more likely to have had manic-depressive illness, committed
suicide, been cyclothymic, or been psychotic. This finding is
supported by the results of Jamisons (1993) study of firstdegree relatives of eminent British and Irish poets, as well
as by the extensive family history (often multigenerational)
of suicide, manic-depressive illness, and psychosis in the
pedigrees of, among others, George Gordon, Lord Byron;
Alfred Lord Tennyson; Robert Schumann; William and
Henry James; Herman Melville; Samuel Taylor Coleridge;
Virginia Woolf; Ernest Hemingway; Mary Shelley and Mary
Wollstonecraft; James Boswell; Samuel Johnson; Vincent
van Gogh; Thodore Gricault; Gustav Mahler; Robert Lowell; John Berryman; Anne Sexton; August Strindberg; Tennessee Williams; and Eugene ONeill.
More systematic investigations have provided a valuable supplement to these case studies. Karlsson (1970), at
the Institute of Genetics in Iceland, showed that firstdegree relatives of psychotic patients, as well as the patients
themselves, were far more likely than the general popula-
tion to be eminent across many fields of artistic and intellectual endeavor. He also showed that there was a significantly increased risk of mental illness in distinguished
Icelandic scholars and their relatives. Although Karlsson
posited a familial relationship between schizophrenia
and creativity, later investigators have concluded that his
data actually show a very strong relationship between
mood disorders, especially bipolar illness, and creativity
(Richards, 1981; Andreasen and Glick, 1988; George et al.,
1988).
Other researchers have looked at familial patterns of creativity and mood disorders in living artists and writers. Andreasen (1987) investigated the family histories of the University of Iowa Writers Workshop writers and controls
discussed earlier (see Table 125). Consistent with the elevated rate of affective illness in the writers, there was a significantly higher rate of affective illness in the primary relatives of the writers than in the primary relatives of the
controls (p < .001). The overall prevalence for any type of
psychiatric disorder was also much higher in the relatives of
the writers (42 percent) than in the relatives of the controls
(8 percent). Additionally, more first-degree relatives of
writers than of controls showed histories of creative accomplishment (20 versus 8 percent).
Using a very different research design to study the relationship between creativity and psychopathology, Richards
and colleagues (1988) at Harvard investigated creativity
broadly defined in a sample of patients and their relatives.
They hypothesized that a genetic vulnerability to manicdepressive illness may be accompanied by a predisposition to creativity, which may be more prominent among
close relatives of patients with bipolar spectrum disorders
than among the patients themselves. Such a compensatory
advantage, they speculated, would be roughly analogous to
the resistance to malaria found among unaffected carriers
of the gene for sickle-cell anemia. To test their hypothesis,
the researchers selected 17 bipolar and 16 cyclothymic patients, along with 11 of their normal first-degree relatives,
using criteria that would ensure inclusion of a spectrum
of disorders. These patients and their relatives were compared with 15 normal control subjects and with 18 controls who had a psychiatric diagnosis but no personal or
family history of major affective disorder, schizophrenia,
or suicide. Unlike other studies in the field, which limited
the definition of creativity to significant, socially recognized
accomplishment in the arts or sciences, these investigators
attempted to measure the disposition toward originality
manifested in a wide range of everyday endeavors. They
administered the Lifetime Creativity Scales, a previously validated instrument that assesses the quality and quantity of
everyday creative involvement in both work and leisure
activities.
395
Creativity
Table 125. Mental Illness in First-Degree Relatives of 30 Writers and 30 Control Subjects
ALL RELATIVES
Family History
Diagnosis
(Research
Diagnostic
Criteria)
Of
Writers
(n = 116)
(%)
Of
Controls
(n = 121)
(%)
18
Bipolar disorder
Major depression
PARENTS
SIBLINGS
Of
Writers
(n = 60)
(%)
Of
Controls
(n= 60)
(%)
.001
.056
15
.01
Alcoholism
NS
Suicide
NS
42
.0001
42
Any affective
disorder
Any illness
Of
Writers
(n = 56)
(%)
Of
Controls
(n = 121)
(%)
.001
20
.001
NS
NS
14
.05
NS
NS
NS
NS
43
.001
.05
.00003
NS = not significant.
Source: Adapted from Andreasen, 1987. Reprinted with permission from the American Journal of Psychiatry, American Psychiatric Association.
Creativity Scores
Richards and colleagues found significantly higher combined creativity scores among the bipolar and cyclothymic patients and their normal first-degree relatives
than among the control subjects (see Fig. 127). The normal index relatives showed suggestively higher creativity
relative to the bipolar patients, and the cyclothymic patients were close to the normal relatives. Modifying their
original hypothesis, the authors concluded (p. 287):
2.0
1.0
Controls
NC Rel
CYC
MDI
(DX)
(N)
Creativity adjusted for effects of:
Gender
Gender, Education, Age and Intelligence
396
Psychological Studies
Biological Parents
(%)
Adoptee Parents
(%)
High creative
30
27.7
5.3
Above average
10
8.3
5.0
12.1
5.1
Adoptee Group
Low creative
Source: Adapted from McNeil, 1971. Reproduced with permission from Blackwell Publishing Ltd.
Creativity
397
heightened distractibility in the tendency to diffusiveness, to spinning out the circle of ideas stimulated and
jumping off to others, a phenomenon which in high degree is peculiar to mania.
398
Psychological Studies
Andreasen and Powers (1975) compared manic patients, schizophrenic patients, and writers from the University of Iowa Writers Workshop on measures of conceptual overinclusiveness (the tendency to combine test
objects into categories in a way that tends to blur,
broaden, or shift conceptual boundaries). They hypothesized that creative writers might show thinking styles similar to those seen in schizophrenic individuals, but this
notion was found to be groundless; instead, they observed
that the writers showed conceptual styles quite like those
of the manic patients: Both writers and manics tend to
sort in large groups, change dimensions while in the process of sorting, arbitrarily change starting points, or use
vague distantly related concepts as categorizing principles (p. 72). The subjects differed primarily in the degree
of control they were able to exert over their patterns of
thought, with the writers able to carry out controlled
flights of fancy during the process of sorting, while the
manics tend to sort many objects for bizarre or personalized reasons (p. 72).
Schuldberg (1990) found that several hypomanic traits
contributed to performance on tests measuring creativity; of
particular relevance here, he found that creative cognition
was far more similar to hypomanic flight of ideas than to
the loose associations that are characteristic of schizophrenia. Relatedly, people having strong emotional responses in
general, who also tend to score higher on measures of being
at risk for developing bipolar illness, often have more elaborate and generalizing cognitive operations (Larsen et al.,
1987). Early studies had found that rhymes, punning, and
sound associations increase during mania, and that many
patients spontaneously start writing poetry while manic
(Kraepelin, 1921; Murphy, 1923). Welch and colleagues (1946),
in an early study of associational fluency in 101 inpatients at
the Payne Whitney Psychiatric Clinic, found that patient
groups that would today be called bipolar scored higher
when elated than other clinical groups; all patient groups
scored higher when elated than when less elated (see Table
127).
Nearly 150 years ago, Richarz noted that in mania
thoughts tend to form strings of ideas . . . that link together by their content, alliteration, or assonance. In racing
thoughts, the ideas come and go rapidly as if they were
hunting each other or continuously overlapping without
any link between them (1858; quoted in Koukopoulos and
Koukopoulos, 1999, pp. 557558). The predominant difference between the two states described is mood; that is, the
elated mood of mania probably is more likely to result in
a linking of ideas than is the dysphoria associated with racing thoughts.
Likewise, in studies of word-associational patterns, researchers have found that the number of original responses
Mean Score
When Not Elated
Anxiety neurosis
3.5
Depression
2.3
Manic excitement
8.8
Manic-depressive
9.9
4.2
Manic-depressive,
psychopathic
7.6
3.1
Paranoid reaction
5.4
Psychopathic
personality
4.3
2.8
Schizophrenia
6.9
3.8
All groups
7.9
3.2
Clinical Group
Creativity
35
30
25
20
15
10
5
0
Figure 128. Mean associative word productiondifferential findings in acute manic versus acute schizophrenic patients. Given for
each group are mean ( standard error [SE]) of associative words
produced to 12 stimulus words. Mean associative word production by
bipolar patients with acute mania (C) was higher in a statistically significant manner than in patients with acute schizophrenia (D) (t = 2.43,
p < .05). Both patients with mania and patients with acute schizophrenia showed significantly higher associative word production than
control subjects (A) (t = 4.5, p < .001; t = 4.5, p < 0.001, respectively).
Patients with unipolar depression (B) or residual schizophrenia (E)
showed mean associative word production similar to the control values. (Source: Levine et al., 1996. Reproduced with permission from
Karger Publishing.)
399
pleasure in taking risk, high energy, independence, exuberance, rebelliousness, and playfulness7 are also characteristic of many who have hypomanic and cyclothymic temperaments. Stanford researchers, for example, found that
bipolar patients and highly creative individuals have more
personality traits in common than do healthy normal controls and creative individuals (Nowakowska et al., 2005; see
also Jamison, 2004).
It may be that the combination of experience, potentiating personality characteristics (see Chapter 10), and cognitive changes that occur during hypomania and may facilitate original thought gives rise to a subgroup of individuals
with bipolar illness that is unusually creative. Two critical
components of creativityan independent, risk-taking,
restless, and enthusiastic personality, and a fluent, disinhibited cognitive styleare found at an increased frequency in the bipolar population, thus producing some of
the conditions that may lead to a disproportionate rate
of creativity in a group otherwise characterized by damaging moods and behavior. Recent research lends credence to
the importance of disinhibition, or an openness to incoming stimuli from the surrounding environment, to creativity. Carson and colleagues (2003), for example, found that
highly creative Harvard students were seven times more
likely to have low inhibition scores than less creative Harvard students. The investigators hypothesized that low inhibition, when coupled with extreme flexibility of thought,
may lead to mental illness in some individuals and to creative accomplishment in others. Presumably it could also
lead to the coexistence of creativity and mental illness in
yet others. Likewise, the ability to function well on a few
hours of sleep and to work at a high energy level are integral
to most hypomanic states; they are also integral to putting
ideas into action. In her studies of outstanding artists and
scientists, for example, Anne Roe (1946, 1951, 1952) found
one trait that stood out: the willingness and ability to work
hard and to work long hours.
Throughout this book, we stress the recurrent, cyclic nature of manic-depressive illnessits natural course, pathophysiology, subjective experience, and seasonal and diurnal patterns. Integrally linked to this conception and of
particular consequence here is the significance of contrasting, recurrent mood states. Cyclic patterns are common to both mood disorders and the nature of creative
work. The ebbing and flowing character of inspiration,
described so often, bears a striking resemblance to changes
from the vitality to nonvitality of different seasons, death
and rebirth, and the antithetical qualities of the bipolar
mood states.
Clinical characteristics such as changes in mood, thinking, energy, and behavior are usually opposite in mania and
depression. This is true for linguistic and artistic patterns as
400
Psychological Studies
Mania
Depression
Color
Content
Affect
Creativity
401
Both Lowell and Sexton wrote of their heightened psychological sensitivity and vulnerability in graphic and quite
similar physical metaphors: seeing too much and feeling
402
Psychological Studies
Theoretical Considerations
Positive aspects of manic-depressive illness, including associations with accomplishment, are, of course, interesting in
their own right. At first glance, the notion of advantage
Creativity
403
decisions and life events. Because the negative consequences are delayed, it is not always clear to the patient
that the costs outweigh the benefits. The clinical implications of this phenomenon are discussed in the next section
and in Chapters 21 and 22. Here it is important to mention
that the addictive or addictive-like qualities of the elated
states raise fascinating issues about the means used to selfinduce these states (sleep deprivation, medication nonadherence, or psychological means), the relevance of this
phenomenon to kindling models, and, of course, the use of
cocaine and other stimulants to self-medicate or to induce
euphoric and high-energy states. The high rate of affective
illness in cocaine abuse (see Chapter 7) may reflect not
only self-medication per se, but also an attempt to recapture a known, previously experienced and highly pleasurable mood state, a reality that makes bipolar individuals
perhaps uniquely vulnerable to cocaine addiction on both
psychological and biological grounds.
Clinical Considerations
The existence of potentiating positive features in bipolar
illness, perceived to be or actually associated with increased
creativity and productivity, affects the willingness of some
afflicted with the illness to seek and comply with treatment.
Many highly accomplished individuals in the arts, the sciences, and business are reluctant to seek treatment for their
mood disorders because they are reluctant to give up the
edge they feel they obtain from it. Others view their serious
mood problems as part of the human condition, the price
one pays for being too sensitive, having an artistic temperament, or leading an artistic lifestyle. Indeed, many such
individuals see emotional turmoil as essential to their identity as performing or creative artists. Additionally, many
writers and artists are concerned that psychiatric treatment
will erode or compromise their ability to create. An appreciation of the potentially productive or up side of mood
disorders may lead to greater credibility on the part of the
treating clinician, as well as a stronger therapeutic bond.
Strict adherence to an often arbitrary distinction between
psychopathology on the one hand and a chaotic, tumultuous, and artistic lifestyle on the other can lead to unnecessary suffering and treatment resistance.
Writers and artists frequently express concern about the
effects of psychiatric treatment on their ability to create and
produce; these concerns are especially pronounced when it
comes to taking medication. Some of this mistrust no doubt
reflects unfounded preconceptions, fears of altering longestablished work patterns and rituals, or simple resistance to
treatment. In some instances, however, these concerns are
grounded in reality. A review of the literature on moodstabilizing medications reveals disturbingly little research
on the effects of the drugs on productivity and creativity.
404
Psychological Studies
It should be noted that Schous study involved a relatively short-term trial of lithium, and there is some indication that patients partially accommodate to lithiums
cognitive effects. Many patients, of course, experience no
significant cognitive side effects, and for those who do, the
risks of no treatment must always be weighed against those
side effects.
What is actually known about the specific effects of
lithium and other medications on productivity and creativity? Polatin and Fieve (1971, p. 864) described their clinical experience of using lithium in creative individuals:
In the creative individual who does his best work in the
course of a hypomanic period, the complaint regarding
the continued use of lithium carbonate is that it acts as a
brake. These patients report that lithium carbonate inhibits creativity so that the individual is unable to express
himself, drive is diminished, and there is no incentive. These
patients also indicate that when they are depressed, the
symptoms are so demoralizing and so uncomfortable that
they welcome the mild high when the depression disappears and prefer to settle for a cyclothymic life of highs
and lows rather than an apathetic middle-of-road mood
state achieved through the use of lithium carbonate.
Their argument is that if lithium carbonate prevents
the high and may possibly prevent the low, they prefer
not to take lithium carbonate, since never to have a high
as a result of the drug seems equivalent to being deprived
No controlled studies of lithiums effects on productivity have been conducted, but Marshall and colleagues
(1970) and Schou (1979) studied a total of 30 artists, writers, and businessmen taking lithium. Their findings are
summarized in Table 129. More than three-quarters (77
percent) of the patients reported no change or an increase in their productivity while on lithium. Approximately one-quarter reported a decrease. In 17 percent,
lithium was seen as leading to problems sufficient to warrant refusal to take it. It is not known how accurately
these figures reflect artists and writers at the upper end of
creative accomplishment. Most of these subjects, although earning their living by their creative work, were
not at that level. Schou (1979) pointed out that lithium
may affect inspiration, the ability to execute, or both, and
saw the following as contributing factors in a creative individuals response to lithium: the severity of illness, the
type of illness, the artists habits of using manic periods
of inspiration, and individual sensitivity to the pharmacological action of the drug.
Three other studies of particular relevance for artistic
creativity yielded conflicting results. Judd and colleagues
(1977) found no effects of short-term lithium treatment
on creativity in normal subjects. A study using bipolar patients as their own controls, however, found substantial
detrimental effects of the drug on associational productivity and originality of responses (Shaw et al., 1986; see
Fig. 129). These differing results may be due in part to
the fact that lithiums effect on cognition is probably quite
different in bipolar patients and normal controls (Pons
et al., 1985). Lithium exerts effects not only on cognition,
but also on drive and personality (see Chapter 10);
although cognitive side effects are undeniably important
to creative work, so, too, are these noncognitive effects.
Kocsis and colleagues (1993) found that lithium discontinuation resulted in improvement on memory and creativity
measures (although not idiosyncratic word associations),
as well as motor performance. In an open, nonrandom
case series of seven bipolar patients who reported cognitive dulling during lithium therapy, Stoll and colleagues
(1996) concluded that the partial or full substitution of divalproex sodium for lithium as the primary mood stabilizer reduced the cognitive, motivational, or creative
deficits attributed to lithium (p. 359). To our knowledge,
Creativity
405
Schou (1979)
6 artists and
businessmen
24 artists and
writers
30
Increased
12
17
57
No change
20
Decreased
23
17
Subjects
Productivity on lithium
Refused to continue
lithium treatment
Total Associations
Number of associations
Idiosyncratic associations
.83
.05
.04
.71
.74
Mean Weekly Lithium Level (millimoles per liter)
406
Psychological Studies
NOTES
CONCLUSIONS
There is strong scientific and biographical evidence linking
mood disorders to artistic creativity. Biographies of eminent poets, composers, and artists attest to the prevalence
of extremes of mood in creative individuals. Systematic
studies are increasingly documenting the link as well. It
should be emphasized, however, that most creative writers,
artists, and musicians have no significant psychopathology. Conversely, most individuals with manic-depressive
illness are not unusually creative.
We have considered the issue of the reliabilityindeed,
the advisabilityof making a posthumous diagnosis of
Creativity
5.
6.
7.
8.
teens or early twenties, with temperamental signs often exhibited much earlier; seasonal aspects to the mood and energy changes; and if untreated, a worsening of the illness over
time. (See Chapter 4.)
This study was brought to the attention of the authors by
Dr. Zoltn Rihmer.
Isen and Daubman, 1984; Isen et al., 1985, 1987; Greene and
Noice, 1988; Fodor, 1999; Isen, 1999; Fodor and Laird, 2004.
Roe, 1946, 1951, 1952; MacKinnon, 1962; Getzels and Jackson,
1963; Hudson, 1966; Barron, 1968; Welsh, 1977, Gardner, 1993;
Winner, 1996; Jamison, 2004.
Among the many writers who have emphasized the importance of the reconciliation of opposite states in the creative process are Aristotle, On the Art of Poetry, Classical Literary Criticism, translated by T. S. Dorsch, London: Penguin, 1965; Percy
Bysshe Shelley, A Defence of Poetry, Shelleys Critical Prose,
407
Part IV
Pathophysiology
13
Genetics
That other inward, inbred cause of melancholy is our temperature, in whole or part, which we
receive from our parents . . . such as the temperature of the father is, such is the sons, and look
what disease the father had when he begot him, his son will have after him, and is as well inherited of his infirmities as of his lands.
Robert Burton (1621, p. 211)
412
Pathophysiology
Genetics
Eugenics
Eugenics had its origins in the work of Francis Galton, who
believed that genetic selection could be employed to improve the genetic fitness of the race. The eugenics movement took hold in many countries around the world, including the United States, where the Cold Spring Harbor
Eugenics Records Office was set up in 1905 to gather data on
family histories of the feebleminded (among other subjects). The aim of this effort was to reduce the societal load
of these illnesses by preventing procreation of the eugenically undesirable and limiting their immigration into the
country (Kevles, 1995, pp. 56, 92). In Germany, the Society
for Race Hygiene was established in 1905, and Ernst Rudin
413
GENETIC EPIDEMIOLOGY OF
MANIC-DEPRESSIVE ILLNESS
The first stage in the study of the genetics of an illness involves defining who is and is not to be considered ill (see
Fig. 131). In the language of genetics, the question is:
What is the phenotype, or trait, under study? Clear criteria must be applied in defining the phenotype to maximize
the homogeneity of the sample. While the field has in recent years focused mainly on the bipolar-I (BP-I) phenotype, much work has also focused on the broader concept
of manic-depressive illness, which encompasses the BP-I,
bipolar-II (BP-II), and recurrent major depression phenotypes, along with some studies including schizoaffective
414
Pathophysiology
Twin
study
Cytogenetics study
Adoption
study
Linkage study
Mode of
inheritance
Linkage
disequilibrium study
Pathophysiology
Identification of candidate genes
Bioinformatics
DNA sequencing
Variation detection in candidate
genes
Association analysis
of gene variant
Functional studies of
variant in cells
Reduced
stigma
Diagnosis
Prognosis
Treatment
Prevention
Pathophysiology
Gene
environment
interaction
Figure 131. The sequence of genetics research on manic-depressive illness (MDI). This figure demonstrates both the
historical sequence through which research on the genetics of manic-depressive illness has progressed and the logical
sequence of reasoning about gene discovery in the illness. See text for details. (Source: Haines and Pericak-Vance, 1998.
Reprinted with permission of John Wiley & Sons, Inc.)
disorder, manic or bipolar type. Systematic case definitions were lacking until the 1970s, when the Research Diagnostic Criteria (RDC) first came into widespread use
(Spitzer and Endicott, 1975). Since the 1980s, the Diagnostic and Statistical Manual (DSM) has provided the standard diagnostic criteria for genetic studies. We note that
while researchers in genetic epidemiology (the term applied to these kinds of studies) have emphasized recurrent
unipolar depression when they have studied the relationship of unipolar to bipolar illness, the DSM-III and -IV
definitions of major depressive disorder do not require
recurrence. Indeed, by separating bipolar disorder out as
a separate illness from the top, with recurrent unipolar
depression (defined perhaps too broadly as simply more
than one episode) becoming a tertiary category under depressive disorders, DSM-III and -IV have made it more
difficult to conceptualize the relationship between bipolar
Family Studies
If a disease has a genetic basis, it is expected to run in families. Studies of familial aggregation typically begin with
Genetics
Hoffman, 1921
139
13.8
Banse, 1929
452
15.5
Humm, 1932
92
4.4
298
12.0
505
7.4
Slater, 1936
704
15.5
Strmgren, 1938
489
9.7
Luxenburger, 1942
1398
15.8
Sjogren, 1948
253
4.8
Kallman, 1952
306
23.2
Stenstedt, 1952
979
13.9
Study
415
Note: Many of the original papers are in German; = not available; MDI = manic depressive illness.
Source: Based on tables in Tsuang and Faraone (1990, p. 38) and Rosenthal (1970, p. 207).
Table 132. Family Studies of Bipolar Illness and Major Depression Since 1960
Age-Adjusted Lifetime Prevalence
in First-Degree Relatives (%)
Proband/Study
BP
BP-I
BP-II
SA
MDD
167
10.2
20.4
781
17.7
22.4
260
6.4
13.2
213
15.5
19.8
47
8.5
6.4
135
14.5
1.5
16.3
223
3.6
11.9
Jakimow-Venulet, 1981
804
11.8
6.1
389
7.0
0.5
21.9
3,019
11.9
0.8
15.6
548
4.5
4.1
1.1
14.0
569
3.9
4.2
0.5
22.8
408
8.7
3.7
0.4
11.6
166
3.6
1.8
16.3
5.2
3.8
0.6
16.6
Bipolar Disorder
Weighted mean
Bipolar-I Disorder
Weighted mean
1,691
Bipolar-II Disorder
Gershon et al., 1982
191
2.6
4.5
0.6
17.3
267
1.1
8.2
0.4
26.2
115
3.5
6.1
0.9
18.3
Weighted mean
573
2.1
6.5
0.6
21.6
Major Depression
Smeraldi et al., 1977
185
0.6
8.0
483
2.0
13.6
106
4.7
7.5
(continued)
416
Table 132. Family Studies of Bipolar Illness and Major Depression Since 1960 (continued)
Age-Adjusted Lifetime Prevalence
in First-Degree Relatives (%)
Proband/Study
BP
BP-I
BP-II
Jakimow-Venulet, 1981
306
0.5
9.5
166
1.5
1.5
0.7
16.6
143
2.2
3.0
17.7
810
0.9
1.9
0.3
17.6
1,171
0.6
2.9
0.2
28.4
315
24.7
697
1.8
0.5
21.6
651
24.4
5,033
1.7
0.8
2.4
0.5
20.5
Scharfetter, 1981
263
4.4
2.5
4.4
84
10.7
6.1
6.1
14.5
64
1.6
3.2
26.5
84
3.9
7.1
138
3.6
5.8
0.7
25.4
149
3.1
2.3
7.7
204
8.0
3.9
20.6
152
4.8
1.8
44.9
1,138
4.8
6.3
5.9
2.7
17.8
541
0.3
7.5
265
0.5
0.5
5.8
521
0.2
1.1
0.2
5.9
Weighted mean
SA
MDD
Schizoaffective Disorder
Weighted mean
Controls
(continued)
417
418
Pathophysiology
Table 132. Family Studies of Bipolar Illness and Major Depression Since 1960 (continued)
Age-Adjusted Lifetime Prevalence
in First-Degree Relatives (%)
Proband/Study
BP
BP-I
BP-II
419
1.8
0.4
10.6
255
5.5
2,001
1.0
0.1
0.9
0.3
7.3
Weighted mean
SA
MDD
Note: The mix of highly recurrent and minimally recurrent patients in the MDD group can obscure the relationship between bipolar disorder
and some forms of unipolar depression.
BP = bipolar disorder; MDD = major depressive disorder; SA = schizoaffective disorder; = not studied or reported.
at the National Institute of Mental Health (NIMH), involved direct interviews of most first-degree relatives using
the Schedule for Affective Disorders and Schizophrenia
Lifetime Version, a semistructured interview (Endicott and
Spitzer, 1978). Two independent clinicians used a modified
version of the RDC to make diagnoses based on these interviews, along with family informant data and medical
records. A consensus diagnosis was then established. In calculating the lifetime risk of mood disorders in relatives, the
raw data were modified to account for the variable age at
onset of the disorders. This was done using the Stromgren
method, which weighs the number of people at risk by the
proportion of the risk period through which they have
passed.
The findings of Gershon and colleagues (1982, 1985,
1986, 1988, 1989) and Gershon and Goldin (1989) provide
among the best accounts available of the familial aggregation of affective disorders. The lifetime risk of BP-I among
relatives in the BP-I proband families was elevated at 4.5
percent (versus 0 percent in controls). The risk for BP-II
among relatives was also elevated in BP-I proband families
at 4.1 percent (versus 0.5 percent in controls). Similarly, the
risk for major depressive disorder in these families was
increased at 14.0 percent (versus 5.8 percent in controls).
There was an overall lifetime risk of 23.7 percent for an affective disorder in the first-degree relatives of the BP-I
probands compared with a risk of 6.8 percent in the control families. Of interest, the risk for BP-I was also increased in relatives of the schizoaffective probands (10.7
percent); the risk for BP-II was elevated as well in relatives
of the BP-II probands (4.5 percent) and schizoaffective disorder probands (6.1 percent); and the risk for major depression was substantialtwo to three times that of controls
in relatives of all affected probands. When all families were
taken together, children of one affectively ill parent had a
27 percent lifetime risk of affective disorder, compared
Genetics
genes act independently in different families to cause disease, and a multiplicative multilocus model, in which multiple genes interact to cause disease. Using this metric, Craddock and colleagues (1995b) showed that the heterogeneity
model is not consistent with the relative risk data available
for bipolar disorder. Instead, the multiplicative model with
at least three, and more likely four or more, risk genes
provides the best fit with the data. Craddock and colleagues
concluded that, although there may be occasional families with a single-gene form of bipolar illness, such families
must be rare and cannot explain the majority of familial
occurrence of the disorder. These results are consistent
with the idea of manic-depressive illness, even in its more
homogeneous bipolar form, as a genetically complex disorder (see the discussion below of the linkage method).
Twin Studies
Familial aggregation of disease suggests, but does not prove,
a genetic contribution to disease. Environmental factors,
such as exposure to toxins or emotionally traumatic family
experiences, could in theory also lead to familial aggregation. Twin studies have been the approach used most widely
to attempt to disentangle these contributions. The logic of
twin studies is this. Identical or monozygotic (MZ) twins
are 100 percent genetically the same, whereas fraternal or
dizygotic (DZ) twins share just 50 percent of their genes;
yet the two twin types are assumed to be no different in the
degree to which they share environments.4 Therefore, any
increased similarity in manifestation of manic-depressive
illness detected in MZ twins compared with that in DZ
twins should be due to the greater genetic similarity of the
former. The main measure in these studies is the concordance rate for illness; that is, starting with an ill twin as the
proband, what is the rate of illness in the co-twin?
Early studies tested for manic-depressive illness (see
Table 133). Six such studies found concordance rates of 77
percent for MZ twins and 23 percent for DZ twins, with a
heritability of .71 (where 1.00 would be complete heritability and 0 would be none). More recent studies have used
the bipolar and major depressive disorder phenotypes.5
Three studies assessed bipolar disorder; they found a 63
percent concordance rate for MZ twins and a 13 percent
rate for DZ twins, with a heritability of .78. Seven studies
assessed major depressive disorder; they found concordance rates of 34 percent in MZ twins and 26 percent in
DZ twins, with a heritability of .34, although this estimate
would be higher if the studies had focused on those patients with more highly recurrent forms of the disorder
(see below).
Among the most meticulously conducted twin studies of
manic-depressive illness is that of Bertelsen and colleagues
(1977), which drew on the Danish Central Psychiatric
419
Sample Size
(Pairs)
MZ
DZ
Heritabilitya
Manic-Depressive Illness
Luxenburger, 1928, 1930
17
80
.80
90
70
16
.64
39
73
32
.60
82
100
26
1.00
Da Fonseca, 1959
60
71
38
.53
Kringlen, 1967
26
50
.50
Weighted mean
314
77
23
.71
71
79
19
.74
Torgersen, 1986
10
75
.75
Weighted mean
81
79
17
.74
49
80
13
.77
49
36
.84
Weighted mean
98
59
10
.80
22
78
31
.68
44
54
24
.39
Torgersen, 1986
92
27
12
.54
82
177
46
20
.48
3,372
23
14
.36
2,662
33
26
.30
Bipolar Disorder
Bipolar-I Disorder
Bipolar-II Disorder
Bertelsen et al., 1977
Major Depression
(continued)
Genetics
421
Table 133. Twin Studies of Manic-Depressive Illness and Bipolar Disorder (continued)
Findings
Concordance (%)
Proband/Study
Kendler et al., 2000
Weighted mean
Sample Size
(Pairs)
MZ
DZ
Heritabilitya
3,790
44
39
.34
10,219
34
26
.34
Note: DZ = dizygotic; MZ = monozygotic. For studies since 1960, only those in which a majority of subjects were directly interviewed are included. DZ, dizygotic; MZ, monozygotic.
a
Where authors calculate heritability, these figures are provided. If heritability is not provided in a report, Holzingers heritability (MZ concordance DZ concordance/100 DZ concordance) has been calculated.
Patterns of concordance can be converted to a heritability valueoften thought of as the percentage of the liability to illness that is geneticin several ways. Current twin
studies employ a liability threshold model (Falconer, 1965),
which simultaneously tests the heritability of and environmental contribution to illness. When individuals cross the
liability threshold, they develop illness. The model requires
the specification of a population prevalence of illness to indicate how many people in the population lie on the ill side
of the threshold. Moreover, heritability estimates will vary
with the prevalence figures used, an issue of particular importance for major depression, for which population estimates have varied dramatically. For example, one depression study reported that heritability was 48 percent when
one estimate was used and 75 percent when another was
used (McGuffin et al., 1996).6
Adoption Studies
A second paradigm for separating genetic from environmental effects is the adoption study. The conceptual basis
for this approach is that in adoptees, the genetic inheritance occurs through one set of parents, while the cultural
and environmental experience occurs through a different
set. The two sets of factors and their potential association
with illness can therefore be disentangled.
There are several possible ways to conduct an adoption
study. One that has been used for manic-depressive illness is
the adoptees relatives method. In this method, ill and control adoptees are identified as probands, and rates of illness
are then compared in the biological and adoptive relatives of
each group. If genetics plays a role, the biological relatives of
ill adoptees will have elevated rates of illness compared with
those in the other three relative groups.
Only four adoption studies have addressed manicdepressive illness (see Table 134). The most methodologi-
422
Pathophysiology
Sample
Biological III
Proband
Group
Biological Control
Group
Adoptive Relatives
443 adoptees
22.2
10.1
1,080 relatives
5.2
2.3
2.8
299 parents
31.6
2.3
12.2
parents
5.1
5.4
2.7
Proband/Study
Manic-Depressive Illness
Bipolar-I
Mendlewicz and Rainer, 1977
Unipolar Depression
von Knorring et al., 1983
Note: = not studied or reported.
ADVANCES IN UNDERSTANDING
THE HUMAN GENOME
In the next section, on the linkage method, the discussion
shifts from the question of whether there is a genetic component to susceptibility to manic-depressive illness to the
question of where the disease genes are located in the human genome. Before examining the progress made in answering that question, however, we must review the remarkable advances that have occurred in our understanding of
Genetics
What does gene function have to do with such vulnerability? Consider a second analogy. Genes are like blueprints that
direct the workings of cells, including brain cells. Genes
made of DNA code for messengers made of a molecule called
ribonucleic acid (RNA). The messenger RNA directs the production of specific proteins. Proteins are the molecules that
do the work in brain cells. They act as building blocks, signal
receptors, and chemical switches. So if the blueprint for a
gene is misdrawn, aberrant proteins will result, and brain
cells may misfire or malfunction. Francis Crick, codiscoverer
of the structure of DNA, called this conceptionDNA
makes RNA, and RNA makes proteinsthe central dogma
of molecular biology.
The investigation of differences in DNA sequence among
individuals became possible in the late 1970s to early 1980s
with the discovery of restriction fragment length polymorphisms (RFLPs). These are single nucleotide variations
among individuals, or polymorphisms, in the DNA sequence that occur at greater than 1 percent frequency and
result in differential susceptibility to being cleaved by bacterial enzymes called restriction enzymes. These enzymes
can thus be used as tools for establishing the sequence at
points in the DNA where variability exists.
In the late 1980s to early 1990s, microsatellite DNA markers were discovered and exploited to assess DNA variation
among individuals. These markers generally are not located within the coding regions of genes, called exons.
These regions code for the production of messenger RNA,
with every three nucleotides forming a codon, which ultimately directs production of a particular amino acid, a
building block for a specified protein. Exons are like islands in a vast sea; only about 3 percent of DNA takes this
form. The noncoding regions of DNA can lie within genes;
between the exons, in which case they are called introns
(an intron thus interrupts the protein-coding sequence of
a gene, being transcribed into RNA but cut out of the message before being translated into protein); or between
genes, in which case they are called intergenic regions. The
microsatellite markers are generally located in these noncoding regions. They comprise stretches of DNA with two-,
three-, or four-nucleotide repeat sequences, such as CACACACA or GATAGATAGATA, where the repeat occurs a
variable number of times. For example, the CA repeat at
a given location in the DNA might occur 7 consecutive
times, 18 consecutive times, or somewhere in between. This
variability allows two copies of a chromosome to be distinguished from each other. This DNA variability in microsatellite markers is extremely useful in linkage studies.
Beginning in the late 1990s, extensive sequencing of the
human genome began to reveal very large numbers of single nucleotide differences, or polymorphismscalled single nucleotide polymorphisms (SNPs)across the genome
423
424
Pathophysiology
Figure 132. Single nucleotide polymorphisms (SNPs): the most common form of genetic variation. SNPs occur about once every 200 nucleotides. They typically have two allelic variants consisting
of one of two nucleotides. a and b here represent an individuals two copies of a segment of chromosome 11 that is part of the coding sequence for the BDNF gene. Note that each chromosome has two
strands, called either forward and reverse or sense and antisense. The sequence of one strand determines the sequence of the other because A and T are always paired, as are G and C. Sequence a contains a G allele on the forward strand, shown as the top strand, which is the one that codes for the
gene. Sequence b contains an A allele on the top strand in the same position, so that this individual is
a heterozygote for this SNP. The third, fourth, and fifth bases in the sequence form a codon, which
codes for an amino acid. GTG codes for valine, while ATG codes for methionine. Some evidence suggests the G allele confers risk for bipolar disorder, while the A allele is protective.
between pairs of similar, or homologous, chromosomes during meiosis, which increases as a function of the distance
between marker and gene (see Fig. 133). The rate of recombination is measured in centimorgans (cM), with each cM
corresponding to a 1 percent likelihood of recombination
and to roughly 1 million base pairs of DNA (1 Mb).
Thomas Hunt Morgan first employed the linkage method
in the development of gene maps of the fruit fly in the early
twentieth century. The method was used to link presumed
genes for one fly trait to presumed genes for another. The
first linkage study of manic-depressive illness was reported
in 1968, before DNA markers were available. ABO blood
types were used as markers, so that the presumed genes for
the blood types were tested for linkage to the illness (Tanna
and Winokur, 1968).
The linkage method has since been widely applied in
mapping of human disease genes, especially since the 1980s,
after Botstein and colleagues (1980) suggested that RFLPs
(the DNA markers discussed in the preceding section)
distributed across the genome could be used to detect
Genetics
across all 23 chromosomes. Newer genomewide scans employing 5,800 SNP DNA markers at an average spacing of
.64 cM are just becoming available.
A positive result in a linkage study implicates a chromosomal region that is typically quite broadas much as
30 cM from a linkage peakwhich means as much as
60 cM in total (Roberts et al., 1999). A linkage region is indicated by the identity of the chromosomal arm (short [p]
or long [q]) and the segment of that arm (numerical designation) on which the linkage peak falls (see Fig. 134).
Figure 133. Recombination: the basis for linkage studies. Genetic linkage between a disease and markers is determined for
each chromosome by identifying how frequently a DNA marker and a presumed bipolar gene are passed together from parent to
child. Circles are females, and squares are males. The solid shapes represent those affected with bipolar illness, and the open
shapes are unaffected individuals. In a, there is a DNA marker, M, that is on the same chromosome as the disease gene, D, but is
physically far from it. For the top-left individual, the father, the thick line represents copy 1 of chromosome 13, and the thin line
represents copy 2 of chromosome 13. During meiosis, as sperm cells are being formed, these two copies of chromosome 13 pair,
and parts of each are exchanged with the other. This process, which occurs for every chromosome in egg as well as in sperm, is
called recombination. Because of recombination, the disease gene and the marker are not necessarily inherited together; the two
are thus not linked. In b, the marker under consideration is physically close to the disease-causing gene, so that recombination
does not separate them. All three children who inherit the bipolar gene also inherit the nearby marker. If the pattern in b were
seen in many families, it would suggest linkage. Note that in linkage, D is not actually observed; D is presumed to be present
when the subject is affected with bipolar illness.
Unlinked
Linked
b
M
M
D
425
M
D
M
D
M
D
426
Pathophysiology
11.32
11.31
11.2
11.1
11.1
11.2
12.1
12.2
12.3
21.2
21.1
21.3
22
23
Findings
There have been 21 genomewide linkage scans for bipolar illness published to date, and these studies have identified a
number of regions potentially harboring genes for susceptibility to the disorder (see Fig. 135). Note that these findings
were sometimes obtained using the bipolar subtype of
manic-depressive illness, but in other instances the broad
definition incorporating recurrent major depression was
used. At least five bipolar linkage findings (and perhaps
more, depending on the interpretation of statistical thresholds) have reached genomewide statistical significance in
multifamily samples: 6q22 (Middleton et al., 2004), 8q24
(Cichon et al., 2001), 15q14 (Turecki et al., 2001), 21q22 (Liu et
al., 2001b), and 22q12 (Kelsoe et al., 2001). Promising though
they are, these findings have not been replicated consistently
across studies. Other regions that have been repeatedly implicated in bipolar disorder include 1q41, 4p16, 4q3235,
12q2324, 13q3133, 16p1213, 18p11, 18q1223, and Xq2428.
Meta-analyses
Three meta-analyses of linkage studies have been performed, with results differing because of differences in
the studies included and the techniques employed. A 2002
meta-analysis of 11 genome scans for bipolar illness used
the multiscan probability technique, which combines p values across scans in regions with clusters of positive scores.
This analysis revealed that two regions reached genomewide
significance across the studies: 13q32 (p < 6 106) and
22q1213 (p < 1 105) (Badner and Gershon, 2002). Despite this suggestion of a convergence of findings in these
two regions, however, a second meta-analysis was less encouraging. This latter analysis used data from 18 genome
scans, supplemented by unpublished data when the published data were incomplete (see Table 135). The authors
used a rank-based method to ensure that the meta-analysis
would not be biased by statistical methodology. They found
Genetics
13
14
15
19
20
21
427
16
12
11
10
17
18
22
X
Figure 135. Chromosomal regions implicated in bipolar disorder, based on individual studies and two meta-analyses. Dark blue stars
represent regions where a genomewide significant linkage has been found. Light blue stars are regions with more than one suggestive
linkage finding. White stars are regions with the strongest evidence for linkage in either of two meta-analyses of genomewide bipolar disorder linkage scans.
428
Pathophysiology
Table 135. Genome Scans for Bipolar Disorder with More Than 20 Affected Subjects
Study
Center
Utah
Costa Rica
National Institute of
Mental Health (NIMH)
Collaborative
51
24
424
5q
11p1314, 18p11.3, 18q2223
10p12, 16p1213
NIMHIntramural
Research Program
Quebec
Johns Hopkins
Psychiatry/Stanford
Bonn
University of California,
San Diego
Toronto
Sydney
UK/Irish
NIMH Collaborative
160
13q32, 18p11
56
301
12q24
8q24, 18q2122
128
76
8q24
22q1112
106
69
367
228
15q14
3q2526
2q37.3, 18p11
4q35, 11p15.5, 16p1213, Xp11.3
Columbia
NIMH Collaborative
297
741
2p1316
6q1622, 17q25
University CollegeLondon
Finland
Montreal
Edinburgh
State University of
New York, Syracuse
Johns Hopkins Epidemiology
Antwerp
39
132
72
41
75
12q2324
4q32, 16p12
15q11.1, 16p12.3, 18q1221
1q42
6q22
97
46
Chromosome 6q1622
This region was first implicated in bipolar disorder in 2003,
when the results of the largest bipolar genome scan to date
were analyzed (Dick et al., 2003). The sample, the third
to come out of the NIMH Bipolar Disorder Collaborative
Strongest
Findings
Chromosome 8q24
Cichon and colleagues (2001) implicated this region at the
significant level in a study of 75 German, Israeli, and Italian families (the Bonn sample). They found a parametric
Genetics
Chromosome 12q24
This region became interesting after investigators reported
the cosegregation of bipolar illness with Darier disease, a
rare dominantly inherited skin disorder located on chromosome 12q24 in one family (Craddock et al., 1994). In a
genome scan of a Quebec region genetic isolate, Morissette
and colleagues (1999b) reported suggestive linkage in the
region, while Ewald and colleagues (1998) found an LOD
of 3.37 in two Danish families using a DNA marker located
nearby. Of interest, the d-amino acid oxidase (DAO) gene,
recently implicated in schizophrenia (Chumakov et al.,
2002), is in this region, about 1.4 Mb from the Darier disease gene.
Chromosome 13q3133
The 22-family genome scan of Detera-Wadleigh and colleagues (1999) identified 13q32 with a nonparametric LOD
of 3.5, just short of genomewide significance. Subsequent
genotyping narrowed the interval, but did not improve the
LOD score (Liu et al., 2001a). The 13q3133 region has also
been implicated at the suggestive level by Kelsoe and colleagues (2001), and by Potash and colleagues (2003b) in a
subset of Johns Hopkins bipolar families characterized by
multiple members with psychotic features (see the discussion below of alternative phenotypic definition). Several
groups have detected association with a pair of overlapping
genes in this region, G72 and G30 (see the later section on
the association method). As noted, this region reached
genomewide significance in the Badner and Gershon (2002)
meta-analysis.
Chromosome 16p1213
Six independent studies have implicated this region.
Ewald and colleagues (1995a) reported an LOD of 2.5 on
16p13, and McInnes and colleagues (1996) reported an
LOD of 1.46 on 16p13. The NIMH Collaborative found
modest evidence of linkage to 16p1213 in its Wave 1 sample (Edenberg et al., 1997) and stronger evidence for the
same region in its Wave 2 sample (Dick et al., 2002).
429
Maziade and colleagues (2004) and Ekholm and colleagues (2003) each found evidence of linkage to 16p12 in
their genome scans. The findings from these six studies
are spread over 50 cM.
Chromosome 18
Chromosome 18 may harbor several regions of interest.
Evidence of possible linkage was first reported in the pericentromeric region, an area straddling the short and long
arms of the chromosome (Berrettini et al., 1994). This linkage was later narrowed to 18p11.2, with an LOD score of
2.32 being obtained (Detera-Wadleigh et al., 1999). Evidence for pericentromeric linkage was also reported in the
Johns Hopkins sample, in which suggestive linkage was
detected in the 18q21 region as well (Stine et al., 1995).
These results are notable for a parent-of-origin effect, the
evidence for linkage being derived primarily from families
with paternal inheritance of bipolar illness and from paternally transmitted DNA marker alleles. The Johns Hopkins group followed up on its original report with evidence from an entirely new set of 30 families that again
supported linkage on 18q (McMahon et al., 1997). A combined analysis of the 58 Johns Hopkins families showed the
strongest evidence for linkage on 18q2122, as did an analysis of a slightly expanded sample of 65 families (McInnis
et al., 2003).
Other groups have also found evidence for linkage on
chromosome 18, though in varying regions, including 18p11.3
(McInnes et al., 1996), 18q12 (Ewald et al., 1997; Maziade
et al., 2001), 18q22 (de Bruyn et al., 1996), and 18q23 (Coon
et al., 1996; Freimer et al., 1996; Nothen et al., 1999). The
meta-analysis by Segurado and colleagues (2003) divided
chromosome 18 into four parts for purposes of the study.
Three of the four parts were significantly linked to bipolar
disorder, at least nominally, when the results from 18 genome
scans were pooled.
Chromosome 21q22
Investigators initially reported linkage on chromosome
21q22 based on a single large multigenerational pedigree with
an LOD score of 3.41 (Straub et al., 1994). The same group
subsequently documented an analysis of this chromosomal region involving 56 families, which yielded an LOD
score of 3.48 (Liu et al., 2001b). In two different datasets,
Detera-Wadleigh and colleagues (1996, 1997) found evidence for linkage on 21q. Smith and colleagues (1997) obtained an LOD score of 1.29 in this region. However, when
they used a model that simultaneously incorporated the effects of two locithe 21q locus and the tyrosine hydroxylase locus on 11p15the LOD score increased to 3.87, suggesting that genes in these two regions may interact to
cause disease.
430
Pathophysiology
Chromosome 22q1113
In a genome scan of 20 families, Kelsoe and colleagues
(2001) found a parametric LOD score of 3.84 at 22q12,
which was genomewide significant. In this same study, the
authors reported results from the NIMH Wave 2 sample,
which yielded LOD scores of 1.58 at 22q12 and 2.72 at a
marker on the border between 22q11 and 22q12. Other suggestive findings in this region include that of DeteraWadleigh and colleagues (1999), who reported a nonparametric LOD score of 2.1, and that of Potash and colleagues
(2003b), who studied a subset of Johns Hopkins bipolar
families characterized by multiple members with psychotic features and found an NPL score of 3.06 in the 22q12
region (see the discussion below of alternative phenotypic
definition). As noted, this region reached genomewide significance in the Badner and Gershon (2002) meta-analysis.
X-Chromosome
Complex Disorders
The linkage method has yielded spectacular successes in
medicine, with detection of linkage being followed by the
discovery of a disease gene for Huntingtons disease, cystic
fibrosis, and Duchenne muscular dystrophy, among others. These illnesses, which are all uncommon, are called simple mendelian disorders because they follow the relatively
simple rules laid out by Mendel. Like many illnesses currently under study, however, including asthma, hypertension, and diabetes mellitus, manic-depressive illness is common and does not follow these mendelian rules. For these
illnesses, referred to as complex genetic disorders, there is not
a one-to-one correspondence between gene and disease;
rather, these disorders may result from the actions of any
one of several genes. A variant of one gene may cause the
illness in one family, while a variant of a different gene may
cause it in another family (genetic heterogeneity). Many
Genetics
Gender-Specific
Because rates of major depressive disorder in women are
about twice those in men, investigators have wondered
whether susceptibility genes may differ to some extent by
gender. One study estimated that the genetic effects for
males and females were just over half correlated (Kendler
431
and Prescott, 1999), while another estimated they were entirely correlated (Kendler and Walsh, 1995). Data from three
family studies are consistent with partial overlap (Merikangas et al., 1985; Faraone et al., 1987; Reich et al., 1987). Sullivan and colleagues (2000) concluded that although the
data are limited, the most parsimonious explanation appears to be that men and women share most but not all genetic influences for major depression.
One study found significant parametric evidence of
linkage to markers in 2q3334 in 170 affected female sibling
pairs, but not in male pairs (Zubenko et al., 2002). The region between the markers that yielded the peak LOD score
includes the CREB1 gene, which encodes a cyclic adenosine
monophosphate (cAMP)-responsive element-binding protein (CREB), an attractive candidate gene because CREB
has been implicated in depression and antidepressant response. This protein appears to be important for many aspects of neuronal functioning. Levels of CREB have been
found to be abnormally low in persons with major depression and in the brain tissue of suicide victims, and have
been observed to be altered by exposure of rat neurons to
antidepressants and lithium (see Chapter 14).
A second study found evidence of linkage uniquely in
families with at least four affected males (Abkevich et al.,
2003). This linkage, in chromosomal region 12q2223.2,
was detected in a sample of Mormon families in Utah in
which ascertainment was restricted to families with a minimum of four affected relatives. In addition to subjects with
recurrent major depressive disorder, individuals with only
a single episode of major depression were considered affected, as were those with bipolar disorder (who made up
about 15 percent of the individuals with mood disorder in
these families).
432
Pathophysiology
Table 136. Family Studies Comparing Schizophrenia and Psychotic Affective Disorder
Risk in First-Degree Relatives (%)
Study
Sample Size
(First-Degree
Relatives)
Psychotic
Affective
Disorder
Schizoaffective
Disorder
Schizophrenia
50
4.3
214a
6.5
5.7
3.3
67
7.5
6.0c
331
6.7
4.9d
2.8e
723
2.5
1.4
3.7
350
4.9
3.0
8.0
84
3.6
2.4f
13.1
1,157
3.3g
2.0h
5.7
1,056
1.0
0.1
0.2
Control Probandsi
Kendler, 1985 (Iowa)
Kendler et al., 1993a,b,c (Roscommon)
710a
1.0
1.1
1.1
136
0.7
0.9
0.5
0.5
Weighted mean
1,902
Genetics
433
Data from a genome scan for bipolar disorder were reanalyzed by Park and colleagues (2004) according to the presence
or absence of psychotic features. Some evidence of linkage to
psychotic bipolar disorder was obtained on chromosome
13q32, though the strongest results were on chromosomes 9q31
and 8p21. No signal emerged for chromosome 22q1113.
The hypothesis of etiologic overlap suggests the existence of either psychosis genes (within an oligogenic model)
or joint mood and psychosis genes. This latter possibility
implies that examination of mood-related subtypes of
schizophrenia would further illuminate the issue of etiologic overlap. Indeed, results of four studies suggest that
elevated familial rates of mood disorder may occur in a
subset of schizophrenic subjects.15 Pulver and colleagues
(2000) tested the hypothesis that some families with
schizophrenia may carry genes predisposing to both psychotic and mood symptoms. In an effort to reduce genetic
heterogeneity in schizophrenia, they analyzed a subset of 6
families (from a set of 54) in which at least one relative had
a psychotic mood disorder. The strongest linkage signal in
the genome for this family subset was on chromosome
22q12, where results were suggestive; linkage evidence was
also suggestive for 13q33.
Bipolar-II
Results of several studies conducted in the 1980s indicated
that the diagnosis of BP-II in genetic studies was unreliable (Andreasen et al., 1981). A more recent study, however,
found that the reliability of the Research Diagnostic Criteria BP-II diagnosis was extremely good in the genetic study
done at Johns Hopkins, with a kappa value of .72 for hypomania (Simpson et al., 2002). One possible explanation for
this difference is that at Johns Hopkins, academic psychiatrists specializing in affective disorders conducted the interviews. The three studies that examined the familial aggregation of BP-II and used a methodology that included
direct examination of the majority of subjects are summarized in Table 132. These studies showed that this form of
the disorder appears to breed true, as rates of BP-II are elevated in relatives of BP-II probands. In the one twin study
that specifically analyzed probands with BP-II, a high heritability was observed (Bertelsen et al., 1977).
Interest in BP-II at Johns Hopkins derived from the observation that it was the most common phenotype in the
first set of 28 BP-I proband families ascertained (Simpson
et al., 1993). Subsequent analyses of the Johns Hopkins
linkage data on chromosome 18q2122 in these families
showed that linkage depended mainly on BP-IIBP-II sibling pairs. Sharing of DNA markers was demonstrated
among 18 of 22 pairs in which both siblings had BP-II in
the original dataset. When a second dataset of 30 more
families was prospectively examined, 9 of 11 BP-II pairs
434
Pathophysiology
Early Onset
As with depression, several studies have found a higher
rate of bipolar disorder among relatives of early-onset bipolar probands than among relatives of later-onset probands
(Strober et al., 1988; Coryell et al., 2001; GrigoroiuSerbanescu et al., 2001). Other studies have revealed significant correlation between bipolar sibling pairs for age at
onset (Baron et al., 1981; Leboyer et al., 1998; Omahony
et al., 2002). Faraone and colleagues (2004) studied the
correlation between relatives with bipolar illness for age at
onset of mania. They found a significant correlation, with
an estimated heritability for age at onset of .41. They went
on to use age at onset of mania as a quantitative trait for
linkage analysisa powerful approach because it provides
a finer-grained assessment of the phenotype than is derived from a simple dichotomous depiction of the data.
The results showed suggestive evidence for linkage in three
regions that had not emerged in the conventional phenotype linkage analysis of their dataset: 12p, 14q, and 15q. A
similar approach was taken by the Johns Hopkins group,
which showed that age at onset was familial (Lin et al.,
2005, 2006) and that early onset was correlated with linkage
on 21q22.13 in two distinct datasets. This region of chromosome 21 is one previously implicated in bipolar disorder (see above).
Cognitive Features
Cognitive decline was one of the defining features of
Kraepelinian dementia praecox (schizophrenia); by definition, Kraepelinian manic-depressive illness was a disorder
in which such decline was not seen. Although the issue has
not been resolved, some evidence from studies of euthymic
bipolar patients supports the hypothesis that residual neuropsychological impairments persist in a subgroup of patients (Ferrier and Thompson, 2002). Studies of this kind
are potentially confounded, however, by the possibility of
residual symptoms in patients and by the potential cognitive
effects of medications (see Chapter 9). The presence of cognitive abnormalities in unaffected family members can provide a more definitive answer to the question of whether
cognitive deficits are a heritable bipolar trait in some cases.
Genetics
Rapid Cycling
Three studies of familial aggregation of rapid-cycling bipolar disorder yielded negative results (Nurnberger et al., 1988;
Coryell et al., 1992; Lish et al., 1993). One recent study assessed a related clinical variablethe rapid switching of
moodand found modest evidence for the familial clustering of this trait in a large sample (MacKinnon et al.,
2003a). In a related study, rapid switching was found to be
more common in bipolar families in which multiple members also had panic attacks (MacKinnon et al., 2003b).
More research is needed to determine whether this variable will prove valuable in resolving the genetic heterogeneity of bipolar disorder.
Endophenotypes
Lithium Responsiveness
Three types of studies have investigated lithium responsiveness as a potentially genetically informative trait: studies of family history of manic-depressive illness, studies of
the familial aggregation of lithium response, and molecular studies. The family history studies have yielded mixed
results: some found a positive family history of bipolar disorder or more broadly defined manic-depressive illness to
be associated with a good response to lithium, while others
did not (see Coryell et al., 2000, for references). Studies of
the familial aggregation of lithium response have been few
and small. These studies, discussed below in the section on
pharmacogenetics, generally support the hypothesis that
lithium response in one family member is predictive of
lithium response in others. Given the biological plausibility of lithium response as an endophenotype in bipolar disorder, Turecki and colleagues (2001) ascertained 31 Canadian bipolar families through excellent lithium responders.
435
A complete genome scan of these families revealed parametric linkage support for chromosome 15q14 at a
genomewide significant level. Further testing with positive
lithium response as the phenotype implicated a locus on
chromosome 7q11.2.
Evoked Potentials
The auditory P300 event-related potential is a brain wave
that appears on an electroencephalogram (EEG) when subjects monitor series of stimuli for rarely presented targets.
The P300 is thought to reflect the operations of short-term
working memory. Results of one study suggest that aspects
of P300 abnormality have a genetic basis. There is a large
Scottish family in which 7 members have schizophrenia,
1 has bipolar disorder, and 10 have major depression. All 18
of these family members, as well as 11 others, carry a balanced chromosomal translocation resulting in chromosomal breakpoints on 1q and 11q. (See the later section on
testing gene- and allele-specific function for a discussion
of cytogenetics and these breakpoints.) When 12 family
members carrying the translocation were tested on the
P300 along with noncarriers and normal controls, the carriers were abnormal by two measuresprolonged latency
and elevated amplitudein comparison with the other
two groups (Blackwood et al., 2001). Further studies are
needed to determine whether other families show cosegregation of P300 abnormalities.
436
Pathophysiology
Figure 136. Family-based association: the transmission disequilibrium test. The test is performed using trios composed of an affected individual and his or her parents. It does not matter
for this test whether the parents are affected. The test determines whether a particular allele is
transmitted to affected individuals more often than it is not transmitted. In this example, there are
four heterozygous parentsthe father in a, the mother in b, and both parents in c (squares are
males, circles are females, and filled-in symbols are affected). Each of these four parents could have
transmitted either the G or T allele to his or her affected child. In all four cases, the G was transmitted. Note that the mother in a and the father in b could transmit only a T because they are homozygous for this allele. Thus, they are not informative for this test. A consistent pattern of overtransmitting the G allele across a large number of trios would implicate this allele in association with disease.
b
GT
TT
GT
c
TT
GT
GT
GT
GT
GG
Table 137. Genes That Have Been Tested for Association in Bipolar Disorder
Gene
Function
Chromosome Location
Positivea
Negativea
Studies
Serotonin System
5-HTT
Transporter
17q11.2
5-HT1A
Receptor
5q12.3
5-HT1B
Receptor
6q14.1
5-HT1D
5-HT2A
Receptor
Receptor
1p36.12
13q14.2
++
5-HT2C
Receptor
Xq23
5-HT4
5-HT6
Receptor
Receptor
5q32
1p36.13
+
+
Table 137. Genes That Have Been Tested for Association in Bipolar Disorder (continued)
Gene
Function
Chromosome Location
Positivea
Negativea
Studies
5-HT7
TPH
Receptor
Synthesis
enzyme
10q23.31
11p15.1
MAOA
Degradation
enzyme
Xp11.3
++++
Dopamine System
438
DAT1
Transporter
5p15.33
DRD1
Receptor
5q35.2
DRD2
Receptor
11q23.2
++++
DRD3
Receptor
3q13.31
+++
DRD4
Receptor
11p15.5
RD5
Receptor
4p16.1
16q12.2
Norepinephrine System
NET
Transporter
Monoamine Metabolism
Monoamine
degradation
22q11.21
DBH
Converts
9q34.2
dopamine to
norepinephrine
Monoamine
7p12.2
synthesis
Norepinephrine
11p15.5
and dopamine
synthesis
+++++
439
COMT
DDC
TH
+
+++++
Table 137. Genes That Have Been Tested for Association in Bipolar Disorder (continued)
Positivea
Gene
Function
Chromosome Location
MAOB
Degradation
enzyme
Xp11.3
GABRA1
GABRA3
Receptor
Receptor
5q34
Xq26
+
+
GABRA5
GABRB1
Receptor
Receptor
15q12
4p12
GABRB3
Receptor
15q12
Angiotensinconverting
enzyme
Adenosine
receptor
Brain-derived
neurotrophic
factor
17q23.3
Negativea
Studies
GABA
Other
ACE
A1AR
440
BDNF
BZRP
CART
CCK
CNR1
CRH
CTLA4
DRP2
ESR1
Benzodiazepine
receptor
Neuropeptide
Cholecystokinin
Cannabinoid
receptor
Corticotropinreleasing
hormone
Immunoglobulin
Regulator of
axonal growth
Estrogen
receptor
1q32.1
11p14
+++
22q13.2
5q13.2
3p22-21.3
6q15
8q13.1
2q33.2
8p21.2
6q25.1
ESR2
FZD3
GNB3
IMPA1
INPP1
NCAM1
NTF3
PENK
PLA2G4A
PLCG1
TNFA
Estrogen
receptor
Wnt receptor
G-protein
Myo-inositol
monophosphatase
Inositol phosphate
1-phosphatase
Neural cell
adhesion
Neurotrophic
factor
Proenkephalin
Phospholipase
Phospholipase
Cytokine
14q23.2
8p21.1
12p13.31
8q21.13
2q32.2
11q23.1
12p13.31
8q12.1
1q31.3
20q12
6p21.33
+
+
KCNN3
SCA2
ASH1
TCF4
MAB21L
NOTCH4
Spinocebellar
ataxia 2
Transcription
factor
Transcription
factor
Protein
regulator
Developmental
signaling
factor
12q24.12
12q23.2
18q21.1
13q13.3
6p21.3
Cytoskeletal
protein
1q42.2
Positional
DISC1
Table 137. Genes That Have Been Tested for Association in Bipolar Disorder (continued)
Gene
Function
Chromosome Location
Positivea
Negativea
Studies
WFS1
Wolframin
4p16.1
DAO
D-amino acid
oxidase
MAP kinase
phosphatase
Phospholipase
Phospholipase
Possible NMDA
receptor
regulation
Adenylate
cyclase
Somatostatin
receptor
NMDA
receptor
subunit
G-protein
Myo-inositol
monophophatase
Mitochondrial
protein
Pituitary adenyl
cyclase
activating
peptide
Transporter
Transcription
factor
Phospholipase
12q24.11
12q21.33
DUSP6
PLA2A
PLA2G1B
G72/G30
ADCY9
SSTR5
GRIN2A
GOLF
IMPA2
NDUFV2
PACAP
ABCG1
XBP1
PLA2G6
12q24.23
12q24.23
13q33
+
++++
16p13.3
16p13.3
16p13.3
18p11.21
18p11.21
18p11.22
18p11.32
21q22.3
22q12.1
22q13.1
Notes: The phenotype here is defined narrowly as bipolar only for some studies, while it is defined as bipolar plus major depression for others. The relatively few studies examining only
major depression are not included.
a
A positive result indicates a finding that was statistically significant; a negative result represents a finding that was not statistically significant. This determination is based
on overall results, and does not take account of secondary analyses.
Genetics
bipolar disorder is the group of genes that contain trinucleotide repeat sequences. This structural feature has been
implicated in numerous neuropsychiatric diseases and has
been hypothesized to play a role in bipolar disorder (see
the later section on consideration of alternative genetic
mechanisms).
The positional candidate genes are those that reside in
linkage regions and are thus in a chromosomal position of
interest. Studies of positional candidate genes conducted in
the 1990s were confined primarily to work on genes that
were both positional and biological candidates. Work is currently under way on larger-scale association testing of many
positional candidate genes in linkage regions. Genes with at
least three positive association findings are discussed below.
443
MAOA
This gene encodes monoamine oxidase A (MAOA), an enzyme that degrades monoamine neurotransmitters, such as
dopamine, norepinephrine, and serotonin. There are several
reasons why MAOA may have a role in manic-depressive illness. First, monoamine oxidase inhibitor (MAOI) medications, such as tranylcypromine, treat depression. Second, in
a large Dutch kindred with a form of X-linked mild mental
retardation, all affected males showed aggressive, impulsive,
and sometimes violent behavior, including arson, attempted
rape, exhibitionism, and attempted suicide (Brunner et al.,
1993). Each of the affected males in the family was shown to
carry a mutation in the MAOA gene. The behavioral phenotype in this family was believed to bear some resemblance to
a manic syndrome.
Thirteen studies have examined the possible association
of four MAOA polymorphisms with either bipolar disorder
or bipolar disorder combined with major depression. Four
of these studies yielded statistically significant positive
findings, while nine failed to show an association (see
Table 137). However, two meta-analyses that examined
pooled data from seven and five studies, respectively,
found significant associations for the two polymorphisms
they examined (Furlong et al., 1999a; Preisig et al., 2000).
One of these polymorphisms, a microsatellite marker in
intron 2, had an allele that was 1.55 times more likely to be
found in Caucasian bipolar subjects than in controls and
an allele that was 2.65 times more likely to be found in Japanese bipolar subjects than in controls. For a single base variant in the coding sequence, one allele was 1.30 times more
likely in Caucasian cases than in controls (Furlong et al.,
1999a). An important caveat is that these meta-analyses, like
all of the positive studies, used the casecontrol method.
The only two studies to use family-based methods both
failed to show evidence for an association (Nothen et al.,
1995; Parsian and Todd, 1997), so the possibility that the
positive findings for this gene are due to undetected population stratification cannot be ruled out.
TH
This gene encodes tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine and norepinephrine. A
total of 21 studies have sought an association between bipolar
disorder and TH polymorphisms, including four RFLPs and
one microsatellite repeat within intron 1; of these, 5 yielded
444
Pathophysiology
positive results and 16 negative (see Table 137). A metaanalysis of 11 studies using the microsatellite marker showed
no evidence for association with bipolar disorder in the
pooled data (Furlong et al., 1999b). Current evidence does
not support involvement of the TH gene in bipolar disorder.
COMT
This gene codes for an enzyme involved in the degradation
of dopamine and norepinephrine. It has been much studied in relation to schizophrenia in part because it lies in
a chromosomal region within 22q11 that has been implicated in psychotic illness through velocardiofacial syndrome
(VCFS). This syndrome, which is often accompanied by
psychotic symptoms, results from microdeletion or loss of a
segment from the 22q11.2 region. Another interesting feature of COMT is the existence of an SNP shown to be functionally significant, with the variant coding for methionine
having a three- to four-fold lower level of enzymatic activity
than the one coding for valine. There have been five positive
and seven negative studies of this variant (see Table 137). A
meta-analysis of seven casecontrol reports, representing
910 bipolar cases and 1,069 controls, found a statistically
significant, though very modest, effect whereby the lowactivity methionine variant was 1.18 times more likely in
subjects with bipolar disorder than in controls (Craddock
et al., 2001). None of the three family-based studies showed
significant evidence for an association (Mynett-Johnson
et al., 1998; Kirov et al., 1999a; Geller and Cook, 2000).
DRD2
The dopamine D2 receptor (DRD2) has been the subject of
intense interest because of its critical role in the mechanism of action of antipsychotic medications. There have
been 4 positive and 11 negative association studies of this
gene in relation to bipolar disorder (see Table 137). Notably, the most recent study had three to four times more
patients than any of the prior studies. This study found
that one allele of a microsatellite marker within intron 2
was 1.7 times more common in bipolar cases than in controls (p = .00035) (Massat et al., 2002b). While this finding
might be construed as indicating that when the sample is
sufficiently large, a real though modest association can be
found with DRD2, again one would like to see confirmatory evidence from family-based association studies. Two
such studies have been done to date; both were negative.
Thus, firm conclusions about an etiologic role for DRD2 in
bipolar disorder cannot be drawn at present.
DRD4
The dopamine D4 receptor (DRD4) has been of interest in
psychiatric genetics since its discovery as a dopamine receptor with a high affinity for clozapine and the discovery
BDNF
At the start of the new century, armed with greater awareness of the neurobiology of manic-depressive illness, a
wider array of identified SNPs, and a greater technical capacity to perform SNP genotyping, Sklar and colleagues
(2002) undertook a family-based association study of 76
functional candidate genes located in diverse regions of the
genome. The study yielded two nominally positive associations with the bipolar subgroup, and only one of these
brain-derived neurotrophic factor (BDNF)was supported,
albeit weakly at a nonstatistically significant level, in two
replication samples. The authors found that two samples
shared an undertransmitted haplotype (an ancestral chromosomal fragment) marked by two SNPs. A second
study (Neves-Pereira et al., 2002) also found an association between BDNF and bipolar disorder using the same
SNP identified in the Sklar et al. screen, which in its G
form leads to synthesis of the amino acid valine, but in its
A form results in methionine. As in the study by Sklar and
colleagues, the A allele was found to be undertransmitted
in this family-based study. Replication attempts in one
European (Oswald et al., 2004) and three Asian (Nakata
et al., 2003) casecontrol datasets were negative, however
(Nakata et al., 2003). Further support for the Sklar groups
finding comes from a report that the G allele of BDNF was
shown to be preferentially transmitted to people with
prepubertal and early-adolescent bipolar disorder (Geller
et al., 2004). Similarly, the G allele was associated with
neuroticism, a personality trait correlated with depression
(Sen et al., 2003), although a Chinese casecontrol study
of major depression was negative (Tsai et al., 2003). The
potential genetic role of BDNF in mood disorder is intriguing because of the part it plays in the brains response
Genetics
G72/G30
The genes discussed above were all studied because they
were thought to have a biological role in bipolar disorder.
Yet our lack of fundamental understanding of bipolar
pathophysiology may mean that positional candidate genes
with no known biological relationship to bipolar disorder,
or perhaps no currently known function at all, may be real
susceptibility genes for the disorder. One intriguing new
finding concerns two genes of unknown functionG72
and G30that overlap each other on the same stretch of
DNA. A group studying schizophrenia genetics discovered
these genes as positional candidates in the 13q32 linkage region. They reported an association of SNPs in and around
these genes with schizophrenia (Chumakov et al., 2002). In
the same study, the protein product of G72 was found to
interact with DAO; DAO is expressed in the human brain,
where it oxidizes d-serine, a potent activator of the Nmethyl-D-aspartatetype glutamate receptor.
The Gershon group, which first reported linkage to this
same region in bipolar disorder, tested for association of
SNPs in G72/G30 in the NIMH Clinical Neurogenetics 22family bipolar sample and in the NIMH Wave 1 and 2
bipolar samples. Using the transmission disequilibrium
test to assess family-based association, they obtained positive results for both samples (Hattori et al., 2003). A second
study of G72/G30, by Chen and colleagues (2004), employed
the Johns Hopkins bipolar sample. Using a casecontrol
approach, they found that two G72/G30 SNPs were associated with illness. A third study also found evidence for an
association of SNPs in G72/G30 with both schizophrenia and
bipolar disorder (Schumacher et al., 2004). Yet another
study examined the G72 gene in two bipolar samples and,
in the context of looking at psychosis in general and individual psychotic symptoms, found an association specifically with persecutory delusions (Schulze et al., 2005). While
promising, the results of these studies cannot be regarded as
conclusive because the associated variations within the genes
differ from one study to the next, and no functional variation has yet been implicated. Nonetheless, G72/G30 does
constitute the first positional candidate gene(s) for bipolar
disorder to be associated with illness in independent reports.
Linkage Disequilibrium
In addition to testing for whether a candidate gene is associated with disease, it is possible to test for such an association with random marker alleles in noncoding regions of
DNA. When an association is found, the marker allele is in
linkage disequilibrium with the disease locus, reflecting the
445
common inheritance of an ancestral chromosomal fragment, or haplotype, among affected individuals. (A haplotype denotes the collective genotype of a number of closely
linked DNA markers or loci on a chromosome.) This approach can be viewed as a linkage test in one enormous
family. Because the family is so big, with numerous generations and thus numerous recombinations of chromosomal
fragments, the chromosomal region implicated by a positive findingthe region left unrecombined, or intactis
much smaller than the region implicated by linkage.
The chromosomal distance across which linkage disequilibrium can be detected in a European population ranges
from a few thousand to 100,000 bases, with an average of
about 22,000 bases (Gabriel et al., 2002). The distance is
smaller for African populations. These regions, called haplotype blocks, are roughly 1,000-fold smaller than the typical size of a linkage region (Roberts et al., 1999). These
short distances have been an obstacle to the use of linkage
disequilibrium mapping because they necessitate large numbers of very tightly spaced DNA markers to detect association with a disease gene. Only since the turn of the century
have large numbers of SNPs become available, allowing for
the conduct of very dense marker studies. A number of
projects are currently using SNPs to narrow the localization of a linkage region, although no study employing this
method in a general bipolar population, as opposed to a
population isolate, has yet been published. It is thought
that 300,000 or more SNPs would be required to conduct a
genomewide association study in a genetically mixed population (Gabriel et al., 2002). Studies that would test 500,000
SNPs in a large bipolar sample are currently being planned.
Population Isolates
Linkage disequilibrium studies have been published for a
population isolate. Such populations are thought to be more
genetically homogeneous than ethnically mixed populations; moreover, linkage disequilibrium may exist over a
larger chromosomal region in these isolates than in a mixed
population, potentially facilitating detection. Population
isolates that have been studied in relation to bipolar disorder include the Amish, Ashkenazi Jews, the population
of the Central Valley of Costa Rica, inhabitants of eastern
Finland, and families from the SaguenayLac-St-Jean region in Quebec. A genome scan on the Costa Rican sample
yielded several strong linkage findings, including one on
18p11.3. SNP genotyping across the region yielded a strong
association with markers in a 19,000-base region that contains just two genes, with the most strongly implicated gene
being CLUL1, clusterin-like 1 (retinal), for which the function is not known (McInnes et al., 2001). Another study
from the same group included a genomewide linkage disequilibrium scan using 1,186 microsatellite markers on 109
446
Pathophysiology
unrelated Costa Rican BP-I subjects. This study found evidence for increased sharing of an ancestral chromosomal
fragment among ill subjects on 8p23.1, suggesting the possibility of a susceptibility gene in this region (Ophoff et al.,
2002).
There are caveats to the population isolate strategy. The
necessary homogeneity may exist only if the isolate has a
particular history, that is, a small number of unrelated
founders (10100) and slow population growth during the
early generations following the initial bottleneck. Some
populations currently regarded as isolates may not meet
these criteria (Wright et al., 1999). Further, the age and frequency of the sought-after disease mutation affect the ability to detect linkage disequilibrium with neighboring markers. In particular, if the disease mutation is significantly
older than the marker mutation, little or no association may
be detected even when the physical distance between the
two is small (Chakravarti, 1999). If gene variants leading to
susceptibility to bipolar disorder are common variants, they
probably developed a very long time ago. Because of their
age, they are likely to have been scrambled by the many recombinations that have occurred during the numerous
meioses between then and now. In this setting, linkage disequilibrium between the marker and the disease allele may
not exist over any greater distance in an isolate than in the
general population.
and a Romanian sample, in which it was restricted to subjects inheriting the disorder from the paternal side (Nylander
et al., 1994; Grigoroiu-Serbanescu et al., 1997; Ohara et al.,
1998a). In a Canadian bipolar sample, evidence for anticipation was also found, although the authors suggested that
a censoring bias may have been partially responsible for this
result (Merette et al., 2000). This bias is due to having apparently normal subjects in the younger generation who might
eventually develop the disorder, though their potentially later
age at onset is not evident at the time of the study. Other potential biases can also influence analyses of anticipation
(Goossens et al., 2001). Anticipation studies of bipolar disorder have attempted to control for these biases, but the possibility of false positive findings cannot be ruled out.
In support of the clinical findings, a few reports have
suggested that expanded trinucleotide repeat sequences
may exist in bipolar disorder; however, the majority of
studies have been negative in this regard (see Table 137 for
trinucleotide repeatcontaining genes that have been tested
for association with bipolar disorder; see Goossens et al.,
2001, for further references). Although the anticipation
and trinucleotide repeat hypothesis has not yet yielded
strong candidate bipolar genes, the possibility remains that
types of repeats not yet carefully examined may play a role
in the etiology of bipolar disorder.
CONSIDERATION OF ALTERNATIVE
GENETIC MECHANISMS
Parent-of-Origin Effect
Mitochondrial Inheritance
The mitochondria are organelles within cells; they have
their own unique genome, composed of 16,569 nucleotides
Genetics
Genomic Imprinting
When heritable differences in gene expression between individuals exist and are not accounted for by variation in
the DNA sequence, epigenetic factors are said to be involved. One important epigenetic mechanism is genomic
imprintingthe parent-of-originspecific silencing of one
allele of a given gene with a corresponding parent-of-originspecific expression of the other allele. Imprinting has
been demonstrated for about 25 genes to date (Morison and
Reeve, 1998), and imprinted genes have been implicated in
such diseases as Angelman syndrome, Prader-Willi syndrome, and Beckwith-Weidemann syndrome. Although imprinted genes are thought to play an important role in
growth, they can also be involved in maternal behavior (Li
et al., 1999a) and in social behavior (Skuse et al., 1997).
Mouse studies of the developing brain employing genetically engineered mice with predominantly maternal or predominantly paternal genomes have indicated that maternal
genes play a disproportionate role in the development of the
cortex, while paternal genes play a disproportionate role in
hypothalamic development (Keverne et al., 1996).
Two bipolar genome scans have examined parent-oforiginspecific linkage. Reporting on the Bonn sample, Cichon and colleagues (2001) identified two regions2p2124
and 2q3132that showed suggestive evidence for linkage
when only maternal transmission was examined, and two
regions14q32 and 16q2123that showed suggestive linkage when only paternal regions were examined (Cichon et
al., 2001). Of interest, the 14q32 linkage region is immediately adjacent to a known imprinted gene, DLK1. Because
imprinting is thought to occur in clusters, there may be
other imprinted genes in the region. McInnis and colleagues
(2003), examining the Johns Hopkins sample, found two
regions1q42 and 13q12that showed linkage with maternally transmitted alleles and one region18q2122that
showed linkage with paternally transmitted alleles (McInnis et al., 2003). The 13q12 region contains 5-HT2A, reported
to be imprinted in fibroblasts (Kato et al., 1996a) and in
brain tissue from some subjects but not others (Bunzel
447
448
Pathophysiology
Figure 137. Genetic to pathogenic pathway to manic-depressive illness. Many levels of pathogenesis intervene between
genetic etiology and the syndrome of manic-depressive illness. Study of the relationship between a potential susceptibility
gene variant and manic-depressive illness requires examination of the impact of the variant on a number of these disease
components. An interaction of environmental factors with gene expression or function, or protein expression or function,
is also possible. (Source: Adapted from McHugh and Slavney, 1998.)
Syndrome
Manic-depressive illness
Clinical subtypes of
illness
Neurophysiological endophenotype?
Pathology
Protein expression/function
Etiology
Gene mutation/variant
Environmental
factors
Sample Sizea
Gene
Change
Brain Region
Frontal, temporal,
occipital
Prefrontal
Hippocampus
Frontal
Frontal
20
G protein (s)
No change
30 (Stanley)
30 (Stanley)
34 (Stanley)
30 (Stanley)
30 (Harvard)
30 (Stanley)
29 (Stanley)
34 (Harvard)
19 (Harvard)
Decreased
Decreased
Increased
Decreased
Increased
Increased
Decreased
No change
Decreased
Decreasedb
No change
Decreased
26 (Stanley)
70 (Stanley2c)
Neuropeptide Y
Complexin I and II
Serotonin transporter and NF-B
TGF-1
CASP8
TOB
GAD65
GAD67
CaMKII
Prodynorphin
GRIN2A
43 genes, including 18 mitochondrial,
GAD67, and somatostatin
53 genes, including LIM1 and HSPF1
27 genes
Hippocampus
Prefrontal
Amygdaloid complex
Anterior cingulate
Hippocampus
Prefrontal
Prefrontal
Decreasedd
Decreased
Increased
Increased
Decreased
Decreased
30 (Stanley)
19
30 (Stanley)
30 (Stanley)
30 (Stanley)
26 (Stanley)
450
Pathophysiology
Genetics
451
Studies using lymphoblast cells or granulocytes from patients have the great advantage that these samples are much
more readily obtainable than brain tissue. A recent study
demonstrates the value of using lymphoblastoid cell lines
to examine variation in gene expression levels. Cheung and
colleagues (2003) examined expression levels in lymphoblastoid cells from normal individuals, including some sibling
pairs and some MZ twin pairs. They found that for some
genes, expression levels varied significantly among the subjects. For five genes that were intensively studied, the variance among individuals was 311 times greater in unrelated
individuals than among MZ twins, and the variance among
sibling pairs was 25 times greater than among these twins.
These results suggest that heritable factors that vary among
individuals contribute to differences in levels of gene expression.
Although studies have indicated that functional abnormalities exist in the lymphocytes of bipolar patients, there
have been few efforts to examine gene expression. The major
weakness of this approach to studying bipolar disorder is
that it is not clear that expression in these white blood cells
mirrors expression in neurons, as control of expression
may be tissue- and cell typespecific.
On the other hand, some abnormalities that have been
detected in lymphocytes appear to mirror changes detected
in postmortem brain tissue from bipolar subjects. For example, low inositol levels have been found in the frontal
cortex of patients, as well as in lymphocytes (Shimon et al.,
1997; Belmaker et al., 2002). A crucial component of the inositol pathway is inositol monophosphatase (IMPase). A
report examining IMPase activity in drug-free bipolar patients using quantitative reverse transcriptionpolymerase
chain reaction (RT-PCR) on lymphocytes found an approximately two-thirds reduction in IMPase-relative
messenger RNA levels compared with control subjects
(Nemanov et al., 1999). Yoon and colleagues (2001) found
decreased IMPA2 messenger RNA levels in lymphoblasotid cell lines from BP-I patients, though only in males
with decreased basal levels of intracellular calcium. Inositol system genes have been considered leading candidates
for involvement in bipolar etiology because of this systems
central involvement in response to mood-stabilizing medications (Williams et al., 2002). One study examined messenger RNA levels of three G protein alpha subunits and of
phosphatidylinositol-3 kinase (PI-3K) regulatory subunit
p85 in the granulocytes of bipolar patients compared with
controls. One of the G protein alpha subunits, alpha(s),
was markedly increased in bipolar patients; this increase
was observed in both lithium-treated and unmedicated
patients.
452
Pathophysiology
Genetics
453
At least 14 studies have examined antidepressant response in relation to gene variants. The serotonin transporter gene promoter region variant has been studied most
extensively because the selective serotonin reuptake inhibitor (SSRI) antidepressants are known to work through
the protein product of this gene (and because the variant
is functionally significant). Eight of eleven published studies have suggested a better response to SSRIs in patients
with long alleles and a slower or worse response in subjects
with short alleles. Of interest, one study included a group
treated with nortriptyline as well as one treated with paroxetine. Those with the long allele in that study did not respond as quickly to nortriptyline as they did to paroxetine
(Pollock et al., 2000), a result suggesting the possibility of
an SSRI-specific effect. The findings of three studies, however, were not consistent with those of the other eight,
showing a better response to SSRIs for carriers of the short
allele or no association (see Table 139). It may be significant that two of the three negative studies involved Asian
populations, while seven of the eight positive studies involved populations of European ancestry. The short and
long alleles have been shown to be composed of subtypes,
and these subtypes have been found to vary between Japanese and Caucasian populations (Nakamura et al., 2000).
Given that one study in a Chinese sample was positive for
the long variant, however, this explanation may be incomplete. Further uncertainty stems from the observation by
Mundo and colleagues (2001a) that bipolar patients who
had experienced antidepressant-induced mania were more
likely to carry the short allele than those who did not have
this response to antidepressants. The authors hypothesized
that the short allele may be associated with an exaggerated
response to antidepressants, which is difficult to reconcile
with the findings noted above.
A number of other gene variants have been studied in
relation to antidepressant response. Variants of the tryptophan hydroxylase gene were found to be associated with
slower or poorer response to SSRIs in two studies (Serretti
et al., 2001; Peters et al., 2004), while variants of the serotonin 2A receptor and of the G-protein beta-3 gene were
associated with response to mixed antidepressants in one
study each. A variant of the norepinephrine transporter
gene was associated with response to milnacipran, a serotonin and norepinephrine reuptake inhibitor, in a small
sample (Yoshida et al., 2004). No association with antidepressant response was found in studies of the dopamine 2
and 4 receptors or of the MAOA gene.
Genetic Counseling
Studies of the familial aggregation of manic-depressive illness (especially the bipolar form) have provided valuable
data that can be used by clinicians to help educate concerned
454
Pathophysiology
Table 139. Studies of the Association of the Serotonin Transporter Gene Promoter Region Variant
with Response to Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants
Study
Sample Size
Medication
Result
Positive
Smeraldi et al., 1998
Zanardi et al., 2000
99
64
Fluvoxamine
Paroxetine
95
Paroxetine
Zanardi, 2001
Yu et al., 2002
Rausch et al., 2002
Serretti et al., 2004
Murphy et al., 2004
155
121
51
220
255
Fluvoxamine
Fluoxetine
Fluoxetine
Fluvoxamine or paroxetine
Paroxetine
120
Fluoxetine/paroxetine
Negative
Kim et al., 2000
Yoshida et al., 2002
Peters et al., 2004
66
96
Fluvoxamine
Fluoxetine
largely unidentified and unstudied in terms of risk, counselors and clinicians do not yet have available the kind of
data that would allow for more exact predictions.
Additional complexities affect the potential benefits of
genetic counseling: manic-depressive illness is for the most
part not a fatal condition; there are several available treatments, and there is good reason to believe that many patients can lead full and meaningful lives with treatment; and
the risk data that exist do not distinguish between those in
whom the illness would be severe and those who would respond well to standard treatments. What is quite predictable
in a family at high risk seeking counseling is that the delay in
recognition and diagnosis of manic-depressive illness in all
affected children will likely be brief compared with the usual
decade-long delay encountered by those with the bipolar
form of the illness. There are many reasons to believe that
much morbidity can be prevented by such early diagnosis.
Our practice has been to ask common clinical psychiatric
questions as well as standard family-history questions of
couples seeking counseling. For example: Why do you want
a child now as opposed to at some other time? What are your
plans for child care? And for a mother with bipolar disorder: What are the risks and plans if a postpartum (puerpual) depression or mania ensues? These standard clinical
questions usually lead to the most fruitful discussions of the
prospective parents expectations. A sensible determination
Genetics
455
mild course of illness, fewer than 10 percent preferred termination, whereas with a 100 percent chance of illness or a severe course, the proportion who said they would terminate
was much higher4055 percent and 7085 percent, respectively.
456
Pathophysiology
Power
Very large samples are now being gathered for bipolar studies. The NIMH Bipolar Disorder Collaborative study has
already ascertained and assessed a linkage sample of 644
families with 921 affected sibling pairs. The collaborative is
currently in the process of acquiring a sample of 5,000 cases
for association studies, including, potentially, studies that
would assay 500,000 SNPs simultaneously across the genome
(whole-genome association). Very large samples have the
power to detect the modest gene effects likely to play a role in
susceptibility to bipolar disorder. Large samples also provide
sufficient power to employ new analytical techniques that
can test for interactions between genes.
Genetic Homogeneity
Use of phenotypic subtypes and endophenotypes may allow linkage and association to be performed on more genetically homogeneous subgroups within bipolar disorder.
This capability would prevent the dilution of individual
gene effects that occurs when all bipolar subjects are considered jointly if multiple genes are contributing to the
broad phenotype. Potential examples of relevant subgroups
are BP-II, BP-I with psychotic features, bipolar disorder
with comorbid panic disorder, BP-I with an early age at onset, and lithium-responsive bipolar disorder. More work is
needed to define genetically meaningful clinical subtypes
and to determine familial endophenotypic measures. Conversely, genetic findings may help clarify the validity of potential subtypes. For example, we may come to better understand how early-onset recurrent major depression differs
from less recurrent severe forms of depression; such understanding could allow us to differentiate the genetics of recurrence or cyclicity from that of polarity. Population isolates may also be of use in limiting genetic heterogeneity.
Genetics
DNA to look at gene expression (RNA), the protein product, and pathogenesis as well. It may be possible to study
genotypeendophenotype correlations. If a gene is involved
in bipolar illness, it should be possible to demonstrate the
effect the disease allele has on, for example, P300 deficits
and white-matter hyperintensities. Given the likelihood of
relatively modest effects for bipolar susceptibility alleles, a
conclusive case for the involvement of an implicated gene
may require demonstration of a pathogenic pathway.
GeneEnvironment Interactions
Once bipolar genes have been discovered, researchers will
want to know whether the illness occurs more often when
people carrying the susceptibility allele are exposed to particular factors or experiences. A number of environmental
exposures that have been suggested as causative factors in
manic-depressive illness, whether bipolar or recurrent depressive, such as loss of a parent at an early age or obstetrical complications, could be assessed to determine whether
they increase the risk of illness in conjunction with the risk
genotype. For example, the interaction between the short
variant of the serotonin transporter promoter polymorphism and stressful life events may play a role in the predisposition to major depressive episodes (Caspi et al., 2003).
457
Gene Therapy
Even variations on gene therapy, where the aim is to modify
gene function directly, could be conceived. The gene itself
could be directly targeted by gene augmentation therapy if
loss of function of a gene were the problem, with extra
copies of the normal gene being introduced. Alternatively,
targeted inhibition of gene expression could be employed
if there were a novel gene product or inappropriate expression of a gene; this could be accomplished using antisense
therapeutics, whereby gene-specific antisense sequences
block the effects of a given susceptibility gene. The desirability of such an intervention is less than clear when a
susceptibility gene rather than a causative gene is at issue, however, because a susceptibility gene may have important positive as well as negative effects (see the section
below on pitfalls).
Diagnosis
There are currently no laboratory methods for diagnosing
bipolar or recurrent unipolar disorder; rather, these diagnoses rest solely on clinical data. Identification of a causative
gene could clarify the diagnostic process by providing physical evidence of the disorder (though see the discussion of
pitfalls for a cautionary note). Presymptomatic diagnosis
may also become possible and could lead to preventive
treatments. Greater precision in prognosis may come
from genotypephenotype correlations, whereby particular symptom clusters and natural course are found to be
associated with specific gene variants. This could be especially helpful in sharpening the definitions within the
broad category of recurrent unipolar, which in DSM-IV
can range from two episodes in a lifetime to highly cyclic
cases with as many lifetime episodes as are typically seen in
untreated bipolar disorder.
Prevention
The role of life events and other environmental factors in the
causation of bipolar or early-onset recurrent unipolar disorder may be defined more clearly by epidemiologic studies
when groups homogeneous for the presence of a bipolar or
recurrent unipolar susceptibility gene can be ascertained.
458
Pathophysiology
Preventive efforts targeted at reducing these factors in vulnerable individuals would logically follow. This has been
done most effectively for phenylketonuria, a rare genetic
disease in which failure to metabolize dietary phenylalanine
leads to severe mental retardation. This devastating outcome is now largely prevented through identification of
newborns with the mutation and the implementation of a
phenylalanine-restricted (and tyrosine-supplemented) diet.
Stigma
Finding a gene for manic-depressive illness would accelerate efforts at destigmatizing the condition by establishing
it even more firmly as a disease rather than a frightening
mystery or a weakness of character. It may also be possible
to define a relationship between disease-promoting gene
variants and adaptive psychological functions, such as
creativity (Jamison, 1993), which would further destigmatize the disorder by illuminating positive aspects of the
genetic endowment.
Pitfalls
Though the promise of genetics is great, expectations have
far outpaced actual progress in the minds of some. Study
participants sometimes ask when they will get back their
results because of the mistaken belief that genetic testing
for manic-depressive illness (especially bipolar disorder) is
already available. Not only is such testing currently unavailable, but it is also not clear that a useful genetic test
will emerge even when a bipolar gene is found. Because
risk alleles for the disorder may elevate risk only to a relatively small degree, they may prove to be of questionable
predictive value. The APOE4 allele of the APOE gene,
which confers increased risk for Alzheimers disease, provides an illustrative example. The risk of Alzheimers across
the population is 9 percent. Having a copy of the APOE4 allele increases the lifetime risk to 17 percent. It is difficult to
know whether this information would be useful to people.
Indeed, experts have generally recommended against performing diagnostic genetic tests for this gene (Liddell et al.,
2001). On the other hand, a study of three susceptibility
genes for deep venous thrombosis showed that, while having a single disease gene variant increased the disease risk
to only a minor degree, having disease variants in all three
genes led to an eight-fold increase in risk (Yang et al., 2003).
Similarly with bipolar disorder, diagnostic and predictive
testing may become valuable after several disease genes
have been identified.
Another area of concern is the possibility of unintended
consequences of obtaining genetic information about
manic-depressive illness. At the beginning of this chapter,
the misuse of genetics in the form of the eugenics movement, and eventually in the form of the mass murder of
While we can envision a time when we may have a comprehensive understanding of manic-depressive illness genes,
their interactions, their role in the brain, and their role in
behavior, as well as a full understanding of the technical
requirements for adroitly manipulating the germ line, that
time is a very long way off.
CONCLUSIONS
Genetic Epidemiology of Manic-Depressive Illness
For the bipolar subgroup, the risk of illness in a first-degree
relative of an ill person is roughly 10 times the risk in a
random person. The risk of having the illness if an identical twin has it is about 63 percent. The calculated heritability for bipolar disorder from twin studies is about .78. For
major depression, the risk to first-degree relatives of depressed probands is about three times higher than the
overall population risk. The risk in identical twins of depressed probands is about 34 percent, and the calculated
Genetics
459
460
Pathophysiology
six bipolar samples, and for being the only replicated positional candidate finding in bipolar studies. The second use
of association studies is for the narrowing of linkage regions through linkage disequilibrium mapping. This approach was taken using a population isolate with linkage
to 18p11.3, and the result was to narrow the region of interest to 19,000 bases, a stretch containing just two genes.
Genetics
461
NOTES
1. Only studies that employed direct interviews of the majority
of relatives are included here.
2. The 12 studies are those in the bipolar and BP-I sections of
Table 132, with the exception of Heun and Maier because
that study used the same sample as Maier et al.
3. This calculation incorporates data from both the bipolar
proband studies and the BP-I proband studies. Heun and
Maier is not counted since the subjects in this study are accounted for by the Maier et al. study.
4. One criticism of twin studies is that the equal-environment
assumption is not necessarily true; rather, MZ twins are
more likely to seek out similar environments or be treated
more similarly by people in the environment than are DZ
twins. The validity of the assumption has been tested in several ways. For example, some studies have refuted this criticism (Kendler et al., 1993c; Hettema et al., 1995; Xian et al.,
2000) by failing to find differences in phenotypic similarity
for psychiatric disorders based on perceived versus actual
zygosity. A more direct approach to the question is that
taken by Lytton and colleagues (1977), who observed young
twins and their parents. They found that parents did respond more similarly to MZ than to DZ twins, but that this
difference was in reaction to the behavior exhibited by the
twins.
5. Only studies that employed direct interviews of the majority
of relatives are included here.
6. Another important aspect of heritability is that it is not expected to be a constant figure, but to be population and environment dependent. Kendler (2001) summarized 10 studies
of behavioral traits that demonstrate changing heritability
over time. For example, Heath and colleagues (1985) showed
that in Norway, heritability of educational attainment was
about 40 percent for men born before World War II and
about 70 percent for men born after. This result is thought to
be due to increased equality of educational opportunity after
the war, leading to a more merit-based system in which the
innate potential of individuals could be expressed more fully
(Heath et al., 1985).
7. As of this writing, the best-known of these websites are those
of the National Center for Biotechnoloy Information (NCBI)
(http://www.ncbi.nlm.nih.gov/), the University of California
at Santa Cruz (UCSC) (http://www.genome.uscs.edu/), and
Celera (proprietary).
8. An earlier study, from an Icelandic and English group, was
the first to use repeat-length polymorphisms to test linkage
in manic-depressive illness, employing markers derived from
larger repeats, called minisatellites (Hodgkinson et al., 1987a).
9. A well-known example of the problems inherent in the approach is the case of the chromosome 11p linkage finding by
Egeland and colleagues (1987), who originally reported an
impressive LOD score of 4.08 at a DNA marker in a single
large Amish family from southeastern Pennsylvania. However, restudy of the same family provided evidence against
the linkage, with the LOD score dropping to 9.31. In the
later reanalysis, additional subjects were included, and the
diagnosis of some of the original subjects changed from unaffected to affected (Kelsoe et al., 1989). This reevaluation led
to recognition of several pitfalls in the traditional linkage
methods, including the precariousness of using unaffected
462
10.
11.
12.
13.
Pathophysiology
family members in an analysis, and contributed to a shift toward a different analytic approach.
Reich et al., 1969; Mendlewicz et al., 1972, 1979, 1980; Baron
et al., 1987, 1993.
The complex phenotype of nonsyndromic hearing loss
deafness without nonauditory symptomsprovides a dramatic example of genetic heterogeneity: 12 different genes have
been identified that each can cause the disorder independently,
with more likely to follow (Griffith and Friedman, 1999).
This appears to be the case, for example, with Hirschsprungs
disease; in this case, the gene EDNRB, encoding a G proteincoupled receptor, and the gene RET, encoding a receptor tyrosine kinase, may interact to contribute to disease susceptibility (Carrasquillo et al., 2002).
Suicide in people with manic-depressive illness has been
studied as an alternative phenotype, and a genetic component
14.
15.
16.
17.
18.
19.
14
Neurobiology
The madness results from an aberrant biochemical process. . . . With all of this upheaval in the
brain tissues, the alternating drenching and deprivation, it is no wonder that the mind begins
to feel aggrieved, stricken, and the muddied thought processes register the distress of an organ
in convulsion.
William Styron (1990, p. 47)
464
Pathophysiology
Neurobiology
n,
io
at
Cognitive
Affective
Sensorymotor
Behavior
rs iv
to epr
c
a d
lF p )
ta lee ids s
n
e , s ro e
nm ors l ste Gen
o
s
vir es da ng ting
En str ona ifyi rin
ng g od Imp
di
M
Systems
clu
(in
465
Synaptic connectivity
Neuroplasticity
Cytoskeletal
remodeling
Cell growth/survival
Critical
neuronal circuitry
Cellular
Molecular
Susceptibility genes
Protective genes
Transcription factors
mRNA stability
Nuclear import/export
Transcriptome
Figure 141. For a complete understanding of the pathophysiology of bipolar disorder, its neurobiology
must be addressed at different physiologic levels (i.e., molecular, cellular, systems, and behavioral levels).
Bcl-2 = B-cell leukemia/lymphoma; BDNF = brain-derived neurotrophic factor; CREB= cAMP response element binding protein; ERK = extracellular receptor-coupled kinase; GSK-3 = glycogen synthase kinase-3;
MAP kinase = mitogen-activated protein kinase; MARCKS = myristoylated alanine-rich C kinase substrate;
PKC = protein kinase C; proteome = the population of cellular protein species and their expression level;
transcriptome = the population of cellular messenger RNA species and their expression level. (Source: Manji
and Lenox, 2000a. Reprinted with permission from Elsevier.)
As discussed in Chapter 13, it is clear that manic-depressive illness arises from the interaction of multiple susceptibility (and likely risk) genes. These genes (and the proteins
for which they code) are undoubtedly related much more
closely to specific biochemical processes and thus specific
symptoms than to bipolar disorder or recurrent depression as defined by the Diagnostic and Statistical Manual, 4th
edition (DSM-IV) (Manji et al., 2003a).
One strategy that may have considerable utility in elucidating the complex neurobiology of the bipolar form of the
illness is an endophenotype-based approach (Lenox et al.,
2002; Gottesman and Gould, 2003; Manji et al., 2003a; Hasler
et al., 2006). Such an approach may allow for the enrichment of study populations based on pathophysiological
considerations, and may ultimately lead to a greater understanding of the illness. It is our strong belief that conceptualizing the disorder through an endophenotypic approach
will also enable a more biologically relevant classification of
patients along dimensional properties of the disorder, rather
than the traditional categorical classifications imposed by
our diagnostic manuals and reimbursement systems.
Additional major problems in the interpretation of biological data are associated with the diagnostic specificity of
patient populations and the lack of comparability of patient states across studies even in those who truly have the
same diagnosis. Are they studied at the same point in their
recurrent illness? Are the effects primary to the illness, or
do they represent the individuals compensatory adaptations to the illness? How long have patients been drugfree? It is now clear, for instance, that withdrawal from
the high therapeutic doses of antidepressants currently
employed produces biochemical changes that persist for at
least 3 and up to 8 weeks following discontinuation. For
more than a decade, the bulk of psychiatric patients available for biochemical studies have been those recently or
currently on medication at the beginning of an investigation. None of the studies reported here, for example, specify a minimum withdrawal over 3 weeks, and most involve
only a 1- to 2-week drug-free period. Indeed, as we discuss
later, it is quite likely that medication has major effects on
brain structure as well, calling into question many of the
volumetric brain imaging studies conducted without regard to medication status. Indeed, there are only a few studies in which a parameter is followed longitudinally over different states in one or two untreated subjects. From a
research point of view, such studies are particularly valuable,
466
Pathophysiology
Neurobiology
models can then be used to study the biological mechanisms underlying those symptoms and to develop new
treatments that alleviate the symptoms. The main limitation of these models is that they may poorly reflect mechanisms involved in the human situation. Thus the biological
basis of the animal symptoms may be different from that of
human symptoms, and drugs that treat the former may
not treat the latter. Another approach is to simply develop
models that can be used to screen for new treatments. Such
models may not have face validity for the human disease,
but this does not matter as long as the models have predictive
value for identifying new treatment agents. Several such
screening tests are available, as outlined below, but the value
of these tests in identifying treatments with novel mechanisms of action will remain unknown until such treatments
are identified (Einat et al., 2002b; Nestler et al., 2002b).
Models of Depression
It should be noted at the outset that, while many of the depression models do show construct, face, or predictive
validity for depression, none model recurrence. The only
paradigms that models recurrence, at least to some extent,
are the kindling models discussed later and circadian/ultraradian rhythm models discussed in Chapter 16.
467
response more analogous to the anaclitic depression observed by Spitz (1946) among newborn human infants suffering from maternal deprivation. Aware of these limitations, some investigators of primates have attempted to
model depression using juvenile monkeys separated from
their peer groups (Kraemer et al., 1984). Of course, one of
the fundamental realities of depressive illness is that it clusters in genetically predisposed individuals. Thus, the observation of considerable individual variability in the development of despair behavior among rhesus monkeys is
of special importance and has prompted cross-fostering
studies, which are beginning to tease apart environmental
and genetic factors in individual vulnerability to separation (Mineka and Suomi, 1978; McKinney, 1988).
Several rodent models involving manipulation of early
life environment have also been used, including prenatal
stress, early postnatal handling, and maternal separation
(Meaney et al., 1994; Caldji et al., 2000; Ladd et al., 2000).
Environmental enrichment has been used as a reciprocal
stimulus. In some of these models, early life stress produces neuroendocrine and behavioral changes in rats and
mice that persist into adulthood. For example, animals
subjected to early stress show a hyperactive hypothalamic
pituitaryadrenal (HPA) axis, as indicated by elevated
corticotropin-releasing factor (CRF) and glucocorticoid
levels in response to stress. They also exhibit increased locomotor responses to novelty and, in some studies, greater
vulnerability to learned helplessness (see below) and drug
self-administration.
Overall, separation models of depression are generally
good in terms of their replicability, and have been used
successfully with a variety of species, from rodent to nonhuman primate. In addition, many of the resulting abnormalities can be reversed by antidepressant treatment, although negative reports have also appeared.
468
Pathophysiology
Neurobiology
Hyperactivity Models
Because models for major depression are relatively available, there have been more attempts to develop valid animal models for the manic state that is a unique feature of
bipolar disorder. Since hyperactivity is one of the simpler
behaviors to detect, monitor, and quantify, a number of
models for mania have focused on this aspect of the disorder. Some of these models are reviewed by Einat and colleagues (2000, 2002b) and are briefly described here.
Psychostimulant-Induced Hyperactivity
Acute treatment with appropriate doses of psychostimulants
can produce a range of mania-like behaviors, including hyperactivity, heightened sensory awareness, alertness, insomnia, and changes in sleep patterns (Gessa et al., 1995; Einat
et al., 2000). The hyperactivity induced by psychostimulants
can be easily detected (Antoniou et al., 1998) and is sensitive
to lithium treatment1 and possibly to anticonvulsant mood
stabilizers (Kuruvilla and Uretsky, 1981; Maitre et al., 1984;
Maj et al., 1985). Yet the sensitivity of this model to mood stabilizers is not universal; rather, it is dependent on the mode
of administration or the specific type of activity measured
(see Einat et al., 2000, 2002a).
Sleep Deprivation
Sleep deprivation has a rapid therapeutic effect in both
unipolar and bipolar depression (see Post et al., 1987; Szuba
469
et al., 1994; Barbini et al., 1998; see also Chapters 16 and 19),
which can be maintained by treatment with lithium or antidepressant drugs (Szuba et al., 1994). At the same time,
sleep deprivation can induce manic episodes in euthymic
bipolar patients and has been suggested as a final common
pathway in the genesis of mania (Wehr et al., 1987).
With the clinical phenomenon in mind, Gessa and colleagues attempted to examine the effects of sleep deprivation in animals. In their studies, they demonstrated that rats
exposed to 72 hours of sleep deprivation exhibit a variety
of behaviors that have face validity for modeling a manic
episode. These behaviors include insomnia (for about 30
minutes, after rats are permitted to sleep), hyperactivity,
irritability (Albert et al., 1970; Fratta et al., 1987; Gessa et al.,
1995), aggressive behavior (Hicks et al., 1979), and hypersexuality (Morden et al., 1968). Furthermore, Gessa and colleagues (1995) demonstrated that lithium treatment alleviates
the insomnia and hyperactivity elements of the behavior,
thereby adding predictive validity to the face validity of the
proposed model.
Gessa and colleagues (1995) suggest that sleep deprivation in the rat may be a valid model for mania and that this
model can offer new directions for the study of the pathological mechanism of the disorder. They attempted to study
the brain mechanisms underlying these manic-like behaviors. Their findings indicate that treatment with the
dopaminergic D2 antagonist haloperidol or with the dopamine D1 receptor antagonist SCH 23390 significantly reduces the sleep latency (time to the onset of sleep after
sleep deprivation) in the model (Fratta et al., 1987), whereas
treatment with the dopamine D1 agonist SKF 38393 prolongs the period of insomnia (Gessa et al., 1995). Interestingly, the dopamine D2/D3 agonist quinpirole produces
a biphasic effect in small doses, possibly acting presynaptically (Eilam and Szechtman, 1990) to reduce sleep latency,
whereas at higher doses, acting postsynaptically, it was
shown to prolong sleep latency (Gessa et al., 1995). Furthermore, naloxone (an opioid antagonist) reduces sleep latency, whereas morphine, beta-endorphin, and [D-Ala2,
D-Leu5] enkephalin prolong the period of insomnia (Fratta
et al., 1987). Neurochemical studies of this model demonstrated that sleep deprivation induces only small effects related to adrenergic or serotonergic receptors (Siegel and
Rogawski, 1988) but has stronger effects on the dopaminergic (DeMontis et al., 1990) and opioid (Fadda et al., 1991,
1992) systems in the brain (Gessa et al., 1995).
Recent molecular and cellular biology studies have renewed interest in sleep deprivation as a possible model.
Thus there is now incontrovertible evidence that the expression of selected critical genes varies dramatically during sleep and waking events, a variation that likely plays
a major role in regulating various long-term neuroplastic
470
Pathophysiology
events. Messenger ribonucleic acid (mRNA) differential display, microarray, and biochemical studies have shown that
short-term sleep deprivation (short-term sleep deprivation has no clear definition regarding number of hours)
is associated with a rapid increase in various plasticityrelated genes. Notably, these are precisely the plasticityrelated molecules whose expression is increased by chronic
antidepressant treatment.
In an extension of the gene expression studies, Cirelli
and colleagues (Cirelli and Tononi, 2000; Cirelli et al.,
2002) hypothesize that a key factor responsible for the induction of the plasticity genes may be the level of activity
of the neuromodulatory noradrenergic and serotonergic
systems. Both of these systems project diffusely to most
of the brain, where they regulate gene expression, and are
quiescent only during REM sleep (Cirelli et al., 2002). Thus
sleep deprivation may be capable of rapidly activating antidepressant/mania-inducing genes (Payne et al., 2002),
and despite the technical difficulties inherent in establishing this model, it is clearly worthy of further study.
Neurobiology
471
manic-depressive patients, have helped clarify the mechanisms underlying the accelerating longitudinal course of the
illness, especially in its bipolar form. Thus when one reviews
the parallels between the two models and bipolar disorder,
the following features are notable:
For each model, evidence exists for the predisposing
effects of both genetic factors and early environmental
stress.
These models show threshold effects (mild alterations
eventuating in full-blown episodes).
Each model can show similarity of episodes through
repeated occurrences.
With each model, a maximum disturbance occurs earlier
in the episode as the number of recurrences increases.
In both models, early episodes may require precipitants,
whereas later ones can occur spontaneously.
With each model, repeated episodes of one phase may
lead to emergence of the opposite phase.
Younger animals appear to be more vulnerable to sensitization and kindling, a finding suggesting a parallel with
the young age of onset of bipolar disorder.
As we discuss later, a growing body of data has shown
that both psychostimulant sensitization and kindling are
associated with activation of the protein kinase C (PKC)
signaling cascade, a pathway whose activity is inhibited
by mood stabilizers.
Thus, these models serve to broaden the conceptual
framework for linking clinical phenomenology to neurobiological mechanisms. The average pattern of cycle acceleration over time could reflect a mix of patients with a variety of patterns. Some might accelerate dramatically over
time, whereas others might do so moderately or not at all.
In patients having a dramatically shorter cycle with each
episode, the form of the illness may be analogous to the pattern of increasingly rapid onset of hyperactivity and stereotypy following repeated administration of a psychomotor
stimulant. The role of environmental stress in enhancing
behavioral sensitization may resemble its postulated role in
the onset of affective episodes. These findings may help
integrate psychosocial and neurobiological perspectives.
Specifically, if one postulates that a psychosocial stress can
precipitate manic or depressive episodes, the sensitization
and kindling models would suggest that, after a certain
amount of repetition, the episodes will develop spontaneously (see Chapter 4). This chain of events fits the clinical histories of many patients with bipolar disorder, in
which clear-cut psychosocial or physical stresses are associated with the onset of early episodes, but in time the
episodes become more autonomous. By the time patients
are seen in treatment settings, they may indeed have an
autonomous illness.
472
Pathophysiology
As Post and Weiss (1989) point out, however, sensitization and kindling phenomena in animals do not yet represent precise models of human cyclic mood disorders. In
addition to the respective time frames being quite different, the models imply a close similarity between stressprecipitated and pharmacological-induced events, a similarity that needs to be demonstrated experimentally.
Extreme Sensitization. An extension of the psychostimulant sensitization model was recently suggested by Antelman and colleagues (Antelman et al., 1995; Antelman and
Caggiula, 1996; Caggiula et al., 1998), who demonstrated
that when animals reach a level of extreme sensitization
to cocaine, some of their behavioral and biochemical responses begin to oscillate. The oscillations can be detected
in some measuressuch as the efflux of striatal and nucleus accumbens dopamine, hippocampal serotonin, and
plasma levels of corticosterone and glucoseand in one
behavioral measureshock-induced hypoalgesia. Moreover, both biochemical and behavioral oscillations are completely prevented by chronic lithium pretreatment, adding
predictive validity to the model (Antelman et al., 1998).
The extreme sensitization model appears to have more
similarities with bipolar disorder than is the case for other
models because it incorporates features of progressive and
oscillating responses. Moreover, a recent study demonstrates
that the behavioral response can be conditioned (Kucinski
et al., 1999); that is, the behavior can be influenced by the
environment, just as a manic or depressive episode can be
triggered or precipitated by the environment. However, the
measures used in the model are far removed from changes
observed in bipolar patients, whereas other measurable
changes induced by extreme sensitization, such as hyperactivity and reward-related behaviors, that are more homologous with human behavior and appear to model mania do
not show cyclicity. These latter behaviors are not easily normalized by mood stabilizers. Moreover, the cycling measures
were normalized by lithium, but further validation will require additional studies testing the effects of other mood
stabilizers as well as other psychiatric drugs. Still, the notion
of a cycling phenomenon is important, and additional study
of this model might be useful.
A different derivative of the psychostimulant-induced
models focusing on the response to the direct D2/D3 agonist
quinpirole has been studied. Unlike other dopamine agonists, quinpirole (in appropriate doses) induces a biphasic
response over time, starting with hypolocomotion and developing into a hyperlocomotion state (Eilam and Szechtman, 1989). This biphasic response can have face validity as
a model for the two states of bipolar disorderdepression
and mania. To assess this possibility, researchers examined
the effects of mood stabilizers on the biphasic response.
Conclusions
If animal models are to realize their promise, they must
incorporate certain cardinal features of recurrent mood
disorders, especially the bipolar subgroup. The first is
spontaneous, progressive behavior that oscillates between
increased and decreased manifestations of the model behavior that is similar to the human phenotypic expression
of mania or depression (face validity). The model behavior
should also be normalized by chronic, but not acute, treatment with mood stabilizers such as lithium and several anticonvulsant drugs, but react in the manic-like direction
to treatment with antidepressants, psychostimulants, and
sleep deprivation (predictive validity). Finally, the models
should involve both genetic vulnerability and cyclicity.
Ideal animal models for bipolar disorder are not available, but a variety of behaviors in animals may represent
certain facets of the disease. Beyond the long-standing debate over the value of models that are not a comprehensive
reflection of a disorder, or its underlying pathophysiology
(Kilts, 2001; Machado-Vieira et al., 2004), it is accepted that
partial models are helpful (McKinney 2001). Furthermore,
there is a growing appreciation that bipolar disorder may
represent a heterogeneous group of disorders that may be
more amenable to study with an endophenotypic approach
(Lenox et al. 2002; Hasler et al., 2006; discussed in greater
detail later in this chapter). Accordingly, changes in behavior that are related to any facet of the depressionmania
continuum may be relevant as models of these components
of bipolar disorder. Behavioral tests for many such components are available and used in different contexts. Animals
are tested for activity, response to drugs, hedonistic properties, resilience and despair, anxiety and risk-taking behaviors, judgment, sexual behavior, distractibility, sleep patterns, and more, all behaviors that may be relevant to bipolar
disorder. Not all these models may be valid for components
of bipolar disorder, and the process of validating models requires significant work (Willner, 1991; Einat et al., 2003a).
However, experimentation done in different contexts may
still help gain insight into possible mechanisms involved
in bipolar disorder.
An increasing number of methodologies are now available that allow for the targeted manipulation of a specific
gene (and protein) in a precise temporal and spatial (brain
regionspecific) manner. These evolving methodologies
represent a new horizon for modeling the disorder, as it is
now possible to attempt and create models that are hypothesis driven and have a sound theoretical base, rather
Neurobiology
473
MAJOR NEUROTRANSMITTER
AND NEUROPEPTIDE SYSTEMS
IN MANIC-DEPRESSIVE ILLNESS
The impetus for the study of the biogenic amines in patients with manic-depressive illness was provided largely
by the discovery of effective pharmacologic treatments for
depression and mania. These treatments led to the formulation of the so-called pharmacological bridge between depressive illness and neurotransmitter systems in the brain.
Unfortunately, as a rule, the studies of neurotransmitters
and neuropeptides in depressed patients have not separately
analyzed those patients with the more recurrent forms, that
is, those who are a part of the manic-depressive spectrum.
An initial foundation for this pharmacological bridge was
formed by the following observations:
Reserpinean antihypertensive later shown to deplete
amine transmitters in rodentsis associated with an
unexpectedly high incidence of depression.
Effective antidepressant drugs increase intrasynaptic
concentrations of serotonin and norepinephrine.
Antihypertensives that deplete these monoamines sometimes precipitate depressive episodes in susceptible individuals.
Psychostimulants and dopamine agonists are capable of
triggering manic episodes in susceptible individuals.
Cholinomimetics (e.g., intravenous physostigmine, a central cholinesterase inhibitor) briefly but dramatically reduce symptoms in manic patients and precipitate depression in euthymic bipolar patients maintained on lithium.
Even more striking pharmacological findings go beyond
effects on a single episode of depression or mania to indicate the effects of drugs on the long-term course of manicdepressive illness, particularly the bipolar subgroup. As
discussed in Chapter 19, antidepressants in general and tricyclics in particular may increase the frequency of cycles
and worsen long-term outcome. Finally, the monoaminergic systems are extensively distributed throughout the network of limbic, striatal, and prefrontal cortical neuronal
circuits thought to support the behavioral and visceral
manifestations of mood disorders.
Given these compelling pharmacological data, it is
not surprising that investigators have postulated that
The noradrenergic system was one of the first neurotransmitter systems examined in studying the pathophysiology
of affective disorders. Early theories of depression postulated that an imbalance in the metabolism of norepinephrine (NE) was responsible for mood disorders (Bunney
and Davis, 1965; Schildkraut, 1965). This postulate has been
extensively investigated but has proven difficult to study
experimentally, in part because of the formidable methodological difficulties involved in assessing central nervous
system (CNS) noradrenergic function in humans. Here we
briefly review, critically appraise, and integrate the research
findings to date on NE in manic-depressive illness, with
a focus on the bipolar subgroup. (See Figure 142 for a
depiction of the regulatory processes involved in NE neurotransmission.)
474
Pathophysiology
Cingulate
gyrus
Thalamus
Cingulum
Striatum
To
Hippocampus
Neocortex
Tyrosine
B
AMPT
TH
VMAT
DOPA
AADC
DA
DBH
Tranylcypromine
Hypothalamus
Amygdala
Hippocampus
Lateral tegmental
NA cell system
Cerebellar
cortex
Clonidine
Yohimbine
Idazoxan
%2A/D
Reserpine
Locus
coeruleus
Amphetamine
Spinal
cord
Prazosin
,D
,B
% 1A
MHPG
NE
G%
PLC
Propanolol
Desipramine
Reboxetine
NET
MHPG Tropolone
NM
MAO
COMT
Go
# 1,2
Gs
AC
,C
% 2A/D,B
Gi
()
(+)
cAMP
IP3, DAG, Ca2+
Cellular responses
Figure 142. A: Gross anatomical relationships. B: The various regulatory processes involved in norepinephrine neurotransmission. The
amino acid L-tyrosine is actively transported into presynaptic norepinephrine (NE) nerve terminals, where it is ultimately converted into NE.
The rate-limiting step is conversion of L-tyrosine to L-dihydroxyphenyalanine (L-DOPA) by the enzyme tyrosine hydroxylase (TH). AMPT
(-methyl-para-tyrosine) is a competitive inhibitor of TH and has been used to assess the impact of reduced catecholaminergic function in
clinical studies. Aromatic amino acid decarboxylase (AADC) converts DOPA to DA. DOPA then becomes decarboxylated by decarboxylase to
form dopamine (DA). DA is then taken up from the cytoplasm into vesicles, by vesicular monoamine transporters (VMATs) and hydroxylated
by DA-hydroxylase (DBH) in the presence of O2 and ascorbate to form NE. Normetanephrine (NM) is formed by the action of catecholO-methyltransferase (COMT) on NE. NE can be further metabolized by monoamine oxidase (MAO) and aldehyde reductase to 3-methoxy-4hydroxyphenylglycol (MHPG). Reserpine causes a depletion of NE in vesicles by interfering with uptake and storage mechanisms (depressivelike symptoms have been reported with this agent). Once released from the presynaptic terminal, NE can interact with a variety of presynaptic
and postsynaptic receptors. Presynaptic regulation of NE neuron firing activity and release occurs through somatodendritic (not shown) and
nerve terminal 2-adrenoceptors, respectively. Yohimbine potentiates NE neuronal firing and NE release by blocking these 2-adrenoceptors,
thereby disinhibiting these neurons from a negative feedback influence. Conversely, clonidine attenuates NE neuron firing and release by activating these receptors. Idazoxan is a relatively selective 2-adrenoceptor antagonist primarily used for pharmacologic purposes. The binding
of NE to G proteincoupled receptors, which are coupled to adenylyl cyclase (AC) and phospholipase C beta (PLC- produces a cascade of
second messenger and cellular effects (see diagram). NEs action is terminated in the synapse by rapidly being taken back into the presynaptic
neuron through NE transporters (NET). Once inside the neuron it can either be repackaged into vesicles for reuse or it undergoes enzymatic
degradation. The selective NE reuptake inhibitor and antidepressant reboxetine and older-generation tricyclic antidepressant desipramine are
able to interfere with or block the reuptake of NE. Amphetamine is able to facilitate NE release by altering NET function. Note: Grey
spheres = DA neurotransmitters; blue spheres = NE neurotransmitters. DAG = diacylglycerol; IP3 = inositol (1,4,5) trisphosphate. (Source:
Schatzberg and Nemeroff, 2004. Reprinted with permission from The American Journal of Psychiatry. Copyright 2004 by the American
Psychiatric Association.)
Neurobiology
475
Goldstein et al., 1987). In the relatively narrow range of values observed in depressed patients and controls, however,
such an equation is of questionable utility for identifying
brain MHPG (Linnoila et al., 1986), and to date has not
provided new insights in studies of depression.
Certain other methodological problems are unique to
CSF measures. First, standards for obtaining spinal fluid,
such as elapsed time between needle insertion and sample
collection, have not been established. Therefore, subjects
may not have the same degree of accommodation to the
stress of the needle stick. Moreover, sampling at a single
point in time may not reflect the biochemical process of depression or mania, but a state-dependent fluctuation from
a recent external or internal stress.
CSF concentrations of NE have been reported to be elevated in depressed patients with an atypical presentation,
higher scores for nurse-rated anxiety, and a longer duration
of hospitalization (Post et al., 1984b). Earlier investigations
showed that CSF NE is higher in mania than in depression
(Post et al., 1978; Gerner et al., 1984). Moreover, in dysphoric
mania, defined by the coexistence of high depression ratings, NE in CSF correlates modestly but significantly (r .5)
with ratings for dysphoria and anxiety but not with ratings
for mania (Post et al., 1989). Post and colleagues suggest that
CSF NE may be positively correlated with the degree of
anxiety across a variety of psychopathologic syndromes,
including depression, mania, and perhaps anxiety.
Reports suggest that CSF MHPG is lower in bipolar-I
depressed patients than in unipolar patients, but as is the
case for CSF NE, variables other than overall diagnosis
may influence values (Potter et al., 1987). Thus, for instance,
within a group of depressed patients, those with increased
anxiety, agitation, somatization, and sleep disturbance were
found to have significantly elevated levels of CSF MHPG
(Redmond et al., 1986). CSF MHPG has been reported to
be elevated in manic patients compared with controls (Post
et al., 1984b; Redmond et al., 1986; Swann et al., 1986). In
one study of mania, CSF MHPG concentration correlated
with certain dysphoric elements of the manic syndrome
namely total manic severity and hostility (Swann et al.,
1987). Moreover, this study found a significant reduction
in CSF MHPG with lithium treatment, even when the treatment was unsuccessful.
Swann and colleagues have conducted the most comprehensive studies of catecholamine function in mania since
publication of the first edition of this text. When they compared biogenic amines in mixed manic (n = 8) and in pure
and nonagitated bipolar depressed (n = 27) inpatients, they
found that MHPG was higher in CSF from mixed manic
than that from agitated depressed patients (Swann et al.,
1994). Moreover, patients in a mixed state had higher urinary excretion of NE and elevated output of NE relative to
476
Pathophysiology
its metabolites, suggesting that mixed manic patients combine certain biological abnormalities considered to be characteristic of both mania and depression.
More recently, the same group investigated relationships between performance on psychomotor tests of motor
speed (reaction time and tapping speed) and visual tracking (trail making and dot placement) and catecholamine
system function, including CSF or urinary concentrations
of catecholamines or their metabolites (Swann et al., 1999).
They found that both unipolar and bipolar depressed patients were impaired in motor speed, dexterity, and visual
tracking, whereas manic and mixed patients did not differ
from controls in these areas. Furthermore, increased catecholamine function correlated with slowing on all other
measures for patients with bipolar disorder; relationships
between catecholamines and psychomotor function were
weaker in unipolar depressed subjects, and psychomotor
function was related to severity of depression only in bipolar patients. These latter findings add to the data suggesting
that catecholamine systems are associated with increased
arousal and psychomotor impairment in patients with bipolar disorder (Goodwin and Ghaemi, 1998).
Taken together, findings from CSF studies of NE and
its metabolite MHPG suggest that NE output is higher in
mania than in depression and that there may be relatively
higher values in unipolar than in bipolar depression. Relative elevation within patient groups may, in turn, be related to anxiety or the overall severity of the condition. As
noted previously, it is possible that the CSF findings reflect
events occurring in the sympathetic nervous system as much
as those occurring in the brain. It is therefore not surprising that the pattern of findings is similar in CSF and plasma.
Nevertheless, in some studies, CSF NE or MHPG was found
to be correlated with dysphoric elements of the manic syndrome, while urinary measures tended to be associated with
euphoric components (Swann et al., 1986; Post et al., 1989),
suggesting that studies examining multiple measures and
components of the noradrenergic system allow for the most
meaningful interpretations.
[5-HIAA]/5-HT and homovanillic acid [HVA]/DA, respectively) were found to be significantly reduced in temporal
and occipital cortex, respectively. In an intriguing preliminary study, Baumann and colleagues (1999a) investigated a
possible unipolarbipolar dichotomy by performing a morphological comparison of the locus coeruleus (LC) obtained
postmortem. They found that bipolar patients (n = 6) had
significantly more neurons on both sides of the LC as
a whole than did patients with unipolar depression (n = 6).
Furthermore, topographical analysis revealed that this difference was restricted to the rostral two-thirds and the dorsal
portion of the LC, in which bipolar patients showed at least
a trend to higher neuron numbers than those of unipolar
patients or controls. However, as is characteristic of most
unipolarbipolar comparisons, the two groups were not
matched for frequency of recurrence, so that one cannot
know whether the differences reflect a difference in polarity
or cyclicity.
Neurobiology
populations taken as a whole; rather, there may be a subgroup of such patients who have elevated MHPG compared
with that of controls and bipolar subjects (Schatzberg et al.,
1982). Furthermore, pretreatment levels of urinary MHPG
have correlated with improvement in manic syndrome
scores (Swann et al., 1999). Consistent with an overall activation of the noradrenergic system during mania, manic
patients also exhibit significantly increased urinary concentrations of NE compared with those of depressed patients or
control subjects (Swann et al., 1987).
Low levels of urinary MHPG in depressed patients have
been reported to approach normal values with clinical
improvement, thus this measure may be state-dependent
(Pickar et al., 1978). Similarly, longitudinal studies of bipolar patients suggest increased MHPG excretion in manic
compared with depressed states (Post et al., 1984b; Potter
et al., 1987). It has also been noted that manic patients responding to lithium have decreased MHPG and increased
NE excretion relative to the total excretion of NE and its
metabolites, a finding suggesting that lithium response is
associated with an alteration of catecholamine metabolism
pathways (Swann et al., 1987). Overall, however, urinary
MHPG by itself has not proven to be a sufficiently robust
and consistent measure to warrant general acceptance as
a useful tool in diagnosis or in prediction of treatment response (Davis and Bresnahan, 1987).
Subsequent investigators have attempted to go beyond
the too little or too much hypotheses of affective disorders.
One approach has been to measure the 24-hour concentrations of urinary catecholamines and their metabolites in an
effort to identify possible abnormalities in the relative activity of NE metabolic pathways in depression and mania.
Since all major metabolites are measured, 24-hour urinary
measures of NE and its metabolites can account for differences among individuals in the relative metabolism of NE,
as well as its turnover (amount formed and excreted per 24
hours at steady state) (Manji and Lenox, 1994, 1998).
Consistent with the findings of elevated basal and/or
stress-induced plasma NE, several investigators have observed elevated urinary excretion of NE and its major extraneuronal metabolite, normetanephrine (NMN), in depressed patients (Roy et al., 1985, 1986, 1988; Maas et al., 1987;
Davis et al., 1988). Moreover, this finding appears more impressive when the excretion of NE and NMN in depressed
patients is examined relative to total NE excretion. Thus in
the study by Maas and colleagues (1987), a modest increase
in total urinary catecholamine excretion (16 percent) was
accompanied by marked increases in urinary NE (57 percent) and NMN (42 percent) in depressed patients. These
results suggest a shift toward extreneuronal metabolic pathways and are consistent with findings suggesting increased
NE release and spillover in depression.
477
478
Pathophysiology
Neurobiology
patients compared with that in healthy volunteers.7 The consistently observed decrease in leukocyte -adrenergic receptor function in depression could reflect an inherited abnormality of the -adrenergic receptor/(Gs)/AC complex, as
suggested by the findings of a study by Wright and colleagues (1984) using Epstein-Barr virus (EBV)-transformed
lymphocytes from manic-depressive patients and controls.
However, these findings need to be replicated and a number
of additional confounding factors considered (Werstiuk
et al., 1990; Manji et al., 1997a).
In another study, Kay and colleagues (1993, 1994) examined -adrenergic receptor binding and AC activity in lymphoblast cell lines established from 12 patients with bipolar
disorder and 10 unrelated healthy controls. The use of immortalized lymphoblasts offers the theoretical advantage of
being able to grow the cells for several months away from
the potentially confounding effects of circulating factors
(catecholamines, hormones, drugs); thus the cells are presumed to reflect closely the individuals genetic contribution to the receptor system in question. It should be noted,
however, that the immortalized cells are not normal, and
display a markedly altered -receptor density relative to
fresh, circulating lymphocytes. Nevertheless, unless the
immortalization process affects the patients lymphocytes
differently from those of the controls, the model can be used
to provide useful information. In Kay and colleagues study,
no significant differences were found in [125I] iodocyanopindolol binding affinity or capacity or in -adrenergic receptor agoniststimulated cyclic adenosine monophosphate
(cAMP) response. As expected, incubation of lymphoblasts
with a -adrenergic receptor for 24 hours prior to assay reduced both the number of receptors and adenylyl cyclase
activity. There was significantly less receptor downregulation in cells of bipolar patients, suggesting that agonist
downregulation of receptor number may be less efficient
than in control cells. Although these results are clearly quite
preliminary, they are intriguing because the inability to
downregulate receptors in the face of excessive stimulation
has been postulated as representing a fundamental defect in
bipolar disorder.
Initial measurements of these -adrenergic receptors
in postmorterm brain tissue from mood disorder patients
( individuals who committed suicide) have yielded mixed
results. Biegon and Israeli (1988) reported a significant, 50
percent increase in -adrenergic receptor density in prefrontal cortical homogenates in postmortem brain tissue
of suicide victims. They noted that the increased binding
was selective, appearing in some cortical regions but not in
basal ganglia or white matter areas. Mann and colleagues
also found increased -adrenergic receptor density in the
postmortem brain tissue of suicide victims (Arango et al.,
1990; Mann et al., 1986). However, Crow and colleagues
479
(1984) demonstrated decreased density of hippocampal adrenergic receptor in the postmortem brain tissue of depressed patients who had been hospitalized. In this latter
group, previous antidepressant treatment may have induced
-adrenergic receptor downregulation.
480
Pathophysiology
Maggi and Enna, 1980; Schultz et al., 1981). However, significant effects have been consistently observed on ARmediated cAMP accumulation, with lithium inhibiting the
response both in vivo and in vitro (discussed in detail below). Lithium is unable to block antidepressant-induced
-adrenergic receptor downregulation (Rosenblatt et al.,
1979) and in fact produces a greater subsensitivity (cAMP
response) (Mork et al., 1990), but it does prevent reserpine
or (6-OHDA)induced AR supersensitivity (Pert et al.,
1978; Treiser and Kellar, 1979; Hermoni et al., 1980).
Additional data from preclinical and clinical studies
suggest that lithium treatment results in subsensitive 2
receptors.10 In preclinical studies, long-term lithium was
found to attenuate 2-adrenergicmediated behavioral effects (G. Goodwin et al., 1986a; Smith, 1988) and presynaptic 2 inhibition of NE release (Moises et al., 1986), while enhancing (K+)-evoked NE release (Ebstein et al., 1983). While
lithium has been reported to reduce high-affinity platelet
[3H] clonidine binding (Wood and Coppen, 1983; GarciaSevilla et al., 1986b; Pandey et al., 1989), compatible with a
functional uncoupling of the receptor from the G protein
(Kim and Neubig, 1987; Neubig et al., 1988), interpretation
of these data is confounded by the coexistence of the imidazoline binding site discovered later.
In clinical investigations, both increases and decreases
in plasma and urinary NE metabolite levels have been reported after lithium treatment.11 Lithium has been reported
to reduce excretion of NE and metabolites in manic patients
while increasing excretion in depressed patients, associated
with higher plasma NE concentrations in some cases.12 As
discussed earlier, however, there is evidence that urinary
excretion of MHPG is low during bipolar depression and
elevated during mania/hypomania.13 In part, these inconsistencies may be related to the inability to control
adequately for state-dependent changes in affective states,
with associated changes in activity level, arousal, and sympathetic outflow. Subsequent studies have demonstrated
that 2 weeks of lithium administration in normal subjects
results in increases in urinary NE and NMN, fractional NE
release, and a trend toward significantly increased plasma
NE, suggesting an enhanced neuronal release of NE (Manji
et al., 1991a). These data are compatible with similar observation of increased levels of plasma dihydroxyphenylglycol
(DHPG), a major extraneuronal NE metabolite (PoirierLittre et al., 1993), raising the possibility that lithium may
regulate (TH) (discussed later).
Thus current evidence supports lithiums action in facilitating the release of NE, possibly through effects on the
presynaptic 2 autoreceptor and through upregulation of
TH, while concurrently reducing the -adrenergicstimulated AC response. This action may contribute to lithiums
attenuation of the euphorigenic effects of amphetamine.
Neurobiology
481
482
Pathophysiology
Plasma NE: Basal levels: BPd < N < UPd (for UPd, especially
melancholic, DST+ve)
BOX 143. Newer Studies Supporting Involvement of the Noradrenergic System in the Pathophysiology
and Treatment of Manic-Depressive Illness (Primarily Bipolar)
Genetic Studies
Other Findings
Different distribution of neurons in LC in bipolar patients
vs. unipolar patients vs. controls (Baumann et al., 1999a)
CSF
Plasma
Urinary
Treatment Related
Preclinical
484
Pathophysiology
BOX 143. Newer Studies Supporting Involvement of the Noradrenergic System in the Pathophysiology
and Treatment of Manic-Depressive Illness (Primarily Bipolar) (continued)
Idaxozan, an 2 antagonist, shown to have efficacy in treatment of BPD in small studies (Grossman and Potter, 1999)
Clonidine, an 2 agonist, shown to have efficacy in
treatment of acute mania in small studies (Bakchine
et al., 1989; Kontaxakis et al., 1989; Diacicov and
Tudorache, 1990;Tudorache and Diacicov 1991)
b-AR
AR = adrenoreceptor; BPD = bipolar disorder; BP-I = bipolar-I; CBZ = carbamazepine; COMT = catechol-O-methyltransferase; CSF = cerebrospinal fluid;
DA = dopamine; GH = growth hormone; LC = locus coeruleus; MHPG = s-methoxy-4-hydroxyphenylglycol; NE = norepinephrine; NMN = normetanephrine;
VMA = vanillylmandelic acid.
Neurobiology
485
486
Pathophysiology
et al., 1987) and in anergic bipolar depression (Himmelhoch et al., 1991; Thase et al., 1992), and phenelzine is superior in unipolar patients refractory to imipramine (McGrath
et al, 1993). An open-label study of high-dose tranylcypromine (average 120 mg/day) in 14 unipolar patients
with a clear history of nonresponse to at least two prior
medication treatments yielded an impressive 50 percent
complete response rate on the Hamilton Depression Rating Scale (HAM-D) (Amsterdam, 1991). The authors speculate that higher plasma concentrations of tranylcypromine
enhance the drugs sympathomimetic (amphetamine-like)
activity. In other words, at higher doses, one may actually recruit a pharmacodynamic effect of the drug beyond MAO
inhibition.
Identifying multiple specific effects in humans, however,
is not simple. Studies with DA reuptake inhibitors such as
nomifensine have shown clear antidepressant effects in major depression. Similarly, bromocriptine, a postsynaptic DA
receptor agonist, has been reported to have efficacy comparable with that of standard tricyclic antidepressants (Silverstone, 1984) and to be useful in antidepressant-resistant
depression (Inoue et al., 1996) and in relapses that occur
with selective serotonin reuptake inhibitor (SSRI) treatment (McGrath et al., 1995).
In a small pilot study of depressed patients, Schaefer
and colleagues (1996) found that 69 percent (9/13) of patients taking pramipexole (a D2/ D3 agonist) had a greater
than 30 percent reduction in (HAM-D) total scores relative to baseline scores. DeBattista and colleagues (2000)
reported the successful augmentation of an SSRI when
pramipexole was added in treatment-resistant major
depression. In a retrospective chart review, Sporn and
colleagues (2000) found that pramipexole (mean dose
.70 mg/day) was effective in 50 percent (6/12) of subjects
with bipolar depression and 40 percent (8/20) of subjects with unipolar depression. Lattanzi and colleagues
(2002) reported that pramipexole in the dose range of
.3751.0 mg/day was effective in treatment-resistant depression (14 unipolar, 17 bipolar patients) when used adjunctively with other antidepressants. Pramipexole was
also tested in a double-blind 8-week, placebo-controlled
study involving 174 subjects with unipolar depression
without psychotic features (Corrigan et al., 2000). In patients with bipolar depression, two double-blind, placebocontrolled trials found pramipexole to be superior to
placebo in the treatment of depressive symptoms (Goldberg et al. 2004; Zarate et al. 2004b,c). In the bipolar II depression study (Zarate et al. 2004b,c), 21 patients treated
with lithium or valproate were randomized to receive addon pramipexole 1.7 .9 mg/day (n = 10) or placebo (n = 11)
for 6 weeks. All subjects except for one in each group completed the study. At the endpoint, changes in both
Neurobiology
487
488
Pathophysiology
prefrontal cortex, effects also seen with clozapine. Moreover, increased prefrontal DA was completely abolished
by the selective 5-HT1A receptor antagonist N-[2-[4-(2methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635, .05 mg/kg).
To elucidate possible mechanisms underlying the effects of carbamazepine and valproate on neurotransmitter
exocytosis, the effects of these neuroleptic drugs and botulinum toxins (BoNTs) on basal, Ca2+- and K+-evoked release of DA and serotonin were determined by microdialysis in the hippocampus of freely moving rats (Murakami
et al., 2001). Perfusion with low and high concentrations of
carbamazepine and valproate increased and decreased basal
DA release, respectively. On the basis of additional studies,
these investigators postulated that carbamazepine and valproate affect both the enhancement of syntaxin-mediated
monoamine release during the resting stage and the inhibition of synaptobrevin-mediated release during the depolarizing stage.
In animal behavioral studies, valproate was found to attenuate the acute locomotor effects of methylphenidate
and, at higher doses, to block the development of sensitization to subsequent administration (Eckermann et al.,
2001). Chronic valproate pretreatment also produced a
borderline significant reduction in quinpirole-induced hyperactivity without effects on the hypoactive phase (Shaldubina et al., 2002).
dients
Antidepressant efficacy of agents whose biochemical effects
include increasing intrasynaptic dopamine
ECT consistently enhances DA function
Depressogenic effects of AMPT and reserpine in susceptible
individuals
Medications that block D2 receptors have antimanic efficacy
Lithium-treated euthymic bipolar patients show a rebound
hypomania following AMPT
Depression very common in Parkinsons disease
Prominent anhedonia, amotivation, and psychomotor retardation in bipolar depression
Critical role of DA in reward, motivation, and motoric circuits
primary abnormality in manic-depressive illness, and perhaps especially in its bipolar form, is a compromised ability
to regulate multiple signals (including those generated by
the dopaminergic system). Indeed, supporting this contention are recent data suggesting that bipolar disorder may
be associated with polymorphisms affecting the functioning
of the G proteincoupled receptor kinase 3 (GRK-3).
The GRKs are a family of proteins whose cellular function is to turn off or dampen the signal when receptors are
exposed to high levels of neurotransmitters. These proteins
are involved in rapidly phosphorylating receptors that are
overstimulated, thereby uncoupling the receptors from
their second messenger systems. Thus, a faulty desensitization system due to a mutation in GRK is of considerable interest with respect to the pathophysiology of bipolar disorder, as it would result in overshooting in response to
multiple neurotransmitter systems, thereby producing excessive excursions from the norm. These observations, if
replicated, would suggest that bipolar disorder is associated
with an abnormality of DA function, but is not due to defects in the dopaminergic system itself, rather in the machinery involved in dampening and fine-tuning dopaminergic signals. Boxes 144 and 145 summarize overall major
findings and findings of newer studies supporting the involvement of the dopaminergic system in the pathophysiology and treatment of bipolar disorder and recurrent unipolar depression.
BOX 145. Newer Studies Supporting Involvement of the Dopaminergic System in the Pathophysiology
and Treatment of Manic-Depressive Illness (Primarily Bipolar)
Genetic Studies
Receptors
Transporter
Enzymes
Other Observations
Treatment Related
Mood
stabilizers
490
Pathophysiology
BOX 145. Newer Studies Supporting Involvement of the Dopaminergic System in the Pathophysiology
and Treatment of Manic-Depressive Illness (Primarily Bipolar) (continued)
Antidepressants
Psychostimulants
BP = bipolar; BPD = bipolar disorder; BP-I = bipolar-I; COMT = catechol-O-methyltransferase; CSF = cerebrospinal fluid; DA = dopamine;
HVA = homovanillic acid; Li-lithium; LiCl = lithium chloride; MAO = monoamine oxidase; TH = tyrosine hydroxylase.
Neurobiology
491
492
Pathophysiology
Challenge Studies
Tryptophan Depletion Challenge Studies. Serotonin is
synthesized from tryptophan, an essential amino acid
derived from the diet. The rating-limiting step in serotonin
synthesis is the hydroxylation of tryptophan by the enzyme
tryptophan hydroxylase to form 5-hydroxytryptophan.
Under normal circumstances, this rating-limiting enzyme is
not saturated by substrate; thus, tryptophan concentration
can impact the rate of synthesis. Tryptophan is then taken
up into the brain via a saturable carrier mechanism.
Tryptophan actively competes with other large neutral
amino acids for transport, and brain uptake of tryptophan
is thus determined by both the amount of circulating
tryptophan and the ratio of tryptophan to the other large
neutral amino acids. (See Figure 143 for a diagram of the
effects of tryptophan depletion.)
Pretreatment plasma tryptophan has been reported to
be lower in depressed patients than in healthy controls
and to be able to differentiate certain subgroups of depression (Meltzer and Lowy, 1987; Maes et al., 1990). Depressed patients exhibit reduced plasma concentrations of
5-hydroxytryptophan after ingestion of test doses of oral
L-tryptophan (Deakin et al., 1990). Lower pretreatment
plasma tryptophan has been reported to be predictive of
response to antidepressant treatment (Moller et al., 1986;
Figure 143. The mechanisms by which tryptophan depletion reduces central nervous system serotonin. CSF = cerebrospinal fluid;
LNAA = large, neutral amino acid; Try = tryptophan; 5-H1AA = 5hydroxy-indoleacetic acid. (Source: Fernstrom and Wurtman, 1997.)
Dietary Protein
(Amino Acids)
Dietary Carbohydrate
(Insulin Secretion)
Plasma
LNAA
Plasma
Tryptophan
Plasma Ratio
Try
LNAA
Tryptophan
Depletion
Brain
Tryptophan
Brain
Serotonin
Brain / CSF
5-HIAA
Neurobiology
Most recently, investigators have studied unaffected relatives of bipolar patients to examine the possibility that
sensitivity to the deleterious mood and cognitive effects of
lowered serotonin may represent an endophenotype for
bipolar disorder. In a double-blind, crossover design, 20
unaffected relatives (URs) from multiplex bipolar families
and 19 control subjects underwent acute tryptophan depletion (ATD) (Quintin et al., 2001). Unlike the control
subjects, URs experienced a lowering of mood during ATD
but not during the placebo. Furthermore, URs tended to
show increased impulsivity in the ATD condition. Measurements obtained before ingestion of the amino acid
(AA) drink indicated that, relative to control subjects, URs
exhibited lower serotonin platelet concentrations, lower
affinity, and fewer binding sites of the serotonin transporter
for imipramine; these differences were unaffected by tryptophan depletion.
In a more recent study, Sobczak and colleagues (2002)
investigated the effects of ATD on cognitive performance
in healthy first-degree relatives of bipolar patients (FHs)
(n = 30) and matched controls (n = 15) in a placebocontrolled, double-blind, crossover design. Performance
on planning, memory, and attention tasks was assessed at
baseline and 5 hours after ATD. The authors found that
speed of information processing on the planning task following ATD was impaired in the FH group but not in the
control group. Furthermore, FH subjects with a bipolar-I
relative (FH-I) showed impairments in planning and memory independent of ATD. In all subjects, ATD impaired
long-term memory performance and speed of information
processing; it did not affect short-term memory or focused
and divided attention. These results suggest serotonergic
vulnerability affecting frontal lobe areas in FH subjects, indicated by impaired planning.
Taken together, the above results suggest that vulnerability to reduced tryptophan availability may represent an
endophenotype for bipolar disorder, a notion that warrants further investigation; also future studies should include a group with highly recurrent unipolar depression.
Neuroendocrine Challenge Studies. A series of neuroendocrine challenge paradigms has been investigated to examine more closely the presynaptic serotonergic neurons
in patients with mood disorders (Shiah and Yatham, 2000;
Mahmood and Silverstone, 2001). In healthy subjects, the
IV infusion of tryptophan increases prolactin plasma levels (Price et al., 1991). In depressed patients, however, this
release of prolactin to IV tryptophan is blunted compared
with that in healthy controls (Price et al., 1991; Cappiello
et al., 1996). As with most of the other serotonergic measures, only a few studies have been undertaken in bipolar
patients, perhaps reflecting the difficulty of maintaining
493
bipolar patients medication-free for a sufficiently long period of time so as to be confident of the lack of confounding residual medication-related effects. The serotonin precursor tryptophan has been used to test neuroendocrine
responses in patients and controls. In a placebo-controlled
study, the cortisol and ACTH responses to tryptophan was
blunted in remitted bipolar patients compared with those
in controls (Nurnberger et al., 1990).
Neuroendocrine challenge with the appetite suppressant fenfluramine produces similar results to the IV infusion of tryptophan. The administration of fenfluramine
causes a rapid increase in the plasma levels of prolactin in
normal subjects. When fenfluramine is administered to
depressed patients, however, the prolactin release is blunted
(Mitchell and Smythe, 1990; Shapira et al., 1993). This
blunted prolactin response has been reported to normalize
with successful treatment and has been proposed as a test for
predicting response to antidepressant treatment (Malone
et al., 1993; Shapira et al., 1993).
Only two studies have employed the fenfluramine challenge test in homogeneous samples of manic patients (Newman et al., 1998). One found that the prolactin and cortisol
responses of manic patients to either fenfluramine (n = 10)
or sumatriptan (n = 9) did not differ from those of normal
controls (discussed in Shiah and Yatham, 2000; Mahmood
and Silverstone, 2001). Thakore and colleagues (1996), by
contrast, found increased basal cortisol levels and reduced
prolactin response to fenfluramine in nine manic patients
compared with nine healthy controls matched for age and
gender. They suggest that mania is associated with a state of
decreased 5-HT responsiveness, similar to that found in the
depressed state and reminiscent of the permissive hypothesis of bipolar disorder discussed earlier.
The growth hormone (GH) response was found to be
blunted in depressed patients in a study using sumatriptan, a 5-HT1D agonist, as the challenge agent (Yatham et al.,
1997). Mahmood and colleagues (2002) found a blunted
GH response to sumatriptan in bipolar patients with migraine compared with bipolar patients without migraine,
pure migraine patients, and healthy controls.
494
Pathophysiology
disorders on the basis of evidence that patients with major depression have blunted physiological responses to
5-HT1A receptor agonists in vivo and abnormal 5-HT1A
receptor binding postmortem (Bowden et al., 1989; Lopez
et al., 1998; Stockmeier et al., 1998). During 5-HT1A receptor agonist challenge, physiological increases in plasma
concentrations of ACTH and cortisol are attenuated in unmedicated subjects with unipolar depression (recurrence
not specified) (Cowen, 2000). Postmortem studies of cerebral 5-HT1A receptor binding and mRNA expression in
unipolar depression and bipolar disorder suggest 5-HT1A
receptor dysfunction in mood disorders, but these data are
limited to two studies with small sample sizes (Bowden
et al., 1989; Lopez et al., 1998). Lopez and colleagues (1998)
found that 5-HT1A receptor mRNA levels were abnormally
reduced in the hippocampus in six subjects with major depressive disorder who died by suicide, and Bowden and
colleagues (1989) found reduced 5-HT1A receptor binding
to [3H] 8-hydroxy-2-(di-n-propyl)aminotetralin (8-OHDPAT) in the temporal polar and posterior ventrolateral
prefrontal cortex in seven patients with unipolar depression or bipolar disorder dying of natural causes.
Supporting the above postmortem findings, recent PET
studies have yielded in vivo evidence of reduced pre- and
postsynaptic 5-HT1A receptor binding in both unipolar
and bipolar depressed patients. Drevets and colleagues
(2000) reported that the regional 5-HT1A receptor binding
of depressed subjects with primary, recurrent, familial
mood disorders (i.e., part of the manic-depressive spectrum) as determined with PET was significantly reduced
relative to healthy controls. The investigators found that
the mean 5-HT1A receptor binding potential was reduced
by 42 percent in the midbrain raphe and 2533 percent in the
limbic and neocortical areas in the mesiotemporal, occipital, and parietal cortex. These findings are consistent with
those of Sargent and colleagues (2000), who found decreased 5-HT1A receptor binding, measured with PET and
[carbonyl-11C]WAY 100635, in 15 unmedicated depressed
patients relative to 18 healthy controls in the raphe, medial
temporal cortex, insula, anterior cingulate, temporal polar
cortex, ventrolateral prefrontal cortex, and orbital cortex.
Seven of the unmedicated subjects were naive to antidepressant drugs, and the other eight had been untreated for a
mean of 63 weeks. No differences were found between depressed patients and controls in the inferior occipital cortex
or angular gyrus. Ten of the subjects were scanned both before and after paroxetine treatment; it was found that 5HT1A receptor binding had not significantly changed in any
area.
Cortisol Hypersecretion and 5-HT1A Receptor Abnormalities. One factor that may contribute to the reduction in
Neurobiology
495
to racial differences in outcomes of antidepressant treatment. Taken together with prior neurobiological findings,
these new genetic data make a compelling case for a key role
of HTR2A in the mechanism of antidepressant action.
Serotonin Transporter Binding. As discussed in Chapter
13, polymorphisms and variable tandem repeats in the
serotonin transporter (SERT) gene have been the focus of
extensive research in a variety of psychiatric disorders.
Furlong and colleagues (1998) undertook a meta-analysis
of over 1,400 individuals of European Caucasian origin.
They used 772 controls and 375 bipolar and 299 unipolar
patients to investigate the 5-HT transporter variable number tandem repeat (VNTR) polymorphism, and 739 controls and 392 bipolar and 275 unipolar patients to study the
promoter polymorphism. They found a significant association with promoter allele 2 in the bipolar groups (estimated
odds ratio 1.21; 95 percent confidence interval 1.001.45),
unipolar groups (odds ratio 1.23; 95 percent confidence interval 1.011.42), and combined bipolar and unipolar groups
(odds ratio 1.22; 95 percent confidence interval 1.041.42).
These results raise the possibility that the promoter allele 2,
previously shown to result in lower levels of SERT transcription, may be associated with risk for affective disorder.
Preliminary reports have also linked SERT gene variants
with antidepressant-induced mania (Mundo et al., 2001)
and antidepressant response to sleep deprivation in bipolar
patients (Benedetti et al., 1999).
Another method for evaluating presynaptic serotonergic
function is measurement of SERT binding. A number of
studies of postmortem brain tissue have been conducted to
investigate SERT in projection regions of serotonergic cell
bodies in suicide victims with depressive disorder. The results of these studies have been mixed. Early studies focused
primarily on suicide victims and used [3H] imipramine, a
less-than-optimum radioligand for measuring SERT. Those
studies found increases, decreases, or no change in [3H]
imipramine binding to frontal cortex in suicide victims
(Stanley et al., 1982; Crow et al., 1984; Arora and Meltzer,
1989a). More recently, other radioligands, including [3H]
paroxetine, [3H] citalopram, and [125I]cyanoimipramine,
have been identified as superior ligands for measuring SERT
(Gurevich and Joyce, 1996). Unfortunately, the results obtained with these newer ligands in subjects with depression
have also been mixed. Studies have found either significant
decreases (Joyce et al., 1993; Arango et al., 1995) or no
changes (Mann et al., 1996a; Bligh-Glover et al., 2000).
Since SERT is transcribed from a single copy gene, the
platelet and CNS SERT are identical. Thus, abnormalities
in platelet SERT may reflect abnormalities in CNS SERT
(Owens and Nemeroff, 1998). A number of studies of platelet
SERT density have been undertaken using [3H]-imipramine
496
Pathophysiology
Neurobiology
497
by causing a subsensitivity of presynaptic 5-HT1A autoreceptors, because the hypothermic response to 5-HT1A receptor agonists has been suggested to be mediated by those
autoreceptors (although mixed pre- and postsynaptic activation has also been suggested for mediation of hypothermia in rats).
In contrast to the positive results of the above studies,
Kusumi and colleagues (1994a) found no in vitro effect of
valproate (100 M) on basal calcium or 5-HTinduced intracellular calcium mobilization in the platelets of 7 healthy
subjects. Although the body of data investigating valproates
effects on the serotonergic system is much smaller than that
for lithium, it does tend to suggest nonidentical effects of the
two drugs. Whether these differences account for observed
clinical differences between the two drugs requires further
study.
498
Pathophysiology
BOX 147. Newer Studies Supporting Involvement of the Serotonergic System in the Pathophysiology
and Treatment of Manic-Depressive Illness (Primarily Bipolar)
Genetic Studies
Enzymes
Transporter
Receptors
Serotonin
and metabolite levels
Challenge Studies
Blunted response of prolactin to fenfluramine in manic patients inconsistently reported (Thakore et al., 1996) (Yatham
1996)
Blunted GH response to sumatriptan (5-HT1D agonist) reported
in BPD patients who also suffered migraine (Mahmood et al.,
2002)
Sumatriptan-induced GH response reported to be blunted
in depressed but not manic patients (Yatham et al., 1997)
Decreased planning and memory function reported in
first-degree relatives of BP-I patients after acute tryptophan depletion. Double-blind crossover trial (Sobczak et al.,
2002)
(continued)
500
Pathophysiology
BOX 147. Newer Studies Supporting Involvement of the Serotonergic System in the Pathophysiology
and Treatment of Manic-Depressive Illness (Primarily Bipolar) (continued)
creased 5-HT-elicited platelet PKC translocation and membrane/cytosol portioning in mania. Li (2 weeks) normalized
the changes (Friedman et al., 1993; J. Wang et al., 1999)
Decrease of 5-HT-induced Ca mobilization by pretreatment
with PKC activator (PMA) (Suzuki, 2001)
Enhanced 5-HT-receptor-mediated G protein coupling in
frontal cortical membranes from postmortem BPD patients
(Friedman and Wang, 1996)
Increase in 5-HT-induced Ca mobilization of untreated manic
patients (Yamawaki et al., 1996; Suzuki et al., 2001). Restored to
control levels in treated euthymic BPD patients (Okamoto
et al., 1995)
Increased Ca response to 5-HT in platelets from BPD patients;
5-HT-induced intraplatelet Ca response reported to represent
a good predictor of mood stabilizer response in a 5-year
follow-up (Kusumi et al., 2000)
Treatment Related
Challenge
studies
Receptor
and
transporter
studies
BPD = bipolar disorder; BP-I = bipolar-I; Ca = calcium; COMT = catechol-O-methyltransferase; GH = growth hormone; IMI = imipramine; Li-lithium;
MAOI = monoamine oxidase inhibitor; MDD = major depressive disorder; PKC = protein kinase C; PXT = paroxetine; TCA = tricyclic antidepressant.
use of donepezil in case reports (Benazzi, 1998, 1999). A recent small, 6-week double-blind, placebo-controlled trial
involving 11 patients with treatment-resistant mania found
no difference in the efficacy of add-on donepezil compared
to placebo in the treatment of manic symptoms in patients
with treatment-resistant mania (Evins et al., 2006).
In a small open study, Stoll and colleagues (1996) gave
choline bitartrate to six lithium-treated outpatients with
rapid-cycling bipolar disorder. Five of the six patients were
reported to have a reduction in manic symptoms and four to
have a marked reduction in all mood symptoms during the
choline therapy. Although these findings are intriguing, the
small sample size and open nature of this study suggest that
caution is required in the interpretation of the results.
Finally, the muscarinic agonist xanomeline has been reported to decrease mood swings and psychotic-like behaviors in Alzheimers patients (Bodick et al., 1997). In preclinical studies, muscarinic agonists have been found to
increase and antagonists to decrease immobility or despair in the forced swim test model of depression. Thus,
the cholinesterase inhibitor physostigmine, but not the peripherally acting neostigmine, increases immobility in the
forced swim test, suggesting depressogenic activity. Interestingly, the enhanced immobility produced by physostigmine was reversed by the 1-adrenergic agonist metoprolol, supporting the contention that a balance between the
cholinergic and adrenergic systems may play an important
role in modulating mood. The hypercholinergic Flinders
Neurobiology
501
502
Pathophysiology
Neurobiology
503
In Vitro Studies
studies to investigate more fully the role of specific muscarinic receptor subtypes in mediating the antimanic effects of nonselective cholinomimetics. The poor selectivity
and tolerability of muscarinic agonists and other cholinomimetics and the low efficacy of agonists for putative
target receptors have precluded extensive study and development of these agents for affective disorders. Box 148
summarizes findings of newer studies supporting the involvement of the cholinergic system in the pathophysiology and treatment of manic-depressive illness, principally
the bipolar subgroup.
504
Pathophysiology
Presynaptic
Glia
Glutamate
GABAA
GAD
Metabolism
GAT
GABAB
GABA
GABA-T
Ca2+ channel
VGAT
GABA
GABAA
GABAB
GAT
K+ channel
Postsynaptic
Figure 144. The various regulatory processes involved in GABAergic neurotransmission. The amino acid (and neurotransmitter) glutamate serves as the precursor for the biosynthesis of gamma-aminobutyric acid (GABA). The rate-limiting enzyme for the process is glutamic
acid decarboxylase (GAD), which utilizes pyridoxal phosphate as an important cofactor. Furthermore, agents such as L-glutamine- hydrazide and allylglycine inhibit this enzyme and thus the production of GABA. Once released from the presynaptic terminal, GABA can interact with a variety of presynaptic and postsynaptic receptors. Presynaptic regulation of GABA neuron firing activity and release occurs
through somatodendritic (not shown) and nerve terminal GABAB receptors, respectively. Baclofen is a GABAB receptor agonist. The binding
of GABA to ionotropic GABAA receptors and metabotropic GABAB receptors mediates the effects of this receptor. The GABAB receptors are
thought to mediate their actions by being coupled to Ca2+ or K+ channels via second messenger systems. Many agents are able to modulate
GABAA receptor function. Benzodiazepines, such as diazepam, increase chloride (Cl) permeability and there are numerous antagonists available directed against this benzodiazepine-binding site. There is also a distinctive barbiturate-binding site on GABAA receptors, and many
psychotropic agents are capable of influencing the function of this receptor (see diagram). GABA is taken back into the presynaptic nerve
ending by a high-affinity GABA uptake transporter (GAT) similar to that of the monoamines. Once inside the neuron, GABA breakdown
can occur by GABA-transaminase (GABA-T), which is localized in the mitochondria; GABA that is not degraded is sequestered and stored
into secretory vesicles by vesicular GABA transporters (VGAT), which differ from vesicular monoamine transporters in their bioenergetic
dependence. (Source: Owens and Kriegstein, 2002. Reprinted with permission from Macmillan Publishers, Ltd.)
Neurobiology
of GABA, the findings were not specific to cases of depression or mania but were also seen in alcoholism (Petty
et al., 1993).
In a longitudinal study of one patient with rapid cycles, Joffe and colleagues (1986) found CSF GABA to be
significantly higher during the patients five manic episodes
than in the four depressed episodes. Two well-state studies
of CSF GABA (Berrettini et al., 1986; Joffe et al., 1986) produced conflicting results; the former noted lower levels
compared with controls whereas the latter did not.
The relationship between GABA in plasma and in CSF
is not clear. In one small study, no correlation was found
(Berrettini and Post, 1984). In contrast, Petty and Sherman
(1984) reported that plasma GABA levels were significantly
lower than normal in a group of 62 medicated depressed
patients. Only four of these patients were bipolar, however,
and their mean levels were very close to those of the controls. Combining data from their four previous studies,
Coffman and Petty (1986) found that manic and remitted
bipolar patients had significantly higher levels of plasma
GABA than those of control subjects, but when the patients were depressed, the plasma GABA levels did not
differ from the controls. Of three studies of GABA in recovered bipolar patients, one, using lithium-treated patients, showed GABA levels significantly higher than normal levels (Petty and Sherman, 1984; Coffman and Petty,
1986), whereas the other two, using patients off all medication for 2 weeks, showed significantly lower than normal
levels (Berrettini et al., 1983, 1985b). This apparent discrepancy might be explained by the longitudinal finding of the
Berrettini group that plasma GABA levels fall significantly
after lithium is discontinued. Interestingly, a small study of
identical twins revealed that plasma GABA levels show
a close intrapair correspondence (Berrettini and Post, 1984).
However, it is too early to assess whether this measure will
be useful as a trait marker for bipolar disorder. Low plasma
GABA differentiates well from ill subjects in about one-third
of bipolar patients (Petty et al., 1993) and is also seen in
euthymic unmedicated bipolar patients (Berrettini et al.,
1982). Plasma GABA levels do not correlate with severity of
symptoms for either depression or mania (i.e., are stateindependent); however, the key research for identifying
whether the marker is familial and segregates with illness in
families with affective disorders has not yet been done.
In a large multicenter trial of valproate in the treatment
of mania (Bowden et al., 1994; see Chapter 18), plasma
concentrations of GABA were measured before and after
treatment in a subset of 63 patients. Interestingly, although
treatment with both lithium and valproate resulted in reductions in plasma GABA levels, pretreatment levels of
plasma GABA predicted response to valproate but not to
lithium. However, it was the patients with higher levels of
505
506
Pathophysiology
Studies of Reelin
As discussed above, postmortem studies have revealed that
an unexpected molecule may be involved in the pathophysiology of severe neuropsychiatric disorders, including
bipolar disorder and schizophrenia (Impagnatiello et al.,
1998; Fatemi et al., 2000a, 2001a,b; Guidotti et al., 2000).
Reelin is a member of a growing group of diverse proteins
whose absence is associated with an almost identical
phenotypeinversion of cerebral cortical layers and reduction or absence of cerebellar foliation.
Costa and colleagues first showed that reelin protein
Neurobiology
507
Enna, 1980; Ahluwalia et al., 1981). Interestingly, following withdrawal of chronic lithium, GABA levels return to
normal in striatum and midbrain, but remain elevated
in pons-medulla (Ahluwalia et al., 1981), possibly as a
result of elevated levels of the GABA-synthesizing enzyme GAD.
Lithium has also been postulated to prevent GABA uptake, and chronic lithium has been shown to significantly
decrease low-affinity [3H]GABA sites in corpus striatum
and hypothalamus. Since lithium has no effect on in vitro
[3H]GABA binding, these receptor changes have been interpreted as downregulation secondary to activation of the
GABAergic system (Maggi and Enna, 1980). Although the
clinical relevance of these findings remains unclear, it is
noteworthy that decreases in CSF GABA have been reported in unipolar depressed patients (Post et al., 1980b;
Berrettini et al., 1982).
In the GABAergic system, the chronic administration
of lithium, valproate, or carbamazepine exerts important
effects, decreasing GABA turnover in frontal cortex
(Bernasconi, 1982). In addition, all three mood stabilizers
are reported to increase GABA(B) receptors in hippocampus following chronic, but not acute, administration (Motohashi et al., 1989). These findings are interesting given
that the GABA(B) agonist baclofen appeared to exacerbate
depression in a small group of patients, and its discontinuation was associated with improvement in mood and behavior (Post et al., 1991). The data suggest the possibility
that GABA(B) antagonists rather than agonists could have
a useful antidepressant effect, and that the effect of mood
stabilizers on GABAergic tone could be related to some of
the drugs psychotropic properties.
A leading hypothesis of how valproate exerts its anticonvulsant effect is that it increases the availability of
GABA in GABAergic synapses (Johannessen, 2000).
GABA, an inhibitory amino acid neurotransmitter, would
be expected to inhibit excessive firing of synapses, thus
inhibiting epileptogenic activity. A number of studies
show that valproate, at therapeutic concentrations, is
an inhibitor of succinate semialdehyde dehydrogenase
(SSADH).30 This enzyme is critical for the GABA shunt,
an enzymatic series of reactions that produces both
glutamate and GABA by circumventing a portion of the
tricarboxylic acid (TCA) cycle. GABA transaminase
(GABA-T) converts GABA to succinate semialdehyde
(SSA), which is then converted to succinate by SSADH.
Valproates effect on SSADH would be expected to increase levels of SSA, which has a strong inhibitory effect
on GABA-T activity. Thus, GABA concentration should
508
Pathophysiology
Increased genotype 1-1 GABRA3 gene (3 subunit GABA receptor) in Xq28 in females with bipolar disorder (Massat et al., 2002)
Figure 145. The various regulatory processes involved in glutamatergic neurotransmission. The biosynthetic pathway for glutamate involves syn-
thesis from glucose and the transamination of -ketoglutarate; however, a small proportion of glutamate is formed more directly from glutamine by
glutamine synthetase. The latter is actually synthesized in glia, and via an active process (requiring ATP) is transported to neurons where glutaminase
is able to convert this precursor to glutamate (see upper part of diagram). (In astrocytes glutamine can undergo oxidation to yield -ketoglutarate,
which can also be transported to neurons and participate in glutamate synthesis.) Glutamate is either metabolized or sequestered and stored into secretory vesicles by vesicular glutamate transporters (VGluTs) (see inset in upper left corner of diagram). Glutamate can then be released by a calciumdependent excitotoxic process. Once released from the presynaptic terminal, glutamate is able to bind to numerous excitatory amino acid (EAA)
receptors, including both ionotropic (e.g., NMDA) and metabotropic receptors. Presynaptic regulation of glutamate release occurs through
metabotropic glutamate receptors (mGluR2/3) that subserve the function of autoreceptors. The middle part of the diagram shows glutamate receptors;
in the upper left are ionotropic receptors. Activation of the AMPA receptor (AMPA R) by glutamate permits the depolarization of the membrane (1).
When glutamate and glycine are present, this depolarization results in the release of magnesium from the NMDA receptor (NMDAR) channel (2).
Calcium also enters through the NMDAR pore (3). Interchange of cations additionally occurs via NMDAR and the kainate glutamate receptor (KAR).
In the upper right of the diagram metabotropic receptors are shown. Activation of Group I metabotropic glutamate receptors (mGlu 1), which are
coupled with a G protein (Gq/11), produces activation of phospholipase C- (PLC-). Activation of Group II metabotropic glutamate receptors (mGlu
2), which are coupled with Gi or Go, produces either inhibition of adenylyl cyclase (AC) or opening of potassium channels (not shown) respectively.
At the bottom of the figure the subunit composition of known receptor subtypes are shown. It is now known that there are a number of important
intracellular proteins able to alter the function of glutamate receptors (see middle section of diagram). Also, growth factors like GDNF and S100 secreted from glial cells have been demonstrated to exert a tremendous influence on glutamatergic neurons and synapse formation. Of note, 5-HT1A receptors have been documented to be regulated by antidepressant agents and to modulate the release of S100. (Source: Schatzberg and Nemeroff,
2004. Reprinted with permission from The American Journal of Psychiatry. Copyright 2004 by the American Psychiatric Association.)
Neurobiology
anxiety disorders, and organic mental disorders. In addition, Mauri and colleagues (1998) found elevated plasma
and platelet levels of glutamate in depressed patients
compared with controls. Conversely, Maes and colleagues
(1998) found no difference in the plasma glutamate levels of
treatment-resistant depressed patients and age- and
gender-matched controls. Berk and colleagues (2001) suggest that the platelet glutamate receptors may be supersensitive in schizophrenia and depression with psychotic
features but not in mania with psychotic features, com-
Glial Cell
Glutamine
Glutamine
5HT1A
Glutaminase
Glutamine
synthase
s100#
Glutamate
Glutamate
GTn
GTg
Mg2+
Na+
NMDAR
Glu
Gly
Glu
Actinin,Spectrin
PKC
nNOS
PP2A
PP2B
Src
Glu
mGluR
CaM
Kll
PSD-95
PKA Yotiao
AKAP
PP1
Na+
Ca2+
%
Ho
m
er
AMPA R
MyoV
GKAP
Shank
SynGAP
PTP1D,SHP2
PYK2
Rap2
H-ras
Rac1
&
#
Hsp70
ERK
Raf
MEK
Rsk
509
Metabotropic
NMDA
AMPA R
Kainate
Group I
Group II
Group III
NR1
NR2 A-B-C-D
NR3 A-B
GluR 1
GluR 2
GluR 3
GluR 4
GluR 5
GluR 6
GluR 7
KA 1
KA 2
mGlu 1 a-b-c-d
mGlu 5 a-b
mGlu 2
mGlu 3
mGlu 4 a-b
mGlu 6
mGlu 7 a-b
mGlu 8 a-b
510
Pathophysiology
Neurobiology
511
Stress, depression
Trophic Factors
Energy Supply
CRF, Cortisol
Glutamate
Unknown
Glial
cells
GR
Ca2+
Hyperactivation of
Ca2+-dependent
enzymes
Oxygen Free
Radicals
Glucose
Transporters
Energy Capacity
BDNF
Trophic Support
could result in high intracellular levels of calcium. Overactivation of the glutamate ionotropic receptors is known
to contribute to the neurotoxic effects of a variety of insults, including repeated seizures and ischemia. Neurotoxicity follows as a response to overactivation of calcium-dependent enzymes and the generation of oxygen
free-radicals. Stress or glucocorticoid exposure also compromises the metabolic capacity of neurons, thereby
increasing the vulnerability to other types of neuronal
insults. Activation of the HPA axis appears to play a critical role in mediating these effects, since stress-induced
neuronal atrophy is prevented by adrenalectomy and duplicated by exposure to high concentrations of glucocorticoids (Sapolsky, 1996, 2000b; McEwen, 1999b). The role
of the corticotropin-releasing hormone (CRH) and glucocorticoid signaling system is discussed in greater detail
later.
512
Pathophysiology
Neurobiology
Taken together, findings of biochemical and behavioral studies investigating the effects of antimanic
(lithium and valproate) and promanic (antidepressants,
cocaine, amphetamine) agents on GluR1 suggest that
AMPA receptor trafficking is an important target in the
pathogenesis and treatment of certain facets of bipolar
disorder. The mechanisms by which glutamate receptors
are actively recruited to synapses have long intrigued the
neuroscience community; the findings reviewed here
suggest that they may also play important roles in the
pathophysiology and treatment of complex neuropsychiatric disorders.
513
514
Pathophysiology
Conventional
Antidepressants
NMDA
Antagonists
Ca2+
MAP Kinases
cAMP
NMDA
Receptor
Throughput
PKA
NMDA Receptor
Subunit Expression
pCREB
AMPA
Receptors
Lyn
PDE
PDE Inhibitors
(e.g., rolipram)
BDNF
MAP
Kinases
Figure 147. Schematic illustrating pathway convergence among conventional (biogenic amine-based) antidepressants, NMDA antagonists, and AMPA receptor potentiators (ARPs). BDNF = brain-derived neurotrophic factor;
MAP = mitogen-activated protein; pCREB = phosphorylated cAMP response element-binding protein; PDE = phosphodiesterase; PKA = protein kinase A. (Source: Skolnick et al., 2001. Reprinted with permission from Elsevier.)
effects was seen very rapidly (occurring within 2 hours postinfusion) and remained significant for 1 week; studies in
bipolar patients are ongoing (Zarate et al., 2006b). In contrast to the dramatic effects observed in this study, a previous controlled study did not show antidepressants effects
of the low- to moderate-affinity noncompetitive NMDA
antagonist memantine when administered orally (Zarate
et al., 2006a). While it is likely that higher-affinity NMDA
antagonists are necessary for antidepressant effects to occur, it must be acknowledged that IV administration may
also be an important factor. Overall, the intriguing results
observed with ketamine support the hypothesis that directly targeting the NMDA receptor complex may bring
about rapid and relatively sustained antidepressant effects.
This line of research holds considerable promise for developing new treatments for depression (see Fig. 148), with
the potential to alleviate much of the morbidity and mortality associated with the delayed onset of action of traditional antidepressants.
Based largely on the observation that AMPA receptor
activation increases expression of brain-derived neu-
rotrophic factor (BDNF, discussed in detail later), Skolnick and colleagues have undertaken a series of studies
investigating the putative antidepressant efficacy of
AMPA receptor potentiators in models of depression
(Legutko et al., 2001; Li et al., 2001; Skolnick et al., 2001).
AMPA receptors are a subfamily of ionotropic glutamate
receptors mediating fast excitatory transmission in the
CNS. As with most other ligand-gated ion channels,
AMPA receptors possess multiple, allosteric modulatory
sites that represent targets for fine-tuning the activity of
the receptor by pharmacological means. In addition to
their ionotropic properties, AMPA receptors have been
functionally linked to a variety of signal transduction
events involving G proteins and the mitogen-activated
protein kinase (MAPK) (Bahr et al., 2002). This raises the
possibility that more subtle modulation of AMPA receptors may be a useful strategy to activate MAPK neurotrophic cascades. One class of compounds, AMPA receptor potentiators (ARPs), dramatically reduces the rate
of receptor desensitization and/or deactivation (Skolnick
et al., 2001).32
Neurobiology
515
Glia
Glutamine synthetase
glutamate
(glu)
glutamine
(gln)
mG
gln
luR
mG
EAAT1/2/(3)
luR
glu
EAAT3
Kainate
mGluR I
MEMANTINE
Glutaminase
mGluR I
?
glu
glu
glu
?
NMDA R
FELBAMATE
(")
mGluR III
TCA
AMPA R
RILUZOLE
mGluR II
%ketoglutarate
EAAT3
glu
gln
II
Presynaptic neuron
2nd generation
mGlu agonist
KA R
Postsynaptic neuron
Figure 148. Receptors that may represent a target for novel agents for the treatment of depression. Glutamate (glu) is synthesized in neu-
ron from -ketoglutarate through the tricarboxylic acid (TCA) cycle. After release, glutamate is reuptaken by glutamate transporters
(EAAT1/2/3), shown in glia and a presynaptic neuron (EAAT3). In the glia, glutamate is catabolized to glutamine (through the enzyme glutamine synthetase), diffuses to the neurons, and is then metabolized back to glutamate (through the enzyme glutaminase). The different
glutamate receptors and the presumed antiglutamatergic drug sites of action are presented. Memantine is a noncompetitive antagonist at
the NMDA receptor (NMDA R). Felbamate is a noncompetitive NMDA receptor antagonist (glycine NR1 and glutamate NR2B), an AMPA
receptor (AMPA R) antagonist, an mGlu group I receptor antagonist, and a glutamate release inhibitor (acting through blockade of Ca2+
and Na+ voltage-dependent channels). Riluzole is a glutamate release inhibitor (acting through blockade of Ca2+ and Na+ voltage-dependent
channels), a GABA(A) agonist and probably an AMPA and kainate antagonist. The sites for second-generation mGlu group II and III receptor agonists are also depicted. KA R = kainate glutamate receptor. (Source: Manji et al., 2003b.)
exciting recent preclinical finding is that lithium and valproate downregulate the synaptic expression of the AMPA
receptor subunit GluR1, whereas the opposite effect is seen
with promanic agents (psychostimulants and imipramine).
These studies suggest that regulation of glutamatergicallymediated synaptic plasticity may play a role in the treatment of mood disorders. Indeed, one recent and very attractive hypothesis is that alterations in neural plasticity in
critical limbic and reward circuits, mediated by increasing the postsynaptic AMPA to NMDA throughtput, may
represent a convergent mechanism for antidepressant action (Zarate et al., 2006b). Box 1410 summarizes direct
and indirect evidence supporting the involvement of the
516
Pathophysiology
BOX 1410. Direct and Indirect Evidence Supporting a Role for the Glutamatergic System in the Pathophysiology
and Treatment of Manic-Depressive Illness (Primarily Bipolar)
CSF, Plasma, and Platelet Studies
Treatment Related
Preclinical
studies
MRS Studies
Clinical
studies
Neurobiology
517
518
Pathophysiology
This latter finding may be most applicable to bipolar illness, where there is some evidence of a subtle decrease in
thyroid function, especially among those with rapid cycles,35 although not all studies agree on this.36 Evidence of
thyroid dysfunction in bipolar illness may have emerged
because of the antithyroid effects of lithium, in effect unmasking subtle preexisting thyroid pathology.
The association between lithium-induced hypothyroidism and rapid cycling is observed predominantly in
women. As noted in Chapter 18, women may also be more
sensitive to the cycle-inducing effects of tricyclic antidepressants. If hypothyroidism (either in the presence or
absence of lithium treatment) is related to the development of rapid-cycling bipolar depression, it is not yet
clear how. Several individual case reports have described
cyclical mood disturbances developing in patients following subtotal thyroidectomy (Hertz, 1964). However,
thyroidectomy per se is not sufficient for the development of rapid cycling; clearly, other predisposing factors
must be present. In Chapter 16, we suggest that the effects
of thyroid hormones on the periodicity of biological
clocks in animals, coupled with altered circadian pacemaker function in bipolar patients, may explain the apparent inductive effect of hypothyroidism in rapidcycling patients. Almost all rapid-cycling bipolar patients
are female (Wehr et al., 1988). Likewise, thyroid dysfunction, including the antithyroid effects of lithium, is much
more common among women (Joffe et al., 1988). These
observations link female sex, hyperthyroidism, and rapid
cycling.
Hatterer and colleagues (1988) propose that relatively
reduced thyroid function among bipolar patients on lithium
may be associated with poor outcome. They report that
plasma T3 levels were significantly lower among patients
who relapsed on lithium, although all values remained in
the normal range (see Frye et al., 1999a). As discussed earlier, Gjessing (1938) described a group of patients with periodic catatonia who, when given large doses of thyroid
hormone, responded with rapid (less than 1 week) and
long-lasting improvement. In a somewhat larger group of
patients with periodic psychoses, Wakoh and Hatotani
(1973) found similar beneficial effects of treatment with
large doses of thyroid hormone. As noted in Chapter 3,
these patients share many clinical features with rapidcycling bipolar patients, and their conditions probably
represent the same illness.
In a later study, Stancer and Persad (1982) gave hypermetabolic doses of T4 (300 to 500 g/day) to 10 rapidcycling bipolar patients. Of the seven women, five responded dramatically, whereas two men and an adolescent
did not. Consistent with this finding are reports that thyroid
hormone in combination with standard mood-stabilizing
Neurobiology
drugs can attenuate cycles in bipolar patients (Goodwin, 1982; Bauer and Whybrow, 1988). High-dose T4
(482 72 g/day) proved to have excellent antidepressant
effects in approximately 50 percent of severely therapyresistant depressed patients (5 unipolar and 12 bipolar) in
an 8-week open label and 27.2 22.0-month follow-up of
responders (Bauer et al., 1998a).
In another study, six resistant bipolar patients (nonrapid-cycling) were treated with supraphysiological doses
of T4 (250 to 500 g/day) adjunctively and followed up for
27.8 12.8 months. The mean number of relapses declined
from 5.3 3.1 to .8 .8, compared with the number of relapses during the same length of time for each patient before the start of treatment with high-dose T4 (Bauer et al.,
1998a,b).37
Another approach to the HPT axis involves the study of
circadian patterns of TSH release. Normally, TSH secretion peaks during the night (Weeke, 1973), but this peak is
absent in some patients with affective disorders (Weeke
and Weeke, 1978; Goldstein et al., 1980), including those
with rapid-cycling bipolar disorder (Kasper et al., 1988;
Sack et al., 1988). Sleep deprivation represents another
challenge test in that it is associated with an increase in
nocturnal TSH. Both bipolar (Sack et al., 1988) and unipolar depressed patients (Kasper et al., 1988) have been
shown to have blunted TSH response to total sleep deprivation.38
Potential Involvement of Thyrotropin-Releasing Hormone.
Preclinical studies have shown that TRH has an extensive
extrahypothalamic distribution including the limbic system, amygdala, and frontal cortex, and in addition to its
neurohormonal role, appears to act as a neurotransmitter
(Griffiths, 1985). Thus in preclinical animal studies, administration of TRH appears to have a mild stimulant effect
including increased arousal and motor activity (Nemeroff
et al., 1984a).
In humans, at least two clinical studies have reported elevated levels of CSF TRH in patients with acute depression
(Kirkegaard et al., 1979; Banki et al., 1988), while a third
found no difference from control subjects (Roy et al.,
1994). A more recent and larger study included both bipolar
and unipolar medication-free depressed patients (n = 56)
compared with normal controls (n = 34) and again found no
differences in CSF TRH. However, there was a gender difference, with females having, on average, lower TRH levels
than mena finding most significant in the bipolar group
(Frye et al., 1999b).
The TRH stimulation test uses a challenge dose and
measures the plasma TSH concentration at baseline and at
30-minute intervals. Multiple studies have used this test in
depressed patients, and all have found that approximately
519
520
Pathophysiology
CBZ = carbamazepine; CSF = cerebrospinal fluid; ECT = electroconvulsive therapy; Li = lithium; TRH = thyrotropin-releasing hormone;
TSH = thyroid-stimulating hormone.
treatment significance remains unclear. There are important gaps in the literature on TRH, including comparisons
of unipolar and bipolar patients, studies of bipolar patients while in a manic state, and postmortem and receptor studies of TRHsubjects that should be further explored. Box 1411 summarizes findings of recent studies
implicating abnormalities of the HPT axis in bipolar disorder.
Corticotropin-Releasing Factor and the HypothalamicPituitary-Adrenal Axis. Evidence of HPA axis activation
Neurobiology
521
secretion. Various neurotransmitters and neuromodulators, including acetylcholine, NE, serotonin, and GABA,
have been implicated in stimulating CRF release (Pepper
and Krieger, 1984); different ones predominate at different
times, depending on environmental stress, circadian periodicity, and other physiological conditions. Human cortisol
secretion can be inhibited by corticosteroids, such as dexamethasone, and this feedback inhibition can readily be
demonstrated at both central and pituitary locations. Preliminary data indicate that the central components of the
axis are ordinarily more sensitive to glucocorticoid negative
feedback than are those in the pituitary gland (P. Gold, unpublished observations). Such distinctions become important in interpreting clinical data on cortisol secretion (with
and without dexamethasone).
The earliest studies showed that depressed patients had
elevated plasma cortisol levels, which decreased after recovery in most but not all patients (Board et al., 1957; Gibbons, 1964). By and large, these studies included a mixed
population of depressive patients and used rather primitive techniques for assaying cortisol. More recent studies,
using highly specific radioimmunoassays, more frequent
sampling of cortisol (to take into account the well-known
diurnal rhythm in cortisol secretion), and more homogeneous groups of patients, including children (Weller and
Weller, 1988), have consistently shown significant cortisol
hypersecretion in many but not all depressed patients.
Although cortisol hypersecretion has been reported in
both bipolar and unipolar patients (Sachar et al., 1973),
whether it occurs with the same frequency in both groups
remains an open question. Several investigators have examined bipolar patients longitudinally and observed significant hypercortisolemia (and/or elevations of urinary
cortisol metabolites) during the depressed but not manic
phase (Rizzo et al., 1954; Bunney et al., 1965; Kennedy et al.,
1989). These results were confirmed and extended by Rubinow and colleagues (1984), who found that both unipolar
and bipolar depressed patients have higher urinary free
cortisol levels than patients in the manic phase or healthy
controls. The urinary free cortisol levels in Rubinows
manic patients were significantly lower than those of normal controls.
Dexamethasone Suppression Test. In addition to cortisol
hypersecretion, other state-dependent abnormalities in HPA
function have been reported in affective illness. The most
common finding is an early escape, or rebound, of cortisol
from the suppression induced by dexamethasone (Carroll
et al., 1968; Stokes et al., 1975). This phenomenon, the basis
for the dexamethasone suppression test (DST), has been
used extensively in psychiatric patients (Goodwin and Jamison, 1990; Rush et al., 1996).
522
Pathophysiology
Neurobiology
523
524
Pathophysiology
with mania are not significantly different from those in control subjects (Banki et al., 1992).
Nemeroff and colleagues (1988) found a 23 percent reduction in the number of CRF binding sites in the frontal
cortex of suicide victims compared with that in controls;
these reductions in CRF binding sites have been postulated
to represent a compensatory downregulation in the face
of sustained CRF elevations. In contrast, Leake and colleagues (1991) found no differences in CRF immunoreactivity or receptor binding in a small group of depressed patients who died from natural causes. In addition, Hucks
and colleagues (1997) found no difference between both
medicated and medication-free suicide victims and matched
controls. Whether these differences are secondary to differences in postmortem time or in clinical sample characteristics remains unclear.
The CRF stimulation test uses a standard dose of CRF
and measures the ACTH response. A subset of depressed patients (both unipolar and bipolar) displayed a suppressed
ACTH response to CRF (Holsboer et al., 1987; Young et al.,
1990). These results have been interpreted as downregulation of CRF receptors as a result of CRF hypersecretion.
In a study by Gold and colleagues (1984b), the CRFinduced release of ACTH was found to be normal in a group
of manic and euthymic bipolar patients, further supporting
the findings above of normal or low HPA axis function in
manic patients as reflected by urinary free cortisol. Apparently, the central mechanisms responsible for the hypersecretion of CRF in depression revert to normal following the
switch to mania or euthymia. As noted previously, several
major neurotransmitter systems (noradrenergic, adrenergic,
serotonergic, cholinergic, and GABAergic) have been implicated in the regulation of CRF release from the paraventricular nucleus of the hypothalamus. In studies of CRF release
by hypothalamic organ culture, Golds group showed that
GABA is inhibitory, whereas NE, acetylcholine, and serotonin are excitatory (Calogero et al., 1988, 1989). Drugs that
mimic the actions of acetylcholine have been reported to increase ACTH and cortisol secretion in animals and humans,
and there is evidence that cholinergic agonists work on the
HPA axis through a receptor-mediated release of hypothalamic CRF. In animals, atropine (a muscariniccholinergic antagonist) has been shown to block both stress-induced elevations of ACTH and cortisol (Hedge and Smelik, 1968; Hedge
and de Wied, 1971) and the normal circadian rhythm of cortisol secretion (Krieger et al., 1968; Ferrari et al., 1977). The
previously discussed depressive-like behavioral effects of
physostigmine (a reversible cholinesterase inhibitor) are
highly correlated with increased blood levels of ACTH, betaendorphin, cortisol, and prolactin (Risch et al., 1980, 1981).
These same investigators also report that depressed bipolar
and unipolar patients secrete significantly more ACTH and
Neurobiology
525
models of learning and memory (i.e., long-term potentiation). Another major reason the hippocampus has been
the focus of stress research is that the highest levels of glucocorticoid receptors are expressed in this brain region
(Lopez et al., 1998). However, it is clear that stress and glucocorticoids also influence the survival and atrophy of
neurons in other brain regions (e.g., prefrontal cortex; see
below) that have not yet been studied in the same detail
as the hippocampus.
Caution in the interpretation of clinical findings is suggested by the results of recent longitudinal studies undertaken to investigate the effects of early life stress and inherited variation in monkey hippocampal volumes (Lyons
et al., 2001). In these studies, paternal half-siblings raised
apart from one another by different mothers in the absence of fathers were randomized to one of three postnatal
conditions that disrupted diverse aspects of early maternal
care. The researchers found that paternal half-siblings with
small adult hippocampal volumes responded to the removal of all mothers after weaning with initially larger relative increases in cortisol levels (Lyons et al., 2001). Plasma
cortisol levels 3 and 7 days later and measures of cortisolnegative feedback in adulthood were not, however, correlated with hippocampal size. Thus, these studies suggest
that small hippocampi also reflect an inherited characteristic of the brain, and their findings highlight the need for
caution in attributing causality in cross-sectional human
morphometric studies of the hippocampus.
Although not as extensively studied as the hippocampus, recent research has demonstrated histopathological
changes in rat prefrontal cortex after corticosterone administration (Wellman, 2001).43 An intriguing finding of
this study, similar to the hippocampal findings summarized above, was a strong heritability of the right ventral
medial prefrontal volume. Thus in this study, certain fathers produced offspring with large right ventral medial
prefrontal volumes, whereas others produced offspring
with small right ventral medial prefrontal volumes (Lyons,
2002). Since the paternal half-siblings were raised apart by
different mothers in the absence of fathers, the phenotypic
similarities in right ventral medial prefrontal volumes likely
represent a major genetic contribution, effects not seen for
other prefrontal regions.
Mechanisms Underlying Stress-Induced Morphometric
Changes. As discussed earlier, considerable data suggest
that abnormal activation of the glutamatergic system plays
a major role in mediating stress-induced morphological
changes. Furthermore, it is clear that activation of the HPA
axis plays a critical role in mediating these effects, since
stress-induced neuronal atrophy is prevented by adrenalectomy and duplicated by exposure to high concentrations
526
Pathophysiology
Serotonin
STRESS
Glucocorticoid
DENDRITIC
ATROPHY
Presynaptic Kainate
receptors
MR + GR
receptors
NMDA
receptors
MR + GR
receptors
NMDA receptors
GABA-BZ
receptors
Entorhinal Cortex
NEUROGENESIS
APOPTOSIS
Interneuron
Dentate Gyrus
CA3
Figure 149. Molecular and cellular determinants underlying the opposing actions of stress and antidepressant treatment on hippocampal structure. Stress can have multiple effects depending on the subregion of
the hippocampus examined. In the dentate gyrus, acute or chronic stress results in decreased neurogenesis of
new neurons. In the CA3 pyramidal cell layer, repeated stress results in atrophy or remodeling of pyramidal
neurons, decreasing the number and length of apical dendrites. Glucocorticoid administration causes a similar effect, and decreased expression of brain-derived neurotrophic factor could contribute to pyramidal cell
atrophy. Chronic antidepressant administration can reverse the atrophy of CA3 neurons. The effects of antidepressant treatment occur via acute regulation of 5-HT and norepinephrine and the regulation of intracellular signaling and gene expression. GABA-BZ = gamma amino butyric acid-benzodiazepine; GR = glucocorticoid receptors; MR = mineralocorticoid receptors. (Source: Adapted from Warner-Schmidt and Duman,
2006. Reprinted with permission.)
Neurobiology
527
mineralocorticoid receptor to the pathogenesis of hippocampal changes observed in chronic stress and affective
disorders (Gass et al., 2000). These observations raise the
interesting possibility that CRF and GR antagonists, currently being developed for the treatment of mood and anxiety disorders, may have particular utility in the treatment
of elderly depressed patients.
Also of potential relevance for our understanding of
the neurobiology and treatment of mood disorders is the
finding that ovariectomy decreases the proliferation of
new cells in the hippocampus, effects that are reversed by
estrogen replacement. The rate of neurogenesis fluctuates
over the course of the estrus cycle in rodents, and the total
rate of cell birth is higher in female rodents than in males.
In addition to potentially playing a role in the beneficial
cognitive effects of estrogen, the regulation of neurogenesis by this gonadal steroid may provide important clues
about certain sexually dimorphic characteristics of mood
disorders.
Targeting of the HPA Axis as a Strategy for the Treatment
of Severe Mood Disorders. Given the evidence reviewed
above, there is a growing appreciation of the potential role
of abnormalities of the HPA axis in mediating the phenotypic expression of certain affective states (Gold and
Chrousos, 2002). Not surprisingly, then, there is increasing interest in targeting this system for the development
of novel therapeutics (see also Chapter 19). Published
double-blind, placebo-controlled clinical studies aimed at
modulating the HPA axis have employed inhibitors of glucocorticoid synthesis (Malison et al., 1999; Wolkowitz et al.,
1999a), antagonists of the glucocorticoid receptor (Belanoff
et al., 2001; Young, 2006), hydrocortisone to downregulate
the HPA axis (in a proof-of-concept study reported by DeBattista et al., 2000), and dehydroepiandrosterone (Bloch
et al., 1999; Wolkowitz et al., 1999b). Some of these drugs
have been investigated for proof of concept rather than for
use as a standard of care, and it is expected that modified
and improved medications would lack some of the limiting
side effects observed with these compounds. We describe
below some of the drugs currently under investigation in
clinical and/or preclinical trials.
CRF1 Receptor Antagonist. A number of small-molecule
CRF 1R antagonists have been evaluated using in vivo paradigms in animal models to attenuate CRF-induced ACTH
release (Saunders and Williams, 2003). Several classes of
CRF 1R inhibitors have been identified, including peptides
(astressin, -helCRF) and small-molecule nonpeptides
(CP-154526, antalarmin, DMP-695, DMP-696, CRA-1000,
R-121919, SSR-125543, NBI 35965, NBI 27914) (Holmes et al.,
2003; Saunders and Williams, 2003). Preclinical studies have
shown that CRF 1R antagonists reduce CRF-induced ACTH
528
Pathophysiology
in the CNS. Thus, DHEA and DHEA-S are neuroactive steroids having a number of effects that can be described as
functional antagonism of the actions of glucocorticoids
(although DHEA does not directly interact with the glucocorticoid receptor, and there is no known receptor for
DHEA in any tissue) (McEwen, 2003). Among its effects,
DHEA counteracts the actions of glucocorticoids to inhibit memory and primed-burst potentiation (a form of
long-term potentiation) and antagonizes oxidative damage in brain (and in other organs) produced by acute hyperglycemia. Although mediated by an unknown cellular
and molecular mechanism, DHEA also interacts with neurotransmitters (serotonin, GABA, excitatory amino acids,
and DA), in addition to its glucocorticoid antagonism (reviewed by McEwen, 2003).
DHEAs antidepressant efficacy has been suggested
by clinical trials in dysthymic and depressed patients.
Wolkowitz and colleagues (1997) reported on a case series
comprising six middle-aged and elderly patients with unipolar depression and low basal plasma DHEA and/or DHEA-S
levels who received DHEA 3090 mg/day for 4 weeks. A
decrease in depression ratings and an improvement in memory performance, correlated with increases in plasma levels
of DHEA and DHEA-S, were observed. The effects of DHEA
were also investigated in a double-blind, placebo-controlled,
randomized crossover treatment study using 90 and 450 mg
of DHEA in patients with midlife-onset dysthymia (a total of
6 weeks on medication and 6 weeks on placebo). The study
was completed by 15 of 17 patients; 60 percent of those patients responded to DHEA, compared with 20 percent on
placebo (Bloch et al., 1999). Finally, a double-blind, placebocontrolled study was conducted in 22 patients with unipolar
depression (medication-free or on stabilized antidepressant
regimens) using DHEA at a maximum dose of 90 mg/day or
placebo for 6 weeks. A decrease of 50 percent or greater in
depressive symptoms was seen in 45 percent of the patients
and none in the placebo group (Wolkowitz et al., 1999b). In
a recent double-blind, randomized, placebo-controlled
crossover study involving 23 men and 23 women with midlifeonset major or minor depression, 6 weeks of DHEA (90
450 mg/day) was found to be superior to placebo in reducing
depressive symptoms (Schmidt et al., 2005).
Glucocorticoid Receptor Antagonists. Mifepristone (RU486) is a nonselective antagonist of the GR receptor that has
shown efficacy in treating psychotic depression (Murphy
et al., 1993; Belanoff et al., 2001, 2002) and is being used in
ongoing trials in bipolar disorder (Manji et al., 2003b).
Young and colleagues (2004) have reported preliminary
data on mifepristone (600 mg) compared with placebo in 19
subjects with bipolar depression. They found a beneficial effect on mood and neurocognitive functioning. In a separate
Neurobiology
study not yet published, 208 patients were randomized to receive 7 days of mifepristone or placebo in addition to their
ongoing treatment for psychotic unipolar depression. Although both groups improved significantly, there was no
statistical difference between them. A post hoc analysis indicated that the mifepristone patients improved more rapidly
than the placebo group (DeBattista et al., 2003). In a recent
study, 20 bipolar patients were treated with 600 mg/day of
the corticosteroid receptor antagonist mifepristone (RU486) or placebo for 1 week in a double-blind crossover design (Young et al., 2004). Following treatment with mifepristone, selective improvement in neurocognitive functioning
was observed. Spatial working memory performance was
significantly improved compared to that of placebo. Hamilton Depression Rating Scale scores and Montgomery-Asberg
Depression Rating Scale scores were also improved. These
data provide preliminary evidence that glucocorticoid receptor antagonists may have useful cognitive-enhancing and
possibly antidepressant properties in bipolar disorder and
perhaps also in recurrent depression.
Other GR antagonists being developed are ORG 34517
(Organon), AL082D06 (Abbott), and cyproterone acetate
(Schering). Bachmann and colleagues (2003) synthesized
three derivatives of mifepristone with higher selectivity for
binding to the glucocorticoid receptor, secondary to decreased binding to progesterone receptors (ORG 34517, ORG
34850, and ORG 34116). Among these agents, ORG 34517 is
highly potent at the glucocorticoid receptor. Preliminary
data for its antidepressant efficacy were presented at the 2002
Collegium Internationale Neuro-psychopharma-cologicum
(CINP) meeting by Hoyberg and colleagues (2002). This
compound is now in Phase III trials.
Miner and colleagues (2003) have reported on a new
compound, AL082D06 (D06), discovered by screening
compound libraries, that binds specifically to the glucocorticoid receptor with no measurable binding affinity to the
progesterone receptor. This compound was found to antagonize glucocorticoid-mediated transcriptional regulation
in in vitro cell-based models of transcriptional activation.
Cyproterone acetate is available outside the United States
as an antiandrogen approved for paraphilias. It is used as a
contraceptive agent added to an estradiol combination that
is also widely used for hair growth. Honer and colleagues
(2003) report on its GR antagonism properties, and while it
could be tested in depression, it is unlikely to be clinically
useful because of its antiandrogenic properties and risk of
severe liver damage.
Inhibition of glucocorticoid synthesis has also been investigated as an antidepressant strategy in unipolar and
bipolar patients. This research has included the compounds
ketoconazole (which poses a risk for hepatotoxicity and
drug interaction), metyrapone, and aminogluthethimide.
529
Gonadal Steroids
Gonadal steroids as a group have wide-ranging neuromodulatory actions. In fact, gonadal steroids play a role in
all stages of neurodevelopment, including neurogenesis,
synaptogenesis, neural migration, growth, differentiation,
cell survival, and death (Pilgrim and Hutchison, 1994).
These various actions, in general, stem from the fact that
gonadal steroids are able to modulate genomic transcription and therefore direct and modulate the synthesis of
various enzymes and receptor proteins. These actions are
tissue-specific and are directed by the presence or absence
of tissue-specific coactivators or corepressors (Katzenellenbogen et al., 1996). Further, gonadal steroid actions on
530
Pathophysiology
ACTH = adrenocorticotropic hormone; BP = bipolar; CRF = corticotropin-releasing factor; CSF = cerebrospinal fluid; DST = dexamethasone suppression test; GR = glucocorticoid receptor; UP = unipolar.
Neurobiology
pregnancy. In addition, two-thirds of women with bipolarI disorder reported frequent premenstrual mood disturbances, and 20 percent reported emotional disturbances
during the menopause transition. Reich and Winokur
(1970) found that 20 percent of women with bipolar disorder suffered from postpartum mania. Dean and colleagues
(1989) found a 50 percent relapse rate (both depression
and mania) in the 6 weeks following childbirth in women
with bipolar disorder. Thus, although hormonal fluctuations may not play a role in the risk of onset of bipolar disorder, they may in fact influence the course and exacerbation of the illness.
Rapid-cycling bipolar disorder is generally defined as
four or more affective episodes (depression, mania, or hypomania) in 1 year. As discussed in Chapter 4, the majority
of patients with rapid-cycling bipolar disorder are female.
In reviewing the available studies on rapid cycling, Leibenluft (1996) calculated that approximately 7174 percent of
patients in these studies were female. Further, when the
definition is made more stringent to require 12 or more
cycles per year, the proportion of women in a sample increases dramatically (Bauer and Whybrow, 1990).
It does not appear that fluctuations in mood symptoms
are correlated with menstrual cycle phase in rapid-cycling
patients. For example, although a retrospective study found
that 60 percent of 25 rapid-cycling patients experienced severe premenstrual symptoms (Price and DeMarzio, 1986),
a prospective study of 47 women found no relationship between mood fluctuations and menstrual cycle phase (Wehr
et al., 1988). This latter finding is supported by a subsequent
prospective study involving 25 women with rapid-cycling
bipolar disorder (Leibenluft et al., 1999). The fact remains,
however, that women with bipolar disorder appear to be
more vulnerable to rapid cycling. There is some evidence to
suggest that rapid cycling can be induced by antidepressant
treatments. It is unclear, however, whether the vulnerability
in women is secondary to an interaction between antidepressants and the female hormonal system or women being
more likely to receive antidepressants (Leibenluft et al.,
1999).
What potential role, then, do estrogen and progesterone
play in the underlying pathophysiology of bipolar and recurrent depressive disorders? Both have been shown to modulate serotonin function, and estrogen, as well as other
gonadal steroids, may influence the effects of antidepressant
treatment.45
Estrogen has also been shown to increase the expression
of nerve growth factors as well as their receptors (Sohrabji
et al., 1994). Preclinical studies in rats indicate that ovariectomy reduces the expression of BDNF in parts of the hippocampus as well as the frontal and temporal cortex, and
that estrogen replacement increases BDNF expression in
531
some but not all of these areas (Singh et al., 1995; Simpkins
et al., 1997). As we discuss later, BDNF has recently been
hypothesized to be involved in the mechanism of action of
antidepressants, thus estrogens effect on BDNF parallels
BDNFs antidepressant action.
There are several case reports of estrogen-induced mania
or rapid cycling in bipolar patients and at least one case of
late-life mania associated with estrogen administration in a
patient with no previous history of bipolar illness (Young
et al., 1997). Further, Chouinard and colleagues (1987) reported on two cases of bipolar disorder that were stabilized
by the addition of an estrogenprogesterone combination in
addition to mood stabilizers.
Several preclinical studies have found that estrogen increases the expression of PKC, an important intracellular
messenger (Maizels et al., 1992; Rebas et al., 1995). As noted
below, both lithium and valproate have been shown to be
inhibitors of PKC. Further, a pilot study using tamoxifen
(a potent PKC inhibitor) in the treatment of mania was
significantly positive.
Taken together, the findings of these studies suggest that
in general, estrogen may have a more positive effect on
mood and progesterone a more negative effect. Both of
these gonadal steroids exert significant intracellular effects
as well as more global effects on neurotransmitter levels
that may ultimately affect mood and mood regulation.
Thus women with an inherent vulnerability to a mood disorder, whether depression or bipolar disorder, may be affected by the monthly fluctuations of estrogen and progesterone or by the more rapid changes induced by delivery.
Obviously, the situation is a complex one that deserves further exploration.
Neuropeptides
The Endogenous Opioid System. The discovery of the
opiate receptor and its endogenous ligand provided the tools
for characterizing endogenous opiate systems involving the
endorphins and enkephalins. The fact that these systems
modulate behavior related to mood, such as pleasure, pain,
and self-stimulation, suggests that they may be involved
in affective illness. One straightforward hypothesized formulation involves decreased endogenous opiate function in
depression and increased opiate function in mania. Such
alterations could occur either in the endogenous opiate
neuromodulator or in the density or sensitivity of opiate
receptors.
Evaluation of these hypotheses has been approached
through several experimental paradigms, such as administrating opiate agonists or antagonists to patients, assessing
endorphins and related opiate-binding activity in spinal
fluid and plasma, conducting neuroendocrine tests following a challenge with exogenous opiates, and examining the
532
Pathophysiology
Neurobiology
533
534
Pathophysiology
manic, euthymic, or depressed unipolar and bipolar subjects and normal volunteers.
Substance P receptors, also known as neurokinin-1 (NK1) receptors, are highly expressed in brain regions that regulate affective behavior and response to stress, such as the
limbic system. An examination of NK-1 receptors in postmortem brain of subjects with bipolar disorder (n = 13),
unipolar depression (n = 13), and schizophrenia (n = 14) and
normal controls (n = 14) (Burnet and Harrison, 2000) found
no differences in autoradiographic binding in the anterior
cingulated gyrus among the four groups, although the possibility of a Type II error cannot be excluded. However, the ratio of superficial to deep laminar binding was lower in the
group with unipolar depression, which the authors theorize
could reflect alterations in specific neural circuits expressing
the NK-1 receptor. Given the important role of the amygdaloid complex in the regulation of emotional behavior,
Carletti and colleagues (2005) compared the mRNA levels of
preprotachykinin A (PPT-A, a precursor of both substance P
and neurokinin A [NKA]) and 3H-SP binding sites in the
amygdala of patients affected by bipolar disorder, major depression, or schizophrenia with those of matched controls. A
significant reduction in PPT-A mRNA expression levels was
detected in all three diagnostic groups, mainly in the basal,
lateral, and accessory basal amygdaloid nuclei, but not in the
temporal cortical area proximal to the amygdala. While these
results support the involvement of the tachykinins in bipolar
disorder, they suggest that there is a generalized impairment
of the substance P system in the amygdala in mood disorders
and schizophrenia rather than this being a disease-related
phenomenon.
Lithium has been shown to increase the substance P
content of striatum when administered chronically to rats,
an effect antagonized by the concurrent administration of
haloperidol (Hong et al., 1983). More recent studies have
demonstrated a lithium-induced increase in tachykinin
levels that appears to be associated with an increase in
transcription of the rat preprotachykinin gene (Sivam
et al., 1989). Studies of the effects of subchronic lithium on
regional brain concentrations of substance P, neurokinin A,
and neuropeptide Y have demonstrated a regionally specific increase in the immunoreactivity of all the peptides
(Mathe et al., 1990; Husum et al., 2001).
Preclinical studies have suggested that NK-1 antagonists
may have anxiolytic effects (File, 1997) and that substance
P agonists have anxiolgenic properties (Aguiar and Brandao, 1996). These findings have led to the development of
potential antidepressants, such as MK-869, an NK-1 antagonist. MK-869 was shown to be as effective as paroxetine
in treating depressive symptoms in a double-blind, placebocontrolled study (Kramer et al., 1998). Unfortunately, the
further development of MK-869 as an antidepressant has
been suspended because of side effects. At any rate, subsequent large clinical studies, which included an active SSRI
comparator, showed no efficacy of an NK-1 antagonist in
the treatment of depression.
Neuropeptide Y. Neuropeptide Y (NPY) is a 36 aminoacid peptide synthesized in the arcuate nucleus of the hypothalamus and found in the raphe nucleus. It is stimulated
by stress and corticosteroids. Preclinical studies have indicated that antidepressants, lithium, and ECT all increase
the concentration of NPY (by immunoreactivity) (Stenfors
et al., 1989; Wahlestedt et al., 1990) and mRNA expression
(Weiner et al., 1992; Zachrisson et al., 1995) in many brain
regions in rats. Further, reduced concentrations of NPY
have been observed in the CSF (Widerlv et al., 1988b) and
plasma (Hashimoto et al., 1996; Nilsson et al., 1996) of patients with major depression. There have been some results
conflicting with the hypothesis that NPY is downregulated in
depression; for example, Berrettini and colleagues (1987)
found no difference in CSF NPY immunoreactivity among
diagnostic groups, and Irwin and colleagues (1991) actually
found an increase in plasma NPY immunoreactivity in depressed patients. Widdowson and colleagues (1992) found reduced immunoreactivity of NPY in the prefrontal cortex and
caudate nucleus of suicide victims, particularly in those with
a diagnosis of major depression. Caberlotto and Hurd (1999)
studied NPY mRNA levels in the prefrontal cortex of patients
diagnosed with schizophrenia, bipolar disorder, and unipolar depression, as well as in normal controls. NPY mRNA
levels were found to be reduced in bipolar patients only, with
no correlation with suicide.
NPY acts through at least five distinct receptor subtypes, with the Y1 and Y2 subtypes being most abundant in
the CNS. Preclinical studies in animal models of depression have indicated that the Y1 receptor mRNA is decreased in specific limbic and cortical regions, while the Y2
receptor mRNA appears to be unaltered. Caberlotto and
Hurd (2001), however, found no alterations of the expression of either Y1 or Y2 mRNA levels in the prefrontal cortex in subjects with bipolar disorder, unipolar depression,
or schizophrenia compared with matched controls. Thus,
despite the conflicting findings on NPY levels in CSF, further exploration of NPY mRNA levels, receptor levels, and
clinical effects is warranted.
Studies from the Mathe laboratory (Zachrisson et al.,
1995; Husum et al., 2001) have demonstrated that lithium,
electroconvulsive treatments (ECT in humans and electroconvulsive shock in rodents), and antidepressants affect
NPY in a specific temporal manner and in specific brain regions. More recently, the same laboratory investigated brain
NPY-like immunoreactivity (NPY-LI) under basal conditions and following a series of electroconvulsive shocks in
Neurobiology
535
536
Pathophysiology
Norepinephrine
Serotonin
Acetylcholine
Dopamine
Glutamate
GABA
Cortisol
CRF
TRH
GH
SST
Signal
Transduction
Pathways
FDG $s
rCBF $s
Circadian
and other
Biological
Rhythms
manic versus bipolar depressed or euthymic patients or normal controls. Carmens group followed up its preliminary
CSF investigations with a double-blind clinical trial of calcitonin in mania and observed a significant and substantial
reduction in hyperactivity in 85 percent of the manic patients. A later study found that calcitonin gene-related peptide immunoreactivity (CGRP-LI) concentrations in CSF
were increased in depressed patients compared with schizophrenic and control subjects (Mathe et al., 1994).
Most recently, Buervenich and colleagues (2001) investigated the frequency of four novel polymorphisms in the
calcitonin/CGRP (CALCA) gene in a number of neuropsychiatric disorders. They found that a 16base pair
microdeletion polymorphism was present in a family with
multiple cases of unipolar or bipolar depressive disorder.
Furthermore, using this polymorphism as a marker, cosegregation with the phenotype was observed in the majority
of individuals. These intriguing findings await independent replication.
abnormalities.53 Signal transduction pathways are in a pivotal position in the CNS, able to affect the functional balance among multiple neurotransmitter systems, and have
therefore been postulated to play a role in mediating the
more-downstream abnormalities in multiple neurotransmitter systems and physiological processes (Manji et al.,
2000a; Warsh et al., 2000; Bezchlibnyk and Young, 2002).
(Figure 1410 illustrates the pivotal position of signal transduction pathways.) Moreover, as we discuss in greater detail below, signaling pathways are clearly targets for our
most effective pharmacological treatments for recurrent
mood disorders.
Neurobiology
of human diseases (Milligan and Wakelam, 1992; Weintraub, 1995; Spiegel, 1998). Pertinent for the present discussion is the observation that a variety of diseases manifest relatively circumscribed symptomatology despite
the widespread, often ubiquitous expression of the affected signaling proteins.
Complex signaling networks are likely present in all
eukaryotic cells and control various metabolic, humoral,
Figure 1411. Four major signaling pathways in the postsynaptic region of a neuron that combine to form a local signaling
network. The major linear routes of signal flow are depicted by the thick arrows of four different colors: light grey (phospholipase
C [PLC)] pathway), light blue (Ras pathway), dark grey (adenylyl cyclase pathway), and dark blue (Ca2+/calmodulin [CaM] pathway).
The interactions between different pathways are represented by black lines with arrows (representing activation) or dots (representing inhibition). Although most major interactions in the network are shown, these connections are not meant to be all-inclusive;
additional connections could exist. The three different shades of background represent three different cell compartments: the plasma
membrane (top level), cytosol (middle level), and nucleus (bottom level). Some of the signaling proteins that translocate between
different compartments are shown in both compartments. Examples include mitogen-activated protein kinase (MAPK), which when
activated translocates from the cytoplasm to the nucleus to phosphorylate and activates transcription factors; and the transcription
factor CREB, which upon phosphorylation by protein kinase A (PKA) translocates to the nucleus. AA = anachiclonic acid;
AC = adenylate cyclase; AMPAR = AMPA-type glutamate receptor; AR = beta-adrenergic receptor; BDNF = brain-derived neurotrophic factor; Ca = Calcium; CaM = calmodulin; CaMK = CaM kinase; cAMP = cyclic AMP; CaN = calcinerinn; CREB = cAMPresponsive element-binding protein; DAG = diacylglycerol; GEF/SOS = guanine nucleotide exchange factor/SOS; GLU = glutamate;
IP3 = inositol triphosphate; MEK = MAP kinase kinase; mGluR = metabotropic glutamase receptor; NE = norepinephrine;
NMDA = NMDA-type glutamate receptor; PDE = phosphodiesterase; PKA = protein kinase A; PKC = protein kinase C; PLA2 = phospholipase A2; PLC- = phospholipase C-beta; PPI = protein phosphatase-1; RTK = receptor tyrosine kinase. (Source: Weng et al., 1999.
Reprinted with permission from AAAS.)
BDNF
IP3
DAG
#& Gq%
GRB2
GEF/SoS
Glu
#AR
#& Ge'
NMDAR
AC1/8
AC2
PLC#
RTK
NE
Ras
Raf
CaM
PDE
MEK 1,2
MAPK 1,2
MAPK 1,2
CaN
cAMP
AA
PLA2
CaMKII
PKA
PP1
Cytoplasm
CREB
CaMKIV
Elk-1
Nucleus
AMPAR
Ca
PKC
Ca
537
CREB
CREB
538
Pathophysiology
Table 141. Clinical Studies of Second Messenger System Abnormalities in Patients with Manic-Depressive Illness (Primarily Bipolar)
Intracellular
Messengers
Tissue
Physiological Change
Study
G proteincoupled
cyclic AMP system
Postmortem cerebral
cortex
Mononuclear
leukocytes (MNLs)
Phosphoinositidegenerated second
messenger system
Postmortem occipital
cortex
Postmortem frontal
cortex
Platelets
AC = adenyl cyclase; BPD = bipolar disorder; BP-I = bipolar-I; Li = lithium; PI = phospoinositide; PIP2 = phosphatidylinositol biphosphate; PKA = protein kinase A; PKC = protein kinase C;
PMA = phorbol 12-myristate 13-acetate.
540
Pathophysiology
G%s
&
#
(()
AC
G%i
&
#
(")
ROLIPRAM
ATP
FORSKOLIN
cAMP
PHOSPHODIESTERASE
PKA
AMP
Activation of other
signaling pathways
CREB
Gene transcription
Neurobiology
541
Physiological Change
Study
Postmortem
cerebral
cortex
Leukocytes and
platelets
542
Pathophysiology
significantly lower in cytosolic fractions of frontal, temporal, occipital and parietal cortex, cerebellum, and thalamus of bipolar patients than in matched controls (Rahman et al., 1997). Furthermore, preliminary findings
indicate that the reduction of regulatory subunits of PKA
in the cytosolic fractions of temporal cortex of bipolar
patients is accompanied by higher basal kinase activity
in the cytosolic fractions of those patients temporal cortex (Fields et al., 1999). These observed changes in PKA
provide additional important evidence for dysregulation
Physiological Change
Study
Postmortem
cerebral
cortex
Leukocytes
and platelets
AC = adenyl cyclase; BPD = bipolar disorder; Li = lithium; MDD = major depressive disorder;
PKA = protein kinase A.
Neurobiology
543
by which chronic lithium may indirectly regulate the activity of these critical signaling proteins.
Although it appears that lithium (at therapeutic concentrations) does not affect G proteins directly, considerable evidence indicates that chronic lithium administration affects
G protein function indirectly.56 Interestingly, for both Gs
(the G protein stimulating cAMP production) and Gi (the
G protein inhibiting cAMP production), lithiums major
effects in both humans and rodents are most compatible
with a stabilization of the heterotrimeric, undissociated,
inactive alpha beta gamma () conformation of the G
protein.57 Lithium also exerts complex effects on the activity of AC, with the preponderance of the data demonstrating an elevation of basal AC activity but an attenuation of
receptor-stimulated responses in both preclinical and clinical studies.58 It has been postulated that these elevations of
basal cAMP and dampening of receptor-mediated stimulated responses may play an important role in lithiums
ability to prevent excessive excursions from the norm
(Manji et al., 1995a; Jope, 1999). These complex effects likely
represent the net effects of direct inhibition of AC, upregulation of certain AC subtypes, and effects on the stimulatory and inhibitory G proteins (Chen et al., 1996a; Li and
El-Mallahk 2000; Manji and Lenox, 2000a).59
Consistent with this hypothesis, lithium has been shown
to potentiate the hyperactivity induced by intra-accumbens
cholera toxin administration (which activates the stimulatory G proteins, Gs and Golf ) (Kofman et al., 1998). An investigation of the effects of lithium on the striatum revealed
that 2 weeks (but not 1 week) of lithium increased the protein
levels by about 50 percent (Miki et al., 2001). Furthermore,
it was found that Golf returned to baseline levels 1 week after withdrawal of lithium. These investigators postulated
that the increased Golf expression after chronic lithium represents a compensatory adaptation to the suppression of
the AC system by lithium (see below) and may be responsible (at least in part) for the rebound increase in manic
episodes observed after abrupt lithium discontinuation (see
Chapter 19). These results suggest that direct inhibitors of
AC (such as carbamazepine) may have utility in the prevention of lithium-discontinuation emergence of mania.
Overall, many of the long-term effects of chronic lithium
on G proteins are likely attributable to an indirect posttranslational modification of the G protein(s) and a relative change in the dynamic equilibrium of the active and
inactive states of protein conformation. In this context, it
is noteworthy that investigators have demonstrated that
lithium alters the levels of endogenous ADP-ribosylation
in C6 glioma cells (Young and Woods, 1996) and in rat
brain (Nestler et al., 1995), suggesting another mechanism
544
Pathophysiology
Neurobiology
hippocampus. Furthermore, the same group has demonstrated that chronic antidepressant treatment increases the
expression of two important genes known to be regulated
by CREBBDNF and its receptor TrkB (Duman et al.,
1997, 2000). Preliminary postmortem human brain studies
have also indicated increased levels of CREB and hippocampal BDNF (B. Chen et al., 2001) in patients treated
with antidepressants, providing indirect support for the
rodent and cell culture studies (Dowlatshahi et al., 1998).
Interestingly, recent studies have shown that shortterm sleep deprivation brings about changes in pCREB
and BDNF similar to those seen with chronic antidepressants. This finding raises the intriguing possibility that
antidepressant- or sleep deprivationinduced activation
of these plasticity cascades may play a role not only in the
antidepressant effect but also in the mania-inducing effect of these modalities. This possibility is discussed in
greater detail later.
545
Physiological Change
Study
Postmortem
cerebral
cortex
Platelets
Erythrocytes
Atack, 1996
Shimon et al., 1997
Ebstein et al., 1988
Friedman et al., 1993
BPD = bipolar disorder; Li = lithium; PIP2 = phosphatidylinositol biphosphate; PKC = protein kinase C;
PLC = phospholipase C.
Source: Bezchlibnyk and Young, 2002.
Neurobiology
547
and a similar injection to A10 area (where the VTA is located) disrupted cocaine sensitization (Steketee, 1994).
Increased hedonistic drive and increased tendency to
abuse drugs are well known facets of manic behavior. Two
models of such behaviors are consumption of reward and
conditioned place preference (CPP) (Papp et al., 1991). PKC
inhibition with H7 in the A10 area blocked the development
of cocaine CPP (Steketee, 1994), ICV injections of the PKC
inhibitor calphostine blocked morphine CPP (Narita et al.,
2001), and intra-accumbens injections of the PKC inhibitor
NPC-15437 blocked amphetamine CPP (Aujla and Beninger,
2003). Furthermore, PKC inhibition in the accumbens inhibited the development of morphine dependence, a measure that may be related to increased drug craving (Valverde
et al., 1996).
PKC-related targeted mutations also support the involvement of PKC in affective-like behaviors. PKC knockout
(KO) mice show reduced morphine-induced CPP (Narita
et al., 2001) and PKC KO mice demonstrate reduced
ethanol self-administration (Olive et al., 2000).
Indeed, abundant evidence has now accumulated to
show that activation of PKC enhances both depolarizationmediated and basal release of DA (Robinson, 1991; Cowell
and Garrod 1999), a neurotransmitter implicated in the
manic syndrome (as discussed above). Release of DA by PKC
activation has been demonstrated in a variety of tissues,
including striatal synaptosomes, effects that have been
demonstrated to be independent of extracellular calcium.
The ability of amphetamine to produce heightened locomotor activity is thought to be due to its ability to enhance
DA release from mesolimbic DA neurons. Furthermore,
PKC inhibitors have been demonstrated to markedly reduce
amphetamine-induced DA release (Giambalvo, 1992a,b). It
is now believed that in addition to blocking the reuptake of
NE and DA, psychostimulants facilitate the release of these
neurotransmitters in large part by activation of PKC (Giambalvo, 1992a,b; Gnegy et al., 1993; Iwata et al., 1997a,b).
Finally, recent nonhuman primate studies investigating cognitive deficits similar to those observed in mania have also
demonstrated the efficacy of a selective PKC inhibitor. Birnbaum and associates (2004) have demonstrated that excessive activation of PKC dramatically impaired the cognitive
functions of the prefrontal cortex, exposure to stress activated PKC and resulted in prefrontal dysfunction, and inhibition of PKC (including indirectly with mood stabilizers)
protected cognitive function. These data suggest that PKC
may play an important role in some of the cognitive features
of mania.
As noted earlier, abnormalities of circulating glucocorticoids are well known to be associated with affective symptomatology (Banki et al., 1987), and interestingly, elevated
glucocorticoids have been associated with both depressive
548
Pathophysiology
Neurobiology
549
Table 145. Intracellular Calcium in Blood Elements of Manic-Depressive Illness (Primarily Bipolar): Platelets
Study
Stimulation
Intracellular Ca level
Treatment Status
Basal
Untreateda
Basal
PAF/thrombin
Basal
Thrombin
Basal
Thrombin
Basal
Basal
5-HT
Basal
Dopamine
Dubovsky et al., 1994
Basal
Basal
5-HT/PAF
Basal
Thrombin
Basal
5-HT
Basal
5-HT
Basal
Thrombin/
5-HT/TGN
5-HT
Basal
5-HT
Haloperidol-treated
b
Untreatedb
Treated and untreatedb
Untreated
BP = bipolar patients; BPd = BP depressed; BPe = BP euthymic; BPm = BP manic; C = controls (healthy volunteers); CBZ = carbamazepine;
DSS = difference statistically significant; Li = lithium; MS = mood stabilizer; PAF = platelet activator factor; SA = schizoaffective patients; TCA = tricyclic antidepressant; UP = unipolar patients; UPd = unipolar depressed patient; UPm = UP melancholic; UPn = UP not melancholic.
a
Statistical significance not calculated.
b
Difference not statistically significant.
c
Follow-up of 5 years.
550
Pathophysiology
Table 146. Intracellular Calcium in Blood Elements of Manic-Depressive Patients (Primarily Bipolar): Lymphocytes
Study
Stimulation
Intracellular Ca level
Treatment Status
Basal
Basal not shown
fMPL
Basal
PHG, concavalin A
Untreated
Basal in neutrophils
fMLP
Basal in BLCL
PHG in T ly
Basal
Thrombin, 5-HT, TGN
BP > C (14)
BPm> C only with TGN
a
a
BLCL = immortalized B lymphoblasts cell line; BP = bipolar patients; BPd = BP depressed; BPe = BP euthymic; BPm = bipolar patient manic;
C = controls (healthy volunteers); CBZ = carbamazepine; fMLP = formylmethionylleucylphenalanin; Li = lithium; PHG = phytohemaglutinin;
UP = unipolar patients; TGN = thapsigargin; T ly = T lymphocytes.
a
Statistical significance not calculated.
b
Difference not statistically significant.
Neurobiology
551
Activity
Study
Erythrocytes
Neutrophils
Leukocytes
and platelets
A number of recent studies have investigated the possibility that lithium and other putative mood stabilizers may
regulate the PI system independently of inhibiting IMPase.
In this context, investigators have examined lithiums effects on the PI system distal to the receptor since, as noted
above, experimental evidence has shown that lithium may
alter receptor coupling to PI turnover.65
A most interesting potential new target for the actions
of structurally dissimilar mood stabilizers is a high-affinity
myoinositol transport system (called SMITSodium
sensitive high-affinity Myo-Inositol Transporter) that has
been characterized in various cell types, including those of
neural origin (van Calker and Belmaker, 2000). Thus it
was recently demonstrated that the activity of the SMIT and
the expression of its mRNA in astrocytes are downregulated
after chronic treatment with therapeutic concentrations
552
Pathophysiology
Ca2(
glutamate
(NMDA subtype)
Ca2(
Ca2(
Voltage gated
calcium channel
Na/Ca
exchanger
Na(
calcium
pump
ATP
ADP
ryanodine
receptor
high calcium
concentration
calmodulin
cl u
enzymes
and other
calcium
targets
IP3
receptor
target proteins
phosphoinositol
signaling pathway
et i
C2-domains
endoplasmic r
calcium
binding/buffering
proteins
Figure 1413. In neurons, Ca2+-dependent processes represent an intrinsic, nonsynaptic feedback system that
provides the competence for adaptation to different functional tasks. Ca2+ is generally mobilized in one of two
ways in the cells: either by mobilization from intracellular stores or from the outside of the cell via plasma membrane ion channels and certain receptors (e.g., NMDA). The external level of Ca2+ is approximately 2mM, yet
resting intracellular Ca2+ levels are in the range of 100nM (2 1 0 4 lower). Local high levels of calcium result in
activation of enzymes, signaling cascades, and at extremes, cell death. Release of intracellular stores of calcium is
primarily regulated by IP3 receptors, which are activated upon generation of IP3 by phospholipase C activity, and
the ryanodine receptor that is activated by the drug ryanodine. Ca2+ is sequestered in the endoplasmic reticulum
(the vast web and framework for Ca2+-binding proteins to capture and sequester Ca2+). Ca2+-buffering and triggering proteins are nonuniformly distributedthus the considerable subcellular variation of Ca2+ concentrations (e.g.,
near a Ca2+ channel). The primary mechanism for Ca2+ calcium exit from the cell is via sodium calcium exchange or
by means of a calcium pump. (Source: Schatzberg and Nemeroff, 2004. Reprinted with permission from The American Journal of Psychiatry. Copyright 2004 by the American Psychiatric Association.)
Neurobiology
Figure 1414. Effects of lithium on the phosphoinositide (PI) cycle. A number of receptors in the central nervous system (including M1, M1, M1, 5-HT2) are coupled, via Gq/11, to activation of PI hydrolysis. Activation of these receptors induces phospholipase C hydrolysis of phosphoinositide 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol-1,4,5-triphosphate (Ins
1,4,5P3). DAG activates protein kinase C (PKC), an enzyme that has many effects including the activation of phospholipase A-2
(PLA2; an activator of arachidonic acid signaling pathways). IP3 binds to the IP3 receptor, resulting in the release of intracellular
calcium from intracellular stores, most notably the endoplasmic reticulum (ER). Calcium, an important signaling molecule, initiates a number of downstream effects such as activation of calmodulins and calmodulin-dependent protein kinases. IP3 is recycled
back to PIP2 by the enzymes inositol monophosphate phosphatase (IMPase) and inositol polyphosphatate phosphatase (IPPase),
both of which are targets of lithium. Thus, lithium may initiate many of its therapeutic effects by inhibiting these enzymes, bringing about a cascade of downstream effects involving PKC and gene expression changes. A = agonist; BBB = bloodbrain barrier;
G = protein; R = receptor. (Source: Schatzberg and Nemeroff, 2004. Reprinted with permission from The American Journal of Psychiatry. Copyright 2004 by the American Psychiatric Association.)
myo-inositol (? BBB)
PIP
PI
PKC
PIP2
R
PLC
DAG
PA
Ins
Lithium
Inhibition
CMP
Inositol
"
LITHIUM
(
(
"
553
1,4
,5P
Ins 4P
Ins 1P
Ins 3P
ER
de novo synthesis
glucose-6-phosphate
Ca((
554
Pathophysiology
Figure 1415. The potential mechanisms by which chronic lithium (Li+) or valproate (VPA), or direct-acting protein kinase C (PKC) inhibitors, may be useful in the treatment of acute mania. Activation of PKC, which is known to occur
through psychostimulants or stress, results in the phosphorylation of key substrates, notably GAP-43 (growth-coneassociated protein) and MARCKS (myristoylated alanine-rich C kinase substrate), facilitating the release of neurotransmitters. Chronic lithium or valproate attenuates PKC signaling, an effect that may be responsible for the treatment of various
facets of the manic syndrome. (Source: Bachman et al., 2005. Reprinted with permission.)
%i/o
Ri
# (")
&
(!)
Li
VPA
NE
DA
Glu
(!)
PKC
(")
Ca2(
GAP-43 (!)
(")
(!)
PKC
Ri
(!)
%i/o
#
&
Ca2(
Ca2(
Ca2(
Phosphorylation of %1 subunit
of P/Q type channels by PKC
Excessive activation of
regulating affective,
cognitive, motoric, and
hedonic circuitry
Neurobiology
PKC activity
PKC
pPKC
PKC
MARCKS levels
Inositol-responsive
Lithium
Valproate
555
556
Pathophysiology
an AA-specific phospholipase A2 (cPLA2). Valproate decreased the turnover of AA by 33 percent with no effect on
cPLA2 protein levels, and was postulated to act directly in
the incorporation of AA into brain phospholipids. Ongoing
studies should serve to delineate the facets of recurrent
mood disorders (perhaps especially bipolar disorder) that
these membrane changes may modulate.
Neurobiology
557
558
Pathophysiology
Wnt
Cadherin
BDNF
Ras
#-catenin
Frizzled
"
(
(
Disheveled
"
Lithium
tau
p
p
Raf
Valproate
Shc
TrkB
Sos
MEK
RSK
Erk
GSK-3#
MAP-1B
p
Ubiquitin
#-catenin
xin
tcf
lef
degradation
T1
AP
FRA
?
#-catenin
AP-1
tcf
lef
C-Jun
O
CH2 CH2 CH2
CH C OH
CH2 CH2 CH2
Valproate
"
(
(
(
"
Lithium
Figure 1416. Signaling through Wnt glycoproteins and frizzled receptors activates disheveled, resulting in inhibition of
glycogen synthase kinase-3fl (GSK-3fl). Phosphorylation of fl-catenin by GSK-3fl results in its degradation by ubiquitin. Nondegraded (nonphosphorylated) fl-catenin binds to lef/tcf transcription factors, targeting transcription of specific genes.
Lithium competes with Mg2+ to inhibit GSK-3fl (Ryves and Harwood, 2001). Valproate may be an inhibitor of GSK-3fl. Alternately, it may exert its action on Wnt signaling through inhibition of histone deacetylase, by its known actions on C-Jun,
through upregulation of fl-catenin mRNA, or by its action on the Ras/RSK pathway (Chen et al., 1997, 1999; Phiel and Klein,
2001; Yuan et al., 2001). BDNF = brain-derived neurotrophic factor; MAP = mitogen-activated protein kinase; MEK = MAP
kinase kinase. (Source: Gould and Manji, 2002b. Reprinted by permission of SAGE Publications, Inc.)
Neurobiology
559
560
Pathophysiology
O
CH2 CH2 CH2
CH C OH
CH2 CH2 CH2
"
(
(
Valproate
(
"
Lithium
PERIOD
DOUBLETIME
SHAGGY/
GSK-3#
TIMELESS
PERIOD
P
PERIOD
TIMELESS
PERIOD
TIMELESS
P
period
timeless
CYCLE
CLOCK
VRILLE
Figure 1417. Schematic of genes involved in the circadian cycles of Drosophila (a) and mammals (b). The
molecular mechanism regulating circadian rhythms relies on a daily cycle of interactions between positive and
negative regulators. In Drosophila (a), CYCLE (Drosophila BMAL1) and CLOCK help mediate transcription of
TIMELESS and PERIOD genes. PERIOD binds to TIMELESS in the cytoplasm. These proteins then enter the
nucleus and act as negative regulators of CLOCK and CYCLE (Allada et al., 2001). SHAGGY (the Drosophila orthologue of GSK-3) appears to phosphorylate TIMELESS, advancing the entry of this protein into the nucleus
(Martinek et al., 2001). Lithium is a direct inhibitor of SHAGGY (Klein and Melton, 1996; Stambolic et al., 1996),
suggesting a method by which lithium lengthens the circadian period in diverse species, including Drosophila
(Klemfuss, 1992). The mammalian circadian cycle (b) has many similarities (Allada et al., 2001) as well as notable
differences, for example, lack of a true TIMELESS orthologue (Reppert and Weaver, 2001). The role of GSK-3 in
mammalian circadian cycles is unknown (see also Chapter 16). (Source: Gould and Manji, 2002b. Reprinted by
permission of SAGE Publications, Inc.)
the anterior cingulate cortex (Cotter et al., 2002a) and dorsolateral prefrontal cortex (Reynolds et al., 2002) in bipolar disorder. (Calbindin-immunoreactive neurons are
known to colocalize with GABA). Elegant detailed studies
from the Rajkowska laboratory have undertaken measurements of the density and size of calbindin-immunoreactive
neurons in layers II and upper part of layer III of the dorsolateral prefrontal cortex, revealing a 43 percent reduction
Neurobiology
561
p
cassien kinase I
PERIOD 1, 2, 3
GSK-3#
?
PERIOD 1, 2, 3
cryptochrome 1 & 2
cryptochrome 1 & 2
PERIOD 1, 2, 3
PERIOD 1, 2, 3
cryptochrome 1 & 2
period 1, 2, 3
cryptochrome 1 & 2
Bmal 1 & 2
CLOCK
in the density of these neurons in major depressive disorder compared with controls (Rajkowska, 2002a,b). Notably, in the rostral orbitofrontal cortex there was a trend
for a negative correlation between the duration of depression and sizes of neuronal cell bodies (Rajkowska et al.,
1999). The longer the duration of illness, the smaller the
neurons were, suggesting changes associated with disease
progression. More subtle than in major depressive disorder, reductions in neuronal soma size have been observed
in bipolar disorder by some investigators (Rajkowska et al.,
2001; Chana et al., 2003) but not by all (Ongur et al., 1998;
Bouras et al., 2001; Cotter et al., 2001). In one other study a
minor increase in the size of small nonpyramidal neurons
was noted in the anterior cingulate cortex in bipolar subjects (Benes et al., 2001). However, given the major trophic
effects of lithium and valproate, it is quite possible that the
more modest findings in bipolar disorder actually represent a long-term protective effect of these medications.
562
Pathophysiology
Acrophase
Control
Li-treated
Mesor
Period
Figure 1418. Chronic lithium treatment and circadian rhythms. The most prominent rhythmic component under normal conditions has a period of 24 hours. This
rhythm usually reflects a complex interaction between endogenous rhythmic and other
mechanisms (homeostatic, adaptive, pathological, etc.). The 24-hour rhythms with a
proven endogenous component are called circadian, reflecting the observation that under constant external conditions the rhythms free run with an endogenous period that
is close to 24 hours. Chronic (but not acute) lithium treatment prolongs the free-running
period in almost all studied biological systems, including humans. The mechanism of
lithiums action on the diverse circadian rhythms probably involves combined effects at
the level of the circadian clock and at the integration of circadian rhythmicity with
other regulatory systems (see also Chapter 16). (Source: Ikonomov and Manji, 1999.)
found in major depressive subjects (Stockmeier, 2003). Neuronal density in major depressive disorder was markedly
increased by 3040 percent above the control level and neuronal cell body size was significantly decreased in the
CA13 subfields and dentate gyrus. An increase in packing
density paralleled by smaller cell sizes in major depressive
disorder suggests a decrease in neuropil consisting of neuronal and glial processes and their synapses (Stockmeier,
2003).
Glial Cell Pathology. In addition to neuronal pathology,
unexpected reductions in glial cell number and density
have recently been found in postmortem brains of both patients with major depression and bipolar disorder. Marked
decreases in overall and laminar (layers IIIIV) glial cell
packing densities were found in subjects with major depressive disorder compared with nonpsychiatric control
subjects (Rajkowska et al., 1999). Comparable reductions in
glial densities were also detected in DLPFC from subjects
with bipolar disorder across all cortical layers except layer
IV (Rajkowska 1997, 2000). Further immunohistochemical
examination of PFC glial cells in major depressive disorder
indicated that the reductions in the population of astroglial
cells account at least in part for the global glial deficit that
has also been found in this disorder (Miguel-Hidalgo et al.,
2000). In bipolar disorder, however, it is possible that a dif-
ferent population of glial cells (oligodendroglia and/or microglia) may be involved in this pathology, since reductions
in a different morphological type of glial cell were consistently observed in all cortical layers of DLPFC in bipolar
subjects (Rajkowska, 2000). An independent histological
study of area sg24 located in the subgenual prefrontal cortex also found striking reductions in glial cell numbers in
patients with familial major depressive disorder (24 percent
reduction) and bipolar disorder (41 percent reduction)
compared to controls (Ongur et al., 1998). However, when
familial and nonfamilial subgroups of depressed patients
were combined, the reductions were not found; these intriguing findings raise the possibility that the subgenual
prefrontal coretx glial cell findings may be most apparent in
a particularly strongly genetic form of the illness. This observation is consistent with this groups neuroimaging report on reductions in cortical gray matter volume found in
the same brain region in a similar diagnostic group. While
these results are intriguing, further immunohostochemical
and molecular studies are needed to definitively determine
if the same types of glial cells underlie the glial deficit that
has been observed in both major depressive disorder and
bipolar disorder, and if this glial loss occurs via similar
mechanisms. While the most prominent findings thus far
have been from the frontal cortex, a growing body of data
suggests that glial pathology extends beyond the frontal
563
Neurobiology
pr
es
yn
ap
5-HT or NE
transporter
SSRIs
SNERIs
tic
ne
uro
n
Wht
BDNF
+
+
PLC &
Pathway
GPCR
G%s
Adenylate
Cyclase
GPCR
G% l
# &
(")
(()
TrkB
&
#
cell membrane
Frizzled
Gasl
Grb-2
PIP3
shC
Lithium
SOS
PI3K
APC
FRAT1
Ras
RAF
AXIN
Akt
GTP
ATP
Disheveled
tau
MAPIB
APOPTOSIS
cAMP
GSK-3
CREB
MEK
BAD
P
BAD
CJun
Bcl-2
#-catenin
Tcf/Lef
phosphodiesterase
P
PKA
ERK
P
nu
cle
RSK
ne
bra
em
rm
Bcl-2
P
Tcf/Lef
CREB
#-catenin
gene transcription
Bcl-2
BDNF
Figure 1419. Glycogen synthase kinase-3 (GSK-3) is a component of diverse signaling pathways. These include G proteincoupled receptor signaling (left), neurotrophic factor signaling (center), and the Wnt signaling pathway (right). Neurotrophins such as brain-derived
neurotrophic factor (BDNF) act through Trk receptors A, B, and C to activate phosphoinositide-3 kinase (PI3K) and Akt and inhibit GSK-3.
Many effectors have been implicated in GSK-3s neurotrophic effects, including transcription factors (e.g., C-Jun, p53, CREB) and recently
the proapoptotic Bcl-2 family member BAX. In the Wnt signaling pathway, secreted Wnt glycoproteins interact with the frizzled family of receptors and through disheveled-mediated signaling inhibit GSK-3. Stability of this process requires the scaffolding proteins axin and adenomatous polyposis coli (APC). Normally, active GSK-3 phosphorylates -catenin, leading to its ubquitin-dependent degradation. However,
when GSK-3 is inhibited in the Wnt pathway, -catenin is not degraded, allowing for its interaction with T-cell-specific transcription factor
(Tcf ) to act as a transcription factor. (Source: Gould and Manji, 2005. Reprinted with permission from Macmillan Publishers, Ltd.)
cortex to the hippocampus. A recent study of the hippocampus in 40 patients with major depression and agedmatched control subjects reported marked increases in glial
cell density and unchanged sizes of glial nuclei in all hippocampal CA subfields and the granule cell layer of the
dentate gyrus (Stockmeier et al., 2004). Increases in glial
cell packing density detected postmortem in patients with
major depression are suggestive of reduction in surrounding neuropil (see above) and may be related to decreases in
hippocampal volume noted by neuroimaging studies in
major depression disorder (see Chapter 15).
Glial Cell Type Affected in Mood Disorders. Glial cells do
not represent a single subtype, and in addition to their
564
Pathophysiology
Reduced Glia
Area; Hemisphere
Methods
Neurons
Glia
Study
Prefrontal Cortex
MDD (12)/C (12)
Nissl
Nissl
MDD (15)/BPD
(15)/C (15)
MDD (14)/C (15)
DLPFC (BA 9)
left + right
DLPFC (BA 9); left
Nissl
GFAPIHC
Nissl
Anterior Cingulate
Cortex
MDD (4f )/
BPD (4f )/C (5f )
Nissl
MDD (15)/
BPD (15)/C (15)
MDD (20)/
BPD (21)/C (55)
Nissl
Nissl
= Density
(continued)
Table 149. Morphological Abnormalities in the Cerebral Cortex in Mood Disorders (continued)
Disease
(No. of Subjects)
Area; Hemisphere
Methods
Neurons
Glia
Study
MDD (15)/
BPD (15)/C (15)
Nissl
MDD (15)/
BPD (15)/C (15)
CB, PV,
CR IHC
Not examined
BA = Brodmanns area; BPD = bipolar disorder; C = control; CB = calbindin; CR = calretinin; DLPFC = dorsolateral prefrontal cortex; f = familial; GFAP = glial fibrillary acidic protein;
IHC = immunohistochemistry; L = layer; MDD = major depressive disorder; ORB = orbitofrontal cortex; PV = paravalbumin; , indicate significantly different from control;
= indicates not significantly different from control.
Source: Reproduced with permission from Rajkowska et al., 2004.
Neurobiology
567
568
Pathophysiology
Neurotrophins are a family of regulatory factors that mediate the differentiation and survival of neurons, as well as the
modulation of synaptic transmission and synaptic plasticity.
They can be secreted constitutively or transiently, and often
in an activity-dependent manner. Recent observations support a model in which neurotrophins are secreted from the
dendrite and act retrogradely at presynaptic terminals to induce long-lasting modifications. Within the neurotrophin
family, BDNF is a potent physiological survival factor that
has also been implicated in a variety of pathophysiological
conditions. The cellular actions of BDNF are mediated
through two types of receptors: a high-affinity tyrosine receptor kinase (TrkB) and a low-affinity pan-neurotrophin
receptor (p75). TrkB is preferentially activated by BDNF and
NT4/5, and it appears to mediate most of the cellular responses to these neurotrophins.
BDNF and other neurotrophic factors are necessary for
the survival and function of neurons, which implies that
a sustained reduction of these factors could affect neuronal
viability. What is sometimes less appreciated, however, is
the fact that BDNF also has a number of much more acute
effects on synaptic plasticity and neurotransmitter release
and facilitates the release of glutamate, GABA, DA, and
serotonin.78
As discussed earlier, BDNF is best known for its longterm neurotrophic and neuroprotective effects, which may
be very important for its putative role in the pathophysiology and treatment of mood disorders. In this context, it is
noteworthy that although endogenous neurotrophic factors have traditionally been viewed as increasing cell survival by providing necessary trophic support, it is now clear
Neurotrophic-Signaling-Mediated
Mitochondrial Function
Neurobiology
569
570
Pathophysiology
Neurobiology
571
BDNF
TrkB
Y Y
P
GAPs
Ras
GDP
Ras
GTP
Long-term neuroplasticity
SHC
GRB2
SOS
Cytoskeletal remodeling
RAF
Neurite outgrowth
Neuronal survival
MEK
Synaptic proteins
Neurotransmitter release
ERK
Neuronal excitability
Synaptic plasticity
RSK
Nucleus
P
Bcl-2
Other critical neurotrophic genes
ERK
P
Elk-1
BAD
Sequestered, inactive
CREB
Figure 1420. The influence of neurotrophic factors on cell survival, as mediated by activation of the mitogen-activated protein (MAP) kinase cascade. Activation of neurotrophic factor receptors, also referred to as Trks, results in activation of the MAP kinase cascade via several intermediate steps, including phosphorylation of the adaptor protein SHC and recruitment of the guanine nucleotide exchange factor SOS. This
results in activation of the small guanosine triphosphatebinding protein Ras, which leads to activation of a cascade of serine/threonine kinases. This includes Raf, MAP kinase kinase (MEK), and MAP kinase (also referred to as extracellular response kinase, or ERK). Ras also activates the PI3 kinase pathway, a primary target of which is the enzyme glycogen synthase kinase (GSK-3). Activation of the PI3 kinase pathway
deactivates GSK-3. GSK-3 has multiple targets in cells including transcription factors (-catenin and C-Jun) and cytoskeletal elements such as
tau. Many of the targets of GSK-3 are pro-apoptotic when activated. Thus, deactivation of GSK-3 via activation of the PI3 kinase pathway results in neurotrophic effects. Lithium inhibits GSK-3 and this may be partially responsible for lithiums psychotrophic effects. One target of the
MAP kinase cascade is RSK, which influences cell survival in at least two ways. Rsk phosphorylates and inactivates the pro-apoptotic factor
BAD. RSK also phosphorylates CREB and thereby increases the expression of the anti-apoptotic factor Bcl-2 and brain-derived neurotrophic
factor (BDNF). (Source: Manji et al., 2003a.)
days, and enhanced response to psychostimulants (reviewed in Chen and Manji, 2006). Very recent studies have
therefore examined the role of the ERK pathway as a behavioral modulator in left anterior cingulate cortex, one of
the brain regions being implicated in the pathophysiology
of mood disorders by human brain imaging and postmortem studies (Chen and Manji, 2006). Rats chronically
infused with an ERK pathway inhibitor directly to left
572
Pathophysiology
Neurobiology
573
Figure 1421. Effects of chronic lithium and valproate treatment on Bcl-2 immunolabeling in frontal cortex. Rats were chronically treated
with saline, lithium, or valproate, and immunohistochemistry of Bcl-2 was performed in parallel for each of the groups. Chronic lithium and
valproate treatment resulted in a doubling of Bcl-2 levels in FCx. (Source: Manji et al., 1999b. Reprinted with permission.)
Subsequent to these findings, lithium was demonstrated to increase Bcl-2 levels in C57BL/6 mice (Chen et
al., 1999), human neuroblastoma SH-SY5Y cells in vitro
(Manji and Chen, 2000), and rat cerebellar granule cells
in vitro (Chen and Chuang, 1999). This latter work was
undertaken as part of research investigating the molecular and cellular mechanisms underlying the neuroprotective actions of lithium against glutamate excitotoxicity
(see below). The investigators found that lithium produced a remarkable increase in Bcl-2 protein and mRNA
levels. Moreover, lithium was found to reduce levels of
the pro-apoptotic protein p53 in both cerebellar granule
cells (Chen and Chuang, 1999) and SH-SY5Y cells (Lu
et al., 1999).
Overall, then, the data clearly show that chronic lithium
exposure robustly increases levels of the neuroprotective
protein Bcl-2 in areas of rodent frontal cortex, hippocampus, and striatum in vivo, and in cultured cells of both rodent and human neuronal origin in vitro. Furthermore, at
least in cultured cell systems, lithium has been demon-
574
Pathophysiology
Increased total gray matter volumes on MRI compared to untreated bipolar disorder patients in cross-sectional studies
Neurobiology
575
Figure 1422. Chronic lithium protects against quinolic acid (QA)induced toxicity and against middle cerebral artery occlusion. Left panel:
Sixteen days of lithium pretreatment decreases the size of QA-induced striatal lesion determined by GAD67 mRNA in situ hybridization. Rats
(n = 1 0 ) were subcutaneously pre-injected with lithium chloride (LiCl) for 16 days and then intrastriatally infused with QA (30nmol). Control
rats (n = 8 ) received subcutaneous injections of normal saline instead of LiCl. Animals were killed 7 days after QA infusion and brains were sectioned for in situ hybridization using a 33P-labeled antisense oligonucleotide probe complementary to 67kDa GAD mRNA. Shown here are autoradiograms of GAD67 mRNA in situ hybridization from a typical saline control and lithium-pretreated experiment. Right panel: Chronic
lithium treatment protects against ischemic brain damage in a focal cerebral ischemia model in rats. Representative photomicrographs show ischemic brain damage in a saline-treated control (top) and LiCl-treated rat (bottom) 24 hours after left middle cerebral artery (MCA) occlusion.
Note that ischemic damage was observed in the cerebral cortex of the frontal, sensorimotor, and auditory areas and in the lateral segment of the
caudate nucleus. Chronic lithium reduced the area of ischemic brain damage. (Source: Nonaka and Chuang, 1998; Wei et al., 2001. Reprinted with
permission from Lippincott Williams & Wilkins.)
576
Pathophysiology
Lithium was the first medication demonstrated to robustly upregulate Bcl-2 in rodent brain in vivo and in cells
with a human neuronal phenotype (see above). Furthermore, these effects of lithium occur well within its therapeutic range (indeed, robust effects occur at levels less
than those required to treat acute mania). Studies were
therefore undertaken to determine whether lithium would
not only prevent injury-induced degeneration of RGCs
and other CNS neurons but also promote the regeneration
of their axons (Huang et al., 2002) (see Fig. 1423). These
studies showed that lithium, acting directly on RGCs, supports both neuronal survival and axon regeneration at its
established therapeutic concentrations (.51.2 mM) (Huang
et al., 2002). These intriguing results not only offer new
clues to a better understanding of the regulation of retinal
and CNS regeneration but also suggest that lithium may
have considerable utility in treating retinal and optic nerve
neurodegeneration (e.g., glaucoma and optic nerve neuritis) and conditions involving optic nerve damage and/or
RGC loss. In view of lithiums well-established safety profile in humans and the fact that robust effects are observed
at well-tolerated levels, clinical trails should be undertaken
for treatment of these devastating illnesses.
Figure 1423. Li+ promotes retinal ganglion cell (RGC) axon regeneration in a dose-dependent
manner in culture. A: Epifluorescence photomicrographs of representative retina-brain slice cocultures
in the absence and presence of lithium chloride (LiCl). Regenerating axons were labeled by placing DiI
(a lipophilic fluorescent label) into retinal explants and were visualized by fluorescence microscope. Arrows indicate labeled axons growing into the brain slices. B, C: Doseresponse curve of Li+ on axon regeneration. B: The number of labeled axons extending into the brain slices. C: Quantification of the
longest distances of axon regeneration into the brain slices, measured from the interfaces of the retinal
explants and brain slices. *p < .05 compared with control. (Source: Huang et al., 2003. Reproduced with
permission of Investigative Ophthalmology and Visual Science.)
577
578
Pathophysiology
In view of Bcl-2s major neuroprotective and neurotrophic role, a study was undertaken to determine whether
lithium, administered at therapeutically relevant concentrations, affects neurogenesis in adult rodent brain. To investigate the effects of chronic lithium on neurogenesis,
mice were treated with therapeutic lithium (plasma levels
.97 .20 mM) for approximately 4 weeks. After treatment
with lithium for 14 days, the mice were administered single
doses of BrdU, a thymidine analog that is incorporated
into the DNA of dividing cells, for 12 consecutive days.
Lithium treatment continued throughout the duration of
the BrdU administration. Following BrdU immunohistochemistry (Chen et al., 2000), three-dimensional cell counting was performed with a computer-assisted image analysis
system (see Rajkowska, 2000). This system is based on the
optical disector method and estimates the number of cells
independent of section thickness and cell shape. It was
found that chronic lithium administration does in fact result in an increase in the number of BrdU-positive cells in
the dentate gyrus (Chen et al., 2000) (see Fig. 1424).
Moreover, approximately two-thirds of the BrdU-positive
Figure 1424. Effects of chronic lithium neurogenesis in the dentate gyrus of adult mice. C57BL/6 mice were treated with lithium for 14 days
and then received once-daily bromodeoxyuridine (BrdU) injections for 12 consecutive days while lithium treatment continued. Twenty-four
hours after the last injection, the brains were processed for BrdU immunohistochemistry. Cell counts were performed in the hippocampal dentate gyrus at three levels along the dorsoventral axis in all the animals. BrdU-positive cells were counted using unbiased stereological methods.
Chronic lithium produced a significant 25% increase in BrdU immunolabeling in both right and left dentate gyrus (p < .05). Many BrdU-labeled
neurons also stained with NeuN, a neuron-specific marker. (Source: Chen et al., 2000; Gray et al., 2003. Reprinted with permission from Blackwell Publishing Ltd.)
Neurobiology
579
Figure 1425. Valproate promotes neurite growth in a time- and concentration-dependent manner. The photographs from a representative
experiment were taken after 1-, 4-, 8-day treatments with valproate (VPA). Data shown in bar graph are mean standard error of 30100 cells
measured in the photographs. Similar results were obtained from two additional independent experiments. Arrow in right panel indicates growth
cone. (Source: Adapted from Yuan et al., 2001. Reproduced with permission of American Society for Biochemistry and Molecular Biology.)
of CNS symptoms in disorders such as demyelinating disease, amyotrophic lateral sclerosis, mitochondrial encephalopathies, and HIV dementia. NAA is synthesized
within mitochondria, and inhibitors of the mitochondrial
respiratory chain decrease NAA concentrations, effects
that correlate with reductions in ATP and oxygen consumption (Manji et al., 2000a). Thus, NAA is now generally regarded as a measure of neuronal viability and function, rather than strictly as a marker for neuronal loss
per se (for an excellent review of NAA, see Tsai and Coyle,
1995).
It has been found that chronic lithium administration
at therapeutic doses increases NAA concentration in the
human brain in vivo (Moore et al., 2000). This finding
provides intriguing indirect support for the contention
that, similar to observations in rodent brain and in human neuronal cells in culture, chronic lithium increases
neuronal viability and function in the human brain. Furthermore, a striking correlation of approximately .97 between lithium-induced NAA increases and regional voxel
gray matter content was observed (Moore et al., 2000),
thereby providing evidence for colocalization with the
region-specific Bcl-2 increases observed (e.g., gray versus
white matter) in rodent brain cortices. These results suggest that chronic lithium may exert not only robust neuroprotective effects (as has been demonstrated in a variety
580
Pathophysiology
lizer lithium via high-resolution volumetric MRI in wellcharacterized bipolar depressed subjects (n = 28) at baseline
(medication-free) and following chronic lithium administration (4 weeks) (Moore et al., 2006). Total brain gray matter, prefrontal gray matter, and left subgenual prefrontal
gray matter were determined by means of validated semiautomated segmentation and region-of-interest methodology. Significant increases in total brain gray matter in bipolar subjects were observed following chronic lithium
administration, confirming the previous preliminary study.
Regional analyses in the bipolar subjects revealed significant
differences between responders (greater than 50 percent decrease in HAM-D) and nonresponders; only responders
showed increases in gray matter in the prefrontal cortex and
left subgenual prefrontal cortex (Moore et al., 2006). The increase in gray matter in these areas that are specifically implicated in the neuropathophysiology of bipolar disorder in
various neuroimaging and postmortem neuropathology investigations suggests that the observed effects may be linked
to clinical response. The findings also support the notion
that future development of treatments more directly targeting molecules in critical CNS pathways regulating cellular
plasticity hold promise as novel, improved long-term treatments for mood disorders (see Fig. 1428).
It is striking that lithium has such robust effects on the cytoprotective protein Bcl-2, exerts neuroprotective effects in
Figure 1426. Mechanism by which lithium may increase N-acetyl-aspartate (NAA) levels.
Lithium, via its effects on Bcl-2 and glycogen synthase kinase 3 (GSK-3), may exert major
neurotrophic effects, resulting in neuropil increases, accompanied by increases in NAA levels.
ERK = extracellular receptor-coupled kinase. (Source: Manji et al., 2000b. Reprinted with
permission from Elsevier.)
Lithium
+ +
+
NAA
ERK
Gray
Matter
bcl-2
0
GSK-3#
Neurobiology
581
Figure 1427. Brain gray matter volume is increased following 4 weeks of lithium administration at therapeutic levels in patients with bipolar
disorder. Brain tissue volumes were examined by means of high-resolution three-dimensional MRI and validated quantitative brain tissue segmentation methodology to identify and quantify the various components by volume, including total brain white and gray matter content. Measurements were made at baseline (medication-free, after a minimum 14-day washout) and then repeated after 4 weeks of lithium at therapeutic
doses. Chronic lithium significantly increases total gray matter content in the human brain of patients with bipolar disorder. No significant
changes were observed in brain white matter volume or in quantitative measures of regional cerebral water. (Source: Gould and Manji, 2002b.
Reprinted by permission of SAGE Publications, Inc.)
582
Pathophysiology
Figure 1428. Neurotrophic mechanisms in depression. Severe stress causes several changes in hippocampal pyramidal neurons, including
a reduction in their dendritic arborizations, and a reduction in brain-derived neurotrophic factor (BDNF) expression (which could be one of
the factors mediating the dendritic effects). Antidepressants increase dendritic arborizations and BDNF expression of these hippocampal neurons via growth factor cascades. By these actions, antidepressants may reverse and prevent the actions of stress on the hippocampus and ameliorate certain symptoms of depression. VPA = valproate. (Source: Adapted from Nestler et al., 2002a. Reprinted with permission from Elsevier.)
Neurobiology
583
Figure 1429. Effects of low-dose lithium treatment on Bcl-2 levels in rat frontal cortex and hippocampus. Chronic lithium was shown to robustly increase the levels of the major neuroprotective protein Bcl-2 at therapeutic levels (.61.0mM). A series of studies was undertaken to determine if low-dose lithium also produced Bcl-2 upregulation. Inbred male Wistar Kyoto rats were treated with Li2CO3 at full dose (resulting
in plasma levels of ~.8mM) or half dose (resulting in plasma levels of ~.35mM) for 3 to 4 weeks. Left panel: Quantification of immunoblotting of
Bcl-2 in frontal cortex, which was conducted by established methods with monoclonal antibodies directed against Bcl-2. Right panel: Immunohistochemistry in rat hippocampus. Treatment of rats with either full-dose or half-dose lithium for 3 to 4 weeks resulted in significant increases in the
levels of Bcl-2. * p < .05 compared with control. These results suggest that low-dose lithium may also confer neuroprotective effects, even in those
patients who are intolerant of full-dose lithium because of side effects.
584
Pathophysiology
Antidepressant Treatment
Inhibit 5-HT and NE
reuptake or breakdown
5-HT or NE
#AR
5-HT
PDE
Inhibitor
5-HT or NE
Gs
Gx
AC
5-HT 2
%1 AR
cAMP
Ca2(-dependent kinases
PKA
nucleus
CREB
BDNF Gene
Expression
Figure 1430. Influence of antidepressant treatment on the cAMPCREB cascade. Antidepressant treatment increases synaptic levels of norepinephrine (NE) and 5-HT by blocking the reuptake
or breakdown of these monoamines. This results in activation of intracellular signal transduction
cascades, one of which is the cAMPCREB cascade. Chronic antidepressant treatment increases Gs
coupling to adenylyl cyclase (AC), particulate levels of cAMP-dependent protein kinase (PKA), and
CREB. CREB can also be phosphorylated by Ca2+-dependent protein kinases, which can be activated by the phosphatidylinositol pathway (not shown) or by glutamate ionotropic receptors (e.g.,
NMDA). Glutamate receptors and Ca2+-dependent protein kinases are also involved in neural plasticity. One gene target of antidepressant treatment and the cAMPCREB cascade is brain-derived
neurotrophic factor (BDNF), which contributes to the cellular processes underlying neuronal
plasticity and cell survival. (Source: Manji and Duman, 2001.)
200
*
150
STL
DSP
100
50
0
Veh
TCP
FLX
ECS
MOR
COC
HAL
200
*
*
150
STL
DSP
100
50
0
Veh
TCP
FLX
ECS
MOR
COC
HAL
Figure 1431. Chronic antidepressant treatment increases CREB and BDNF expression in rat hippocampus. Upregulation of CREB mRNA (a) occurs in response to several different classes of antidepressant treatments, including norepinephrine- and serotonin-reuptake inhibitors, and electroconvulsive seizure, indicating that the cAMPCREB cascade is a common postreceptor target of these
therapeutic agents (Nibuya et al., 1995, 1996). Notably, CREB mRNA increases were not observed with
several nonantidepressant psychoactive agents (including morphine, cocaine, or haloperidol), indicating specificity of effects. Upregulation of BDNF mRNA (b) also occurs in response to several different
classes of antidepressant treatments, including a norepinephrine/NE reuptake inhibitor, SSRIs, and
electroconvulsive seizure. Notably, BDNF mRNA increases were not observed with several nonantidepressant psychoactive agents (including morphine, cocaine, or haloperidol), indicating specificity of
effects. In addition, upregulation of both CREB and BDNF is dependent of chronic treatment, consistent with the therapeutic action of antidepressants. As discussed in the text (not shown here), lithium
and valproate have also been shown to upregulate CREB and BDNF mRNA and protein levels. Indirect human evidence comes from studies showing increased hippocampal BDNF and CREB expression in postmortem brain of subjects treated with antidepressants at the time of death compared with
that of antidepressant-untreated subjects. COC = cocaine (a psychostimulant); DSP = desipramine (a
noradrenergic antidepressant); ECS = electroconvulsive shock (an animal model of ECT); FLX = fluoxetine (an SSRI); HAL = haloperidol (a typical antipsychotic); MOR = morphine (an opioid);
STL = sertraline (an SSRI); TCP = tranylcypromine (an MAOI); Veh = vehicle control. (Source: Unpublished data from Ronald S. Duman, Ph.D. Professor of Psychiatry and Pharmacology, Director, Abraham Ribicoff Research Facilities Yale University School of Medicine.)
585
586
Pathophysiology
Neurobiology
587
Figure 1432. Neurotrophic effects of antidepressants. Left: Antidepressant treatment increases synaptic levels of norepinephrine (NE) and
serotonin (5-HT) by blocking the reuptake or breakdown of these monoamines. This results in activation of intracellular signal transduction
cascades, one of which is the cyclic adenosine monophosphatecAMP-responsive element-binding protein (cAMPCREB) cascade. Chronic antidepressant treatment increases Gs coupling to adenylyl cyclase (AC), particulate levels of cAMP-dependent protein kinase (PKA), and CREB.
CREB can also be phosphorylated by Ca2+-dependent protein kinases, which can be activated by the phosphatidylinositol pathway or by glutamate ionotropic receptors (e.g., NMDA, not shown). One gene target of antidepressant treatment and the cAMPCREB cascade is brain-derived
neurotrophic factor (BDNF), which contributes to the cellular processes underlying neuronal plasticity, and restoration/enhancement of neural
connectivity mechanisms, which are essential for healthy affective functioning. Right: At the dendritic level, antidepressants increase synapse formation and neural outgrowth, restoring critical circuitry function. AR = adrenoreceptors; DAG = diacylglycerol; IP, inositolmonophosphate;
NMDA = N-methyl-D-aspartate; P = phosphorylated; PIP2 = phosphoinositide 4,5-biphosphate; PLC, phospholipase C; TrkB, specific tyrosine
kinases receptor. (Source: Manji et al., 2003b.)
588
Pathophysiology
intact and that altered synaptic activity will thus be transduced to modify the postsynaptic throughput of the system.
However, the evidence presented here suggests that, in addition to neurochemical changes, many patients also have
pronounced structural alterations (e.g., reduced spine density, neurite retraction, overall neuropil reductions) in critical neuronal circuits. Thus, optimal treatment may be attained only by providing more direct trophic support. The
trophic support would be envisioned as enhancing and
maintaining normal synaptic connectivity, thereby allowing
the chemical signal to reinstate the optimal functioning of
critical circuits necessary for normal affective functioning.
While lithium and valproate clearly exert neurotrophic
effects, they do so through indirect mechanismsthat is,
many of their direct biochemical targets are considerably
upstream of neuroprotective proteins such as GSK-3, ERK,
and Bcl-2. Thus many patients with endogenous or acquired defects in the machinery involved in mediating the
effects of mood stabilizers on neurotrophic proteins would
Figure 1433. Antidepressant treatment increases neurogenesis in adult hippocampus. Left panel: A typical section of dentate gyrus that has
undergone immunohistochemical analysis for bromodeoxyuridine (BrdU), the thymidine analog used to label newborn cells. The darker cells in
the subgranular zone (SGZ) represent BrdU-positive cells. Chronic antidepressant treatment increases the number of BrdU-positive cells, determined 24 hours after BrdU administration. Right panel: Quantification of immunocytochemical data, showing antidepressant treatments increase the number of BrdU-labeled cells in dentate gyrus. Con = control; ECS = electroconvulsive shock; Fluox = fluoxetine, a 5-HT selective inhibitor; Reb = a norepinephrine selective reuptake inhibitor reboxetine; TCP = a monoamine oxidase inhibitor tranylcypromine. (Source: Gray et
al., 2003; unpublished data from Ronald S. Duman, Ph.D. Professor of Psychiatry and Pharmacology, Director, Abraham Ribicoff Research Facilities, Yale University School of Medicine.)
Neurobiology
589
Figure 1434. Resolution of the tryptophan depletion conundrum of the neurotrophic hypothesis of antidepressant drug action. Treatment
of depression is attained by providing both trophic and neurochemical support; the trophic support restores normal synaptic connectivity,
thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. Brainderived neurotrophic factor (BDNF) also facilitates the release of neurotransmitters that act on this restored, intact circuit. Acute reduction in
synaptic serotonin levels via its effects on reducing BDNF levels is capable of rapidly reducing the release of a number of neurotransmitters.
Thus, tryptophan depletion diets are capable of inducing a depressive relapse in selective serotonin reuptake inhibitortreated patients via the
effects on neurotransmitter release, although likely not having major effects on structural brain changes. AC = adenylyl cyclase; cAMP = cyclic
adenosine monophosphate; CREB = cAMP-responsive element-binding protein; DAG = diacylglycerol; GABA = gamma-aminobutyric acid;
Glu = glutamate; IP, inositolmonophosphate; NE = norepinephrine; NMDA = N-methyl-D-aspartate; P = phosphorylated; PIP2 = phosphoinositide 4,5-biphosphate; PKA = protein kinase A; PLC, phospholipase C; TrkB, specific tyrosine kinases receptor. (Source: Manji et al., 2003b.)
rizes findings to date on potential targets for the development of new agents for the treatment of mood disorders (see
Fig. 1435).
CONCLUSIONS
The first edition of Manic-Depressive Illness was published
in 1990; since then, there have been tremendous advances
in our understanding of both the normal and abnormal
functioning of the brain. Indeed, it is our firm belief that
the impact of molecular and cellular biologywhich has
been felt in every corner of clinical medicinewill ultimately also have major repercussions for our understanding about the fundamental core pathophysiology of manicdepressive illness, and will lead to the development of
improved treatments. Recent years have witnessed a more
wide-ranging understanding of the neural circuits and the
Table 1410. Potential Targets for the Development of New Antidepressants and Antibipolar Agents
Function Plausibly
Relevant to Mood
Disorders
5-HT1A/
5-HT1B
antagonists
5-HT2
antagonists
5-HT7
antagonists
590
Molecule
Hypothesized
Involvement in Mood
Disorders or Treatment
2 antagonists
administered
during REM
sleep
Observations from
Clinical Treatment
Studies
Direct or Surrogate
Human Evidence
Somatodendritic 5-HT1A
receptors regulate 5-HT
neuron firing; nerve
terminal 5-HT1B receptors
facilitate 5-HT release.
Blockade increases 5-HT
throughput via two
mechanisms.
CNS distribution; may
regulate DA throughput;
important roles in regulating sleep and appetite
Coadministration of
5-HT1A/5-HT1B antagonists
facilitates AD-induced
5-HT throughput.
Equivocal results to
date; pindolol may
not be the ideal
drug to test
hypothesis
2 antagonists
(idazoxan, mirtazapine) have been
shown to exert AD
effects. Use of an 2
antagonist during
REM sleep is quite
novel; human studies are just getting
under way.
Enhanced throughput of
CRF receptors may
mediate some of the
signs and symptoms
of depression and
anxiety; CRF antagonists may be effective
ADs and/or anxiolytics.
Regulates NE LC firing;
activated by stress; CRF
receptors are well placed
to regulate many of the
neurovegetative symptoms of depression.
Short-term
treatment
with GR
antagonists
Hypercortisolemia may
play an important role
in the pathophysiology
and/or deleterious
long-term consequences of mood
disorders.
NPY receptor
agonists
Injection of a GR antagonist
into the dentate gyrus
attenuates the acquisition
of learned helpless behavior; transgenic and KO
mice exhibit some symptoms of anxiety and
depression. ADs exert
complex effects on GR
expression and function.
Efficacy in animal models of
depression; stress regulates
re-distribution of NK1
receptors; NK1 KO shows
reduced anxiety in certain
models
Efficacious in animal models
of anxiety; NPY KO shows
reduced anxiety in certain
models. ADs and lithium
may increase NPY
expression.
NK1 antagonists
(substance P
receptors)
Hippocampal atrophy
mediated in part by
hypercortisolemia. (Most
studies have concentrated
on the hippocampus,
but other brain areas
may likely show similar
changes.) Diabetes, bone
mineral density also
affected
Play important roles in
mediating pain (? psychic
pain); NK1 receptors
reduce 5-HT neurotransmission.
591
CRF antagonists
(continued)
Table 1410. Potential Targets for the Development of New Antidepressants and Antibipolar Agents (continued)
Hypothesized
Involvement in Mood
Disorders or Treatment
Function Plausibly
Relevant to Mood
Disorders
NMDA
antagonists
Enhanced throughput of
the NMDA receptor
may contribute to
brain-regional volumetric changes observed in depression;
NMDA antagonists
may have antidepressant efficacy.
AMPA
potentiators
AMPA-potentiating agents
have shown efficacy in
animal models of
depression. An ampakine
(CX516) has been shown
to produce a marked
facilitation of performance
in a memory task in rats.
PDE4 inhibitors
Reduced throughput of
cAMP signaling cascade may be involved
in depression; enhancement of cAMP signaling may be AD
Molecule
Direct or Surrogate
Human Evidence
592
Very indirectimpairment
of neuronal plasticity
and cellular resilience
Observations from
Clinical Treatment
Studies
Amantadine and
especially lamotrigine have antidepressant efficacy;
preliminary results
suggest that ketamine may have
antidepressant efficacy. Studies with
other NMDA
antagonists are
planned.
No studies yet on
mood disorders;
preliminary human
studies suggest a
positive memory
encoding effect in
certain spheres;
beneficial effects
seen on measures
of attention and
memory when
added to clozapine
in schizophrenia
Preliminary early clinical studies suggested AD efficacy
of rolipram; newer
clinical studies with
PDE inhibitors
as AD adjuncts are
under way
593
MAP kinase
phosphatase
inhibitors
Isozyme
selective
PKC
inhibitors
Enhancement of PKC
activity may play a role
in the symptomatology of mania; PKC
inhibitors may be
antimanic.
GSK-3
inhibitors,
-catenin
upregulators
GSK-3 inhibitors,
-catenin upregulators
may have moodstabilizing effects.
Very indirectregional
No clinical studies
volumetric reductions in
with specific agents
mood disorders; evidence
to date
for glial and neuronal loss/
atrophy in mood disorders
(continued)
Table 1410. Potential Targets for the Development of New Antidepressants and Antibipolar Agents (continued)
Molecule
Bcl-2
upregulators
Hypothesized
Involvement in Mood
Disorders or Treatment
Function Plausibly
Relevant to Mood
Disorders
Direct or Surrogate
Human Evidence
Preliminary postmortem
brain studies suggest
possible involvement of
Bcl-2 in mood disorders;
lithium increases gray
matter volumes in brain
areas of reported atrophy
in humans.
Observations from
Clinical Treatment
Studies
594
AD = antidepressant; BDNF = brain-derived neuotrophic factor; BPD = bipolar disorder; CNS = central nervous system; CRF = corticotropin-releasing factor; CRH = corticotropin-releasing
hormone; CSF = cerebrospinal fluid; ECS = electroconvulsive shock; ECT = electroconvulsive therapy; GR = glucocorticoid receptor; GSK = glycogen synthase kinase; HPA = hypothalamic
pituitaryadrenal; KO = knockout; LC = locus coeruleus; MAP = mitogen activated protein; NE = norepinephrine; NK = neurokinin; NPY = neuropeptide Y; PET = positron emission
tomography; PKC = protein kinase C; REM = rapid eye movement.
Note: See text for references.
Source: Adapted from Nestler and Manji, 2002.
Neurobiology
595
Stress
Depression
5HT
NE
BDNF
Glutamate
BDNF
Cortisol
NMDA
trk trk
B B
P
Antidepressants
Lithium
Akt
Ca2(
GR
GSK-3
ROS
Energy
Capacity
Neuroplasticity
and
Cellular Resilience
BAD
Bcl-x
trk B
trk B
BDNF
ROS
Ca2(
(S)
Cytochrome C
Bcl-2
MEK
Failure of
Neuroplasticity
Signal
RSK-2
ERK
Lithium
Genetic and
Developmental
Factors
Repeated Episodes
Illness Progression
Raf
CREB
Bcl-2
Lithium
VPA
Ras GTP
VPA
Cerebrovascular
Insufficiency
Figure 1435. The multiple influences on neuroplasticity and cellular resilience in mood disorders. Genetic and neurodevelopmental factors, repeated affective episodes, and illness progression might all contribute to the impairments of cellular resilience, volumetric
reductions, and cell death and atrophy observed in mood disorders. Stress and depression likely contribute to impairments of cellular
resilience by a variety of mechanisms, including reductions in the levels of BDNF, facilitating glutamatergic transmission via NMDA
and non-NMDA receptors, and reducing the cells energy capacity. Neurotrophic factors such as BDNF enhance cell survival by activating two distinct signaling pathways: the PI3kinase pathway, and the ERKMAP kinase pathway. One of the major mechanisms by
which BDNF promotes cell survival is by increasing the expression of the major cytoprotective protein, Bcl-2. Bcl-2 attenuates cell
death through a variety of mechanisms, including impairment of the release of calcium and cytochrome c, sequestering of proforms
of death-inducing caspase enzymes, and enhancement of mitochondrial calcium uptake. The chronic administration of a variety of
antidepressants increases the expression of BDNF and its receptor TrkB. Lithium and valproate robustly upregulate the cytoprotective
protein Bcl-2 and inhibit GSK-3, biochemical effects shown to have neuroprotective results. Valproate also activates the ERKMAP kinase pathway, which may play a major role in producing neurotrophic effects and neurite outgrowth. BAD = pro-apoptotic members of
the Bcl-2 family; Bcl-2 and Bcl-x = anti-apoptotic members of the Bcl-2 family; BDNF = brain derived neurotrophic receptor;
CREB = cyclic AMP-responsive element-binding protein; GR = glucocorticoid receptor, GSK-3 = glycogen synthase kinase-3;
MEK = ERK, components of the ERK-MAP kinase pathway; Ras = Raf; ROS = reactive oxygen species; RSK-2 = ribosomal S-6 kinase;
TrkB = tyrosine kinase receptor for BDNF; VPA = valproate. (Source: Manji et al., 2001a. Reprinted with permission from Macmillan
Publishers, Ltd.)
various mechanisms of synaptic transmission, the molecular mechanisms of receptor and postreceptor signaling,
and a finer understanding of the process by which genes
code for specific functional proteins that in toto reduce
the complexity in gene-to-behavior pathways (Gould and
Manji, 2004). Here we synthesize and summarize the major advances pertaining to manic-depressive illness.
596
Pathophysiology
are separate disease entities with different underlying etiologies, emerging findings from many fields of psychiatric
research do not fit well with this model (Craddock et al.,
2005). Most notably, the pattern of findings emerging from
genetic studies shows increasing evidence for an overlap in
genetic susceptibility across the traditional classification
categories. It is clear that there is not a one-to-one relationship between genes and behaviors so that different combinations of genes (and resultant changes in neurobiology)
contribute to any complex behavior (normal or abnormal)
(Hasler et al., 2006). It is also critically important to remember that polymorphisms in genes will very likely
simply be associated with bipolar disorder or recurrent depression; these genes will likely not invariably determine
outcome, but only lend a higher probability for the subsequent development of illness. In fact, genes will never code
for abnormal behaviors per se, but rather code for proteins
that make up cells, forming circuits, that in combination
determine facets of both abnormal and normal behavior.
These expanding levels of interaction have made the study
of psychiatric diseases so difficult. The next task of psychiatric genetic research is to study how and why variations in
these genes impart a greater probability to develop manicdepressive illness (to understand pathophysiology) and
then to direct therapeutics at that pathophysiology (Gould
and Manji, 2004). There is no doubt that knowledge of the
genetics and subsequent understanding of their relevant
biology will have a tremendous impact on diagnosis, classification, and treatment of psychiatric disease.
An Endophenotype Strategy
It is becoming increasingly clearer that, while the pathways
beginning with genes and then expressed through simple
biological processes do not necessarily have a single quantifiable endpoint (i.e. behavior), it may be possible to assay
the result of aberrant genes through biologically simpler
approaches (Hasler et al., 2006). The term endophenotype
is described as an internal, intermediate phenotype (i.e.,
not obvious to the unaided eye) that fills the gap in the
causal chain between genes and distal diseases (Gottesman
and Shields, 1973), and therefore may help to resolve questions about etiology. The endophenotype concept assumes
that the number of genes involved in the variations of endophenotypes representing more elementary phenomena
(as opposed to the behavioral macros found in the DSM)
are fewer than those involved in producing the full disease
(Gottesman and Gould, 2003).
Will an endophenotype strategy lead to a major payoff?
Endophenotypes provide a means for identifying the upstream traits underlying clinical phenotypes, as well as the
downstream biological consequences of genes. The
methods available to identify endophenotypes include
Neurobiology
597
Liability to
Bipolar Disorder
Reaction Surface
Bipolar Disorder
Bipolar
Spectrum
Envir
onme
Harmful
nt
Protective
-9 Months
28 Years
Age
PRODROMAL
SYMPTOMS
Candidate
Endophenotypes
early onset
white matter
abnormalities
attention
deficits
reduced anterior
cingulate volume
QTLs in Genome
ipto
tran
ics
eom
prot
bioinformatic
inspirations
response to
psychostimulants
scr
dysmodulation
of motivation &
reward
mic
s
arcadian rhythm
instability
etc.
epigenetic
influences
SYMPTOMS
Candidate
Regions
2p13-16
4p16,q32
?
6q16-22
8q
9p21-22
Candidate
Genes
BDNF
SERT
10q21-22
12q23-24
13q32-34
G72/G30
14q24-32
Epistasis + g x e ? x ?
15q14
18p11-12,q12,q21-23
COMT
22q11-22
DISC1,P2X7
GRK3,MAO A
GSK-3,XBP1
Figure 1436. Endophenotypes in bipolar disorder. A heuristic model whereby underlying bipolar disorder gene susceptibility loci and implicated genes, modulated by
environmental, epigenetic, and stochastic events, predispose to the development of
bipolar disorder. Along this lengthy continuum between genes and distal phenotype
lie putative bipolar endophenotypes, the identification of which will be useful for
studies of the underlying neurobiology and genetics of bipolar disorders, as well as for
preclinical investigations, such as the development of animal models. This figure is
meant to represent a guide to future studies rather than a definitive portrait of loci,
genes, and endophenotypes. QTL = quantitative trait locus. (Copyright 2005 by
I.I. Gottesman. Source: Hasler et al., 2006. Reprinted with permission from Elsevier.)
respective promoters caused by the selective increase of DNAmethyltransferase 1 in GABAergic neurons (Tremolizzo et
al., 2005). In sum, although considerable additional research is needed, our growing appreciation of the molecular mechanisms underlying geneenvironment interactions
raise the intriguing possibility that environmentally induced
neurobiological changes in early life may be amenable to
subsequent therapeutic strategies targeting the epigenome
(Petronis 2003, 2004).
598
Pathophysiology
mutations in expressed proteins have little effect on nonCNS functions, but major effects on behavior (Manji
et al., 2003a).
Abnormalities in cellular signaling cascades that regulate
diverse physiologic functions likely explain the tremendous comorbidity with a variety of medical conditions
(notably cardiovascular disease, diabetes mellitus, obesity, and migraine) and substance abuse. As a corollary, it
is worth noting that genetic abnormalities in signaling
components are often fully compatible with life, and in
many instances, despite the often-ubiquitous expression
of the signaling protein, one sees relatively circumscribed
clinical manifestations (i.e., the abnormalities are only
manifest in some physiologic systems, despite being potentially more widespread). These overt, yet relatively circumscribed, clinical manifestations are believed to ultimately arise from vastly different transcriptomes (all of
the transcripts present at a particular time) in different
tissues because of tissue-specific expression, haploinsufficiency, genetic imprinting, alternate splicing, varying stoichiometries of the relevant signaling partners in different
tissues, and differences in the ability of diverse cell types
to compensate for the abnormality (Manji et al., 2003a).
Signaling pathways are clearly major targets for hormones that have been implicated in the pathophysiology
of manic-depressive illness, including gonadal steroids,
thyroid hormones, and glucocorticoids.
Alterations in signaling pathways very likely represent
the neurobiological substrates subserving the evolution
of the illness over time (e.g., cycle acceleration). Thus,
signaling networks play critical roles in cellular memory;
cells with different histories, expressing different repertoires of signaling molecules, interacting at different levels, may respond quite differently to the same signal over
time. As discussed already, experimental sensitization or
kindling models have clearly shown that changes in signaling pathways play important roles in the long-term
neuroplastic adaptations observed.
Alterations in signaling pathways have major effects on
circadian rhythms known to be abnormal in manicdepressive illness. It is noteworthy that although this tendency to recur is among the most distinguishing features
of manic-depressive illness, in both its bipolar and its
highly recurrent unipolar forms, it is poorly described
and not well understood. It is noteworthy that studies
have begun to uncover the molecular underpinning of
circadian cycles (Chang and Reppert 2001). The core
clock mechanism appears to involve a transcriptional/
translational feedback loop in which gene products are
involved in negative feedback of themselves and other
genes in the pathway (see Chapter 16). The synchronized
multioscillators system offers several advantages; notably,
Neurobiology
599
600
Pathophysiology
5-HT
5-HT 1A
Dorsal
Raphe
NE
%2AR
Locus
Coeruleus
Stress
Glu
5-HT reuptake
transporter
Stress
Stress
Antidepressant
Glu reuptake
transporter
BDNF
Glia
NE reuptake
transporter
5
AMPAR
Gs
AKT
AC
cAMP
NMDAR
Ca2(-dependent or
MAPK cascades 2
11
Lithium
GSK-3
12
P
PKA
HDAC
BDNF
10
GC
GR
CREB
Stress
8
CRH
Stress
GC
GC
GR
Bcl-2
TrkB
Enhancement of cellular
plasticity and resilience
Figure 1437. Targets for novel treatments. The functional interactions among monoamine neurotransmitters, glutamate, and neurotrophic
signaling cascades, as well as various sites where stress affects these systems are illustrated. Genetic factors and life stress are both likely to contribute to the neurochemical alterations, impairments in cellular resilience, reductions in brain volume, and cell death and atrophy observed in
depression. Targets for increasing neuroplasticity and cellular resilience and facilitating new classes of antidepressant medications include the
following: (1) Phosphodiesterase inhibitors increase levels of pCREB. (2) MAPK modulators increase the expression of Bcl-2. (3) mGluR II/III
receptor agonists modulate the release of excessive levels of glutamate. (4) Drugs such as riluzole and felbamate act on Na+ channels to attenuate
glutamate release. (5) AMPA potentiators upregulate the expression of BDNF. (6) NMDA receptor antagonists such as memantine enhance plasticity and cell survival. (7) Drugs that increase glial release of trophic factors and clear excessive glutamate may have antidepressant properties.
(8) CRH antagonists may reverse the anxiogenic and depressogenic effects of extrahypothalamic CRH. (9) Glucocorticoid antagonists may attenuate the deleterious effects of hypocortisolemia. (10) Agents that upregulate Bcl-2 (such as pramipexole) may have antistress and antidepressant actions. 2-AR = 2-adrenergic receptor; AC = adenylyl cyclase; AMPAR = -amino 3-hydroxy-5-methylisoxazole propionate; BDNF = brainderived neurotrophic factor; CREB = cAMP-responsive element-binding protein; CRH = corticotrophin-releasing hormone; Gi = family of
G protein subunits that includes Gi and Go; Gq = family of G protein subunits that includes Gq and G11; Glu = glutamate; GR = glucocorticoid
receptor; GSK-3 = glycogen synthase kinase; HDAC = histone deacetylases; MAPK = mitogen-activated protein kinase; mGluR = metabotropic
glutamate receptor; NE = norepinephrine; NMDAR = N-methyl-D-aspartate receptor; PKA = protein kinase A; 5-HT = serotonin. (Source:
Charney and Manji, 2004. Reprinted with permission.)
be over as there are a number of pharmacologic plasticityenhancing strategies which may be of considerable utility
in the treatment of manic-depressive illness. Indeed, these
next-generation drugs, in addition to treating the core
symptoms of bipolar and/or highly recurrent unipolar disorder, might be able to target other important aspects of
the illness. They may, for example, be able to enhance cog-
Neurobiology
NOTES
1. For example, Robbins and Sahakian, 1980; Smith and Helms,
1982; Lerer et al., 1984; Berggren, 1985; Ushijama et al., 1986.
2. Wada et al., 1976; Leviel and Naquet, 1977; Albright and
Burnham, 1980; Post et al., 1984c, 1998; Azorin and Tramoni,
1987; Weiss et al., 1990.
3. Wyatt et al., 1971; Louis et al., 1975; Barnes et al., 1983; Koslow
et al., 1983; Roy et al., 1985, 1987, 1988; Rudorfer et al., 1985;
Veith et al., 1988, 1994; de Villiers et al., 1989. Maas et al., 1987;
4. To begin with, receptors on blood cells are by definition
noninnervated, exist in a markedly different environment,
and may therefore poorly reflect central, innervated, adrenergic receptors. Another major (often overlooked) consideration when interpreting studies of dynamic receptor regulation in blood cells is that white blood cell counts and the
relative proportions of subsets of lymphocytes may vary.
Recruitment of cells with different characteristics into the
circulation may frequently explain altered receptor function. Precisely such a mechanism appears to be operative in
studies demonstrating the seemingly paradoxical increase in
lymphocyte beta-adrenergic receptor (AR) density and responsiveness during short-term isoproterenol infusion,
mental arithmetic, and dynamic exercise (procedures that
stimulate the sympathetic nervous system) (Maisel et al.,
1990; Van Tits et al., 1990). The mechanism appears to be a
release of subsets of fresh lymphocytes from the spleen
into the circulation (Van Tits et al., 1990; Werstiuk et al.,
1990). These fresh, activated lymphocytes express enhanced
AR responsiveness, and this probably accounts for the exercise and catecholamine-induced increases in AR responsiveness.
5. Extein et al., 1979b; Pandey, 1987, 1990; Carstens et al., 1988;
Magliozzi et al., 1989.
6. Sarai et al., 1982; Zohar et al., 1983; Cooper et al., 1985; Healy
et al., 1985; Mann et al., 1985; Pandey et al., 1985. See Werstiuk
et al. (1990) for a critical appraisal of these studies and possible methodological sources of the differences in results (e.g.,
methods of tissue preparation, types of ligand used, subtypes
of patient populations, length of drug-free interval).
7. Extein et al., 1979b; Pandey et al., 1979; Healy et al., 1983;
Mann et al., 1985; Klysner et al., 1987; Ebstein et al., 1988;
Halper et al., 1988.
601
602
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
Pathophysiology
Neurobiology
603
604
52.
53.
54.
55.
56.
57.
58.
59.
Pathophysiology
60.
61.
62.
63.
Neurobiology
67.
68.
69.
70.
605
606
Pathophysiology
74.
75.
76.
77.
78.
79.
80.
81.
82.
Neurobiology
607
15
After largely regaining my reason, I had another most distinct sensation in the brain. . . . It
seemed as though the refreshing breath of some kind Goddess of Wisdom were being blown
gently against the surface of my brain. It was a sensation not unlike that produced by a menthol
pencil rubbed ever so gently over a fevered brow. So delicate, so crisp and exhilarating was it
that words fail me.
Clifford Beers (1908, p. 73)
610
Pathophysiology
Moods
Temperaments
Duration
Seconds to minutes
Hours to days
Weeks to monthsa
Years to decades
Relative intensity
High
Intermediate
Low
Precipitants
Acute
Variable/absent
Genetic/chronic
Autonomic arousal
Acute, robust
Variable/subtle
Absent/subtle
Products
Actions
Cognitions
Cognitiveaffective interactions
Possible neural
substrates
Anterior
limbic/brain stem
Anterior
cortical/anterior limbic
Anterior cortical/anterior
limbic/brain stem
a
In mood disorders.
Source: Reproduced from Ketter et al., 2003, with permission.
Figure 151. Limbic basal gangliathalamocortical circuits. Solid lines indicate positive feedback
loops, and dashed lines indicate negative feedback loops. GABA (gamma aminobutyric acid) indicates
inhibitory (GABAergic) connections; + glut indicates excitatory (glutamatergic) connections.
AM = anterior medial nucleus of thalamus; MDmc = medial dorsal nucleus of thalamus pars magnocellularis; VAmc = ventral anterior nucleus of thalamus pars magnocellularis. (Source: Adapted from
Alexander et al., 1990, with permission from Elsevier.)
Anterior Paralimbic Loop
Amygdalar
orbitofrontal
insular, ant. cing.
cortex
+ glut
Ventral
Pallidum
+ glut
GABA
GABA
Subthalamic
Nucleus
Ventral
Striatum
GABA
+ glut
Ventral
Pallidum
GABA
MDmc
VAmc, AM
Thalamus
ve feedback loop
+ ve feedback loop
+ glut
mood disorder symptoms in patients with stroke, Huntingtons disease, Parkinsons disease, traumatic brain injury, epilepsy, multiple sclerosis, and brain tumors fueled
interest in a provocative but at times controversial literature concerning the neuroanatomy of secondary mood
disorders.
Thus, the risk of depression may be greater after anterior compared with posterior and left compared with right
strokes, while the risk of mania may be greater after right
than after left strokes (Starkstein and Robinson, 1989;
Stern and Bachmann, 1991). Such a lateralityvalence association has been contested, however (Carson et al.,
2000). Basal ganglia strokes may also be associated with
secondary depression (Mendez et al., 1989). The profound basal ganglia damage noted in Huntingtons and
Parkinsons diseases and the high prevalence of mood
symptoms in these disorders also support a role for
basal ganglia dysfunction in secondary depressions.1 Left
dorsolateral prefrontal and/or left basal ganglia traumatic brain injuries may increase the risk of depression
(Federoff et al., 1992), while right temporal basal polar
injuries may increase the risk of mania (Jorge et al.,
1993). The risk of secondary depression in patients with
epilepsy may be greater with left than with right temporal lobe lesions (Altshuler et al., 1990). Temporal
(Honer et al., 1987) and left frontal (George et al., 1994)
lesions may also increase the risk of depression secondary to multiple sclerosis, although there are discordant
data here as well (Moller et al., 1994). Finally, frontal lobe
brain tumors may be associated with secondary depression (Direkze et al., 1971; Kanakaratnam and Direkze,
1976).
Primary mood disorders such as bipolar disorder and
MDD may be related to the above secondary mood disorders in that similar cerebral circuits are affected by different (more subtle) processes that, although not evident
with older technologies such as gross neuropathology
and light microscopy, are increasingly being revealed by
newer, more sensitive neurochemical, neuropathological,
and functional neuroimaging methods. In this chapter,
we review neuroimaging studiesfirst structural, then
functionalin bipolar disorder and MDD. In many cases,
such studies implicate the expected anterior cortical and
anterior paralimbic components of basal gangliathalamocortical circuits. In addition, there is increasing evidence of relationships between neuroimaging findings in
such regions and important clinical parameters, such as
symptoms and treatment response. Emerging data from
studies using neurochemically specific radiotracers, now
beginning to yield insights into the nature of specific
neurochemical changes in such regions, are described in
Chapter 14.
611
612
Pathophysiology
ence structural neuroimaging findings, as lithium treatment can increase prefrontal gray matter volume in patients with bipolar disorder (C. Moore et al., 2000) (see
Chapter 9).
Although structural neuroimaging methods have
proven useful in detecting brain abnormalities in some
secondary mood disorders, as well as differences between
groups of patients with primary mood disorders and
healthy controls, these techniques have lacked the necessary sensitivity or specificity to permit their use as instruments to diagnose primary mood disorders in individual
patients. Below we review the findings of such studies in
the areas of LVE, cortical sulcal enlargement (CSE), and
third ventricular enlargement (TVE); SCHs; frontal, cerebellar, and hippocampal volume decreases; and other
structural aspects salient to bipolar disorder and MDD.
Figure 152. Lateral ventricular enlargement and subcortical hyperintensities. Left: T1-weighted
SPGR (SPoiled GRASS; 15-degree flip angle) gradient-echo magnetic resonance imaging (MRI) scan
showing lateral ventricular enlargement. Right: T2-weighted (TR 2000; TE 25, 70; slice thickness 2.5 mm)
spin-echo axial MRI scan showing subcortical hyperintensities. (Source: Ketter and Wang, 2002.)
No. of
Studies
with:
Increases
in Patients
vs. Controls
Decreases in
Patients vs.
Controls
28
26
24
22
20
18
16
14
12
10
8
6
4
2
0
2
4
6
8
613
Significant increases
Nonsignificant increases
Nonsignificant decreases
Significant decreases
BD
MDD
Lateral Ventricular
Enlargement
BD
MDD
Cortical Sulcal
Enlargement
BD
MDD
Third Ventricular
Enlargement
614
Pathophysiology
Table 152. Summary of Meta-Analyses of Studies of Ventricular Enlargement and Cortical Sulcal Prominence in Mood Disorders
No. of
Studies
Percent
Unipolar
No. of
Significant
Studies
No. of
Nonsignificant
Studies
No. of
Significant
Not Reported
Composite
Effect Size
p for
Composite
Effect Size
More ventricular
enlargement in
mood disorders
than in healthy
controls
29
58.4
11
15
+.437
.001
More cortical
sulcal prominence
in mood disorders
than in healthy
controls
10
58.5
+.421
.001
Less ventricular
enlargement in
mood disorders
than in schizophrenia
11
31.3
11
.201
.002
Hypothesis
Insufficient data
616
Pathophysiology
(p <.002) but small in magnitude (.2), and was not systematically related to gender or illness polarity. There are
too few studies to allow conclusions regarding differences
in CSE between mood disorder and schizophrenic patients. Thus, these generalized structural brain abnormalities (increased LVE and CSE) in the former patients may
differ less from those in schizophrenic patients than from
those in controls, consistent with a continuum model of
mood and schizophrenic disorders.15
A recent meta-analysis used more robust threshold
criteria for inclusion (McDonald et al., 2004). In five
studies, bipolar patients compared with controls had a
significant (p = .03) 14 percent increase in right lateral
ventricular volume, but only a nonsignificant (p = .32) 8
percent increase in left lateral ventricular volume. In six
studies, bipolar patients compared with controls tended to
have (p = .06) a 17 percent increase in total lateral ventricular volume.
Thus, bipolar and MDD patients appear to have increased LVE and CSE. The clinical significance of these
findings remains to be established, however. LVE has received more attention than CSE in this regard. As noted
below, there are variable reports on the relationships
between LVE and clinical phenomena, and unfortunately
meta-analyses regarding such relationships are not yet
available.
LVE may increase with age in bipolar patients (Pearlson
and Veroff, 1981; Rieder et al., 1983), MDD patients,16 and
healthy subjects.17 However, negative findings have also
been reported in bipolar patients (Pearlson et al., 1984a;
Dewan et al., 1988b; Brambilla et al., 2001b), MDD patients,18 and healthy subjects.19 Longitudinal studies suggest that LVE may increase with disease duration in patients
with mood disorders, perhaps in excess of the increase
noted with normal aging (Vita et al., 1988; Woods et al.,
1990). In bipolar and MDD patients, LVE has been associated with later or late-life onset in some studies,20 but not
in others.21
One study found that multiple-episode bipolar patients
compared with both first-episode patients and healthy
subjects had larger lateral ventricles, with the degree of enlargement being related to number of prior manic episodes
(Strakowski et al., 2002). Another study found that right
LVE increased with the number of episodes (Brambilla
et al., 2001b). Other studies have reported variable findings
on the relationships between LVE and illness chronicity
and course,22 occupational function (Pearlson et al., 1984b;
Dewan et al., 1988b), and biological markers (Kellner et al.,
1983; Van den Bossche et al., 1991).
LVE was found to be related to psychosis in 31 bipolar-I
and 9 bipolar-II patients (Kato et al., 1994b); 66 patients
with late-onset depression (Simpson et al., 2001); 22 mood
617
Subcortical Hyperintensities
Increased SCHs have been observed in mood disorder patients compared with healthy controls. SCHs are bright areas in deep white, periventricular white, or subcortical
gray matter on T2-weighted MRI images. Taken together,
41 studies since 1989 suggest that younger and older bipolar and older MDD patients compared with healthy controls have increased SCHs.32
SCHs in bipolar patients were found to be significantly
increased overall in 10 studies33 and in bipolar-I (but not
bipolar-II) patients (Altshuler et al., 1995), nonsignificantly
increased in 7 studies,34 and nonsignificantly decreased in
2 studies (Brown et al., 1992; Sassi et al., 2003). With the exception of 2 small pediatric studies (Botteron et al., 1995;
Pillai et al., 2002), 1 small elderly adult study (McDonald et
al., 1991), and 1 large study involving a broad age range
(McDonald et al., 1999), these were studies of nonelderly
adult bipolar patients. Altshuler and colleagues (1995) performed a meta-analysis of 8 studies35 including 198 bipolar
patients and 307 controls and found increased frequency of
SCHs in the former, with a common odds ratio of 3.3
and 95 percent confidence interval of 1.95.6 (p = .00001).
Videbech (1997) performed an expanded meta-analysis of
10 studies36 including 296 bipolar patients and 516 controls
and found that in all but 1 of these studies (Brown et al.,
1992), the odds ratios pointed toward increased frequency
of SCHs in the bipolar subjects, with a common odds
ratio of 3.3 and 95 percent confidence interval of 2.15.1
(p = .0000001).
As noted above, SCHs may be more common in
bipolar-I but not bipolar-II patients compared with controls (Altshuler et al., 1995), although Krabbendum and
618
Pathophysiology
colleagues (2000) failed to detect such a difference. In another study, there were no apparent changes in SCHs on
repeat scanning 1 year later (Dupont et al., 1990). One
study found that 6 of 10 unaffected relatives of patients
with bipolar disorder from a loaded pedigree had subcortical gray SCHs (Ahearn et al., 1998).
SCHs in MDD patients were found to be significantly
increased overall in 14 studies37 and in patients with later
(over age 50) but not earlier (under age 35) onset (Lesser
et al., 1996), nonsignificantly increased in 12 studies,38 and
nonsignificantly decreased in 1 study (Sassi et al., 2003). In
contrast to the studies involving bipolar patients noted
above, studies involving MDD patients have assessed primarily elderly patients. Videbech (1997) performed a metaanalysis of 7 studies39 including 254 MDD patients and 511
controls and found that in nearly all of these studies, odds
ratios pointed toward increased frequency of SCHs in
MDD patients, with a common odds ratio of 3.3 and 95
percent confidence interval of 2.14.8 (p = .00000001).
Thus, there has been some variability in findings with
regard to SCHs across studies of bipolar and MDD patients
compared with controls. Although the direction of change
has generally been consistent, only slightly more than half
of the studies have demonstrated statistical significance.
Increases
in Patients
vs. Controls
Decreases or
Unspecified
Nonsignificant
Findings in
Patients vs.
Controls
24
22
20
18
16
14
12
10
8
6
4
2
0
2
4
6
8
Significant increases
Nonsignificant increases
Nonsignificant decreases
Unspecified nonsignificant findings
BD
MDD
Deep White
BD
MDD
Periventricular
BD
MDD
Subcortical Gray
619
620
Pathophysiology
et al., 1995) or MDD patients,65 although two studies detected such a relationship in the latter patients (MacFall
et al., 2001; Murata et al., 2001). SCHs likewise do not appear
to be related to psychosis in bipolar patients66 or MDD patients.67 SCHs may (Dupont et al., 1990, 1995a) or may not
(Altshuler et al., 1995) be related to psychiatric hospitalizations in bipolar patients, and may not be related to psychiatric hospitalizations in MDD patients (Dupont et al., 1995a;
Iidaka et al., 1996). SCHs do not appear to be related to
dexamethasone suppression status or post-dexamethasone
cortisol levels (Rao et al., 1989; Deicken et al., 1991; Coffey
et al., 1993b).
SCHs may be more (Sassi et al., 2003) or less (Hickie et al.,
1995) common in MDD patients lacking a family history of
mood disorders. In contrast, SCHs in bipolar patients have
been reported to be unrelated to a family history of mood
disorders (Sassi et al., 2003).
Studies have found no relationship between SCHs and
prior ECT in either bipolar patients (Swayze et al., 1990;
Figiel et al., 1991a) or MDD patients.68 Prospectively, ECT
did not cause or exacerbate SCHs in MDD patients.69
Basal ganglia lesions may yield patients more susceptible
to ECT-induced delirium, however (Figiel et al., 1989b,
1990a,b). Limited evidence suggests that white matter
SCHs may predict poorer response to ECT in MDD patients (Coffey et al., 1987; Hickie et al., 1995), perhaps because these SCHs may represent subtle vascular insufficiency (Sackeim, 1996). Other data suggest, however, that
SCHs in MDD patients are not related to ECT response
(Figiel et al., 1989b).
SCHs do not appear to be related to prior treatment
with lithium,70 carbamazepine (Altshuler et al., 1995), antidepressants (Altshuler et al., 1995), antipsychotics (Dupont
et al., 1990; Swayze et al., 1990), or benzodiazepines (Swayze
et al., 1990), or to prior alcohol abuse (Swayze et al., 1990),
drug abuse (Swayze et al., 1990), or substance abuse generally (Strakowski et al., 1993b). As noted above, earlieronset MDD patients (who have longer illness duration and
greater treatment exposure) compared with later-onset patients may have fewer SCHs, an observation inconsistent
with the notion that illness or treatment duration markedly
affects these lesions. Moreover, it should be recalled that
MDD with an early age at onset is part of the manicdepressive spectrum and as such is genetically different
from later-onset MDD (see Chapter 13).
Deep white matter and basal ganglia SCHs may be associated with resistance to antidepressants (Hickie et al.,
1995; Simpson et al., 1998). Basal ganglia lesions may increase the risk of antidepressant-induced delirium (Figiel
et al., 1989b) and adverse effects on the central nervous system (Fujikawa et al., 1996). After 2 years of naturalistic
treatment, MDD patients who had achieved and sustained
621
Strakowski et al., 1999), but they were not seen in two studies
(Strakowski et al., 1993b; Zipursky et al., 1997). A recent metaanalysis using robust threshold criteria for inclusion (McDonald et al., 2004) found that in three studies, bipolar patients and controls had similar left (4 percent smaller, p = .19)
and right (5 percent smaller, p = .11) prefrontal volumes. In
MDD patients, these decreases were found to be present in
eight studies71 and absent in only three studies (Pantel et al.,
1997; Bremner et al., 2000; Janssen et al., 2004). As noted
below, prefrontal CBF and metabolism are commonly decreased in depressed bipolar and MDD patients. Frontal and
prefrontal volume decreases may be related to poorer performance on neuropsychological tests (Coffman et al., 1990),
such as the continuous performance task (Sax et al., 1999).
Methodological advances (improved scan resolution
and graywhite segmentation) have led to emerging data
on gray and white matter volumes. Prefrontal gray matter
may (Drevets et al., 1997; Lopez-Larson et al., 2002) or may
not (Dupont et al., 1995b; Zipursky et al., 1997; Lim et al.,
1999) be decreased in bipolar patients compared with
healthy controls. Prefrontal gray matter density may also
be decreased in bipolar disorder (Lyoo et al., 2004). Findings of a preliminary study suggest that men with bipolarI disorder (but not men with bipolar-II or women) may be
at risk for decreases in left frontal lobe gray matter that
tend to correlate with decreases in NAA as assessed by
MRS (Dieckmann et al., 2002). One study, however, found
that dorsolateral prefrontal cortex, inferior parietal lobule,
and superior temporal gyrus gray matter volumes were
unchanged in bipolar patients compared with healthy controls (Schlaepfer et al., 1994), and another found that depressed adolescents compared with controls had increased
frontal gray matter volumes and decreased frontal white
matter volumes (Steingard et al., 2002).
Recently, voxel-based morphometry (VBM) has allowed
automated voxel-wise assessments of gray and white matter volumes and densities. Studies to date in patients with
bipolar disorder72 and MDD (Bell-McGinty et al., 2002;
Pizzagalli et al., 2004) have had variable findings, perhaps
as a result of confounds with respect to age, mood disorder
subtype, mood state, prior pharmacotherapy (in view of
the putative neurotrophic effects of lithium), current medication status, and methodological variability.
Evidence suggests that gray matter volume is decreased
in the prefrontal cortex ventral to the genu of the corpus
callosum in both familial bipolar disorder and familial
MDD (Drevets et al., 1997), consistent with decreased CBF
and metabolism (Drevets et al., 1997) and histopathological
changes (Rajkowska, 1997) observed in that region. Gray
matter volume decreases in the subgenual portion of the
left ventral anterior cingulate cortex in bipolar and MDD
patients have been demonstrated by both MRI-based
622
Pathophysiology
morphometric measures73 and postmortem neuropathological studies of patients with a family history of bipolar
disorder and MDD (ngr et al., 1998). This reduction in
volume was seen in patients with a family history of bipolar disorder (Hirayasu et al., 1999), but was notably not
demonstrable in bipolar patients with no family history of
mood disorders. The reduction was found early in MDD
patients (Botteron et al., 2002) and may follow illness
onset, as indicated by preliminary evidence in twins discordant for MDD (Botteron et al., 1999).
Coryell (2005) found decreased volume in a nearby region in patients with psychotic MDD. Kimbrell and colleagues (2002) reported that subgenual anterior cingulate
metabolism was inversely correlated with the number of
lifetime depressive episodes in MDD patients. Other studies, however, have failed to detect subgenual prefrontal
cortical volume decreases in mood disorder patients.74 A
recent meta-analysis using robust threshold criteria for inclusion (McDonald et al., 2004) found that in four studies,
bipolar patients compared with controls had nonsignificantly decreased left (20 percent, p = .31) and right (6 percent, p = .36) subgenual prefrontal volumes. Studies in
MDD patients that failed to find a volume decrease in this
region, however, found decreased cerebral metabolism in
the region in patients with melancholia (Pizzagalli et al.,
2004) and decreased gyrus rectus volumes in MDD patients compared with controls (Bremner et al., 2002).
Other studies in bipolar patients that failed to detect a volume decrease in this area found more posterior and dorsal
cingulate gray matter volume (Lochhead et al., 2004; Nugent et al., 2006) and density (Doris et al., 2004) decreases,
as well as decreased left dorsolateral prefrontal cortical
gray matter volume in pediatric patients (Dickstein et al.,
2005). In addition, MTI demonstrated decreased macromolecular density in the right subgenual anterior cingulate
and adjacent white matter (Bruno et al., 2004). Still other
studies found that bipolar patients compared with controls
had decreased gray matter density in the anterior cingulate
close to subgenual prefrontal cortex (Lyoo et al., 2004) and
decreased left dorsal anterior cingulate volume (Sassi et al.,
2004; Kaur et al., 2005). One study found decreased left
cingulate, right medial frontal, and left middle frontal cortical thickness in bipolar patients compared with healthy
controls (Lyoo et al., 2006). Ventral prefrontal gray and
white matter volumes may decline more rapidly with age
in adolescents and young adults with bipolar disorder
compared with healthy controls, and rapid cycling may exacerbate and pharmacotherapy may attenuate ventral prefrontal volume deficits (Blumberg et al., 2006). Of interest,
decreased orbitofrontal total (Lai et al., 2000) and gray
matter (Lacerda et al., 2004; Lavretsky et al., 2004) volumes
have been observed in MDD patients.
623
250
200
150
100
50
21
15
21
Controls
Bipolar
on chronic
lithium/valproate
Bipolar
off chronic
lithium/valproatea
Unipolar
! Sample Size
Figure 155. Decreased subgenual prefrontal cortical (PFC) gray matter volumes in depressed patients with familial major depressive disorder and familial bipolar disorder. Decreased volumes were
accompanied by reductions in cerebral activity (see Fig. 1511 below). Reduced volumes were not evident, however, in bipolar patients taking chronic lithium or valproate. (Source: Adapted from Drevets
et al., 2004.)
624
Pathophysiology
neurogenesis may be one way in which antidepressants exert their effects (Malberg, 2004). In a longitudinal study,
although no significant hippocampal volume changes were
observed in MDD patients or controls between baseline
and 1-year follow-up, patients with unremitting illness at
follow-up had reduced left and right hippocampal volumes at both baseline and the 1-year follow-up compared
with remitting patients, and smaller right hippocampal
volumes compared with healthy controls (Frodl et al.,
2004). Similarly, in another study, smaller hippocampal
volumes were associated with poorer response to antidepressants (Hsieh et al., 2002).
In a study of hippocampal volume, decreases were
observed in multiple-episode but not first-episode MDD
patients (MacQueen et al., 2003). (MDD with multiple
episodes is part of the manic-depressive spectrum.) Another study, however, found hippocampal volume decreases
(left-sided gray matter in men and bilateral white matter in
men and women) in first-episode MDD patients and failed
to detect a relationship between volume decreases and illness duration (Frodl et al., 2002b). Three studies found
that greater volume decreases tended to occur with lateronset depression (Steffens et al., 2000; Lloyd et al., 2004;
MacMaster and Kusumakar, 2004b), whereas other studies
have failed to detect such a relationship (Ashtari et al.,
1999; Frodl et al., 2002a).
In some studies, volume decreases were found to be correlated with severity of depression (Ashtari et al., 1999; Vakili et al., 2000), but other investigators have failed to detect
such a relationship (Frodl et al., 2002a; MacQueen et al.,
2003). One group found hippocampal volume decreases in
women with MDD and a history of severe prolonged childhood physical or sexual abuse, but not in MDD patients
without such histories. One study found that MDD patients
compared with controls had similar hippocampal volumes,
but had altered hippocampal shape (Posener et al., 2003).
Janssen and colleagues (2004) failed to detect a relationship between hippocampal volumes and subcortical hyperintensities in MDD patients.
MDD patients with the homozygous L/L serotonin transporter genotype were found to have smaller hippocampal
gray and white matter volumes than those of controls with
this genotype, and significantly smaller hippocampal white
matter volumes than those of patients with the L/S or S/S
genotype (Frodl et al., 2004). No significant differences were
found between patients and controls with the L/S or S/S
genotype. The authors suggested that serotonergic influence on neurotrophic factors and excitatory amino acid
neurotransmission could account for their findings. Some
study findings are consistent with relationships between
hippocampal volume loss and poorer cognitive/memory
function.84 For example, Shaw and colleagues (1998) found
625
626
Pathophysiology
627
(while performing a passive introspection task) and CMRglu (while performing an auditory continuous performance task) may occur in MDD patients, but not in bipolar
patients or healthy volunteers (Dunn et al., 2005). In another study, MDD patients compared with healthy controls were found to have differential left basal ganglia coupling of simultaneously assessed resting CBF and CMRglu
(Conca et al., 2000).
CMRglu changes with age. Thus, gray matter CMRglu
is low at birth, rises rapidly to adult values by age 2 years,
continues to rise to supra-adult values between ages 3 and
12, then declines to adult rates again by the latter part of the
second decade (Chugani et al., 1987), similar to the nonlinear developmental patterns seen with gray matter volume
(Giedd et al., 1999) and ratios of NAA to choline (Horska
et al., 2002). In healthy adults, CMRglu tends to decrease
with age,108 but there is some variability in findings in this
regard.109 Differential regional effects may contribute to
such variability. For example, Willis and colleagues (2002)
found that in adults, increased age was correlated with decreased global and widespread cortical and increased cerebellar and focal occipital cortical CMRglu.
Although gender has not been found to be related to
global CMRglu in most studies,110 regional differences
have been reported. Thus, CMRglu in healthy women
compared with men was found to be increased in widespread (Baxter et al., 1987a; Yoshii et al., 1988; Willis et al.,
2002) and orbital and medial frontal, caudate, and posterior cingulate regions (Andreason et al., 1994), the thalamus (Murphy et al., 1996), and the cerebellum (Volkow
et al., 1997). Compared with men, however, women were
observed to have decreased anterior paralimbic (Andreason et al., 1994) and hippocampal (Murphy et al., 1996) or
generally similar (Miura et al., 1990) CMRglu. Phase of
menstrual cycle may contribute to this variability, as only
two studies attempted to control for this parameter (Baxter et al., 1987b; Volkow et al., 1997). Indeed, healthy women
during midfollicular phase (lower estradiol and progesterone) were found to have increased thalamic, prefrontal,
temporoparietal, and inferior temporal CMRglu, and during midluteal phase (higher estradiol and progesterone) to
have increased superior temporal, anterior temporal,
occipital, cerebellar, cingulate and anterior insular CMRglu
(Reiman et al., 1996).
628
Pathophysiology
629
Figure 156. Overlapping limbic regional cerebral blood flow (rCBF) activation with transient induced emotion. Anterior paralimbic activation accompanies both neuropsychologically and pharmacologically induced acute affective changes in healthy volunteers. Images are statistical parametric maps
of cerebral blood flow activation in black rendered on the mesial aspect of the left hemisphere. Left: Regions activated during transient self-induced sadness in 11 healthy women (George et al., 1995b). Right:
Regions activated during acute intravenous procaineinduced affective symptoms in 32 healthy
volunteers (Ketter et al., 1996b).
630
Pathophysiology
Figure 157. Hypofrontality in secondary and primary depression. Transaxial images depicting cerebral metabolic rate (CMR) for glucose in patients with (top row) and without (bottom row) depression. Arrows indicate decreased frontal metabolism in patients with depression secondary to neurological disorders, as well as in those with primary (unipolar) depression. (Source: Reproduced with
permission from Mayberg et al., 1994.)
631
Figure 158. Regional cerebral metabolism in moderately to severely depressed unmedicated bipolar
patients compared with healthy controls. Z-maps of differences in absolute (top) and normalized (bottom) cerebral metabolism in 17 moderately to severely depressed unmedicated bipolar patients compared with 17 healthy controls. The legend indicates two-tailed p values. Numbers in the upper right
corners indicate distances from the intercommissural plane. L = left. Absolute prefrontal and anterior
paralimbic cortical metabolic decreases and normalized anterior paralimbic subcortical metabolic increases evident in these images may be state markers for depression in bipolar disorder. Decreased dorsomedial and dorsolateral prefrontal activity has commonly been reported in other studies of bipolar
depression. Left (L) ventrolateral structures failed to show the absolute metabolic decreases seen in
other prefrontal cortical regions in these moderately to severely depressed bipolar patients (top) or the
relative metabolic increases seen in left ventrolateral structures in mildly depressed bipolar patients
(Fig. 159, bottom). (Source: Ketter et al., 2001.)
632
Pathophysiology
paralimbic structures, including ventral striatum, thalamus, and right amygdala (Fig. 158, bottom), consistent
with a corticolimbic dysregulation model of depression
positing that dorsal neocortical hypofunction may lead to
ventral paralimbic overactivity or vice versa (Mayberg,
1997; Drevets, 1999, 2000) (see Fig. 1510). Relative activation of bilateral medioposterior thalamus was also seen,
consistent with altered thalamic relay and gating function
with respect to communication between subcortical and
cortical regions. Drevets and colleagues (1995, 2002c) confirmed the findings of elevated metabolism in the right
amygdala and ventral striatum, as well as elevated metabolism in the left amygdala, in depressed bipolar patients relative to healthy controls. Increased ventral striatum and
left amygdala metabolism has also been reported in depressed MDD patients meeting criteria for melancholia or
familial pure depressive disease.134
Another study found decreased CBF (by H15
O PET)
2
and CMRglu in the prefrontal cortex ventral to the genu of
Figure 159. Regional cerebral metabolism in mildly depressed unmedicated bipolar patients compared with healthy controls. Z-maps of differences in absolute (top) and normalized (bottom) cerebral
metabolism in 16 mildly depressed unmedicated bipolar patients compared with 16 healthy controls.
The legend indicates two-tailed p values. Numbers in the upper right corners indicate distances from
the intercommissural plane. L = left. Increased normalized (but not absolute) metabolism was noted in
left (L) inferior, middle, and superior frontal gyri; left insula and left transverse temporal gyrus; left
postcentral gyrus; lingular gyrus, cuneus, and hippocampus; and bilateral cerebellum (sparsely). In
contrast, decreased normalized (but not absolute) metabolism was noted in right inferior and middle
temporal gyri. Ventrolateral metabolic increases have also been reported in depressed unmedicated
major depressive disorder patients in the resting state. (Source: Ketter and Drevets, 2002.)
633
Figure 1510. Corticolimbic dysregulation model of depression. Regions with known anatomical
connections are grouped into two compartments: dorsal (black) and ventral (gray). Curved black arrows
and color-filled regions emphasize inverse correlations between right dorsal prefrontal cortex (dFr
9/46, in black) and subgenual cingulate (Cg 25, in gray) seen with both transient sadness in healthy
volunteers (Fr decreases, Cg increases) and mood symptom resolution in depressed patients
(Fr increases, Cg decreases). Nonshaded regions are potentially critical to the schematic model. Short
black arrows indicate known subcortical pathways. Numbers are Brodmann area designations.
Abbreviations, from top to bottom: dFr = dorsolateral prefrontal; inf Par = inferior parietal; dCg = dorsal
anterior cingulate; pCg = posterior cingulate; Cg 24a = rostral anterior cingulate; BG = basal ganglia;
Th = thalamus; aIns = anterior insula; Hc = hippocampus; Cg25 = subgenual cingulate; Hth = hypothalamus;
mb-p = midbrain-pons. (Source: Reproduced with permission from Mayberg et al., 1999.)
the corpus callosum (subgenual) in both depressed familial bipolar disorder and depressed familial MDD patients
(Drevets et al., 1997) (see Fig. 1511). Decreased subgenual
prefrontal cortical activity was accompanied by reductions
in gray matter volume (Drevets et al., 1997; Hirayasu et al.,
1999), as noted above (Fig. 155). Of interest, Kimbrell and
colleagues (2002) reported that subgenual anterior cingulate metabolism was correlated inversely with the number of
lifetime depressive episodes in MDD patients. In contrast,
Videbech and colleagues (2002) found that nonfamilial
depressed MDD patients compared with healthy controls
had increased subgenual prefrontal cortical activity.
Drevets (1999) observed that, although baseline subgenual prefrontal cortical CBF and metabolism appeared to be
abnormally decreased in PET images during depressive
episodes, computer simulations that corrected the PET data
for the partial volume effect of reduced gray matter volume
suggested that the actual metabolic activity in the remaining subgenual prefrontal cortical tissue may be increased in
depressive patients relative to controls and decrease to normative levels during effective treatment. This result appears
to be compatible with evidence that effective antidepressant pharmacotherapy results in a decrease in metabolic
activity in this region in MDD patients135 and that during
depressive episodes, metabolism shows a positive relationship with depression severity in both depressed bipolar (Ketter et al., 2001) and depressed MDD patients.136 This mood
state dependency of subgenual prefrontal cortical metabolism is also consistent with functional neuroimaging data
showing that CBF increases in this region in healthy, nondepressed individuals during sadness induced internally by
contemplation of sad thoughts or memories (George et al.,
1995b; Damasio et al., 1998; Mayberg et al., 1999).
Variable anterior cingulate/medial prefrontal activity has
been noted in other studies of depressed bipolar patients.
Some studies of such patients compared with healthy controls have detected decreased anterior cingulate/medial
prefrontal metabolism assessed with 18FDG PET (Buchsbaum et al., 1997a), and CBF assessed with H15
O PET (Ketter
2
et al., 1996b) and 99mTc-HMPAO SPECT (Ito et al., 1996).
One study detected decreased superior but increased inferior anterior cingulate metabolism in depressed (primarily
bipolar-II) patients with summer seasonal affective disorder (Goyer et al., 1992). Others, however, failed to detect
differences in anterior cingulate activity in depressed bipolar patients compared with healthy controls.137 In a study
by Ketter and colleagues (2001), anterior cingulate/medial
prefrontal metabolism was found to be similar in depressed
634
Pathophysiology
Figure 1511. Decreased subgenual prefrontal cortical metabolism in depressed patients with familial major depressive disorder and familial bipolar disorder. Coronal (31 mm anterior to the anterior
commissure, or y = 31) and sagittal (3 mm left of midline, or x = 3) sections showing negative voxel
t values where glucose metabolism was decreased in (7 bipolar and 10 unipolar) familial depressed
patients compared with controls. Decreased activity was accompanied by reduced gray matter volume
(Fig. 155). A = anterior, L = left, PFC = prefrontal cortex. (Source: Drevets, 2001; Drevets et al., 1997.
Reprinted with permission from Macmillam Publishers Ltd: Nature.)
Depressed MDD patients may also have decreased temporal cortical activity. Thus these patients compared with
healthy controls were found to have decreased temporal
cortical metabolism with 18FDG143 and 11C-glucose PET
(Kishimoto et al., 1987) and increased CBF with H215O
PET (Drevets et al., 1992) and SPECT employing 99mTcHMPAO,144 99mTc-EMZ (Austin et al., 1992; Curran et al.,
1993; Edmonstone et al., 1994), 123IMP (OConnell et al., 1989;
Kanaya and Yonekawa, 1990), and 195mAu (Schlegel et al.,
1989c). Most of the above studies found bilateral decreases,
but five found left145 and three found right (Hurwitz et al.,
1990; Drevets et al., 1992; Edmonstone et al., 1994) lateralized decreases. One group noted possible modest lateralized increases in right more than left temporal activity in
depressed MDD patients compared with medical controls
(Amsterdam and Mozley, 1992), which normalized with
recovery (Amsterdam et al., 1995). Other studies by this
group, however, failed to detect consistent laterality differences in depressed MDD patients compared with healthy
controls (Mozley et al., 1996; Hornig et al., 1997). Kowatch
and colleagues (1999) found increased temporal lobe CBF
in depressed adolescent MDD patients compared with
healthy controls. About half of the studies, however, found
that depressed MDD patients and healthy controls had
similar temporal cortical activity.146
Increased amygdala activity may occur in depressed
mood disorder patients compared with healthy controls.
Thus in comparison with healthy controls, increased amygdala activity has been noted in depressed bipolar patients
through 18FDG PET (Ketter et al., 2001; Drevets et al.,
2002b) and in depressed MDD patients through 18FDG
(Nofzinger et al., 1999; Drevets et al., 2002c) and H215O PET
(Drevets et al., 1992; Videbech et al., 2002) and 99mTc HMPAO SPECT (Kowatch et al., 1999). All of the above
studies yielded lateralized findings, with four detecting
left147 and two right (Kowatch et al., 1999; Ketter et al.,
2001) amygdala activity increases. In one of these studies,
left amygdala (but not right amygdala or hippocampus)
metabolism was found to be increased in both depressed
bipolar and depressed MDD patients, and positively correlated with stressed (PET scan) plasma cortisol levels in
both groups (Drevets et al., 2002a). This study also found
that in euthymic bipolar patients, left amygdala metabolism was elevated in those patients off but not on mood
stabilizers (Drevets et al., 2002c).
In an f MRI study, in a masked (outside of conscious
awareness) faces paradigm, depressed MDD patients were
found to have exaggerated left (but not right) amygdala activation in response to all faces that was even greater for
fearful faces (Sheline et al., 2001). In another study, although depressed MDD patients and controls were found
to have similar amygdala CMRglu, negative affect was
635
636
Pathophysiology
637
638
Pathophysiology
639
640
Pathophysiology
and NAA/Cr levels in bipolar patients and healthy controls171 and have commonly been used as control regions.
NAA has variable relationships with age.
In bipolar patients, some studies found that dorsolateral
prefrontal (Winsberg et al., 2000) and basal ganglia (Kato
et al., 1996a; Ohara et al., 1998) NAA/Cr decreased with age,
while others found no relationship between age and dorsolateral prefrontal NAA (Brambilla et al., 2005; Sassi et al.,
2005), dorsolateral prefrontal NAA/Cr in juveniles (Chang
et al., 2001), medial prefrontal NAA (Hamakawa et al., 1999),
hippocampal NAA/Cr (Bertolino et al., 2003), or basal ganglia NAA (Hamakawa et al., 1998). In a postmortem study
of bipolar patients, superior temporal lobe and frontal
NAA were not found to be related to age (Nudmamud et al.,
2003). In MDD patients, age was observed to affect caudate
NAA/Cr (Vythilingam et al., 2003), but not to be related to
anterior cingulate NAA (Pfleiderer et al., 2003) or basal ganglia NAA or NAA/Cr (Hamakawa et al., 1998).
Variable, but most often negative, gender effects have
been reported for NAA and NAA/Cr. Hamakawa and colleagues (1998) detected an overall (in euthymic and depressed bipolar and MDD patients and healthy controls)
gender effect for left basal ganglia NAA (but not NAA/Cr),
but the direction of the effect was not specified. In other
studies, however, the same group noted no overall (in euthymic bipolar patients and healthy controls) gender effect
on left basal ganglia NAA/Cr (Kato et al., 1996a) and no
overall (in euthymic and depressed bipolar patients and
healthy controls) gender effect on bilateral medial prefrontal NAA (Hamakawa et al., 1999). In a postmortem
study of bipolar patients, superior temporal lobe and frontal
NAA were not found to be related to gender (Nudmamud
et al., 2003).
NAA/Cr may vary across the menstrual cycle. Thus medial prefrontal (but not occipital) NAA/Cr was found to
decline from follicular to luteal phase in women with premenstrual dysphoric disorder (PMDD) by 19 percent and
in healthy controls by 16 percent, and there were no statistically significant differences in NAA/Cr between these
groups (Rasgon et al., 2001).
Although in one study, bipolar-I patients had bilateral
dorsolateral prefrontal NAA/Cr decreases while bipolar-II
patients had only unilateral (left) decreases (Winsberg
et al., 2000), other researchers found that bipolar-I and -II
patients had similar prefrontal (Hamakawa et al., 1999)
and basal ganglia (Kato et al., 1996b; Hamakawa et al.,
1998) NAA or NAA/Cr. Moreover, one of the latter studies
found no basal ganglia NAA differences between bipolar
and MDD patients when either depressed or euthymic
(Hamakawa et al., 1998).
In bipolar patients, dorsolateral prefrontal NAA/Cr
(Winsberg et al., 2000; Chang et al., 2001) and hippocampal
641
642
Pathophysiology
643
644
Pathophysiology
Myoinositol (mI) is a storage form of six carbon carbohydrate inositol, an agent important in signal transduction
that may have antidepressant effects (Levine et al., 1995).
Inositol depletion has been proposed as a mechanism of
action of lithium (Berridge et al., 1989).
Although findings vary, some evidence suggests that mI
and mI/Cr may be altered in patients with mood disorders.
Thus, mI and mI/Cr in bipolar patients compared with
healthy controls showed a tendency to be increased in five
studies,186 decreased in no studies, and similar in five studies.187 In MDD patients compared with healthy controls, mI
and mI/Cr were found to be (or tend to be) increased in no
studies, decreased in two studies (Frey et al., 1998; Gruber
et al., 2003), and similar in three studies (Auer et al., 2000;
Rosenberg et al., 2000; Vythilingam et al., 2003). One study
found decreased prefrontal mI/Cr but not mI in MDD patients, perhaps related to increased Cr (Gruber et al., 2003).
Findings regarding mI and mI/Cr in bipolar patients
may vary on a regional basis. Thus in bipolar patients
compared with healthy controls, mI or mI/Cr was found to
be increased in basal ganglia by Sharma and colleagues
(1992), to tend to be increased by Winsberg and colleagues
(2000) and Cecil and colleagues (2002), or similar to controls in dorsolateral prefrontal regions by Chang and colleagues (2001), and to tend to be increased in anterior cingulate regions by Davanzo and colleagues (2001, 2003). In
multiple other studies, however, bipolar patients and controls were found to have similar mI or mI/Cr in anterior cingulate (Moore et al., 2000a), medial prefrontal (Cecil et al.,
2002), frontal and temporal (Silverstone et al., 2002), parietal (Brhn et al., 1993), and occipital (Sharma et al., 1992)
regions. One study found that bipolar patients had gray
and white matter and regional mI similar to that of controls (Dager et al., 2004).
Two studies found that frontal mI/Cr was decreased in
depressed MDD patients compared with age- and gendermatched healthy controls (Frey et al., 1998; Gruber et al.,
2003). Multiple other studies, however, found that MDD
patients and controls had similar mI or mI/Cr in anterior
cingulate (Auer et al., 2000), basal ganglia (Rosenberg et al.,
2000; Vythilingam et al., 2003), thalamus (Vythilingam
et al., 2003), parietal (Auer et al., 2000), and occipital
(Rosenberg et al., 2000) regions.
Oral inositol administration may transiently increase
cerebral inositol. By 4 days, 12 g/day mI was found to increase occipital gray (but not parietal white) mI/Cr in
healthy volunteers by 20 percent. By 8 days, however, this
effect was no longer evident (Moore et al., 1999).
Variable relationships have been noted between mI
and age in healthy volunteers. One study found that in
depressed MDD patients, right frontal mI/Cr was correlated positively with age (Frey et al., 1998). Variable,
on mI/Cr in bipolar patients and healthy volunteers (Silverstone et al., 1999). In contrast, Friedman and colleagues
(2004), studying primarily depressed adult bipolar-I and -II
patients, found that lithium for a mean of 3.6 months, but
not valproate for a mean of 1.4 months, increased gray but
not white matter mI.
Compared with healthy controls, euthymic bipolar patients taking chronic lithium showed increased basal ganglia (Sharma et al., 1992), but similar temporal (Silverstone
et al., 2002) and occipital (Sharma et al., 1992) mI/Cr and
parietal mI (Brhn et al., 1993). No relationship was
found between serum lithium concentrations and basal
ganglia or occipital mI/Cr (Sharma et al., 1992). Also,
bipolar patients taking chronic lithium or valproate compared with healthy controls showed similar anterior cingulate mI/Cr (Moore et al., 2000a). Bipolar patients taking
chronic lithium compared with those taking chronic valproate were found to have similar temporal (Silverstone
et al., 2002) and anterior cingulate (Moore et al., 2000a)
mI/Cr.
If lithium decreases mI or mI/Cr, the presence or absence of chronic lithium could contribute to the variability
in mI and mI/Cr findings in bipolar patients compared
with healthy controls. In studies conducted to date, the
percentage of patients taking lithium was nonsignificantly
lower in studies detecting increases in mI and mI/Cr in
bipolar patients compared with healthy controls (17/73, 23
percent)188 than in studies finding no difference (34/100, 34
percent).189 This nonsignificant difference is consistent
with the notion that mI and mI/Cr decreases caused by
chronic lithium could be a confounding factor in detecting
putative baseline (unmedicated) increases in mI and mI/Cr
in patients with bipolar disorder.
There are few data on the potential effects of other medications on mI and mI/Cr. Euthymic bipolar patients taking chronic valproate compared with healthy controls were
found to have similar temporal mI and mI/Cr and frontal
mI (Silverstone et al., 2002). Depressed bipolar patients
taking and not taking antidepressants showed similar anterior cingulate mI/Cr (Moore et al., 2000b) that was also
similar to that of healthy controls. Depressed MDD patients taking antidepressants (but not those taking antidepressants) compared with healthy controls, however, displayed decreased frontal mI (Frey et al., 1998).
The MRS creatine (Cr or Cr + PCr) peak consists of signals from Cr and PCr. Cr is converted to PCr, which appears to function as an intracellular energy buffer. There
are limited data regarding Cr changes in patients with mood
disorders. Thus in bipolar patients compared with healthy
controls, Cr was found to be increased in one study (Deicken et al., 2001), to be decreased in one study (Deicken
et al., 2003a), to tend to be decreased in one study (Sassi
645
et al., 2005), and to be similar in eight studies.190 MDD patients and healthy controls have consistently shown similar
Cr,191 with the exception of one report of increased prefrontal Cr in MDD patients (Gruber et al., 2003). The latter
finding is noteworthy in that it appeared to drive decreased
NAA/Cr, Cho/Cr, and mI/Cr in MDD patients, as absolute
NAA, Cho, and mI in patients and healthy controls did not
differ (Gruber et al., 2003).
Cr findings in bipolar patients may vary on a regional
basis. One group found that bipolar patients compared
with healthy controls had decreased hippocampal (Deicken et al., 2003a) and increased thalamic (Deicken et al.,
2001) Cr. Another group found that dorsolateral prefrontal
Cr tended to be decreased in bipolar disorder (Sassi et al.,
2005). Other studies, however, found that bipolar patients
and healthy controls had similar Cr in dorsolateral prefrontal (Cecil et al., 2002; Michael et al., 2003; Brambilla
et al., 2005), anterior cingulate (Davanzo et al., 2003), medial prefrontal (Hamakawa et al., 1999; Cecil et al., 2002),
and basal ganglia (Hamakawa et al., 1998). Dager and colleagues (2004) found that bipolar patients had gray and
white matter and regional Cr that was similar to that of
controls. MDD patients and healthy controls have consistently shown similar Cr in dorsolateral prefrontal (Farchione et al., 2002), anterior cingulate (Auer et al., 2000;
Pfleiderer et al., 2003), hippocampal (Ende et al., 2000a),
basal ganglia (Hamakawa et al., 1998; Rosenberg et al.,
2000), parietal (Auer et al., 2000), and occipital (Rosenberg et al., 2000).
Cr has shown variable relationships with age. Studies
detected no overall age effect (in euthymic and depressed
bipolar patients and healthy controls) on medial prefrontal
Cr (Hamakawa et al., 1999), no overall age effect (in euthymic bipolar patients) on dorsolateral prefrontal Cr (Sassi
et al., 2005), and no overall age effect (in euthymic and depressed bipolar and MDD patients and healthy controls)
on basal ganglia Cr (Hamakawa et al., 1998).
Gender effects on Cr have not been extensively reported.
Healthy women compared with men were found to have
similar Cr in frontal, parietal, occipital, insular (Pouwels and
Frahm, 1998), basal ganglia (Charles et al., 1994b), and hippocampal (Ende et al., 2000a). One study (in euthymic and
depressed bipolar patients and healthy controls) detected
an overall gender effect on right (but not left) medial prefrontal Cr, but the direction of the effect was not specified
(Hamakawa et al., 1999). However, another study by the
same group (in euthymic and depressed bipolar and MDD
patients and healthy controls) found no overall gender effect
on left basal ganglia Cr (Hamakawa et al., 1998).
There are limited data on the effect of oral Cr administration on cerebral Cr. In healthy volunteers, Cr 20 g/
day for 4 weeks was found to yield increased gray matter,
646
Pathophysiology
patients, ECT was found to modestly increase hippocampal Cr (Ende et al., 2000b), but not to alter anterior cingulate (Pfleiderer et al., 2003) or parietal (Felber et al.,
1993) Cr.
Investigators commonly assume that regional Cr is stable
enough within individuals and across diagnoses to be used
as an internal standard, and thus report other metabolites
normalized to Cr.192 Such a strategy is potentially useful because it increases statistical power by decreasing variability,
but it runs the risk of yielding spurious results if Cr varies
with time, environmental factors, or diagnosis. As noted
above, in healthy volunteers, for example, chronic (4-week)
administration of Cr monohydrate 20 g/day was found to
increase paramedian parietal gray matter, parieto-occipital
white matter, central cerebellum, and thalamus Cr concentrations (Dechent et al., 1999b). In this study, average (across
four regions) Cr (but not NAA, Cho, or mI) increased by
8.7 percent, varying between 4.7 percent and 14.6 percent
across regions. NAA (but not NAA/Cho and NAA/mI ratios) showed a decrease in cerebellum and thalamus, and
Cho (but not Cho/mI ratios) a decrease in thalamus. Hence
the confounding influence of referencing metabolites to Cr
could be circumvented to some degree by also inspecting results referenced to other metabolites (Mervaala et al., 2000;
Steingard et al., 2000; Winsberg et al., 2000).
Some investigators prefer to report metabolite concentrations in absolute units193; to report either absolute or
normalized concentrations, depending on the study (Kato
et al., 1996a; Hamakawa et al., 1998, 1999); or to report both
absolute and normalized concentrations.194 In one such
study, it appeared that increased Cr in MDD patients compared with controls drove a finding of decreased NAA/Cr,
Cho/Cr, and mI/Cr in MDD, as absolute NAA, Cho, and
mI in patients and healthy controls did not differ (Gruber
et al., 2003).
Recent advances have allowed MRS assessment of brain
GABA and glutamate, which are the main cerebral inhibitory and excitatory amino acid neurotransmitters, respectively. The ability to measure these substances in the
brain is of considerable interest because plasma GABA
appears to be decreased in bipolar disorder, whereas
higher (nearer to normal) levels may predict antimanic
(Petty et al., 1996) and possibly even antidepressant (Ketter
et al., 2000) responses to the GABAergic agent valproate.
Moreover, several new anticonvulsants with GABAergic
and/or antiglutamatergic mechanisms appear to have potential roles in the treatment of various symptoms of bipolar disorder (Ketter and Wang, 2003; Ketter et al., 2003)
Emerging data suggest differential cerebral gammaaminobutyric acid changes in depressed MDD and depressed bipolar patients. Thus depressed MDD patients
compared with healthy controls were found to have
52 percent lower occipital GABA, but severity of depression (as measured by the HAM-D) showed no correlation
with cerebral GABA (Sanacora et al., 1999). Preliminary
data from an extension of this work indicate that depressed MDD patients compared with healthy controls
and depressed bipolar patients had occipital GABA decreases of 27 percent and 23 percent, respectively, with depressed bipolar patients compared with healthy controls
having only a nonsignificant (5 percent) decrease in occipital GABA (Mason et al., 2000). In contrast, euthymic
bipolar patients taking GABAergic agents (valproate
gabapentin) may have occipital and medial prefrontal
GABA levels about 50 percent higher than those of healthy
controls (Wang et al., 2002).
Gender effects on GABA and GABA/Cr have not been
extensively reported. Healthy women and men showed similar orbitofrontal, cingulate, insula, and thalamus GABA/Cr
(Grachev and Apkarian, 2000, 2001). Women compared
with men, however, showed decreased dorsolateral prefrontal GABA/Cr in young adulthood (ages 1931) (Grachev
and Apkarian, 2000), but not over a more extensive age
range (ages 1952) (Grachev and Apkarian, 2001). In another study involving both depressed MDD patients and
healthy controls, women compared with men were found
to have increased occipital GABA (Sanacora et al., 1999).
GABA appears to vary across the menstrual cycle. Thus,
occipital GABA from follicular to luteal phase was found
to decrease by 32 percent in healthy controls, but to increase by 63 percent in women with PMDD (Epperson
et al., 2002). Also, PMDD patients compared with healthy
controls showed lower follicular phase GABA (Epperson
et al., 2002). Occipital GABA was found to be correlated
with plasma estradiol and progesterone concentrations
negatively in healthy women and positively in those with
PMDD (Epperson et al., 2002). Occipital GABA also
showed a correlation with plasma allopregnanolone concentrations negatively in healthy women, but not in those
with PMDD (Epperson et al., 2002).
In depressed MDD patients, treatment with fluoxetine
or citalopram yohimbine was found to yield clinical improvement and a 34 percent increase in occipital GABA
(Sanacora et al., 2002). Changes in occipital GABA were
not correlated with improvement in depression, however.
Although no correlation was detected between baseline occipital GABA and clinical improvement, subjects with the
lowest and highest baseline occipital GABA showed robust
increases or no change in occipital GABA, respectively. In
depressed patients, treatment with ECT was found to yield
clinical improvement and a 78 percent increase in occipital
GABA (Sanacora et al., 2003). No correlation was found,
however, between changes in occipital GABA and antidepressant or adverse (memory impairment) effects.
647
648
Pathophysiology
was detected between age and anterior cingulate Glx (Pfleiderer et al., 2003). Degree of depression (as measured by the
HAM-D) showed no relationship to anterior cingulate or
parietal Glx (Auer et al., 2000).
There are also few data relating Glx or Glx/Cr to clinical
interventions. In bipolar patients, anterior cingulate Glx/Cr
showed no change with acute (1-week) lithium administration and no relationship to plasma lithium concentrations (Davanzo et al., 2001). In primarily depressed adult
bipolar-I and -II patients, however, longer-duration lithium
(for a mean of 3.6 months) but not valproate (for a mean
of 1.4 months) decreased gray but not white matter Glx,
suggesting that lithium may attenuate gray matter increases
observed by the same investigators in primarily depressed
bipolar patients at baseline (Friedman et al., 2004). However, Cecil and colleagues (2002) found an inverse correlation between duration of valproate therapy and prefrontal
Glx. In depressed MDD patients, ECT was found to increase
anterior cingulate Glx in responders, but not in nonresponders (Pfleiderer et al., 2003).
Euthymic bipolar patients compared with healthy controls showed increased parietal glutamate/Cr (Glu/Cr)
(Brhn et al., 1993). On the other hand, depressed MDD
patients compared with healthy controls had similar parietal but decreased anterior cingulate Glu (Auer et al., 2000).
In the latter study, no relationship was noted between regional Glu and degree of depression (as measured by the
HAM-D).
In summary, 1H-MRS studies suggest that patients with
mood disorders compared with healthy controls may have
metabolite changes in elements of anterior cortical/anterior
paralimbic basal gangliathalamocortical circuits more
than in parietal and occipital regions. Findings may differ
to varying degrees with the metabolite considered, region,
age, gender, phase of menstrual cycle, diagnosis, illness duration, mood state, and treatment.
Thus about half of the studies of bipolar (but not MDD)
patients compared with healthy controls detected NAA or
NAA/Cr decreases more than increases, in dorsolateral prefrontal and temporal more than other regions. Lithium may
increase NAA or NAA/Cr, confounding efforts to detect putative baseline (unmedicated) NAA and NAA/Cr decreases
in bipolar patients.
In about one-fourth of bipolar disorder and one-half of
MDD studies, Cho or Cho/Cr tended to be increased compared with that in healthy controls, most often in basal
ganglia. In a small number of studies, mI or mI/Cr tended
to be increased, compared with that in healthy controls, in
about one-half of bipolar and decreased in about one-half
of MDD studies. Lithium may decrease mI and mI/Cr in
bipolar patients but not in healthy controls, confounding
649
650
Pathophysiology
651
Bipolar-I
Bipolar-II
15
14
13
12
BP-I
14.1
HC
13.5
BP-I
Correctly
Classifies
18/21
BP-II
12.1a
BP-II
11
HC BP-II
11.2 12.2
BP-I
9.6b
10
10
15
Figure 1512. Low prefrontal phosphocreatine in euthymic bipolar-II (BP-II) patients and low
phosphomonoesters in euthymic bipolar-I (BP-I) patients. Prefrontal phosphocreatine levels are
shown on the vertical axis, and phosphomonoester levels on the horizontal axis. Euthymic
bipolar-I patients (squares) have significantly lower phosphomonoesters and nonsignificantly
higher phosphocreatine compared with euthymic bipolar-II patients (circles). These relationships allow correct classification of 18/21 patients as bipolar-I (above the diagonal line) and
bipolar-II (below the broken line). HC = healthy controls. ap <.05 versus BP-I, healthy controls;
b
p <.01 versus BP-II, healthy controls. (Source: Reproduced with permission from Kato
et al., 1994b.)
652
Pathophysiology
10
CONCLUSIONS
Structural Neuroimaging
5
r ! .64
p < .05
0
0.2
0.4
0.6
Figure 1513. Correlation between cerebral lithium concentrations and antimanic responses. Change in Petterson Mania Rating
Scale (PMRS) scores are shown on the vertical axis and brain lithium
levels on the horizontal axis. The correlation coefficient is .64
(p < .05). The regression is shown as a dotted line. (Source: Reproduced with permission from Kato et al., 1994c.)
To date, structural neuroimaging cannot be used to diagnose bipolar disorder or MDD. For example, despite there
being mean differences in structural parameters between
groups of mood disorder patients and groups of healthy
controls, the ranges overlap so that the groups are not
discretely separated. Moreover, the abnormalities seen in
groups of mood disorder patients compared with groups
of healthy controls are nonspecific, as they can occur in
other psychiatric disorders, such as schizophrenia. For
example, compared with healthy controls, both schizophrenic and bipolar patients had frontal, temporoparietal,
and corpus callosum white matter volume decreases,
while volumes in these areas were statistically similar in
the two patient groups (McDonald et al., 2005). However,
the deficits in schizophrenia may be more severe and widespread than those seen in bipolar disorder. Thus, schizophrenic patients had anterior paralimbic thalamorcortical
(amygdala, hippocampus, insula, caudate, thalamus, lateral
prefrontal and temporal cortex) gray matter volume decreases compared with both bipolar patients and healthy
controls, whereas the latter two groups had statistically
similar volumes in these regions (McDonald et al., 2005).
This pattern of findings was also evident in first-degree
relatives of patients with schizophrenia and bipolar disorder (McDonald et al., 2004). In a similar fashion, another
group found that, compared with healthy controls, anterior thalamic gray matter density was decreased in both
schizophrenic and bipolar patients and their relatives, with
schizophrenia but not bipolar disorder also being associated with decreased middle prefrontal gyrus and dorsomedial thalamus gray matter density (McIntosh et al., 2004).
Moreover, this group found that, compared with healthy
controls, anterior limb of internal capsule white matter
density was decreased in both schizophrenic and bipolar
patients, with schizophrenia but not bipolar disorder also
being associated with decreased corpus callosum and frontal
subgyral white matter density (McIntosh et al., 2005).
Structural neuroimaging can be used to diagnose general
medical conditions associated with secondary mood disorders. Primary (bipolar disorder and MDD) and secondary
(due to substance abuse or general medical conditions)
mood disorders may represent extremes of a continuum,
bracketing intermediate mood syndromes with varying
ratios of primary to secondary components. For example,
it has been suggested that SCHs may contribute to the
development of depression in at least some patients (Alexopoulos et al., 1997; Krishnan et al., 1997; Steffens and Krishnan, 1998). Thus, these structural brain changes suggestive
of mild cerebrovascular insufficiency not severe enough to
merit a diagnosis of depression secondary to stroke may
contribute to mood symptoms, treatment resistance, and
poor prognosis in late-life or late-onset depression.
Further along the continuum, frank vascular lesions in
basal gangliathalamocortical circuits may lead to secondary mood disorders. Thus, vascular subtypes of mania and
depression have been proposed, with criteria including
clinical and/or neuroimaging evidence of cerebrovascular
disease (history of stroke, transient ischemic attacks, focal
neurological signs, SCHs) or neuropsychological impairment (decreased cognitive processing quality or speed)
(Steffens and Krishnan, 1998). Proposed supporting features include onset of or change in affective symptoms after age 50, marked anhedonia, psychomotor retardation,
marked impairment in basic activities of daily living, and
lack of family history of mood disorders.
Methodological advancesincluding new methods of
image acquisition, such as DTI, and new image processing
techniques, such as the ability to segment images into gray
and white matterpromise to advance structural neuroimaging studies. Limited statistical power related to clinical heterogeneity and small sample sizes in individual
studies needs to be addressed, however. This problem is
particularly salient with respect to understanding the clinical correlates of structural imaging abnormalities in
mood disorder patients. Large collaborative studies and/or
standardized designs that facilitate meta-analyses may
help surmount this problem.
Functional Neuroimaging
Taken together, the functional neuroimaging literature reviewed above suggests that elements of anterior cortical/anterior paralimbic basal gangliathalamocortical circuits may
contribute importantly to affective processing in health,
and can have altered function in bipolar and MDD patients
(see Box 152).
The cerebral activity studies reviewed here have important limitations, including small sample sizes, varying
methodology, and reliance on measures of patterns of activity across cerebral structures rather than assessment of
specific neurochemical differences. Their findings need to
be combined with emerging data from studies of specific
cerebral neurochemistry using specific neurochemical radiotracers (reviewed in Chapter 14) and MRS (described
above) to yield more comprehensive understanding of the
nature of the neurobiology of mood disorders.
Methodological advances in MRS studies are beginning to allow in vivo assessment of specific cerebral
653
patients)
Decreased dorsolateral prefrontal activity
Decreased temporal cortical activity
Decreased basal ganglia activity (in MDD)
Variable anterior cingulate and medial prefrontal activity
Increased amygdala activity
Decreased prefrontal phosphomonoesters (in euthymic bipolar
patients versus healthy controls and depressed bipolar
patients)a
a
neurochemistry that is less invasive (no ionizing radiation) and more generally available (no need for an on-site
cyclotron, radiochemistry team, or PET scanner) than
PET techniques using specific neurochemical radiotracers. MRS studies are limited, however, by relatively poor
spatial resolution, and by the ability to assess only a small
and in some cases inadequately characterized group of
metabolites.
Studies of specific cerebral neurochemistry share important limitations with those of cerebral activity, such as
small sample sizes and varying methodology. Technical
advances, including new methods of image acquisition
(such as MRS sequences to detect GABA and glutamate
with enhanced spatial and temporal resolution), promise
to advance functional neuroimaging studies. As with
structural neuroimaging studies, however, limited statistical power related to clinical heterogeneity and small sample sizes in individual studies remains problematic. Also as
with structural neuroimaging studies, large collaborative
studies and/or standardized designs that facilitate metaanalyses may help address these difficulties.
Future Directions
Despite providing substantial contributions to our understanding of which cerebral structures mediate affective processing in health and mood disorders, neuroimaging has
not yet realized its potential to be a clinically relevant tool
in the diagnosis and treatment of major mood disorders.
Technological innovations to enhance spatial and temporal resolution, decrease or eliminate exposure to ionizing
radiation, increase neurochemical specificity, increase
availability, and decrease expense are needed if research is
to further advance our knowledge of the neuroanatomical
and neurochemical substrates of these disorders. As these
technological innovations unfold, it becomes even more
654
Pathophysiology
important that we put considerably more effort into improved methods for diagnosis and clinical evaluation, including an agreed-upon standard for distinguishing the
more recurrent forms of MDD that fall within Kraepelins
concept of manic-depressive illness. More careful differentiation between state and trait is also needed, as are consensus protocols for assessing the multiple sources of
variance in these measures. Given the great promise and
expense of these technologies, we can afford to do no less.
While it remains to be seen whether such advances will ultimately yield clinical applications to facilitate diagnosis
and target treatments more effectively in patients with
mood disorders, it is clear that this potential will not be realized unless we invest more effort in standardizing the
clinical characterization of the patients we study.
NOTES
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152. Martinot et al., 1990; Cohen et al., 1992; Goyer et al., 1992;
Ebert et al., 1993.
153. Cohen et al., 1992; Goyer et al., 1992; Ebert et al., 1993; Ketter
et al., 1996b.
154. Baxter et al., 1985; Kuhl et al., 1985; Kling et al., 1986; Hurwitz et al., 1990; Kanaya and Yonekawa, 1990; Bench et al.,
1992, 1993; Dolan et al., 1992; Wu et al., 1992; Kumar et al.,
1993; Biver et al., 1994; Edmonstone et al., 1994; Bonne et al.,
1996b; Mozley et al., 1996; Delvenne et al., 1997a; Hornig
et al., 1997; Awata et al., 1998; MacHale et al., 2000; Navarro
et al., 2001; Videbech et al., 2001; Kimbrell et al., 2002.
155. Drevets et al., 2001; Sheline et al., 2001; Thomas et al., 2001;
Lawrence et al., 2004; Blumberg et al., 2005.
156. George et al., 1995b; Mayberg et al., 1999; Liotti et al., 2002;
Krger, 2003, 2006.
658
Pathophysiology
157. Matsuo et al., 2000, 2002; Curtis et al., 2001; de Asis et al.,
2001.
158. Baxter et al., 1989; Kanaya and Yonekawa, 1990; Drevets and
Raichle, 1992; G. Goodwin et al., 1993; Bench et al., 1995;
Buchsbaum et al., 1997b; Tutus et al., 1998a,b; Smith et al.,
1999; Mayberg et al., 2000; Brody et al., 2001a; Kennedy
et al., 2001; Nofzinger et al., 2001; Sheline et al., 2001;
Drevets et al., 2002a,d.
159. Ebert et al., 1991; Wu et al., 1992, 1999; Volk et al., 1997;
Holthoff et al., 1999; Smith et al., 1999.
160. Ebert et al., 1991, 1994; Wu et al., 1992, 1999; Holthoff et al.,
1999.
161. OConnell et al., 1995; Rubin et al., 1995; al-Mousawi et al.,
1996; Blumberg et al., 1999.
162. Drevets et al., 1995, 1997; G. Goodwin et al., 1997; Blumberg
et al., 2000.
163. Drevets et al., 1995, 1997; G. Goodwin et al., 1997; Blumberg
et al., 2000.
164. Renshaw et al., 1995; Winsberg et al., 2000; Chang et al.,
2001; Frye et al., 2001; Cecil et al., 2002; Bertolino et al.,
2003; Deicken et al., 2003a; Sassi et al., 2005.
165. Sharma et al., 1992; Deicken et al., 2001; P. Silverstone et al.,
2003; Dager et al., 2004.
166. Stoll et al., 1992; Kato et al., 1996a; Hamakawa et al., 1998,
1999; Ohara et al., 1998; Soares et al., 1999; Castillo et al.,
2000; Moore et al., 2000a; Davanzo et al., 2001; Amaral
et al., 2002; Michael et al., 2003.
167. Charles et al., 1994b; Renshaw et al., 1997; Hamakawa et al.,
1998; Auer et al., 2000; Ende et al., 2000b; Mervaala et
al., 2000; Rosenberg et al., 2000; Steingard et al., 2000;
Kusumakar et al., 2001; Farchione et al., 2002; Pfleiderer
et al., 2003.
168. Soares et al., 1999; Davanzo et al., 2001; Amaral et al., 2002;
Bertolino et al., 2003; Dager et al., 2004.
169. Castillo et al., 2000; Moore et al., 2000b; Amaral et al., 2002;
Bertolino et al., 2003; Dager et al., 2004.
170. Kato et al., 1996b; Hamakawa et al., 1998; Ohara et al., 1998;
Bertolino et al., 2003.
171. Sharma et al., 1992; Stoll et al., 1992; Moore et al., 2000b;
Frye et al., 2001; Bertolino et al., 2003.
172. Renshaw et al., 1995; Winsberg et al., 2000; Frye et al., 2001;
Cecil et al., 2002; Bertolino et al., 2003; Deicken et al., 2003a;
Sassi et al., 2005.
173. Stoll et al., 1992; Kato et al., 1996a; Hamakawa et al., 1998,
1999; Ohara et al., 1998; Castillo et al., 2000; Moore et al.,
2000a; Davanzo et al., 2001; Amaral et al., 2002; Michael
et al., 2003; Brambilla et al., 2005.
174. Lafer et al., 1994; Kato et al., 1996a; Hamakawa et al., 1998;
Moore et al., 2000a; Sharma et al., 1992.
175. Demopulos et al., 1996; Cecil et al., 2002; Silverstone et al.,
2004.
176. Stoll et al., 1992; Brhn et al., 1993; Renshaw et al., 1995;
Ohara et al., 1998; Hamakawa et al., 1999; Castillo et al.,
2000; Winsberg et al., 2000; Chang et al., 2001; Davanzo
et al., 2001, 2003; Deicken et al., 2001, 2003a; Amaral et al.,
2002; Bertolino et al., 2003; Michael et al., 2003; Brambilla
et al., 2005; Sassi et al., 2005.
177. Charles et al., 1994b; Hamakawa et al., 1998; Mervaala et al.,
2000; Rosenberg et al., 2000; Steingard et al., 2000; Farchione et al., 2002; Vythilingam et al., 2003.
16
For our body is like a clock; if one wheel be amiss, all the rest are disordered, the whole fabric
suffers: with such admirable art and harmony is a man composed.
Robert Burton, The Anatomy of Melancholy (1621, p. 171)
As surely as the sun rises in the morning and bears hibernate in the winter, human functioning heeds its own innate rhythms. Body temperature rises and falls in oscillations, as do hormone secretions, cell division, heart rate,
urine flow, allergic reactions, motoric activity, even mathematical finesseand, most obvious of all, the need for
sleep. Mood also fluctuates, waxing and waning, although
the regularity of mood cycles is not synchronized with the
clock as precisely as is the case with other biological rhythms.
Indeed, abnormalities of biological rhythms have been proposed to represent endophenotypes or markers of manicdepressive illness (perhaps particularly the bipolar subgroup), presumably being present not only in patients but
also in some relatives without manifest mood disorder.
Sleep disruption is closely associated with recurrent affective illness. Sleep loss is a major symptom as well as a trigger of manic episodes, and when applied clinically (sleep
deprivation) is one of the most effective antidepressant
interventions1certainly the fastest acting. In addition to
the diurnal, or circadian, rhythms associated with sleep,
the observation that the seasons of the year influence the
expression of mood disorders is as old as the classical descriptions of manic-depressive illness itself.
In this chapter we review the literature on circadian
rhythms, sleep disturbances, and their relationship to affective illness. We also review the less extensive body of
work on the relationship between seasonal rhythms and
mood disorders. We begin by reviewing the physiology of
circadian rhythms and of sleep. Next we look at the relationship between sleep and affective disorders, and that
between disturbances of circadian rhythms and manicdepressive illness. We then examine the literature on experimental alterations of sleep and other biological rhythms as
treatments for affective illness. Finally, we review what is
660
Pathophysiology
A
B
B/A
661
662
Pathophysiology
Biological Dawn
entrained to dawn
Biological Dusk
entrained to dusk
Biological Dusk
entrained to dawn
BIOLOGICAL DAY
BIOLOGICAL NIGHT
No melatonin secretion
Increasing core body temperature
Decreasing sleepiness
Decreasing waking EEG theta activity
Decreasing REM sleep propensity
Melatonin secretion
Decreasing core body temperature
Increasing sleepiness
Increasing waking EEG theta activity
Increasing REM sleep propensity
Figure 162. Temporal organization of the human circadian timing system. Profiles of a number of
circadian rhythms in humans exhibit distinct diurnal and nocturnal states with abrupt switch-like transitions between them. These states and transitions can be conceptualized as a biological day and night
and a biological dawn and dusk. They are generated within the organism and mirror or anticipate features of the solar day to which they correspond and with which they are synchronized. EEG = electroencephalogram; REM = rapid eye movement. (Source: Wehr et al., 2001b. Reprinted with permission from
Blackwell Publishing, Ltd.)
PHYSIOLOGY OF SLEEP
Sleep is a distinct behavioral and physiological state, as
defined by EEG and behavioral characteristics. In preparation for sleep, animals seek a protected environment, assume
a characteristic sleep posture, and pass briefly through a
drowsy state before falling asleep. Despite intense research,
the function of sleep remains unknown. Nevertheless, it is
well known that sleep serves a vital function, this despite its
evolutionary disadvantages, such as increased vulnerability
to predators. Mammals totally sleep deprived for 23 weeks
die, as they would if deprived of food for a similar duration.18
Stages of Sleep
The discrete stages of sleep are marked by variations in
EEG patterns, eye movements, and muscle tone. By convention, human sleep is divided into two major phases that alternate throughout the night: a REM phase and a non-REM
(NREM) phase. On falling asleep, healthy adults go into
NREM sleep, the period of rest and energy conservation,
when the brain literally cools while respiration, blood pressure, heart rate, and other physiological processes slow
down, eyes are still or move only slowly, and muscles are relaxed but not flaccid. This first phase comprises four stages
of progressively deeper sleep. On EEG recordings, the frequency of electrical waves decreases steadily from stage 1 to
stage 4, while the amplitudethe energy discharged at each
impulseincreases (see Fig. 163). Stages 3 and 4 consist of
predominant slow and ample delta waves (slow-wave sleep),
the result of highly synchronized brain activity.
Following the NREM phase is REM sleep, marked by intense mental activity, vivid dreaming, and rapid and diffuse
cerebral metabolism. Blood flow and most neuronal firing
rates, and probably brain temperature, are higher than during either NREM or awake states, while, paradoxically, the
large muscles are virtually paralyzed. Bursts of REM occur,
pulse and blood pressure rise and fall, and respiration becomes irregular. EEG activity shows a sawtooth pattern, low
in amplitude (voltage) and variable in frequency, similar to
stage 1 NREM sleep (the brief transition period between
wakefulness and sleep). Dement and Kleitman (1957) observed that in normal individuals, the distribution of REM
sleep during the night was skewed, with more occurring toward the end of the night than at the beginning.
In the normal sleep of a young adult, the first period of
NREM sleep (through all four stages) is followed, after an
average of about 90 minutes, by a 15- to 20-minute period of
REM sleep. Slow-wave sleep (stages 3 and 4, part of the
NREM phase) predominates during the first part of the
night, whereas REM sleep periods become progressively
longer and are most concentrated in the hours before waking. While an internal self-sustaining circadian pacemaker
appears to govern the propensity for REM sleep, homeostatic
processes determine other sleep patterns, such as the amount
of slow-wave sleep, which turns out to be proportional to the
length of time the person has been awake prior to sleep.
Advances in understanding of the neurophysiological
basis of the sleep EEG (Steriade, 1994; Amzica and Steriade, 1998), in conjunction with quantitative EEG analysis
(Borbely et al., 1989; Aeschbach and Borbely, 1993; Achermann and Borbely, 1998), have confirmed that the EEG is
WAKE
NREM SLEEP
REM SLEEP
Behavior
Stages
Awake
Polygraph
REM
II
III
IV
EMG
EEG
EOG
Sensation and
Perception
663
Vivid,
Externally Generated
Dull or Absent
Vivid,
Internally Generated
Thought
Logical
Progressive
Logical
Perseverative
Illogical
Bizarre
Movement
Continuous
Voluntary
Episodic
Involuntary
Commanded
but Inhibited
664
Pathophysiology
blockers of muscarinic receptors suppress REM sleep. Noradrenergic neurons in the locus ceruleus and serotonergic
neurons of the dorsal raphe are active during waking, less
active during NREM sleep, and inactive during REM sleep.
These neurons inhibit the cholinergic neurons of the pontine tegmentum to terminate REM sleep. A less-than-active
serotonergic or noradrenergic system (perhaps in depression) may result in disinhibition of REM sleep. While these
discrete pontine structures are involved in REM sleep initiation, other neurons, such as those in the lateral hypothalamus, the amygdala, and other limbic structures, are involved
in the maintenance of REM sleep.
In addition to GABA, histamine, acetylcholine, serotonin, norepinephrine, and orexin/hypocretin (described
briefly above and in the associated notes), other neurotransmitters have an important role. For example, dopaminergic
neurons promote wakefulness. In addition, cholecystokinin,
prostaglandins, interleukin-1, and adenosine have a modulatory role. Adenosine in particular has been implicated in
mediating the homeostatic mechanisms of sleep. Caffeine
increases alertness by blocking adenosine receptors, which
are widespread in the brain. Receptors on the cholinergic
neurons of the basal forebrain appear to regulate adenosines effect on sleep.26
665
666
Pathophysiology
667
668
Pathophysiology
Figure 164. Hypothesized relationship among genetic vulnerability, stress, circadian rhythm disturbances, neurotransmitterneuroendocrine immune dysregulation, and the symptoms of manic-depressive illness.
Neurotransmitter
Dysregulation
Genetic
Vulnerability &
Stress
Altered Immune
Responses
Behavioral
Disturbance
(symptoms)
Circadian
Rhythm
Disturbances
Neuroendocrine
Changes
669
670
Pathophysiology
and motor activity. Taken together, the results of these studies suggest that phase-advanced rhythms are quite common,
although there is considerable variability among individuals
and studies. It is of interest that reports of a phase delay
have been strikingly less frequent than would be expected
by chance. One might conclude that circadian rhythms
tend to be abnormal or unstable in affective illness, with a
bias toward assuming a phase-advanced position some of
the time (see the review of Duncan et al., 1996). In mania,
Linkowski and colleagues (1994) showed an early timing of
the nadir of cortisol.
In circadian phase interpretation, age must be controlled,
since circadian abnormalities associated with aging have
been reported. These abnormalities consist mainly of a phase
advance of sleep and delay of temperature and melatonin
rhythms compared with normal sleep (Duffy et al., 1998,
2002; Dijk et al., 2000). Other important variables are diagnostic: whether patients are unipolar or bipolar, and whether
the disorder is cyclic (that is, highly recurrent) or relatively
noncyclic. Thus Linkowski and colleagues (1985a,b) found
a significant phase advance in the cortisol nadir among
unipolar patients, but only a trend among bipolar patients.
One clinical antidepressant treatment that appears to
support the phase-advance hypothesis (described in more
detail later) is a sleep schedule manipulation that advances
the time of morning wakening, producing a temporary antidepressant response in a significant proportion of patients
with nonseasonal depression.42 Figure 165 illustrates how
depriving patients of sleep in the second half of the night or
advancing their sleep might help synchronize the abnormally advanced rhythm of REM sleep, temperature, and
cortisol with the oscillator controlling sleep and wakefulness. By advancing sleep (or eliminating its second half), the
abnormal phase relationship in the second half of the night
would be corrected.
It would be consistent with the phase-advance hypothesis for the antidepressant effect of light to be observed with
evening administration (delaying cortisol, melatonin, and
temperature rhythms and thus realigning them with the
sleepwake rhythm), coupled with a worsening of depression with morning light (which should further advance
circadian rhythms). However, it has been found that the
timing of light administration in nonseasonal depression
is unimportant to its effect (Yamada et al., 1995; Kripke,
1998; Wirz-Justice et al., 1999a) and further, that morning
light, rather than being detrimental, is as effective as evening light (Yamada et al., 1995). Light therapy is discussed
in more detail later in the chapter.
Riemann and colleagues (1996) compared an experimentally advanced (from 5 PM to 12 AM) sleep period
with a normal (from 11 PM to 6 AM) sleep period in patients who had responded to total sleep deprivation. Twothirds of subjects in the latter group relapsed after one
night of sleep, while two-thirds of subjects in the former
group did not. Thus phase advance of the sleepwake cycle
can prolong the antidepressant effect of sleep deprivation.43 In a subsequent study, Riemann and colleagues
(1999) compared the ability of sleep phase advance and
sleep phase delay to preserve the antidepressant effects of
total sleep deprivation. They hypothesized that sleep phase
advance would be more effective in preventing relapse in
responders to the treatment. Among their original sample
of 54 depressed patients, 77.2 percent were found to be responders to total sleep deprivation and were randomized to
either the phase-advance or phase-delay experimental condition. After 7 days, 75 percent of the sleep phaseadvance
patients were still stabilized, compared with only 40 percent
of the sleep phasedelay patients. (See also the later section
on therapeutic sleep deprivation.)
SLEEP
1. Euthymic
SLEEP
2. Depressed
Oscillator is phase-advanced
SLE
SLEEP
671
circadian amplitudes of temperature, cortisol, or TSH in patients. More recently, experimentally lengthening the duration of the dark period has been shown to increase the amplitude of circadian rhythms and been proposed as one of
the plausible theoretical premises for the application of extended rest and darkness in the treatment of rapid-cycling
bipolar illness (Wehr et al., 1998), as described in more detail
below.
If relatively low-amplitude rhythms were somehow
intrinsic to recurrent depression or bipolar illness, one would
expect such rhythms to be more vulnerable to perturbation
by internal or external influences, since the stability of a
circadian system is positively correlated with amplitude
(Aschoff and Wever, 1980; Wever, 1980). Not only do the frequency and timing of environmental zeitgebers vary considerably under normal conditions, but the dramatic behavioral
shifts associated with manic-depressive illness (especially
the bipolar subgroup) also multiply this variability. Thus,
blunted amplitudes associated with affective disorder would
be expected to be associated with phase instability. For example, using actigraphic recordings, Jones and colleagues
(2005) have demonstrated that bipolar patients, even in
recovery, have less stable and more variable circadian activity patterns than normal controls. This decreased stability/
increased variability in activity patterns has recently been
reported among individuals deemed to be at risk for bipolar disorder as defined by a threshold score on the Hypomanic Personality Scale (Meyer and Maier 2006).
One explanation for decreased circadian amplitude
is poor entrainment by external zeitgebers (Aschoff and
Wever, 1981), as observed in normal individuals isolated
from time cues under free-running conditions. Such reduced or irregular entrainmentinitially the consequence
of depression (due, e.g., to loss of social zeitgebers during
withdrawal)could then feed the depression through the
resulting disturbance in rhythms (Ehlers et al., 1988).
In this context, it is necessary to consider a paradox.
Lewy and colleagues (1981, 1985) found that, compared
with normal controls, bipolar (but apparently not unipolar) patients (Cummings et al., 1989; Lam et al., 1990) are
supersensitive to light, as reflected by a lower threshold required to reduce nighttime plasma melatonin levels; moreover, this supersensitivity appears to be state independent.
However in a subsequent study of euthymic bipolar patients subjected to a 500 lux light between 2 AM and 4 AM
on one night and left in the dark for a comparable time period on another night, no group-level differences in melatonin suppression were found among the bipolar group,
the unipolar group, and controls (Nurnberger et al., 2000).
While the hypothesis that bipolar patients have an increased
sensitivity to light was not confirmed, abnormalities in
melatonin secretion were found in the bipolar-I subgroup.45
672
Pathophysiology
673
674
Pathophysiology
Therapeutic Latency
Response Duration
Hours
Hours
~1 day
~1 day
Hours
Hours
Days/weeks
Weeks/months
~3 days
12 weeks
Hours
12 weeks
Hours
Weeks
Hours
Weeks
Hours
Months
Days
Weeks/months
Weeks
Weeks/months
12 weeks
Weeks/months
Days
Throughout maintenance
of treatment
much-needed rapid-acting antidepressant; dont clinicians want a drug that works within a day?
675
value. Wehr and Sack (1988, p. 208) emphasized the importance of sleep deprivation studies:
The single most important argument that sleep is an important factor in mental illness is the observation that
sleep deprivation rapidly induces remissions in the majority of depressed patients, and induces mania in bipolar
patients, and that recovery sleep after sleep deprivation
rapidly induces depression in the majority of patients
who have responded to sleep deprivation.
Are there differences between unipolar and bipolar patients in the efficacy and safety of response to sleep deprivation? From the occasionally dramatic mania-inducing
effect of losing one night of sleep, one might presume
a more intense effect in bipolar patients. Indeed, Barbini
and colleagues (1998) reported that bipolar patients had a
greater response than unipolar depressed patients to three
cycles of total sleep deprivation and, contrary to some expectations, that no unipolar patient switched to bipolar
during the treatment. It is not known, however, what proportion of the unipolar group had the more recurrent forms
of unipolar depression (which in some patients may be associated with a diathesis for bipolar disorder). Another intriguing observation of this study is that subjective ratings
of mood (on visual analogue scales) improved only in the
bipolar group.
A large study of 206 bipolar depressed patients who underwent three nights of sleep deprivation alternated with
three nights of sleep (Colombo et al., 1999) found that the
risk of switch into mania was 4.85 percent and into hypomania was 5.83 percent (the rate of antidepressant response
was not reported). Initial estimates suggested a risk of one
in four bipolar patients, but these estimates were based on a
small population of patients with a history of rapid cycling,
a subgroup especially vulnerable to mood switches.
In general, there is a feed-forward relationship between
sleep deprivation and mania in bipolar patients (the mania
maintaining insomnia and arousal) (Wehr et al., 1987), in
contrast to a feedback relationship between sleep deprivation and fatigue (causing sleepiness) in nonbipolar depressed patients. Lenox and colleagues (2002) hypothesized
the response to sleep deprivation to be a genetically heritable condition and possibly an endophenotype of bipolar illness (Lenox et al., 2002).
Predictors of response to sleep deprivation include diurnal variation in mood, with spontaneous improvement
in mood occurring in the afternoon and evening hours
(Reinink et al., 1990); increased diurnal variation in mood
independent of the direction (Reinink et al., 1993); decreased
REM latency (Riemann et al., 1991), which normalizes after sleep deprivation (Duncan et al., 1980; Riemann and
Berger, 1990); and endogenous rather than reactive or
676
Pathophysiology
Figure 166. Relationship between the timing of sleep and the antidepressant effect
of sleep deprivation. (Source: Wehr and Goodwin, 1981.)
Night
Day
Less
Depressed
SLEEP
SLEEP
SLEEP
677
More
Depressed
SLEEP
Sleep-Sensitive
Circadian Phase
678
Pathophysiology
with ongoing sleep phase advance is more stable. One possible explanation for the efficacy of sleep phase advance is
a realignment of the sleepwake cycle with other circadian
endogenous rhythms, such as cortisol and temperature,
which tend to occupy a phase-advanced position in major
depression.
Initiating sleep phase advance (Sack et al., 1985) in the
evening following total sleep deprivation (as it is easier to
fall asleep at 5 PM after a night without sleep) maintains
the antidepressant effect of sleep deprivation in a proportion comparable to that of treatment with antidepressant
medication.60 Benedetti and colleagues (2001a) observed
that, compared with unmedicated patients, those taking
lithium showed greater improvement with a combination
of total sleep deprivation and sleep phase advance. The authors explained their results as a double action to realign
sleepwake with other biological rhythms, the sleep phase
advance bringing sleep earlier and lithium delaying the
metabolic rhythms.
The clinical lore surrounding affective disorders has alluded to their seasonal nature since ancient times. Seasonal
trends emerge in the epidemiology of populations of patients, and seasonal patterns become evident in the course
of manic-depressive illness in individual patients. Onsets
of episodes tend to cluster in the spring and fall, especially
among those prone to annual recurrences. As Wehr and
Rosenthal (1989) pointed out, these patterns imply that environmental changes can both cause and ameliorate episodes
of affective illness.
Nineteenth-century psychiatrists, unlike those of today,
had the opportunity to observe the course of untreated
manic-depressive illness for long periods (see Chapter 1).
Several leading psychiatrists of the era64 recorded many
cases in which the pattern of recurrence was seasonal. In
one pattern, depressions began in spring and summer. In
another, the onset of depression occurred in fall or winter,
while mania or hypomania appeared in the summer. These
patterns also emerge in longitudinal data published by Baastrup and Schou (1967) in their now-classic lithium studies
and by Kukopulos and Reginaldi (1973). Analysis of the
frequency distribution of the cycle lengths of episodes
drawn from a longitudinal study of 105 bipolar patients
(Zis and Goodwin, 1979) shows a very large peak at 12
months, with smaller peaks at subsequent multiples of 12
(see Fig. 167). Although reporting bias may account for
some of these findings, it is probably not sufficient to explain the magnitude of the seasonal effect.
Slater (1938) was the first to apply systematic statistical
analysis to the study of seasonal patterns among manicdepressive patients. He noted that for each patient, recurrences were significantly more likely to occur at the same
679
60
Number of Cycles
50
Patients N ! 105
Cycles N ! 755
40
30
20
10
12
24
36
48
60
72
84
Cycle Length (months)
96
108
120
Figure 167. Seasonal variation in the length of the photoperiod and in its rate
of change: relationship to seasonal peaks in depression, mania, and suicide. (Source: Zis
and Goodwin, 1979.)
680
Pathophysiology
While most of the earlier studies of the seasonal incidence of depression did not differentiate bipolar and
unipolar patients, some more contemporary studies, taken
together, suggest that a spring peak is predominant in
unipolar depression, while bipolar depression is more
likely to show a (smaller) fall/winter peak.70 A recent study
of 958 consecutively admitted patients with major depression (Sato et al., 2006) found that those with depressive
mixed states (see Chapter 1) showed a seasonal pattern
similar to that of the bipolar group and different from that
of the unipolar patients without such states, which is
consistent with the hypothesis that these states are part of
the bipolar spectrum. While the above studies employed
clinical samples, Shin and colleagues (2005) recently confirmed the high rate of seasonality in bipolar patients
compared with patients with major depression or normal
controls in a large community sample.
Although the data on mania are somewhat more limited
and therefore a bit less compelling, peak incidences tend to
occur in the summer months (Takei et al., 1992). Analyzing
hospital admissions, Cassidy and Carrol (2002) found that
admissions for pure mania were more frequent in spring
(when photoperiod increases rapidly), which coincided
with the peak for total admissions for mania. However, the
peak for mixed episodes was in late summer, when photoperiod starts decreasing more rapidly, and the ambient
temperature is still high. Myers and Davies (1978) and Carney and colleagues (1988) showed significant correlations
Figure 168. Frequency distribution of cycle lengths among bipolar patients, showing
12-month peaks. BP-I = bipolar-I; BP-II = bipolar-II. (Source: Zis and Goodwin, 1979.)
Winter
J
Spring
Summer
M
Fall
Suicide
Major Depression
BP-I, Depression
BP-I, Depression
Winter Dep
(BP-II?)
Rate of Change
Mania / Hypomania
Length
Photoperiod
Winter
Suicide
Major Depression
Winter Dep
(BP-II?)
Winter
A
Spring
681
J
Summer
O
Fall
Winter
682
Pathophysiology
Ethnicity
According to a review by Magnusson (2000), the prevalence
of SAD (diagnosed using criteria based on the Seasonal
Pattern Assessment Questionnaire) across 20 retrospective
studies varied from 0 to 9.7 percent. Winter SAD was found
to be more prevalent than summer SAD in all but four
studiesthree in China and Japan (Ozaki et al., 1995a;
Han et al., 2000a) and a fourth in the tropics (Morrisey
et al., 1996). It may be that a specific ethnic factor, genetic
or environmental, protects those of Asian ethnicity from
winter SAD and makes these individuals more vulnerable
to summer SAD.72 Given the size of the Chinese population,
summer SAD is not a small problem at the global level.
Acclimatization
Is SAD a dysfunctional response, or is it adaptive? Over
time, does longer exposure to a higher latitude result in
more drastic and consolidated behavioral changes, or do
683
Table 162. Criteria for Seasonal Affective Disorder and Seasonal Pattern
Seasonal Affective Disorder
(Rosenthal et al., 1984)
1. Recurrent fallwinter depressions
Seasonal Pattern
(DSM-IV, 1994)
1. Regular temporal relationship between
onset of episode of affective disorder and a
particular 60-day period of the year.
2. Do not include cases in which there is an
obvious effect of seasonally related
psychosocial stressors (e.g., regularly being
unemployed every winter).
3. Full remissions (or a change from
depression to hypomania or mania) during a characteristic time of year (e.g., depression disappears in the spring).
4. In the last 2 years, two major depressive
episodes have occurred that demonstrate
the temporal seasonal relationships described in previous points, and no nonseasonal major depressive episodes have occurred during the same period.
5. The corresponding criterion is implicit
here, as seasonal pattern is provided as
a modifier of other DSM-IV diagnoses:
bipolar disorder or recurrent major depression.
6. Seasonal episodes of mood disturbance
substantially outnumbered nonseasonal
episodes.
684
Pathophysiology
loading on depression with little or no loading on seasonality, a nonseasonal major depression would be expected.
This dual-vulnerability hypothesis was initially proposed
by Young and colleagues (1991) and further developed by
Lam and colleagues (2001a,b,c). Light treatment was known
to be effective for both subsyndromal SAD and SAD (Kasper
et al., 1989a; Norden and Avery, 1993). Subsequently, however,
Lam and colleagues (2001c) showed that subsyndromal SAD
(more loading on seasonality than on depression) appears to
be more responsive to the treatment. On the other hand, a
meta-analysis by Kripke and colleagues (1997) found that the
antidepressant effect of light treatment in nonseasonal depression is equivalent to that seen in seasonal depression.76
Genetic Factors
A large study involving 4,639 adult twins pairs from Australia found that genetic factors accounted for 29 percent of
the variance in seasonality (Madden et al., 1996). The heritability of seasonality was associated with a preponderance
of the vegetative symptoms of depression, such as increased appetite, weight gain, and increased sleep, which
are also good predictors of response to light therapy (Lam
et al., 1993; Sher et al., 2001). This latter association also
provides circumstantial support for a dual-vulnerability
model, as seasonality in appetite, weight, and sleep is associated with loading on vulnerability for seasonality as opposed to dysphoria and anhedonia, which result from loading on vulnerability for depression. Another twin study
involving 339 twin pairs (Jang et al., 1997b) found a more
substantial genetic contribution than that found in the
study by Madden and colleagues (1996). The authors also
reported that heritability accounted for more variance in
seasonality in men (69 percent) than in women (45 percent).
Linkage studies have reported genetic associations between
SAD and the serotonin 5-HT2A promoter polymorphism
1438G/A (Enoch et al., 1999)as well as the 218C allele of
tryptophan hydroxylase (Levitan et al., 1999a,b). An association between seasonality as a trait and the short allele
Neurotransmitter Dysfunction
It is important to note that the subjects for the studies discussed below were patients with SAD. Therefore, the degree to which the study findings are related to seasonality
in manic-depressive illness, either bipolar or recurrent depression, is unknown (see the earlier discussion of the
overlap between SAD and bipolar disorder).
Serotonin. Certain indirect measures of serotonin activity, such as levels of precursors and metabolites, fluctuate
markedly with the seasons. For example, plasma L-tryptophan, the precursor of serotonin, is at its highest levels in
spring, declining in late (Wirz-Justice and Richter, 1979) or
early (Wirz-Justice et al., 1979; Swade and Coppen, 1980)
fall. In a recent study of 101 healthy men in which serotonin
metabolites in the jugular vein were measured, turnover of
serotonin by the brain was found to be lowest in winter
(p = .013). In addition, the rate of production of serotonin
by the brain was correlated positively with the level of ambient light, and the strongest correlation was with the day of
testing (i.e., the relationship was not particularly lagged)
(Lambert et al., 2002). Results of animal studies indicate
that serotonin content in the hypothalamus shows a
marked seasonal variation, with a minimum in the winter
(Carlsson et al., 1980). The major metabolite of serotonin,
5-HIAA, measured in the cerebrospinal fluid, has its trough
in springtime, which may reflect low serotonergic activity
during winter (Brewerton et al., 1988). Neumeister and
colleagues (2001) reported reduced serotonin transporter
availability in the hypothalamic/thalamic area in winter
compared with summer in healthy subjects.
Because dietary carbohydrates enhance serotonin synthesis and transmission through increased tryptophan
uptake into the brain (Fernstorm and Wurtman, 1971), the
observation that patients with SAD feel activated following high-carbohydrate meals whereas normal controls feel
more sedated (Rosenthal et al., 1989) may suggest altered
serotonin metabolism in SAD. Several studies have shown
that treatment with tryptophan can improve mood in patients with SAD to a degree similar to that achieved with
light treatment (Ghadirian et al., 1998; McGrath et al., 1990).
Tryptophan may also augment light treatment, one study
finding that it converted 9 of 14 patients from nonresponders to responders (Lam et al., 1997).
The hypothesis that SAD may involve serotonin has also
been examined using tryptophan depletion, by which central serotonin synthesis can be reduced. Tryptophan depletion results in a relapse of depressive symptoms in SAD
patients who formerly responded to light treatment in winter, as shown in three different studies (Lam et al., 1996;
Neumeister et al., 1997, 1998a). Tryptophan depletion in
summer resulted in relapse in one study (Neumeister et al.,
1998a) but not in another (Lam and Levitan, 1996). The association of tryptophan depletion with depressive relapse is
not specific to seasonal depression, also being seen in nonseasonal cases (Bremner et al., 1997), which suggests that
the phenomenon is related more to depression than to seasonality per se. Preliminary data suggest that D-fenfluramine, a serotonin-releasing agent, may benefit SAD patients (ORourke et al., 1987). Selective serotonin reuptake
inhibitors (SSRIs) are also effective in the treatment of
SAD, as reported for fluoxetine (Lam et al., 1995) and sertraline (Moscovitch et al., 1995). When added to light treatment, citalopram improves the efficacy of the treatment in
the long run, but not in the short run (Thorell et al., 1999).
One serotonergic finding appears to be specific to SAD.
Whereas patients with nonseasonal major depression do not
show altered hormonal or abnormal behavioral responses
to the 5-HT2C agonist m-chlorophenylpiperazine (m-CPP)
(Anand et al., 1994), patients with SAD show blunted hormonal responses and experience activation euphoriaa
consistent finding in both uncontrolled (Joseph-Vanderpool
et al., 1993; Jacobsen et al., 1994; Garcia-Borreguero et al.,
1995) and controlled (Schwartz et al., 1997; Levitan et al.,
1998) studies. These changes are normalized after successful
light therapy, suggesting that the response to m-CPP is a
state marker in SAD.
In conclusion, there is convincing evidence that serotonergic dysfunction plays a role in SAD. Some of these abnormalities, involving either 5-HT2C or 5-HT7, may be specific to the state of winter depression rather than being
associated with depression in general.
Dopamine. There is some evidence, mostly indirect, suggesting dopamine involvement in SAD. Low resting prolactin levels independent of season have been reported in
SAD patients (suggesting a trait marker), a finding interpreted as reflecting upregulation of D2 receptors secondary to reduced presynaptic dopamine (Depue et al., 1989,
1990). Another presumed indicator of altered dopamine
function is blunted thermoregulatory heat loss in the winter in patients with SAD compared with normal controls
(Arbisi et al., 1989, 1994), which is reversed by successful
light treatment. A more direct test of the dopamine hypothesis failed when a double-blind, placebo-controlled trial
of L-dopa/carbidopa yielded negative results (Oren et al.,
1994b). On the other hand, the antidepressant bupropion,77
whose mechanism of action is thought to involve enhanced
dopamine (and norepinephrine) function, was found to be
effective in one placebo-controlled study of SAD (Modell
685
et al., 2005). Perhaps also consistent with dopamine involvement in SAD, findings of a recent study indicate that adults
with residual attention deficit disorder may have high seasonality scores (Levitan et al., 1999a).
Norepinephrine. An inverse relationship between depression scores in patients with SAD and levels of norepinephrine metabolites in cerebral spiral fluid has been reported
(Rudorfer et al., 1993). Results of other studies, however,
suggest a lower plasma norepinephrine concentration in
untreated SAD patients relative to controls and in untreated
versus light-treated conditions (Schwartz et al., 1997).
Also after light treatment, plasma norepinephrine levels
(Skwerer et al., 1988), as well as norepinephrine turnover,
were found to increase (Anderson et al., 1992); both of
these findings are consistent with the effectiveness of
bupropion, as cited above.
Neumeister and colleagues (1998c) subjected SAD patients to both tryptophan and catecholamine depletion78
(i.e., both dopamine and norepinephrine) and sham depletion with an active placebo (benztropine). A temporary
relapse in depressive symptoms resulted from both interventions, leading the authors to conclude that catecholamines, not just serotonin, are involved in the effect of
light treatment on SAD.
Chronobiological Dysregulation
There are two hypotheses regarding dysregulation of seasonal rhythms in patients with SAD. The first is based on
a different duration (specifically, the duration of melatonin secretion) of the internal night between winter and
summer. The second is based on a shift of the phase of the
circadian rhythms.
Melatonin Duration Hypothesis. According to this hypothesis, inspired by the animal literature, a longer internal night in patients with SAD matches a longer external
night in winter, and this wintersummer difference in the
duration of the internal (biological) night is what drives
seasonal changes in behavior. This hypothesis found additional support in initial findings of an increased prevalence of SAD with a more northern latitude characterized
by more drastic changes in photoperiod, although these
findings were not confirmed in studies in clinical populations (reviewed by Magnusson, 2000). A consequence of
this hypothesis was the administration of light in early
morning (6 AM to 9 AM) and late afternoon (4 PM to
7 PM), designed to reduce the duration of winter darkness
to a level similar to that in the summer.
Because in many mammals the photoperiod signal is
encoded in the duration of melatonin secretion and because
light suppresses melatonin secretion, it was hypothesized
that light in the morning and evening reduces the duration
686
Pathophysiology
of melatonin secretion, bringing it to summer levels. However, suppression of melatonin secretion is not sufficient to
produce an antidepressant effect (Wehr et al., 1986).
Specifically, more drastic suppression, as with atenolol, a
long-acting beta-blocker, did not result in improvement
(Rosenthal et al., 1988). On the other hand, a short-acting
beta-blocker administered in early morning resulted in
maintenance of improvement in SAD patients (Schlager,
1994). A problem in the study, however, was that propranonol was administered at a time when it may have been
too late to suppress the melatonin secretion in most patients, so that the study may not represent a valid test for
the melatonin duration hypothesis.
A strong argument against the melatonin duration hypothesis is the effectiveness of a late-afternoon dose of
melatonin (Lewy et al., 1998, 2006).79 According to the
theory, the presence of melatonin in the blood for an increased duration would make patients more depressed.
The findings of two other studies are also inconsistent with
the melatonin duration hypothesis. Winton and colleagues
(1989) measured melatonin profiles in SAD patients receiving two schedules of combined morning and evening light
treatment. Although both treatments resulted in an equivalent shortening of melatonin secretion, the antidepressant
effect was greater in the treatment group with more exposure to light. Wehr and colleagues (1986) found that two
regimens of light treatment were equally effective even
though only one of them was expected to shorten the
photoperiod. This study cannot be considered conclusive,
however, because melatonin profiles were not obtained,
sample sizes were small, and patients were exposed to room
lighting from 7 AM to 11 PM, which could have diminished
the contrast between the two conditions.
Interest in the melatonin duration hypothesis was revived after Wehrs group (Wehr, 1991a,b; Wehr et al., 1991,
1993) showed that in humans, as previously described in rodents, the duration of nocturnal melatonin secretion reflects
the extent of light exposure in the immediately preceding
photoperiod. Because no changes in normal volunteers were
found between winter and summer, it was suggested that artificial light suppresses melatonin and thus the hormones
response to changes in photoperiod (Wehr et al., 1995).
Young and colleagues (1991, 1997) found that photoperiod
may be related to the onset of vegetative symptoms in SAD,
symptoms that, according to the dual-vulnerability hypothesis, are an expression of seasonality more than of depression per se. Wehr and colleagues (2001a,b) found that SAD
patients, but not controls, had a wintersummer difference
in the duration of active melatonin secretion. This study
showed for the first time that patients with SAD generate a
signal of change in season similar to that used by nonhuman mammals to regulate seasonal behavior.
687
and masking of effects of environmental factors, sleep, activity, and social cues. Light administered at a constant external clock time may vary greatly according to individual
circadian time, by up to several hours. Thus the magnitude
of a phase shift will vary considerably among individuals.
According to Terman and colleagues (2001), the ideal timing of light treatment is related to a circadian marker and
not to clock time. However, Terman appears to have assumed that all SAD patients are phase delayed, whereas
Lewy and colleagues (2006) recently confirmed that a subgroup of patients are phase advanced and should be treated
with evening bright light and/or morning low-dose melatonin administration. Lewy also cautioned against overshifting across the therapeutic window (DLMO = 6 hours
before midsleep).
688
Pathophysiology
CONCLUSIONS
Sleep reflects a critical phase of a core circadian rhythm in
humans, and thus our coverage of sleep and biological
rhythms belongs in the same chapter. Sleep disturbances
are central to the pathophysiology of manic-depressive
illness; they are not only a key symptom of both mania
and depression, but also the earliest indication of major
NOTES
1. In the United States, however, sleep deprivation remains little known and seldom used, perhaps because of its loss of efficacy after even a short nap and a society that has become
increasingly concerned about the consequences of sleep loss.
9.
10.
11.
12.
13.
689
690
14.
15.
16.
17.
18.
19.
20.
21.
22.
Pathophysiology
period of 24.7 hours (Campbell et al., 1993). Thus the duration of the circadian period in humans is longer than 24
hours, but only slightly. In normal everyday life, the intrinsic
human circadian period adjusts to 24 hours to synchronize
with the environment as a result of periodic factors that serve
as 24-hour time cues, or zeitgebers. Light is probably the
principal zeitgeber.
For example, the PRC to light in a subject who is flown to a
geographic location with a 12-hour difference from the point
of departure (e.g., 2 PM is equivalent to 2 AM) will accord
with the time of origin rather than that of destination.
Prior to the cloning of the clock genes, the retina was considered the only structure other than the SCN to contain a circadian clock. With the cloning of these genes, it became apparent that the clock genes are widely expressed, both in the
brain and in many peripheral tissues, and that they oscillate
independently in these tissues (Reppert and Weaver, 2001).
The rhythms of cortisol and sleep onset are delayed approximately 1 to 3 hours as compared with melatonin, temperature, prolactin, EEG theta waves, and REM sleep propensity
rhythms (Wehr et al., 2001a).
In the Pittendrigh and Daan (1976) model of the rodent circadian system and in the elaboration of that model by Illnerova
and Vanecek (1982), it is proposed that the circadian pacemaker consists of two component oscillators. One is entrained
to dusk and controls an evening bout of locomotor activity
and the onset of melatonin secretion in nocturnal rodents.
The other is entrained to dawn and controls a morning bout of
locomotor activity and the offset of melatonin secretion. Separate entrainment of the oscillators to dawn and dusk makes it
possible for the pacemaker to adjust the duration of nocturnal
periods of activity and melatonin secretion to conform to seasonal changes in night length. As applied to humans, the duskand dawn-entrained components of the complex circadian
pacemaker could be considered to control evening and morning transitions in melatonin secretion, core body temperature, sleepiness, EEG theta activity, sleep propensity, REM
sleep propensity, cortisol secretion, and sleepawake state. The
pacemaker also adjusts the timing of these transitions in response to seasonal changes in day length.
A major argument that sleep is vital for survival comes from
marine mammals, which must be awake constantly to surface for air. Instead of being permanently alert, they sleep
with one cerebral hemisphere at a time.
With regard to REM sleep distribution in mice, associations
were found with loci on chromosomes 2, 17, and 19 (Tafti
et al., 1999).
Knockout micethose missing a single gene that has been
knocked outare used in biomedical research.
Induced mutations in serotonin receptors, somnogenic cytokines (such as interleukin 1 and tumor necrosis factor ),
and the prion protein gene, implicated in the human condition of fatal familial insomnia (Chapman et al., 1996), result
in alterations of sleep (for a review and a note of caution in
interpreting these data, see Toth, 2001).
Transections of the brain stem at the midpons or below do
not reduce wakefulness, while transections at or above a
midcollicular level cause an acute loss of wakefulness. The
tissue at the rostral pontincaudal midbrain interface is thus
essential for maintaining wakefulness. One set of neurons is
located in a group of nuclei that have been identified as the
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
691
692
Pathophysiology
39. Wehrs group (Wehr and Wirz-Justice, 1982; Wehr et al., 1982)
found that most patients who had rapid (1- to 6-week)
manic-depressive cycles experienced one or more doublelength (48-hour) sleepwake cycles at the onset of each manic
phase of their mood cycle. Upon switching from the depressed to the manic phase, they often had alternate nights of
total insomnia. Conceivably, these recurring escapes of the
sleepwake cycle from its primary (1:1) mode to its secondary
(1:2) mode of coupling to the daynight cycle result from its
driving oscillator having an overly long intrinsic period. Because the sleepwake oscillator is weak, its oscillations remain
relatively well coordinated with the daynight cycle and other
circadian rhythms. Thus, the dissociation of its oscillations is
expressed only in the periodic 24-hour phase jumps associated with double-length sleepwake cycles. In free-running
circadian rhythm experiments in which all external time cues
have been eliminated, normal individuals sometimes experience similar 48-hour sleepwake cycles (Wever, 1979, 1983;
Wehr and Wirz-Justice, 1982; Wehr et al., 1982; Weitzman,
1982). Thus, 48-hour sleepwake cycles in manic patients may
resemble the behavior of normal sleep-regulating mechanisms under free-running conditions, perhaps associated
with uncoupling of oscillators that are normally linked.
40. According to Georgi (1947, p. 1267), In the true endogenous
depressive we see a shift in the 24-hour rhythm, a phase shift,
that can express itself from a slight phase shift to a complete
reversalthe night becomes day. Anyone knowing the material would look for the CNS origin in the midbrain, where
the entire vegetative nervous system is controlled by a central
clock whose rhythmicity . . . regulates and balances the biological system.
41. The literature on circadian rhythms in depression has focused on nonseasonal depression. Seasonal (winter) depression (described later in the chapter) may involve a circadian
phase delay.
42. Wehr et al., 1979; Sack et al., 1985; Soutre et al., 1985; Vollmann
and Berger, 1993; Berger et al., 1997; Albert et al., 1998; Riemann et al., 1999.
43. Contrary to expectations, REM latency was not different between the two groups, and the REM density was decreased to
a greater degree in the normal sleep period group. It is thus
unlikely that phase advance combined with sleep deprivation
acts by reducing REM disinhibition.
44. von Zerssen et al., 1985; Soutre et al., 1988, 1989; Nagayama
et al., 1992; Dietzel and Ciullo, 1996.
45. These abnormalities included a trend to increased darkadjusted melatonin suppression compared with matched controls, significantly lower baseline melatonin levels and nadir
levels on the light night, a trend to greater amplitude of variation in melatonin secretion compared with matched controls
on the dark night, and significantly later peak time (Nurnberger et al., 2000).
46. This increased sensitivity is also present in offspring of bipolar
patients more commonly than in healthy controls (Nurnberger
et al., 1988), making it a candidate for an endophenotype for
bipolar disorder.
47. Kavaliers and Ralph, 1981; Welsh and Moore-Ede, 1990;
Klemfuss and Kripke, 1995; Kripke, 1995; Abe et al., 2000.
48. Johnsson et al., 1979, 1980, 1983; Klemfuss, 1992.
49. As described in Chapter 14, the enzyme glycogen synthase kinase 3-beta (GSK-3) appears to be a target of lithium action
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
693
disputes, role transitions, and interpersonal deficitsthe circadian and sleepwake component focuses on the disruption
of social zeitgebers (e.g., personal relationships and social
demands and tasks) that entrain biological rhythms and the
occurrence of zeitstrers (time disrupters) that may be physical (e.g., exposure to light as in transmeridian travel), chemical (e.g., medications), or psychosocial (e.g., a new baby or
work deadlines). Monk and colleagues (1990) designed the
Social Rhythm Metric (SRM) that is used in IPSRT. The patient and therapist review the first 34 weeks of SRM measures to find rhythms that are particularly unstable, such as
variation in the time of going to bed from day to day or from
weekday to weekend days. The therapist encourages stabilization of such social rhythms, searching for rhythm disrupters, especially ongoing environmental stressors, and
making recommendations for life changes to enhance protection of circadian rhythms and the sleepwake cycle. A
slightly more regular day job, even if less lucrative, is highly
desirable for some patients. Difficulty may arise with certain
patients (analogous to medication nonadherence; see Chapter 24) as a very stable lifestyle may appear unappealing, and
some patients may mourn their lost hypomanias. The therapist works toward achieving a healthy balance between stability and spontaneity. Another area of focus is the anticipation of changes in routines with changes in ones social
climate (e.g., breakup with a partner, divorce or separation,
death of a spouse, leaving for college), resulting in the loss of
social zeitgebers.
An analogy with alcohol may be appropriate. Many individuals can use small amounts of alcohol intermittently with
no apparent detrimental effect, but there is some consensus
that a recommendation for its intermittent use is not okay
for alcoholics. Similarly, while some degree of instability in
social rhythms is likely okay for a majority of individuals, it
is highly detrimental for bipolar patients. Even in recovered
individuals, craving persists. Just as alcoholics may continue
to crave alcohol, bipolar patients may continue to crave the
roller coaster, the spontaneity of living, and hypomania. Ongoing therapy (e.g., Alcoholics Anonymous for the alcoholic,
the preventive phase of IPRST for the bipolar patient) helps
reduce the risk of relapse.
Baillarger, 1854; Griesinger, 1867; Falret, 1890; Kraepelin, 1921.
The enzyme responsible for the conversion of serotonin to
melatonin is pineal N-acetyltranspherase.
Two peaks have been identified in human conceptionsone
in fall and one in spring. Usually the spring peak is dominant, although a shift toward the fall peak has been noted in
the United States over the last several decades. Seasonal variation in conception has decreased in amplitude over the last
100200 years, possibly as a result of the advent of artificial
lighting and indoor temperature control. An alternative explanation is changes in nutrition. In female rats, for example,
ad libitum feeding renders the pituitaryovarian axis insensitive to melatonin, while restricted feeding sensitizes it to
the effects of melatonin (Wilamowska et al., 1992). Since
subsistence-level feeding may have been prevalent in earlier
periods of human history (Wehr, 2001), it may have contributed to greater seasonality of reproduction. (For further
support see Journal of Biological Rhythms, June 2004.)
Among them Petridou and colleagues (2002) in the United
States, Rasanen and colleagues (2002b) in Finland, Morken
694
68.
69.
70.
71.
Pathophysiology
72. One study showed that aborigines from Northern Scandinavia have less variation in mood than other Scandinavians
(Saarijarvi et al., 1997). SAD is less common in the Icelandic
population (which has lived in virtual isolation during the
past 1,000 years) (Magnusson and Stefansson, 1993) and its
descendants in Canada (Magnusson and Axelsson, 1993)
than on the eastern coast of the United States (Magnusson,
2000). This difference may be due to environmental factors
most likely portable environmental factors associated
with lifestyle, such as diet or activity schedule, rather than
fixed environmental factors, such as climateor to genetic factors.
73. Young and colleagues (1997) hypothesized that weather may
explain the year-to-year variation in the onset of depressive
symptoms in SAD. After careful adjustment for photoperiod,
however, they found no significant effect of weather on the
onset of depressive symptoms in SAD.
74. In a recent study by Postolaches group (Yousuffi et al., 2003),
African college students living in the Washington, D.C., metropolitan area for at least 3 years reported more problems with
changes in season than their African American colleagues, a
finding consistent with a habituation hypothesis. Results of
only one study, however, support the sensitization hypothesis:
Murase and colleagues (1995) reported increased prevalence of
winter-type SAD in long-staying as compared with shortstaying Japanese residents of Sweden. In contrast, Murase and
colleagues (1995) reported increased prevalence of winter-type
SAD in long-staying as compared with short-staying Japanese
residents of Sweden.
75. If the loading on seasonality exceeds that on depression, one
would expect SAD with full remission in the summer; on the
other hand, if the loading on depression exceeds that on
SAD, summer remissions would be incomplete.
76. The term hypophyseal insufficiency associated with lack of
light (first used by Marx, a German physiologist, in 1946)
represents the first scientific description of SAD. Marx also
hypothesized that light affected patients behavior via the
retino-hypothalamic tract, which he termed the hypothalamic root of the optic nerve.
Animal seasonal rhythms provided the analogies and the
impetus for SAD research. In photoperiodic animals, seasonal changes they experience are mediated by the duration
of melatonin secretion. The report of Lewy and colleagues
(1980) that melatonin is suppressed by bright light in humans was followed somewhat logically and somewhat
serendipitously by the description of the first SAD patient
and his treatment with light (Lewy et al., 1982), and then a
more complete description of the syndrome and a preliminary evaluation of light treatment (Rosenthal et al., 1984).
Light treatment was proven effective in a double-blind,
placebo-controlled paradigm (Eastman et al., 1998; Terman
et al., 1998). Wehr and colleagues (2001b) showed that patients with SAD, and not matched controls, have a longer duration of active melatonin secretion in winter than in summer, similar to changes in melatonin duration in animals.
Individual variability is high in humans, but even in species
with more drastic and uniform behavioral changes in response to photoperiodic changes than those experienced by
humans, some individual animals do not respond at all to
changes in photoperiod (Puchalski and Lynch, 1986; Gorman and Zucker, 1997).
695
Part V
Treatment
17
Fundamentals of Treatment
Of all our conversations, I remember most vividly [Robert Lowells] words about the new drug,
lithium carbonate, which had such good results and gave him reason to believe he was cured:
Its terrible, Bob, to think that all Ive suffered, and all the suffering Ive caused, might have
arisen from the lack of a little salt in my brain.
Robert Giroux, 1967
development of todays formal diagnostic systems, the Diagnostic Statistical Manual (DSM)-IV and the International
Classification of Diseases (ICD)-10. Because the early psychopharmacology researchers required reliable diagnoses
to define their study populations, the Research Diagnostic
Criteria were developed and subsequently became the basis for todays diagnostic systems. Moreover, lithium and
the drugs that followed gave substantial impetus to modern
neuroscience. Prior to the discovery of the clinical effects of
lithium, the phenothiazines, and the antidepressants, basic
and clinical scientists focused largely on neuroanatomy. Efforts to understand how these new drugs were exerting their
powerful and often specific effects required a shift from a
predominantly structural to a functional neuroscience focused on neurotransmitters, neuromodulators, receptors,
and, more recently, mechanisms of postsynaptic signal transduction and gene induction. Today, of course, the cutting
edge of neuroscience reflects the integration of functional
and anatomical approaches. Here, too, the mechanisms of
action of lithium continue to be a major emphasis (see
Chapter 14).
700
Treatment
Fundamentals of Treatment
REAL-WORLD PHARMACOTHERAPY
AND ITS EFFECTIVENESS
In the three chapters that follow, we review the efficacy of
various drugs in treating mania and depression and in preventing recurrences; the knowledge base for these chapters comes almost entirely from controlled studies of single
drugs, and substantially from patients not only without comorbidities but also well enough to give informed consent
for research. To understand this growing knowledge base in
a larger context, it is useful first to understand the reality of
how medications are actually being used in the community
and how effective they are, that is, how well they work under
circumstances in which the average patient has both physical and psychiatric comorbidities and is taking more than
one drug. Obviously, patterns of use and effectiveness are
inexorably intertwined with the illnesss human and economic costs as discussed above. While available treatments
could allow many manic-depressive patients to lead relatively normal liveslives less painfully interrupted by illness and less often ended prematurely by suicidethe reality falls far short of meeting this modest expectation. One
has only to recall the naturalistic follow-up studies of the
modern era (see Chapter 4), during which contemporary
treatments have been available, to find support for this conclusion. Myriad interrelated factors contribute to this therapeutic shortfall, including long delays in seeking and receiving treatment and differences in health care delivery
systems, in patients attitudes toward treatment, in clinicians skills and training, in the availability of family and
social supports, in comorbid conditions, and so on. Before
briefly examining some of these factors (many of which are
also covered in the individual treatment chapters that follow), we must restate the fundamental reality emphasized
in the first edition of this text: we simply do not yet have an
adequate understanding of the illness in all of its various
forms and complexities, including its interactions with individual differences that is, differences in environment and
in the patients character and psychological and physical resilience. By thus citing the limits of our knowledge, we in
no way intend to diminish the very substantial progress
that has been made since the first edition was published.
On the contrary, it is most encouraging that this progress
has occurred on virtually all fronts, not the least of which is
the development of new pharmacological and psychosocial
treatments, as described in the following chapters.
In their recent review of epidemiological studies from
around the world, Schaffer and colleagues (2006) concluded
that anywhere from one-fourth to nearly two-thirds of individuals with bipolar disorder have never sought any sort of
treatment for a mental disorder. For those who do seek
701
702
Treatment
Stages of Treatment
In reading this section, it is important to keep in mind the
natural course of manic-depressive illness, described in
Chapter 4. Although many treatments can alter acute symptoms dramatically, the nature and logic of planning treatment should be shaped by respect for the course of the illness: its inherently, insidiously recurrent nature, as well as
its tendency to worsen over time. Throughout these chapters, we use several terms to describe stages of medical and
psychotherapeutic treatment that are linked conceptually
to aspects of the illnesss natural course:
Acute treatment is treatment administered during the period from the beginning of a manic or depressive
episode to a clinical responseideally, remission. This
phase usually lasts from 6 to 12 weeks.
Continuation treatment is the ongoing treatment of a
depressive or manic episode from the point of clinical
response to the point at which spontaneous recovery
would be expected to occur in untreated patients. Although overt clinical symptoms of illness may remit
within a few weeks, an underlying tail of vulnerability
can remain for some time. The duration of continuation
Fundamentals of Treatment
treatment is determined by the natural course of the illness. In nonrecurrent unipolar patients, antidepressants
are usually recommended for a period of 9 to 12 months
after remission, but the natural course of bipolar disorder suggests a somewhat shorter continuation phase after a depressive episodeapproximately 6 months. While
the natural course of mania would suggest a continuation phase of about 4 months, clinically it can be longer,
involving the management of a postmania depression
or a sometimes protracted period of mood instability
dominated by dysphoria as the patient attempts to repair the external and internal damage wrought by the
manic episode.
Maintenance treatment is intended to prevent or attennuate future mood episodes in patients with bipolar or
recurrent unipolar illness, and it is used somewhat more
selectively than are acute and continuation treatment. A
word of clarification is in order, however. Although commonly used, the term maintenance treatment is less precise
than long-term prophylactic treatment, or prophylaxis, in
referring to the effects of treatment on the long-term
course of manic-depressive illness. The concept of maintenance overlaps both the continuation and prophylactic
phases of treatment, whereas prophylactic effects range
from prevention of future episodes to attenuation of
their frequency, duration and/or severity. Thus while we
use the common term maintenance treatment throughout the volume, particularly in Chapter 20, we intend it
to refer specifically to prophylaxis.
703
Medical Evaluation
The medical evaluation preceding treatment, like the psychiatric evaluation, should be shaped by the clinical situation. When lithium treatment is being considered, emphasis must be given to thyroid and renal function; for
carbamazepine and valproate, hepatic and hematopoetic
function, and for valproate, gonadal hormone function in
females; for lamotrigine, prior sensitivity to rashes; and for
some atypical antipsychotics, risk factors for weight gain,
metabolic syndrome, and diabetes. Since pretreatment medical evaluation is most critical for long-term treatment, specific recommendations for laboratory tests are discussed in
Chapter 20. Finally, clinicians often discover previously undiagnosed medical problems in the course of their routine
pretreatment evaluations. This potential dividend provides
a further reason to exercise care in the initial phase of treatment.
704
Treatment
BOX 171. Some General Principles for the Management of Manic-Depressive Illness
Fundamentals of Treatment
705
Summary
Competent and compassionate treatment assumes a thorough knowledge of the diagnosis, clinical description, and
natural course of manic-depressive illness. In addition, it assumes an understanding of the pharmacological and psychotherapeutic options available and the lifestyle changes
that can optimize treatment, as well as the ability to establish
a good therapeutic relationship and a willingness to communicate clearly with patients, their families, and the other professionals involved in patient care. The healing role of the clinician and the potentially life-saving influence of competent
and compassionate psychotherapy are too often overlooked
in an era of increasingly sophisticated psychopharmacology.
The extraordinarily important role of the therapeutic relationship in treatment and recovery was described thus by
Morag Coate (1964, p. 214) in Beyond All Reason:
Because the doctors cared, and because one of them still
believed in me when I believed in nothing, I have survived
706
Treatment
Fundamentals of Treatment
707
708
Treatment
Limitations
Limitations
Fundamentals of Treatment
709
710
Treatment
rate was very high, and for 75 percent of the patients the relapse occurred in the first 12 months after initiation of the
study, which may represent withdrawal relapse after recent
acute efficacy. Such results really reflect continuation-phase
efficacy, not maintenance-phase or prophylactic efficacy,
which, as noted above, is generally defined as starting
6 months to a year or longer after resolution of the acute
episode.
Still another generalizability issue emerges from studies
of combination therapy, often a comparison of an atypical
antipsychotic plus a standard mood stabilizer with mood
stabilizer monotherapy in treatment of acute mania (see
the review by Zarate and Quiroz, 2003). Such studies tend
routinely to show benefit with combination treatment,
yet it is important to note that the patients in almost all
these studies must fail to respond initially to mood stabilizer monotherapy. Indeed, the few studies of combination
therapy that have started with fresh patients have tended
to show no difference between monotherapy and combined therapy.
Fourth, meta-analysis is an observational study, and thus
cannot be accepted at face value. Meta-analysis represents
an observational study of studies; in other words, one combines the results of many different studies into one summary measure. The apples and oranges dilemma is, to
some extent, unavoidable in that clinicians and researchers
must attempt to pull different studies together into some
useful summary of the state of the literature on a topic.
There are different ways to go about this, with meta-analysis
perhaps being the most useful, but all such reviews have
their limitations.11 Meta-analysis weights studies by their
samples sizes, but in addition, it corrects for the variability
of the data (some studies have smaller standard deviations,
and thus their results are more precise and reliable). The
problem still remains that studies differ from each other;
this problem of heterogeneity introduces confounding bias
when the actual results are combined. One option is to exclude certain confounding factors. For instance, a metaanalysis may include only women, so that gender is not a
confounder, or may be limited to the elderly, thus excluding confounding by younger age. Often, meta-analyses are
limited to randomized controlled trials, as in the Cochrane
Collaboration, the idea being that patient samples will be less
heterogeneous in the highly controlled setting of such trials than in observational studies. Nonetheless, given that
meta-analysis itself is an observational study, it is important to realize that the benefits of randomization are lost.
Often readers may not be aware of this, and thus it may
appear that a meta-analysis of 10 randomized controlled
trials is more meaningful than each trial alone. However,
each large, well-conducted randomized controlled trial is
basically free of confounding bias, which is never the case
Fundamentals of Treatment
711
712
Treatment
both the professional and the patient. We become concerned when they are used by managers of care and thirdparty payors in an effort to enhance the cost-effectiveness
of care by reducing the number of treatment options. This
has already happened to those patients in Texas whose
treatment is funded by the state. If the tendency to make
guidelines coercive continues to grow, both quality and innovation will be threatened (G. Goodwin, 2003a). Since
guidelines are, by definition, yesterdays practice of medicine, they inevitably begin going out of date even before
they are published.
In their review, Fountoulakis and colleagues (2005)
identified a total of 27 guidelines for the treatment of bipolar disorder published since 1994. Table 173 lists, in reverse
chronological order, the major guidelines for the treatment
of adults that have been published since 2002 from North
America, Europe, Australia/New Zealand, and the World
Federation of Societies of Biological Psychiatry. (Guidelines
for the treatment of children and adolescents with bipolar
disorder are reviewed in Chapter 23.) Direct comparisons
of even the more recent guidelines are limited by the reality that each was developed in its own time frame. Obviously, the more recent guidelines are the most relevant, but
even they can quickly become obsolete as new findings
emerge from the research literature. Nevertheless, it is useful to examine the existing guidelines to highlight those general approaches for which there is broad consensus, and to
take note of important cross-national differences.
The process by which guidelines are developed also differs in ways that may affect the recommendations made. In
general, the process begins with a committee of experts
who undertake an evaluation of the existing treatment research literature, ranking studies according to the levels of
evidence outlined in Box 172. Because of the inherently
limited generalizability of controlled trials, as discussed
above (see also Box 173), guideline developers have, to
varying degrees, attempted to incorporate expert opinion,
thus allowing observational studies and clinical experience
to fill in some of the gaps left by controlled studies, such as
combined medications, the treatment of comorbid conditions, and drugpsychotherapy interactions. Developers of
the Expert Consensus Guidelines in the United States
(Keck et al., 2004) have assessed expert opinion most systematically, using a statistical analysis of the answers given
independently by 47 experts in bipolar disorder to a series
of specific questions about what they would do in particular circumstances. This approach avoids the problem associated with conclusions arising from the deliberations of
a committeethat the strongly held opinions of a few
members may carry more weight, given that the committees task is to reach agreement.
Fundamentals of Treatment
713
Year of Publication
Reference
2002
2003
2003
Expert Consensus
Guidelines (U.S.)
2004
2005
2005
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Treatment
Most guidelines are based primarily on randomized, placebocontrolled trials (RCTs), and are thus affected by the limited
generalizability of such trials. For example:
In placebo-controlled trials, the sickest patients are underrepresented because of ethical concerns about exposing
them to placebo, particularly over an extended period of
time.
Most large RCTs are of monotherapy, whereas most bipolar
patients are taking combined medications.
Patients with comborbid conditions are excluded from most
RCTs, yet most bipolar patients have comorbid diagnoses.
The level of agreement across guidelines varies with the proportion of RCTs focused on particular states. These differences
are especially pronounced between European and North
American guidelines.
Because the majority of RCTs have been of treatments for
acute mania, there is a high level of agreement across those
guidelines.
Prophylactic treatment has been addressed by an intermediate number of RCT; accordingly, the level of agreement
across those guidelines is intermediate.
Bipolar depression has been the subject of the fewest RCTs,
and therefore the level of agreement across those guidelines
is lowest.
Guidelines follow classification systems (primarily the Diagnostic and Statistical Manual [DSM]-IV), and thus are affected by
the limitations of those systems (see the text and Chapters 1
and 3 for discussion of these limitations).
While we refer in the chapters that follow to recommendations from various guidelines as they apply to specific
treatment situations, we must pause to note that to date,
there is scant evidence that guidelines are having much effect on clinical practice in the community. For example, a
recent analysis of prescriptions in the community for 7,760
bipolar patients (Baldessarini et al., 2006) found that half
received antidepressants, while only a quarter were prescribed a mood stabilizer.14 Turning to psychiatric settings,
a survey of prescribing patterns for 1,864 bipolar-I patients
in more than 100 psychiatric inpatient units in the United
States (Lim et al., 2001) found that in the treatment of
manic or bipolar depressed patients without psychosis,
guidelines were followed only 1617 percent of the time
(the percentages were higher for those with psychosis, but
still only 38 and 31 percent for mania and depression, respectively). A 1999 survey revealed that one in six psychia-
trists was not even aware that guidelines existed (Jaffe and
Yager, 1999), and almost half had not read the guidelines
for bipolar disorder. Consistent with these findings are
those of Blanco and colleagues (2002), who analyzed data
on psychiatrists from the National Ambulatory Medical
Care Survey for the years 1992 to 1999. Over one-third of
bipolar patients did not receive a mood stabilizer, whereas
antidepressant use was common: 45 percent of office visits were associated with such a prescription, and for half of
these visits there was no accompanying prescription for a
mood stabilizer. Unfortunately, this apparent underuse of
mood stabilizers accompanied by the apparent overuse of
antidepressants was no different when data for the early
and late 1990s were compared.
Not surprisingly, the correspondence between guidelines and practice is better in academic settings and in staff
model HMOs (where almost all bipolar patients are pharmacologically treated by psychiatrists, and adherence to guidelines tends to be tracked). Two large U.S. datasets reflecting
real-world open treatment as provided by psychiatrists
associated with academic centers (which provide largely
tertiary care) are those of the Stanley Foundation Bipolar
Network and the NIMH STEP-BD program. An analysis of
457 bipolar-I patients who participated in a Stanley center
voluntary registry revealed that 82 percent were taking a
mood stabilizer upon entry into the registry (Levine et al.,
2000); most were receiving combined treatment involving
more than one mood stabilizer. Thus among the 50 percent of the total group taking lithium and the 40 percent
Fundamentals of Treatment
taking valproate, only 18 percent and 10 percent, respectively, received the mood stabilizer as monotherapy. Similarly, in an analysis of medications received just prior to
the entry of the first 500 patients into the STEP-BD program (73.6 percent of whom were bipolar-I), Ghaemi and
colleagues (2006) found that 72 percent were taking mood
stabilizers, but only 11 percent as monotherapy. In another
tertiary care setting (the NIMH Intramural Program), it
was observed that the proportion of patients receiving
combined medications increased sharply from the mid1970s to the mid-1990s; the proportion of discharged bipolar patients taking three or more medications rose from 3
to 44 percent. By contrast, in two staff model HMOs (Kaiser
Northern California and Group Health of Puget Sound)
providing primary care psychiatry (whose guidelines for
bipolar disorder reserve combined therapy for those who
fail monotherapy), only 11.5 percent of patients were treated
with more than one mood stabilizer (Hunkeler et al., 1995).
While the largely tertiary-care populations involved in
the STEP-BD program and the Stanley centers reflected
recent North American guidelines with respect to the
central role of mood stabilizers in bipolar disorder, there
was less correspondence with guidelines for the adjunctive use of antidepressants: 57 percent of the Stanley patients (including 55 patients not on a mood stabilizer)
and 41 percent of the STEP-BD patients were taking antidepressants. The Stanley data reflected treatment patterns in the mid-1990s, whereas the STEP-BD data were
collected later, in 1998 and 1999. It is possible that this
difference in time frame is relevant to the modest differences reported in antidepressant use, given that the first
U.S. guidelines cautioning about the use of antidepressants in bipolar disorder were published in 1994 (American Psychiatric Association, 1994) and 1996 (Frances
et al., 1996). While it might be argued that the relatively
high rate of antidepressant use is related to the presence
of sicker patients in tertiary care settings, antidepressant
use was also common in the two HMO primary psychiatric care settings referred to above: 75 percent of patients
had received at least one such prescription. The primary
care (HMO) data were collected from 1994 to 2001, a period that includes some time prior to the publication of
the above-mentioned guidelines.
It is of interest that even though the 2003 British guidelines include antidepressants as a first-line option, the
Maudsley Bipolar Project (Frangou et al., 2002) and a survey conducted in northeast England (Lloyd et al., 2003)
found that only 14 and 23 percent, respectively, of bipolar
patients were taking an antidepressant, whereas in both
surveys the use of mood stabilizers was similar to that in
the United States.
715
Lithium
Although the mechanism of lithiums action in acute treatment of mania and depression and in prophylactic therapy
for bipolar disorder is unknown, several productive theories are being tested (see Chapters 18, 19, and 20, respectively, and Chapter 14). The standard oral formulation is
the carbonate salt of lithium, whereas the liquid formulation uses the citrate or chloride salt. The U.S. Food and
Drug Administration (FDA) has approved lithium carbonate for both the treatment of manic episodes and maintenance treatment of bipolar disorder.
Lithium carbonate is readily absorbed throughout the
gastrointestinal tract. There are preparations that delay absorption somewhat (Eskalith CR, Camcolit, Priadel, and
Lithobid) and to some extent reduce the peaks and valleys
of serum lithium levels throughout the day. The principal
advantage of these preparations is a lower frequency of initial gastrointestinal side effects, which may enhance adherence. These preparations also appear to have less of an effect on urinary osmolarity, which would be consistent
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Treatment
with a reduced long-term impact on renal function (although this has not yet been studied directly) (Vestergaard and Schou, 1987). Lithium is excreted primarily in
urine; renal excretion is rapid under normal circumstances. The drug is passed into the glomerular filtrate and is
indistinguishable from sodium in the proximal tubule,
where both are reabsorbed. It is reabsorbed to a much
lesser extent in the loop of Henle and is not reabsorbed at
all in the distal tubule.
The half-life of lithium is initially about 12 hours, but
reaches approximately 24 hours once steady-state serum
levels have developed at about 5 days. The conventional
trough serum lithium level occurring 12 hours after the last
dose is the standard level for measurement. The dose/bloodlevel ratio is influenced by the individuals clinical state
(manic or depressed), gender, age, weight (especially muscle
mass), salt intake, extent of sweating, intrinsic renal clearance capacity for lithium, and use of other medications. A
relatively higher dose/blood-level ratio is associated with
being manic, younger, male, and heavier and having a
higher salt intake. Although controlled studies are lacking,
results of open trials suggest that therapeutic blood levels
for children and adults are about the same.
To predict dosage requirements, some investigators
recommend a test dose of lithium, followed 24 hours later
by a plasma-level determination (Cooper and Simpson,
1976; Fava et al., 1984; Perry et al., 1984). Although this technique probably can be applied reliably when the mood
state is stable, its practical value in treating acute mania is
limited. Errors in the predicted dose may, for example, be
due to changes in patients sleep and activity, which cause
changes in glomerular filtration rate (Perry et al., 1984).
In addition, use of this method necessitates a 24-hour delay
in treatment.
Because the proximal tubule reabsorbs lithium as it
does sodium, it is essential for the patient to maintain normal salt and adequate fluid intake to prevent the development of lithium intoxication. Although decreased tolerance to lithium has been reported to ensue from protracted
sweating, the only test of this effect in a small number of
healthy long-distance runners did not find a tendency toward increased lithium levels following vigorous exercise.
Nonetheless, some caution is warranted. The risk of elevation of serum lithium levels as a result of diarrhea and
vomiting is undeniable. Should these conditions occur, supplemental fluid and salt should be administered, and lithium
therapy may need to be stopped temporarily until fluid and
salt balance can be restored.
The gap between therapeutic and toxic levels of lithium
is narrow. Thus the frequency of serum monitoring of
lithium should be proportional to the risks associated with
particular patient profiles. When there is reason to believe
Anticonvulsants
Valproate
Valproate is a gamma-aminobutyric acid (GABA)-enhancing anticonvulsant approved by the FDA for the treatment of epilepsy and acute mania and for migraine prophylaxis. Preparations include capsules, elixir, rectal
forms, and, most recently, an intravenous (IV) formulation; none of these forms appears to offer any particular
advantage for treatment of bipolar disorder. Nor has the
rapid oral loading protocol that most patients tolerate
(McElroy et al., 1998) been shown to result in a faster onset
of antimanic action compared with slower titration protocols. The level of gastrointestinal irritation is dramatically
reduced with the sodium divalproex formulation of valproate, which has largely replaced the original formulation. Still, indigestion and nausea, along with sedation, are
the most common side effects.
Valproate inhibits the enzymes that metabolize several
other drugs, including, most notably, lamotrigine. The therapeutic range of this and other psychotropic drugs is difficult to define precisely, but it would appear that levels above
70 and below 120 milligrams per milliliter (mg/ml) are as
close to optimal as is practical for most patients (Ellenor
and Dishmon, 1995).
Carbamazepine
Carbamazepine, a tricyclic compound that is classified as
an iminostilbene derivative, has been shown to be effective
in the treatment of mania. Results of trials comparing its
prophylactic effect with that of lithium suggest that it probably has maintenance efficacy, but it has never been submitted to the FDA for this indication.
Carbamazepine17 is reported to be absorbed slowly and
erratically from the gastrointestinal tract. After chronic use,
the time to peak plasma concentrations is several hours following ingestion (Pugh and Garnet, 1991). Carbamazepine
is lipophilic; therefore, no parenteral forms have been developed, and different brands of the drug cannot be assumed
Fundamentals of Treatment
to produce the same blood levels. Bioavailability can be estimated at about 80 percent (Ketter et al., 1999). Although
carbamazepine undergoes only modest first-pass metabolism, it is extensively metabolized in the liver. Approximately
75 percent of the drug is protein bound. Carbamazepine
can induce its own metabolism such that over time, dose increments may be needed. The drug can also impact the metabolism of some other agents, most notably inducing lamotrigine metabolism such that the dose of the latter may
need to be increased when the two drugs are used in combination.
Oxcarbazepine
717
metabolized, and is excreted almost exclusively in its original form by the kidney. Thus it has a very short half-life of
about 6 hours, indicating the need to give it in multiple daily
doses. Because there is no known relationship between
blood level and therapeutic response for the drug, there is
no indication for therapeutic monitoring, and perhaps most
difficult, a wide range of possible therapeutic doses exists
(6004500 mg/day). From a kinetic point of view, the drug
would be advantageous in patients with liver function problems or those taking other drugs that affect hepatic metabolism, but there would be a corresponding need for caution in
patients with impaired or unstable renal function.
Topiramate
Lamotrigine
Gabapentin
Gabapentin is structurally related to GABA but does not
bind to the GABA receptor as a GABA analogue, as was
originally believed when the drug was developed in the early
1970s. It does enhance GABA function in some indirect
manner. What role, if any, the drug has in the management
of bipolar patients is unclear, especially after it failed to separate from placebo in controlled trials of treatment of mania. It has looked somewhat more promising as an adjunctive agent based on the results of uncontrolled studies.
Gabapentin is readily absorbed, is not protein bound, is not
Tiagabine
Antidepressants
Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) inhibit enzymes
responsible for the neuronal breakdown of catcholamine
and idoleamine neurotransmitters. The original MAOIs
were irreversible inhibitors of both types of monoamine
oxidase enzyme, A and B, which are found primarily on
the outer membrane of mitochondria. In the past decade,
both reversible MAO-A inhibitors and a selective MAO-B
inhibitor in patch form have been developed, adding the
potential for greater specificity and safety to the profile of
this group of antidepressants.
MAOIs are absorbed quickly when administered orally.
Peak MAO inhibition occurs within several days following
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Treatment
Tricyclics
Tricyclic antidepressantsthe first widely studied agents
to treat depression successfullyputatively act by inhibiting the norepinephrine and serotonin uptake in nerve endings. Imipramine was the first tricyclic used and remains
the most thoroughly studied (Kuhn, 1957). Amitriptyline,
clomipramine, desipramine, doxepin, nortriptyline, protriptyline, and trimipramine are other widely available tricyclic preparations.
Tricyclic antidepressants are absorbed quickly and almost completely by the small bowel. Peak plasma concentrations usually occur within 23 hours of ingestion. The
half-lives of tricyclic antidepressants are relatively long
and variable, ranging from 6 to 198 hours. Protriptyline,
for example, has a half-life of 80 hours. Tricyclic antidepressants are highly lipophilic and bind strongly to plasma
proteins in the heart and to brain tissue.
Plasma levels have been correlated with both therapeutic (Ziegler et al., 1978) and toxic (Spiker and Pugh, 1976)
effects. Wide variation in plasma levels is due largely to genetic differences in the hepatic enzymes responsible for the
drugs metabolism. Sampling should be performed 1 week
following administration to ensure a steady-state level, and
1012 hours following the last dose to ensure complete
absorption and distribution. The therapeutic ranges suggested in the literature are 50140 nanograms per milliliter
(ng/ml) for nortriptyline and 110180 ng/ml for all other
tricyclic antidepressants (except protriptyline).
Fundamentals of Treatment
Typical Antipsychotics
In 1952, the first conventional antipsychotic, chlorpromazine, was found to be therapeutic for schizophrenia, an
effect thought to be related to its blockade of dopamine D2
receptors. Since that time, a multitude of new antipsychotic
drugs have been introduced. These drugs are categorized
into five distinctive classes: phenothiazines, butyrophenones,
dibenzoxazepines, thioxantheses, and dihydroindolones. All
typical antipsychotics act equally to relieve psychotic symptoms, such as hallucinations, delusions, and thought disorders.
All antipsychotics are well absorbed; however, oral administration can result in less predictability in absorption,
and food and antacids can affect absorption by the gastrointestinal tract. Most antipsychotics peak at approximately 3 hours following oral administration, but peak
plasma levels can occur within 30 minutes or after up to
5 hours. Steady-state blood levels are reached within 3 to
5 days. Metabolism occurs mainly in the liver, but also in
the intestinal wall. The bioavailability of most of the antipsychotics is relatively high, but for some is considerably
lower. Haloperidol tablets, for example, have an average
bioavailability of only 60 percent. The elimination half-life
of typical antipsychotics can range from 1.5 hours to 26
days.18
Atypical Antipsychotics
Following oral administration of atypical antipsychotics,
the gastrointestinal system absorbs the drug rapidly and almost completely. Food appears to have no effect on the rate
and extent of absorption of these agents with the exception
719
Benzodiazepines
Although benzodiazepines are now prescribed for a wide
range of indications, they were introduced in the 1970s as
powerful and rapid-acting antianxiety or hypnotic drugs.
These drugs bind benzodiazepine receptors, which allosterically modulate GABA receptors, the most ubiquitous inhibitory neurotransmitter in the brain. In bipolar disorder,
the high-potency benzodiazepines (clonazepam and lorazepam) are used either for their sedative properties (for
example, to abort an emerging hypomanic/manic episode
by aiding sleep) or as treatments for comorbid anxiety symptoms.
Following oral administration, lorazepam is absorbed
rapidly and completely, whereas clonazepam is absorbed
more slowly. Peak serum levels for lorazepam occur within
12 hours, whereas clonazepam requires several hours. All
benzodiazepines exhibit first-order kinetics over the therapeutic dosage range, with metabolism occurring in the liver;
they all bind to plasma proteins at levels of 70 percent or
higher. Lorazepam has a relatively short half-life of 1020
hours, whereas that of clonazepam is 1850 hours.
NOTES
1. Indirectly, lithium also made possible the birth of the first
patient-run support/advocacy group, the National Depressive and Manic Depressive Association (now the Depressive
and Bipolar Support Alliance [DBSA]), by helping many
patients function well enough to form and run an effective
national organization.
2. Tohen et al., 1990, 1992, 2000, 2006; Coryell et al., 1993;
Strakowsky et al., 1998, 2000.
3. In a recent survey in Norway, bipolar patients were more
than three times as likely as controls to be unemployed and
three times as likely to be on disability, despite the fact that
the patients enjoyed a significantly higher educational level
than that of the controls (Schoyen et al., 2006).
4. Earlier studies, largely from academic health centers, while
noting the expected relationship between substance abuse and
symptomatic and/or syndromal outcome, did not find such
a relationship with functional outcome (reviewed in Bauer
et al., 2001). The difference between these studies and that of
Conus and colleagues (2006) may reflect the fact that patients
in tertiary referral academic centers are generally sicker, with
both high rates of substance abuse and poor functional outcome, making it more difficult to demonstrate a relationship.
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Treatment
5. The word predicts is used here in the statistical sense, reflecting an association between two variables without implying
the direction of causality.
6. See, e.g., Lish et al., 1994; Ghaemi et al., 2002; Goldberg and
Ernst, 2002; Hirschfield et al., 2003.
7. Not surprisingly, the bulk of the data establishing this relationship comes from studies of lithium.
8. Prien et al., 1974; Abou-Saleh and Coppen, 1986; Gelenberg
et al., 1989; OConnell et al., 1991; Winokur et al., 1993; Lish
et al., 1994; Baldessarini et al., 1999; Franchini et al., 1999;
Swann et al., 1999.
9. One managed care problem that is rarely addressed is the
practice of pharmacy benefit managers allowing patients to
obtain only 30 days of a prescription at one time; this practice substantially increases the likelihood of patients missing
medications and thus going through periods of withdrawal.
10. See, for example, Calabrese and Rapport, 1999; Baldessarini
et al., 2000; Post et al., 2000; Rush et al., 2000; Licht et al.,
2002; Rothwell et al., 2005.
11. The least acceptable approach to a review of the literature is
the classic selective review, in which the reviewer selects those
articles that agree with his or her opinion and ignores those
that do not. In this approach, any opinion can be supported
by selectively choosing among studies in the literature. Unfortunately, most reviews of the literature on bipolar disorder fall into this category. The opposite of the selective review
is the systematic review. In this approach, some effort is
made, usually with computerized searching, to identify all
studies on a topic. Once all studies have been identified (ideally including some that may not have been published), the
question is how these studies can be compared.
The simplest approach to reviewing a literature is the
box score method: How many studies were positive and
how many negative? The problem with this approach is that
it fails to take into account the quality of the various studies
(i.e., sample sizes, randomized or not, control of bias, adequacy of statistical testing for chance). The next-most rigorous approach is a pooled analysis. Unlike the box score, this
approach corrects for sample size, but nothing else. Other
features of studies are not assessed, such as bias in design,
randomization or not, and so on. Sometimes, those features
can be controlled by inclusion criteria that might, for instance, limit a pooled analysis to randomized studies.
12. Sometimes a sensitivity analysis can be done, where one assumes a best-case scenario (all dropouts remain well) and
a worst-case scenario (all dropouts relapse) to see whether
the conclusions change. Nonetheless, a high percentage of
dropouts means one cannot be certain whether results are
valid.
13. The Texas Medication Algorithm does include the olanzapinefluoxetine combination (OFC) as one third-line option,
given that it was approved by the U.S. Food and Drug Administration for bipolar depression based on adequate data
from randomized controlled trials. However, when comparing treatment options, it is important to note that OFC is not
14.
15.
16.
17.
18.
a drugit is two drugs marketed as a single pill. Scientifically, it should be compared with other combinations of two
drugs.
It should be noted that these data include all prescriptions,
not just those written by psychiatrists.
In the lithium treatment of acute mania, the patients clinical
state is one of the factors affecting the dose/blood-level ratio.
Some patients when manic retain lithium in body pools outside the plasma, possibly in bone (Greenspan et al., 1968;
Almy and Taylor, 1973). In practice, more lithium may be
needed to achieve a given blood level during mania than
during euthymia or depression (Goodwin et al., 1969; Serry,
1969; Kukopulos et al., 1985).
When renal concentrating ability is substantially impaired or
the patient excretes in excess of 4 liters of urine per 24 hours,
careful monitoring (by the patient and the physician) of
fluid balance is required to avoid dehydration and lithium
intoxication (Vestergaard and Shou, 1987). Although renal
concentrating ability usually improves if lithium is discontinued, the improvement can be quite delayed and incomplete if the impairment has been long-standing. Lithium
discontinuation studies indicate that increases in 24-hour
urine output remain the same or decrease only slightly after
lithium is discontinued.
More sedation and ataxia occur with rapidly rising levels of
carbamazepine than with most other modern anticonvulsants, and as a consequence, titration often needs to be
slowed, especially when multiple drugs are being used together. Most of these cases have occurred in the elderly and
within the first 4 months of treatment.
Serious side effects are associated with the typical antipsychotics. Common central nervous system side effects involve
altered thermoregulation, extrapyramidal syndrome, neuroleptic malignant syndrome, and tardive dyskinesia. Orthostatic
hypotension is also observed. Erectile dysfunction, blurred vision, constipation, and urinary retention are common anticholinergic effects. Cardiovascular effects include electrocardiogram changes, tachycardia, and torsade de pointes. Changes
in the endocrine system, including amenorrhea and galactorrhea, occur as well. Occasionally the hematological system can
be involved, with agranulocytosis and leucopenia occurring.
Liver enzyme elevations are sometimes seen early in treatment;
they usually resolve even with continued treatment, but can
cause bilirubin with cholestatic jaundice to occur. Other pertinent side effects include allergic reactions and skin photosensitivity and all immune-mediated agranulyctopenia. Sedation
and weight gain are observed as well. So-called low-potency
antipsychotics cause more sedation and vascular side effects
(orthostasis), whereas the more potent drugs are more commonly associated with extrapyramidal syndrome. The greatest
concern arises for extrapyramidal syndrome, the potentially fatal neuroleptic malignant syndrome, and potentially irreversible tardive dyskinesia. These severe side effects have led to
a recent trend toward the use of atypical antipsychotics, especially for patients newly diagnosed.
18
[Robert Lowell] showed me the bottle of lithium capsules. Another medical gift from Copenhagen. Had I heard what his trouble was? Salt deficiency. This had been the first year in
eighteen he hadnt had an [manic] attack. Thered been fourteen or fifteen of them in the past
eighteen years. Frightful humiliation and waste. . . . His face seemed smoother, the weight of
distressattacks and anticipation both gone.
Richard Stern (cited in Hamilton, 1982, p. 370)
The chapter begins with a discussion of clinical management, emphasizing proven and/or widely accepted approaches to treatment. We then review the literature supporting these approaches, as well as newer and less proven but
nevertheless promising interventions that may become more
standard in the future. All of the drugs mentioned in the first
section of the chapter are discussed in detail in the second.
CLINICAL MANAGEMENT
A patient in the throes of a manic or mixed episode can be
intensely agitated, uncooperative, psychotic, aggressive, and
quite dangerous. By the time the clinician is contacted,
both patient and family may be confused and distraught,
and the clinician may have little time to ponder available
choices. Ideal treatment involves both persuasion and medication, but is the patient persuadable, and which drug is
best for this patient in this situation? To what degree is
there a danger to staff, accompanying family, or the patient in the manic or mixed state? Should the selected
drug be offered orally, or will parenteral administration
be quicker and more effective? Each decision calls for
balancing the high-risk manic agitation against the consequences of interventiona medications potency against
its side effects, for example, or the patients safety against
the risks and responsibilities of forced medication and
possible involuntary hospitalization. Our recommendations for the selection of appropriate treatments for particular patients are presented later in the chapter.
This section addresses the key aspects of clinical management of hypomania, mania, and mixed states. Discussed in
turn are evaluation of the manic, mixed-state, and hypomanic patient; hospitalization; general considerations involved in medical treatment; clinical features that modify
721
722
Treatment
medication management; medication dosages and therapeutic monitoring; hypomanic symptoms; and general psychological issues related to the medical treatment of mania.
Detailed discussion of special considerations in treating
children and adolescents is presented in Chapter 23, and of
issues involving drugs and pregnancy in Chapter 20.
Hospitalization
Patients exhibiting severe mania will need to be hospitalized, often involuntarily. When manic symptoms are still
in the mild to moderate range, judging the need for and
the timing of hospitalization is more difficult. In deciding
whether to hospitalize a patient, the clinician must keep in
mind that mild mania can progress rapidly and unexpectedly to more severe forms. The medical, social, occupational, and legal risks of such extreme behavior must be
weighed against the financial, social, and personal consequences of hospitalization.
The uncomfortable affect of the mixed state, together
with its disinhibition paranoia, and behavioral activation,
can be an especially dangerous combination. Such patients
are at very high risk of self-harm, sometimes higher than
that for patients with pure major depression (see Chapter
8). A history of serious suicide attempts, as well as of previous hospitalizations, further increases the risk of suicide.
Expressions of desperation or hopelessness in a manic patient indicate the need for immediate hospitalization.
The interpretation of commitment laws and the details
of the commitment process vary considerably from community to community, even within the same state. Therefore, familiarity with local commitment laws is indispensable for the clinician involved in the treatment of manic,
mixed-state, or hypomanic patients. Many states require
that the clinician have first-person knowledge of disturbed
behavior or suicidality before a psychiatric patient is hospitalized involuntarilyknowledge sometimes not available to the clinician who is at the receiving end of a phone
call from a desperate family member. The clinician may
have to spend considerable time educating family members about the steps necessary to initiate involuntary commitment of their loved one. Family members may resist
taking on this responsibility, regarding it as a betrayal of
their relative; some may worry about future physical or psychological reprisals. First-hand knowledge of the commitment process will enable the clinician to provide the necessary guidance and support. Advance directives, executed
when the patient was euthymic, can be of help (see Chapter 22).
Emergency Management
In general, the sooner an agitated manic patient can be effectively medicated, the better. A medication that is easy
to use, safe, and rapidly calming is the ideal. Haloperidol
given intramuscularly (IM) is the most widely used emergency treatment for acute mania (although other highpotency typical antipsychotics, such as fluphenazine, are
just as effective and slightly less likely to cause extrapyramidal syndrome [EPS]).2 Three of the atypicalsolanzapine,
ziprasidone, and risperidone (a depot preparation)are
now available in parenteral form. IM ziprasidone, 210 mg,
was shown in one study to offer a short-term advantage over
IM haloperidol for acute agitation and to be associated with
less EPS (Brook et al., 2000). IM clonazepam (.51.0 mg)
and IM lorazepam (12 mg) have also been used for shortterm treatment of agitated manic states; however, they are
not as effective as the high-potency antipsychotics in calming most manic patients. For example, IM olanzapine has
been shown to be superior to IM lorazepam for the treatment of acute manic agitation (Meehan et al., 2001). Nevertheless, benzodiazapines can be highly effective and provide some welcome drowsiness for patients in a mixed
723
724
Treatment
Mood Stabilization
The likelihood that manic symptoms will resolve rapidly
or slowly often becomes apparent within the first 4 to 5 days
of inpatient care. While the occasional extremely agitated
and delusional patient will remain calm for days after a single IM injection of antipsychotic medication, other patients
will remain manic to the point of requiring seclusion and
physical restraint for a week or more despite receiving highdose antipsychotics combined with an anticonvulsant and
lithium. Most patients response to treatment falls somewhere between these extremes, and the length of time to recovery cannot be predicted accurately.
who missed appointments, virtually eliminated suicide attempts in bipolar patients in the period following an acute
manic episode.
18
16.3
16
Extreme Hyperactivity
Extreme hyperactivity poses substantial direct and indirect
risks to manic patients; these include dehydration, cardiovascular stress, and the medically necessitated physical restraint and seclusion often associated with intense agitation.
It should not be forgotten that many manic patients died
of exhaustion before the advent of modern treatments (see
Fig. 181). Typical antipsychotics are the most rapidly effective agents in controlling this set of symptoms; in these situations, they are often combined with lithium, an anticonvulsant, or an atypical antipsychotic.
Psychotic Symptoms
Approximately 50 percent of inpatient manic patients suffer
from delusions, usually grandiose or paranoid in nature.
Formal thought disorder and auditory hallucinations, although less common, also occur relatively frequently (see
Chapter 2). Antipsychotics (both typical and atypical) are
quite effective in treating these symptoms.
86
80
70
60
50
40
30
20
8
10
19461950
19561960
Divalproex
Lithium
12
10
9.7
8.9
8
6
4
2
0
Mixed Mania
Classic Mania
p < .025
states. Some studies have shown lithium to be more effective in typical manic states than in dysphoric/mixed or
rapid-cycling acute states, whereas valproate is particularly
effective in mixed or acute rapid-cycling states (Juckel et al.,
2000). Two separate analyses of the original divalproex registration trial showed divalproex monotherapy to be superior to lithium monotherapy for the treatment of manic
states in patients with elevated depression scales and in
those with multiple previous episodes. However, this is
confounded by the high number of prior lithium failures
in the sample. Carbamazepine may be superior to lithium
for mixed states (Emilien et al., 1996).
It is important to note that in the divalproex registration trial, lithium was more effective than divalproex
among patients with the classic manic features of euphoria and grandiosity (see Fig. 182). This trial is also noteworthy for finding that prior good response to lithium predicted a good response during subsequent manic episodes
and a poorer response to anticonvulsantsan argument for
using lithium in some patients with mixed states despite the
apparent superiority of valproate in treating such states.
Olanzapine, either as monotherapy or adjunctively, has
been shown to be as effective in mixed mania as in pure mania. There are similar data for other atypical antipsychotics,
suggesting a class effect. However, each atypical is unique in
its clinical profile, and many patients do poorly on one but
very well on another.
Percent Responders
14
725
19661970
726
Treatment
treatment of acute mania in that it makes sense to start medications in the short term that have proven beneficial for this
subgroup of patients in the longer term. Early studies of
lithium prophylaxis suggested that patients with a history of
at least four affective episodes in 1 year were disproportionately overrepresented among those who failed to experience
a prophylactic effect from lithium (Dunner and Fieve, 1974).
However, a more recent naturalistic study of rapid-cycling
and non-rapid-cycling patients found that lithium was
equally effective in both groups (Baldessarini et al., 2000), a
finding that may, in part, be related to the relatively conservative use of antidepressants in this particular group of patients. Another important consideration is that in the Dunner and Fieve study, the minimum criterion for treatment
failure was a single new episode, whereas Baldessarini and
colleagues examined the overall reduction in morbidity associated with lithium treatment in the two groups of patients; clinically, the latter is a more relevant measure. Indeed,
Dunner (2000) himself advocated starting lithium acutely in
patients with a history of rapid cycling and only adding an
anticonvulsant later if needed. Likewise, McElroy and Keck
(2000), based on their review of the literature, recommended
that manic or mixed-state patients with a history of rapid cycling be started on lithium, reserving adjunctive valproate
for those who fail to respond to lithium. However, contemporary North American guidelines recommend that rapidcycling patients be started on an anticonvulsant acutely (valproate is recommended most frequently; see Sachs et al.,
2000), with the option of adding lithium later depending on
the response to the anticonvulsant. This recommendation
may be modified in light of the recent carefully controlled
trial of Calabrese and colleagues (2005) showing that lithium
and divalproex monotherapy had equivalent (poor) maintenance efficacy in rapid-cycling patients who had been stabilized on the combination (see Chapter 20).
Rapid cycling has also been shown to predict an acute
antimanic effect for carbamazepine (Post et al., 1986a),
although results of other studies indicate that this effect
does not translate into prophylaxis against mania in patients with a history of rapid cycling (Denicoff et al.,
1997). In the initial studies that established olanzapine as
an antimanic agent, it was equally effective among rapid
and nonrapid cyclers (Tohen et al., 2004), and this appears to be true for other atypicals as well. Furthermore,
among patients with a history of rapid cycling who are
nonresponders to lithium or anticonvulsants, the addition of atypical antipsychotics has been shown to be effective for the treatment of acute mania (Sanger et al.,
2003), although the data do not support giving an atypical to all patients with a history of rapid cycling in the
absence of other indications.
Anticonvulsants
As with lithium, the therapeutic benefit of anticonvulsants
in mania appears to correlate with serum levels rather than
with dosage. Thus studies of valproate suggest that levels
above 45 micrograms per milliliter (g/ml) are necessary for
antimanic efficacy (Bowden et al., 1996) and that side effects
become increasingly problematic at levels above 125 g/ml.
Oral medication loading strategies have been devised for
speeding up the onset of the antimanic action of anticonvulsants. For valproate, the strategy is to dose at 30 milligrams
per kilogram (mg/kg) of body weight for days 1 and 2 of
therapy, followed by 20 mg/kg on days 310 (Hirschfeld et
al., 1999). In one double-blind study, valproate loading was
shown to be at least as rapid in reducing manic symptoms
as treatment with haloperidol (McElroy et al., 1996), and in
a pooled analysis of randomized, double-blind studies, the
loading strategy was found to be more rapidly effective
than standard-titration valproate and equivalent to olanzapine (Hirschfeld et al., 2003). Intravenous loading has
also been reported to be rapidly effective and may be an
option for some patients (Grunze et al., 1999a).
727
is started at 1 mg every 68 hours and usually does not exceed 610 mg/day. Aripiprazole doses of 30 mg/day are
generally recommended, with an option to decrease this
dose to 15 mg/day if tolerability is a problem. Oral ziprasidone is started at 40 mg twice daily (BID) with food, increased to 60 or 80 mg BID on the second day, then adjusted in the range of 4080 mg BID. The IM dose in acute
psychotic states is usually about 1020 mg every 4 hours,
up to 40 mg/day.
It has been suggested that there may be clinically important differences among the various atypical antipsychotics in the initial onset of antimanic effects (Keck,
2005). However, such a conclusion is premature given the
design differences among the various registration trials for
these drugs. For the risperidone and ziprasidone trials, the
first ratings were obtained at 1 or 2 days, for aripiprazole at
4 days, and for olanzapine at 7 days. The impression that
ziprasidone and risperidone have a more rapid onset of action than the other drugs is probably an artifact of these
design differences.
Benzodiazepines
A major change in the treatment of mania since 1990, especially in the United States, has been the emergence of atypical antipsychotics as effective antimanic agents. Olanzapine,
risperidone, quetiapine, ziprasidone, and aripiprazole have
received the approval of the U.S. Food and Drug Administration (FDA) as antimanic agents, and as of this writing, the
European regulatory agency has approved olanzapine,
risperidone, and quetiapine. In the United States, olanzapine, quetiapine, and clozapine have largely replaced chlorpromazine and thioridazine as the favored sedating antipsychotics. However, it is worth noting that these new drugs are
not always an adequate replacement for the typical agents,
especially in cases of more severe mania and when rapid
control of psychosis and hyperactivity are required, such as
in an emergency room setting. As Licht and colleagues (1997)
pointed out, placebo-controlled trials of atypicals have, of
necessity, tended to involve more moderately ill patients in
order to obtain ethically acceptable informed consent.
Olanzapine is usually begun at oral doses of 2.55 mg
every 6 hours for treatment of mania, titrated up to
20 mg/day (although some studies suggest 2.55 mg/day
may work as well). Quetiapine is dosed on the basis of
height, weight, and clinical response, but not blood levels;
the usual starting dose is 100 mg/day, with a target dose
ranging from 400 to 800 mg/day and averaging 600 mg/day.
Clozapine is begun at 2550 mg every 6 hours and titrated
up to 1,000 mg/day.
Use of the less sedating oral antipsychotics risperidone,
aripiprazole, and ziprasidone is also increasing. Risperidone
Hypomanic Symptoms
Hypomanic symptoms need not always be treated aggressively, as they will often resolve with watchful waiting. However, repeated episodes of hypomania can be indicators of
more general mood instability that should lead the clinician to reassess the adequacy of the maintenance strategy
(see Chapter 20). The threshold for treating hypomanic
symptoms in a particular patient depends on diagnostic
considerations: the threshold should be lower in patients
with a history of similar symptoms evolving into full-blown
mania (i.e., bipolar-I disorder) than in those whose hypomanic episodes have never progressed to mania (i.e.,
bipolar-II). Hypomania with depressive features (dysphoric
hypomania) is not uncommon (see Chapters 1 and 2), and
this makes it more likely that pharmacological intervention
will be sought and needed.
The decision regarding treatment can often be difficult,
however; patients early in the course of illness whose diagnosis is less than clear and those who are unreliable present obvious challenges. It is important to remember that
728
Treatment
729
If not on a mood
stabilizer
1.
2.
3.
If on a mood stabilizer
1.
2.
3.
4.
5.
1.
2.
3.
If euphoric and
without history of
rapid cycles,
consider lithium first.
If mixed and/or with
history of rapid
cycles, consider
valproate first.
In the presence of
psychotic features,
add an atypical to
the mood stabilizer.
Increase clinical
contact.
Assess for possible
precipitating factors,
such as substance
use, prescription
drugs, and life
stressors.
Increase mood
stabilizer dose.
Discontinue
antidepressants.
Stabilize sleep with
short-term use of
benzodiazepines or
other hypnotics.
If no response at week
2, consider either:
1.
2.
Addition of an atypical
antipsychotic to the mood
stabilizer.
Addition of a second
mood stabilizer
(lithium or valproate)
Lithium
In this section we review the literature on the various medications used to treat hypomania, mania, and mixed states:
lithium, anticonvulsants, typical and atypical antipsychotics,
and benzodiazepines. Other treatments, including ECT,
TMS, calcium channel blockers, omega-3 fatty acids, and
cholinergic agents, are discussed as well. Results of randomized, double-blind monotherapy trials for each of the major
pharmacological agents are summarized in Table 181 and
Figure 184, while results of non-placebo-controlled trials
and placebo-controlled add-on trials are summarized in
Table 182.
730
Treatment
Sample Sizea
No. of Studies
Lithium
358
Carbamazepine
600
Valproate
215
Olanzapine
254
Risperidone
549
Ziprasidone
412
Quetiapine
386
Aripiprazole
534
Phenytoin
27
20
2,137
Totals
a
Mood Stabilizers
Atypical Antipsychotics
Placebo
60
50
40
30
707
mg/d
N = 223
4.9
mg/d
N = 273
16
mg/d
N = 304
575
mg/d
N = 208
121
mg/d
N = 268
28
mg/d
N = 260
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
N = 1265
Placebo
1694
mg/d
N = 255
Risperidone
1950
mg/d
N = 134
Carbamazepine
10
Divalproex
20
Lithium
Percent Responders
(> 50% Mania Rating Decrease)
Figure 184. Response rates for acute mania monotherapy. Mg/d = milligrams/day. (Source: Bowden et al., 2005.)
731
No. of Studies
Sample Size
16
775
Carbamazepine
230
Valproate
620
Oxcarbazepine
72
Phenytoin
39
Clozapine
27
Chlorpromazine
521
Haloperidol
901
Clozapine
115
Risperidone
463
Olanzapine
1,539
Quetiapine
440
Electroconvulsive
therapy (ECT)
64
65
5,246
Lithium
Totals
Findings
Note: Many of the individual studies comparing two active drugs without a placebo control lack sufficient statistical power to make it possible
to evaluate whether the observed absence of a difference actually means equivalence.
732
Treatment
10
Placebo (N = 63)
Lithium (N = 29)
Divalproex (N = 62)
0
0
10
12
14
16
There has been one trial of rapid administration (loading doses) of lithium to treat acute mania, aimed at assessing the potential to reduce the delay in the drugs onset of
action (Keck et al., 2001b). In this trial, 15 manic and mixedstate patients were treated with 20 mg/day of lithium given
in two doses. Concomitant lorazepam up to 4 mg/day
through day 6 and up to 2 mg/day through day 8 was also
allowed during the study. All patients achieved lithium levels above .6 mEq/l after 1 day of treatment. Two could not
tolerate the rapid titration and stoppedone because of
tachycardia and the other because of tremor, fatigue, and
diarrheaand one subject did not adhere to the regimen.
Among the remaining 12 subjects, 7 were well enough to be
discharged before the 10-day trial was completed. The mean
YMRS score for these subjects was 11. Overall, 9 of 15 patients had achieved a greater than 50 percent reduction
in YMRS scores by day 10 (by definition they were responders).
As noted in Chapter 14, one hypothesis for the therapeutic action of lithium in mania is its inhibition of inositol
monophosphatase, which by reducing brain inositol levels
decreases the ability of neurons to generate certain second
messengers. In a recent pilot open study, Shaldubina and
colleagues (2006) evaluated the effect of an inositol-deficient
diet on the clinical efficacy of lithium in a mixed group of
15 bipolar patients. Seven of these patients were in a manic
episode that had not responded to lithium, and the remainder were lithium- or valproate-resistant rapid cyclers. Ten
of the patients evidenced a substantial reduction in symptom severity, beginning in the first 12 weeks of treatment;
of the 5 who did not respond, 3 did not adhere to the diet.
A controlled replication of this intriguing observation is
awaited.
Anticonvulsants
The use of anticonvulsant agents for the treatment of
bipolar disorder was a watershed event for psychiatry in
the late twentieth century. The clear effectiveness of some
anticonvulsants for patients who do not respond well to
or cannot tolerate lithium has made these drugs a welcome
addition to the armamentarium. Controlled trials have
shown both valproate and carbamazepine (including the
new extended-release formulations of each) to be more effective than placebo and, as noted above, as effective as
lithium for treatment of acute mania.10 Moreover, a series
of small non-placebo-controlled studies has found that
oxcarbazepine, the 10-keto metabolite of carbamazepine,
appears to have antimanic action similar to that of its parent compound, but requiring a higher dose. It has also become clear that not all anticonvulsants are effective antimanic agents. Thus while several case reports and open
studies had suggested that topiramate might be effective
for the treatment of acute mania, controlled studies have
failed to show its efficacy as monotherapy for this state. Results of open studies suggest its usefulness as an adjunct,
but these results need to be confirmed with placebocontrolled studies. There are also a few case reports of apparent precipitation of manic symptoms with topiramate.11
One controlled study supports the efficacy of phenytoin as
an adjunct, while monotherapy studies of gabapentin and
the gamma-aminobutyric acid (GABA) analogue tiagabine
have shown no apparent benefit in manic patients. Results
of open studies suggest some efficacy for levetiracetam in
treating acute mania, but there are as yet no controlled data.
Other, newer anticonvulsants that have not been assessed in
systematic studies of bipolar patients include losigamone,
progabide, and vigabatrin.
Carbamazepine
Starting in the 1970s, a number of studies showed carbamazepine to be superior to placebo, although not necessarily equivalent to lithium, in the short-term treatment
of mania.12,13 Okuma and colleagues (1990) conducted a
double-blind, placebo-controlled study of manic patients
who were undergoing treatment with antipsychotics without substantial benefit. Half of the 105 patients were given
4001200 mg/day of carbamazepine, and the other half
were given lithium in amounts sufficient to establish relatively low mean serum levels of .46; all the patients continued on haloperidol. The final assessment revealed moderate
733
Valproate
The French psychiatrist Lambert first reported a possible
role for valproate in the treatment of bipolar disorder in the
course of its first clinical trials in patients with epilepsy in
the 1960s (Lambert et al., 1966). Many years later, Calabrese
734
Treatment
Oxcarbazepine
Oxcarbazepine is one of two major products of the microsomal metabolism of carbamazepine. It is nearly devoid of
hematological side effects, and, compared with carbamazepine causes fewer allergic skin reactions, and appears to
be much less active as a hepatic enzyme inducer (i.e., causes
less autoinduction). It is, however, a significant contributor
to the occasional gastrointestinal, teratogenic, endocrine,
and central nervous system toxicity seen with carbamazepine. Hyponatremia is the one adverse effect that may
occur more frequently with this drug than with the parent
compound (see the recent review by Ketter, 2005).
Several 2-week open clinical trials conducted in Germany in the 1980s indicated that relatively high doses of
oxcarbazepine had an effect equivalent to that of haloperidol (mean dose of 42 mg/day) in acutely manic patients;
the oxcarbazepine was very well tolerated compared with
the high-dose haloperidol regimen. Two randomized comparisons, one with valproate (Emrich et al., 1985) and one
with lithium (Emrich, 1990), found that oxcarbazepine
had comparable efficacy over 2 weeks, with roughly similar
side-effect profiles; however, the absence of a placebo group
in these studies renders their conclusions tentative. A more
recent study of oxcarbazepine for treatment of mania using an onoff design had a high dropout rate that likewise
makes its results difficult to interpret (Hummel et al., 2002).
Nevertheless, some of these mild to moderately manic patients had a greater than 50 percent reduction in their YMRS
scores, suggesting that further studies should be done to assess this agent for antimanic efficacy. A comparative study in
which 23 of 42 patients with mania being treated with valproate were switched to oxcarbazepine found comparable
reductions in the Clinician Administered Rating Scale for
Mania (CARS-M) at 10 weeks. More of the patients who
continued on valproate had a significant weight gain compared with those who switched to oxcarbazepine (Hellewell,
2002).
Given that oxcarbazepine appears to have a relatively
benign side-effect profile, it has been the subject of considerable clinical interest, and some open studies have suggested its usefulness as an adjunct (Benedetti et al., 2004).
To date, however, a single adequately powered placebocontrolled study of its efficacy as monotherapy in treating
mania is still lacking.
Topiramate
There have been several single-case reports and open studies indicating the apparent benefits of topiramate in the
treatment of mania.18,19 McElroy and colleagues (2000)
treated more than 50 bipolar patients with topiramate in
addition to other medications in an open design as part of
the Stanley Foundation Bipolar Network studies. In patients with manic symptoms (N = 30), the mean YMRS
score was 10 at the start of the study, indicating relatively
mild manic symptoms. At 10 weeks, the reduction in score
was statistically significant, albeit of questionable clinical
salience given the long duration of antimanic treatment
and the relatively mild symptoms at the outset. The patients
lost an average of 2.4 pounds in 4 weeks and remained stable in weight over 10 weeks.20 However, in a recent randomized placebo controlled trial of topiramate in bipolar patients experiencing a manic/mixed episode while on lithium
or valproate, the addition of topiramate (400 mg) was no
more effective than placebo (Chengappa et al., 2006).
Given its failure to separate from placebo in five large
randomized controlled trials (Powers et al., 2004; Kushner
735
et al., 2006; Chengappa et al., 2006), one cannot recommend topiramate monotherapy for the treatment of mania
in adults, and indeed none of the guidelines do so. There is,
however, some evidence suggestive of a beneficial effect in
adolescents (see Chapter 23), although this controlled trial
was unfortunately terminated early by the manufacturer
after the failure of the adult trials (DelBello et al., 2005). Yet,
unlike many other anticonvulsants, topiramate does not
cause weight gain and actually causes weight loss in many
patients. In light of this advantageous side-effect profile, it
is unfortunate that the controlled attempts to demonstrate
the drugs efficacy in treating adult mania failed. We can
hope that the somewhat encouraging results with adolescents will spur further work in this age group, given how
problematic weight gain can be in the young bipolar patient. Moreover, the drug has also shown promise as an adjunctive agent, making randomized, double-blind adjunctive trials another potentially valuable area for future work.
Lamotrigine
Lamotrigine is an anticonvulsant with sodium channel
blocking activity similar to that of carbamazepine and
phenytoin. Case reports and open studies have suggested
some efficacy for this drug in treating mania,21 but this
finding was not confirmed in controlled studies. A small
(30 subjects) 4-week randomized controlled trial compared
lamotrigine with lithium for treatment of hospitalized
manic patients (Ichim et al., 2000). Patients in the lithium
group received a fixed dose of 800 mg/day, achieving an average plasma level of .743 millimoles per liter (mmol/l) arguably not an adequate lithium dose for mania. The
lithium and lamotrigine groups shared similarly reduced
YMRS scores, but the absence of a placebo group renders
the results of this underpowered study inconclusive. Other
controlled studies in patients with mania/mixed states and
hypomania found no significant difference between lamotrigine and placebo (Anand et al., 1999; Frye et al., 2000). An
open study of patients with a history of rapid cycling found
lamotrigine to be helpful in some rapid-cycling patients
with mania, but not in those with the most severe manic
symptoms (Bowden et al., 1999).
Gabapentin
A number of case reports and uncontrolled studies of
gabapentin in patients with manic and mixed states have
suggested a beneficial effect when the drug is used adjunctively.22 On the other hand, Pande and colleagues (2000)
found that gabapentin was less effective than placebo as
an adjunctive agent for treating mania in patients taking
lithium, valproate, or both, while Frye and colleagues (2000)
found that it was no different from placebo in refractory
bipolar disorder. There have also been a number of reports
736
Treatment
Other Anticonvulsants
Tiagabine is a GABA uptake inhibitor used for the adjunctive treatment of partial complex seizures. One open
study of patients with bipolar disorder treated with this
agent indicated a possible benefit (Schaffer et al., 2002).
In another open study, however, fewer than one-quarter
of 13 treatment-refractory patients with bipolar disorder
appeared to be helped by adjunctive tiagabine (Suppes et
al., 2002). In a third study, none of 8 acutely manic patients
appeared to benefit from tiagabine as either monotherapy
or an adjunctive agent (Grunze et al., 1999b).
Some case reports and small open studies have indicated
beneficial responses in manic patients treated with zonisamide (Kanba et al., 1994; Berigan, 2002), a drug associated
with weight loss in obese bipolar patients. In an open-label
trial of adjunctive zonisamide, investigators in the Stanley
Network (McElroy et al., 2005) noted significant improvements in YMRS and CGI scores among 34 manic or mixed
patients who had not responded to conventional treatment
(p < .001); 14 of the 34 patients were much or very much
improved after 8 weeks of treatment. In an open study, adjunctive zonisamide (300600 mg/day) at bedtime was associated with significant weight loss in obese euthymic bipolar
patients on maintenance medication (Yang et al., 2003).
Other open studies have noted antimanic and/or moodstabilizing effects associated with levetiracetam.23,24 A 6-week
open-label, add-on study of mexiletine (an antiarrhythmic
drug with anticonvulsant properties) in treatment-resistant
bipolar patients found that four of the five patients with
manic or mixed states in the study had a full response and
the remaining patient a partial response as measured by a
derived scale that estimated symptom burden (Schaffer and
Levitt, 2005).
Surprisingly little work has been done on one of the
oldest anticonvulsantsphenytoinin the treatment of
bipolar disorder. Mishory and colleagues (2000) in Israel
reported on 39 patients in whom they examined the antimanic efficacy of phenytoin given with haloperidol in a
double-blind, placebo-controlled study. Significantly more
improvement was observed in the manic patients who received phenytoin and haloperidol than in those who received placebo and haloperidol.
Typical Antipsychotics
As reviewed extensively in the first edition of this volume,
from the 1960s through the early 1990s, typical antipsychotics, particularly haloperidol, were unchallenged as the
fastest-acting treatment for acute manic agitation. They were
generally considered the treatment of choice for acute mania,
Atypical Antipsychotics
As noted above, during the past decade the treatment of mania has been significantly altered by the introduction of
atypical antipsychotics, especially in North America. The
more favorable side-effect profile of these drugs, particularly the lower incidence of extrapyramidal symptoms (at
least as compared with haloperidol in controlled monotherapy trials in schizophrenia), was a significant factor prompting research into their efficacy for patients with bipolar disorder. It soon became apparent, however, that these agents
also have effects on mood more specific than those of the
typical antipsychotics, with antimanic and possibly some
antidepressant and maintenance efficacy in bipolar patients
(including those with mixed states; see Suppes et al., 1992;
Benabarre et al., 2001) not shared to the same extent by their
predecessor compounds.
Table 183 summarizes key findings from the literature
on the efficacy of the various atypicals. Essentially, the controlled data indicate equivalent antimanic efficacy for each
of these drugs, whether studied as monotherapy (Perlis
et al., 2006a) or in combination with lithium or valproate. It
is important to note that the studies of atypicals as adjunctive agents all started with patients who had already failed to
have a satisfactory response to lithium or an anticonvulsant.
Differences in the drugs tolerability profiles, as outlined
737
Clozapine
Clozapine has been studied for treatment of mania only
in open studies, presumably because of its side-effect profile (including sedation, hypotension, and hematological
dyscrasias). In the earliest such study, Muller and Heipertz
(1977) found that about half of 52 patients with mania responded quickly to clozapine treatment. Nearly 20 years
later, investigators at the McLean Hospital reported a small
case series of treatment-resistant bipolar patients who
improved substantially on clozapine, especially in manic,
mixed, and rapid-cycling states (Zarate et al., 1995). Calabrese and colleagues (1996) reported on an open trial of
clozapine monotherapy in 10 bipolar and 15 schizoaffective
patients who had failed to either tolerate or respond to
lithium.29 All but 3 of the patients completed the 13-week
trial, and 18 (72 percent) showed marked improvement on
the YMRS and BPRS. It was clear that the bipolar patients
experienced more improvement than the schizoaffective
patients, and those with rapid cycling did not respond to
clozapine as well as the other patients.
An open prospective clozapine trial involving 22 psychotic manic patients who had failed other therapies found
that the 14 patients who completed at least 10 weeks of the
trial had a better than 50 percent improvement on the
YMRS and BPRS and a 39 percent improvement on the CGI
(Green et al., 2000). Barbini and colleagues (1997) found
clozapine to be as effective as but more rapidly acting than
chlorpromazine in a group of 27 manic patients. Suppes
and colleagues (1999) compared clozapine adjunctive therapy with treatment as usual in bipolar and schizoaffective
patients with a history of mania. Although their study was
conducted primarily to assess outcome at 1 year, they also
observed that 65 percent of the clozapine-treated patients
showed at least 30 percent improvement by 3 months.30
738
Treatment
Table 183. Efficacy and Side-Effect Profiles of Various Atypical Antipsychotics for Treatment of Mania
Agent
Efficacy Summary
Side-Effect Profiles
Clozapine
Olanzapine
Risperidone
Quetiapine
Ziprasidone
Aripiprazole
Sedating; weight gain ++; dyslipidemia +; prolactin elevation 0; dose-related EPS +/0
The studies of adjunctive atypicals were conducted in patients who had failed to respond adequately to lithium or an anticonvulsant
and cannot be generalized beyond that population. Number of plus signs indicates severity of side effects. For individual literature
references see the text.
Olanzapine
This atypical agent has been shown to be superior to
placebo in several randomized, double-blind comparisons
in acutely manic patients. In the first of these studies, olanzapine at a dose of 520 mg/day resulted in substantially
greater improvement over that seen in placebo-treated subjects in a 3-week study (Tohen et al., 1999). The olanzapinetreated patients response rate (defined as a reduction in
YMRS score) was 48 percent, compared with 24 percent for
the placebo-treated group. The difference favoring olanzapine was not apparent, however, until the third week of the
study. Even though twice as many patients responded to
olanzapine as to placebo, it is sobering to consider that at
3 weeks, fewer than half of the patients on the atypical met
response criteria, an observation that can also be made
about acute mania trials with other atypical antipsychotics.
There was no significant EPS in the olanzapine-treated subjects, but several had transient elevation of liver enzymes,
and the olanzapine-treated group gained an average of
3 pounds during the 3-week study. A second randomized,
placebo-controlled study yielded similar results, except that
the difference in efficacy between olanzapine and placebo
appeared after only 1 week of treatment and was sustained
throughout the remainder of the trial (Tohen et al., 2000).31
The olanzapine-treated subjects with mixed mania experienced improvement in depressed mood that was statistically
superior to that among the placebo group. It is also worth
noting that in both studies, the improvement rate for the
olanzapine-treated manic subjects was equivalent for those
with nonpsychotic and psychotic mania; similar findings
have been reported with other atypical agents.
Taken together, these findings support the conclusion
that the effect of the atypicals in treating mania is truly
antimanic, rather than nonspecifically antipsychotic or sedative (Baker et al., 2003b). Along the same lines, Baldessarini
and colleagues (2003) found olanzapine response to be independent of number of prior episodes, rapid cycling, and lifetime substance abuse.32 It is likely that such findings represent a class effect for the atypicals rather than being unique
to olanzapine.
In addition to the comparisons of typical and atypical
antipsychotics discussed above, a number of studies have
compared olanzapine with other mood stabilizers. In a randomized, double-blind comparison of lithium and olanzapine monotherapy, impressive improvements were seen in
manic symptoms for both agents over the 4 weeks of the
study. All but one of the four scales employed33 showed
equivalent, dramatic improvement; the fourth34 indicated
greater improvement among the olanzapine-treated patients.
Mean lithium level was only .74 mg/L, however, which almost certainly favored the olanzapine treatment regimen
(Berk et al., 1999).
In a 3-week randomized, double-blind study comparing olanzapine (520 mg/day, mean dose 17.4 mg/day) with
divalproex (5002,500 mg/day, mean dose 1,401 mg/day,
achieving a mean blood level of 82 mg/ml) for the treatment
of acute manic or mixed episodes in 248 patients, Tohen and
colleagues (2002) demonstrated a slight but significant advantage for olanzapine over divalproex as measured by the
percentage of patients achieving a greater than 50 percent
decrease in YMRS score, by the percentage achieving remission as defined by a YMRS score of 12 or lower, and by the
mean reduction in score among the two groups. A 44-week
double-blind extension of this study found that only after
15 weeks of treatment was the efficacy of valproate comparable to that of olanzapine (Tohen et al., 2003b). Zajecka
and colleagues (2002), by contrast, found that olanzapine
and valproate had comparable efficacy in a 12-week randomized, double-blind study involving 120 patients with
acute mania. The difference between the results of these
two studies appears to be explained by dose: compared with
the Lilly-funded Tohen et al. study, the Abbott-funded
Zajecka et al. study used a lower dose of olanzapine (mean
daily doses were 14.7 mg) and a higher dose of valproate
(2,115 mg/day). In both studies, patients in the olanzapine
group experienced significantly more side effects, especially somnolence and weight gain, than those in the valproate group. Finally, Baker and colleagues (2004) found
that, for those with mixed states not responding adequately
to a mood stabilizer, adjunctive olanzapine produced significantly more improvement in scores on the Hamilton Rating Scale for Depression (HAM-D) compared with the
mood stabilizer alone.35
Some case reports (primarily from the schizophrenia literature) have suggested that olanzapine might occasionally
739
exacerbate mania. This question was examined systematically by Baker and colleagues (2003a), who pooled the
results of two large randomized, placebo-controlled studies of manic patients. Among the 254 patients in these
studies, manic exacerbations were significantly more frequent in the placebo group (38 versus 22 percent). However,
patients in controlled trials are less likely to have some of
the risk factors (such as substance abuse) associated with
switching, and they have just experienced a spontaneous
manic episode to qualify for the trial.36
To our knowledge, there has been only one comparative
study of the IM formulation of olanzapine, in which it was
compared with IM lorazepam and placebo as a sedating
agent in acutely agitated manic patients in a randomized
trial (Meehan et al., 2001). The investigators found that
10 mg of olanzapine was superior to 2 mg of lorazepam or
placebo at 2 hours and remained superior to placebo in reducing manic agitation at 24 hours. Olanzapine had no
more side effects than lorazepam during the acute period.
Risperidone
In open studies of manic patients, Tohen and colleagues
(1996) found a 50 percent or greater reduction in manic
symptoms in 10 of 12 patients when risperidone was added
to lithium. Keck and colleagues (1995) studied a mixed group
of patients treated with risperidone, noting that all 9 bipolar patients with mania showed moderate to marked improvement when the drug was added to a mood-stabilizing
regimen consisting of lithium, valproate, or carbamazepine.
Ghaemi and Sachs (1997) found that 9 of 14 bipolar patients, most with mania or mixed states, responded well to
the addition of risperidone in small doses, averaging under
3 mg/day. In contrast to some early reports of antidepressant activity (Hillert et al., 1992) and even aggravation of
manic symptoms (Dwight et al., 1994), Ghaemi and Sachs
saw no evidence of worsening of mixed or manic symptoms, a finding consistent with those of the controlled studies described below.
Three large randomized, double-blind trials have demonstrated the superiority of risperidone over placebo in
the treatment of mania/mixed states (Vieta et al., 2003;
Hirschfeld et al., 2004; Khanna et al., 2005); these studies
constitute the database for FDA registration of this drug as
an antimanic agent. The largest of the three (Khanna et al.,
2005) was conducted in India, where 144 hospitalized manic
or mixed patients were randomized to placebo and 146 to
a flexible dose of risperidone (16 mg/day) for 3 weeks; at
end point, a clinical response (50 percent or greater decrease in YMRS scores) was observed in 73 percent of the
risperidone patients versus 36 percent of the placebo patients (p < .001). The major side effect was EPS (primarily
mild), in 35 percent of risperidone-treated patients versus
740
Treatment
poor responders to a mood stabilizer. In a recent randomized double-blind comparison, risperidone and olanzapine
had equivalent antimanic efficacy; olanzapine was associated with a greater reduction in depressive symptoms but
more weight gain (Perlis et al., 2006b).
Quetiapine
Several case reports (Dunayevich and Strakowski, 2000)
and retrospective case series40 suggest a useful role for the
atypical antipsychotic quetiapine when used as adjunctive
treatment for mania and/or mixed states.
Two large international multicenter randomized, doubleblind, placebo-controlled trials evaluated the efficacy of quetiapine monotherapy (400800 mg/day) in hospitalized
manic patients. In one (Bowden et al., 2005), 302 patients
were randomized to quetiapine (n = 107), lithium (n = 98),
or placebo (n = 95). At 3 weeks the decrease in YRMS scores
was significantly greater (p < .001) for both drugs compared
with placebo; the extent of the improvement was virtually
identical for the two drugs. The other study (McIntyre et al.,
2005) was of the same size and design, except that the active
comparator was haloperidol; results were similar as well, except that at 3 weeks, the effect of haloperidol was slightly
more robust than that of quetiapine. In both studies, quetiapine had a significantly greater effect than placebo on
depression ratings (see Chapter 19). On the basis of these two
studies, quetiapine (Seroquel) received FDA approval for
treatment of acute mania associated with bipolar disorder.
Somnolence, dry mouth, and postural hypotension were the
principal side effects differentiating quetiapine from placebo.
Two large randomized, placebo-controlled trials (Sachs
et al., 2004; Yatham et al., 2004) examined the efficacy of adjunctive quetiapine in 402 hospitalized manic patients who
were still substantially symptomatic (YMRS scores 20) after a minimum of 7 days of lithium or divalproex. In both
studies, the combined treatment was significantly better
than the mood stabilizer alone. As noted above regarding
adjunctive olanzapine and risperidone, it is important to
note that patients entered these studies after at best a partial
response to a week or more on the mood stabilizers alone;
thus the generalizability of the study findings is limited.
Ziprasidone
The neuropharmacology of this atypical is of interest because its effects include monoamine reuptake inhibition,
which might suggest efficacy in depression. Also, ziprasidone stands with aripiprazole (see below) as one of only
two atypicals producing little or no weight gain.
Keck and colleagues (2003a) conducted a multisite randomized, double-blind, placebo-controlled study involving 210 inpatients in a manic or mixed state. They assigned
140 of the patients to ziprasidone monotherapy at a dosage
Aripiprazole
This atypical antipsychotic (now available as orally disintegrating tablets) has a pharmacodynamic profile that distinguishes it from other antipsychotics by virtue of its being
a partial agonist rather than an antagonist at dopamine D2
receptors. Keck and colleagues (2003a) conducted a 3-week
741
Amisulpiride
In a trial in schizophrenic patients, this selective, dosedependant D2D3 antagonist appeared to be more effective
against affective symptoms than haloperidol or risperidone
(Peuskens et al., 2002). This finding led to a preliminary
open prospective 6-week study in 20 patients meeting DSMIV criteria for mania (Vieta et al., 2005). Among the 14 patients who completed the study, a significant improvement
was seen in mania ratings, as was a significant albeit less robust effect on depression ratings. The principal side effect
was sedation; 10 percent of the subjects experienced EPS.
Zotepine
This first-generation atypical antipsychotic, which, like
ziprasidone, inhibits reuptake of monoamines, has been
studied in two small open-label trials. Harada and Otsuki
(1986) reported beneficial effects in the majority of their 16
moderately manic patients, most of whom were already on
lithium. More recently, Amann and Grunze (2005) evaluated zotepine somewhat more formally as monotherapy in
a group of more severely manic patients. Nine of the 12 patients met response criteria (a 50 percent reduction YMRS
scores), and 5 of them achieved this improvement within
4 days. There have as yet been no randomized, placebocontrolled trials.
742
Treatment
Benzodiazepines
In the 1980s, the potential value of two high-potency benzodiazepinesclonazepam and lorazepamfor the treatment of mania was noted. Previously, it had been hoped
that these agents might become alternatives to the antipsychotics that would not share their tendency to cause tardive dyskinesia. Results of early open studies suggested
that efficacy and speed of onset were similar for highpotency benzodiazepines and antipsychotics, and that the
benzodiazepines could be used as short-term antimanic
agents for patients who had not taken lithium long enough
for it to have an antimanic effect (Modell et al., 1985).
Edwards and colleagues (1991) compared clonazepam
with placebo in 40 manic patients, with additional doses of
chlorpromazine being given to patients in either group
as needed. The clonazepam-treated group showed greater
improvement on the YMRS and had a trend toward requiring fewer doses of chlorpromazine. In a crossover study
comparing clonazepam with lithium in acutely manic patients, Chouinard and colleagues (1983) found the former
to be more effective in reducing manic symptoms. However, the length of the study was only 10 days, with patients
receiving either drug for only 5 days before switching to
the other. Thus the study findings are probably better seen
as reflecting the sedating effect of clonazepam and the
known lag time in lithiums antimanic effect than a superior antimanic effect for clonazepam. Also of note, patients in both groups were able to receive haloperidol as
needed, further casting doubt on any claim to antimanic
efficacy for the benzodiazepine.
Lenox and colleagues (1992) compared lorazepam and
haloperidol as adjuncts to lithium in a double-blind study
involving 20 hospitalized patients. They found no significant difference between the two drugs in length of time to
response. More patients in the haloperidol group dropped
out because of side effects, and more patients in the lorazepam group dropped out because of lack of efficacy. Gouliaev and colleagues (1996) obtained similar results comparing clonazepam with the antipsychotic zuclopenthixol. A
comparably designed study of clonazepam versus haloperidol found that the haloperidol-treated patients responded
more quickly, probably reflecting that drugs more rapid onset of action (Chouinard et al., 1993). Bradwejn and colleagues (1990) found lorazepam to be superior to clonazepam in a double-blind study involving 24 acutely manic
patients, a finding that in retrospect also probably reflects
differences in pharmacodynamics between the two agents.
On the other hand, a recent meta-analysis of the controlled
studies concluded that while clonazepam is effective for
the treatment of mania, the evidence for lorazepam is not
as conclusive (Curtin and Schultz, 2004).
Electroconvulsive Therapy
Although it is clear from clinical experience that ECT is
an effective and rapidly acting treatment for mania (Fink,
2006), there have been only a handful of controlled
prospective studies to support this conclusion. This is a reflection, perhaps, of four factors. First, given the efficacy
and wide range of available pharmaceutical agents, few patients receive ECT for mania. Second, the effect is often so
dramatic as to make controlled study appear unnecessary.
Third, it is difficult to justify and maintain blinded conditions with sham ECT for such a controlled trial in acutely
manic patients. Finally, unlike drug treatments, ECT requires written informed consent (Fink, 2006), which can be
difficult to obtain, particularly from more severely ill patients for whom ECT may well have an advantage over
medication.
Given this lack of data, it is difficult to say how ECT is
best used for treating mania. The optimal electrode placement and number of treatments also remain unclear. For
example, some have suggested that mania might be expected to respond more favorably to right-sided placement
and depression more to left-sided placement. In one study
of seven manic patients, however, right unilateral ECT was
not effective (Milstein et al., 1987).
Although systematic and controlled studies are lacking,
an excellent review of the published experience with lithium
by Mukherjee and colleagues (1994) suggested that about
80 percent of manic patients treated with ECT showed
marked improvement or full recovery. On the other hand,
an analysis of manic and schizoaffective manic patients receiving ECT (Winokur et al., 1990) confirmed the earlier
observation (Winokur and Kadrmas, 1989) that these patients had more subsequent hospital admissions for mania
than those not receiving ECT, although the ensuing total
number of episodes of mania and depression did not differ between ECT- and non-ECT-treated patients. The authors concluded that this finding probably reflects some
Other Treatments
Calcium Channel Blockers
The use of calcitonin, verapamil, and diltiazem for treatment of mania was proposed in the early 1980s, but few
controlled data were brought forth to support this recommendation.42 Subsequent controlled studies have shown
mixed results. Two parallel studies compared verapamil
743
with lithium. In one (Garza-Trevino et al., 1992), no difference was seen between the two agents over a 4-week period. In the other (Walton et al., 1996), lithium was found
to be superior to verapamil. Janicak and colleagues (1998)
found no benefit from verapamil compared with placebo
in a 3-week double-blind study.
Post and colleagues (2000) studied the L-type calcium
channel blocker nimodipine in patients with ultrarapid
(ultradian) bipolar illness (patients who cycle several times
in a 24-hour period). They noted marked improvement in
some patients (Pazzaglia et al., 1998), including one whose
mood again destabilized when verapamil was substituted
for nimodipine.
Magnesium sulfate, used in a variety of clinical contexts,
including treatment of cardiac arrhythmias, exerts at least
some of its pharmacological effects through competitive
antagonism with calcium at cellular calcium channels. Heiden and colleagues (1999) added intravenous magnesium
sulphate to the drug regimens of 10 patients with severe,
treatment-resistant manic agitation and noted a marked
improvement in 7.
Levy and Janicak (2000) reviewed these and other studies
of calcium channel antagonists and concluded that there is
at best quite limited support for their efficacy. Because of
their lack of demonstrated superiority over other agents, the
calcium channel blocking agents have been relatively neglected in the clinical research literature. Thus their role in
the treatment of acute mania remains to be determined.
Tamoxifen
This nonsteroidal antiestrogen is widely used in the treatment and relapse prevention of estrogen-dependent cancers, particularly of the breast. Because it is also a potent
inhibitor of phosphokinase C, which is thought to be involved in the mechanism of action of mood stabilizers (see
Chapter 14), it has been used experimentally for treating
mania and found to be effective in a small series of patients
(Manji and Chen, 2002).
Cholinergic Agents
Reports on the use of cholinergic agents, such as pilocarpine, for the treatment of mood states appeared as early
744
Treatment
CONCLUSIONS
The discovery of the antimanic effects of lithium launched
the psychopharmacology revolution in psychiatry, and today lithium remains one of the most documented choices
for the treatment of euphoric nonpsychotic mania or hypomania. Beyond lithium, however, our armamentarium
has been considerably enriched by anticonvulsants and
atypical antipsychotics. In comparison with the treatment
of bipolar depression or maintenance treatment, the clinician enjoys the choice of a wide range of drugs that have
been shown to be effective in treating acute mania and/or
mixed states. Indeed, in the United States alone there are
nine FDA-approved agents for mania. Recall, however, that
in the placebo-controlled literature, response means an
improvement of 50 percent or better, and that even with
this modest definition of improvement, the response rates
from monotherapy studies average around 50 percent.
Thus most manic patients will ultimately require a combination of medications, although when possible, it is generally advisable to evaluate monotherapies first. Given that a
drug or drug combination initiated for mania or hypomania will likely be carried forward into the continuation
phase of treatment (not to be confused with true maintenance or prophylactic treatment; see Chapter 17), both efficacy and tolerability must be considered from the outset.
For the acute management of more severely ill patients, the
older typical antipsychotics still have a role, while for the
patient with moderate to moderately severe symptoms, the
atypical antipsychotics represent an important addition to
the armamentarium.
The manic patient presents multiple clinical challenges
beyond the issue of choice of medication, such as dealing
with law enforcement and deciding when to hospitalize
involuntarily, how best to involve the family, and how to
enhance adherence to the treatment regimen. For those patients whose manic episodes are heralded by a hypomanic
NOTES
1. Delirious maniaa syndrome of the acute onset of the insomnia, excitement, grandiosity, emotional lability, and psychotic symptoms characteristic of mania, accompanied by
the disorientation and altered consciousness characteristic of
deliriumis fortunately now rare. See Chapter 2 and Fink
(1999) for a review.
2. IM droperidol had also been widely used for emergency sedation until concerns about cardiac arrhythmia and reports
of sudden death led to its virtual elimination from the armamentarium in the late 1990s. More detailed analyses have cast
some doubt on the wisdom of abandoning this highly effective agent so quickly (Chase and Biros, 2002).
3. To our knowledge there have been no studies comparing
ECT with atypical antipsychotics in the treatment of mania.
4. For example, a Finnish study of bipolar patients who committed suicide found that about 1 in 10 were in or had recently recovered from a period of psychotic mania at the
time of their death (Isometsa et al., 1994).
5. However, in a randomized study, Rifkin and colleagues (1994)
compared three doses of haloperidol for mania (10, 30, and
80 mg/day) and found no difference among the three doses.
They concluded that more than 10 mg/day offers no additional advantage in treating mania.
6. Adapted from the first edition of this text: Comparisons of
lithium and neuroleptics have been limited largely to chlorpromazine. The largest such study, the Veterans Affairs (VA)
National Institute of Mental Health (NIMH) study (Prien
et al., 1972), warrants extensive discussion because of its size
255 newly admitted manic and schizoaffective patients in
18 VA hospitalsand its unusual findings. Patients were differentiated not only by diagnosis but also by activity level:
highly active or mildly active. Among the highly active
patients who completed the 3-week treatment trials, both the
lithium-treated and the chlorpromazine-treated groups improved significantly on a wide range of symptoms. However,
38 percent of the lithium-treated patients dropped out, compared with only 8 percent of those treated with chlorpromazine, in part reflecting more side effects attributable to
lithium in this group since the dose was pushed in an effort to
control the hyperactivity. Both drugs produced significant improvement in the mildly active patients who completed the
study, but in this group severe side effects were more frequent
among the chlorpromazine-treated patients. The investigators
concluded that chlorpromazine was superior to lithium in the
initial treatment of the highly active patients. The neuroleptic
not only reduced motor activity, excitement, grandiosity, hostility, and psychotic disorganization, but also sharply decreased the patients need for ward supervision in the first
week. By the end of 3 weeks, however, the two drugs were
equivalent. Among the mildly active patients, there were fewer
dropouts related to lithium than to chlorpromazine, primarily because lithium did not make them feel as sluggish and
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
745
746
Treatment
28. The absence of a placebo group in this aripiprazolehaloperidol comparison limits interpretation of the results.
29. Most patients had also had poor responses to carbamazepine
or valproate. All 25 subjects had experienced at least one
episode of mania in the 24 months prior to the trial. The mean
number of hospitalizations was 15.
30. A chart review study of bipolar-I patients treated with adjunctive clozapine, risperidone, and olanzapine found no
difference in efficacy among the groups (Guille et al., 2000).
Olanzapine caused the greatest weight gain, although olanzapine plus lithium was associated with less weight gain than
olanzapine plus valproate.
31. However, there was an even higher placebo response rate in
this series43 percent, compared with the 25 percent rate
in the earlier study.
32. A secondary analysis of the first placebo-controlled trial (Tohen et al., 1999) by Baker and colleagues (2002) indicated
that the efficacy of olanzapine in acute mania was independent of whether the patient had previously failed to respond
to lithium or valproate.
33. Brief Psychiatric Rating Scale, Clinical Global Impression for
Bipolar Disorder scale identifying manic, hypomanic, depressive, or mixed symptoms.
34. Simpson-Angus Scale.
35. Generalizability is quite limited for studies in which the new
agent is added to ongoing treatment to which the patient is
not yet responding since this is, in effect, selecting for nonor partial response to the original agent, in this case lithium
or valproate.
36. The Baker et al. (2002) data could also be interpreted as suggesting that olanzapine was superior to placebo in preventing
early relapses into mania after acute treatment of the episode.
37. This difference may relate to the fact that in India, families can
give consent for participation in treatment research when the
validity of a patients consent is compromised by the illness.
38. In this study, there was also a haloperidol-treated group. It is
interesting that three placebo- and three haloperidol-treated
subjects on lithium or valproate became manic, but none of
the risperidone-treated patients did.
39. In Segal and colleagues (1998) study, mean serum lithium
levels were .53, .62, and .72 mmol/l at the end of weeks 1, 2,
and 3, respectively.
40. Ghaemi and Katzow, 1999; Zarate et al., 2000; Chisholm
et al., 2001; Sajatovic et al., 2001.
41. Coexisting lamotrigine does not appear to require any increase in the electrical stimulus.
42. Giannini et al., 1984; Dose et al., 1986; Dubovsky et al., 1986;
Barton and Gitlin, 1987.
19
Monsieur le Docteur, since you are quite aware of what in me is capable of being attacked (and
healed by drugs). . . . I hope you have the knowhow to give me the quantity of subtle liquids,
of specious agents, of mental morphine which will uplift my abasement, balance what is crumbling, reunite what is separated, recompose what is destroyed.
Antonin Artaud (1924, pp. 2728)
748
Treatment
CLINICAL MANAGEMENT
This section addresses the key aspects of the clinical management of depression. Discussed in turn are the evaluation
of the depressed patient, hospitalization, general considerations involved in medical treatment, and selection of a
treatment approach. Our recommendations for the selection
of appropriate treatments for particular patients are presented later in the chapter. Detailed discussion of special
considerations in treating bipolar children and adolescents
is presented in Chapter 23, and issues involving side effects
of psychiatric medications and their use in pregnancy are
addressed in Chapter 20.
Hospitalization
The first treatment decision the clinician must make is
whether a depressed patient can safely be treated on an outpatient basis. More than two-thirds of completed suicides
by persons with bipolar disorder occur during a major depressive episode (Isometsa et al., 1994) (see Chapter 8). The
patient expressing fear of acting on suicidal urges clearly
needs to be considered for hospitalization, but the decision
is often less than clear-cut, depending, for example, on
whether there is a previous history of serious suicide attempts, whether the patient expresses hopelessness, whether
the patient has a history of impulsiveness and/or violence,
and whether the patient has access to lethal means and/or
lives alone. Comorbid substance abuse substantially increases the suicide risk; thus the threshold for hospitalizing
the depressed patient who is actively abusing drugs or alcohol should be lower than that for a patient who is not.
The patient with severe psychomotor retardation should
usually be hospitalized. Even if the close support of family
members is available to these patients, their nutritional status and ability to comply with treatment recommendations
are poor, and their illness can decompensate quickly into an
acutely life-threatening condition. The risk of suicide may
actually rise as these patients begin to emerge from their depression. Under some circumstances, a patient may need to
be placed under one-to-one observation, or suicide watch
(see Chapter 8). Energy level and volition often increase well
749
750
Treatment
Lithium
Given data demonstrating the apparent ability of longterm treatment with lithium to protect patients with bipolar disorder against suicidal behavior (see Chapter 25), one
can argue that lithium should be included in the regimen
for many if not most bipolar patients. Lithium remains
a strong choice for monotherapy for bipolar-I depression
in patients presenting with no previous treatment history.
Indeed, the practice guidelines of the American Psychiatric Association (APA) (2002) for the treatment of patients with bipolar disorder recommend lithium as an
initial treatment for bipolar depression of mild to moderate severity. The most recent guidelinesthe Texas Algorithm (Suppes et al., 2005)recommends as a first step for
bipolar depressed patients already taking lithium that the
lithium level be increased to above 0.8 mEq/l.
A typical clinical scenario is the patient presenting with
depressive symptoms who, on closer questioning of both
patient and family member(s), is found to have experienced
previous episodes of clear hypomania (or even mania) that
did not come to clinical attention or were not properly diagnosed and treated. Patients with such a history will often
resist the idea of having bipolar disorder rather than just
depression and may recoil at the mention of lithium, a
medication they may associate with severe mental illness.
Thus, before some patients will agree to take lithium, they
must be educated about its well-demonstrated, albeit often
751
752
Treatment
If on lithium or valproate
If no response at
week 4:
If no response at
week 4:
Add quetiapine.
If no response at
week 6:
Consider olanzapine plus fluoxetine
as an alternative to quetiapine.
If no response at
week 8:
Discontinue olanzapine plus
fluoxetine and add bupropion or
a selective serotonin reuptake
inhibitor (SSRI), depending on
symptom pattern,a while maximizing
the antimanic mood stabilizer.
If no response at
week 10:
Consider ECT or an alternative
antidepressant, such as a
monoamine oxidase inhibitor (MAOI)
(preferably), a tricyclic;
pramipexole, or a stimulant and/or
sleep deprivation.
If no response at
week 6:
Consider olanzapine plus fluoxetine
as an alternative to quetiapine.
If no response at
week 8:
Discontinue olanzapine plus
fluoxetine and add bupropion or
SSRI, depending on symptom
pattern,a while maximizing the
antimanic mood stablizer.
If no response at
week 10:
Consider ECT or an alternative
antidepressant, such as an MAOI
(preferably), a tricyclic,
pramipexole, or a stimulant
and/or sleep deprivation.
Figure 191. a: Recommendations for treatment of bipolar-I depression. Bupropion is preferred for psychomotor retardation/slowing; SSRIs are preferred for irritability or comorbid anxiety, panic, or obsessive-compulsive
disorder. b: Recommendations for treatment of bipolar-II depression. Note: There have been very few controlled
studies focusing on bipolar-II depression; therefore, any recommendations for treating this condition must be
considered more tentative than those for treating bipolar-I.
753
If on a mood stabilizer
1. Start lamotrigine.
a. For severe depression,
consider
electroconvulsive therapy
(ECT) or an
antidepressant plus an
antimanic mood stabilizer.
b. For psychotic depression,
add an atypical
antipsychotic to
lamotrigine.
c. If the patient has
seasonal depression, use
adjunctive bright light in
the morning.
d. For persistent irritability,
consider adjunctive
valproate.
If no response at week 4:
Consider a second-generation
antidepressant plus an antimanic
mood stabilizer or quetiapine.
If no response at week 4:
Consider a second-generation
antidepressant plus an antimanic
mood stabilizer or quetiapine.
If no response at
week 6:
If no response at
week 8:
Consider other combinations
(quetiapine plus lamotrigine,
lithium plus lamotrigine,
olanzapine plus fluoxetine, MAOI
plus antimanic mood stabilizer).
754
Treatment
Anticonvulsants
For patients who remain depressed on lithium, recommendations regarding the choice of an adjunctive agent were
based in the past on whether the patient had a history of
symptoms associated with a more complex and brittle bipolar disorder, usually thought to be indicated by a history of
rapid cycling or mixed episodes. The literature supporting
the efficacy of certain anticonvulsants in the treatment of
mixed states and rapid cycling supports the adjunctive use
of these agents in patients with such a history who experience lithium-resistant bipolar depression, as do studies indicating synergistic or at least additive effects of lithium
and valproate at both the clinical (Young et al., 2000) and
cellular levels (see Manji et al., 2001; see also Chapter 14).
Some patients with bipolar depression will respond to
valproate monotherapy; compared with lithium, however,
there is less data supporting valproate as a first-line agent
for depression. However, when a bipolar depressed patient
is suffering from comorbid anxiety, valproate or carbamazepine may be a reasonable first-line choice. (See also
our review of the literature below.)
Lamotrigine is different from the other anticonvulsants
(such as valproate or carbamazepine) in that the evidence
indicates it to be effective in treating the core symptoms of
bipolar depression, and unlike traditional antidepressants, it
is much less likely to be associated with a switch into mania
(although switches into hypomania have been reported). Indeed, lamotrigine has joined lithium as a first-line agent for
bipolar depression. In the Texas Algorithm (Suppes et al.,
2005), for patients not already taking lithium, lamotrigine is
the first-line recommendation for bipolar depression (together with an adjunctive antimanic agent for bipolar-I patients). Because of the slow titration schedule required to
minimize the risk of a serious rash, there is some concern
that the acute antidepressant effect of the drug may not be
rapid enough for some clinical situations. While this may
well be true for severe depression, for many patients at least
partial antidepressant effects can begin at doses as low as
50 mg; indeed, as noted in the review of the literature below,
50 mg of lamotrigine was found to be superior to placebo, a
dose that can be reached in the third week of administration. Patients who are going to respond completely usually
do so at doses between 100 and 200 mg/day, but some (who
may be rapid metabolizers) fail to respond until higher
doses, up to 400 mg/day.6 For bipolar-II depression, lamotrigine can be used as monotherapy, while for bipolar-I depression, it is generally best combined with another stabilizer that works more effectively in the prevention of mania.
The British guidelines (G. Goodwin et al., 2004) specify that
lamotrigine monotherapy for bipolar-I depression may be
appropriate where depressive symptoms are less severe.
Antidepressants
Analysis of U.S. prescribing patterns in the 1990s indicates
that approximately half of all visits to a psychiatrist by
bipolar patients involved the administration of an antidepressant, often in the absence of a mood stabilizer (Blanco
et al., 2002; Baldessarini et al., 2006). While such practice
is, in our view, clearly inappropriate, adding an antidepressant to a mood stabilizer can be justified in some circumstances. By and large, the North American treatment
guidelines suggest that antidepressant monotherapy is not
appropriate for bipolar depression (especially bipolar-I depression) and that even in combination with a mood stabilizer, antidepressants should be reserved for more severe
cases of depression.8 It should be noted that some European experts believe the North American guidelines are too
negative with regard to antidepressants. At any rate, earlier
reluctance (especially in the United States) to recommend
antidepressants for patients with bipolar disorder because
of concerns about precipitating manic symptoms has been
attenuating somewhat in the face of evidence (albeit limited) that, compared with the tricyclics, the newer antidepressants (in the presence of a mood stabilizer) are less
likely to be associated with acute switching into manic/
hypomanic episodes (Gijsman et al., 2004). With regard to
long-term cycle induction, however, the newer agents may
be no safer than the older ones (Ghaemi et al., 2004).
Given the reality that most patients with bipolar disorder experience substantially more morbidity from depressive than from manic/hypomanic symptoms, antidepressants continue to have some role in the treatment of bipolar
depression, perhaps especially for the bipolar-II patient. In
our view, however, antidepressants should generally be reserved for patients who are severely depressed or those for
whom a combination of two mood stabilizers (including
lamotrigine) or a combination of a mood stabilizer and
quetiapine has failed. Our conclusion, which is similar to
the recommendation of the Texas Algorithm (see below)
755
with lithium alone. Of relevance to the newer secondgeneration antidepressants, a recent randomized study
within the NIMH STEP-BD program (detailed in our review
of the literature below) found that over 1-year follow-up
of bipolar patients who had responded to a mood stabilizer
antidepressant combination, the adjunctive antidepressant
was not associated with a better outcome compared with the
mood stabilizer alone.
Ghaemi and Goodwin (2005) applied the technique of
decision analysis to all of the available literature addressing
the role of antidepressants in bipolar-I disorder (the analysis was weighted toward the newer agents, as well as toward
randomized controlled trials, and involved conservative
assumptions). They concluded that the available literature
supports mood stabilizer monotherapy or a mood stabilizer
plus short-term use of an antidepressant, but does not support long-term use of an antidepressant, even with a mood
stabilizer.
Among second-generation agents, the APA and Expert
Consensus guidelines recommend bupropion or paroxetine, whose use for treating bipolar depression has been
supported by the results of randomized, placebo-controlled
studies. Ultimately, however, the clinician must tailor this
decision to the particular patient, based on such factors
as symptom pattern, individual or family history of response to a particular agent, and side-effect profile. For
example, when psychomotor retardation/decreased energy
and lack of motivation are the most prominent features of
the depression, bupropion, with its activating profile, is
preferred; when comorbid anxiety, panic, or obsessivecompulsive symptoms predominate, a selective serotonin
reuptake inhibitor (SSRI) is likely to be the best choice. A
moderate amount of crossover data is available to support
such choices. On the basis of studies covered in our review
of the literature, as well as our clinical experience, the following conclusions and recommendations are particularly
relevant:
Tricyclics are problematic for the treatment of bipolar
depression with regard to both stabilization and efficacy.
For a contrary view see Moller and Grunze (2000), as
well as a detailed critique of that paper11 (Ghaemi et al.,
2003a).
The MAOIs remain underutilized for treating bipolar
depression (Himmelhoch et al., 1991; Balon et al., 1999).
Although they are well documented to be effective for
that purpose and uniquely effective for some patients who
fail to benefit from any other agent, many psychiatrists
never prescribe them because of misapprehensions about
side effects and required diet. Many published diets are
overly restrictive, however, being based on case report
data on drug reactions that are of questionable validity
756
Treatment
Box 191 outlines our conclusions about the role of antidepressants in treating bipolar disorder.
Given the differential response of individuals with major depression to different agents, tapering and switching
is a reasonable strategy when a patient does not respond to
one antidepressant. Most guidelines recommend switching
to an antidepressant in a class different from the failed
agent, for example (as noted above), to bupropion in a patient showing no response to an SSRI (see Fava, 2000, for
a discussion of switching strategies with a focus on avoiding discontinuation syndromes). Differential responses to
different drugs in the same class have certainly been demonstrated, however; for example, some (unipolar) depressed
Antipsychotics
Some patients with bipolar depression will benefit from
antipsychotic medications. These agents are certainly indicated for patients with depression complicated by delusions and hallucinations. The agitation and extreme dysphoria and distress associated with severe depression can
be significantly ameliorated with antipsychotics as well.
And given in the evening, these agents can be especially
helpful in stabilizing sleep.
The newer, atypical antipsychotics have positive effects
on mood while also being somewhat less prone to cause
acute or delayed extrapyramidal symptoms; thus they are
clearly preferred over the older agents. Indeed, given the
ability of some of these drugs to improve mood, even when
the clinical picture does not include psychotic features, they
may be preferable to benzodiazepines in patients with severe
insomnia or extreme anxiety with physical restlessness and
agitation. It should be noted that the doses of these agents
useful in treating depression are often lower than those
needed to treat schizophrenia or manic states. The atypicals are 5-hydroxytryptamine(2) (5-HT2) receptor antagonists at low doses, and it has been suggested that as a result,
they may have an antidepressant effect through serotonergic mechanisms at these doses.
Olanzapine has been studied extensively in bipolar disorder. In addition to its clear antimanic action, there is evidence of a modest antidepressant effect, even in monotherapy (Tohen et al., 2003a), although the size of this effect is
757
small and derives almost entirely from the drugs beneficial effect on insomnia, anxiety, and irritability. When
olanzapine is combined with fluoxetine (Tohen et al., 2003b)
or other antidepressants (Thase, 2002), the effect is more robust. Recently, another atypical, quetiapine, was found to
have a robust antidepressant effect, including some effect
on core depressive symptoms, in two large randomized,
placebo-controlled studies of bipolar patients; indeed, quetiapine is the first drug to have attained an FDA indication for
bipolar depression (see our review of the literature below).
There have been reports of olanzapine and other atypical
antipsychotic medications causing hypomanic and manic
symptoms in patients with bipolar disorder. Two critical reviews by the same group (Aubry et al., 2000; Rachid et al.,
2004) evaluated published case reports covering a total of
60 patients and concluded that for more than half of these
patients, a causative role for an atypical antipsychotic was
highly suggestive. On the other hand, an analysis of 129
patients participating in controlled trials of olanzapine
found a significantly higher switch rate in the placebo group
than in those taking the drug (Baker et al., 2003). It should
be noted, however, that patients participating in controlled
trials are less likely than nonparticipants to have some of the
risk factors (such as substance abuse) associated with switching. Also, because the participants had to have just experienced a spontaneous manic episode to qualify for the trial,
their situation was different from that of the bipolar patient
being treated for depression.12
Although the risk of causing extrapyramidal symptoms
is likely lower with the atypical than with the typical antipsychotics (see Chapter 20), some, though not all, of the
former have metabolic side effects, including increased
serum lipids, triglycerides, and glucose (Osser et al., 1999).
Weight gain associated with the use of some of these medications is well documented,13 and cases of new-onset diabetes mellitus have been reported (Wirshing et al., 1998).
Monitoring of weight is therefore essential when certain of
these medications are prescribed, as is the usual attention
to the serum lipids that are important to cardiac health
(see Chapter 20 for details on the individual drugs).
clinical utility of the latter strategy cannot be overemphasized; increased mood instability from adding an antidepressant can take many months to become apparent, and
even then it is easily missed by clinicians not employing a
life chart methodology (see Chapter 11).
Complex Regimens
Many bipolar patients with refractory depressive symptoms will need to take lithium as well as an anticonvulsant,
such as lamotrigine, and clinical experience has shown
that a few will need to take lithium and more than one anticonvulsant, an atypical antipsychotic, and an antidepressant as well. The clinician must be sure to approach such
complex regimens cautiously. Optimizing of dosages (using serum drug-level determinations when possible) or
simply watchful waiting for full benefit to be achieved from
the addition of an agent may be all that is necessary. The
Thyroid Augmentation
Attention to the thyroid status of the depressed bipolar
patient is essential. Determination of thyroid-stimulating
hormone (TSH) and free thyroxine (f T4 ) by dialysis should
be part of the assessment of patients with depression at
the first sign of resistant symptoms. Correction of thyroid
deficiencies is obviously important, but patients with normal thyroid determinations may benefit from adjunctive
treatment with thyroid hormone as well (see our review of
the literature below). In the next chapter, we review studies indicating that lower mean thyroid indices (albeit in
the normal range) are associated with incomplete recovery from bipolar depression. Psychiatrists should thus
be familiar with thyroid physiology, know the signs and
symptoms of hyper- and hypothyroidism, and, most important, understand the concept of subclinical hypothyroidism.
Recommendations as to which depressed patients to treat
with adjunctive thyroid hormone and at what point can be
difficult to make. Female patients, those with rapid-cycling
disorders, and those with levels of TSH above the 50th percentile of normal and with f T4 below the 50th percentile
have shown particular benefit from thyroid augmentation.
Given that about 50 percent of patients with treatmentresistant depression benefit from augmenting antidepressant medication with triiodothyronine (T3), a low-risk intervention, it would be reasonable to recommend adding
T3 to an antidepressant sooner rather than later, perhaps
even after concluding that the patient has not benefited
from the second or even the first antidepressant added
to lithium and anticonvulsant(s). For long-term management of bipolar patients, it is appropriate to shift gradually
to T4 (see Chapter 20).
758
Treatment
Electroconvulsive Therapy
In our opinion, it is unfortunate that ECT is often relegated
to last-resort status in treatment guidelines and protocols.
We believe the clinician should not hesitate to recommend
ECT to severely ill patients as a first-line treatment. For the
delusional or suicidal patientindeed, for any depressed
patient who is so ill that only the most reliably and rapidly
effective treatments should be consideredECT is the
clearly superior alternative. ECT should also be offered to
patients with treatment-resistant depression who have a
history of adverse reactions to antidepressants (increased
cycling, induced mania or agitation) whenever their symptoms threaten to become chronic or begin to have a significant negative impact on family or on occupational or academic functioning.
Depression in elderly patients is especially responsive to
ECT. Since older patients often need to be started on lower
doses of medications and their dosages titrated up more
slowly than is the case for younger patients, ECT is frequently the most rapidly effective treatment for severe depression in this population.
It is important to remember that the antidepressant
effect of a standard course of ECT is generally temporary,
and that patients who are not started on medication at
the conclusion of their course of treatment are likely to
relapse. For a discussion of maintenance ECT, see Chapter 20.
Alternative Treatments
A variety of alternative treatments have been claimed to
benefit some patients with bipolar depression. These include
novel antidepressant combinations, stimulant medications,
dopamine agonists, the wakefulness agent modafinil, nutritional supplements (including omega-3-fatty acids), and
others. (See our review of the literature for details.) It is
appropriate here to comment on one especially important
form of alternative treatmentregular exercise (see Chapter 17). Not only has regular vigorous aerobic exercise been
shown to have an antidepressant effect in numerous studies, but when at least some exercise is done at approximately
the same time every day and not too close to the time for
Lithium
Several early reports on lithiums efficacy in treating mania
suggested that it lacked significant antidepressant effects
(Cade, 1978). Subsequent studies, however, demonstrated
its effectiveness in preventing depressive relapses in patients
with recurrent major depression (see, e.g., Baastrup and
Schou, 1967; Baastrup et al., 1970). By the early 1980s, several studies, focused on patients hospitalized for depression, had found that lithium was superior to placebo (see
Table 193, as well as the review by Zornberg and Pope,
1993). Several of these studies suggested that lithium was
more likely to be effective in patients with bipolar than
unipolar depression (especially less recurrent forms) and
that the time to therapeutic response was longer than was
typically reported for tricyclic antidepressantson the order
of 3 to as long as 8 weeks. In several double-blind studies
comparing lithium with tricyclics, lithium was found to be
as effective as amitriptyline, desipramine, and imipramine
Sample
Sizea
10
179
Carbamazepine
30
Lamotrigine
432
Olanzapine
833
Valproate
89
Imipramine
638
Desipramine
12
Flouxetine
255
Meclobemide
537
31
3,005
Drug
Lithium
Total
a
759
Findings
Moderate effect size
Small effect size
Sample
Size
Lithium
144
Valproate
27
Topiramate
36
Risperidone
22
Bupropion
99
Imipramine
191
Desipramine
15
Tranylcypromine
56
Pramipexole
43
Drug
Findings
Table 193. Lithium Treatment in Patients Hospitalized for Depression: Results of Placebo-Controlled Studies
Study
Sample
Size
Patient Characteristics
Results
10 of 13 bipolar patients showed some
response, versus only 2 of 5 noncyclic
depressed patients
Lithium trial lasted only 10 days, showed a
nonsignificant trend toward response
32 of 40 bipolar patients responded, versus
4 of 12 unipolar patients (p < .05)
6 of 6 bipolar patients responded, versus 7
of 16 unipolar patients (p < .05)
18
18
Manic-depressive
52
22
Johnson, 1974
10
23
Note: Response rates (complete and partial) for all studies combined are bipolar, 64/81 = 79%; unipolar, 20/55 = 36%.
761
Sample
Design
Results
21 bipolar
Imipramine comparison
12 bipolar and
12 unipolar
45 mixed
29 bipolar and
unipolar
Desipramine comparison
Khan, 1981
Arieli and Lepkifker,
1981
Linder et al., 1989
Total sample size
Imipramine comparison
Imipramine comparison
with elimination of initial placebo responders
30 recurrent
unipolar
33 bipolar
Amitriptyline comparison
Clomipramine comparison
22
Clomipramine comparison
276
Note: Most of these relatively small studies were underpowered to detect modest differences between active treatments.
762
Treatment
Studies Analyzed
Bauer and
Dpfmer, 1999
Bauer and
Dpfmer, 1999
(strict criteria)
Patients
Conclusions
99
Response rate of
approximately 40%
6.85 (2.2720.00)
234
3.89 (2.147.08)
110
3.31 (1.467.53)
CI = confidence interval.
Anticonvulsants
Reports of the antidepressant effects of anticonvulsant medications have appeared in the clinical literature for several
decades, resulting in the incorporation of these agents into
several algorithms for the treatment of bipolar disorder, including bipolar depression. Unfortunately, however, there
have been few controlled studies of the use of anticonvulsants as antidepressants to inform their use in depressed
bipolar patients. An exception is a growing literature on the
antidepressant uses of lamotrigine, an agent that appears to
be effective in treating bipolar depression.
Valproate
Results of case reports and open studies suggest that valproate has antidepressant properties in some patients.20
An open study of 33 unipolar depressed outpatients (some
of whom had not responded to previous antidepressant
treatment) found a 54 percent response rate (Davis et al.,
1996). However, in a review of four open studies of 195
acutely depressed patients with bipolar (-I or -II not designated) or schizoaffective diagnoses, only 30 percent had
an antidepressant response to valproate (McElroy and
Keck, 1993). With regard to the three controlled studies of
the efficacy of valproate as an antidepressant, the results
are modest. In one study, Sachs and colleagues (2004)
found a 45 percent response rate for valproate compared
with 27 percent for placebo, but with only 45 subjects, this
difference failed to reach statistical significance (p < .3).21
On the other hand, a relatively small 8-week study of
25 outpatients by Davis and colleagues (2005) was able to
show a 43 percent decrease in HAM-D scores with valproate compared with 27 percent with placebo, which was
statistically significant in a random regression analysis.
As might be expected with a gamma-aminobutyric acid
(GABA)ergic anticonvulsant, the effect on anxiety was
greater than that on depression. Finally, in a recent randomized double-blind study of 19 bipolar depressed patients (mostly type I) (Dunn et al., 2006), valproate was
found to be superior to placebo. Analysis of individual
MADRS items, the primary outcome, demonstrated some
benefit in treating core mood symptoms. The effect size in
this study was larger than that in the previous studies.
With regard to bipolar-II depression, there has been
one small open study of valproate in 11 medication-nave
patients, 82 percent of whom responded (as measured by
a 50 percent decrease in HAM-D scores) (Winsberg et al.,
2001). As in Sachs and colleagues (2004) study, the effect
of valproate nearly reached statistical significance among
the bipolar-II subgroup. In a recent review of the literature,
Bowden, the investigator associated most prominently with
the evaluation of valproate in treating bipolar disorder,
and his colleagues (2006) concluded that the acute effectiveness of valproate in depression is modest. It has been
suggested that response to valproate may be predicted by
failure to respond to lithium and vice versa. That is, lithiumresponsive and valproate-responsive depressed patients may
represent distinct clinical subgroups (Bowden et al., 1994;
Ghaemi and Goodwin, 2001b).
There are even fewer controlled data on the commonly
used strategy of combining valproate and lithium. A
double-blind study of 27 patients with bipolar-I or -II disorder who had experienced major depression while taking
763
either lithium or valproate compared the antidepressant response to the SSRI paroxetine with that to a second mood
stabilizer (valproate was added if the patient had become
depressed on lithium, and vice versa). Significant and comparable improvement in depression scores was seen among
the SSRI and adjunctive mood stabilizer groups after 6
weeks of treatment (Young et al., 2000). These results can
be interpreted as supporting the suggestion that, with respect to lithium and valproate, patients who do not respond to one will benefit from the other; the results may
also suggest a synergistic effect of the two agents. It should
be noted that in this study, more patients in the mood
stabilizer group than in the SSRI group developed drug
intolerance, perhaps reflecting the side-effect burden when
full doses of these agents are used simultaneously.22 We
await a controlled study of drug combinations in which
less-than-full doses of each drug are used. Such a study
would provide a more accurate test of both clinical practice and the laboratory-based conclusion that lithium and
valproate (and perhaps other anticonvulsants) can act
synergistically.
Lamotrigine
Lamotrigine differs from the GABAergic anticonvulsants
(carbamazepine and valproate) by virtue of its modulating
effects on glutaminergic transmission, which appear to contribute to its activating profile. Antidepressant efficacy was
reported in the early 1990s in case reports and small open
case series.23
There have been three positive randomized, placebocontrolled trials of lamotrigine monotherapytwo with a
764
Treatment
Riluzole
This drug is related to lamotrigine by virtue of its effects
on glutamatergic transmission; it is FDA-approved for the
treatment of amyotrophic lateral sclerosis. In an 8-week
open-label study of riluzole in 14 treatment-resistant bipolar
depressed patients, Zarate and colleagues (2005) found significant antidepressant effects across a wide range of items
on the MADRS. There were no switches into hypomania or
Topiramate
Interest in the possibility that the novel anticonvulsant
topirimate may provide some benefit in bipolar depression has been heightened by its ability to reduce weight.
Several case reports and open studies in fact do suggest
that the drug may have some effect in treating bipolar depression, especially in the 100200 milligrams per deciliter
(mg/dl) range (Marcotte, 1998; Ghaemi et al., 2001). In an
open trial, topiramate was given to 45 bipolar-I and 18
bipolar-II patients who were suffering from a major depressive episode and had not benefited from or were intolerant of two mood stabilizers. Although nearly a third
of these patients dropped out of the study because of side
effects or lack of efficacy, 42 percent had an essentially
complete antidepressant response within 4 weeks (HAMD scores below 7), and another 27 percent had a partial
antidepressant response (HAM-D scores between 8 and
12) (Hussain and Chaudhry, 1999).
McIntyre and colleagues (2002) found that topiramate
compared favorably with bupropion as an adjunctive
treatment in depressed bipolar-I and -II patients who had
not improved despite 2 weeks of treatment with either
lithium (13 patients) or valproate (23 patients). In this
randomized, single-blind study (blind rater), the addition
of either topiramate or bupropion resulted in a reduction
in HAM-D scores of at least 50 percent in about half of the
patients, and about a quarter of both groups had scores
below 7.27 As is typically the case with new agents, an assessment of the safety and efficacy of topiramate must rely
on sometimes conflicting case reports and small open
studies in complex, often treatment-refractory patients
who are frequently taking other medications as well. Although results thus far are encouraging, further research
and clinical experience will be required before the role of
this agent in the treatment of bipolar depression becomes
clear.
Other Anticonvulsants
Data on the efficacy of other anticonvulsants in treating
bipolar depression are quite preliminary. To our knowledge there has been only one double-blind, randomized
clinical trial involving gabapentin as monotherapy, and it
had negative results.28 Gabapentin has, however, been reported to be useful as an adjunctive agent (primarily for its
765
Antidepressants
Tricyclics and Monoamine Oxidase Inhibitors
The existing literature on the efficacy of tricyclic antidepressants is dominated by studies in patients with unipolar
depression. The consensus of this literature is quite clear:
tricyclics have been more effective than placebo in more
than two-thirds of controlled trials, with an overall efficacy rate in the treatment of major depression ranging from
50 to 85 percent and averaging 65 to 70 percent. The data
766
Treatment
Second-Generation Antidepressants
Selective Serotonin Reuptake Inhibitors. As is true of the
tricyclics, SSRIs have clearly been shown to be effective
in the acute treatment of unipolar depression. However,
this general conclusion may be more applicable to the
mainstream unipolar depressed patient without frequent
recurrences. Thus it is interesting that in the recent
report from the real-world NIMH Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) trial of
the antidepressant citalopram, only 28 percent of patients
with fairly recurrent forms of unipolar depression (average
of six prior episodes) achieved remission (Trivedi et al.,
2006).
Compared with unipolar depression in general, data on
767
the efficacy of SSRIs in the acute treatment of bipolar depression are more limited (see Table 196). Kupfer and colleagues (2001) conducted an 8-week open study of citalopram added to lithium, valproate, carbamazepine, or a
combination of these agents in 33 patients with bipolar-I or
-II depression. They found that 64 percent experienced a
reduction in depressive symptoms (Kupfer et al., 2001).35
The largest controlled study of the acute antidepressant
effect of an SSRI in bipolar disorder, noted above in our
discussion of tricyclics, involved comparing fluoxetine
plus olanzapine with olanzapine alone; there was no
fluoxetine-alone group. While there is no question that this
combination is effectiveindeed, it was given an FDA indication for the treatment of bipolar depressionone cannot use these results to assess the efficacy of SSRIs themselves in treating bipolar depression.
A 6-week double-blind study of 89 patients with bipolar
depression (-I or -II not specified) found response rates for
fluoxetine, imipramine, and placebo of 86 percent, 57 percent, and 38 percent, respectively (Cohn et al., 1989). The results are difficult to interpret, however, because about half
of the study participants were also taking lithium, and a
disproportionate number of those patients were in the
fluoxetine group.36 In the largest and best-designed study
comparing the efficacy of paroxetine and imipramine in
bipolar depressed patients (mentioned previously), Nemeroff and colleagues (2001) compared each antidepressant
with placebo over 10 weeks under double-blind conditions
in 117 patients who were also taking lithium (some were taking valproate or carbamazepine as well). No significant differences in efficacy among the three groups were found. In a
post hoc analysis, the groups were stratified according to
their lithium levels. It was found that imipramine and
paroxetine were superior to placebo (and equivalent to each
other), but only in patients with lower lithium levels (less
than .8 mEq/l). Thus lithium was as effective as the two antidepressants when given at doses that achieved levels of
.8 mEq/l or greater.
There has been considerable interest in using secondgeneration antidepressants to treat bipolar-II depression
(see Box 192). Several studies of SSRI monotherapy for
this indication are available. In a post hoc analysis of
pooled data from randomized clinical trials involving patients with unipolar depression (in which some bipolar-II
patients were included), Amsterdam and colleagues (1998)
noted that the efficacy of fluoxetine in 89 bipolar-II patients was comparable to its efficacy in matched and unmatched unipolar depressed patients.
Bupropion. This drug, which enhances both noradrenergic and dopaminergic transmission through different
mechanisms, may have unique advantages in the treatment
768
Treatment
Table 196. Studies of Selective Serotonin Reuptake Inhibitors in Treating Bipolar Depression
Study
Sample
Design
Results
89 bipolar (-I or
-II not specified)
Simpson and
DePaulo, 1991
16 bipolar-II
11 bipolar-I,
16 bipolar-II
30 bipolar-I,
15 bipolar-II
Nemeroff et al.,
2001
Ghaemi et al.,
2004
78 patients (41
bipolar, 37 unipolar); 63% of bipolar patients were
bipolar-I
Note: In evaluating this literature, it is important to be aware of the observation by Sachs and colleagues (2003) that there is no systematic method
for correcting for improved depression scores that occur as part of a switch into mania. For example, about a quarter of the impressive response rates
reported in some studies of tranylcypromine and imipramine monotherapy represent subjects who became manic during the study.
Source: Adapted from Ghaemi and Hsu, 2005.
769
770
Treatment
70
60
50
Bupropion
Sertraline
Venlafaxine
40
30
20
10
0
Response
Remission
Manic Switch
Remission and
No Switch
Figure 192. Outcomes for patients taking bupropion, sertraline, and venlafaxine. Note: Response
and remission rates based on Inventory of Depressive Symptomatology (IDS) criteria only; mania
switch and remission/no switch rates based on Young Mania Rating Scale or Clinical Global Impressions-Bipolar criteria. (Source: Post et al., 2006. Reproduced with permission.)
may be more like tricyclics, with a less favorable ratio of responses to switches compared with other second-generation
antidepressants, especially bupropion.
Results of several open studies of the use of nefazodone
in treating bipolar depression have not been encouraging.
El-Mallakh (1999) found only transient improvement over
a period of 8 weeks in 5 outpatients who took nefazodone
with other medications. In another open trial, Goldberg
and colleagues (2002) noted that about two-thirds of 13
patients who took nefazodone in addition to lithium, anticonvulsants, and antipsychotics had a 50 percent reduction in HAM-D scores during the course of the study, but
that half of these patients experienced some relapse of depressive symptoms by the eighth week.
The new SNRI duloxetine was approved by the FDA for
the treatment of major depression in 2004 on the basis of
several large placebo-controlled trials involving more than
1,400 patients (Detke et al., 2002; Goldstein et al., 2002; Nemeroff et al., 2002). To our knowledge, studies of this agent
focused on bipolar depression have not yet been published.
Selective Noradrenergic Reuptake Inhibitors. Reboxetine
is a norepinephrine reuptake inhibitor with a structure
distinct from that of the tricyclics. Although it is comparable in norepinephrine reuptake inhibition potency to the
tricyclics, its selectivity for noradrenergic reuptake inhibition can be compared with that of the SSRIs in inhibiting
serotonin reuptake. Reboxetine has thus been referred to
as the first selective norepinephrine reuptake inhibitor, and
a history of treatment-resistant depression (30 versus 15 percent). Approaching this relationship from a different direction, Hantouche and colleagues (2005) evaluated the lifetime treatment history of 256 patients diagnosed as having
unipolar major depression and found that those whose antidepressant had been augmented by a mood stabilizer
(implying antidepressant resistance) had higher scores
on a hypomania checklist and were more likely to have
cyclothymic temperaments. However, not all studies have
found a relationship between bipolar features and antidepressant resistance in unipolar patients (personal communication, D.J. Smith, October 14, 2005, University of
Edinburgh).
Figure 193. Switch rate of hospitalized depressed patients (unipolar or bipolar). Note: Only one episode per patient was considered.
(Source: Angst, 1985.)
10
9
% Switches into Mania
their bipolar-I patients given a second-generation antidepressant in addition to a mood stabilizer were much or
very much improved (as measured by the CGI scale),
only 19 percent were able to complete the intended 1 year of
continued antidepressant use. In a similar vein, Sachs and
colleagues (2003) reported preliminary outcomes for the
first 1,000 subjects enrolled in the NIMH STEP-BD program. During the first year of follow-up, 181 subjects experienced the new onset of at least one episode of major depression, and 50 of these patients experienced multiple
depressive episodes38; no statistically significant advantage
was associated with the adjunctive use of second-generation
antidepressants.39 Finally, a recent randomized study within
the NIMH STEP-BD program (mentioned briefly in the
section on clinical management) evaluated 69 bipolar patients who had recovered from a depressive episode on a
combination of a second-generation antidepressant and a
mood stabilizer (Ghaemi et al., 2006). After being stable for
2 months, the patients were openly randomized to continue
with the combined treatment or the mood stabilizer alone
(that is, antidepressants were tapered and discontinued);
after adjusting for other clinical variables,40 antidepressant
continuation did not result in lower overall mood morbidity at 1-year follow-up compared with mood stabilizer
alone.41 Note that these results are quite different from those
of the three nonrandomized studies reviewed in the section
on clinical management that have, unfortunately, been interpreted by some as indicating that bipolar patients who
have responded acutely to antidepressants should be continued on them. Clearly only a minority of bipolar patients do
well when kept on antidepressants plus mood stabilizers,
but the results of observational studies do not provide
clinicians with a basis for judging which of their patients
might be expected to do so.
The reader will note that scattered throughout our review
of the literature are studies of the effectiveness of various
agents in treatment-resistant depression. The importance
of such studies is underscored by evidence that resistance to
standard antidepressants is one of the characteristics that
may make the condition of a given patient more likely to be
part of the bipolar spectrum (see Chapter 1). For example,
Sharma and colleagues (2005) studied 61 patients with major
depression who had failed to respond to two adequate antidepressant trials, two-thirds of whom had initially been diagnosed as unipolar. Upon careful diagnostic reevaluation
in the course of 1-year follow-up, only 21 percent were still
diagnosed as unipolar, with 79 percent now meeting criteria
for bipolar disorder, primarily bipolar-II. Rybakowski and
colleagues (2005) reported on a cohort of 447 unipolar
depressed patients, 106 of whom met criteria for bipolar
spectrum disorder; those with bipolar spectrum features
were twice as likely as the pure unipolar patients to have
771
Tricyclics n = 509
ECT
n = 100
8
7
6
5
4
3
2
Spontaneous
n = 200
Neuropleptics
n = 100
1
0
1920
1930
1940
1950
Year
1960
1970
772
Treatment
Table 197. Observational Studies Since the First Edition (1990) Focused on the Emergence
of Mania/Hypomania Following Initiation of Antidepressants
Study
Sample
Study Design
Results
Altshuler et al.,
1995
38 bipolar-I, 13 bipolar-II
Benazzi, 1997
Boerlin et al.,
1998
Bottlender et al.,
1998
Ghaemi et al.,
2000
85 bipolar or unipolar
Henry et al.,
2001
31 bipolar-I, 13 bipolar-II
(95 treatment phases)
Goldberg and
Whiteside,
2002
Joffe et al.,
2002
51 bipolar-I, 18 bipolar-II
(113 trials)
(continued)
774
Treatment
Table 197. Observational Studies Since the First Edition (1990) Focused on the Emergence
of Mania/Hypomania Following Initiation of Antidepressants (continued)
Study
Sample
Study Design
Results
Post et al.,
2003
Serritti et al.,
2003
Ghaemi et al.,
2004
41 bipolar depression, 37
unipolar depression
A number of studies have addressed potential risk factors for drug-related switching. One such factor is gender.
In a randomized, double-blind, 3-year prospective comparison of lithium versus lithium plus imipramine, Quitkin
and colleagues (1981) noted 2.5 times more switches in the
combined-treatment group, but this differential was significant only among females, a finding similar to that of
Yaldez and Sachs for antidepressant-related cycling (see
below). In an observational study, by contrast, Goldberg
and Whiteside (2002) found no difference in the gender
ratio of bipolar patients who switched on antidepressants
versus those who did not.
Another factor examined is episode sequence. Koukopoulos and colleagues (1980) noted that the episode sequence
maniadepressioninterval (MDI) was less likely to be associated with switching than the depressionmaniainterval
(DMI) sequence, a conclusion presumably related to his observation that the MDI pattern was associated with longer,
Medication
Sample
Size
Study
Duration
Mean Dose
Switch
Rate
Comments
Cohn et al.,
1989 (95)
Fluoxetine
Imipramine
Placebo
30
30
29
36 weeks
36 weeks
36 weeks
62 mg/day
62 mg/day
N/A
0.0%
7.0%
3.0%
Himmelhoch et al.,
1991 (71)
Tranylcypromine
Imipramine
16
16
6 weeks
6 weeks
37 mg/day
246 mg/day
21.0%
25.0%
No concomitant mood
stabilizers used
Thase et al.,
1992 (91)
Tranylcypromine
Imipramine
12
4
412 weeks
412 weeks
39 mg/day
246 mg/day
17.0%
25.0%
Double-blind crossover of
study of nonresponders from
a prior tranylcypromine study
Sachs et al.,
1994 (75)
Bupropion
Desipramine
9
10
8-week acute
1-year
continuation
358 mg/day
140 mg/day
11.0%
50%
Young et al.,
2000 (78)
Paroxetine
Lithium or
valproate
11
16
6 weeks
6 weeks
36 mg/day
Lithium
1,300 mg/day
Valproate
1,200 mg/day
0.0%
6.3%
Nemeroff et al.,
2001 (77)
Paroxetine
Imipramine
Placebo
35
39
43
10 weeks
10 weeks
10 weeks
33 mg/day
167 mg/day
N/A
0.0%
7.7%
2.3%
Silverstone,
2001(81)
Moclobemide
Imipramine
78
78
8 weeks
8 weeks
450750 mg/day
150250 mg/day
3.7%
11.0%
Vieta et al.,
2002 (92)
Paroxetine
Venlafaxine
30
30
6 weeks
6 weeks
32 mg/day
79 mg/day
3.0%
13.0%
Open-label randomized;
paroxetine and venlafaxine
both effective and safe in
treatment of depressive breakthrough episodes in bipolar
disorder; there was a suggestion
of a slightly higher risk for
switch to mania or hypomania
with venlafaxine
776
Treatment
Medication
Sample
Size
Study
Duration
Mean
Dose
Fogelson et al.,
1992 (65)
Bupropion
Baldassano et al.,
1995 (64)
11
6 weeks
286 mg/day
54.5
Paroxetine
20
8 weeks
23 mg/day
5.9
1 patient on lithium +
carbamazepine developed
hypomania
Kupfer et al.,
2001 (93,94)
Citalopram
45
8-week acute,
then 16-week
continuation
34.5 mg/day
6.7
Erfurth et al.,
2002 (90)
Bupropion
13
4 weeks
286 mg/day
0.0
more stable depressions. More recently, Serretti and colleagues (2003) conducted a retrospective casecontrol
study of 169 bipolar patients who switched while taking
an antidepressant versus 247 who did not (matched for
age and gender); they also found switches more likely
with the DMI pattern. On the other hand, MacQueen and
colleagues (2002) presented detailed life-chart data for 42
bipolar depressed patients indicating that those whose
depression was preceded by a manic/hypomanic episode
(presumably the MDI pattern) were more likely to have an
antidepressant-related switch than those whose depression
was preceded by a period of euthymia. Given the design and
size of these studies, it appears fair to conclude that the
weight of the literature suggests switching is more likely to
be associated with the DMI pattern. A third factor studied is
comorbid substance abuse. Goldberg and Whiteside (2002)
found that switch risk was associated with a history of substance abuse and/or multiple previous antidepressant exposures.
What about the relative risk in bipolar-I versus bipolarII? By far the majority of the data on switching has come
from studies of bipolar-I patients, although some of the
studies reviewed above included both bipolar-I and -II patients. Two studies (Joffe et al., 2002; Serretti et al., 2003)
noted more switching in bipolar-I than in bipolar-II, while
two found no difference (Henry and Demotes-Mainard,
2003; Bauer et al., 2005). The resolution of this question has
been advanced considerably by two sets of data from the
Switch
Rate (%)
Comments
Stanley Networkone concerning acute treatment (Altshuler et al., 2006) and the other focused on long-term
follow-up (Leverich et al., 2004). Both reveal that, compared
with bipolar-I patients, those with bipolar-II have a lower
switch rate, and when they do switch, it is into hypomania.
Finally, as might be expected, Sato and colleagues (2004)
found that bipolar patients with depressive mixed states
(see Chapters 1 and 2) are more likely to switch when antidepressants are added to mood stabilizers than are bipolar
patients with pure depression. Related findings come from
an analysis of the NIMH STEP-BD database (Goldberg et
al., 2004), which found that among bipolar patients with
depressive mixed states, antidepressants worsened manic
symptoms without improving depressive ones. In a recent
comparison of switchers and nonswitchers among bipolar
patients on antidepressants in the Stanley Network, Frye and
colleagues (2006) found three specific manic-like symptoms
during depression that were associated with a switchmore
motor activity, more talkative, and showing new interests;
increased sexual activity just missed significance. The results
of these last three studies are important for the clinician to
keep in mind because such depressive mixed states are often confused with agitated depression; the specificity of the
individual symptom predictors in Frye and colleagues study
should prove especially useful to the clinician.
Do antidepressant-related switches differ from spontaneous ones? In a prospective study of consecutive admissions, Tamada and colleagues (2004) compared 12 patients
on mood stabilizers who switched within 12 weeks of starting an antidepressant and 12 patients with spontaneous mania. Those who switched while taking an antidepressant had
been ill longer with more previous episodes, had a higher
prevalence of subclinical hypothyroidism, and had a history of more previous antidepressant-related switches. In
the largest observational study comparing spontaneous
and antidepressant-related switches, Akiskal and colleagues
(2003) evaluated 493 consecutive patients with DSM-IV
major depression (196 were bipolar-II or bipolar-NOS;
bipolar-I patients were excluded). Spontaneous hypomania was experienced by 29 percent of the entire cohort; an
additional 10.5 percent were hypomanic only while on antidepressants. The latter group had experienced significantly
more psychotic features, greater suicide risk, a more chronic
course with more previous hospitalizations, and more previous treatment with mood stabilizers, and were less responsive to lithium. Finally, in an interesting retrospective
casecontrol study of 56 bipolar depressed patients on an
antidepressant, Mundo and colleagues (2001) found that
those with the short allele of the promoter region of the serotonin transporter gene experienced twice as many switches
as those without that allele.49
In summary, the most consistently reported predictors
of antidepressant-related switching among patients with
bipolar-I disorder are a history of multiple acute episodes
(particularly those with a course characterized by the DMI
sequence), exposure to multiple antidepressant trials, a
history of previous antidepressant-related switches, a history of substance abuse, and isolated manic-like symptoms (depressive mixed states). Risk among patients
with bipolar-II disorder is also associated with substance
abuse and perhaps with psychotic features, but appears to
differ from bipolar-I risk by its association with a more
chronic course. In light of the two recent Stanley Network
studies, it now appears likely that the relative risk is greater
in bipolar-I than in bipolar-II, but more data are needed to
settle this point, particularly with respect to long-term
destabilization. For comprehensive reviews of clinical and
demographic predictors of antidepressant-related switching, see Goldberg and Truman (2003) and Visser and Van
der Mast (2005).
Related to switching is the phenomenon of conversion
from a unipolar to a bipolar diagnosis, which bears on the
question of which patients with unipolar depression might
be vulnerable to an antidepressant-related switch. Examining the relationship between the likelihood of such a
conversion and premorbid personality characteristics,
Akiskal and colleagues (1995) followed 559 patients with major depressive disorders for up to 11 years.50 They reported a
temperamental triad of mood lability, energy/activity,
777
778
Treatment
to identify episodes of rapid cycling that are temporally related to initiation of the antidepressant. A large observational study of patients with bipolar disorder conducted
by Coryell and colleagues (1992) found no association between periods of antidepressant use and rapid cycling. In
this study, 919 patients were followed for at least 1 and up
to 5 years, with semiannual evaluations; patients treatment
was monitored but not controlled by the study. Nearly 1 in
5 patients experienced a period of rapid cycling; after controlling statistically for episodes of major depression, the
authors found that treatment with tricyclics or MAOIs did
not seem to anticipate rapid cycling (p. 129). Rather, the
authors suggested that an episode of major depression
heralding a period of rapid cycling is a feature of the natural
history of the illness, and that any association between antidepressant treatment and rapid cycling is thus an epiphenomenon. However, this conclusion appears to be overstated
since the patients were not randomized to receive or not receive antidepressants, and it is impossible to know why clinicians chose to use or not use the drugs for some patients
or at certain times.
In the first edition we made a similar point about the influential study of Lewis and Winokur (1982), who opened the
debate when they reported no increase in switching or cycling among a group of bipolar patients receiving acute and
continuation treatment with tricyclics chosen by the physician. The interpretation of their finding is quite problematic,
however, in view of the high switch rate among the untreated
controls (41 percent) and the variety of uncontrolled factors
that could lead to such a high rate among patients whose
779
Study
Wehr and
Goodwin,
1979a
Quitkin et al.,
1981
Wehr et al.,
1988
Sample
Size
Mean Duration
of Follow-up
(Months)
Treatments
Results
4 times more rapid cycling in lithium
+ desipramine treatment vs.
lithium + placebo treatment alone
2.4 times more manic episodes in
lithium + imipramine group vs.
lithium + placebo group
33% higher rapid-cycling rate with
lithium + tricyclics vs.
lithium + placebo
27
75
19
51
59
Note: Long-term mood destabilization in these studies is limited to cycle acceleration, defined as two or more DSM-IV affective episodes during
antidepressant treatment versus similar exposure times immediately before antidepressant treatment. The Quitkin and colleagues (1981) finding was
a post hoc finding. Other randomized controlled trials with tricyclics failed to find evidence of worsened course in post hoc analyses. The Wehr and
Goodwin (1979) and Wehr and colleagues (1988) studies were the only studies designed to assess prospectively the issue of antidepressant-induced
mood destabilization, and they both found evidence for this association.
Source: Ghaemi et al., 2003b. Reprinted with permission.
780
Treatment
Figure 194. Inability of mood stabilizer to prevent antidepressantrelated cycling during a 3-year randomized double-blind prospective
study. Note: Average relapse time was 719 months, reflecting cycle
induction rather than acute switching. (Source: Quitkin et al., 1981.)
30
25
Depressive Relapse
Manic Relapse
20
% 15
10
5
0
Lithium + Placebo
Lithium + Imipramine
Antipsychotics
Prior to the introduction of the newer atypical antipsychotic agents, the literature on the use of antipsychotic
medications in the depressed phase of bipolar disorder was
quite sparse. In one open study, flupenthixol decanoate
was given to 30 lithium-intolerant periodic and cyclic de-
781
782
Treatment
Evidence for the efficacy of another atypicalquetiapinein the treatment of depressive symptoms in a variety of psychotic and mood disorders (including bipolar
disorder, rapid-cycling bipolar disorder, and adolescent
mania) has been reported in several open-label studies.57
More recently, two large randomized, placebo-controlled
trials revealed robust antidepressant effects for quetiapine
in bipolar patients. These 8-week multisite studies involved
a total of 506 bipolar depressed patients (339 on quetiapine and 167 on placebo; two-thirds bipolar-I, one-third
bipolar-II) (Calebrese et al., 2005). The first study found
a 58 percent response rate (greater than 50 percent decrease in MADRS scores) compared with 36 percent for
placebo; the rate for remission (decline in MADRS scores
of less than 12) was 53 percent for quetiapine versus 28 percent for placebo. The core depressive items on the MADRS
scale58 showed significant separation from placebo (p <.001).
Onset of action was rapid, with separation from placebo at
the end of week 1; both doses of quetiapine300 and
600 mg were roughly equivalent in efficacy, but side effects (dry mouth, sedation/somnolence, dizziness, constipation) were more common at the higher dose. The effect
size with the 300 mg dose was equivalent to that achieved
with the olanzapinefluoxetine combination (OFC), and
at 600 mg it exceeded the latter results. However, the
magnitude of the quetiapine effect was substantially reduced when the items related to insomnia and anxiety
were removed from the analysis. Similar results were obtained in the replication study (Hirschfeld et al., 2006),
and the FDA has now approved quetiapine for the treatment of bipolar depression.
It is important to note that studies of DSM-IV-defined
bipolar depression (such as the above quetiapine studies)
can include patients with up to three manic-like symptoms (because of the strict DSM-IV definition for a mixed
episode, that is, meeting full criteria for both mania and
depression). Whether these depressive mixed-state patients may respond preferentially to antipsychotics has not
yet been reported, but the possibility should be assessed.
Most formal studies of antipsychotics in mixed states per
se use the DSM-IV criteria and therefore involve dysphoric
mania rather than depressive mixed episodes, but such
data may still have relevance to the evaluation of these
agents as possible antidepressants. For example, GonzalezPinto and colleagues (2001) compared two groups of patients with dysphoric mania, all of whom were treated with
either valproate or lithium but also took either typical antipsychotics (haloperidol and/or levomepromazine) or an
atypical (olanzapine). Patients treated with the adjunctive
atypical had statistically significant reductions in HAM-D
scores (as well as Young Mania Rating Scale scores) compared with those who took the typical antipsychotic.
Electroconvulsive Therapy
There is an extensive literature on the use of ECT in the
treatment of major depression (see Fink, 2001, for a review,
and Abrams, 1997, for a comprehensive discussion). Approximately 50 years after the introduction of ECT, Janicak
and colleagues (1985) conducted a careful meta-analysis of
25 studies selected for their rigorous methodology, which
together included more than 1,200 patients. These studies
variously compared ECT with simulated ECT, placebo, tricyclics, and MAOIs and found indisputable evidence of the
superiority of ECT over all these other treatments for severe depression. Most of these studies included patients
with both unipolar and bipolar illness. This conclusion was
reinforced by the most recent and most extensive metaanalysis comparing ECT with pharmacotherapy, conducted
by the UK ECT Review Group (2003). Examining 18 trials
(1,144 patients), they found that ECT was significantly better than antidepressant medication. As noted earlier, ECT
has been shown to be a safe and especially effective treatment for elderly patients, including the very elderly (Salzman et al., 2002); it has also proven to be safe in pregnant
patients (Miller, 1994) and even those with intracranial
mass lesions (Zwil et al., 1990). Indeed, one can find reports of ECT having been administered to patients safely
and successfully regardless of almost any imaginable medical or psychiatric complication.
There is a modest amount of data on the use of ECT
specifically to treat bipolar depressed patients. Zornberg
and Pope (1993) reviewed nine studies of the use of ECT in
723 such patients. Of the seven trials comparing ECT with
antidepressant agents, five found it be more effective. ECT
appears to be equally effective for unipolar and bipolar depressed patients. Daly and colleagues (2001) compared the
response rates and rapidity of response to ECT in 228
patients with unipolar and bipolar-I and -II depression
who were participating in three different protocols. There
was no difference in efficacy rates59 among the diagnostic
groups, although the bipolar patients who responded to
ECT needed fewer treatments than the unipolar responders.
783
784
Treatment
Psychostimulants
The use of amphetamine drugs and related compounds,
such as methylphenidate, in the treatment of symptoms of
depression has a long history. These agents have been used
alone, as well as in conjunction with antidepressant and
other psychotropic agents, for several decades in the treatment of mood disorders, and a large but often rather confusing body of literature is frequently cited in support of
these uses. The verdict on stimulants as the sole agents for
treating major depression is, however, quite clear. In a review of the literature on the use of stimulants as monotherapy for the treatment of primary depressive disorders, Satel
and Nelson (1989, p. 248) concluded that these agents
demonstrated no significant advantage over placebo in
the treatment of primary depression. Nevertheless, a large
body of literature supports the use of stimulants to treat
depressive symptoms for patients with debilitating medical
conditions in which fatigue and lethargy are prominent
features, such as acquired immunodeficiency syndrome
(AIDS) (Wagner and Rabkin, 2000), as well as for those
who experience the opiate-related fatigue and somnolence
that occur in the palliative care of patients with cancer) (see
Rozans et al., 2002, for a review). Whether the improvement seen in these patients can be called an antidepressant
effect or simply the amelioration of primarily somatic depressive symptoms seen in seriously ill patients is a matter
of debate, however. The lack of significant and sustained
efficacy in patients who have more uncomplicated depression would appear to argue for the latter conclusion.
Several case reports and open series support the use of
stimulants as an augmentation strategy in patients with
major depression who have only a poor or incomplete response to antidepressant medications. Stoll and colleagues
(1996), for example, reported on five patients who cited robust symptom reduction when methylphenidate was added
to SSRI antidepressants. The literature on the use of stimulant medications in treating bipolar depression is very
limited, however, perhaps in part because of clinicians reluctance to report their experiences treating patients with
a controlled substance. A retrospective chart review of
eight adolescent bipolar patients (both bipolar-I and -II)
treated consecutively with adjunctive stimulants for comorbid attention-deficit hyperactivity disorder (ADHD)
indicated moderate symptomatic improvement and substantial functional improvement, with no evidence of
switching or abuse (Carlson et al., 2004). Still, a number of
case reports suggest that stimulants can induce manic and
hypomanic states (see Lake et al., 1983, for a review), and
this work is often cited as a reason to avoid the use of these
785
Hormonal Agents
HypothalamicPituitaryThyroid Axis
There is a substantial literature on the use of thyroid hormones in the treatment of mood disorders, as well as on
the interrelationships between mood disorders and abnormalities of the hypothalamicpituitarythyroid axis. A
higher-than-expected prevalence of clinical and subclinical hypothyroidism, elevations of circulating antithyroid
antibodies, and levels of f T4 significantly lower than those
786
Treatment
Although the importance of normal thyroid functioning for the regulation of mood appears clear, the
mechanisms by which thyroid function, dysfunction,
and manipulation affect mood are unclear, and apparent
contradictions abound. It is well known, for example, that
depression can be a symptom of both hyperthyroidism
and hypothyroidism. The administration of thyroid hormones, sometimes in supraphysiologic doses, to some depressed patients is effective in treating depression. Yet increased levels of T4 are consistently reported in association
with major depression, and a reduction of circulating T4
(free and/or total) is seen after successful treatment with
ECT, antidepressants, and bright light, as well as after cognitive psychotherapy (see Bauer et al., 1998).
Whether the addition of thyroid hormones to other treatments for depression corrects a subtle thyroid dysfunction in
some patients, sensitizes a target cortical system important to
mood regulation through manipulation of monoamine
mechanisms, or works by some other as yet unknown mechanism remains to be elucidated. (These issues are also discussed in Chapter 20.)
HypothalamicPituitaryAdrenal Axis
Abnormalities in the functioning of the hypothalamic
pituitaryadrenal (HPA) axis have been reported in association with mood disorders for several decades (see Chapter 14). Elevated plasma cortisol levels in depressed patients
were first reported in the 1950s. Subsequent investigations
have demonstrated in depressed patients elevated cortisol
levels in the urine and cerebrospinal fluid, enlarged pituitary and adrenal glands, and a loss of the normal circadian rhythm of cortisol secretion by the adrenal gland (as
demonstrated by a positive dexamethasone-suppression
test). This HPA overactivity is thought to be caused by oversecretion of corticotropin-releasing hormone (CRH) by
the hypothalamus, possibly in response to a dysfunction of
glucocorticoid receptors in patients with mood disorders.64
Chronically high levels of circulating glucocorticoids have
been implicated in the mood symptoms and cognitive impairment seen in depressed patients.
Cortisol-lowering agents have been used to treat
unipolar and bipolar depressed patients, with mixed results. Ketoconazole has been the most frequently investigated cortisol-lowering drug, but aminoglutethimide and
metyrapone have been used as well. Case reports and small
open series in unipolar and bipolar depressed patients have
shown encouraging results, with some patients experiencing
dramatic and long-lasting symptom remission (see Brown
et al., 2001, for a review). One small placebo-controlled
study found significant reductions in HAM-D scores in nine
patients with major depression (unipolar or bipolar not
specified) treated with ketoconazol monotherapy for 4
787
788
Treatment
HypothalamicPituitaryGonadal Axis
As with the other endocrine systems discussed above and
in Chapter 14, clinical research and epidemiological data
clearly indicate that the physiology of the hypothalamicpituitarygonadal (HPG) endocrine axis is important in
mood disorders. The increased prevalence of depressive
illness in women and the striking vulnerability of women
with bipolar disorder to manic episodes during the postpartum (puerperal) period are but two examples of the
probable influence of this system on mood. The mechanisms of these influences are, however, even more obscure
than in the case of other endocrine systems. HPG abnormalities in patients with mood disorders have yet to be convincingly demonstrated, in either women (for an overview see
Young and Korszun, 2002) or men (see Schweiger et al.,
1999).
There is some evidence that depressive symptoms in
women who also have low serum estrogen levels can be ameliorated by the administration of estrogen. Several open
studies have demonstrated the benefits of estrogen therapy
in women with postpartum depression. Ahokas and colleagues (2001) found that the administration of 17-estradiol
reduced MADRS scores from a mean of over 40 to 11 in 23
postpartum women who had abnormally low serum estrogen levels. The authors found similar results in 10 women
with postpartum psychosis also having abnormally low estrogen levels (Ahokas et al., 2000). Although these studies
did not include women diagnosed with bipolar disorder,
their findings may have some relevance to the treatment of
bipolar depression, given the high risk of developing mania
during this period for women with bipolar disorder.
The addition of estrogen did not improve the response of
premenopausal depressed women to imipramine in several
early studies (see, e.g., Shapira et al., 1985). Results of more
recent studies in perimenopausal and postmenopausal
women, however, support the efficacy of physiologic doses
of estrogen in treating a variety of depressive disorders. The
largest study to date was a double-blind, placebo-controlled
study conducted by Soares and colleagues (2001) in which
50 women received transdermal 17-estradiol for 12 weeks
as monotherapy for major depression, minor depression,
or dysthymia. More than 68 percent of the patients experienced remission as measured by scores of less than 10 on
the MADRS, compared with 20 percent of the patients who
received placebo.
Although there have to our knowledge been no studies
on the treatment of bipolar depressed women with estrogen
Sleep Deprivation
Since first being described in the 1970s, the antidepressant
effect of sleep deprivation has been replicated in numerous
studies involving various diagnostic groups: unipolar as
well as bipolar depression, depression with psychotic features, premenstrual dysphoria, depression associated with
dementia, and even negative symptoms of schizophrenia
(for a review see Wirz-Justice and van den Hoofdakker,
1999, and Wu and Bunney, 1990). Indeed, nearly two-thirds
of depressed patients will experience an improvement in
mood after sleep deprivation. Unfortunately, about 80 percent of such (unmedicated) patients experience a relapse
into depressed mood after their next nights sleep (Wu and
Bunney, 1990). Indeed, even a brief nap has been found to
result in relapse of depressed mood in 50 percent of patients (Wiegand et al., 1987), with morning naps being more
detrimental than those in the afternoon (Weigand et al.,
1993). Repeated sleep deprivation has been evaluated as a
stategy for maintaining the initial antidepressant effect, and
studies alternating 3 nights of total sleep deprivation (three
cycles of 36 hours of wakefulness) with 3 nights of sleep
(Benedetti et al., 1996; Barbini et al., 1998; Colombo et al.,
2000) have found some sustained benefit.
There is some evidence that patients with bipolar depression respond better than unipolar depressed patients to
sleep deprivation. In a carefully designed study, Barbini and
colleagues (1998) compared the response to sleep deprivation in patients with bipolar-I depression, bipolar-II depression, a first episode of major depression, and unipolarity
(defined as having had three or more previous major depressive episodes and no family history of bipolar disorder
789
Phototherapy
A seasonal pattern of symptoms is common among mood
disorder patients (see Chapter 16). A retrospective analysis
of the records of more than 1,500 patients with affective
disorders entering outpatient treatment in Italy found that
about 10 percent had a seasonal pattern of symptoms. Of
these patients, about half had a unipolar and half a bipolar
affective disorder, with bipolar-I diagnoses outnumbering
bipolar-II about three to two in the group (Faedda et al.,
1993). In the first edition of this text, we reviewed 11 studies
of SAD, reporting that the proportion of patients who met
criteria for bipolar disorder (-I or -II) ranged from 8 to 90
percent, a degree of variation that may reflect both regional differences in seasonal extremes and variation in diagnostic criteria. Our weighted average of the 11 studies in
the first edition (45 percent) is higher than that of the
Faedda data, as well as that of other more recent studies.
This difference may reflect some broadening of the diagnostic criteria for SAD since the syndrome was first described by Goodwins group at NIMH (Rosenthal et al.,
1984).
Since the first description of the improvement of symptoms of SAD in response to bright light (Rosenthal et al.,
1984), there have been numerous studies of phototherapy
in depressed patients. An early meta-analysis of trials involving a total of 332 patients found improvement rates of
67 percent in mildly depressed patients and 40 percent in
patients with moderate to severe depression (Terman
et al., 1989); maximum improvement was correlated with
exposure to at least 2,500 lux for 2 hours a day. Morning
light exposure appears to be more effective than evening
(Lewy et al., 1998). More recently, shorter exposure to
higher-intensity light has been demonstrated to have equal
benefit.66
While these open studies have demonstrated the benefits of monotherapy with bright light in depressed patients, the results of attempts at placebo-controlled studies
have been much more mixed, perhaps because these studies have been hampered by methodological problems. The
studies have varied in the timing and intensity of light exposure, and designing true placebo-controlled studies has
been challenging. A study comparing light exposure of
6,000 lux for 1.5 hours a day in the morning or evening
with sham negative ion generators in 96 patients with
SAD found a statistically significant difference between
morning light and the sham condition in the number of
790
Treatment
Nutritional Supplements
Various herbal preparations and other nutritional supplements reported to help individuals with mood disorders have
received extensive publicity in the lay press. Often touted
as natural and therefore supposedly superior to synthetic
pharmaceuticals, nutritional preparations have fervent
adherents and equally fervent critics (a rather striking exception is the tendency to overlook lithium as a natural substance). Frequently, neither group is well informed about the
scientific literature, or lack thereof, that supports their use.
Patients will frequently ask about nutritional supplements,
and the clinician should have some familiarity with them
and be comfortable in making suggestions regarding their
use (for an overview, see Wong et al., 1998a; Desai and Grossberg, 2003).
791
Inositol
About 1 gram/day of inositol, a precussor of the phosphatidyl
inositol second messenger system, is present in a normal
diet. There have been reports of reduced inositol in the cerebrospinal fluid (CSF) of patients with unipolar and bipolar
depression (Coupland et al., 2005), as well as in the frontal
cortex of bipolar patients (Shimon et al., 1997), and one of
the proposed mechanisms of action of mood stabilizers involves stabilization of inositol signaling. Orally administered
inositol has been shown to increase CSF levels in humans
substantially, and at doses of 620 g/day has been associated
with improvement in unipolar and bipolar depression
(Levine et al., 1995; Chengappa et al., 2000). Recently, Edens
and colleagues (2006) reported that among 17 bipolar patients allready on lithium or valproate, compared with those
on placebo, there was a trend for more subjects on inositol to
show improvement in depressive symptoms; this was the
case especially in those with high baseline levels of anger and
hostility.
S-Adenosylmethionine
S-adenosylmethionine (SAMe) is formed in the body
when methionine, one of the essential amino acids, is
activated by adenosine triphosphate (ATP) in a reaction
catalyzed by methionine adenosyltransferase. SAMe serves
as a methyl donor in numerous important transmethylation reactions, including deoxyribonucleic acid (DNA)
methylation reactions involved in gene regulation, as well
as the catalysis of proteins, phospholipids, and neurogenic amines, including norepinephrine, dopamine, and
serotonin (see Lieber and Packer, 2002, for an introduction to this compound). SAMe has been a prescription
antidepressant in some parts of Europe for several decades, where it has often been administered parenterally,
792
Treatment
CONCLUSIONS
Even though depression accounts for the preponderance
of the morbidity in bipolar disorder, research on bipolar
depression has until very recently been minimal compared
with that on the acute treatment of mania or the treatment
of unipolar depression. As an illustration of this imbalance,
one has only to note that every drug developed for the treatment of bipolar disorderwith one recent exception (lamotrigine)has been introduced as an antimanic agent.
Furthermore, we believe the tacit assumption that the antidepressant drugs developed for unipolar depression will
show the same risk/benefit ratio for bipolar depression can
now be challenged, primarily by data on switch rates and
increased cycling among patients taking antidepressants;
while such data are not yet conclusive, they are highly suggestive.
The relatively recent findings on the antidepressant effects of the anticonvulsant lamotrigine, the atypical antipsychotic quetiapine, and the combination of olanzapine
plus fluoxetine have significantly enlarged the armamentarium for dealing with bipolar depression and clearly represent good news. The bad news, however, is that even with
these agents, most patients do not achieve remission. Thus
for the majority of patients with bipolar depression, a combination of medications will still be required, a situation
that only highlights the unfortunate reality that virtually all
of the available controlled data are on monotherapy.71
NOTES
1. These new medications include the anticonvulsant lamotrigine and the atypical antipsychotic quetiapine. In addition,
the combination of olanzapine and fluoxetine, marketed as
a single pill, has been shown to be efficacious in treating
bipolar depression.
2. A rapid response to an antidepressant may presage a subsequent manic switch.
3. The mini relapses associated with drug-related recovery
from a depressive episode can be very discouraging to the
patient until they are explained as evidence that the drug is
beginning to work.
4. An excellent patient-generated mood chart with instructions on its use can be downloaded from the Web site of the
Harvard Bipolar Research Program at <http://www.manicdepressive.org/moodchart.html>, as can the mood chart of
the National Institute of Mental Health (NIMH). See the further discussion in Chapter 22.
5. In addition to the literature review that forms the second
part of this chapter, these recommendations are drawn from
Sachs et al., 2000; Grunze, et al., 2002; and Thase et al., 2003.
6. In the positive parallel-group controlled trial, the 400 mg
arm was not statistically different from the 200 mg arm, but
these represent averages.
7. The fact that topiramate has been reported to produce depressive symptoms in some patients (Physicians Desk Reference, 2006) should be kept in mind.
8. It has also been suggested that this combination may be called
for when a more rapid antidepressant response is needed, but
there are no controlled data to support this suggestion.
9. Altshuler and colleagues (2001a) found that over two-thirds
of bipolar patients treated with an antidepressant had a relapse of depression within a year of discontinuing the drug,
versus less than a third of those who continued it. The incidence of manic relapse was the same in both groups. However, treatments were not randomly assigned, and it appears
likely that the patients taken off their antidepressant were
doing poorly, including cycling. Further, of the original sample exposed to antidepressants, only 15 percent remained well
on antidepressants for up to 1 year, despite continuation. The
others either did not respond, became manic, or had other
adverse reactions. Thus it is not clear that there are grounds
for generalizing these results to more than a minority of
bipolar patients.
10. In response to a letter to the editor about potential confounds in the Altshuler et al. study, the authors noted that no
subjects with a history of rapid cycling were included among
those remaining on an antidepressant during the 1-year observational study; that is, no rapid-cycling patients remained
well on long-term antidepressants.
11. For example, Moller and Grunze (2000) cited naturalistic
data supporting antidepressant effectiveness in bipolar depression, but not similarly naturalistic data supporting the
opposite conclusion.
12. Baker and colleagues (2003) data could be interpreted as
suggesting that olanzapine was superior to placebo in preventing early relapses into mania after acute treatment of the
episode.
13. Clozapine appears to pose the highest risk of causing weight
gain, followed by olanzapine and quetiapine. There is a lower
14.
15.
16.
17.
18.
19.
20.
793
risk with risperidone and sertindole. Ziprasidone and aripiprazole do not appear to cause weight gain (McAskill et al.,
1998; Taylor and McAskill, 2000).
Common side effects include headache, eyestrain, jitteriness,
and insomnia. It has been suggested that prolonged exposure
to full-spectrum light in the absence of a mechanism to
screen out ultraviolet wavelengths (which most light boxes
have) poses a risk for the development of cataracts and skin
cancer. There have also been case reports of the induction of
manic symptoms by phototherapy (Terman and Terman,
1999).
Although there is now at least one marketed product that
employs blue light, almost all efficacy and safety studies have
used bright white light.
While it may be intuitively appealing to expect that depressed bipolar patients will respond better than unipolar
patients to lithium augmentation, this notion has never been
studied. A related questionwhether a favorable response to
lithium augmentation in bipolar patients is simply a response to lithium rather than to the combination of agents
also remains unanswered (see Austin et al., 1991; Ernst and
Goldberg, 2002).
One study examined the lithiumMAOI combination in
patients who had not responded to lithium added to other
antidepressants. In this open trial, 12 patients who had not
responded to 2 weeks of lithium augmentation of a nonMAOI antidepressant (either desipramine, bupropion, or the
experimental drug adinazolam) took the MAOI tranylcypromine with lithium instead (Price et al., 1985). All 12 patients experienced significant improvement in their depression, including two patients with bipolar-II depression who
were discharged from the hospital either much or very
much improved.
A double-blind, placebo-controlled study involving bipolar
and unipolar depressed patients found that 6 of 10 patients refractory to treatment with citalopram alone had a greater
than 50 percent reduction in HAM-D scores when lithium
was added, whereas only 2 of 14 patients taking citalopram
and placebo experienced a similar reduction in symptoms
(Baumann et al., 1996). On the other hand, Fava and colleagues (1994) randomized depressed patients refractory to
20 mg of fluoxetine to three groups: an increased dose of fluoxetine (4060 mg) and augmentation with either lithium or
desmethylimipramine (DMI); the 4060 mg fluoxetine group
did significantly better than either augmented group, leading
the authors to the conclusion that high-dose fluoxetine is the
most effective treatment for partial responders to previous
treatment.
In a study conducted by Hoencamp and colleagues (2000),
23 patients who had a less than 50 percent reduction in their
initial HAM-D scores despite 7 weeks of treatment with 225
mg/day of venlafaxine were given a dose of lithium sufficient
to maintain serum levels of .61.0 mEq/L. After 7 weeks of
this combination treatment, 35 percent of the subjects had a
HAM-D score reduction of at least 50 percent. Likewise, Walter and colleagues (1998) found that two adolescents with
major depression experienced a rapid improvement in their
symptoms when lithium was added to venlafaxine.
Some studies purporting to investigate the effect of pharmaceuticals on bipolar depression actually focused on the
reduction of depressive symptoms in patients in a mixed
794
Treatment
affective state, a common finding for a number of anticonvulsants. Unless otherwise noted, the studies of efficacy in bipolar depression detailed here involved patients without mixed
symptoms.
21. Given that there were only 45 subjects, this failure to find a
difference between valproate and placebo may well reflect
a type II error (false negative); such data might be analyzed
more meaningfully by using odds ratios with confidence intervals, as suggested by Ghaemi and Hsu (in press). In this
study, response to valproate occurred 50 percent more often
than response to placebo.
22. Given the evidence suggesting that lithium and valproate
(and perhaps other anticonvulsants) may act synergistically
on postsynaptic signal transduction, studies of these agents
used simultaneously at less than full doses are needed.
23. Kusumakar and Yatham, 1997; Sporn and Sachs, 1997; Calabrese et al., 1999a; Suppes et al., 1999.
24. Patients were randomly assigned to receive one of the three
treatmentslamotrigine, risperidone, or inositol. Since many
patients had previously taken at least one of these three
medications, they could be randomized to two of the three
or only one of two, a strategy referred to as equipoise randomization.
25. See our later discussion of the possibility of underestimating
the risk of manic switches when examining data from controlled studies.
26. In an analysis of all controlled studies to date (Ghaemi, personal communication, 2006), the combined frequency of
mania, hypomania, or mixed states was 3.7 for lamotriginetreated patients versus 2.5 for placebo (risk ratio 1.45; 95 percent confidence interval [CI] .623.41). To properly evaluate
whether this 45 percent difference is real would require a
sample size of over 1,000, nearly three times the sample available from the controlled studies. For further discussion of
this point, see Chapter 17.
27. On the other hand, Klufas and Thompson (2001) reported on
three patients with bipolar disorder taking a variety of other
medications who became profoundly depressed shortly after
being prescribed topiramate for mild symptoms of irritability, agitation, or depression, a state that remitted within days
of discontinuation of the drug. It should also be noted that induction of mania has been reported with topiramate (Schlatter et al., 2001).
28. As noted above, Frye and colleagues (2000) compared
gabapentin monotherapy with lamotrigine monotherapy
and placebo in 31 patients suffering from refractory bipolar
depression (11 bipolar-I and 14 bipolar-II) or unipolar depression (6 patients) using a crossover design. Gabapentin
was no more effective than placebo in treating either manic
or depressive symptoms.
29. See, for example, Young et al., 1997; Ghaemi et al., 1998; Altshuler et al., 1999; Ghaemi and Goodwin, 2001a.
30. Patients with sensitivity to sulfa compounds should probably
not take zonisamide.
31. Of the 8 subjects who completed the 8-week study, 5 had a
greater than 50 percent reduction in HAM-D scores and were
much improved on the Clinical Global Impressions of Improvement (CGI-I) scale.
32. The conclusion of Ghaemi and colleagues is consistent with
results of an earlier retrospective chart review that found no
difference in the length of the depressive episode among
bipolar patients on mood stabilizers and those on mood stabilizers plus antidepressants (Frankle et al., 2002).
33. Fifty-nine percent of those treated with moclobemide were
on lithium or an anticonvulsant, compared with 64 percent
of those treated with imipramine.
34. Several selective reversible MAO-A inhibitors have been reported to be effective in studies on depression. None are
available in the United States. Brofaromine is discussed by
Waldmeier (1993) and moclobemide by Waldmeier (1993)
and Kennedy (1997).
35. The open design of the Kupfer et al. study was intended to
minimize barriers to enrollment in treatment studies: the use
of placebo and the need to accept randomization. Surprisingly, however, not only did the study fall far short of its recruitment target, but only 21 of the 45 (47 percent) enrolled
subjects met the acute response criteria, and only 31.1 percent
achieved sustained remission.
36. Another problem with the study by Cohn and colleagues
(1989) was that the imipramine group was titrated up to a
target dose of 300 mg, which induced many dropouts due to
intolerance, distorting the efficacy comparison with the more
tolerable fluoxetine.
37. Three patients who had no response to one agent after 8
weeks made a blind switch to the other agent, for a total of 19
acute treatment trials (10 bupropion and 9 desipramine). No
attempt was made to classify the patients as bipolar-I or -II.
38. A standardized clinical monitoring form is used in STEP-BD
to collect prospective assessments of symptom severity and
assigns a clinical status based on DSM-IV criteria at every
follow-up visit.
39. A subsequent report on 349 bipolar depressed patients with
concomitant manic or hypomanic symptoms (mixed-state
patients) from the STEP-BD program (Goldberg et al., 2004)
noted that, while time to recovery was not altered by the addition of an antidepressant to a mood stabilizer, those with
a higher level of manic symptoms at baseline experienced
more severe manic symptoms later when on the antidepressantmood stabilizer combination.
40. Patient expectations were one of the variables included in the
regression analysis because the study was not blinded.
41. Also, it appeared that antidepressant continuation led to
more rapid relapse into a full mood episode, although less
frequently a depressive one.
42. Angst actually concluded in this later paper that his data did
not support treatment-induced switching. He suggested that
the apparent increase in switching since the introduction of
medical treatments for depression was due to an increase in
the diagnosis of bipolar disorder in the later decades of the
study.
43. A comprehensive listing of references on agents reported to
induce manic states, dating from the 1960s through the mid1990s, can be found in Moller and Grunze (2000).
44. See the studies of Fogelson et al. (1992), Sachs et al. (1994),
Amsterdam and Garcia-Espana (2000), Goren and Levin
(2000), Nemeroff et al. (2001), Vieta et al. (2001), Erfurth et al.
(2002), and Peet (2004).
45. For example, Stoll and colleagues (1994) retrospectively
matched the charts of 49 patients who met their criteria for
an antidepressant-related switch to 49 patients with spontaneous mania and reported that the antidepressant-related
episodes were shorter and less severe.
46. For example, studies of outpatients that do not include family members as sources of information will certainly underestimate the occurrences of mania/hypomania.
47. See, for example, Prien (1984), Bottlender et al. (1998), Serretti
et al. (2003), and Mundo et al. (2006); not all studies agree,
however (see, for example, Goldberg and Whiteside, 2002).
48. In this meta-analysis, however, important issues of heterogeneity were not explored. In two studies comparing use of an
antidepressant without a mood stabilizer and no treatment
(placebo only), no mania was observed in any patientsan
oddity, if true, since it would suggest that even spontaneous
mania did not occur while those patients were studied or that
perhaps manic symptoms were not adequately assessed. Another study preferentially prescribed lithium more in the antidepressant group (Cohn et al., 1989), providing possibly
unequal protection against mania. While the olanzapine/
fluoxetine data suggest no evidence of switch while using antipsychotics, it is noteworthy that in our reanalysis of the
lithium plus paroxetine (or imipramine) study, there was a
three-fold higher manic switch rate with imipramine versus
placebo (relative risk 3.14), with asymmetrically positively
skewed confidence intervals (.34, 29.0). As discussed earlier,
these studies were not powered to assess antidepressantinduced mania, and thus lack of a finding is liable to be due to
type II (false negative) error. It is more effective to use descriptive statistics as above, which suggest some likelihood of a
higher manic switch risk at least with tricyclics compared with
placebo. Taken together with the results of other studies reviewed showing higher switch rates with tricylics than with
other antidepressants, this heterogeneity suggests that one cannot rule out antidepressant switch. Thus, apparent agreement
among studies masks major conflict between the results of the
only adequately designed study using the most proven mood
stabilizer, lithium, and the results of the remaining studies
(which used either no mood stabilizer or less proven agents).
49. Unfortunately, Mundo and colleagues (2001) nonrandomized study did not analyze important potential differences
between the two groups, such as treatment duration and use
of mood stabilizers.
50. The patients were from the NIMH Collaborative Program on
the Psychobiology of Depression-Clinical Studies and had
initially sought treatment at one of five university centers, 80
percent of which was inpatient treatment. During prospective follow-up, they received routine care in the community.
51. Rao and Nammalvar, 1977; Coryell et al., 1995; Hantouche
et al., 1998; Geller et al., 2001.
52. Of course, at these levels the dose of bupropion must be divided, and with half of it given in the late afternoon, the
likelihood of sleep disruption may increase. This in turn may
increase the risk of switch.
53. This difference did not achieve statistical significance by t test.
Since this study was not powered to rule out mania, the finding is more appropriately evaluated as relative risk ratio with
confidence intervals (RR 4.00; 95 percent CI .4733.7).
54. Defined as an increase of 2 on the 7-point CGI scale for mania. Using the CGI, the mean switch rate for all three drugs
was 21 percent, whereas by the more stringent requirement of
a Young Mania Rating Scale score of 13 or above, the mean
was only 9 percent.
55. Overall mood morbidity, which was the primary outcome of
this study, relates to the roughening concept. Mood morbidity
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
795
796
Treatment
20
Art is long, life short, opportunity fleeting, experiment dangerous, judgment difficult, nor is it
sufficient that the physician should attend to his work, but it is necessary also that the patient
and those around him should do theirs.
Hippocrates (cited in Whitwell, 1936, p. 61)
798
Treatment
As reviewed by Bech (2006) in an essay written in tribute to Mogens Schou, the use of lithium in endogenous
affective disorder was first recommended by Frederick
Lange in 1893 and subsequently by his brother Carl Lange in
1897 (reviewed more extensively by Schioldann [2001] in an
excellent commemorative tribute to Carl Lange). After the
rediscovery of lithium by Cade half a century later (for the
acute treatment of mania), lithium prophylaxis in manicdepressive illness was first described by Noack and Trautner
(1951), who observed that the drug appeared to prevent additional manic episodes in patients in whom it had alleviated
acute mania. Shortly thereafter, Schou and colleagues (1954)
provided the first case report demonstrating the benefits
of lithium for treating both manic and depressive episodes.
The 10 to 12 episodes a year that their patient had experienced before treatment were markedly attenuated in duration and severity after 2 years of taking lithium continuously.
In the above-mentioned essay, Bech (2006) reminds us of
some important history:
The term mood normalizer for lithium (Cade, 1949)
was originally introduced by Mogens Schou in 1963,
with reference to Baastrups findings regarding longterm therapy of lithium and its high recurrence prevention of both manic and depressive episodes in bipolar
patients. In the 1950s, clinicians used the term mood
stabilizer to refer to a combination of amphetamine
and a barbiturate to treat patients with neurotic instability, but not patients with bipolar disorders. By moodnormalizer Schou meant a compound acting specifically on a disease process rather than on a symptom
level (Schou, 1963). During long-term therapy with
lithium in bipolar disorder, Schou and Baastrup saw a
normalisation of the abnormal mood swings, while normal emotions seemed not to be affected in any way, as
they were when the combination of amphetamine and
barbiturate was used. Now, fourty [sic] years later, the
definition of a mood stabilizer has changed to exactly
what Schou had called mood-normalizer, i.e. a drug
with prophylactic properties in regard to mania and depression, and in this sense lithium still is the only drug
that meets the criterion.
CLINICAL MANAGEMENT
In this section we discuss key aspects of clinical management
for maintenance treatment of manic-depressive illness. Following an overview of the issues involved, we address, in
turn, embarking on maintenance treatment, selecting medications, treating the elderly patient, treating pregnant and
breastfeeding women, and dealing with breakthrough
episodes. Note that issues of maintenance treatment for children and adolescents are addressed separately in Chapter 23.
Overview
Manic-depressive illness, especially the bipolar-I form, is
the prototypical diagnostic indication for maintenance
treatment. When to commence maintenance therapy and
whether it is ever reasonable to stop are currently matters of
only modest controversy.2 As detailed in Chapter 4, mood
disorders are often highly recurrent illnesses, frequently
characterized by residual symptoms and substantial risk of
chronicity (this appears to be especially true of illness characterized by more prominent depressive symptomatology).
One 5-year prospective follow-up study found that nearly 90
percent of 172 individuals with bipolar-I disorder experienced a relapse of illness within 5 years after their recovery
from an acute mood episode (Keller et al., 1993). Many of
these patients had been actively in treatment throughout the
period since recovery (see also Keller et al., 1992). In a recent
prospective study of 1,469 bipolar patients participating in
the National Institute of Mental Healths (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder
(STEP-BD) (Perlis et al., 2006), 58 percent achieved recovery, but nearly half of these patients (49 percent) had a recurrence of illness during the follow-up period of up to
2 years. Recurrence was associated with the persistence of
residual symptoms after treatment of the acute episode.3
The substantial morbidity (including medical morbidity) and significant mortality associated with recurrences
of bipolar disorder, the financial burden resulting from the
decreased productivity of affected persons and associated
health care costs, and the toll in human misery (including
substance abuse, violence, and suicide) all argue for making every possible effort to prevent new episodes. Patients
who have had a manic episode and a major depressive
episodethus all patients with bipolar-I disorderare at
high risk of relapse throughout their lives; barring contraindications, long-term maintenance therapy is indicated for all such patients. We agree with the recommendations of the various North American treatment guidelines
that long-term prophylactic treatment should generally
begin after the first manic episode; in most of the European guidelines, prophylaxis is recommended after the second episode of mania, but it can be considered after the
first manic episode if that episode is severe enough (Vestergaard, 2004). At the same time, it is important to note that
treatment decisions must be made in context of individual
patients and their diagnoses. In clinical situations, moreover, a significant amount of time, often several months,
is usually required to determine whether an individual
can tolerate a particular long-term maintenance medication at a dose that is likely to be helpful. And it takes at least
a year, and more often 2 to 3 years, to develop a clear picture
of how effective the treatment is in preventing recurrence.
When evaluating treatment times of less than 1 year, it is
difficult to distinguish prevention of relapse back into the
acute episode from true prophylaxis (prevention of a new
episode). Thus decisions about prophylactic medications
must be made and reconsidered over periods of many
years.
Long-term maintenance is also indicated for bipolar-II
patients, primarily because of the toll of depressive morbidity (Judd et al., 2005) and the availability of new mood stabilizers that can reduce the likelihood of new depressive
episodes in a significant percentage of bipolar patients.
Bipolar-II disorder differs from bipolar-I in several ways that
suggest a modification of the usual maintenance recommendations for the latter. The defining characteristic that differentiates bipolar-II from bipolar-I is, of course, the absence of
full-blown manic episodes. For example, the risk of manic
switch is lower, which may make antidepressants safer than
they are in bipolar-I patients. The importance of maintenance treatment for bipolar-II is underlined by the finding
that individuals with the disorder have more frequent mood
episodes and are ill a greater percentage of time than those
with bipolar-I disorder (Tondo et al., 1998; Judd et al., 2005).
There are suggestions that patients with bipolar-II disorder
are at greater risk of suicide as well; this may increase the importance of lithium prophylaxis in these patients (see Chapter 25), the clear benefits of which for bipolar-II patients have
repeatedly been demonstrated in studies extending back several decades (Suppes and Dennehy, 2002). Fewer data are
available on anticonvulsant medications in treating bipolarII disorder. The increased cycling seen in patients with the
disorder suggests that valproate may have a role, although its
antidepressant efficacy (like that of lithium) has been shown
to be modest at best in patients with rapid cycling (Calabrese
and Delucchi, 1990; Calabrese et al., 2005). Valproate may be
useful in treating the impulsiveness, irritability, and dysphoric moods often seen in bipolar-II patients, features that
may be associated with more self-harming behavior and psychosocial disability.
Lamotrigines demonstrated maintenance effect against
depression in bipolar disorder suggests an important role
for this agent in the treatment of patients with bipolar-II. In
contrast to bipolar-I patients, for whom it is recommended
799
800
Treatment
that this recommendation is based on studies in which recurrent represents patients with as few as two episodes
(the minimum Diagnostic and Statistical Manual [DSM]IV definition). It has been estimated that as many as half of
patients with DSM-IV recurrent unipolar depression will
experience a relapse despite maintaining a full dose of the
antidepressant to which they have responded acutely
(Byrne and Rothschild, 1998). This phenomenon is variously referred to as poop out, tachyphylaxis, or tolerance. All of these terms imply that the relapse represents a
loss of the drugs therapeutic effect, a phenomenon for
which many explanations have been advanced (Fava, 2003;
Solomon et al., 2005). Yet rarely is the possibility considered
that in some patients, the phenomenon may reflect the ongoing efficacy of the antidepressant, bringing the next depression on sooner by accelerating the natural cycle of the
more recurrent forms of unipolar depression (Goodwin,
1989).4 In this regard, it is interesting that in the recent report from the real-world NIMH Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) trial of the
antidepressant citalopram, only 28 percent of patients with
fairly recurrent forms of unipolar depression (average of
six prior episodes) achieved remission (Trivedi et al., 2006).
With regard to the use of mood stabilizers for prevention of recurrent unipolar depression, as reviewed in the
first edition of this text and more recently in two metaanalyses (Souza et al., 1990; Davis et al., 1999), substantial
evidence indicates that lithium is highly efficacious in the
prevention of recurrent unipolar depression. Most of this
evidence has involved patients with frequent recurrences,
often as frequent as those experienced by the typical bipolar patient. Thus in their careful analysis, Davis and colleagues (1999) noted that most of the earlier maintenance
studies of unipolar patients had involved subjects with two
to three episodes during the 2 years before the study, a frequency well within the range of that of the typical bipolar
patient. For highly recurrent unipolar patients, recommended lithium monotherapy levels are in the same range
as those for bipolar-II (.4 to .6 mEq/l). While some of the
patients in these earlier studies might today be considered
as falling within the bipolar spectrum, the size of the effect (which is as large as that in all of the lithium studies of
bipolar disorder taken together) and the remarkable consistency across studies argue against misdiagnosis as an adequate explanation for these findings. To our knowledge,
there have been no studies of other putative mood stabilizers in the prevention of recurrent unipolar depression.
Selecting Medications
Clinical decision making is the art of making prudent
choices based on insufficient information. Controlled data
have not yet caught up with the realities and exigencies
of clinical practice in the treatment of bipolar disorder
(including, among other things, individual differences, comorbidities, and combined medications), especially in the
area of long-term prophylactic treatment. Clearly, lithium
is the most proven agent for the prevention of affective
episodes, followed by lamotrigine, both of which have generated FDA maintenance indications; valproate may be
effective in long-term prevention, but this conclusion is
based on secondary analysis of one controlled trial, insufficient to support an FDA indication. In the North American guidelines (with the notable exception of those for the
Veterans Health Administration), lithium and valproate
are nonetheless given equal rank as first-line maintenance
treatments. However, other guidelines around the world
still rank lithium ahead of valproate, a position in line with
801
the most recent (and rigorous) Cochrane review of controlled studies of valproate, which concluded that at
present, the observed shift of prescribing practice [from
lithium] to valproic acid is not based on reliable evidence
of efficacy (Macritchie et al., 2001). Olanzapine and aripiprazole have also been approved by the FDA for maintenance treatment of bipolar disorder (although, as discussed later, the evidence for atypicals is focused less on
long-term prophylaxis and more on prevention of relapse
into mania shortly after recovery from a manic episode,
which is more properly referred to as continuation treatment). Finally, substantial data, primarily European, support use of the nonFDA-approved anticonvulsant carbamazepine. Other agents and combinations clearly have a
role as well, as discussed in detail later in this chapter. A
medication regimen for an individual patient will be based
on diagnosis, the relative preponderance and severity of
manic versus depressive symptoms, responses of the patient
and family members to particular agents, comorbid conditions, cost, and drug allergies and sensitivities.
The 2006 prescription data for bipolar disorder in the
United States show that lithium is the most prescribed
agent, followed closely by lamotrigine, then divalproex,
then quetiapine. In 2001, divalproex was the most prescribed, followed closely by lithium. For 2006, carbemazepine and oxcarbazepine combined had less than half
the market share achieved individually by lithium, lamotrigine, or divalproex. The most dramatic change in U.S.
prescription patterns from 2001 to 2006 is the sharp increases in market share for lamotrigine and quetiapine,
accompanied by comparable decreases in divalproex and
lithium. The European market for medications for bipolar
disorder is somewhat different. Lithium remains the market leader with a share almost identical to that in the
United States; valproate and valpromide combined are second, followed by olanzapine, then lamotrigine, then carbemazepine. Between 2001 and 2006, lithiums market share
in Europe declined by 24 percent, while carbemazepines
share dropped by 48 percent and valproates share doubled. It should be noted that these data reflect all uses of
the drugs in bipolar patients, including both acute and
maintenance treatment.
It is important to bear in mind that some fluctuations of
mood in patients being treated for bipolar disorder reflect
cyclic or phasic changes of the illness that will normalize
with time and do not necessarily call for additional pharmaceutical intervention. Patients may have brief depressive
periods following a period of mania or transient episodes of
mild hypomania following recovery from depression. Experienced clinicians know that being too quick to intervene during these periods can result in the prescription of
unnecessary additional medications that may ultimately
802
Treatment
be destabilizing in the case of antidepressants or oversedating in the case of anticonvulsants and antipsychotics. During the maintenance phase of treatment, mood stability
should be a treatment goal comparable with that of euthymia. At times, interventions designed to further one of
these goals may require restraint in interventions addressing the other.
The decision as to when and how quickly to attempt tapering off and discontinuing a medication that may have
been used for an acute episode must always be an individualized one as well. The patients previous course of illness,
demonstrated response to and requirement for particular
medications, and willingness to accept the risks of ongoing
medication treatment versus the risk and consequences of
relapse will offer important guidance. Likewise, although
the best available research data indicate that lithium should
be the mainstay in the treatment of bipolar disorder in
most circumstances, an individual patients inability to tolerate lithium therapy, as well as breakthrough or residual
symptoms, may dictate the selection of alternative or adjunctive agents. That said, it is beyond regrettable that
many young psychiatrists in the United States have never
really learned the science and art of lithium treatment, and
that they excuse their ignorance by convincing themselves
that lithium has been surpassed by more effective medications or that it is too difficult to usea self-fulfilling
prophesy. It is our belief that clinicians who are unable or
unwilling to include the skillful use of lithium in their armamentarium should not be considered competent to treat
bipolar disorder.
There are, of course, many patients who legitimately
need and benefit from alternatives or adjuncts to lithium,
and fortunately, controlled data and clinical experience are
increasingly available to guide the clinician in identifying
those agents. Emerging data suggest that lamotrigine may
be especially helpful for the prevention of depressive
episodes, and valproate and carbamazepine for the prevention of manic episodes. As noted earlier, the role of the
atypical antipsychotics, such as olanzapine and aripiprazole, in the long-term prevention of new manic episodes is
less clear. Although these two drugs have maintenance
indications from the FDA, results of existing studies are
probably best interpreted as demonstrating their prevention of relapse back into the acute manic episode (continuation treatment), leaving open the question of whether
they can prevent future new episodes, especially of depression (that is, whether they are true prophylactic agents).
The full range of available clinical data will be necessary
in making decisions for individual patients, many of whom
inevitably resemble the subjects that are excluded from or
drop out of controlled studies because of severe and/or
complex illness or inability to tolerate particular agents. For
Lithium
Some debate continues regarding optimal serum lithium
levels for maintenance monotherapy of recurrent affective
disorders, particularly the bipolar subgroup. How to balance the greater efficacy and increased side-effect burden
with increasing serum levels is a clinical decision that must
be individualized for each patient (Luby and Singareddy,
2003). Gelenberg and colleagues (1989) compared the ability of standard (.8 to 1.0 mEq/l) and lower (.4 to
.6 mEq/l) levels to prevent recurrences among bipolar-I patients. Although the higher levels were associated with superior protection against relapse, they were also associated
with greater dropout rates due to side effects. A major
problem with this study, however, is that the findings actually reflect the effect of lowering the lithium level from the
Table 201. Pretreatment Evaluation and Ongoing Monitoring for Maintenance Mood Stabilizers
Agent
Therapeutic Range
(blood level)
Monitoring
Other Considerations
Lithium
Carbamazepine
412 g/ml
Valproate
Lamotrigine
Not determined
804
Treatment
Table 201. Pretreatment Evaluation and Ongoing Monitoring for Maintenance Mood Stabilizers (continued)
Agent
Therapeutic Range
(blood level)
Monitoring
Other Considerations
Oxycarbazepine
Not determined
Notes: General pretreatment evaluation for mood stabilizers encompasses medical history focusing on renal, endocrine, cardiac, hepatic,
hematopoietic, and nervous systems; catalog of present and past drug use, including prescriptions, over-the-counter drugs, illicit drugs, caffeine,
nicotine, and alcohol; baseline blood pressure, complete blood count (CBC), electrolytes, hepatic profile, creatinine, thyroxine (T4), thyroidstimulating hormone (TSH), and urinalysis; and pregnancy test (serum human chorionic gonadotrophine [HCG]) where appropriate.
Only lithium and lamotrigine have been approved by the U.S. Food and Drug Administration for maintenance use.
Source: Adapted with permission from Bowden et al., 2000b.
Monitoring
Other Considerations
Clozapine
Risperidone
Olanzapine
Quetiapine
(continued)
806
Treatment
Monitoring
Other Considerations
Ziprasidone
Aripiprazole
Notes: General pretreatment evaluation for atypical antipsychotics: medical history focusing on endocrine, cardiac, hepatic, hematopoietic, and nervous systems; catalog of present and past drug use, including prescriptions, over-the-counter drugs, illicit drugs, caffeine, nicotine, and alcohol; baseline blood
pressure, complete blood count (CBC), electrolytes, hepatic profile, creatinine, thyroxine (T4), thyroidstimulating hormone (TSH), urinalysis; pregnancy test (serum human chorionic gonadotrophine [HCG])
where appropriate. In addition (for clozapine, olanzapine, risperidone, and quetiapine), weight (and body
mass index [BMI]), waist measurement, personal/family history of weight problems and/or diabetes, fasting plasma glucose, and fasting lipid profile. Olanzapine and aripiprazole are FDA-approved for relapse
prevention. Data derived primarily from controlled monotherapy trials with little or no comorbidity.
Prevalence of extrapyramidal syndrome (EPS) with use of atypical antipsychotics in bipolar patients
appears to be considerably higher among those treated in the community (Ghaemi et al., 2006).
Source: Reprinted with permission.
807
Table 203. Principal Adverse Effects of Drugs Used as Monotherapy at Recommended Doses
for Maintenance Treatment
Neurocognitive
Impairment
Sedation
Weight Gain
++
0/+
++
+ / ++
+
+ / ++
+
+
+ / ++
+
+/0
++
Lamotrigine
Clozapine
0
?a
0
++
0
+++
Olanzapine
Risperidone
?a
?a
++
++
+++
+
Quetiapine
Ziprasidone
?a
0
++
0
++
0
Aripiprazole
0/+
Drug
Lithium
Carbamazepine
Oxycarbazepine
Valproate
a
To varying degrees, atypical antipsychotics cause sedation, which some may regard as a neurocognitive side effect.
EPS = extrapyramidal syndrome; PCOS = polycystic ovary syndrome.
caused by lithium; this problem generally responds to reducing the dosage, shifting the entire dose to bedtime,13 and/or
enhancing thyroid function. Fine tremor is another doserelated side effect. Tremor sometimes subsides spontaneously after several weeks of treatment, and it can be worsened by coadministered medications such as selective
serotonin reuptake inhibitors (SSRIs) and bupropion; it generally responds to treatment with beta-blockers. Dermatological problems associated with lithium use include acne
and, occasionally, hair loss, problems that are usually minor. Acne responds to local treatment and antibiotics;
isotretinoin should be used with caution because of the possible risk of exacerbating suicidality. Lithium can exacerbate
preexisting psoriasis so severely as to preclude its use, although some patients with psoriasis will respond to the
agents usually effective for the condition (Tsankov et al.,
2000).14 Lithium has also been associated with a variety of
benign electrocardiogram (ECG) changes, but significant
cardiac conduction changes or arrhythmias are very uncommon (Steckler, 1994).
As the long-term effects of lithium on the kidney have
become clearer, earlier concerns about its nephrotoxicity
have eased significantly.15 While the risk of reduced
glomerular function with lithium appears to be very low,
808
Treatment
Valproate
Compared with lithium, there are fewer data on effective
levels of valproate for maintenance treatment; at this point
it appears reasonable to use the levels published in the large,
multisite 1-year maintenance trial conducted by Bowden
and colleagues (2000a) (see Table 201). Side effects become
increasingly problematic at levels greater than 125 g/ml.
Dose-related side effects of valproate (see Table 203) include neurocognitive dysfunction and weight gain, as well
as nausea, vomiting, and other gastrointestinal complaints,
such as abdominal pain and heartburn. If possible, the
drug should be started gradually to avoid these gastrointestinal symptoms, and a temporary reduction in dose can
often alleviate them. Sedation is a common side effect, so
it is best to take most if not all of the daily dose at bedtime.
Indeed, given the importance of maintaining sleep stability in bipolar patients, this particular side effect can be
turned into an advantage. Tremor is not uncommon; indeed, in the 1-year comparison of lithium, valproate, and
placebo carried out by Bowden and colleagues (2000b),
both drugs produced tremor at the same rate, sedation and
hair loss were significantly greater with valproate, and
weight gain showed a trend to be more frequent with valproate than with lithium. There are reports that adjunctive
topiramate can reduce valproate-induced weight gain
(McElroy et al., 2000; Chengappa et al., 2002), but as with
lithium, additive cognitive side effects limit the usefulness
of this combination for many patients. Transient minor elevations in hepatic transaminases are common when treatment with valproate is initiated and usually subside over
time. Valproate can cause severe hepatotoxicity, but the risk
to adults appears to be very low; most fatalities have occurred within 4 months after initiation of therapy. Careful
809
monitoring of liver function is recommended when valproate is first administered as the hepatotoxicity is reversible in some cases if the drug is withdrawn. Similarly,
rare cases of hemorrhagic pancreatitis have been reported
that appear to be related to initiation of the drug or dosage
increase in susceptible individuals. Delay of diagnosis has
been implicated as a factor contributing to these rare cases,
and patients should be warned about the symptoms and
potential severity of pancreatitis. Another observed idiosyncratic response with valproate is thrombocytopenia, although documented cases of abnormal bleeding are lacking.
Some though not all reports of women treated for
epilepsy have linked valproate with a high rate of gynecological problems, including menstrual irregularities, polycystic
ovary syndrome (PCOS), and androgenization.22 A recent
large, multicenter study of epileptic patients compared valproate (n = 225) and lamotrigine (n = 222)23 and found significantly more PCOS symptoms among the valproatetreated patients (54 versus 38 percent; p <.01). Although it
has been suggested that women taking valproate for psychiatric conditions have less risk of these reproductive abnormalities, two small studies of bipolar patients taking
valproate obtained results similar to those of the Isojarvi
study of epileptic patients (ODonovan et al., 2002; McIntyre et al., 2003). More important, a recent NIMH STEPBD study of 230 bipolar women aged 18 to 4524 found 7.5
times more PCOS (10.5 versus 1.4 percent, p <.002) in the
12 months following initiation of valproate compared with
women who had initiated a variety of other mood stabilizers (Joffe et al., 2006). Obviously, regular monitoring of reproductive function in female patients taking valproate is
needed, with questions being raised during visits regarding menstrual disorders, fertility, weight gain, hirsutism,
and galactorrhea. Table 201 summarizes the monitoring
that should be performed when valproate and the other
anticonvulsants (discussed in the following sections) are
used for maintenance treatment of bipolar disorder.
Carbamazepine/Oxcarbazepine
A therapeutic range for carbamazepine in the maintenance
treatment of bipolar disorder has not been determined by
studies correlating serum levels with clinical efficacy (see
Table 201). In clinical trials, however, levels comparable to
those used to treat epilepsy have typically been attained
(Post et al., 1986, 1987). Carbamazepine has the ability to induce the hepatic microsomal enzymes responsible for its
own metabolism, and considerable dosage adjustments may
be necessary during the first weeks of therapy. In several
studies of epileptic patients or volunteers on dosage regimens exceeding 1 month, the clearance of carbamazepine
810
Treatment
Phenytoin
8.3
Phenobarbital
8.1
Lamotrigine
2.5
Carbamazepine
1.4
Valproate
0.4
Lamotrigine
Clinical trials of lamotrigine for acute and maintenance
treatment of bipolar disorder have employed doses ranging
from 50 to 400 mg/day, and a target daily dose of 200 mg/day
for maintenance treatment appears to be reasonable (Calabrese et al., 1999a; Bowden, 2003b). Adjunctive use of an
anticonvulsant drug that induces hepatic microsomal enzymes (e.g., carbamazepine, phenobarbital, phenytoin,
primidone) increases the clearance of lamotrigine; conversely, valproate interferes with the metabolism of lamotrigine, approximately doubling its half-life. Although
serum levels of lamotrigine are routinely available, a therapeutic range for the treatment of bipolar disorder has not
been determined.
As noted in Table 203, lamotrigine has a very favorable
side-effect profile, with transient headache and dizziness
being the most common complaints. In contrast to lithium
and valproate, when lamotrigine is used as monotherapy
at recommended doses, it does not appear to be associated
with neurocognitive side effects (Lieberman and Goodwin, 2004) and unlike lithium and valproate and most of
the atypical antipsychotics, it does not cause sedation or
weight gain (Sachs et al., 2006). Indeed, it has been associated with weight loss in obese bipolar patients (body mass
index greater than 30 kg/m2 [Bowden et al., 2006]).
Of particular concern with lamotrigine, however, are
reports of severe dermatological reactions associated with
rapid initial upward titration of the dose, including
Stevens-Johnson syndrome and toxic epidermal necrolysis.
Serious rash may be more common in younger patients,
and lamotrigine therefore is not approved for use in patients
under age 16.27 Based on results of clinical trials in bipolar
patients, the incidence of serious rash has been estimated to
be 1 in 1,200 (the current FDA labeling), but this estimate
was derived by counting all patients who had a rash of any
sort in whom the drug was discontinued and the patient was
hospitalized. In reality, the drug was typically discontinued
for any rash, and the hospitalizations were not necessarily
related to rash. Indeed, among 2,624 patients in the clinical
trials, only 1 was hospitalized for a rash, and that patients
dose had reached 100 mg by the end of the second week
(data on file, GlaxoSmithKline). The most reliable rash data
come from the German rash registry, which estimates the
risk of serious rash to be about 1 in 5,000 lamotrigine exposures among patients being treated for epilepsy. Since almost all of these data are based on the use of the drug by
neurologists, even this estimate is probably too high when
applied to the more gradual titration employed in the treat-
811
ment of bipolar disorder. Because benign rashes are not uncommon with this drug (about 2 to 5 percent greater frequency than with placebo), it is important to be able to distinguish them28 from those rare cases in which a rash may
signal the development of Stevens-Johnson syndrome or
toxic epidermal necrolysis.
Figure 201 provides a decision-making flowchart for
dealing with rash in patients taking lamotrigine. Dangerous rashes typically are confluent (covering virtually all of
the skin) and/or involve the facial or genital area given the
proximity of each to mucous membranes; also, dangerous
rashes are almost always accompanied by systemic symptoms such as fever, elevated white blood cell count, and flulike symptoms. It is of interest to note that in the German
registry, a number of other drugs, including some anticonvulsants, rank ahead of lamotrigine in the frequency with
which they are associated with serious rashes (see Table
204). Kanner and Frey (2000) reported that valproate can
be added to lamotrigine safely if the dose of the latter is
lowered by 50 percent after the start of valproate therapy.
These findings suggest that rash resulting from the combination of the two drugs is not due to a pharmacodynamic
interaction, but to a pharmacokinetic one in which a sudden increase in lamotrigine levels occurs in the presence of
valproate. Finally, there have been a few case reports of
agranulocytosis among patients taking lamotrigine (de Camargo and Bode, 1999; Solvason, 2000), but a causal relationship has not been established.
Other Anticonvulsants
No therapeutic ranges have been established for gabapentin,
tiagabine, or topiramate. These agents generally have favorable side-effect profiles, with the exception of the dulling
cognitive effects of topiramate. Thus no routine therapeutic monitoring is presently recommended for patients taking these agents.
Atypical Antipsychotics
Typical antipsychotic medications have been used mainly
as adjunctive agents in the acute phases of bipolar disorder, especially for manic states (see Chapter 18), and they
still form the mainstay of acute treatment for mania in
many European centers. Given the risk of tardive dyskinesia with the typical antipsychotics,29 they have usually been
viewed as having only a temporary role in the treatment of
bipolar disorder, with discontinuation recommended as
soon as symptoms stabilize. Because they were for a long
time the only psychotropics available as long-acting depot
agents,30 they have been used, when effective, in a small
number of patients who have failed to adhere to oral medication regimens (Littlejohn et al., 1994).
812
Treatment
Rash Occurs
Probably non-drug-related
Possibly drug-related
Rash characteristics:
Peaks within days, settles
in 1014 days
Spotty, nonconfluent,
nontender
No systemic failure
Normal laboratory tests
(CBC, LFT, urea
creatinine, urine analysis)
Figure 201. Lamotrigine Rash Decision-Making Flowchart. CBC = complete blood count; LFT = liver function
test. (Source: Calabrese et al., 2002. Reprinted with permission.)
While the atypical antipsychotics are generally considered safer than the typicals because they are less likely to
cause extrapyramidal syndrome (EPS), the relatively low
EPS rates found in large multicenter registration trials may
be misleading because they reflect monotherapy in patients without psychiatric or medical comorbidities and
813
814
Treatment
Lithium (n = 2,442)
Valproate (n = 2,918)
Benztropine (n = 4,870)
50
100
150
200
250
300
Time from First Claim (days)
350
Figure 202. Kaplan-Meier survival curves for incidence of delirium in new users of lithium, valproate, or benztropine among older
adults. (Source: Shulman et al., 2005. Reprinted with permission.)
815
Table 205. Fetal and Neonatal Risks Associated with Drugs Used for
Maintenance Treatment
Drug
Fetal Risks
Lithium
Carbamazepine and
oxcarbazepine
Valproate
Typical antipsychotics
Atypical antipsychotics
Benzodiazepines
Lamotrigine
Other anticonvulsants
Antidepressants
Applies to most SSRIs, including fluoxetine; some tricyclic medications are in Category D.
Source: Adapted from Viguera et al., 2002; Lamotrigine Pregnancy Registry; Nonacs and Cohen, 2003.
Reprinted with permission.
Description
817
Notes: These categories can be quite misleading because they are, by and large, based on data available
at the time of the drugs initial approval. Typically, once a drug is off patent, new data are not submitted to
the FDA. For example, newer data indicate that lithium (Category D) is safer than either carbamazepine
(Category D) or valproate (Category C). Adequate human data for valproate were not available at the time
it was approved, and newer data indicate a substantial risk of spina bifida with the drug.
818
Treatment
72 percentis found in breast milk (Chaudron and Jefferson, 2000). Because of this and a handful of case reports of
adverse effects, the American Academy of Pediatrics (AAP)
recommends that if lithium is administered to a breastfeeding woman, it should be done with caution and with careful
monitoring of the infant, especially for lethargy and hypotonia (see the review by Ernst and Goldberg, 2002).45
Chaudron and Jefferson (2000) and the AAP consider
use of anticonvulsants to be compatible with breastfeeding. The concentration of valproate in breast milk is low,
representing less than 10 percent of maternal levels. For
carbamazepine, a higher percentage of the drugs maternal
blood level gets into breast milk than is the case with valproate, and there are at least nine case reports of adverse
effects of carbamazepine in breastfed babies (Ernst and
Goldberg, 2002). There are fewer data on lamotrigine in
breast milk (and very little of this is monotherapy data), but
because the amount found in breast milk represents a relatively high proportion of maternal levels (estimated at 60
percent), caution is advised (Ernst and Goldberg, 2002;
data on file, GlaxoSmithKline).
Few or no data exist on the penetration of the atypical
antipsychotics, as a group, into breast milk; however, use of
these agents is generally considered compatible with breastfeeding, perhaps because of older (albeit still limited) evidence that a low proportion of the mothers dose of typical
antipsychotics enters breast milk.
A prospective, controlled study of mothers exposed
throughout pregnancy to either tricyclic antidepressants
(n = 46) or fluoxetine (n = 40) (half of whom breastfed their
babies) compared with 36 mothers who were not exposed
to antidepressants (Nulman et al., 2002) found no adverse
effect of drug exposure on the childrens global intelligence
quotient (IQ), language development, or behavior when
they were tested between ages 15 and 71 months. In contrast, IQ and language development were significantly and
adversely affected by uncontrolled depressive symptoms in
the mothers. Further discussion of the risk/benefit calculation for the use of psychotropic drugs in pregnancy and
breastfeeding can be found in two recent reviews (Gentile,
2004, 2006; Malone et al., 2004).
prescribed by other physicians, such as steroids or interferon; or endogenous factors, such as the onset of thyroid
abnormalities. The symptomatic patient may not be the
best source of information on these factors, an observation that reinforces the need to develop collaborative relationships with family members and other professionals
involved in the patients care.
True relapseOnly after other possibilities have been
ruled out should the clinician contemplate changes in
medication to address breakthrough symptoms. Even
then, questions will remain. How aggressively should the
symptoms be treated? The severity of the immediate
symptoms will naturally inform this decision, as will
consideration of the course of the patients illness. Have
mild symptoms progressed to severe illness previously,
and if so, how quickly? Can this breakthrough episode
be related to previous ones in a way that suggests a specific intervention? (For example, if depressive symptoms
recur in winter months, supplemental phototherapy may
be helpful.) Once the decision has been made to treat
breakthrough symptoms, a reasonable first step is to maximize the effectiveness of the patients current medication
regimen. Therapeutic monitoring is crucial in determining whether dosages can be increased safely. Dosages of
agents with dose-related efficacy should generally be maximized before the addition of new agents is considered. As
noted previously, the trigger for or earliest indication of
a breakthrough manic or hypomanic episode often is
decreased sleep. Thus the early, short-term use of sedative hypnotics may be able to abort an emerging episode
before it escalates. Agents useful for this purpose include benzodiazepines, zolpidem, eszopiclone, ramelton,
gabapentin and some other sedative anticonvulsants, and
some atypical antipsychotics.
Approaches to managing breakthrough manic/hypomanic and depressive symptoms are discussed in Chapters
18 and 19. Here we only emphasize that there are almost no
controlled data to guide the clinician in choosing a particular combination regimen for an individual patient. Medication combinations are clearly effective for many patients.
Goodwin and Goldstein (2003), for example, reviewed data
on several medications, such as valproate, that may work
synergistically with lithium (allowing reduced dosages of
each drug), potentially enhancing maintenance treatment
by increasing the ratio of therapeutic to side effects. Another frequently used combination is lithium plus lamotrigine, combining a stabilizer that works best from above
(lithium) with one that works best from below (lamotrigine) (Ketter and Calabrese, 2002). When using combinations, however, downward dosage adjustment should generally be attempted (which is feasible for both of the
819
Lithium
In the introduction to this chapter, we noted the pioneering work of the Lange brothers, as well as that of Cade and
Noack and Trautner. But the first major systematic study of
lithiums prophylactic efficacy in manic-depressive illness
occurred through the collaboration of Baastrup and Schou
(1967). They analyzed the results of a retrospective study
initiated at the Psychiatric Hospital in Glostrup, Denmark,
involving all patients with recurrent affective disorders
admitted from 1960 through 1966 (a total of 88 patients).
Those selected for analysis had an episode frequency ranging from two or more episodes in a year to one episode per
year for at least 2 years before lithium administration. All
had taken lithium for at least 1 year.
The studys results were striking. Following the initiation of lithium, episodes (defined as rehospitalization) had
become clearly less frequent among 83 (94 percent) of the
88 patients. The magnitude of the effect is suggested by the
fact patients were ill on average 13 weeks a year before
starting lithium, compared with less than 2 weeks a year
while taking lithiuman almost seven-fold reduction.
The frequencies of manic and depressive episodes were affected equally; however, lithiums ability to prevent rehospitalization for depression, not always evident initially, appeared to improve with time. In this sample, lithium was
equally effective in patients with bipolar and recurrent
unipolar depression46 (see the review below of lithium
studies in this group) but was less so in schizoaffective patients (Baastrup and Schou, 1967). In a follow-up study,
Angst and colleagues (1970) obtained similar results.
Baastrup and Schous 1967 report, a medical landmark,
stimulated many trials of the use of lithium in the prophylactic management of manic-depressive illness. By 1972,
more than 60 clinical studies comparing the course of the
820
Treatment
illness before and while taking the drug had been published. Virtually all showed decreases in the frequency, duration, and severity of episodes; those studies that distinguished between manic and depressive episodes found
that lithium reduced both.
By this time, most clinicians who had studied lithiums
effects on recurrent affective illness were favorably impressed. Skeptics such as Blackwell and Shepherd (1968),
however, noted that patients selected for a trial because of
a history of relatively frequent episodes might be expected
to experience a decreased frequency of episodes during the
study period as part of the natural course of the illness, reflecting a regression toward the mean rather than a drug
effect. But the assumption underlying this viewthat the
natural course of manic-depressive illness is randomwas
contradicted by data indicating a strong tendency for the
average frequency of manic-depressive episodes to be nonrandom and to increase with time (see Chapter 4). Three
independent studies (Laurell and Ottosson, 1968; Isaksson
et al., 1969; Angst et al., 1997) examined the natural course
of manic-depressive illness in patients with 2-year histories
of frequent episodesthe kind of patients selected for the
trials just discussed. Patients in all three studies were found
to be at high risk for subsequent episodes in the next 2
years if they remained off lithium. Blackwell and Shepherd
(1968) had also noted that in the absence of double-blind
procedures, observer bias or patient expectation may have
accounted for the favorable results obtained. Clinicians
highly familiar with the illness knew, however, that fullblown mania (and probably also severe depression) is
unlikely to respond meaningfully to psychological suggestion alone.
In the remainder of this section, we review in turn the
results of placebo-controlled studies of the prophylactic efficacy of lithium conducted before 1980, the renewed controversies that arose during the mid-1980s regarding the
drugs effectiveness and results of contemporary studies in
which lithium served as an active comparator in maintenance trials of new agents, lithiums relative prophylactic
efficacy in treating mania and depression, its effect on normal mood, the issues of withdrawal and rebound, clinical
features that may predict the drugs prophylactic effectiveness, its prophylactic efficacy in bipolar-II disorder, and finally the surprisingly robust literature supporting its prophylactic efficacy in recurrent unipolar depression. Finally,
we should note that maintenance lithium can prolong life,
not only by dramatically reducing the likelihood of suicide, but also by reducing the elevated cardiovascular mortality associated with manic-depressive illness (Ahrens et
al., 1995) (see Chapter 7). The relationship between lithium
and the risk of suicide in patients with recurrent affective
disorders is reviewed in Chapter 25.
80
% of Patients
70
60
56
50
40
37
34
30
21
20
23
10
0
Overall Relapse
Relapse into
Depression
Relapse into
Mania/Hypomania
Figure 203. Results of double-blind lithium versus placebo maintenance trials conducted in the 1970s. Blue bars = lithium treatment
(n = 251); white bars = placebo treatment (n = 263). (Source: Gyulai
et al., 2003. Reprinted with permission.)
821
Lithium showed a clear prophylactic effect against the return of symptoms only during the first 32 weeks of treatment following an episode of mania or depression; during
weeks 33 through 96, there appeared to be no relationship
between lithium treatment and relapse. The authors questioned the necessity of longer-term lithium prophylaxis for
patients who have had 8 months or more of euthymia, suggesting that lithium discontinuation studies be performed
to elucidate the issue. They also speculated that patient selection bias in treatment decisions may have reduced the
size of the lithium treatment effect, and that only a minority
of patients with bipolar disorder are at risk of relapse over
the longer term and thus require continuous treatment.
Kleindienst and colleagues (1999) reanalyzed these data using a complex mathematical model assuming that lithiums
efficacy is not transient and, most important, that some patients are at high risk of relapse and others at lower risk.
They were thereby able to generate survival curves virtually
identical to those of Coryell and colleagues (1997). They
concluded that individuals at low risk for relapse would inevitably predominate in the later months of a nonrandomized naturalistic study, thus accounting for the very small
treatment effect observed for that period.
Maj and colleagues (1996) reported on 65 patients with
bipolar disorder who had remained well on lithium for
5 years and who were followed for another 5 years during
which they remained adherent to treatment. During the
5 years of follow-up, 12.7 percent of these stable patients
experienced at least two episodes despite good adherence.
These late nonresponders had experienced a significantly
higher number of previous affective episodes and hospitalizations and a significantly longer duration of illness. The
authors argued that these factors indicate a more severe illness that will eventually overwhelm the prophylactic efficacy
of lithium, a conclusion they suggested is supported by
their review of previous studies.
It is not surprising that the notion that the intrinsic inadequacies of lithium as a prophylactic treatment for bipolar
disorder emerged at a time when alternatives to lithium were
becoming available. Overlooked in most of these reviews was
the inherent selection bias that arises once a treatment has
become established in the community: those who tend to respond to the treatment are likely to remain in the care of
practitioners, while those who are less responsive become
overrepresented in samples available to investigators, who
usually work in referral centers. Indeed, a recent naturalistic
comparison of lithium and valproate among 201 bipolar-I
patients followed for 1 year after hospitalization (Revicki
et al., 2005) found that the two treatments were equally effective for those patients who stayed in treatment.49 Nevertheless, it is likely that certain secular trends (such as increased
substance abuse and much greater use of antidepressants)
822
Treatment
823
The inclusion of more psychotic features in the diagnostic criteria for mania, especially in the United States
Lower age at onset
Increased comorbidity with substance abuse (the
rates of which vary across countries)
Substantially increased use of antidepressants
The latter three factors are associated with atypical features of bipolar disorder (e.g., rapid cycling, mixed states,
psychotic features) that may respond better to some of
the newer drugs, such as anticonvulsants (lamotrigine,
valproate, carbamazepine) and the atypical antipsychotics, than to lithium (Bowden et al., 1994; Goodwin
and Goldstein, 2003).
The development of potential alternatives to lithium maintenance (especially anticonvulsants and the newer atypical antipsychotics), which remain under patent protection and thus can support substantially more marketing
and sponsored educational events for psychiatrists than
is the case for lithiumthe perennial low earning orphan drug.
Nonetheless, contemporary reviews and meta-analyses
of older data, as well as new data generated during investigations of more recently introduced agents, support the
conclusion that reports of the demise of lithiums central
role in the treatment of manic-depressive illness, including bipolar disorder, were, indeed, premature.
824
Treatment
even deadening normal mood variability may be quite undesirable for many patients.
Several researchers have compared mood states and dayto-day mood variation in normal subjects and euthymic
bipolar patients taking lithium. Folstein and colleagues
(1982) reported the results of two such studies, in which
they found that bipolar subjects had mean mood ratings
similar to those of controls but less day-to-day mood variation as measured by visual analog mood scales (DePaulo
et al., 1982; Folstein et al., 1982). Although these results
were consistent with a mood-constricting effect of lithium,
the authors cautioned that it may not be valid to compare
the mood ratings of bipolar subjects, who have experienced major depressions and manias, with those of control subjects, who have not. Two crossover comparison
studies of lithium and placebo were conducted to assess
whether lithium attenuates mood fluctuations to the same
extent in bipolar patients and controls. Both studies showed
no difference in mood variation related to lithium use in
those without a history of mood disorders, suggesting that
lithium does not have a significant effect on normal mood
(Calil et al., 1990; Barton et al., 1993). As more putative
mood stabilizers appear, it will be important to evaluate
their effects on normal mood fluctuations as well.
825
Sample
Design
Conclusion
55 BP NS
Dunner et al.,
1977
390 BP NS
Okuma, 1993
215 BP NS
402 BP NS
Bowden et al.,
1999
75 BP NS
Baldessarini et al.,
2000
218 BP-I,
142 BP-II
Baldessarini et al.,
2000
360 BP NS
Calabrese et al.,
2000
225 BP-I,
98 BP-II
372 BP NS
3,709 BP NS
317 BP NS
Meta-analysis
827
Sample
Design
Conclusion
Calabrese et al.,
2005
24 BP-I, 36 BP-II
mood-incongruent psychotic features for 5 years and compared the course of their illness with that of a control group
of patients with no such history. They found that the former
patients were more likely to have stopped taking lithium at
the 5-year point (78 versus 57 percent), and although about
half of them had experienced at least a 50 percent reduction
in time spent in the hospital, as a group they did not fare as
well as those without psychotic features, 80 percent of whom
had a comparable decrease in hospitalization time. In a randomized controlled trial that compared lithium and carbamazepine for prevention of mood episodes in bipolar patients with mood-incongruent features, the two agents were
found to be equally effective (Greil et al., 1997).
Recently, Kleindienst and colleagues (2005) made a substantial contribution to the response-predictor literature.
They found nearly 2,000 papers on lithium response predictors written from 1966 through 2003, 43 of which met their
criteria for analysis.57 Seven of the studies were randomized
controlled trials, 10 involved a prospective cohort design, and
26 were retrospective casecontrol studies. Because of substantial heterogeneity in the effect sizes of different studies
and the well-known publication bias in favor of positive
studies, the authors applied a highly conservative fail safe
procedure to increase the likelihood that a predictor reported
in several studies was real: they added two large (N = 1,000)
hypothetical studies with zero correlation; if a particular predictor was still statistically significant after this maneuver, it
was considered likely to be real. Among the 42 possible response predictors, this conservative analysis could identify
only 5 for which there was enough agreement across studies to consider them likely predictors. The two predictors
of good lithium response were the maniadepressioninterval (MDI) course pattern and an age at onset in the intermediate range. Predictors of poor lithium response
were a large number of previous hospitalizations, the
course pattern of depressionmaniainterval (DMI), and
continuous cycling. Given that the effect sizes for any one
predictor are, at best, moderate, the authors suggested that
828
Treatment
Table 208. Clinical Characteristics Likely to be Associated with Differential Maintenance Response to Lithium
versus Anticonvulsants
VALPROATE, CARBAMAZEPINE,
LAMOTRIGINE
LITHIUM
Good
Poor
Good
Course variables:
Intermediate age at onset
Negative family
history for bipolar
disorder
Course variables:
Maniadepressioninterval
course sequence
Fewer previous hospitalizations
and/or episodes
Non-rapid-cycling
Depressionmaniainterval
course sequence
More previous hospitalizations
and/or episodes
Rapid-cyclinga
Multiple previous
episodes (valproate)
Non-rapid-cycling;
rapid-cycling bipolar-II
(lamotrigine)
Chronic course with
comorbid substance
abuse and anxiety
(lamotrigine)
Poor
Rapid cycling
(valproate)
May not apply in the absence of antidepressant use; see text for details.
829
Table 209. Results of Studies of Maintenance Treatment with Lithium for Bipolar-II Disorder
Study
Sample
Size
Duration
Drugs Studied
Results
26
33 mo
18
48 mo
22
24 mo
Lithium, imipramine,
lithium + imipramine
129
75 mo
(6.3 yr)
30 mo
57
Note: Studies with an observation period of 6 mo or less are not considered maintenance and are not included here.
Source: Adapted from Suppes and Dennehy (2002).
Valproate
Although valproate is clearly an effective antimanic agent,
its role in maintenance therapy is less clear than that of
lithium. As early as the 1970s, Lambert and colleagues (1971)
reported preliminary evidence of a long-term benefit of the
drug in treating bipolar disorder. In the United States, much
of the initial interest in what was then, for psychiatry, a new
agent was focused on its potential usefulness in patients who
were not doing well on lithium, principally rapid cyclers.
Calabrese and colleagues (1993) reviewed six open trials that
assessed the efficacy of valproate in the maintenance treatment of 124 rapid-cycling bipolar patients; the two largest of
these studies, comprising 101 patients, found that both valproate and lithium had marked antimanic but poor antidepressant effect.60 Denicoff and colleagues (1997a), studying
18 rapid-cycling patients, found that only 6 of 18 responded
to valproate, and all but one of the responders were also taking lithium (the question of the efficacy of valproate in combination with lithium is discussed later in the section on
combined treatments). Indeed, in their review, Calabrese
and colleagues (2001) concluded that rapid cyclers have
a relatively poor response to all treatments for bipolar disorder, especially monotherapies. In the most careful and
830
Treatment
Carbamazepine/Oxcarbazepine
Carbamazepine, initially used to treat a wide range of seizure
disorders and various paroxysmal pain syndromes, was tried
in manic-depressive (primarily bipolar) patients because it
had stabilized the moods of some patients with convulsive
disorders and because it counteracted kindling in laboratory animals. Much of the early work on carbamazepine in
treating bipolar disorder was done in Japan during a time
when lithium was unavailable for treatment of the disorder
in that country because of regulatory issues, making identification of alternative treatments an urgent need. Okuma
and colleagues (1973) found a prophylactic effect in 14 of
their 27 bipolar patients in an open study, which they followed up with a 1-year placebo-controlled prophylactic
trial in 22 bipolar patients (Okuma et al., 1981). Six of the 10
carbamazepine-treated patients, compared with 2 of the 9
taking placebo, had no affective recurrences during the
trial, a result that tends to indicate a prophylactic effect. In
what was actually the first double-blind trial, Ballenger and
Post (1980) noted a prophylactic effect in 13 bipolar patients (many of whom had rapid-cycling illness or had
failed to respond to lithium) maintained on carbamazepine
for up to 4 months.64 Kishimoto and colleagues (1983) suggested that responders to carbamazepine prophylaxis are
likely to be those with onset of illness before age 20 and
with frequent illness episodes, a conclusion similar to the
analysis of the divalproex data by Swann and colleagues
(1999). Additional studies that appeared through the 1980s
suggested that carbamazepine is useful for the prophylactic management of bipolar patients who respond poorly
to lithium (Placidi et al., 1986; Watkins et al., 1987). In the
ensuing decades, five published controlled studies compared carbamazepine with lithium for the treatment of
acute mania or depression.65 Although these cannot be
viewed as straightforward studies of prophylaxis of recurrences, they support some prophylactic benefit for carbamazepine.
There have been several prospective, parallel, randomized, double-blind trials comparing carbamazepine with
lithium as a prophylactic agent in treating bipolar disorder. Coxhead and colleagues (1992) carried out such a
Lamotrigine
1.0
0.9
Cumulative Survival
831
0.8
Lithium
0.7
0.6
p = .0336
0.5
0.4
Carbamazepine
0.3
0
20
10
Survival Time (months)
30
832
Treatment
No. of Studies
Sample Size
17
1,551
Carbamazepine
32
Lamotrigine
645
182
Divalproex
372
Fluoxetine
10
Olanzapine
361
Aripiprazole
567
26
3,720
Lithium
Total
Findings
About half of the studies involved abrupt
lithium withdrawal before
randomization, but lithiumplacebo
differences were similar in studies with
and without abrupt withdrawal.
The carbamazepineplacebo difference
was modest.
833
No. of Studies
Sample Size
Lithium
261
Valproate
251
Equivalent to olanzapine.
Carbamazepine
64
Oxcarbazepine
15
Flupenthixol
53
Olanzapine
778
Equivalent to lithium or
valproate; more effective than
placebo when added to
lithium or valproate among
nonresponders or partial
responders.
Clozapine
38
Imipramine
192
30
18
1,682
Total
Findings
834
Treatment
1.0
0.9
Survival Estimate
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Figure 205. Comparison of lithium or lamotrigine with placebo for the prevention of mood
episodes. Shown are Kaplan-Meier survival curves for time to intervention for any mood episode
(e.g., need for additional medication) in 171 patients with bipolar disorder. (Source: Bowden et al.,
2003b, p. 392. Reprinted with permission.)
study of lamotrigine, the drug showed a small but not significant advantage over placebo in time to additional intervention for symptoms in the entire sample, but in a post
hoc analysis of the bipolar-II group, it was found to be superior to placebo (Calabrese et al., 2000)73 (see the discussion of bipolar-II that follows). This stands as the first
placebo-controlled maintenance study with rapid-cycling
bipolar patients. In a 1-year open trial of lamotrigine versus
lithium in 14 rapid-cycling bipolar patients, those taking
lamotrigine were much more likely to have fewer than four
affective episodes during the year of the study (Walden
et al., 2000). The authors acknowledged that, as in the earlier lithiumdivalproex comparisons, their protocol favored inclusion of prior lithium-nonresponsive patients,
which obviously could bias any comparisons with lithium.
Passmore and colleagues (2003) compared several clinical
and family history characteristics of 21 patients with bipolar disorder14 classified as responders to lamotrigine and
7 as responders to lithium. They found that the lamotrigine
responders tended to have more chronic symptoms, rapid
cycling, and comorbid panic disorder and substance abuse
and to have larger numbers of family members with
schizoaffective disorder, major depression, and panic disorder. They suggested that lamotrigine may be especially
helpful for patients with these clinical characteristics. An
overall impression of lamotrigines effectiveness in a clinical setting can be gleaned from recently reported STEP-BD
data from Stanford University in the United States (Champion et al., 2006). Among 201 trials with a mean duration of
432 days, lamotrigine was continued throughout in 64 percent of the trials (32 percent as monotherapy, 42 percent
with an additional drug).74 Six percent of patients discontinued lamotrigine because of lack of efficacy. There were
no serious rashes, but 3 percent discontinued the drug because of a benign rash.
Other Anticonvulsants
Emerging but not definitive maintenance data exist for
several other anticonvulsants. Some of these agents were
studied in the past with ambiguous results as to their efficacy; several others are being actively studied as of this
writing.
Gabapentin
Although some evidence supports an anxiolytic and sedative effect of gabapentin, no evidence from controlled trials supports its benefit as monotherapy in maintenance
treatment of bipolar disorder. Trials of gabapentin versus
lamotrigine and placebo at NIMH provided no evidence
that gabapentins benefit exceeded that of placebo (Frye
et al., 2000). This result, coupled with the drugs failure as
an antimanic agent (Pande et al., 2000), has discouraged
835
Tiagabine
To date there have been no controlled studies of tiagabine in
bipolar disorder (Young et al., 2006). As noted in Chapter 18,
the drug did not have obvious antimanic benefit in an early
study of eight acutely manic inpatients for whom other
treatments had failed (Grunze et al., 1999). However, Schaffer and Schaffer (1999) reported on two patients with recurrent manic, mixed, and to some extent depressive relapses
who appeared to improve over 3 and 5 months, respectively,
when tiagabine was added to their medication regimen. A
later study conducted by the same authors (Schaffer et al.,
2002) assessed tiagabine as an adjunctive treatment for patients with refractory bipolar disorder and found that 8 of 22
patients (36 percent) were much or very much improved
on the CGI scale after 6 months of taking tiagabine.75
Topiramate
Topiramate has been used to treat acute phases of bipolar
disorder, and the results reported have been equivocal at
best (see Chapters 18 and 19). Results of several open reports on slightly longer-term use of the drug are also inconclusive. Nevertheless, topiramate is a fairly common
component of the pharmacotherapy of bipolar disorder,
given its ability to reduce appetite and weight. Yet for
many patients it can be a challenge to find a dose that
produces positive effects without causing unacceptable
836
Treatment
Phenytoin
Mishory and colleagues (2003) studied 23 subjects with
bipolar-I or schizoaffective disorder taking a variety of
other medications in a double-blind, placebo-controlled,
crossover study of add-on phenytoin, with a 6-month observation period for each phase. During a total of 30 observation periods in these subjects, 3 relapsed while taking
phenytoin and 9 while taking placebo. These results suggest that phenytoin may be helpful in prophylaxis, but
more controlled studies clearly are needed.
Antipsychotics
Until fairly recently, there had been few studies of antipsychotic medications for the long-term treatment of bipolar disorder except in combination with other agents. In the
mid-1990s, however, the development of the atypical antipsychotics led to a resurgence of interest in antipsychotics
for maintenance treatment of bipolar disorder. Actually, the
first evaluation of an antipsychotic as maintenance treatment for manic-depressive illness predated the atypical
drugs by nearly 20 years. In an early open study whose coauthors included Schou and Baastrup, the typical antipsychotic
flupenthixol was given to 93 patients with manic-depressive
illness (bipolar disorder or recurrent unipolar depression)
who had experienced a poor response to or were unable to
tolerate lithium (Ahlfors et al., 1981). The patients experienced a significant decrease in manic episodes but an excessive number of depressive episodes compared with when
they were taking lithium alone. Overall, the antipsychotic
was considered a suitable substitute for lithium therapy only
for those patients who failed to respond to lithium or who
would not or could not take it. A second study, with a randomized, double-blind, crossover design, failed to show any
benefit of flupenthixol (Esparon et al., 1986).
During the mid-1990s, the first atypical antipsychotic,
clozapine, was the subject of case reports and open series reporting that it was helpful as an adjunctive treatment in patients with bipolar disorder (Banov et al., 1994; Zarate et al.,
1995). Ciapparelli and colleagues (2000) retrospectively reviewed the naturalistic use of clozapine in 91 patients with
treatment-refractory symptoms of schizophrenia, bipolar
disorder with psychotic features, or schizoaffective disorder
and found that those with mood disorders showed significantly greater improvement than those with schizophrenia.
In a randomized study of adjunctive clozapine versus treatment as usual in 38 patients over a period of 1 year, the
clozapine-treated group showed significant improvement on
scales for global functioning, psychotic symptoms, and mania, but not on those for depression (Suppes et al., 1999b).77
There have been preliminary but promising reports as
well on the efficacy of risperidone for maintenance treatment of bipolar disorder. Ghaemi and Sachs (1997) prospectively assessed the outcome of openly adding risperidone to
the medication regimen of 12 outpatients with bipolar-I disorder who suffered breakthrough episodes despite adequate
maintenance medication (lithium, divalproex, or carbamazepine, or a combination of these).78 Four patients discontinued medicationtwo because of lack of efficacy and
two because of side effects. Among the remaining eight patients, four experienced an improvement of 10 to 25 points
in Global Assessment of Functioning scores and were rated
much better on the CGI-Improvement scale. Although one
patient suffered a major depressive recurrence (at week 22),
none experienced worsening of mania. A more recent continuation study of adjunctive risperidone, while somewhat
larger, was limited by the brevity of the follow-up period
just 10 weeks. Among 48 bipolar patients who completed
the 10 weeks of treatment after an acute manic episode,
those who received a mood stabilizer plus risperidone
showed significantly more improvement in mania and
depression ratings than those who were taking a mood stabilizer plus placebo (Bowden et al., 2004). The recent availability of a long-acting (about 2 weeks) form of injectable
risperidone (Respiridol Consta in the United States) expands the options for dealing with adherence problems.
The atypical antipsychotic that has been studied most extensively as a maintenance treatment for bipolar disorder is
olanzapine. Several open studies of the adjunctive use of this
atypical agent have showed encouraging efficacy in reducing
breakthrough symptoms and preventing relapses in patients
whose illness was difficult to control (Narendran et al., 2001;
Vieta et al., 2001b). These findings led to interest in the use of
this agent as monotherapy for the maintenance treatment of
bipolar disorder, first investigated in the continuation phase
of a placebo-controlled study of the drug for treatment of
acute mania (Sanger et al., 2001). In this study, 113 patients
who had responded acutely in the open-label extension and
remained well on olanzapine during the 3-week placebocontrolled phase continued into a 49-week open-label phase.
The investigators had the option of adding lithium or fluoxetine for residual or breakthrough symptoms and did so for
nearly two-thirds of the patients. Like many longer-term
studies of patients with bipolar disorder, this study had a
high dropout rate (over 60 percent). Nevertheless, the 41 percent of patients who received olanzapine monotherapy recovered and remained well over a period of 1 year. Somnolence and weight gain and complaints of depression were
the most frequently reported side effects.
Tohen and colleagues reported on three separate doubleblind studies of olanzapine for relapse prevention after
successful treatment of a manic or mixed episode with
olanzapineone comparing olanzapine with lithium in
431 patients (Tohen et al., 2002), one comparing it with divalproex in 248 patients (Tohen et al., 2003), and one comparing it with placebo in 361 patients (Tohen et al., 2006).
In the olanzapine versus lithium study, patients were entered into the maintenance phase if they both tolerated
and had a complete antimanic response to the open-label
combination of olanzapine plus lithium (representing 33
percent of the initial population); they were then randomized to have one of the drugs discontinued abruptly and
followed for up to 52 weeks. The group that remained on
olanzapine had a significantly lower rate of relapse back
into mania (28.0 versus 14.3 percent) than the group that
remained on lithium, while relapses into depression were
nearly identical in the two groups. This international collaborative study, which included many sites with considerable experience in the use of lithium, represents the first
large-scale demonstration of any drugs surpassing lithium
in the prevention of relapse back into mania. In a subsequent post hoc analysis, Ketter and colleagues (2006) examined treatment response in relation to the number of
837
838
Treatment
100%
Olanzapine
Placebo
80%
60%
40%
20%
0%
0
50
350
400
Figure 206. Time to relapse into mania or depression with olanzapine versus placebo. (Source: Tohen et al., 2003. Reprinted with permission.)
pointing to two post hoc analyses.83 However, those analyses did not address the fundamental issuethat most of the
drugplacebo difference occurred within the first 2 months,
a period of time we believe is too short to allow evaluation
of whether olanzapine prevents the occurrence of new
episodes. Although the FDA has approved olanzapine for
maintenance treatment,84 studies of the drugs long term
prophylactic efficacy are still needed. The reader is referred
to Chapter 17 for a discussion of maintenance designs and
their meaning.
The most recent evaluation of an atypical antipsychotic
for use beyond the acute episode involved aripiprazole. Following stabilization of an acute manic/mixed episode with
open-label aripiprazole for a minimum of 6 weeks, 567
Table 2012. Strength of the Evidence for Efficacy of Mood Stabilizers from Placebo-Controlled
Monotherapy Studies
Depression
Mania
True Prophylaxisa
(prevent recurrence)
Lithium
++
+++
++++
++++
Valproate
+++
+?
+?
Carbamazepine
+/
+++
Lamotrigine
++
+++
+++
Olanzapine
+++
+?
Aripiprazole
No data
+++
No data
Quetiapine
++
+++
No data
No data
Drug
Continuation/Maintenance
(FDA) (prevent relapses)
Prophylaxis is defined based on data from placebo-controlled studies demonstrating efficacy during the maintenance phase (>6 mo after the
acute phase).
Note: The + signs indicate the strength of the data, not the size of the effect.
839
Table 2013. Blind, Controlled Trials of Long-Term Antidepressant Treatment in Bipolar Disorder a
Study
Design
Duration (mo)
Outcome Assessed
Results
Prien et al.,
1973b
Wehr and
Goodwin,
1979
Quitkin et al.,
1981
Kane et al.,
1982
BP-I (44)
Up to 24
27 (mean)
Hospitalized or
new treatment
Nurse ratings
19 (mean)
RDC episodes
11 (mean)
RDC episodes
Up to 24
RDC episodes
Up to 12
DSM-III-R episodes
Up to 14
DSM-III-R episodes
9 (3-mo baseline,
3-mo SSRI or
placebo, 3-mo
placebo or SSRI)
Various self-ratings
daily, monthly
HAM-D and
YMRS
BP-I (5)
BP-I (75)
BP-II (27), UP (22)
Prien et al.,
1984
Sachs et al.,
1994
Amsterdam
et al., 1998
Parker et al.,
2006
Escitalopram vs.
placebo, followed by
crossover
a
See the companion Web site for an updated version of this table.
Note: Efficacy results related to BP depressive symptoms unless otherwise stated.
BP = bipolar disorder; DSM-III-R = Diagnostic and Statistical Manual, 3rd edition, revised; HAM-D = Hamilton Rating Scale for Depression; RDC = Research Diagnostic Criteria; SSRI = selective serotonin reuptake inhibitors; UP = unipolar depression; YRMS = Young Mania Rating Scale.
Source: Adapted from Ghaemi et al., 2001a.
841
842
Treatment
Thyroid Hormones
Thyroid indices in the normal range do not necessarily
indicate sufficiently robust thyroid functioning for some
patients with bipolar disorder to remain well. Cole and
colleagues (2002) examined the relationship between pretreatment thyroid hormone levels and time to treatment
response in 65 depressed bipolar-I patients and found
a significant association between delayed response to
treatment and lower-normal free thyroxin index (FTI) and
higher-normal TSH levels. They concluded that nearly
two-thirds of bipolar patients may have a thyroid profile
that, although technically in the normal range, is nevertheless inadequate for an optimal treatment response. Related
findings were published by Frye and colleagues (1999),
who found that among bipolar patients with free T4 in the
normal range, those below the median were more depressed, had poorer antidepressant responses to lithium or
carbamazepine, and had more mood instability regardless
of their mood stabilizer status.
Substantial numbers of patients with bipolar disorder
have a blunted TSH response to thyrotropin-releasing hormone (Hendrick et al., 1998), and under these circumstances, the absence of a TSH elevation may be misleading.
Psychiatrists should be familiar with thyroid physiology, especially the concept of subclinical hypothyroidism, and become comfortable with the assessment and therapeutics of
thyroid replacement for their patients taking lithium. T4
supplementation is an effective strategy for managing hypothyroidism associated with lithium therapy (Kusalic,
1992; Kirov et al., 2005).
Supraphysiological doses of T4 have been reported to increase the efficacy of pharmacological treatments for affective disorders. A prospective open-label study of 21 patients
included 13 patients with bipolar disorder who had failed
two previous prophylactic trials. These 13 patients took a
mean dose of 378 g of T4 along with their other medications
and were followed for a mean of about a year. They showed
improvement on the CGI-BP, as well as having fewer relapses and spending less time in the hospital compared with
the period before starting treatment (Bauer et al., 2002).92
Baumgartner (2000) reviewed eight open trials of the use of
supraphysiological doses of T4 involving a total of 78 patients, and concluded that the T4 benefited approximately 50
percent of patients who were entirely resistant to all other
antidepressant and prophylactic treatments. Further detail
on the use of thyroid hormones in treating bipolar disorder is provided in Chapter 19.
Psychostimulants
843
Nutritional Supplements
CONCLUSIONS
844
Treatment
NOTES
1. This classic distinction between continuation and maintenance derived from consideration of the natural history of
the disease. For noncyclic unipolar depression, there was a
clear consensus that the continuation phase comprised the
first year after the episode, and anything beyond that was
considered maintenance or prophylactic treatment (Frank
et al., 1991). For the average bipolar patient, an untreated depressive episode would be expected to last about 6 months,
with a manic episode lasting 3 to 6 months; hence the shorter
continuation phase for bipolar treatment.
2. Coryell and colleagues (1997) speculated that lithium may protect against relapse in the period immediately following an
episode of illness, but not against recurrence of illness months
later. They also questioned the necessity of longer-term lithium
prophylaxis for patients who have had 8 months or more of euthymia and suggested that lithium discontinuation studies be
performed to elucidate the issue. This argument, however, has
been rebutted by several other groups (see the section on Renewed Controversies in our later review of the literature).
3. Moreover, the tendency of the illness to accelerate in some
patients as they age, with episodes occurring more frequently
and lasting longer, has been noted since Kraepelins descriptions of the disorder more than a century ago.
845
27. In a retrospective case review at five epilepsy centers in England, Wong and colleagues (1999) found that higher starting
doses, a rapid titration (increase) of the dose of lamotrigine,
and the combined use of lamotrigine with valproate (which
increases the half-life of lamotrigine, resulting in higher serum
levels) were associated with the greatest risk of serious rashes
requiring hospitalization. Gradual dose titration is therefore
recommended by the manufacturer for patients starting lamotrigine, with an extremely slow titration recommended for
those who are taking valproate (starting at 25 mg every other
day for 2 weeks).
28. Ketter and colleagues (2005) have developed antigen precautions for consideration prior to the initiation of lamotrigine; using this approach, they have been able to reduce
rates of benign rash substantially.
29. Serious side effects are associated with typical antipsychotics.
Common CNS side effects involve altered thermoregulation,
extrapyramidal syndrome (EPS), neuroleptic malignant syndrome, and tardive dyskinesia. Orthostatic hypotension is
also observed. Erectile dysfunction, blurred vision, constipation, and urinary retention are common anticholinergic effects. Cardiovascular effects include ECG changes, tachycardia, and torsade de pointes. Changes in the endocrine
system, including amenorrhea and galactorrhea, occur as
well. Occasionally, the hematological system is involved, with
agranulocytosis and leucopenia occurring. Liver enzyme elevations are sometimes seen early in treatment; they usually
resolve even with continued treatment, but can cause release
of bilirubin with cholestatic jaundice. Other pertinent side
effects include allergic reactions and skin photosensitivity
and all immune-mediated agranulocytopenias. Sedation and
weight gain are observed as well. So-called low-potency antipsychotics cause more sedation and vascular side effects
(orthostasis), whereas the more-potent drugs are more commonly associated with EPS. The greatest concern arises for
EPS, the potentially fatal neuroleptic malignant syndrome,
and for potentially irreversible tardive dyskinesia.
30. Risperidone is now available in a long-acting depot form.
31. Risk of EPS was assessed using the Abnormal Involuntary
Movement Scale, Barnes Akathisia Rating Scale, and SimpsonAngus Scale. Mean duration of treatment was 25.5 weeks, and
61 percent of the patients were female. The EPS rate found in
this study63 percentis somewhat higher than that reported in similar studies of patients with schizophrenia, consistent with earlier findings that bipolar patients are more sensitive to antipsychotic-induced EPS (Goodwin and Jamison,
1990).
32. Leucht and colleagues (2003) referred to meta-analyses by
Baldessarini (1988) and Bollini and colleagues (1994), which
concluded that no additional efficacy is achieved in the treatment of schizophrenia when doses of chlorpromazine or its
equivalent exceed 500 to 600 mg/day.
33. Also relevant are the findings of the recent NIMH Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) (Dettling and Anghelescu, 2006), comparing a typical antipsychotic
with several different atypicals in real-world settings. No differences in rates of EPS were noted between the typical agent,
perphenazine, and the atypicals.
34. Ziprasidone is the one atypical antipsychotic in which the start
low, go slow approach is not recommended because at low
doses its activating effects, predominate.
846
Treatment
35. In a recent cross-sectional study of 171 bipolar-I and schizoaffective patients in a clinic, almost half met the National Cholesterol Education Program criteria for abdominal obesity,
and 30 percent met criteria for metabolic syndrome. Most patients were taking more than one medication, 29 percent were
taking one of the atypicals associated with weight gain, and 44
percent were taking lithium (Fagiolini et al., 2005). Among
367 patients taking atypicals, the presence of the metabolic
syndrome (in 37 percent of the patients) was associated with a
two-fold increase in the risk of coronary events (angina, myocardial infarction, and sudden cardiac death) (Correll et al.,
2006).
36. Guo and colleagues (2006) used a large managed-care database to conduct a retrospective, population-based casecontrol
study of the relative risk of diabetes among bipolar patients
treated with various atypicals. After controlling for age, gender, other drugs, and psychiatric and medical comorbidities,
they found significant risk ratios for clozapine (7.0), risperidone (3.4), olanzapine (3.2), and quetiapine (1.8).
37. Adjunctive topiramate has also been reported to control
olanzapine-induced weight gain in schizophrenic patients
(Levy et al., 2002).
38. For a review of management options for the weight gain associated with antipsychotics, see Birt (2003) and Keck and
McElroy (2003).
39. When low doses of some atypical antipsychotics are added to
mood stabilizers, enhanced cognitive organization is sometimes observed.
40. Applaby et al., 1998; Ernst and Goldberg, 2002; Newport et
al., 2002; Bonari et al., 2004; Spinelli, 2004; Yonkers et al.,
2004; Eberhard-Gran et al., 2005.
41. Austin, 1992; Viguera et al., 2000; Wisner et al., 2004; Jones
and Craddock, 2005.
42. For a more comprehensive discussion of these issues, see
Viguera et al. (2002).
43. Anticonvulsants such as valproate can be used for a few weeks
before parturition and in the postpartum period. However,
the effectiveness of valproate for the prevention of postpartum
episodes has been called into question by a study failing to find
any benefit (Wisner et al., 2004).
44. See Stewart (2000) for a discussion.
45. On the other hand, Moretti and colleagues (2003) followed 11
babies who were breastfed while their mothers were taking
lithium and found that for half of the mothers, the calculated
dose the infant received via breast milk averaged only about
10 percent of the mothers weight-adjusted dose; more important, no overt adverse effects were observed among the 11
infants. Accordingly, some experts suggest that the benefits of
breastfeeding probably outweigh the risk posed by lithium
(see, e.g., Chaudron and Jefferson, 2000).
46. The recurrent unipolar group in this study may have included some patients who today would be diagnosed as having bipolar spectrum disorder.
47. The study of Prien and colleagues (1974) also included some
patients already taking lithium, so the question of a bias toward lithium is relevant.
48. Although mirror-image studies are frequently criticized, in
their meta-analysis of the literature, Davis and colleagues
(1999) showed convincingly that the efficacy suggested by the
results of such studies is of the same magnitude as that reported in randomized, placebo-controlled trials.
62. HAM-D ratings are weighted toward items that might be expected to respond favorably to divalproex, such as anxiety
and insomnia.
63. A 2-year randomized trial comparing lithium monotherapy,
valproate monotherapy, and a combination of the two in
patients with a history of mania studied in real-world settings is currently under way in the United Kingdom (Geddes
et al., 2002). An attempt is being made to recruit more than
1,000 subjects for this study.
64. In most of the patients, carbamazepine was added to lithium,
and so this evaluation is, in reality, an assessment of adjunctive carbamazepine.
65. Okuma et al., 1976; Ballenger and Post, 1978; Placidi et al.,
1986; Watkins et al., 1987; Luznat et al., 1988.
66. In this study, 29 (69 percent) of 42 patients completed the year
on lithium, 12 (34 percent) of 35 patients completed the year on
carbamazepine, and 22 (76 percent) of 29 patients completed
the year on the combination. The proportion of patients with
moderate to marked improvement was 33 percent for lithium
alone, 31 for carbamazepine alone, and 55 for the combination.
67. The authors pointed out that a large fraction of the patients
had previously received lithium alone, carbamazepine alone,
and/or a combination of the two. Thus, the results of the
study must be seen in the context that these patients were not
nave to the study drugs and had, for the most part, responded poorly to them in the past.
68. A small double-blind trial of carbamazepine versus lithium for
treatment of bipolar disorder was carried out by Hartong and
colleagues (2003). In this study, 12 (27 percent) of 44 patients assigned to lithium had recurrences during treatment, compared
with 21 (14 percent) of 150 patients assigned to carbamazepine.
69. The mean serum carbamazepine level was 6.4 g/ml, and the
average serum lithium level was .63 mEq/l.
70. In the Calabrese et al. (1999b) open study, conducted over 48
weeks, lamotrigine was added to the currently used maintenance treatment in 60 bipolar-I and -II patients and was
used as monotherapy for another 15 patients. Fifty percent
(48) of the patients had depressive symptoms at the onset
of the trial, while 40 percent (31) were experiencing hypomanic, manic, or mixed symptoms. The majority of patients
showed significant improvement in ratings on depression
and mania scales, although several developed manic symptoms, perhaps not unexpected in this preliminary study involving patients with complex illnesses and taking a variety
of other medications (more than one in most cases), including antidepressants, lithium, valproate, carbamazepine, and
antipsychotics.
71. Thus among those patients on placebo, later recurrences after
an index depression were 6 times more likely to be a mania/hypomania than another depression; conversely, for those whose
index episode had been mania/hypomania, later recurrences
were 6 times more likely to be a depression than another mania/hypomania. In other words, overall, 85 percent of the recurrences were of the opposite polarity.
72. Walden and colleagues (1996) reported on a patient with
lithium-resistant rapid-cycling bipolar disorder who improved within days when lamotrigine was added to valproate
monotherapy; the improvement was sustained for more than
a year.
73. However, for the entire group there was a small but significant advantage of lamotrigine over placebo when treatment
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
847
848
84.
85.
86.
87.
88.
89.
90.
Treatment
91.
92.
93.
94.
21
Medication Adherence
The endless questioning finally ended. My psychiatrist looked at me; there was no uncertainty
in his voice. Manic-depressive illness. I admired his bluntness. I wished him locusts on his
lands and a pox upon his house. Silent, unbelievable rage. I smiled pleasantly. He smiled back.
The war had just begun.
Patient with manic-depressive illness1
The consequences of medication nonadherence are profound and can be life-threatening, clinically equivalent
to those of untreated or inadequately treated manicdepressive illness. Nonadherence commonly precipitates
the recurrence and intensification of affective episodes
that may in turn result in personal anguish, conjugal
failure, chaos in other family and interpersonal relationships, alcohol and drug abuse, financial crises, psychiatric hospitalization, suicide, and violence. A recent study
850
Treatment
the key findings of the literature on nonadherence, particularly among bipolar patients. Before proceeding, however, we must note two issues of terminology. First, the
term compliance has been roundly criticized as having a
paternalistic connotation, suggesting a doctorpatient relationship not typical of current practice. Many believe
that the term adherence reflects more accurately the complex processes of collaboration and mutual decision making involved. Therefore, we use the latter term in this
chapter. Second, most of the research and clinical discussion concerning the problem of medication adherence has
CLINICAL MANAGEMENT
As discussed in earlier chapters, both clinician and patient
face a number of challenges in maintaining an effective
treatment regimen. From the patients point of view, many
daunting issues arise concerning the meaning of the illness,
attitudes and expectations about the role of medication,
the supportive resources available, and the consequences
of adherence or nonadherence. These issues are complex,
involving both rational and irrational, conscious and nonconscious processes. Moreover, adherence is a dynamic
phenomenon, changing over time.
The clinicians task is critical, as well as difficult, with
respect to the goal of treatment adherence, and it encompasses multiple potential roles: a teacher providing clear,
complete, and accurate information; a skilled therapist allowing for an open, safe, accepting discussion of the patients concerns, beliefs, and expectations; a skilled psychopharmacologist knowledgeable about options, dosages,
side effects, and drug interactions; an advocate/facilitator
informing significant others and enlisting their positive participation in treatment; and a scientist maintaining knowledge and skills concerning effective treatment practices in
the context of rapidly expanding research on the etiology
and course of illness. Among the inherent obstacles to
the effective management of adherence are several noted
briefly in the following sections; suggestions for addressing these issues and facilitating adherence are also provided. Chapters 18, 19, 20, and 22 elaborate in greater detail
some of these considerations in psychopharmacology and
psychotherapy.
Clinician Attitudes
Patients who fail to follow their therapists suggestions have
in the past been perceived as motivated by pathological processes and nefarious personal traits, labeled resistant, and
thereby in some measure blamed for the failure of their treatment. Yet nonadherence rarely involves only the patients
pathological or irrational side; the truth is far more complex.
The clinician plays a vital role in creating a collaborative,
honest, and supportive environment in which to raise issues concerning treatment adherence with the patient.
Clinicians, of course, experience frustration, impatience,
and even anger when patients discontinue medication or
fail to follow the prescribed regimenparticularly when
the stakes are high and involve personally devastating
Medication Adherence
851
along with many other researchers and clinicians, emphasized the importance of patient education. He recommended
that patients and their families be given instruction booklets concerning the benefits and costs of using and not
using medications, as well as the costs of interrupting or
discontinuing treatment. He noted that constructing life
charts of the course of illness may help patients understand
the recurrent nature of the disorder and how the risk of recurrence is magnified by nonadherence. Advocacy of such
patient and family education is reflected in many psychoeducation programs, increasingly sophisticated psychotherapeutic techniques, and the development of a wide
852
Treatment
853
Medication Adherence
Predictive of
Adherence
Predictive of
Nonadherence
Not
Predictive
Unclear
Disease
Chronicity of illness
Amount of time asymptomatic
Severity of disease
As a general factor
Number of symptoms experienced
Extent of disability
Type of illnesspsychiatric
Patient
Demographics
Age (except extremes)
Sex
Intelligence
Education level
Personality and attitudes
Personality
Health beliefs
Seriousness of illness
Perceived efficacy of treatment
Social supports
Living alone
Unstable/nonsupportive family
Treatment
Treatment regimen
Complexity of regimen
Number and cost of medications
Oral administration
Safety caps
Frequency of dosage
Side effects of medication
Health care delivery
Clear information
Counseling
Reminding strategies
Convenience of clinical setting
Continuity of care
Extent of supervision by others
Source: Based on data in Haynes et al., 1979, 2003; Blackwell, 1980; McDonald et al., 2002; World Health Organization, 2003; DiMatteo, 2004;
Osterberg and Blaschke, 2004.
A great deal of research on nonadherence among psychiatric patients has focused on schizophrenia and has yielded
findings of considerable relevance to bipolar disorder. Young
and colleagues (1999) reviewed 29 studies of nonadherence
to antipsychotic oral medications, conducted between 1986
854
Treatment
Medication Adherence
855
856
Treatment
Table 212. Rates of Nonadherence to Mood Stabilizers and Antipsychotic Medications (Percentage)
Study
Lithium
Divalproex
18a
2030
24
47
Cochran, 1982
52
25
52
23a
53
46
23a
51
42b
30
41
52
79c
50
Bonin, 1999
37
55d
39b
33e
46
14
Carbamazepine
Antipsychotics
38
89
18
48f
22
medications, populations, and facilities, a lack of adherence to medication regimens is a substantial problem for
patients with bipolar disorder. The consequences of this
nonadherence appear obvious but bear emphasis: patients
who discontinue medication or use it incompletely or
inappropriately greatly increase their risk for relapse and
Medication Adherence
857
the Health Belief Model, which emphasizes complex interactions among variables, including a mental calculus of attitudes about the costs and benefits of adherence in relation to
personal goals and resources.
While all of these research perspectives contribute important information, they also remind us that each investigators approach may encompass some but not all of the
important factors. Moreover, the various factors likely interact in highly complex ways for different individuals.
And some of the most important variables may be exceptionally difficult to measure. These include beliefs, expectations, personal predictions, and subjective weighing of
costs and benefitsall cognitive operations that may be
distorted by mood and judgment.
858
Treatment
rejection of lithium, the most concrete symbol of the illness. After several decades of work with patients taking
lithium, Schou (1997, p. 361) summarized the factors that
he and other researchers believe are involved in lithium
nonadherence as follows:
Non-adherence is a complex phenomenon and may have
a number of causes. Patients may be inadequately instructed or negligent, they may stop taking lithium because it is not as effective as they had expected it to be,
or they may stop taking the drug because it is so effective
that there are no further recurrences and they think that
they no longer need medication. Patients may stop taking
lithium because of side-effects, because they dislike having their mood regulated by a drug, or as a result of antidrug pressure by the media or the patients immediate environment.
Patients may also stop lithium because they miss the
exhilaration and excess energy experienced during previous hypomanias. If, despite lithium maintenance treatment, patients develop a slight manic recurrence, they
may feel unusually well, on top of the world, and in no
need of further lithium. They may then discontinue the
treatment, with the result that the impending mania develops into a full-blown one. . . .
It is also clear that attitudes toward medication and adherence may change over time. Cochran (1982), while conducting a brief intervention focused on adherence among
bipolar patients, noted that during treatment of nonadherence, patients often followed a pattern in their ability and
willingness to articulate their attitudes toward lithium. Initially, they discussed their appreciation of the drug and expressed little ambivalence. By the third session, however,
they frequently spoke of extreme ambivalence about lithium
and expressed considerable concern about future adherence. Cochran observed that patient concerns centered on
the following issues:
Personal controlfrustrations with the medical model,
which patients perceived as focused more on symptoms
than on personal gains, and insufficient emphasis on the
establishment of alternative means of control, such as
changes in diet or reduction in stress.
Changes in life brought about by successful lithium
treatmentmissing of highs and the impact of stabilization on relationships.
Lack of predictability in the course of the illness, possible
breakthrough episodes, and length of time on lithium
and discomfort about having to be passive in light of
possible impending episodes.
Issues concerning lithium, such as its safety, mechanism
of action, side effects, and efficacy.
Sample Size
Adherence
74
(49 BP)a
47
(38 BP)
48
(40 BP)
37 BP
216 BP
73
(36 BP)
48 BP
133
(61 BP)
67a
(53 BP)
133
(61 BP)
Miklowitz, 1992
23 BP
114 BP
Mood-congruent psychosis;
better social functioning
Male; Caucasian
140 BP
44 BP
149 BP
76
(38 BP)
200 BP
Aagaard and
Vestergaard, 1990
32 BP
98
(78 BP)
Nonadherence
Sample Size
111 BP
72
(61 BP)
171 BP
101 BPc
184 BP
32,993 BPd
Adherence
Nonadherence
Disliked the idea of moods being
controlled by medication; felt
well, saw no need for medication;
felt illness more related to life
events than biologically based
Disliked the idea of moods being
controlled by medication; disliked
the idea of having a chronic
illness; felt depressed
Greater number of
medications
Note: Most earlier studies focused primarily on lithium treatment; more recent studies have included anticonvulsants and antipsychotic
medications.
BP = bipolar; SES = socioeconomic status.
a
35 patients on lithium, 32 on carbamazepine, all female.
b
For lithium but not carbamazepine patients.
c
101 patients matched with identified caregivers.
d
Prescribed antipsychotic medications.
Table 214. Rank Ordering of General Reasons for Nonadherence: UCLA Study
Rank
Order
1
2
3
4
5
6
7
8
9
10
Total Patient
Sample (n = 47)
Missed highs
Felt less creative
Felt less productive
Felt less attractive to friends
Independent Clinician
Sample (n = 50)
Felt well; saw no need for lithium
Missed highs
Bothered by idea of chronic illness
Felt less creative
Felt less productive
Bothered by idea that moods are
controlled by medication
Hassle to take medication
Felt less attractive to friends
Felt depressed
Felt less attractive to spouse
Medication Adherence
Figure 211. Primary reasons for stopping medication identified by clinicians (n = 41) and by previously nonadherent (PNAD, n = 33) and adherent (AD, n = 37) patient groups. (Source: Pope and Scott, 2003. Reprinted with
permission from Elsevier.)
35
30
% Endorsing Item
25
20
15
10
5
0
Clinicians
Bothered, chronic illness
Hassle to take medication
861
PNAD
Bothered, mood controlled
Felt well, saw no need to take medication
AD
Felt depressed
Miss highs
862
Treatment
Additional studies have attempted to understand patients subjective reasons for nonadherence or to predict
adherence over time. Some studies have tested versions of a
health belief model in which patients perceptions of the
severity of their illness and beliefs about the benefits
of medication, about themselves, and about control over
their illness combine to predict adherence. For instance,
Cochran and Gitlin (1988) assessed various attitudes and
beliefs among a later sample from the UCLA Affective
Disorders Clinic and tested a complex social psychological
model of adherence. For the most part, their results confirmed the model, indicating that attitudes about lithium
and its effects can predict adherence. An important finding was patients belief that if their psychiatrist and their
friends and family had positive views of the treatment and
its effectsand if they themselves were motivated to meet
the psychiatrists and others expectationsadherence was
more likely. The investigators noted that relevant relationships, including the patientphysician relationship, may be
important sources of adherence-related attitudes.
Keck and colleagues (1997) assessed patients reasons for
nonadherence to their medication regimen (various mood
stabilizers and combinations of drugs) using a questionnaire
derived from previous studies of reasons for nonadherence.
In their sample of 140 hospitalized manic patients followed
for a 1-year period, they found that only 31 percent were totally adherent. The most commonly cited reasons for total or
partial nonadherence were denial of illness or poor insight
(63 percent); side effects (27 percent); belief that they had recovered from the illness (11 percent); and others, including
practical considerations such as the cost of medication.
Schumann and colleagues (1999) reported on a 6-year
retrospective study of reasons for nonadherence among 76
patients in two clinics in Vienna and Berlin; 50 percent of
the patients were bipolar, with the remainder being unipolar or schizoaffective. Although results were not reported
by diagnostic group, the investigators indicated that diagnosis was not significantly associated with adherence or
reasons cited for discontinuation of medication. They found
that 54 percent of the patients had discontinued treatment
at least once during the 6-year period. The most commonly
cited reason was resistance against long-term treatment.
Comparisons of adherent and nonadherent patients revealed
significant differences on three attitude items: resistance to
prophylaxis, denial of the effectiveness of lithium, and denial of the severity of illness.
Greenhouse and colleagues (2000) specifically tested
the role of cognitive acceptance or denial of illness in predicting self-reported adherence during a 1-week period.
Acceptance and denial were defined by items on a coping
questionnairefor example, Ive been accepting the reality of the fact that it [diagnosis of bipolar-I disorder] has
Medication Adherence
to their medication. Not only may mood symptoms be misperceived as medication side effects, but mood symptoms
especially depressionmay affect the degree to which patients experience and are bothered by somatic side effects
(e.g., Abou-Saleh and Coppen, 1983). Indeed, it is likely
that personality and interpersonalenvironmental characteristics influence patients perceptions and tolerance of
medication side effects.
Side effects, therefore, represent both real deterrents to
medication adherence and psychological issues that may
play a complex role in adherence. There are some indications that different mood stabilizers may have fewer or differing side effects, resulting in varying levels of adherence
to the prophylactic regimen, but significant differences have
not been convincingly documented. One study of adherence to antipsychotic medication among a sample of outpatient veterans (most diagnosed with schizophrenia) is
suggestive. The investigators found significantly better rates
of adherence to atypical than to typical antipsychotic medications, as measured by prescription refills (Dolder et al.,
2002). Yet while better adherence was found for the medications with fewer side effects at 6-month follow-up, no differences were seen at 12 months. A recent large study of
claims data for antipsychotic treatment in more than 15,000
commercially insured bipolar patients found greater adherence for individuals taking atypical rather than typical antipsychotics (Gianfrancesco et al., 2006). British researchers,
however, found significantly lower adherence to atypical
antipsychotics than to lithium (Horne et al., 2006).
Greater availability of medical resources to treat adverse
side effects may enhance acceptance of long-term medication. Certainly, education about side effects is essential. A
recent British study found that more than 60 percent of the
223 patients surveyed were dissatisfied with the information they received about side effects from their physicians
(Bowskill et al., 2006). It must be emphasized, however,
that subjective and psychological factors also play an important role in patients reactions to side effects. In their
prospective study of adherence in bipolar patients, for example, Kleindienst and Greil (2004) demonstrated that
concepts patients hold about their illness strongly influence the subjective impairment caused by medication.
Chapters 18 through 20 address side effects and their management in greater detail.
863
Patient-Related Factors
As noted earlier, few demographic variables (age, gender,
income, education) appear to predict adherence to lithium
or other medications reliably, an observation consistent
with results of medication adherence studies in general
(see Table 211). Among the exceptions to this rule are findings that being married is associated with better adherence
and that living alone is associated with poorer adherence3;
less consistently, adherence increases with age.4
Clinical features are also inconsistently associated with
adherence, with the exception of a constellation of variables related to elevated mood. As discussed earlier, Jamison and colleagues (1979) found that missing of highs was
one of the few factors significantly differentiating adherent from nonadherent patients (see Table 214). Likewise,
Connelly and colleagues (1982) observed that nonadherence was associated with elevated mood. Lenzi and colleagues (1989) found that grandiosity was significantly associated with nonadherence, while Rosen and Mukherjee
(unpublished data) noted that nonadherence was associated with a history of grandiose delusions. Similarly, a
study of patients with bipolar-I disorder showed lithium
adherence to be less likely among those who experienced
recurrent manic episodes (without evidence for clinical
depression) than among those who experienced both
disabling depressive and manic episodes (Lenzi et al.,
1989).
Miklowitz (1992) found that among manic patients, those
with more severe psychotic symptoms (and schizoaffectivemanic patients generally) were more nonadherent. Other illness factors, such as polarity of episodes, severity, family history, diagnostic subtype, and frequency of affective episodes,
are ambiguously or inconsistently related to adherence.
Nonetheless, it might be predicted that number of years ill, in
complex interaction with age and clinical history, would affect adherence. Clinical experience suggests that younger patients tend to be less accepting of their diagnosis and prognosis, and their attitudes change with experience and the
consequences of the illness over time.
The role of mania, and perhaps psychosis in particular,
may be especially relevant to the patients level of insight,
864
Treatment
awareness, and acceptance of illness. Ghaemi (1997) reviewed studies examining insight (awareness that one has a
mental disorder or that one is exhibiting symptoms of psychopathology) among patients with severe psychopathology
and its correlation with clinical features. In general, he
found that lack of insight is just as prevalent in patients with
mania as in those with schizophrenia. Yen and colleagues
(2004) found that poorer insight in bipolar illness is more
likely in males and in patients with a shorter duration of illness and a history of psychosis. It is also related to the nature
of the clinical episodes experienced by patients (see Chapter
22). Patients who experience pure mania show less insight
than those who have predominantly mixed states (Cassidy
et al., 2001; DellOsso et al., 2002); depressed patients show
greater insight than manic patients5; and bipolar-II patients
appear to show less insight than bipolar-I patients (Pallanti
et al., 1999). Ghaemi (1997) found no studies examining the
role of insight in medication adherence among bipolar patients; however, results of studies previously mentioned concerning patients beliefs that they are not ill, or no longer ill,
clearly reflect a similar concept. Research in the field of
schizophrenia has demonstrated a strong association between lack of insight and nonadherence (e.g., Fenton et al.,
1997; Young et al., 1999), and further studies of the meaning,
correlates, and consequences of lack of insight among bipolar patients are needed. Treatment for bipolar illness often
results in improved insight,6 but the effect of this on adherence has not been adequately studied.
Two further patient characteristics warrant consideration in the context of adherence. The first is substance
abuse, which is increasingly recognized as a common and
complicating feature of the course of bipolar disorder (see
Chapter 7). It may play a particularly pernicious role in
poor adherence to medication, as several studies have now
reported.7
A second salient patient characteristic is one that has
rarely been examined: personality disorders that may interact with clinical and attitudinal variables to affect adherence. One large study of 200 bipolar-I and -II patients
found that personality disorders assessed by the Structured
Clinical Interview for the Diagnostic and Statistical Manual
(DSM) (SCID) II were strongly associated with medication nonadherence (Colom et al., 2000), as did an earlier,
considerably smaller study (Danion et al., 1987) and a
Danish one (Aagaard and Vestergaard, 1990). On the other
hand, another study, which did not report details on the
method used for assessing personality disorders, did not
find such an association (Schumann et al., 1999), nor did a
recent prospective study of 171 bipolar patients conducted
in Germany (Kleindienst and Greil, 2004). It might be
speculated that the relatively poor clinical course associated with many forms of personality disorder (see Chapter
10) involves medication nonadherence as a key mechanism of the effects of personality pathology. Personality
pathology is highly likely to contribute not only to behavioral problems, such as poor perseverance and inadequate
environmental supports, but also to increased substance
abuse and maladaptive understanding of the illness, its
consequences, and the role of medication. However, patients with personality pathology may also respond more
poorly to medication and thus perceive less benefit from
adhering to their treatment regimen.
In their comprehensive review of 25 studies of medication adherence in bipolar patients, Perlick and colleagues
(2004b) concluded that the most consistent risk factors for
nonadherence are comorbid substance abuse, comorbid
personality disorder, being single or living alone, having
limited insight or knowledge about bipolar illness, and
difficulties with side effects (especially cognitive changes,
weight gain, lethargy, and problems with tremor and coordination). For an important subgroup, manic symptoms
and missing highs are also important. Less clearly related
are gender, number of affective episodes, and age.
Environmental Factors
Supportive resources and practical matters have been
identified as key contributors to medication adherence in
patients with schizophrenia, but have been studied far less
often in the context of bipolar disorder. Many studies have
found that living alone or being single is predictive of nonadherence in bipolar patients8; in a related finding, Lenzi
and colleagues (1989) noted that adherence was associated
with degree of social support (see also Tables 211 and
213). The existence of positive relationships doubtless affects adherence in both direct and indirect ways, and such
issues deserve considerably more investigation. Also, of
course, marriage and adherence may both be associated
with positive personal attributes and a relatively better clinical course. Obviously, too, if supportive relationships help
facilitate medication adherence, psychotherapy may be an
important source of support and may influence adherence
directly as well as indirectly (see Chapter 22).
Environmental factors also include the occurrence of
chronic and episodic stressors and the extent to which such
experiences may undermine efforts to adhere to medication. To date, only one study has directly investigated the
potential effect of life events on symptomatology through
the mechanism of changes in adherence. Johnson and colleagues (1998) examined this model among a sample of 67
bipolar-I patients over a 1-year period but found no such effect; instead, they found that both adherence and life events
affected symptomatology independently and directly.
Other issues concerning practical mattersin particular, medication costs and treatment affordability and
Medication Adherence
Clinician-Related Factors
The therapeutic alliance has rarely been studied in the
context of bipolar patients adherence to medication, although its importance has been well documented in studies of schizophrenia (see, e.g., the review by Fenton et al.,
1997). As noted previously, Cochran and Gitlin (1988)
tested a complex model of attitudes associated with adherence and found that patients perceptions of physicians attitudes about lithium were important to the patients own
attitudes, although that study did not examine the quality
of the therapeutic relationship. Yet it appears probable that
the clinicians role is critical, extending well beyond the
mechanics of appropriate prescribing (Frank and Frank,
1991; Slavney, 2005).
Medication-Related Factors
Patients perceptions of both the efficacy and the side
effects of the medications they take, or do not take, are
clearly important. The relationship between perceived efficacy of medication and adherence is complex and little
studied. Two studies (Jamison et al., 1979; Connelly et al.,
1982) found no association between adherence and patients evaluation of medication efficacy, but two others
found to the contrary (Bech, 1982; Bonin, 1999). Adherence, as we have seen, is complexly affected by individual
differences in perception and toleration of side effects.
Several studies have found that nonadherence is associated
with the severity or number of subjective concerns about
side effects.9 Other investigators, however, have not found
this association.10
Certain intrinsic features associated with the pharmacological treatment of bipolar patients may result in exceedingly difficult clinical situations that clinicians must
work to overcome. These intrinsic qualities of lithium and
the other medications used to treat bipolar illness are listed
below with respect to lithium; their generalizability to
other medications is apparent, although incomplete.
Lithium (unlike analgesics, neuroleptics, or benzodiazepines) has a long-delayed therapeutic action: 5 to 7
days for an antimanic effect, usually much longer for an
antidepressant effect.
Patients are expected to stay on the drug for an indeterminate time, much of it in a more or less normal clinical
state, with no immediate felt need for the drug.
If a patient stops the medication, the negative consequences of nonadherence (recurrence of mania and/or
depression) are often delayed. Rarely is there an immediate negative effect.
865
The cessation of lithium, on the other hand, is often accompanied by relatively immediate positive experiences,
either because of the disappearance of side effects or because of breakthrough hypomania (often a contributing
factor to lithium nonadherence in the first place).
The initiation of lithium treatment often is associated with
unpleasant events in the patients memory (e.g., psychosis,
hospitalization, violence, agitation).
If lithium is first prescribed for a manic episode, the natural history of the illness predicts that the patient is at
significant risk for a postmanic depression, which further associates the onset of lithium treatment with unpleasant psychological and physical experiences.
Compounding these difficulties, lithium has no known
intrinsic reinforcing qualities, either immediate or delayed.
CONCLUSIONS
Many clinicians, having once diagnosed bipolar illness and
prescribed an effective medication, tend to assume that the
difficult part is over. On the contrary, in the words of one
patient, the war has just begun. Nonadherence to the use
of lithium and other medications is costly not only to
bipolar patients, but also to those who know them, and to
society as a whole.
Research on the factors involved in nonadherence
among bipolar patients is relatively sparse, but much information exists in research conducted on related illnesses,
such as schizophrenia. One set of factors includes patient
variables such as attitudes about the illness and the role of
medication, as well as reactions to side effects. The role of
the patients insight into the disorder may be crucial, with
Table 215. Summary of Studies of Interventions to Enhance Treatment Adherence among Patients with Bipolar Disorder
Design
Intervention
Participants
Outcome
Comments
Shakir et al.,
1979
Mirror design
Weekly interpersonal
group psychotherapy
Cochran,
1984
Randomized
controlled trial
Weekly modified
cognitive-behavioral
intervention for 6 wk
N = 28; 14 to intervention,
14 to usual care
Randomized
controlled trial
Harvey and
Peet, 1991
Randomized
controlled trial
N = 26 partners of
patients; 14 to
intervention, 12 to
control group
N = 59; 29 to educational
group, 30 controls
Clarkin et al.,
1998
Randomized
controlled trial
Five theme-oriented
groups for partners
of patients with
bipolar disorder
Videotaped lecture on
lithium, handout,
and home visit
Manual-driven marital
therapy (25 sessions)
Lithium levels;
pretreatment = .53
mEq/l; post-treatment =
.94 mEq/l
Significantly enhanced
adherence immediately
after intervention and
at 6 mo
Nonadherence did not
differ between groups
Perry et al.,
1999
Randomized
controlled trial
Individual teaching of
early symptom
recognition (7 to 12
sessions)
N = 69; 34 to intervention,
35 to control group
866
Study
N = 42; 19 to intervention,
23 to usual care
867
Weiss et al.,
2000
Controlled trial,
sequential block
enrollment
Weekly integrated
group therapy
(1220 sessions)
Miklowitz
et al., 2000
Randomized
controlled trial
Lam et al.,
2000
Randomized
controlled trial
Colom et al.,
2003
Randomized
controlled trial
Manual-driven
family-focused
psychoeducational
treatment; 21 sessions
over 9 mo
Cognitive-behavioral
therapy, 1220
sessions within 6 mo
(mean = 16.3 sessions)
Psychoeducational group
program, 21 sessions,
90 min each
Lam et al.,
2003
Randomized
controlled trial
Individual manual-driven
cognitive therapy
N = 45; 21 to intervention,
24 to control
conditions; all
participants had dual
diagnosesb
N = 101; 28 to family
treatment, 51 to control
group; 22 terminated
early
No difference in
adherence between
groups
Improvements in substance
dependence and mania but not
depression for intervention group
No main effect of
psychosocial treatment
on predicting
medication adherence
N = 25; 13 to intervention,
12 to control group
Therapy group
showed significantly
better adherence over
12 mo (p <.05)c
At 2 yr follow-up,
intervention patients
had higher lithium
levels ( p = .03)
N = 120 euthymic
bipolar-I and -II
patients; 60 to
intervention, 60 to
control group
N = 103; 51 to intervention,
52 to control group
Significantly greater
adherence in treatment
group (p = .02 for
self-report; p = .06 for
serum levels)
868
Treatment
NOTES
1. This description and others by a patient with manicdepressive illness were written by one of the authors, Kay R.
2.
3.
4.
5.
6.
7.
8.
9.
10.
22
Psychotherapy
At this point in my life, I cannot imagine leading a normal life without both taking lithium and
being in psychotherapy. Lithium prevents my seductive but disastrous highs, diminishes my depressions, clears out the wool and webbing from my disordered thinking, slows me down, gentles me out, keeps me from ruining my career and relationships, keeps me out of a hospital,
alive, and makes psychotherapy possible. But, ineffably, psychotherapy heals. It makes some
sense of the confusion, reins in the terrifying thoughts and feelings, returns some control and
hope and possibility of learning from it all. Pills cannot, do not, ease one back into reality; they
only bring one back headlong, careening, and faster than can be endured at times. Psychotherapy is a sanctuary; it is a battleground; it is a place I have been psychotic, neurotic, elated, confused and despairing beyond belief. But, always, it is where I have believedor have learned to
believethat I might someday be able to contend with all of this.
No pill can help me deal with the problem of not wanting to take pills; likewise, no amount
of analysis alone can prevent my manias and depressions. I need both. It is an odd thing owing
life to pills, ones own quirks and tenacities, and this unique, strange and ultimately profound
relationship called psychotherapy.
Patient with manic-depressive illness1
870
Treatment
use of adjunctive psychosocial therapies to alleviate the behavioral and social adjustment problems associated with
the disorder (Prien and Potter, 1990). Likewise, Vasile and
colleagues (1987) found that psychiatrists and mental
health professionals often de-emphasize psychotherapy in
the treatment of affectively ill patients. Patients themselves,
by contrast, often find psychotherapy a potent adjunct
to mood stabilizers. In the one study in which patients
and therapists were actually asked about the value of psychotherapy in the treatment of bipolar illness, twice as
many patients as physicians thought psychotherapy was
helpful to them in remaining adherent to medication (Jamison et al., 1979). These findings are consistent with those
of a survey of a national depression and bipolar support
group completed two decades later (Goodale and Lewis,
1999).
While medication is the central treatment for bipolar
disorderin both the acute and maintenance phases
psychotherapy is a particularly important adjunct to medication in maintenance treatment. This is true for several
reasons.
First, problems that typically accompany bipolar illness invite psychotherapeutic intervention. The personal,
interpersonal, and social consequences of the disorder,
which are usually severe, can include suicide, violence, alcoholism, drug abuse, unemployment, divorce, parental
neglect, and hospitalization. Although biological variables
predominate in the etiology, the primary manifestations
of bipolar illness are behavioral and psychological, with
profound changes in perception, attitudes, personality,
mood, and cognition. Psychotherapeutic interventions can
be of unique value to patients undergoing such devastating
changes in the way they perceive themselves and are perceived by others, providing the needed monitoring of mood
and life changes. Indeed, some of the newer psychotherapies focus on monitoring these changes as a way of preventing recurrences. The psychosocial consequences of bipolar
disordersuch as loss of employment or a significant decline in employment status, alcohol or other substance
abuse, alienation from loved ones, and frequent marital
and other interpersonal disputesare also precipitants of
recurrences of the disorder. Such life events, often the
subject matter of psychotherapy sessions (Coryell et al.,
1993; Goldberg et al., 1995), may trigger manic or depressive
episodes through, for example, disruption of circadian
rhythms, loss of sleep, or distorted cognitions (Wehr et al.,
1987a; Frank et al., 1994; Miklowitz et al., 1996). In helping to
alleviate the stress-related precipitants of manic and depressive episodes, psychotherapy may temper the progression of
the natural course of the illness (Post et al., 1986).
Second, suicide tends to occur early in the illness (see
Chapters 8 and 25), when patients have the least support
and information and are most likely not to adhere to medication. Indeed, nonadherence to lithium or other mood
stabilizers becomes a major theme in the therapy of many
patients (Jamison et al., 1979; Jamison, 1995; Keck et al.,
1997) (see Chapter 21). Confusion often arises because the
illness itself, as well as its pharmacological treatments, can
affect cognition, perception, mood, and behavior. Psychotherapeutic sessions frequently involve concerns about
being on medication. For example, the effectiveness of medication in ameliorating the illness is not always welcome
because it deprives some patients of energy and muchsought-after highs and can burden them with bothersome
side effects. Moreover, some patients (at least 10 to 15 percent) have a poor response to mood stabilizers (Goldberg
and Harrow, 1999), which may be due in part to nonadherence. Close monitoring of adherence is therefore important, especially because discontinuation of medication
may lead to recurrences of mania and/or depression and
increased risk of suicide.
Third, there are times when clinicians treat bipolar patients who are not taking medication, such as those who
refuse it, those who have medical contraindications or
need surgery, and women who stop taking medication
during their pregnancies. In such cases, psychotherapy
may have to serve as the sole treatment, providing critical
support and monitoring. Psychotherapy, in conjunction
with medication or electroconvulsive therapy (ECT), may
also be the treatment of choice for acutely suicidal patients or for breakthrough depressions in patients prone
to antidepressant-induced cycling.
The emphasis in this chapter is on psychotherapeutic
interventions for patients maintained on mood stabilizers.
The first section focuses on psychotherapeutic issues of
importance in the clinical management of bipolar illness.
These issues are relevant to all aspects of clinical management, whether the patient is being seen for medications only
(the most common clinical situation) or for medications
in conjunction with formal psychotherapyindividual,
group, or familyor with involvement in a self-help group.
The discussion encompasses new developments in psychotherapeutic practices, as well as educational and informational resources, including books, self-help groups, and
websites. Some psychotherapies have been modified for
bipolar patients and described in manuals for testing in
clinical trials; a number of such trials are either completed
or ongoing. The literature on these psychotherapies and
their efficacy is reviewed in the second section of the chapter, with a focus on treatment modalities combining psychotherapy and mood stabilizers. Psychotherapeutic techniques per se, however, are not discussed in detail, in part
because we assume a basic knowledge of the principles and
practice of psychotherapy and in part because no one type
Psychotherapy
of psychotherapy has been demonstrated to be uniquely effective in this patient population. The lack of psychotherapeutic specificity in the discussion here reflects the reality of
clinical practice, namely, the predominance of pharmacological treatments for bipolar disorder and the relatively recent emphasis on psychological interventions. However, we
wish to reemphasize our belief that formal psychotherapy is
beneficial to many, if not most, bipolar patients and is unquestionably essential for many others, especially those who
are suicidal or unwilling to take medication in the manner
prescribed. The limitations of even the most beneficial medications are increasingly apparent to clinicians treating affective illness. It may be hoped that ongoing and future research efforts will determine the specific nature of the most
effective psychological interventions.
CLINICAL MANAGEMENT
We begin this section by summarizing the historical context
for the psychotherapeutic treatment of bipolar disorder. We
then review key issues that arise during such treatment. The
section ends with discussion of important aspects of psychotherapeutic treatment of bipolar illness, including
mood charting, patient education, family education and
family therapy, and the self-help programs of national and
local support associations.
Historical Context
Clinical pragmatism, buttressed by biological assumptions
about etiology, long ago determined the dominance of
medical therapies in the treatment of bipolar illness. Thus
physicians, ancient and modern, have for the most part
sought cures for mania and melancholia not through talking
and listening, but through direct actions of control: mineral
baths, bloodletting, herbs, chains, vapors, bromides, opiates,
warm waters, cold waters, and physical and chemical restraints.2
Psychotherapy, as generally conceptualized, is a set of
formal psychological procedures or exercises that are followed by a therapist and patient and that are designed to
relieve symptoms, improve function, or produce insight.
These procedures, discussed at length later in the chapter,
are derived from a particular theory of psychological development or change.3
Even the pioneers of psychotherapy, the psychoanalysts, tended to perceive patients suffering from bipolar illness as not very good candidates for psychotherapeutic
treatment. Fromm-Reichmann (1949) characterized them
as lacking in complexity and subtlety; Abraham (1911) as
impatient, envious, exploitive, and with dominating possessiveness; and Rado (1928) as continually involved in a
raging orgy of self-torture. Bipolar patients generally were
871
Psychotherapeutic Issues
The competent and compassionate psychotherapy of bipolar illness is predicated on a solid knowledge of the disorder. Kraepelins injunction to his turn-of-the-century
medical students remains compelling: It is one of the
physicians most important duties to make himself, as far
as possible, acquainted with the nature and phenomena of
872
Treatment
insanity (Kraepelin, 1904, p. 3). A solid knowledge of bipolar disorder encompasses phenomenology, the natural
history of the illness (including its recurrent nature, problematic course, high mortality rate, and seasonal patterns),
biological aspects (including medication responses in mania and depression), biological theories of etiology, and
mechanisms of action of the drugs used for treatment.
Therapists with a good scientific grasp of the psychological
phenomenology of the illness, as well as the biological, will
be more therapeutically competent. They will also be more
likely to avoid the biological determinism that is common
in therapists who are well grounded in biological theories
but poorly trained in psychological studies such as personality theory and development, neuropsychology, and social
psychology.
The psychotherapy of bipolar illness requires considerable flexibility in style and technique. Flexibility is necessary because of the patients changing moods, thinking,
and behavior, as well as fluctuating levels of therapeutic
dependency intrinsic to the illness. Fluctuations in functioning that occur within as well as between episodes of
the illness pose a serious challenge to therapists, who must
adjust their treatment options, strategies, and attitudes to
meet the demands of the individual patient and the specific phase of the illness. In the therapeutic relationship,
a long-lead approach is often useful to maximize the patients awareness of and sense of control over his or her behavior. It is important not to attempt to control the patient
unduly and not to allow medications to become the focus
of a power struggle; various psychoeducational treatments
have been developed and tested for this purpose (see the
later discussion). A thin line exists between too much
and too little therapeutic control: too much may lead to
increased dependency, maladaptive rebellion, decreased
self-esteem, or nonadherence; too little may lead to feelings of insecurity, an unnecessarily tenuous hold on reality, and feelings of abandonment. The patient may see
signs of caring in the therapists firm, consistent orders
for routine medication levels or tests of thyroid, liver, and
kidney functioning but engage in unnecessary power
struggles and refuse to comply with medication regimens
when the therapist places undue emphasis on precise
medication patterns (e.g., not allowing for some degree of
self-titration).
Because bipolar disorder has a long-term course with
highly variable manifestations, therapeutic alliance and support play a central role in treatment. The alliance is the product of good rapport, combined with knowledge about the
course of the individual patients illness. Collaborative aspects of management through self-ratings, chartings, and
patient and family education (using films, lectures, books,
or handouts), discussed later in the chapter, are integral to
Perspectives of Patients
The following description of the bipolar form of manicdepressive illness was written by a patient who, by age 30,
had been through two violently psychotic, ecstatic manic
episodes, countless expansive and euphoric hypomanias,
occasional mixed states, several lengthy and incapacitating
suicidal depressions, and a nearly lethal suicide attempt:
There is a particular kind of pain, elation, loneliness, and
terror involved in this kind of madness. When youre high
its tremendous. The ideas and feelings are fast and frequent like shooting stars and you follow them until you
find better and brighter ones. Shyness goes, the right
words and gestures are suddenly there, the power to seduce and captivate others a felt certainty. There are interests found in uninteresting people. . . . Feelings of ease,
intensity, power, well-being, financial omnipotence, and
euphoria now pervade ones marrow. But, somewhere,
this changes. The fast ideas are far too fast and there are
far too many; overwhelming confusion replaces clarity.
Memory goes. Humor and absorption on friends faces
are replaced by fear and concern. Everything previously
moving with the grain is now againstyou are irritable,
angry, frightened, uncontrollable, and enmeshed totally
in the blackest caves of the mind. You never knew those
caves were there. It will never end. Madness carves its own
reality.
It goes on and on and finally there are only others recollections of your behavioryour bizarre, frenetic, aimless
behaviorsfor mania has at least some grace in partially
obliterating memories. What then, after the medications,
psychiatrist, despair, depression, and overdose? All those
incredible feelings to sort through. Who is being too polite
to say what? Who knows what? What did I do? Why? And
Psychotherapy
Alluded to here are many of the fears and worries common to most individuals with bipolar illness: the frightening, tumultuous, and extremely damaging aspects (to self
and others) of mania and depression; the powerful effects
of the illness on subsequent functioning and ongoing and
potential relationships, as well as general expectations of
the future; the inherent unpredictability of the course of
the disease; and the pervasive fear, often terror, of recurrence. Practical consequences of mania and depression
usually include, among others, the alienation of friends,
lovers, and family members; the inability to move forward or naturally in a career; and major financial problems
stemming from overspending, ill-considered investments,
substantial and often uninsurable medical expenses, and
legal difficulties. Alcohol and substance abuse are common
(see Chapter 8). Additionally, many individuals who have
bipolar illness find it difficult to adjust to the idea of having
a serious, chronic, and life-threatening illness, one that
generally requires lifelong maintenance medication, with
side effects, for its control. Consequential features pervade
this illness, including a fundamental, if usually transitory,
inability to perceive reality with accuracy and to judge a
course of action with prudence. Once an acute episode is
over, the person is left with palpably shaken self-confidence.
For a considerable period after a manic or depressive
episode, many patients continue to question their judgment,
their ability to assess situations, and their capacity to understand their relationships with other people.
Etiological assumptions about the disorder deeply affect
the highly individualized experience of bipolar illness. Despite the compelling arguments for its biological origins
and despite the potential of such arguments to alleviate the
associated guilt and stigmapatients often find these explanations intuitively unpersuasive, especially in the early
stages of illness. Thus although some patients come to believe that profound depression is biologically rooted, others
interpret it as a character problem or a spiritual crisis, and
873
Another typical concern derives from the heritable component of bipolar illness and recurrent depression. Many
patients, having grown up in an environment of mental illness and/or extreme mood swings, express fear that they will
end up like the affected parent, especially if that parent has
been severely disabled, repeatedly hospitalized, violent, or
alcoholic. The fear is even greater if the parent died by suicide. The daughter of a woman with bipolar disorder described her fear of inheriting the illness and her difficulty in
establishing an independent identity (Anthony, 1975, p. 292):
Ever since I was small, I have been told that I was just like
my mother. I was named after her, and very soon I took to
thinking that I was going to be committed when I was 21,
like she was. . . . I was sure that they were going to come
and haul me away. . . . I felt that the only way I could
874
Treatment
Psychotherapy
to interfere or intrude in the lives of others. Third, suppose it were true that I was depressed. How could they
handle it without embarrassing me? The fact that I was
chairman might have been another factor. Because the
show was running smoothly, there was no need to question the chief executive officer. My guess is that my
friends didnt say anything because they probably
couldnt believe that it was true. . . . when I was hypomanic, none of my colleagues confronted me. Here,
again, they were following the social norm of not interfering. Because I had previously been depressed, they probably perceived it as a recuperative period and gave me the
benefit of the doubt.
Inevitable ruminations about behavior when ill, especially when manic, are part of the recovery phase (Lowell,
cited in I. Hamilton, 1982, p. 218):
Ive been out of my excitement for over a month, I think,
now, and am in good spirits, though I dont feel any rush
of eloquence to talk about the past. Its like recovering
from some physical injury, such as a broken leg or
875
876
Treatment
and make storage of memories or good recall unlikely. Denial often leads to medication nonadherence, an issue discussed in detail in Chapter 21.
The treatment of denial, although not always successful,
frequently becomes easier as time passes and the illness reappears too often to be disowned, even unconsciously. Denial
can be dealt with effectively in psychotherapy by exploring
the meaning and consequences of the illness for the patient.
Ongoing education about the natural history of the illness,
with emphasis on its high relapse rate, undercuts the process
of denial as well, as do straightforward and informed discussions of the risks and benefits of medication.
Ambivalence is another common reaction among patients with bipolar disorder, especially when caused by the
incongruence between the behavioral expression of the illness and its biological treatment. As a disorder of mood
and behavior, bipolar illness has symptoms and consequences that are largely psychological and interpersonal in
nature. At the same time, effective mood stabilizers can result in relatively rapid improvement. The treatment response is obvious and gratifying to the clinician, if not the
patient, and lends credence to a strongly biological treatment program. This belief is further encouraged by the
demonstrated inability of psychotherapy alone to relieve
or prevent bipolar episodes. Also encouraging a biological
focus is the fact that treatment with mood stabilizers is imbued with a medical ambiance and embedded in a highly
structured medical regimen: the physician orders laboratory tests of serum levels of mood stabilizers, as well as
kidney, liver, and thyroid functioning, and asks specific
medical questions about side effects, usually somatic rather
than cognitive in nature. This understandable focus of
physicians on the medical aspects of bipolar illness often
stands in a pointcounterpoint relationship to the perspective of patients, who are likely to be more focused on
the psychological aspects of their illness and its treatment.
These disparate perspectives can easily lead to a quite arbitrary split between the biological and the psychological.
Conceptualizing bipolar illness as fundamentally a medical disorder has many advantages for the patient. It can decrease stigma, result in effective and specific treatment, and
minimize unwarranted family and individual responsibility for the emergence of the illness. At the same time, however, it can discourage discussion of significant life issues
and problems involved in adjusting to the illness and its
consequences. An overly medical approach can also mean
that psychological concerns about taking medication may
be ignored. Furthermore, taking medication can create its
own stigma because society and patients themselves often
disparage the continuing need for psychiatric drugs.
Biological assumptions about the illness can also make it
more difficult for patients to feel a sense of personal control.
Psychotherapy
877
878
Treatment
may hinder the patients adjustment to treatment. Moreover, the side effects of a medication can be difficult to separate from the medications effect on hypomanic symptoms; they are also sometimes indistinguishable from
symptoms of inadequately treated depressive episodes.
Treatment management under such circumstances is
not straightforward. For example, adherence to a mood
stabilizer regimen, which at best has a tenuous and delayed
relationship to alleviation of the dysphoric features of bipolar illness, competes with behavior maintained by a highly
positive and intermittent reinforcement schedulean exceedingly difficult behavior pattern to modify. It is in some
ways analogous to a drug self-administration paradigm in
which a highly pleasurable and relatively rapid state can
be obtained. For some patients, hypomania or even mania
itself may represent, in effect, an endogenous stimulant
addiction. Clinical experience suggests that patients may
attempt to induce mania by discontinuing medication not
just when they are depressed, but also when they face problematic decisions and life events. Because the negative consequences of such behavior are delayed, it is not always clear
to the patient that the benefits of medication outweigh its
costs. Thus the clinician must be aware of the positive features of mood swings to better understand and thereby treat
the bipolar patient.
Other realistic losses include cognitive, perceptual, physical, emotional, or social changes that result from the side
effects of medications, as well as negative social consequences, such as self-labeling or social stigma (Jamison,
2006). Among the more significant side effects from a psychotherapeutic point of view, described further in Chapters 20 and 21, are those detailed in early papers by Schou
and Baastrup (1973) and Schou (1980): decreased energy,
enthusiasm, and sexuality (all of which can be a factor in
increased marital problems); curbing of activities; and the
common perception that life is flatter and less colorful.
Cognitive dulling and weight gain are also important
indeed, more important to many patients (Gitlin et al.,
1989; Perlick et al., 2004). Moreover, the need to adhere to
a regimented lifestyle, underscored by frequent monitoring of medical and psychiatric status, may trigger the patients feelings of being controlled and hopeless (Jamison,
1995; McAlpin and Goodnick, 1998).
Unrealistic losses include circumstances in which medication and psychotherapy come to symbolize the patients
personal failures. In addition to experiencing the normal
difficulties of adjusting to the need for treatment, patients
occasionally project their other life failures, thwarted ambitions, and personal and professional inadequacies onto
medication, which can thereby become the psychological
scapegoat and represent a rationalization for other failures
that predate the onset of the illness.
Psychotherapy
Fears of Recurrence
The worst fear for most bipolar patients is recurrence of the
illness. Many patients maintain a deep and fatalistic pessimism, however entwined with denial and optimism, about
again becoming manic or depressed. In a poem from Day by
Day, Robert Lowell (1977, p. 31) wrote,if we see a light at the
end of the tunnel, / its the light of an oncoming train. This
is a sentiment to which many of Lowells fellow sufferers can
relate only too well. Some patients become preoccupied with
such fears of recurrence and are almost illness-phobic. They
become unduly self-protective and hyperalert for signs of an
impending episode. These concerns are often reflected in
the process of learning to differentiate normal from abnormal moods and states (see the later discussion). A perceived
decreasing tolerance for affective episodes is a concern that
is usually secondary to the stress of the illness and to the
large amount of psychological energy consumed by earlier
bouts. Patients, often with good cause, fear that their families and friends will grow ever more intolerant with each
new recurrence. Bipolar illness also takes a severe toll on
other relationships, professional activities, finances, and patients ability to handle the emotional stress of their affective
episodes. Thus Lowell wrote, but the breakage can go on
repeating once too often (1977, p. 113). Likewise, in his autobiography, Joshua Logan (1976, p. 338) described a certain
weariness after yet another manic attack: I was only fortyfive years old, but I felt exhausted by this last experience,
hollowed out, as though I were a live fish disemboweled.
879
The need to help patients discriminate normal from abnormal affect is common in psychotherapy. Patients must
learn to live within a narrower range of emotions, yet
master the skill of using those emotions with greater subtlety and discretion. Closely related to the discrimination
of moods is the slow, steady process involved in patients
learning to disentangle what is normal personality from
what the illness has superimposed upon itturbulence,
impulsiveness, lack of predictability, and depression. Patients whose premorbid temperament has been predominantly depressive may have unrealistic expectations about
how much change can be brought about by medication.
Likewise, those with an underlying exuberant temperament may have to become more finely tuned to discerning
normal from pathological enthusiasms (Jamison, 2004).
880
Treatment
Psychotherapy
881
Mood Charting
Before turning to a discussion of psychotherapy, we examine the role of other components of psychological care:
mood charting, patient and family education, and selfhelp groups. Mood charting by patients can provide invaluable information about seasonal and premenstrual
patterns of moods; psychological, environmental, and biological correlates of mood swings; and response to treatment, including possible worsening of the illness (e.g., increased cycling induced by antidepressant therapy; see
Chapter 19).
Administration of a visual analogue scale is straightforward, requiring little time on the part of the patient (see
Chapter 13 for further discussion). The patient is given
sheets of paper, each with a 100 mm line, anchored by 1
(worst Ive ever felt) on the left or the bottom and 100
(best Ive ever felt) on the right or the top. The patient is
then asked to put a mark across the line at the point most
representative of his overall mood (or whatever other variable, such as energy or anxiety level, is being assessed) for
the day. To control for diurnal variations in mood and behavior, ratings should be recorded at approximately the
same time of day or evening. Significant life events and
additional medications required are noted on the rating
sheet. After completion, the dated form is set aside to avoid
influence from earlier ratings. The results can then be
graphed, with time plotted along the horizontal axis and
mood ratings, from 1 to 100, along the vertical. In some instances, patients can do their own graphing.
Two other instruments have been developed for mood
charting: the retrospective Life-Chart Method (LCM-r)
(Leverich and Post, 1993) and the NIMH prospective LifeChart Method (NIMH LCM-p) (Denicoff et al., 1997). The
two follow the same guidelines but differ in the unit of
measureLCM-r is monthly, whereas LCM-p is daily. For
LCM-p, patients are given a computer-readable form to
take home once a month, with instructions to rate their
mood and functioning each day, morning and evening. Selfratings of mood are plotted along a 100 mm line with 25
882
Treatment
relapses on the way to remission is important in minimizing serious, potentially lethal discouragement in a highrisk (i.e., transitional) period. It also alerts patients to the
potential danger of transitional and mixed states, which
should be reported to the clinician.
Patient Education
Am I manic-depressive? We dont use that term, but I
would guess from the record that you are bipolar. Which
is a nice way of saying that yes, Im manic-depressive? . . .
that Im lucky as all get-out to be a complete nut because
we real bats get much more help from lithium than simple neurotics can Ive never heard it put just that way,
but there is some truth in it. (Sloan Wilson, describing
a conversation with his psychiatrist, 1976, p. 436)
100
80
Start Nortriptyline
Figure 221. Course of recovery in a female patient with bipolar-II disorder treated
with antidepressant medications.
60
40
20
0
0
1
2
3
4
5
6
7
8
9
10 11
Time after Onset of Antidepressant Therapy (weeks)
12
13
Psychotherapy
The collaborative nature of the patientclinician relationship is central to effective treatment. Not only must
patients be taught about the natural course and symptoms
of bipolar illness, but they should also be actively encouraged to question their clinicians about diagnosis and treatment, to discuss their concerns about undue delays in
achieving the desired results, and to seek second opinions
when appropriate. If the treating physician or psychotherapist disparages second opinions or consultations, patients
should be encouraged to challenge this view and obtain
the consultation anyway.
In the course of patient education, the chronic and
highly recurrent nature of bipolar illness should be emphasized and reemphasized to the patient. Charts illustrating the relapse rate and worsening course of the untreated
illness (e.g., Fig. 222) and the dramatic effect of a mood
stabilizer can highlight these points for patients, as well as
their families (Fig. 223). Patients should be encouraged to
read about the illness and its treatment (suggested reading
is listed in the appendix to this volume), including the potential neuroprotective effects brought about by lithium
and other mood stabilizers (see color plates 14 and Chapter 14). They should also be given specific information about
their medications and potential risks and side effects. The
safety and efficacy of various treatments and the risks of
no treatment should be outlined. Special attention should
be paid to discussing the potential dangers of antidepressant use in bipolar patients, such as induction of mania
or mixed states, worsening of the natural course of the illness (i.e., shortening of the cycle length), and severe agitation (see Chapter 19). Patients prescribed lithium should
be advised that sudden discontinuance may substantially
increase the risk of relapse and suicide (see Chapter 25).
Education and informed consent do not end with a discussion of risks and benefits and the distribution of fact
sheets, however. Ongoing talks between patient and clinician are essential, perhaps supplemented with lectures
and/or videotapes.
Patients need to be alerted to the symptoms of impending episodes and, with the therapists assistance, encouraged to identify their own individual prodromal patterns.
These patterns have been studied extensively.7 Changes
in sleep patterns are particularly important because they
precede, exacerbate, and accompany mania, and because
mania may be precipitated by sleep loss. As discussed in
Chapter 16, environmental factors leading to insomnia
(e.g., anxiety, excitement, grief), as well as other circumstances (e.g., hormonal changes, travel, drugs), can lead
to mania through sleep deprivation. Wehr and Goodwin
(1987) advised warning bipolar patients that a single
night of unexplainable sleep loss should be taken as an
early warning of possible impending mania. They further
883
884
Treatment
Severe
MANIA
Moderate
Mild
* Admission to NIMH
Missing data
Mild
Moderate
DEPRESSION
Severe
40
42
44
46
48
50
52
54
56
58
60
62
64
66
68
70
72
74
76
78
AGE 47
PATIENT
8 episodes 4 episodes
7 BC
22 UR
AGE 13
9 episodes 4 episodes
*38
15 episodes
16 episodes
AGE 18
PSYCHOTIC
EPISODE
34 SK
81 KD
95 WT
15 episodes
5 episodes
*41
AGE 24
*22
AGE 15
*41
AGE 22
105 BB
108 GM
133 MS
53
AGE 15
19
AGE 16
AGE 52
66
24
152 SM
153 KC
159 ME
AGE 17
28
AGE 21
AGE 36
55
Figure 222. Life course of manic and depressive episodes in bipolar affective illness. Patterns of recurrent affective illness are illustrated in
individual bipolar-I patients (those hospitalized for a manic episode). Manias are plotted above the line and depressions below. Hospitalizations are shaded, and dotted lines indicate uncertain or missing data. Note that most patients show a course of increased severity or frequency
of affective episodes over time. NIMH = National Institute of Mental Health. (Source: Squillace et al., 1984.)
Psychotherapy
1961
1960
1962
1963
1964
1965
90
92
93
94
94
96
96
97
97
99
99
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14
Case
No.
Year
of
first
episode
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1962
1919
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1936
1917
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1956
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22
30
12
04
27
02
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08
09
25
18
10
02
30
08
03
01
23
01
19
01
29
08
04
23
17
02
21
27
19
12
12
27
28
885
SIGNATURES
mania
depression
Figure 223. Effect of lithium in decreasing the frequency and duration of subsequent manic and depressive
episodes. The patient records are arranged according to age; the first two digits of each case number indicate the
year of birth. In the second column is shown the year when the first manic or depressive episode appeared. The diagram shows, for each patient, all psychotic episodes that occurred between January 1, 1960, and July 1, 1966. (Source:
Baastrup and Schou, 1967.)
preferences for treatment. Derived from the same principle as that used by Odysseus when he sought protection
from seduction by the Sirens, such agreements allow patients to consent in advance to certain treatments. General guidelines for drawing up advance directives are
given in Box 221.
886
Treatment
Events with
Somatic Effects
Events with
Psychic Effects
Administration or
withdrawal of drugs or
hormones, medical illness
(e.g., hypothyroidism),
surgery, injury, etc.
Separation, loss,
role change, etc.
Emotional
Reactions
Excitement, anxiely, grief,
etc.
Insomnia
Sleep Deprivation
Sleep Reduction
Mania
Figure 224. Diagram of the hypothesis of sleep reduction as the final common pathway of diverse
factors thought to precipitate mania. (Source: Adapted from Wehr et al., 1987b. Reproduced with permission from the American Psychiatric Association.)
In addition to being educated about the illness and medications, family members should be informed about the importance of recognizing the early signs and symptoms of hypomanic, manic, and depressive episodes. Changes in sleep
patterns, sexual and financial behavior, mood (expansiveness or undue enthusiasm, volatility, pessimism and hopelessness), and judgment, as well as involvement in excessive numbers of projects, are all highly characteristic of
impending affective episodes. As noted earlier, such prodromes, as well as others more subtle or idiosyncratic (e.g.,
increased religious or political interest, avoidance of eye contact), can escape the patients attention. These changes often
are first noted by family members, who therefore can play a
crucial role in early intervention, although Highet and colleagues (2005) found that many family members who care
for patients with depression are able to recognize prodromal
symptoms only in hindsight. In a comprehensive review of
studies of early symptom identification by patients, Jackson
and colleagues (2003) found that a median of 82 percent of
patients could identify early symptoms of bipolar depression, such as changes in mood (48 percent) and psychomo-
Psychotherapy
887
Note: This information is not meant to take the place of consultation with a qualified legal professional.
888
Treatment
Psychotherapy
Psychoeducation
Psychoeducation for bipolar disorder focuses on education about the illness, including symptoms (prodromal
889
and during the episode), treatment options, and the importance of sleep regulation and adherence to medication.
An essential component of almost every new psychotherapy for bipolar disorder, it has also been tested as a specific
method. Its purpose is to encourage the active and informed involvement of patient and family in the treatment
process, following an alliance, not adherence philosophy
(Frank et al., 1995; Toprac et al., 2000; Berk et al., 2004). In
a recent survey, 500 British and American psychiatrists
cited the education of patients as one of their most important clinical priorities (Roy and Williams, 2005). A Brazilian study of 106 bipolar patients found that level of knowledge about treatment, in this case lithium, was directly
related to treatment adherence (Rosa et al., in press).
Psychoeducation deals with two of the most predominant problems in the management of bipolar disorder:
nonadherence to medication and relapse despite adherence. Nearly one-half of patients with bipolar illness fail to
adhere to their treatment (see Chapter 21); however, even
highly adherent patients can suffer relapses (Keck et al.,
1998). As discussed earlier, psychoeducation can help prevent relapses by teaching patients to recognize prodromal
signs and symptoms and notify their treatment team and
relatives. A summary of the results of studies examining
the effect of psychoeducation and psychotherapy on medication adherence is presented in Table 215 in Chapter 21.
Various approaches to psychoeducation were employed
in the studies listed in Table 221, including lectures; videotapes; group discussion; and fact sheets on symptoms, their
management, and medication. Sometimes only the patient
was included and sometimes key relatives, in individual or
group settings. The length of the intervention varied from 2
to 6 weeks; all of the studies included follow-up at periods
of 3 to 18 months. Outcomes ranged from improving
knowledge and understanding and medication adherence
to reducing rates of relapse. (Clinical trials of psychoeducation using CBT techniques are included in Table 222 and
discussed in that section.)
In general, the results of these studies were modest.
Some demonstrated significantly increased knowledge
about the illness. Results varied regarding improvement in
adherence to medication, and in some cases revealed improvement in relatives attitudes. The one study that assessed impact on clinical status found no effect of brief
psychoeducation on relapse rate.
The most comprehensive psychoeducation program, the
Patient and Family Education Program, was developed by
the Texas Medication Algorithm Project (Toprac et al.,
1998, 2000). The aim was to develop medication algorithms
for the treatment of individuals with bipolar disorder,
depression, or schizophrenia and to test the clinical and
cost-effectiveness of these algorithm-driven treatments
Table 221. Clinical Trials of Brief Psychoeducation in the Treatment of Bipolar Patients
Intervention
Study Design
Results
Clinical Observations
Haas et al.,
1988
Peet and
Harvey,
1991
Group psychoeducation
involving a videotaped lecture
on lithium action and side
effects, followed by a home
visit (2 sessions).
Van Gent
and Zwart,
1991
Families of BP patients
randomized to
psychoeducation plus standard
hospital care (n = 12) or
standard inpatient care alone
(n = 8). Follow-up at 6 and
18 mo.
BP patients in remission
randomly assigned to group
psychoeducation (n = 30) or a
wait-list control group (n = 30).
Follow-up at 6 mo. Blood
levels and tablet omission
monitored to determine
adherence.
Partners of BP outpatients
randomly assigned to
psychoeducation (n = 14) or
no intervention (n = 12).
Follow-up at 6 mo (partners)
or 12 mo (patients).
890
Study
Honig et al.,
1997
Multifamily group
psychoeducation (6 biweekly
sessions). Focus on symptoms
of BP, coping strategies, patient
support and advocacy.
Suppes et al.,
2000
Psychoeducation as part of
patient care in the Texas
Medication Algorithm Project
for BP, depressive, and
schizophrenic patients.
Miller et al.,
2004
Multifamily psychoeducational
group therapy (6 sessions) or
family therapy (average of 12
sessions), plus standardized
pharmacotherapy.
891
Note: Clinical trials of psychoeducation using cognitive-behavioral therapy are reviewed in Table 222.
BP = bipolar disorder.
No significant difference in
relapse and medication
adherence was observed in the
two groups. Significantly more
relatives in the psychoeducation group changed from
high to low expressed emotion.
Both inpatient and outpatient
groups experienced significant
symptom improvement.
Improvement in social
functioning was significant for
the inpatient group.
No differences were found
among groups in rates of
recovery or time to recovery.
No measures of psychosocial
functioning or recurrence of
illness were used. The study
involved a relatively small
number of therapy sessions.
The patient population may
have been particularly
refractory.
Table 222. Clinical Trials of Cognitive-Behavioral Therapy for Patients with Bipolar Disorder
892
Study
Intervention
Study Design
Results
Clinical Observations
Cochran, 1984
HirschfeldBecker
et al.,
1998
Perry et al.,
1999
Weiss et al.,
2000
In addition to psychoeducation
and support, groups focused on
identifying and coping with
triggers, recognizing prodromal
symptoms, and dealing with
setbacks.
Scott et al.,
2001
893
Lam et al.,
2000
Table 222. Clinical Trials of Cognitive-Behavioral Therapy for Patients with Bipolar Disorder (continued)
Study
Colom et al.,
2003a
Colom et al.,
2003b
894
Lam et al.,
2003
Lam et al.,
2005b
Intervention
Study Design
Results
Clinical Observations
895
Ball et al.,
2006
Scott et al.,
2006
No significant differences
between groups were
observed in recurrence rates
or medication adherence.
CBT appeared to be more
effective in those with a
history of fewer episodes.
Table 223. Clinical Trials of Interpersonal and Social Rhythm Therapy for Patients with Bipolar Disorder
Intervention
Study Design
Results
Clinical Observations
Frank, et al.,
1999; Frank,
2000
Frank et al.,
2005
896
Study
Table 224. Clinical Trials of Family/Couples Therapy for Patients with Bipolar Disorder
Intervention
Study Design
Results
Clinical Observations
Miller et al.,
1991
Clarkin et al.,
1998
Miklowitz
et al., 2000
At termination, medication
adherence and overall functioning were significantly
better for the psychotherapy
group. There was no difference in symptomatology
between the two groups.
The FFT group experienced
significantly fewer depressive relapses and longer
interepisode intervals than
the comparison group. The
FFT group also showed an
overall decrease in depressive
but not in manic symptoms.
Miklowitz
et al., 2003
897
Study
The effects of FFT were independent of medication adherence, although higher adherence in both groups was associated with
greater stabilization of manic symptoms.
FFT was associated with a more positive
nonverbal interactional style, which partially mediated a more favorable outcome.
BP patients from families with high expressed emotion showed the most dramatic symptom reduction.
FFT involved more extensive therapist
contact. There was a lack of control over
patients medical regimens.
Table 225. Effectiveness Studies Involving Psychotherapy for Patients with Bipolar Disorder
Study
Intervention
Study Design
Results
Clinical Observations
Sachs et al.,
ongoing
A multisite randomized
effectiveness study. BP
patients (n = 5,000) to be
recruited in 17 centers.
Callahan
and Bauer,
1999
Simon et al.,
2005
BP = bipolar disorder.
Psychotherapy
Cognitive-Behavioral Therapy
CBT, developed by Beck and colleagues (1979), is currently
the most widely used and tested psychotherapeutic approach for which a manual has been created. It was originally developed for major depression but has been adapted
and tested for numerous other conditions, including bipolar disorder. The underlying assumption is that depressionprone individuals possess negative self-schemata (beliefs),
labeled the cognitive triad. Specifically, depressed patients
have negative views of themselves as worthless, inadequate,
unlovable, deficient; of their environments as overwhelming, filled with obstacles and failure; and of their futures
as hopeless, as though no effort will change the course of
their lives. There have been far fewer studies of cognitive
style in bipolar disorder than in major depression. The results of those that have been conducted suggest that cognitive styles in both mood disorders are similarly fragile and
that negative self-esteem is a robust predictor of depressive
and manic relapses (Scott et al., 2000; Scott and Pope, 2003;
Jones et al., 2005). In administering CBT, the therapist is active and directive and, applying principles of logic and the
scientific method, facilitates a rational approach to thinking
with regard to the patients current life circumstances. The
patients thoughts and assumptions are treated as hypotheses that can be tested to verify their accuracy.
To foster a spirit of collaborative empiricism, CBT therapists typically begin treatment by educating patients about
their disorder. When a new technique is introduced, the
therapist begins by presenting its rationale. In educating
patients, the therapist builds the therapeutic alliance. To
maximize rapid response to treatment, emphasis is placed
899
900
Treatment
Introduction
What is bipolar illness?
Causal and triggering factors
Symptoms (I): Mania and hypomania
Symptoms (II): Depression and mixed episodes
Course and outcome
Treatment (I): Mood stabilizers
Treatment (II): Antimanic agents
Treatment (III): Antidepressants
Serum levels: Lithium, carbamazepine, and valproate
Pregnancy and genetic counseling
Psychopharmacology vs. alternative therapies
Risks associated with treatment withdrawal
Alcohol and street drugs: Risks in bipolar illness
Early detection of manic and hypomanic episodes
Early detection of depressive and mixed episodes
What to do when a new phase is detected
Lifestyle regularity
Stress management techniques
Problem-solving techniques
Final session
Source: Colom and Vieta, 2006. John Wiley & Sons. Reproduced with
permission.
Psychotherapy
dysfunction and not in personality. The initial phase includes a systematic diagnostic evaluation, psychoeducation, a review of medication, and an examination of current relationships and changes proximal to the emergence
of symptoms. At least one of four problems (grief, interpersonal disputes, role transitions, role deficits) becomes
the focus of treatment.
Frank and colleagues (1994) adapted interpersonal psychotherapy for bipolar disorder by adding a behavioral
component to regulate patients social rhythms and termed
their approach IPSRT. The importance of regulating such
rhythms had been demonstrated earlier in research conducted at NIMH (Wehr et al., 1987a,b). The focus of the
method is on disruptions in interpersonal relationships
that precede the onset of recurrence of an episode (manic
or depressive). The four problem areas of interpersonal
psychotherapy are also considered potential triggers of
episodes in this adaptation. In IPSRT, grief includes not
only grief for the death of a loved one, but also the mourning frequently experienced by bipolar patients over the loss
of a healthy self that used to function productively (see
Jamison and Goodwin, 1983; Jamison, 1991, 1995). Frank
and colleagues (1994) argued that if this issue is not addressed, it may manifest itself in medication nonadherence
and other self-destructive behavior. Interpersonal disputes
are common among bipolar patients, especially in the
manic phase, when angry and impulsive outbursts may
alienate and frighten loved ones. Role transitions or life
changessuch as starting a new job; relocating; having a
new baby; experiencing the death of a spouse, family
member, or close friend; or undergoing a divorcemay
disrupt a routine that has provided a sense of familiarity
and predictability, and may also disturb patients
sleepwake cycle and daily rhythms. Interpersonal deficits
are prominent in bipolar patients, as the damage and turmoil that follow manic episodes lead some patients to reduce their involvement in social relationships and work.
As noted earlier, major interpersonal disruptions may
precipitate a manic or depressive episode. Based on findings from earlier research carried out by Wehr and colleagues (1987a,b) at NIMH, IPSRT postulates that the link
between the patients biological vulnerability and interpersonal events lies in the interplay between zeitgebers (events
that stabilize the biological clock) and zeitstorers (events
that disrupt the biological clock) (see Chapter 16). Thus,
the mediating mechanism that may lead to an episode is
disruption of the patients circadian rhythms and daily
routines (Wehr et al., 1987a; Ehlers et al., 1988; Frank et al.,
1994). Early in the treatment, the therapist introduces the
Social Rhythm Metric to chart the regularity and stimulation of 17 daily activities (e.g., getting out of bed, having
the first meal), as well as the patients mood at the end of
901
each day. This procedure is intended to help the patient become more aware of the patterns of change in daily
rhythms and life events and their relationship to mood.
IPSRT is conducted in four phases:
In the initial phase, the therapist takes a thorough history of previous episodes and their interpersonal context; provides psychoeducation on bipolar disorder; introduces the Social Rhythm Metric, focusing on the
most recent episode; and identifies the patients main interpersonal problem area(s). The therapist is looking for
evidence of disruption of daily rhythms that preceded
episodes and educating the patient about the impact of
rhythm dysregulation on mood.
In the second phase, therapist and patient work toward
regulating the patients routine, as well as resolving the
interpersonal problem areas relevant to episodes.
The goal of the third phase is for the patient to become
more independent and proficient in the use of IPSRT to
address the links among events, biology, and mood.
Termination is the fourth phase, with particular emphasis on enhancing the patients independent functioning
and developing strategies for relapse prevention.
Frank and colleagues conducted an efficacy study of
IPSRT (Frank et al., 1999, 2000), comparing it with clinical
status and symptom review treatment, a form of intensive
clinical management (see Table 223). All patients also received medication. Preliminary results for 90 patients who
participated in the preventive phase showed significantly
more regular social/circadian rhythms in the IPSRT than
in the comparison group. There was no significant difference in the number of episodes (manic or depressive) between the two conditions. However, IPSRT was associated
with significantly longer periods of euthymia relative to the
comparison group, which experienced more depressive
symptoms over time. There was no difference between the
two conditions in the proportion of manic/mixed and euthymic states over time (Frank et al., 2000). Preliminary
findings also indicated that patients assigned during the
preventive phase to a treatment different from that received
during the acute phase (regardless of what that treatment
was) were at higher risk for relapse, suggesting that stability
in treatment delivery can be a regulating factor for bipolar
patients (Frank et al., 1999). IPSRT is also being tested in
the NIMH STEP-BD study (see the later discussion).
In a study of 175 acutely ill bipolar patients, Frank and
colleagues (2005) compared two psychosocial interventions, IPSRT and intensive clinical management (ICM), in
a randomized controlled trial involving four treatment
strategies: acute and maintenance IPSRT, acute and maintenance ICM, acute IPSRT followed by maintenance ICM,
and acute ICM followed by maintenance IPSRT. During
902
Treatment
Family/Couples Therapy
Because bipolar disorder takes a considerable toll on marriage and family life, early psychotherapy studies focused on
families and couples (see Chapter 10). It has been found that
families with high levels of expressed emotion toward the
patient, characterized by hostility, rejection, and overinvolvement, are associated with higher rates of relapse (Fallon et al., 1984; Miklowitz et al., 2004). Patients sensitivity to
such criticism is also predictive of poorer outcomes (Miklowitz et al., 2005). In an adaptation of behavioral family
management methods tested with schizophrenic patients
(Fallon et al., 1984), FFT was developed for bipolar patients
recently treated for an acute episode as inpatients or outpatients (Miklowitz and Goldstein, 1990). Family attitudes,
communication, and problem-solving style are the targets
of treatment. FFT, lasting 9 months and usually delivered in
21 sessions, has five stages:
In the joining phase, the therapist introduces the protocol to the family.
The initial assessment phase focuses on evaluation of levels of expressed emotion in the family and on the quality
of communication and problem-solving styles.
Family psychoeducation consists of 7 sessions during
which information on bipolar disorder is introduced, including the patients particular patterns of onset for both
manic and depressive episodes, symptom course, and
suicidal ideation. A central component of family psychoeducation is the relapse drill discussed previously.
The therapist also explores patient and family attitudes
toward medication and emphasizes the importance of
adherence, including regular monitoring of blood levels.
A vulnerabilitystress model is adopted, and the therapist identifies risk and protective factors that affect relapses. In this context, the entire family is encouraged to
promote a regular, predictable, and low-stress environment.
Communication enhancement training, lasting about 7
sessions, teaches family members skills of listening actively, expressing positive and negative feelings in an accepting and nonintrusive manner, and making nonjudgmental requests for change.
Psychotherapy
Miklowitz and colleagues developed a manual for adolescents aged 13 to 17 with bipolar-I disorder. This manual,
an adaptation of the FFT model for bipolar adults, is designed to make the approach appropriate for this age group
and to address clinical issues specific to juvenile bipolar
disorder. In an open trial of 20 bipolar adolescents (mean
age 14.8 years; standard deviation = 1.6), this adapted approach was associated with improvements in depression
and mania symptoms, as well as in behavioral problems
(Miklowitz et al., 2004).
Greene (2001) developed a collaborative problem-solving
model that focuses on parents assistance to their children.
This approach helps parents avoid engaging their children
when the children are in the midst of a rage attack. Only
after an attack subsides can the parent encourage collaborative problem solving. The approach is controversial since
the model emphasizes no consequences for the rage behavior or associated actions.
Pavuluri and colleagues (2002) developed a treatment
program that involves parent-and-child sessions for 8to 12-year-olds with bipolar disorder, termed Child- and
Family-Focused Cognitive-Behavioral Therapy. Central to
this approach is building the youths self-esteem and helping all involved parties understand that pediatric bipolar
disorder is a neuropsychiatric problem of affect dysregulation, rather than willful misbehavior. Over 12 sessions,
parents are trained as coaches while engaging in parallel
therapy to address their own affect regulation in dealing
with their children, restructure their thoughts regarding
their effectiveness as parents, and learn to resolve conflicts
with their children through empathy. Both parents and
children are instructed in the use of RAINBOW:
R = the importance of a routine (including sleep hygiene).
A = affect regulation/anger control (including knowledge about the disorder, medication, and life charts).
I = I can do it (positive self-statements).
N = no negative thoughts (restructuring negative thinking)/living in the now.
B = be a good friend/balanced lifestyle (also for parents).
O = Oh, how can we solve it? (letting the rages pass,
interpersonal and situational problem solving).
W = ways to ask for and get support.
The childs school receives a work folder documenting
what has been accomplished in the individual sessions. In addition, a teleconference is held with school staff members to
educate them in the use of the RAINBOW program. A preliminary investigation of 34 patients with pediatric bipolar
disorder (mean age 11.3 years, standard deviation = 3.1) found
that the RAINBOW child- and family-focused intervention
resulted in significant reductions in severity of symptoms of
903
aggression, mania, psychosis, depression, and sleep disturbance (Pavuluri et al., 2004).
Finally, an interpersonal psychotherapybased preventive intervention for adolescent children of bipolar mothers is under way at New York State Psychiatric Institute
(Verdeli, 2004). Seven adolescents whose mothers are receiving treatment for bipolar-I disorder and who themselves have subsyndromal bipolar symptomatology and/or
mild functional impairment attend sessions of family psychoeducation about the mothers disorder and also receive
individual interpersonal psychotherapybased counseling
(12 sessions). The intervention aims to (1) educate the adolescents and their parents/caretakers about bipolar disorder; (2) help the family make realistic plans in the event of
the mothers relapse; (3) help the adolescents deal more
adaptively with stressful interpersonal situations (including the mothers disorder); and (4) when necessary, help
the adolescents regulate their circadian rhythms, social
stimulation, and daily habits.
904
Treatment
CONCLUSIONS
Both clinical experience and emerging evidence suggest
that bipolar illness is treated most effectively with a combination of mood stabilizers or other medications and psychotherapy. Drug treatment, which is primary, frees most
patients from the severe disruptions of manic and depressive episodes. Psychotherapy can then help patients come to
terms with the repercussions of past episodes and comprehend the practical and existential implications of having
bipolar illness. When medications are administered in an
emotionally supportive atmosphere, patients are more likely
to express their concerns, physicians are better able to assess
the need for psychotherapeutic interventions, and medication adherence is enhanced. Moreover, educating patients
and their families is essential because it aids them in recognizing symptoms of emerging episodes. It is also essential to
informed consent for treatment, which is imperative for
both clinical and legal reasons. Charting of moods appears
to be useful to provide an objective record of patterns of
mood and treatment response and to give patients a sense
of control and collaboration in their treatment.
Although not all patients need psychotherapy, most may
benefit from one of its many formsindividual, group, or
family. Participation in a self-help group can supplement or,
on occasion, supplant formal psychotherapy. Which option
Figure 225. Odds ratios of relapse in randomized controlled trials of psychological treatments for
bipolar disorder. (Source: Scott and Gutierrez, 2004. Reproduced with permission from Blackwell Publishing, Ltd.)
Early, smaller trials
Study
Cochran, 1984
Lam et al., 2000
Perry et al., 1999
Scott et al., 2001
Fixed combined (4)
Random combined (4)
Effect
0.12
0.02
0.59
0.38
0.28
0.22
Sample Size
28
23
68
42
161
161
0.01
0.1
10
p -value
0.02
0.00
0.34
0.17
0.00
0.01
100
Favors Psychotherapy
Recent, large-scale trials
Study
Colom et al., 2003a
Lam et al., 2003
Miklowitz et al., 2000
Fixed combined (3)
Random combined (3)
Sample Size
120
96
101
317
317
Effect
0.41
0.26
0.46
0.37
0.37
0.01
0.1
Favors Psychotherapy
10
100
p -value
0.02
0.00
0.08
0.00
0.00
Psychotherapy
is most appropriate can usually be determined by the psychiatrist or psychopharmacologist who supervises the patients medications. No one psychotherapeutic approach,
even among the newer techniques, has been shown to be
uniformly superior for bipolar patients. The therapist must
be guided by knowledge of the illness itself and its manifestation in the individual patient. In style and technique, the
therapist must remain flexible to adjust to the patients fluctuating moods, cognition, and behavior. The therapist must
be especially alert to the emotions commonly engendered
in clinicians who work with bipolar patients.
Psychotherapeutic issues are dictated by the character of
the illness. Although reactions vary widely, patients typically feel angry, confused, and ambivalent about both the
illness and its treatment. They may deny the existence of
the illness, its severity, or its consequences; such denial
may cause them to stop taking their medication. When
treatment is not completely successful, patients are understandably disappointed and frustrated. Patients also may
be disturbed at losing the energy and vitality that accompany mania. They fear recurrences. They have difficulty
discriminating normal from abnormal moods. And they
are concerned about relationships and the possibility of
transmitting a genetic illness to their children.
During the 1970s and 1980s, research in psychotherapy
for bipolar patients was characterized by small open trials,
without the guidance of treatment manuals or attention
to therapists adherence to the treatment. Functional and
symptomatic outcomes were not systematically assessed,
and treatment randomization was rare. The empirical evidence for the efficacy or effectiveness of psychotherapy for
bipolar disorder remains limited for adults and is virtually
nonexistent for children and adolescents. In the 1990s, a
number of randomized clinical trials of the efficacy of various psychotherapeutic approaches set the stage for multisite
effectiveness trials now under way. Psychotherapy manuals,
independent evaluators blinded to the treatment being
given, and expanded outcome measures (including symptoms, social functioning, cost-effectiveness, and medication
905
adherence) are now the recognized tools for testing the new
approaches. Of course, the demonstrable efficacy of manualdriven psychotherapeutic interventions does not rule out
the efficacy of other, as yet untested types of psychotherapy.
Clinically, psychotherapy aimed at patient and family
education and/or management of the consequences and
environmental triggers of the illness makes sense, but there
is still a gap between clinical wisdom and evidence. The results of ongoing trials should provide the strong base of
empirical evidence that is needed to fill this gap.
NOTES
1. This passage, as well as others by a patient with manicdepressive illness, was written by one of the authors, Kay R.
Jamison. Some were modified slightly and incorporated into
her memoir, An Unquiet Mind (Jamison, 1995).
2. For obvious reasons, psychotherapy has never been as integral
or comfortable a part of the treatment of bipolar illness as it
has been of unipolar illness. Clearly, the psychotic disorders
and their empirically derived remedies long predate psychological treatments. Both history and necessity have embedded
bipolar illness in medicine, much more so than other psychiatric disorders. Unipolar depressions, on the other hand, have
had an easier alliance with psychotherapy, partly because they
generally constitute a wider spectrum of psychopathology
that shows a range of milder syndromes with prominent psychological factors. Because the concept of depression encompasses a relatively normal spectrum of emotions and feeling,
it has traditionally stimulated counsel from priests, physicians, and friends.
3. For a more comprehensive discussion of the nature and
methods of psychotherapy, see Jerome Franks classic book,
Persuasion and Healing (1961), and Phillip Slavneys Psychotherapy (2005).
4. Many of these reactions are discussed further in Chapter 10.
5. Ghaemi, 1995; Peralta and Cuesta, 1998; DellOsso et al., 2000,
2002; Pini et al., 2001.
6. G. Goodwin (2002) has described many of the difficulties
that arise from attempts to establish clear boundaries between the manic states.
7. Molnar et al., 1988; Smith and Tarrier, 1992; Basco and Rush,
1996; Lam and Wong, 1997; Perry et al., 1999.
23
The prognosis of insanity in children must of course be very variable. . . . Judicious management, which is the most essential condition of amendment, is very difficult to obtain.
D. H. Tuke (1892, p. 204)
tion in at-risk youths. Next we review the literature supporting our recommendations for acute and maintenance
pharmacological treatment, focusing on bipolar disorder
(while there is essentially no literature on recurrent unipolar depression per se in this age group, we do discuss prepubertal depression and the frequency with which it evolves
into bipolar disorder). In this section we also examine the
literature on the offspring of adults with bipolar disorder,
on psychiatric and medical adverse events, and on the use
of electroconvulsive therapy (ECT) and psychotherapy in
pediatric patients.
907
908
Treatment
trajectories into classic bipolar illness . . . (p. 115). We certainly agree. We also agree that there are many children
with markedly labile mood and episodic behavioral dyscontrol who appear to need and benefit from the mood stabilizers used in the treatment of adolescents and adults with
bipolar disorder. But the relationship between these serious and very real syndromes in children and adolescent
and adult bipolar disorder has not yet been clarified (see
the discussion later in this chapter and in Chapter 6).
Furthermore, although DSM-III-R and -IV have been
used to diagnose bipolar disorder in children as well as adolescents and adults, there is little uniformity in how these
criteria are operationalized for children. Leibenluft and
colleagues (2003) proposed an approach that requires strict
adherence to criteria for mania in adults for a narrow phenotype, as opposed to an intermediate phenotype (based
on the DSM-IV criterion for mania but with a duration of
less than 4 days) and a broad phenotype (encompassing
severe mood dysregulation that many believe characterizes
what is being called juvenile mania). This approach, inherently inclusive, strikes us as quite sensible.
Geller and colleagues (2002a) have reoperationalized
several of the DSM criteria (most notably euphoria and
grandiosity) to make them what the authors believe to be
developmentally appropriate for children. Not everyone
agrees with this reformulation, however (Harrington and
Myatt, 2003). In a recent cross-national study (United States
and United Kingdom) of five cases of children with mood
symptoms in whom bipolar disorder might have been a diagnostic consideration, disagreement on diagnosis occurred in three of the five cases. The reason for this appears
to be differing interpretations of specific symptoms. DSMs
reliance on symptom counts (used in the United States)
may result in a conceptualization that differs from the
gestalt of bipolar disorder as described in the International
Classification of Diseases (ICD)-10, used in the United Kingdom. Specifically, in a preadolescent patient with classic
mania, agreement was close (96.4 percent of U.S. and 88.9
percent of U.K. physicians made a manic diagnosis). In the
prepubertal child with both attention-deficit hyperactivity
disorder (ADHD) and manic-like symptoms, however,
86.2 percent of U.S. child psychiatrists diagnosed mania, in
contrast to only 31.1 percent of their U.K. colleagues (Dubicka et al., 2005).
Other Challenges
Beyond diagnosis, other unique challenges posed by earlyonset bipolar disorder ultimately have an impact on treatment. First, most clinical trials include only adolescents, or
include mixed samples that are not large enough to permit
separate analysis of children and adolescents. By our rough
estimate, fewer than one-third of clinical trials discussed
909
CLINICAL MANAGEMENT
Overview
The American Academy of Child and Adolescent Psychiatry (AACAP) has developed practice parameters, the most
910
Treatment
recent of which were published in 1997 and are being updated as of this writing. In the interim, given the immediate
need to have something more current available for treatment
of the manic, depressive, and maintenance phases of bipolar
disorder in pediatric populations, a consensus conference
was convened in July 2003, initiated and supported by the
CABF. Experts in child and adolescent bipolar disorder
summarized recommendations for the field based on interpretation of existing information (Kowatch et al., 2005). Our
treatment recommendations, which follow, integrate our
own views with those consensus recommendations.
Adequate assessment of bipolar disorder in a child or
adolescent takes several hours and may require multiple
visits (Youngstrom et al., 2004). The assessment should include interviews with parent(s) and child, as well as information gathered from other observers of the child (e.g.,
teachers). The information thus obtained should encompass not only symptoms of mania and depression, but also
symptoms of other psychiatric disorders that may be confused with or co-occur with bipolar disorder. Standardized rating scales and interviews are often useful adjuncts.
Evidence of psychiatric disorders in the youths immediate
family is essential not only because it can provide important genetic information, but also because such evidence
can bring into focus issues that need to be addressed in
psychotherapy. A developmental history, including ascertainment of social, academic, and family functioning, is
necessary as well. Psychoeducational testing is often extremely helpful in formulating a treatment plan for school.
Decisions regarding the impairment produced by mood
symptoms can be addressed by the FIND approach
(Kowatch et al., 2005), encompassing frequency (symptoms occur most days during the week), intensity (extreme
disturbance caused in two or more settings), number
(symptoms occur three or four times a day), and duration
(symptoms occur a total of 4 or more hours a day, not necessarily contiguous). The information obtained should include whether the predominant mood is mania or depression and whether there are comorbidities in addition to the
mood disorder. If there has been a positive response to
medication treatment (or lack thereof), it is important to
know the details, such as the dose and the length of the
trial. It is equally important to determine what adverse effects may have occurred.
After assessment, psychoeducation of the patient and
family members is important, and it should accomplish
the following:
The education of all concerned about the nature of the
disorder(s) being treated (not only what is known about
child, adolescent, and adult bipolar disorder, but also the
comorbidities that may exist).
911
becomes more irritable or aggressive with ADHD treatment, however, it makes most sense to switch to an
atypical or a mood stabilizer, than retrying the ADHD
treatment.
Bipolar depressionOne open trial of lithium monotherapy for hospitalized adolescents with bipolar depression
found a reduction in depressive symptoms, although most
of this amelioration occurred during the hospitalization. There has also been a positive open trial using lamotrigine alone or with other medication in adolescents. No
placebo-controlled or otherwise randomized data exist,
however. Thus for adolescents with clear bipolar depression, it may make sense to apply the findings from the
literature on adult bipolar depression, which increasingly advocates the use of lamotrigine or quetiapine. The
long-term use of quetiapine may be problematic, however, given the dramatic increase in obesity among adolescents, especially in the United States. This caution applies as well, of course, to some of the other atypicals,
especially olanzapine and the olanzapinefluoxetine
combination.
First episode of depression with a bipolar family history
This is another thorny issue on which there is no clear
consensus, and for which it is necessary to have a discussion with family members of the risks and benefits of alternatives (Carlson, 2005a). In a young person at risk for a
bipolar course, the clinician must weigh the risk that an
antidepressant may precipitate mania or hypomania,
versus the risk that a mood stabilizer alone may not alleviate the depression, versus the risk of using two drugs,
one of which may not be needed. Adult data cited in
Chapter 19 suggest that the beginning of an antidepressant response to lamotrigine is often evident by 3 weeks,
which may help in the decision-making process. Regarding the use of traditional antidepressants to treat earlyonset depression, there is as yet no consensus in child
psychiatry on the importance of trying a mood stabilizer
first or even on the need to combine the antidepressant
with a mood stabilizer. We have seen young people destabilized by antidepressants, as well as others kept on mood
stabilizers alone in the face of persistent depression. Regarding some mood stabilizers, moreover, it should be
noted that children and adolescents may balk at taking
medication at all if blood must be drawn or if there is a
possibility of weight gain. Thus the clarity of a history
suggestive of a bipolar diathesis (including a clear history of bipolar disorder in first-degree relatives), the reliability of parent observation and the patients adherence
to treatment, and family preference should all be carefully
weighed in the decision-making process.
MaintenanceResults of the few extant maintenance
studies suggest that even with good medical follow-up,
912
Treatment
Mania/Hypomania
How one initiates treatment for bipolar disorder in children
and adolescents depends on whether the patient is acutely
manic or hypomanic. Evidence is best for adolescents with
mania, for whom randomized, double-blind, controlled trials of atypical antipsychotics have shown clear efficacy, as
have large open trials of lithium. In smaller samples of children and adolescents with mania, hypomania, and bipolar
disorder-not otherwise specified (NOS) and/or those at risk
for bipolar disorder, there are placebo-controlled data on
lithium, which is the only antimanic medication approved
by the FDA for adolescents. Lithiums approval was grandfathered from the FDAs requirement for efficacy and safety
data specifically on children and adolescents. Data from open
studies exist for anticonvulsants and atypicals.
The guidelines of Kowatch and colleagues (2005) (described earlier) include two treatment algorithms for use
when the mania presents with versus without psychosis.
Here again, what follows is an integration of our own recommendations with these guidelines. When a child or adolescent presents with manic or mixed symptoms without
psychosis, monotherapy is generally preferred initially, for
reasons of safety. Treatment can be initiated with lithium, a
sedating anticonvulsant (the most data exist for valproate),3
or an atypical antipsychotic (such as olanzapine, quetiapine,
or risperidone, for which the most data are available), while
keeping in mind the adolescents vulnerability to weight
gain. If the clinical response is only partial, a drug of a different class should be used adjunctively (adding an atypical to a
mood stabilizer or vice versa), with appropriate dose adjustments to minimize additive side effects. If there is no response to the initial monotherapy, we recommend switching
to a drug of a different class (from lithium to an anticonvul-
The overlap between ADHD and mania raises three therapeutic questions. First, when both conditions occur, which
should be treated first? Second, if it is unclear whether one is
dealing with mania or severe ADHD and oppositional defiant disorder, which should be treated first? Third, if a child
has an adverse response to a stimulant or atomoxetine, is
that reaction suggestive of bipolar disorder? Some issues are
clearer than others. When one is treating both mania and
ADHD, results of clinical trials support treating the mania
first, then proceeding with treatment for ADHD. Two small,
systematic trials (Carlson et al., 1992; Scheffer et al., 2005)
have examined combined treatment with a mood stabilizer
and a stimulant. Neither found worsening of manic symptoms or significant side effects.
Atypical antipsychotics also appear to decrease rates of
hyperactivity/impulsivity as measured by ADHD rating
scales, although it is unclear whether this represents a nonspecific sedating effect. Teacher ratings and other measures
of academic impact, which are traditionally part of efficacy studies in ADHD, have not been obtained. The implication of studies involving atypicals is that they can improve ADHD behavior through their ability to enhance
cognitive organization, but this effect has not been studied
formally. Clinically, it appears that additional specific ADHD
treatment is often necessary.
When it is not clear whether the clinical picture reflects
mania or ADHD with oppositional defiant disorder (or
when a positive family history of mania indicates a risk for
the development of bipolar disorder), we believe the clinician should talk with family members to advise them of the
various alternatives and their risks. While there is concern
that ADHD treatments may hasten the onset of bipolar
disorder in children with ADHD and some manic symptoms (DelBello et al., 2001; Soutullo et al., 2002), more definitive data are needed on this critical question.
There are two important treatment issuesefficacy and
adverse events. With regard to efficacy, in outpatient children who clearly have ADHD and also display some mood
lability (which some call manic symptoms), limited data
suggest that both the ADHD and manic symptoms not
uncommonly show a robust response to stimulants immediately, as well as over the next 14 months (Galanter et al.,
2003). Moreover, the majority of inpatient children with
ADHD and manic symptoms studied systematically by
Carlson and Kelly (1998) improved with and could tolerate
stimulants, though stimulants alone clearly were inadequate to treat severely disruptive children with multiple comorbidities.
In contrast to its effectiveness in treating mania, the
available data indicate that lithium is ineffective for the
treatment of ADHD and mood lability (Greenhill et al.,
1973; DeLong and Aldershof, 1987; Carlson et al., 1992a).
913
Sample
Size
Age (yr)
Diagnosis
Medication
Duration
Measures
Outcomea
61
CPRS
Lithium compared
with haloperidol
Lithium
6 wk
50
1 mo
CPRS
40
12.5
CD/aggression
(inpatient)
CD/aggression
(inpatient)
CD
Lithium
6 wk
CGI, OAS
20
1018
CD, ODD
Divalproex
12 wk
OAS, SCL 90
16
CD
Divalproex low
vs. high dose
8 wk
CGI severity,
CGI improvement
Rating of Aggression
against People and
Property Scale
CGI Severity Overt
Aggression ScaleModified Aberrant
Behavior Checklist
Nisonger Child
Behavior Rating
Lithium
Campbell
et al., 1984
Campbell
et al., 1995
Malone
et al., 2000
Divalproex
Donovan
et al., 2000
Steiner et al.,
2003
58
males
Risperidone
Findling
et al., 2000
20
614
CD
Risperidone
10 wk
Buitelaar
et al., 2001
38
Adolescent
(IQs 3684)
Disruptive
behavior
disorders
Risperidone
6 wk
Aman
et al., 2002
118
512
(IQs 3684)
Disruptive
behavior
disorders
Risperidone
6 wk
a
Better than indicates a statistically significant difference at the p <.05 level or better.
CD = conduct disorder; CGI = Clinical Global Impressions scale; CPRS = Comprehensive Psychopathological Rating Scale; IQ = intelligence quotient; OAS = Overt Aggression Scale;
ODD = oppositional defiant disorder; SCL = symptom checklist.
Bipolar Depression
In young people, as in adults, there have been far more attempts to study treatment response in mania than in
bipolar depression. The few studies in which lithium or
adjunctive lithium was administered to depressed prepubertal children or adolescents with or without predictors
of future bipolarity have demonstrated little or no efficacy.
While further studies under controlled conditions are
needed, recommendations for adults with bipolar depression appear to be relevant to pediatric populations, at least
to adolescents. On the other hand, antidepressant responses in children do not necessarily mirror those in
adults (placebo responses are more frequent, and drug responses may differ), so direct extrapolation becomes more
tenuous.4
Emerging data on adults with bipolar depression suggest
that mood stabilizers, such as lamotrigine, can stabilize primarily against depression (that is, from below; see Chapter 20), apparently without destabilizing the illness. In adults,
bupropion is often cited as having advantages for the treatment of bipolar depression since it appears to have a lower
switch rate (perhaps because it has little or no disruptive effect on sleep when given early in the day) and a favorable
clinical profile for most bipolar patients (especially those
with psychomotor retardation). Bupropion also has the
most benign side-effect profile of any antidepressant. For
this reason, it may be especially suitable for young patients,
who tend to be more sensitive than adults to side effects.
Thus in the absence of data, but based on clinical experience (including that with adults), the consensus panel
(Kowatch et al., 2005) recommended using bupropion or
an SSRI adjunctively with a mood stabilizer when treating
bipolar depression in youths.
More problematic is treatment of depression when future
bipolarity is uncertain. In adolescents, bipolar illness commonly starts with depression rather than mania, a fact that
is troubling clinically because of the risk of precipitating
a manic episode in a vulnerable patient by using antidepressants. This concern escalates in the case of a seriously depressed young person with a history of bipolar disorder in
first-degree relatives. As with ADHD and mania, scant controlled data exist on which to base advice on the treatment
of early-onset depression when the possibility of converting to a bipolar course is uncertain. Results of follow-up
studies of clinical samples of children and adolescents
with depression indicate that on average, 20 percent subsequently develop bipolar disorder, with a range of 6 percent
(Weissman et al., 1999a) to 48.6 percent (Geller et al., 2001)5
(see Chapter 6). Thus the clinician using an antidepressant
915
Maintenance Treatment
Maintenance trials are generally undertaken after definitive
acute studies have been conducted. Since data from acute trials of treatment of bipolar children and adolescents are just
beginning to emerge, it is not surprising that information on
916
Treatment
to maintain it. Obviously, the less robust the treatment response, the more reason there is to discontinue medications
associated with significant adverse events. Recommendations for the use of antipsychotics to treat aggression in children and adolescents have been discussed by Schur and colleagues (2003) and Pappadapulos and colleagues (2003).
It is premature to draw conclusions about the clinical or
pharmacological significance of apparent drug-related activation in young people because the data on this issue are
so limited. How specifically to address the issue depends on
what the symptoms are, how severe they are, and how effective the medication is. Choices obviously range from stopping the drug, to lowering the dose and/or changing the
dosing schedule, to adding another medication that mitigates the unwanted symptoms. Before any medication is initiated, families should always be warned about the potential
for psychiatric adverse events, with particular caution being
exercised for young children; those with developmental disabilities; and those with preexisting problems involving severe emotional dysregulation, such as ADHD and bipolar
disorder.
Psychosocial Treatments
Psychosocial treatments have an important complementary role to play in the treatment of bipolar disorder in
young people. The reasons for this include (1) the impact
of the disorder on overall functioning in school and within
the family, (2) the high rates of comorbidity and treatment
nonadherence in these patients (one study, for example,
found nonadherence rates of 31 percent, even over a short,
6-week trial [Kowatch et al., 2000]), and (3) higher-thannormal rates of family psychopathology (see Chapter 22).
Research supports the importance of both psychoeducation and approaches aimed at reducing expressed emotion within the family (i.e., destructive criticism that
sometimes characterizes families with mental illness).
There are a number of common themes in three promising family therapy treatments developed for children
(Fristad et al., 2003; Pavuluri et al., 2004a) and adolescents
(Miklowitz et al., 2004). The underpinnings consist of psychoeducation and problem solving within a cognitivebehavioral framework. The premise of the former is that if
parents are given information about the biology of bipolar
disorder, they will be less likely to blame each other and/or
their children, allowing a greater focus on positive solutions. Additionally, by educating families about aspects of
the disorder that are worsened by environmental stresses
(disordered routine, decreased sleep, harsh criticism,
parental fighting and inconsistency) and by helping families develop constructive ways of solving problems, many
aspects of the illness can be brought under more effective
control.
917
(DelBello et al., 2006); quetiapine versus divalproex (DelBello et al., 2006), oxcarbazepine versus placebo (Wagner et
al., 2006), olanzapine versus placebo (Tohen et al., 2006),
and divalproex-extended release (ER) versus placebo (data
on file, Abbott Laboratories, December 2006). The largest
lithium studies have been open trials, some involving hospitalized adolescents with acute mania (Kafantaris et al.,
2004) and some involving outpatient children and adolescents with mania/hypomania or bipolar-NOS or children
considered at risk for developing bipolar disorder. Placebocontrolled trials of other atypical antipsychotics (risperidone, aripiprazole, ziprasidone) and anticonvulsants (valproate) approved for adults are ongoing as of this writing.
There have also been open and discontinuation studies. As
noted earlier, there has been one controlled trial of maintenance therapy (Findling et al., 2005).
Table 232 summarizes the currently available information for children and adolescents on drugs used to treat
mania in adults, organized by the level of evidence. As
noted in the table, safety data are available for several other
medications (anticonvulsants) because they are approved
for the treatment of convulsive disorders in youths. Placebocontrolled trials in mania have not yet established efficacy for any of the anticonvulsants or the atypical antipsychotics; hence they have not been approved by the FDA for
this purpose. The FDA has requested that drug sponsors
conduct more clinical trials in youths, and NIMH is also
supporting treatment trials. Although the following summary reflects considerable advances since the first edition
of this text was published, the evidence base, including
placebo-controlled trials, is expected to grow considerably
over the next decade. In addition to the traditional randomized, placebo-controlled designs, there is a need for
more practical, clinician-friendly trials (see Chapter 17),
such as crossover and randomized open comparative studies that can assess differences in tolerability (and perhaps
even efficacy) (Post and Kowatch, 2006). As Post and colleagues pointed out (2002), such designs are more likely to
be accepted by parents, especially when very young children are involved.
Lithium
As discussed previously, the overall evidence base for treating pediatric bipolar disorder in general and acute mania in
particular is sparse when compared with the extensive database from studies of adults, as reviewed in Chapter 18. There
have been a few placebo-controlled studies of lithium involving a small number of children or adolescents, most of
whom had conditions other than acute mania (see the later
discussion). Five industry-sponsored clinical trials of
medications for children and/or adolescents with acute
mania have been completed: topiramate versus placebo
918
Treatment
Table 232. Summary of Evidence for Drugs Used to Treat Mania in Children and Adolescents
Drug
Lithium
U.S. Food and Drug Administration (FDA) approved for treatment of mania in adults and in
youths aged 12 and above. Placebo-controlled trials in samples that included some children and
adolescents with acute mania, but acute mania was not specifically studied; results mixed.
Otherwise, open and discontinuation trials with mostly positive results.
FDA approved for treatment of mania in adults. Safety data in youths because of approval for
treatment of seizures. For mania in children and adolescents, positive open trials, discontinuation
trials, add-on trial, and randomized comparator trials. The one placebo-controlled trial
(divalproex-extended release [ER]) was negative.
Off label in adults and children. Safety data in youths because of approval as anticonvulsant in
children and adolescents. For mania, open randomized trial and case reports in children and
adolescents with positive results.
Off label in adults and children. Some safety data because of approval for partial-onset seizures in
children aged 216 years. For mania, one placebo-controlled trial in children and adolescents
aged 617 years; inconclusive results because underpowered.
Off label in adults and children. Some safety data in youths because of approval as adjunctive
treatment for partial complex seizures in youths aged 416 years. For mania, case reports.
FDA approved for mania in adults. Chart review series, positive open trials, positive add-on trial,
placebo-controlled trials in children with irritable aggression associated with conduct disorder
and autism, ongoing industry-sponsored randomized controlled trial for youths aged 1017
years.
FDA approved for mania in adults. In children and adolescents, 10 positive open trials and case
reports. Randomized controlled trial found olanzapine significantly better than placebo.
FDA approved in adults for treatment of mania. In adolescents, positive add-on study and
randomized comparison with divalproex; ongoing randomized controlled trial for youths aged
1017 years.
FDA approved in adults for treatment of mania. In children and adolescents, chart reviews and
small case series. Randomized controlled trial under way in youths aged 1017 years.
FDA approved in adults for treatment of mania. In children and adolescents, chart reviews.
Randomized controlled trial under way for youths aged 1017 years.
FDA approved only for treatment-resistant schizophrenia in adults. Off label for mania in adults. In
children and adolescents, case series.
FDA approved for maintenance treatment of adults with bipolar-I disorder to delay time to
occurrence of mood episodes (depression, mania, hypomania, mixed states). Safety data in
youths because approved for patients aged 2 and older with simple or complex partial seizures.
For bipolar disorder, chart review and one positive open study for bipolar depression in
adolescents.
FDA approved for treatment of bipolar depression in adults. No studies of bipolar depression in
children and adolescents, although fluoxetine is FDA approved for treatment of major depression
in children and adolescents.
Divalproex
Carbamazepine
Topiramate
Oxcarbazepine
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Clozapine
Lamotrigine
Symbyax (combined
olanzapine and
fluoxetine)
(1978) found 211 cases; of these, there was sufficient information for only 46 to allow tentative conclusions about the reasons lithium was used. Twenty-two patients were children:
2 had manic-depressive illness, 2 had an atypical mood
disorder, 8 were hyperkinetic, and 10 had autism/childhood
schizophrenia. Twenty-four of the 46 were adolescents: 9
had manic-depressive illness, 13 had atypical mood disorder, and 2 had hyperkinesis. Thus, there were very few studies of children or even adolescents who could be considered
bipolar. Even placebo-controlled trials had heterogeneous
subjects and few with classic bipolar disorder. Samples encompassed youths with a variety of psychotic-like and developmental disorders (Gram and Rafaelsen, 1972), hyperkinesis and equivocal stimulant response (Dyson and Barcai,
1970; Greenhill et al., 1973), and autism and schizophrenia
(Campbell et al., 1972), as well as offspring of lithiumresponding parents (McKnew et al., 1981).
Several observations can be made about these early
studies of lithium in youths: (1) the rarity of classic bipolar
disorder in children compared with adolescents; (2) the
early interest in trying to find a symptom constellation, especially in younger children, that would be lithium responsive; and (3) the poor treatment response in these subjects,
which may have deterred clinicians from conducting more
studies. Early studies in adults, whose samples appeared
equally heterogeneous, showed higher response rates. These
results with adults were promising enough to encourage
not just further investigation, but a whole revolution in
treatment. The fact that the response rates were highest in
adults with what is considered classic manic-depressive illness (bipolar disorder and recurrent unipolar depression)
may explain why young people, whose presentation is less
likely to be classic, were less likely to respond.
Placebo-controlled lithium trials that occurred prior to
the first edition of this volume are summarized in Table
233. Those occurring since the first edition are listed in
Table 234.
Lithium Treatment for Mania in Hospitalized Adolescents.
Although lithium has been used in young people for more
than 40 years, there have been no published randomized,
double-blind, placebo-controlled studies of adolescents
meeting DSM-IV criteria for acute mania. One placebocontrolled discontinuation study has been conducted
(Kafantaris et al., 2004), and other studies are in progress.
The largest open trial (Kafantaris et al., 2003) involved 100
adolescents initially hospitalized for mania and treated
with lithium over 4 weeks; 55 percent were responders, as
defined by a 50 percent reduction in scores on the Young
Mania Rating Scale (YMRS). If the psychotic or aggressive
manic adolescents received an adjunctive antipsychotic,
the response rate improved to 65 percent. Of interest, 40 of
919
the responders to open lithium monotherapy were subsequently randomized under double-blind conditions to
placebo or continued lithium and followed for 2 weeks
(Kafantaris et al., 2004); both groups relapsed at about the
same rate52.6 percent of those on lithium and 61.9 percent of those on placebo. The adolescents who relapsed on
lithium in the blind phase were subsequently restabilized
on lithium under open conditions (V. Kafantaris, personal
communication, 2006). It is likely that in the double-blind
phase, the investigators tended to withdraw patients on
blind lithium from the trial prematurely if they were showing even mild breakthrough symptoms (perhaps assuming
that any given patient might be on placebo), and thus these
lithium patients were scored as relapses even though they
went on to respond to open lithium.
In an open study of manic adolescents, the response rate
to lithium (defined as a 33 percent reduction in YMRS scores
and a Clinical Global Impressions [CGI] rating of 1 or 2)
was 53.5 percent; the presence of prior ADHD made no difference in the likelihood of responding to the drug (Kafantaris et al., 1998). On the other hand, psychotic features were
associated with a significantly lower response rate. Subsequently, the same group treated 42 hospitalized manic adolescents with both lithium and antipsychotic medication. Ultimately, of 28 adolescents who completed at least 4 weeks of
treatment, only 14 were judged clinically stable enough to
discontinue their antipsychotic medication. Of these 14,
only 8 maintained their response on lithium monotherapy
for an additional 4 weeks (sustained responders). The other
6 experienced a clinically significant exacerbation of symptoms on lithium monotherapy and resumed treatment with
their adjunctive antipsychotic (Kafantaris et al., 2001).
There have been two systematic case series of hospitalized manic adolescents. Strober and colleagues (1988, 1998)
found response rates of 67 to 80 percent in adolescents with
classic mania, while response rates in manic adolescents
with a prior history of ADHD were lower (33 to 40 percent).
An 18-month naturalistic follow-up study of adolescents
who had discontinued lithium (because of nonadherence)
after inpatient stabilization revealed that 90 percent had relapsed, compared with only 37.5 percent of those who had
remained on lithium (Strober et al., 1990). Whether this result reflects the effectiveness of lithium or simply the difference between adherent and nonadherent youngsters cannot
be determined for this nonrandomized study.
Lithium Treatment for Mania in Hospitalized Children.
There have been two clinical trials of lithium in hospitalized children with mania or manic-like symptoms. In the
first, 11 patients with bipolar-NOS were treated with lithium
and tested by a trained rater, teachers, and nursing staff at
baseline, 4 weeks, and 8 weeks (7 of these children also
Table 233. Early Placebo-Controlled Trials of Lithium in Children and Adolescents with a Variety of Conditions
Study
Sample
Gram and
Rafaelsen,
1972
Psychopathology
Addressed
Methodology
Results
Comments
Greenhill
et al., 1973
920
Campbell
et al., 1972
DeLong,
1978
Disruptive, nonpsychotic
behavior problems, rages/
aggression, or cyclical behavior patterns
McKnew
et al., 1981
A discontinuation study of
children who had already
improved
921
Sample
Carlson
et al., 1992a
N = 11; ages 5 yr 11
mo to 12 yr 10 mo;
inpatient
Geller
et al., 1998
Kafantaris
et al., 2004
Psychopathology
Addressed
Methodology
Results
Comments
ADHD = attention-deficit hyperactivity disorder; CDRS-R = Childrens Depression Rating Scale-Revised; CGI = Clinical Global Impressions scale; K-SADS = Kiddie Schedule for Affective Disorders
and Schizophrenia; ODD = oppositional defiant disorder; YMRS = Young Mania Rating Scale.
923
Anticonvulsants
Several controlled and uncontrolled trials of valproate and
other anticonvulsants have been conducted in various inpatient or outpatient populations (see Tables 235 and
236). A number of open studies and chart reviews of valproate had results encouraging enough to stimulate controlled trials in outpatients.7 The numbers studied were
small, however, and the studies suffered from the usual
methodological problems (see Table 235).
There have been several positive open-label trials with a
reasonable sample size in which children and adolescents
were treated with divalproex alone or in combination with
other medications (see Table 236). One was a trial of divalproex in 40 children and adolescents, 61 percent of whom
improved (>50 percent decline in YMRS score) over the 8
to 10 weeks of initial stabilization. However, the study had
been designed as a discontinuation trial and was hampered by the fact that 23 of 40 subjects had to discontinue
prior to randomization because of poor efficacy, inability
to discontinue concomitant lithium or haloperidol as required, nonadherence, or refusal to continue in the study
once stable (Wagner et al., 2002). Pavuluri and colleagues
(2005) reported the results of an open trial of divalproex in
34 children and adolescents with mania or mixed mania.
They found that 73.5 percent responded (50 percent decline from baseline YMRS score and 40 score on CDRS-R),
and 52.9 percent remitted.
A randomized, open-label, 8-week trial compared the
benefits of lithium, divalproex, and carbamazepine in 42
outpatient youths aged 8 to 18 (Kowatch et al., 2000).
Twenty of the subjects had bipolar-I and 22 bipolar-II; 71
percent had comorbid ADHD, among other comorbidities.
Forty-six percent of subjects responded to divalproex, 42
percent to lithium, and 34 percent to carbamazepine, with
response defined as a 50 percent reduction in YMRS score
and designation as improved or very much improved on
Table 235. Open Acute Trials of Divalproex in Children and Adolescents with Manic or Mixed States
Sample and Type of Study
West et al.,
1994
Papatheodorou
et al., 1995
Deltito et al.,
1998
N = 36, 20 manic or
bipolar mixed episode;
ages 1318 yr, mean
age 15.6; no gender
noted; inpatient chart
review
924
Author
Haloperidol63.4%,
perphenazine36.4%,
thioridazine9%,
lithium45.5%; divalproex added to these
medications
Mild improvement18.2%,
moderate improvement54.5%,
marked improvement27.3%;
sedation in 2 cases
ADHD = attention-deficit hyperactivity disorder; BPRS = Brief Psychiatric-Rating Scale; CGI = Clinical Global Impressions scale; DSM-III-R = Diagnostic and Statistical Manual, 3rd edition, revised;
F = female; GAS = Global Assessment Scale; K-SADS = Kiddie Schedule for Affective Disorders and Schizophrenia; M = male; MMRS = Modified Mania Rating Scale; SCID = Structured Clinical Interview for
DSM; YMRS = Young Mania Rating Scale.
Table 236. Controlled Acute Trials of Divalproex in Children and Adolescents with Manic or Mixed States
925
Study
Kowatch
et al., 2000
n = 42 in open comparison
of lithium, carbamazepine,
divalproex; n = 15 received
divalproex as outpatients
DelBello
et al., 2006
Wagner
et al., 2002
Findling
et al., 2003a
Chlorpromazine PRN
allowed; 3 subjects
needed it
Mania, hypomania,
mixed state diagnosed
by K-SADS, Mania
Scale (Endicott and
Spitzer, 1978), BPRS,
CGI severity; 23% had
ADHD
Mania or hypomania
diagnosed by K-SADS,
YMRS, CGI; 71%
comorbid for ADHD,
38% for ODD
Mania or mixed state diagnosed by Washington
University (WASH-U)
K-SADS, YMRS,
PANSS-P, CDRS,
CGAS; 60% ADHD,
47% psychosis; duration: 6 wk
(continued)
Table 236. Controlled Acute Trials of Divalproex in Children and Adolescents with Manic or Mixed States (continued)
Study
Findling
et al., 2005
Pavuluri
et al., 2005
Abbott
Laboratories (data
on file,
Dec. 2006)
domized DB to placebo
or divalproex-ER
DSM-IV-TR mania or
mixed state diagnosed
by WASH-U KSADS;
minimum YMRS
score 20 on entry;
assessed by CGAS,
CGI, CDRS-R;
duration: 4 wk
ADHD=attention-deficit hyperactivity disorder; BPRS=Brief Psychiatic Rating Scale; CDRS=Child Depression Rating Scale; CGAS=Childrens Global Assessment Scale; CGI=Clinical Global Impressions; DB=double blind; DSM-IV-TR = Diagnostic and Statistical Manual, 4th edition, text revised; ER = extended release; K-SADS=Kiddie-Schedule for Affective Disorders and Schizophrenia;
ODD=Oppositional Defiance Disorder; PANSS-P=Positive and Negative Syndrome Scale; PRN=Practice Research Network; TR=text revised; YMRS=Young Mania Rating Scale.
927
case report on its utility (Soutullo et al., 1998). A placebocontrolled study of topiramate involving 56 manic and
mixed-state adolescents was recently undertaken simultaneously with a trial involving manic adults as part of a registration study, but was halted because of a lack of antimanic efficacy in the adults. There was some suggestion of a
positive treatment effect of the drug in the adolescents,
however (DelBello et al., 2005). The mean total reduction
in YMRS scores was twice as large for those adolescents
treated with topiramate (n = 29) as for those receiving
placebo (n = 27), but given the small number of subjects,
this difference did not reach statistical significance. At the
final visit, however, 34.5 percent of the topiramate-treated
subjects versus 22.2 percent of the placebo-treated subjects
had improved either much or very much on the CGI-I scale
relative to baseline (df = 1, p = .310).
Atypical Antipsychotics
Until recently, the available database on atypical antipsychotics as treatment for bipolar disorder in children and
adolescents included only chart reviews for risperidone
(Frazier et al., 1999), olanzapine (Soutullo et al., 1999; Chang
and Ketter, 2000), quetiapine (Schaller and Behar, 1999),
and clozapine (Fuchs, 1994; Masi et al., 2002; Kant et al.,
2004). However, the status of atypicals in the treatment of
child and adolescent bipolar disorder is evolving (Findling
and McNamara, 2004). The strong incentive for the pharmaceutical industry to conduct trials to determine the
safety and efficacy of the drugs in children and adolescents
has been a major impetus for the emergence of a controlled
database on their use in treating bipolar disorder in these
populations. To this end, multicenter placebo-controlled
studies are now under way within the broad framework espoused by the consensus conference discussed earlier (Carlson et al., 2003).
An 8-week open trial of olanzapine was conducted
among outpatient children and adolescents aged 5 to 15, 61
percent of whom improved (Frazier et al., 2001). The definition of improvement in this study was problematic,
however, requiring only a 30 percent decline in YMRS score
or a CGI score of 3 or greater. Biederman and colleagues
(2005a) conducted an 8-week open trial of risperidone
as monotherapy among 30 youths with mania, mixed mania, and hypomania. Stimulants were used as needed. The
authors reported a 70 percent response rate (CGI scores
improved or very much improved). Other symptoms of
psychopathology were also responsive. Data on clozapine
are limited to a chart review that found decreases in mania, depression, and aggression ratings in 10 adolescents
with mania/mixed episodes in residential treatment for
whom other treatments had failed (Masi et al., 2002). With
regard to aripiprazole, data from retrospective chart reviews
928
Treatment
Drug Combinations
In an open trial of combined medications, 90 bipolar-I and
-II children and adolescents who had not responded to either lithium or valproate were treated with a combination
of both (Findling et al., 2003). Using a strict definition of
remission (YMRS score < 12.5, with a mean score of 21.8 entering the study), 42 of the subjects (46.7 percent) remitted.
It is of note that this remission rate is in the same range as
response rates in the monotherapy trials, which require
only 50 percent improvement. The dropout rate due to
side effects or nonadherence was high, but if the subjects
could tolerate the combination of medications, they appeared to improve substantially. It would be interesting to
know whether a combination of less-than-full monotherapy doses of lithium and valproate (given the evidence that
their postsynaptic mechanisms show some synergism and
their side-effect profiles are somewhat different) would
produce a more favorable ratio of benefit to side effects.
In a small placebo-controlled crossover study of seven
inpatients with mixed manic symptoms and ADHD, Carlson and colleagues (1992b) found that measures of inattention and overactivity showed greater improvement with
lithium and MPH than with MPH alone. Scheffer and colleagues (2005) examined 40 children and adolescents with
bipolar mania treated openly with valproate and then randomized to added placebo or added dextroamphetamine
(Adderall). The added stimulant led to greater improvement
on the YMRS compared with the added placebo (i.e., valproate alone), and also was effective for the ADHD symptoms. The study did not find worsening of manic symptoms
or significant side effects. In another study of combined
treatment, Pavuluri and colleagues (2004b) examined the
combination of risperidone (up to 3 mg/day) and either
lithium or divalproex in a 6-month, nonrandomized open
trial. The study included 37 subjects aged 5 to 18 with mania or mixed episodes.11 Based on three outcome measures
(YMRS, CGI-BP, and CDRS-R), divalproex in combination
with risperidone was found to be as effective and as well tolerated as the combination of lithium and risperidone.
Finally, as part of a double-blind, placebo-controlled
study of adjunctive quetiapine, DelBello and colleagues
(2002) randomized 30 hospitalized adolescents with mania
or mixed episodes to divalproex plus placebo or divalproex
plus quetiapine. There was a significant decline (p <.01) in
YMRS scores with divalproex plus placebo (i.e., divalproex
alone) and significant additional improvement with quetiapine. The response rate (improved or very much improved on the CGI or 50 percent decline in YMRS scores)
was 53 percent for divalproex. Adding quetiapine (versus
adding placebo) raised the response rate an additional 15
percent, a statistically significant difference.
Treatment of Aggression
Although a thorough discussion of the treatment of aggression and conduct disorder is beyond the scope of this
chapter, it is important to state that most of the medications approved for the treatment of acute mania in adults
have also demonstrated some efficacy in treating affective
aggression in pediatric populations (see Table 231). Ironically, far more children with aggression and conduct disorder than with mania have been studied using lithium
under controlled conditions (Campbell et al., 1984, 1995;
Malone et al., 2000). One randomized trial of divalproex
found that a higher dose was better than a lower dose for
treating conduct disorder (Steiner et al., 2003).
Antipsychotics have also proven effective in randomized, placebo-controlled trials involving more than 500
children with aggression associated with either conduct
disorder/ADHD12 or autism/pervasive developmental disorder (McCracken et al., 2002). For example, with a responder defined as a subject with an end-point rating of
much or very much improved on the CGI scale, the percentage of responders in one study (Aman et al., 2002) was
53.8 percent for the risperidone group and 7.9 percent for
the placebo group, a significant difference.
One problem with these studies is that outcome measures
of irritability/aggression (Aman et al., 1985, 1996) include
behaviors elevated in mania: temper tantrums; irritability;
depressed mood; demanding behavior; crying over minor
annoyances; rapid mood changes; deliberately hurting oneself; arguing; explosive behavior; being easily angered; getting into physical fights; and talking back to teachers, parents, or other adults (Biederman et al., 1995; Carlson et al.,
1998; Mick et al., 2003). In trials involving bipolar children
and adolescents in which both aggression and mania have
been measured directly,13 the decline in aggression has been
similar to the decline in mania scores.
929
has a notoriously high placebo response in youths); moreover, the major improvement in mood symptoms took
place within the first 2 weeks of treatment, during which
82 percent of the adolescents remained hospitalized. Indeed, 6 weeks is a brief time frame for measuring antidepressant response.
Current understanding of lamotrigine treatment in youth
began with a study by Kusumakar and Yatham (1997) that
included 7 adolescents among a sample of bipolar adults
and found an improvement in scores on depression rating
scales. Carandang and colleagues (2003) reported on a case
series of lamotrigine (both as monotherapy and as an adjunct) in 9 adolescents with refractory depressive disorders, 6 of whom were bipolar. In this series, 8 of the 9 patients
responded well (mean dose 142 mg/day), as determined by
achieving a score of 1 or 2 on the CGI-BP scale. Finally,
Chang and colleagues (2006) recently completed a study using up to 150 mg/day of lamotrigine over 8 weeks in youths
aged 12 to 18. Remarkably, of 19 subjects, 16 (84 percent) were
considered responders by virtue of achieving a score of 1 or 2
on the CGI-I-BP. Remission was achieved in 11 of 19 (58 percent) of the subjects.14
Quetiapine is another promising agent for adults with
bipolar depression (see Chapter 19). A controlled study examining this treatment option is currently in progress.
Maintenance Treatment
The question of how long a child or adolescent with bipolar disorder should be treated is clearly important. Insofar
as youths have a condition in which clear episodes of mania, depression, and euthymia are occurring, one can probably extrapolate from adult monotherapy studies. In broader
pediatric bipolar populations, however, the limited data
currently available suggest that maintenance with single
mood stabilizers generally does not provide adequate coverage. For instance, using subjects from their sample of
children and adolescents stabilized on combined lithium
and valproate (and adding other subjects to form a sample
size of 60), Findling and colleagues (2005) conducted a
maintenance trial in which those patients who had responded to combined lithium and divalproex were randomized to monotherapy. The study hypothesis, based on
an adult trial (Calabrese et al., 2005), was that divalproex
would be superior to lithium as maintenance monotherapy
in patients with rapid cycling (50 percent of the subjects).
Outpatients ranging in age from 5 to 17 were first openly
stabilized on combined lithium and divalproex for 20
weeks and then randomized under double-blind conditions to have one of the mood stabilizers withdrawn while
continuing on the other. Relapses were frequent and rapid
over the next 3 to 4 months, with only 10 of the 60 subjects
completing the trial. Moreover, neither drug was found to be
930
Treatment
931
932
Treatment
drugs).18 It is important for the clinician to follow carefully the gradual upward titration schedule outlined in
Chapter 20.
Electroconvulsive Therapy
The body of knowledge on the use of ECT in young people
has grown to the point that a practice parameter has been
developed to provide advice to child and adolescent psychiatrists (Ghaziuddin et al., 2004). Several reviews have
summarized the literature on ECT, including its successful
use in treating mania in bipolar adolescents (at least those
without comorbid personality disorder) (Rey and Walter,
1997; Walter et al., 1999; Walter and Rey, 2003). There have
933
been no controlled studies, but these reviews have identified 60 reports (63 percent of which were case studies) describing the use of ECT in 396 patients. Rates of improvement across studies were 63 percent for depression, 80
percent for mania, 80 percent for catatonia (which is often
related to bipolar disorder), and 42 percent for schizophrenia. One study evaluated adolescents about 5 years after
they had undergone ECT. Compared with carefully matched
psychiatric controls, 11 adolescents given ECT for psychotic
depression or mania were similar in school and social functioning. Bipolar disorder was the most common follow-up
diagnosis, however, suggesting that for some, the antidepressant effectiveness of the procedure was accompanied
by a switch into mania (Taieb et al., 2002). The only data on
prepubertal children come from a report on 2 successfully
treated patients with refractory mania (Hill et al., 1997) and
1 with severe depression with catatonic features (Russell
et al., 2002).
Psychotherapy
Fristad and colleagues (1998) used a manual-driven, adjunctive, multiple-family group treatment approach for
children aged 8 to 12 with bipolar and depressive disorders.
This method includes psychoeducation about the disorder
and the role of medications, training in communication
skills to improve interactions between parents and children, stress management, and development of coping
strategies. In a randomized controlled trial, this same group
(Fristad et al., 2002) showed that multifamily psychoeducation was associated with increased knowledge about bipolar disorder and treatment options, better skills in dealing
with the bipolar child, more active attitudes toward mobilizing resources to benefit the child, and an increased sense
of support compared with a wait-list control group.
Miklowitz and colleagues (2000, 2004) developed a manual for adolescents aged 13 to 17 years with bipolar-I disorder. This manual is an adaptation of the family-focused
therapy model for bipolar adults, designed to make it appropriate for this age group and to address clinical issues specific to juvenile bipolar disorder. In an open, 1 year observational study of 20 bipolar adolescents, the approach, in
combination with mood stabilizers, moderately improved
symptoms of depression and mania and behavior problems
(Miklowitz et al., 2004). Greene and colleagues (Greene
et al., 2003; Greene and Ablon, 2005) developed a collaborative problem-solving model that focuses on parents assistance to their children. Parents are encouraged to avoid
engaging their children until after a rage attack subsides, at
which point collaborative problem solving can be encouraged. This approach is controversial, however, since the
model emphasizes no consequences for the rage behavior
or associated actions. Pavuluri and colleagues (2004a)
934
Treatment
developed a treatment program that involves parent-andchild sessions for 8- to 12-year-olds with bipolar disorder,
termed child- and family-focused cognitive-behavioral
therapy, described in detail in Chapter 22.
CONCLUSIONS
A serious psychiatric condition such as bipolar disorder that
begins in childhood or adolescence does more than interfere with the patients life: it also interferes with development. Thus it is encouraging that information on the treatment of bipolar disorder in children and adolescents, while
still lagging behind that for adults, is improving. In the nottoo-distant future, ongoing research is expected to resolve
the dilemma of how to diagnose children (younger than age
12) more accurately and how to distinguish bipolar disorder
in this population from a host of common comorbidities,
including ADHD. Once consensus exists on how to classify
children, more advanced treatment strategies for this age
group can be pursued in clinical trials. In the meantime,
most of our knowledge about treatment for children comes
from open studies and clinical experience, combined with
what is known from controlled studies of adolescents.
Although the evidence base is far from strong, this chapter provides clinical guidance on the use of medical and
psychotherapeutic treatments for both children and adolescents. As of this writing, a number of clinical and industrysponsored trials have just been launched, and their results
can be expected to greatly increase the current knowledge
base.
To summarize our treatment recommendations, mania
should be treated with lithium, an anticonvulsant, and/or
an atypical antipsychotic, depending on the clinical presentation. One common and perplexing question is how to
treat a youngster whose symptoms of bipolar disorder may
actually be symptoms of ADHD, or one who has ADHD
comorbid with bipolar disorder. When a diagnosis of mania is clear, a mood stabilizer should be prescribed first,
followed by treatment for the ADHD. When a mania diagnosis is less clear, we believe the ADHD should be addressed; if the child becomes more irritable, an atypical
antipsychotic may be used and the ADHD readdressed as
needed. With regard to a first depression in youths with
a clear positive family history of mania in first-degree relatives, lamotrigine should be offered initially; if there is
a family history of lithium response, lithium may be preferred over lamotrigine. An antidepressant can be added
later if the response to the mood stabilizer is inadequate. If
the clinical situation makes it appear unwise to wait, however, the antidepressant can be started simultaneously with
the mood stabilizer. If the family or child resists a mood stabilizer or is simply unhappy with taking two medications,
NOTES
1. Duffy et al., 1998; Egeland et al., 2000, 2003; Shaw et al., 2005.
2. For the acute treatment of mania in children and adolescents,
side-effect considerations appear similar to those in adults, although some investigators have noted fewer side effects in children (see McClellan and Werry, 1997). Lithium has a shorter
half-life in children because of their more efficient renal physiology and, therefore will reach steady-state levels more quickly.
Children may be more susceptible to the cognitive dulling seen
in adults at higher serum levels (Silva et al., 1992).
3. The issue of a possible effect of valproate on female reproductive function is important for girls and young women who are
taking the drug. Regular monitoring of reproductive function
in female patients taking valproate is recommended, including
questioning patients during visits regarding menstrual disorders, fertility, weight gain, hirsutism, and galactorrhea.
4. Compared with adult trials, ethical constraints make it more
difficult to get seriously ill children admitted to trials with
placebo controls. Therefore, placebo responses are often high,
which can obscure an active drug effect.
5. The Geller and colleagues (1999) data emerged from a tricyclic antidepressant trial that found no relationship between
antidepressant use and the development of subsequent bipolar disorder.
6. Odds and odds ratios are based on comparison of rates of
bipolar disorder in the offspring of adults with the disorder
versus another sample, usually a population sample. Rates of
bipolar disorder are just over 1 percent, and of depression are
nearly 10 percent. Thus if rates of disorder in bipolar offspring are 5 percent for bipolar disorder and 20 percent for
unipolar depression, more have unipolar depression. But the
rate of bipolar disorder is 5 times higher than that in the general population, whereas the rate of unipolar depression is
only 2 times higher.
7. West et al., 1994, Papatheodorou et al., 1995; Deltito et al., 1998.
8. Oxcarbazepine is a 10-keto analogue of carbamazepine that
apparently is without the parent compounds hematopoietic
problems.
935
15. Clearly, if 20 percent of bipolar adults destabilize on antidepressants, 80 percent do not, as is suggested by other studies
(Maj et al., 2002; Altshuler et al., 2003; Gijsman et al., 2004;
Joffe et al., 2005; Carlson et al., 2006).
16. We can only assume that if some early-onset depressive patients are going to become bipolar but have not yet manifested
mania, some will inadvertently be included in these trials.
17. The possibility that clinicians treating young versus older people are quicker to use mood stabilizers if they perceive that certain side effects are occurring cannot be ruled out.
18. The safety profiles of the anticonvulsants are well characterized for children and adolescents taking these agents for
epilepsy. Younger patients may be at greater risk of rare idiosyncratic hepatic and dermatological reactions, as these problems have generally been reported more frequently in children
than in adolescents and adults. The manufacturers of lamotrigine do not recommend its use in patients younger than age
16 years, except for special antiepilepsy indications, because
of the apparently higher incidence of toxic epidermal necrolysis in the young.
24
Treatment of Comorbidity
anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder), eating and personality disorders,
and general medical disorders (cardiovascular disease, obesity, and thyroid dysfunction). Since the management of
comorbid ADHD involves primarily children and adolescents, it is covered in Chapter 23.
SUBSTANCE ABUSE
The first step in the treatment of any disorder is to conduct
a comprehensive assessment. For patients with substance
abuse comorbidity, an initial assessment must include an
evaluation of the effects of the substance(s) on the patients
affective stability. Differentiating mood changes brought
about by affective illness from those brought about by alcohol or drug abuse can be a subtle and complex process.
In some cases, simple coincidence accounts for the coexistence of two disorders in the same individual, whereas
in others, the alcohol and drug abuse may reflect genetically influenced behavioral traits that overlap the mood
and addictive disorders (such as stimulus seeking and poor
impulse control). Alternatively, the substance abuse may
simply reflect an attempt at self-treatment of depression,
mania, or especially mixed states.
Just as affective illness can mask substance abuse, the
reverse is also true. Accurate diagnosis of both disorders is
vital because it is the basis for important treatment decisions. For example, it is unnecessary and unwise to prescribe mood stabilizers or antidepressants for transient
mood symptoms secondary to substance abuse that will
spontaneously remit with abstinence. Many investigators
(e.g., Schuckit, 1983; Driessen et al., 2001) have noted that
with primary alcoholism and an apparent secondary affective disorder, affective symptoms usually remit within 2 to
937
938
Treatment
4 weeks after cessation of alcohol use. Treating only substance abuse in the presence of an independent affective
illness, on the other hand, risks persistence of the problems
associated with mood disorders.
Adequate assessment of a patient with possible diagnoses of bipolar or recurrent unipolar disorder and substance abuse requires systematic inquiry using standardized diagnostic criteria. Family histories of affective and
substance abuse problems, as well as a detailed chronicling
of symptom onset, also are important. Such histories aid in
teasing out the more probable or primary diagnosis; moreover, they assist the clinician in identifying and counseling
the manic-depressive patient who has a family history of
alcoholism, a history that makes the patient more liable to
become an alcoholic (Morrison, 1975). It is also important
to differentiate between adolescent-onset affective disorders
and early-onset alcoholism, which, like the bipolar form of
manic-depressive illness, can be associated with aggressive
and impulsive behavior. Indeed, early-onset alcoholism
tends to be associated with a high degree of comorbidity.
For example, Famularo and colleagues (1985) diagnosed
bipolar illness in 7 of 10 cases of alcohol abuse developing
before the age of 13. Driessen and colleagues (1998) studied
a sample of 250 hospitalized alcohol-dependent patients
and found that the majority of late-onset subjects were either not comorbid at all or had Axis I comorbidity only.
Early-onset alcohol dependence, on the other hand, was
preferentially associated with personality disorders. Gender
differences also play a role. Goldstein and colleagues (2006),
in a large-scale study of data from the 20012002 National
Epidemiologic Survey on Alcohol and Related Conditions,
found that among those with comorbid bipolar-I and alcohol abuse disorders, the former was more likely to go
untreated among males and the latter more likely to go untreated among females.
In addition to a comprehensive diagnostic interview,
a urine screen for drugs is important, as indicated by the
finding of Estroff and colleagues (1985, p. 38) that there
existed little relationship between patients self-reported
patterns of drug abuse . . . and the results of the urine
analysis. On the other hand, another study that evaluated
patients seeking treatment specifically for drug problems
found that self-reports of drug use were generally reliable
(Brown et al., 1992), as reflected in the .65 reliability coefficient (kappa) between self-report and urinalysis results for
most of the substances studied.
As with comorbid conditions in general, there is a
paucity of data on how best to treat patients with comorbid mood and substance abuse disorders. Unfortunately,
alcohol and drug abuse disorders are among the most common exclusionary criteria for patients entering clinical trials. At the same time, studies of substance abusers generally
Treatment of Comorbidity
939
bipolar disorder and substance abuse found that the treatment for the addiction was more successful than the treatment for the mood disorder. Over the course of 3 years,
symptoms of bipolar disorder improved only modestly,
whereas 61 percent of the subjects were in full remission
from their substance abuse disorder at the end of the study
period (Drake et al., 2004). Successful treatment of the substance abuse in this study was associated with greater rates
of independent living, employment, social contacts with
nonsubstance abusers, and overall quality of life. Indeed,
measuring psychosocial functioning is the most appropriate way to evaluate a behavioral intervention.
Before taking a more detailed look at pharmacological
and psychosocial treatments for comorbid manic-depressive
illness and substance abuse, we wish to reemphasize that although comparatively little is known about the most effective ways to treat these patients, recovery is unlikely unless
both illnesses are addressed. Recognition of the substance
abuse problem is the essential first step, and lack of recognition is a common obstacle to effective treatment. Substanceabusing patients with comorbid mood disorders are more
difficult to treat, and long-term abstinence may take longer
to achieve. Nevertheless, the extensive literature demonstrating that noncomorbid substance abuse disorder can be
managed successfully with currently available treatments
suggests the possibility, or even the likelihood, of good outcomes for appropriately treated manic-depressive patients
as well.
Pharmacological Treatment
Although pharmacological treatment in the absence of psychosocial intervention is not an adequate treatment for
substance abuse, effective medication can contribute to a
positive outcome. This strategy may also allow the clinician
to reduce the total number of drugs a patient must take,
which may increase treatment adherence. Table 241 presents the results of open-label and placebo-controlled trials
of mood stabilizers in patients with affective disorders and
comorbid substance abuse (Levin and Hennessy, 2004).
Bipolar disorder in the presence of a comorbid substance
abuse disorder may not respond well to lithium. A retrospective review of the medical records of 204 bipolar-I inpatients found that patients with substance abuse histories
who received divalproex or carbamazepine remitted during
hospitalization more often than did those who received
lithium as the sole mood stabilizer (Goldberg et al., 1999).
Additionally, an assessment of 44 patients using a structured
interview found that dually diagnosed patients were more
likely to be adherent to valproate than to lithium (Weiss
et al., 1998). It may be that patients who are good lithium
responders, that is, those with predominantly euphoric, or
classic manias, may be less likely to use alcohol and drugs
Table 241. Open-Label and Placebo-Controlled Trials of Mood Stabilizers in Mood Disorders (Primarily Bipolar)
with Comorbid Substance Abuse
Study
Substance
(Sample Size)
Affective
Disorder
Diagnosed
(Diagnostic
Criteria)
Type of
Trial/Setting
Medication/
Duration
(weeks)
Concurrent
Therapy
Affective
Disorder
Outcomesa
Drug
Cravinga
Drug Usea
Cocaine (16)
4 cyclothymia,
3 dysthymia,
2 major depressive disorder
(MDD), 7 no
diagnosis (Diagnostic and Statistical Manual,
3rd edition
[DSM-III])
Open-label/
outpatient
Lithiumb/12
Weekly individual
and group
therapy
Not assessed
for 3-year
lithiumtreated
cyclothymic
patients only;
measured by
a 20-point
analog scale
Self-reported for
lithium-treated
cyclothymic
patients only;
urine drug screen
(UDS) collected
every 3 to 6 weeks
during the trial
Nunes
et al., 1990
Cocaine (10)
Hypomania or
cyclothymia
(DSM-III,
revised
[DSM-III-R])
Open-label/
outpatient
Lithium/12
Drug counselor
weekly
in 5 patients
as assessed by
Cocaine Craving Scale
3 patients
cocaine-free for
3 weeks, as assessed by weekly
UDS; of these,
one achieved
sustained
abstinence
Brady
et al., 1995
Alcohol, cocaine,
or multiple
substances (9)
Bipolar-I disorder
(DSM-III-R)
Open-label/started Valproate/24
medication
inpatient, then
followed outpatient
None
Not assessed
in days and
amounts of substance used as
assessed by TimeLine Followback
(TLFB); UDS
collected every
other month
940
Gawin and
Kleber, 1984
941
Geller
et al., 1998
Alcohol (7);
marijuana (2);
alcohol and
marijuana (14);
inhalant (1);
alcohol,
inhalant, and
cough syrup (1)
(total of 25
adolescents)
Bipolar-I or -II
disorder, or
MDD with bipolar predictors
(DSM-III-R)
Placebocontrolled/
outpatient
Lithium or
placebo/6 (13
lithium treated,
12 placebo
treated)
Percentage of
positive UDS
significantly
decreased in the
lithium group
compared with
the placebo
groupc; UDS
collected
weekly
Calabrese
et al., 2001
Alcohol,
marijuana,
and/or
cocaine (56)
Rapid-cycling
bipolar-I or -II
disorder (DSM,
4th edition,
[DSM-IV])
Open-label/
Outpatient
Lithium +
divalproex/24
12-stepbased
intensive outpatient chemical
dependency
program
HAM-D and
YMRS, Global
Assessment Scale
(GAS) after 4
weeks of treatment; statistical/
clinical significance not
reported
Not assessed
14 patients met
DSM-IV criteria
for full remission
of alcohol or
drug abuse
disorder after 6
months; no UDS
Brady
et al., 2002
Cocaine (139: 57
with affective
disorder [ADd],
82 with no affective disorder
[NAD]d)
Lifetime diagnosis
of bipolar-I or-II
disorder, MDD,
cyclothymia,
dysthymia, or
NAD (DSMIII-R)
Placebocontrolled/
outpatient
Carbamazepine
(CBZ) or
placebo/12
(AD: 30 CBZ,d
27 placebod;
NAD: 42CBZ,d
40 placebo)
Not significant
(NS) HAM-D
and Beck Depression Index (BDI)c
but not YMRS
for the CBZ/AD
group
Compared with
other three
groups, CBZ/AD
group had NS
trend toward
percentage of
positive UDS and
significantly
longer time to
first cocaine use,
as assessed by
TLFB and Cocaine Use Inventoryc; UDS
collected weekly
(continued)
Table 241. Open-Label and Placebo-Controlled Trials of Mood Stabilizers in Mood Disorders (Primarily Bipolar)
with Comorbid Substance Abuse (continued)
Study
Substance
(Sample Size)
Affective
Disorder
Diagnosed
(Diagnostic
Criteria)
Type of
Trial/Setting
Medication/
Duration
(weeks)
Concurrent
Therapy
Affective
Disorder
Outcomesa
Drug
Cravinga
Drug Usea
Brown
et al., 2002
Cocaine (17)
Bipolar-I or -II
disorder
(DSM-IV)
Open-label/
outpatient
Adjunctive
quetiapine (12)
Non-studyrelateda
HAM-D, YMRS,
and Brief
Psychiatric Rating
Scalec (BPRS)
as assessed by
Cocaine
Craving
Questionnaire
(CCQ)c
NS days of
cocaine use,
money spent on
cocaine; slight
increase in
positive UDSc
Brown
et al., 2003
Cocaine (30)
Bipolar-I, -II,
or not otherwise specified
(NOS) (DSMIV)
Open-label/
outpatient
Lamotrigine,
adjunctive or
monotherapy/
12
24 patients in
non-studyrelated substance abuse
treatment
HAM-D and
YMRS, BPRSd
as assessed by
CCQc
NS days of use,
money spent
on cocaine; no
change in positive UDSc; UDS
collected weekly
Treatment of Comorbidity
943
944
Treatment
Treatment of Comorbidity
Psychosocial Treatment
The most widely known and used psychosocial program
for alcoholism, AA, has more than 1 million members participating in more than 30,000 groups that convene in at
least 70 different countries. Determining the programs efficacy and delineating the types of individuals for whom
it is most beneficial are difficult in anonymous, self-help
group settings, however. As Ogborne and Glaser (1985)
pointed out, it remains unclear (1) what proportion of any
population of problem drinkers would either accept or
benefit from a referral to AA; (2) whether benefits derived
from involvement with AA are greater than those gained
from other substance abuse treatment programs; and (3)
whether involvement with AA can have any detrimental effects on some of those who participate. A meta-analysis of
the literature on AA found that the correlation between
participation and drinking outcomes was more positive
among outpatient than inpatient samples; better-designed
studies were more likely to report positive psychosocial
outcomes related to AA attendance. In general, however,
studies of AA have lacked sufficient statistical power to detect relationships of interest (Tonigan et al., 1996).
While there is a paucity of well-controlled studies, our
clinical experience supports the widely held belief that AA
benefits many individuals at little or no cost to themselves
or to society. The program apparently derives much of its
success from the continuous support, hope, and help provided by peers; from exposure to successfully abstinent alcoholics; from the substitution of other AA members for
former drinking companions; and from increased selfregard gained through helping others in like circumstances
(Vaillant, 1978). On the other hand, not all alcoholics are
attracted to or able to tolerate AAs self-examining approach or religious underpinnings. Of particular relevance
to manic-depressive patients with drinking problems is the
opposition expressed by some AA members to the use of
chemicals other than alcohol, including mood-stabilizing
medications. Yet AA neither endorses nor prohibits the use
of psychiatric medications by its members. The pamphlet
AA: Medications and Other Drugs, published by the AA
General Service Conference, clearly distinguishes necessary and important prescription medications from selfadministered drugs.
To assess systematically the attitudes of AA members toward the use of medications, 277 AA members were surveyed anonymously. They were asked about their attitudes
toward the use of alcohol relapse prevention medication
and their experiences with any psychotropic medications
while in AA. Nearly a third (29 percent) reported personally experiencing some pressure to stop taking a medication (of any type); however, 69 percent of these individuals
945
continued taking the medication. Only 12 percent of respondents said they would tell another member to stop
taking medication (Rychtarik et al., 2000).
Double Trouble in Recovery (DTR) is a 12-step self-help
program specifically designed for persons with chronic
mental illness and a comorbid substance abuse disorder.
The program was started in 1989 and currently has more
than 200 groups in the United States. DTR specifically supports both abstinence from intoxicating substances and adherence to psychiatric medication regimens. Indeed, a 1-year
prospective longitudinal study of 310 participants in the
program found that consistent attendance at DTR meetings
was associated with better adherence to medication regimens (Magura et al., 2002). Although the study was not
randomized, this relationship persisted after controlling
for baseline variables that were independently associated
with adherence (living in supported housing, having fewer
stressful life events, and having a lower severity of psychiatric symptoms). A fifth of the patients in the study had bipolar disorder, a fifth had unipolar depression, and about
half had schizophrenia.
More recently, 129 stabilized outpatients meeting Diagnostic and Statistical Manual (DSM) criteria for drug dependence (cocaine, heroin, or cannabis) and serious mental
illness (55 percent affective disorders, polarity not specified) were randomly assigned to 6 months of Behavioral
Treatment for Substance Abuse in Severe and Persistent
Mental Illness (BTSAS) or to a manualized control condition, Supportive Treatment for Addiction Recovery (STAR)
(Bellack et al., 2006). BTSAS entails a social learning intervention, including motivational interviewing, social skills
training, and a urinalysis contingency. Participants were
taught how to refuse drugs, engage in alternative social activities, and develop non-drug-using social contacts. The
STAR program consisted of support groups, some education, and checking of urine samples, but with no systematic
feedback. The BTSAS program was significantly more effective than STAR in terms of attendance at treatment sessions, clean urine test results, and survival in treatment. BTSAS participants reported a significant increase in general
life satisfaction, were less likely than STAR participants to
be hospitalized, and were less likely to be arrested.
Group therapy has been shown to be effective for treatment of both bipolar disorder and substance abuse disorders; however, few structured group therapies have been
developed to address comorbid substance abuse and bipolar
disorder simultaneously. An exception is Integrated Group
Therapy (IGT), a manualized relapse prevention therapy
that achieves an integrated approach by addressing topics
that are relevant to both disorders and by highlighting common aspects of recovery from, and relapse to, each disorder (Weiss et al., 1999, 2007). A 6-month, nonrandomized
946
Treatment
pilot study found that, compared with patients who did not
receive group therapy, those who received IGT had significantly better outcomes on the Addiction Severity Index
drug composite score, spent more months abstinent, and
were more likely to achieve at least two consecutive abstinent months. The nonrandom design of this study did not
make it possible to compare the efficacy of IGT and other
forms of group therapy, however. A more recent, randomized study of 62 patients found that those receiving IGT had
significantly less substance abuse (Weiss et al., 2007).
In contrast to the benefits of the manualized IGT, unstructured therapy does not appear to be helpful, and it
may actually be harmful, for substance-abusing patients.
Weiss and colleagues (2000) followed 24 patients receiving
unstructured psychosocial treatment after hospital discharge. It was found that psychotherapy and AA attendance decreased over time among the study subjects, and
the focus of patients psychotherapy gradually became more
general, so that decreasing emphasis was placed on their
specific disorders. During this period, there was a trend toward more frequent drug use, while the patients mood
symptoms did not change significantly.
ANXIETY DISORDERS
Panic Disorder
Uncomplicated panic disorder is generally treated pharmacologically with selective serotonin reuptake inhibitors (SSRIs) or high-potency benzodiazepines. While the use of SSRIs in unipolar depression is relatively straightforward, in
bipolar patients the risk of switches into mania/hypomania/
mixed states and the risk of long-term destabilization must
be taken into account (see Chapter 19 for a full discussion of
these critical issues). The risk of switch/destabilization with
antidepressants may be increased by substance abuse comorbidity. For example, in a sample of 48 bipolar patients,
20 of whom had comorbid substance abuse, the probability
of having a history of an antidepressant-induced mania was
seven times greater among the comorbid patients. Overall,
60 percent of the bipolar patients with comorbid substance
abuse had become manic when given an antidepressant
(Goldberg and Whiteside, 2002). Although comorbid panic
disorder represents a case in which an SSRI may well be
needed, it is critical to first optimize mood stabilization. Indeed, as noted later, some mood stabilizers themselves have
been shown to have therapeutic effects in panic disorder
that could obviate the need for an SSRI.
Benzodiazepines, which are also effective in panic disorder, are frequently used during acute mania. Although they
may not possess inherent mood-stabilizing properties, they
can be highly effective in helping to normalize sleep, which
Treatment of Comorbidity
Atypical antipsychotics are playing an increasingly important role in the treatment of bipolar disorder. All have
significant effects on the serotonin system; in contrast to the
SSRIs, however, this effect consists of direct stimulation or
inhibition of presynaptic and postsynaptic serotonin receptors. Results of some studies suggest that certain of these
agents, as well as the typical antipsychotics, including trifluoperazine (Mendels et al., 1986), may have anxiolytic properties in general (Wilner et al., 2002; Gao et al., 2006) as well
as in bipolar patients (Hirschfeld et al., 2006). To our knowledge, however, there have been no controlled trials of atypical antipsychotics in the treatment of panic disorder per se,
so their utility for this purpose remains speculative.
For optimal results, psychotherapeutic interventions
should generally be part of the comprehensive management
of comorbid panic disorders. Cognitive-behavioral therapy has been shown to be effective in treating many anxiety disorders and is considered a first-line treatment.
Obsessive-Compulsive Disorder
Serotonergic antidepressants are the most frequently used
treatment for obsessive-compulsive disorder (OCD); benzodiazepines (Hollander et al., 2003) and antidepressants
without serotonergic activity (Vulink et al., 2005) are not
effective for patients with this disorder. The use of antidepressants carries risks for these patients, however. A study
of 263 patients with OCD who had not been diagnosed
with bipolar disorder nevertheless found that 13 percent
had experienced a hypomanic episode, and that many of
the hypomanias occurred after treatment with an antidepressant (Lensi et al., 1996). Only 1.5 percent had experienced full manias, a finding consistent with data showing
that most patients with comorbid OCD and bipolar disorder have the bipolar-II type (Perugi et al., 1997).
947
948
Treatment
Treatment of Comorbidity
949
with borderline personality disorder (Frankenburg and Zanarini, 2002; Bellino et al., 2005; MacKinnon and Pies, 2006),
and there is evidence that some patients with both bipolar
illness and borderline personality disorder show marked improvement with a combination of pharmacotherapy and
psychotherapy (Bieling et al., 2003; Swartz et al., 2005).
Obesity
The efficacy of most treatments for obesity is modest at
best, and often temporary. Short-term caloric restriction,
in particular, can lead to weight cycling. From the perspective of mood disorders, weight cycling is associated not
only with physiological problems but also with psychological problems, such as diminished self-esteem and life satisfaction and a more negative body image (Friedman et al.,
1998). From a dietary standpoint, the most effective approach to weight control among bipolar and recurrent
unipolar patients is carbohydrate restriction.
Most agents used in the treatment of bipolar disorder are
associated with weight gain, as well as with other components of the metabolic syndrome, such as insulin resistance
and atherogenic dyslipidemia (see Chapter 20). Among the
atypical antipsychotics used in the treatment of mania,
ziprasidone and aripiprazole are relatively weight-neutral.2
It is important to note that with this class of drugs, medical
950
Treatment
complications associated with obesity, such as insulin resistance, can occur even in the absence of obesity (Henderson
et al., 2005). It remains to be seen whether the lack of
weight gain associated with ziprasidone and aripiprazole is
accompanied by a fully benign metabolic profile. Risperidone appears to cause fewer problems with glucose utilization compared with clozapine and olanzapine (Henderson
et al., 2005). Among the established mood stabilizers, only
lamotrigine does not cause weight gain, nor does it increase
the risk of diabetes, atherogenic dyslipidemia, or other
components of the metabolic syndrome.
As noted earlier, unlike many medications used in psychiatry, topiramate has been associated with weight loss rather
than weight gain. Because so many mood stabilizers cause
weight gain, topiramate may play a significant role as an antidote to iatrogenic weight gain in patients with bipolar disorder. A 6-month placebo-controlled, dose-ranging trial of
topiramate for weight loss in obese patients found that all
doses of the drug (64 to 384 mg/day) resulted in comparable
weight loss, which was significantly greater than that observed with placebo. Mean weight loss from baseline to week
24 ranged from 4.8 to 6.3 percent of pretreatment body
weight, compared with 2.6 percent with placebo (Bray et al.,
2003). However, neurocognitive side effects, which are dose
dependent, can interfere with patients acceptance of topiramate; difficulty with memory, concentration, and attention
were the most frequently observed of these effects.
Zonisamide has been associated with weight loss in patients with epilepsy; in a 16-week controlled trial involving
61 obese patients, zonisamide and a hypocaloric diet resulted
in more weight loss than a hypocaloric diet alone (Gadde
et al., 2003). The drug has also been reported to have therapeutic properties in a small number of open studies and case
series of bipolar patients (see Chapter 18) (Kanba et al., 1994).
Bupropion was shown to be superior to placebo in facilitating weight loss in three controlled studies (Gadde et al.,
2001; Anderson et al., 2002; Jain et al., 2002). In one of
these, the weight loss was maintained for 48 weeks (Anderson et al., 2002). Moreover, in expert consensus guidelines,
bupropion has been identified as a preferred antidepressant
for patients with bipolar depression, although there is only
limited supporting evidence from controlled trials.
Sibutramine, an antiobesity agent, is a serotoninnorepinephrine reuptake inhibitor that has been shown to improve
depressed mood in patients with binge eating disorders (Appolinario et al., 2003). Although no studies have been done
in patients with bipolar disorder, a dual reuptake inhibitor
of this nature might be expected to lead to mood destabilization. Venlafaxine, an antidepressant dual reuptake inhibitor that has been associated with switches into mania,
has not been associated with long-term weight loss. Duloxetine has not been formally evaluated for weight loss activity.
Thyroid Dysfunction
The thyroid gland produces two hormonesthe prohormone thyroxine (T4) and the more biologically active triiodothyronine (T3). T4 is partly converted into T3 by deiodinases. Thyroid hormones enter the cell, bind to nuclear
receptors, and alter the expression of specific genes that affect the synthesis of key enzymes required for neurotransmitter production, as well as glial cell proliferation and
myelination.
As reviewed in Chapter 19, T3 is used mainly in the adjunctive treatment of major depression and has been shown
to accelerate the response to tricyclic antidepressants
(Prange et al., 1969; Goodwin et al., 1982). Women in particular appear to benefit from the combination of T3 and a tricyclic antidepressant. T3 has also been used as an augmentation strategy in treatment-resistant depression (Aronson
et al., 1996).
T3, the most active thyroid hormone, carries the risk of
inducing a hyperthyroid state. Because T4 is the prohormone, the homeostatic mechanism of reduced conversion
to T3 allows the body to maintain a euthyroid state more
easily. Unlike T3, moreover, T4 has not been associated with
osteoporosis (Nuzzo et al., 1998).
Supraphysiological doses of T4 were shown to be effective in the maintenance treatment of prophylaxis-resistant
Treatment of Comorbidity
CONCLUSIONS
Given the frequency of occurrence of comorbid conditions
in manic-depressive illness, especially the bipolar subgroup,
clinicians should screen specifically for comorbid substance
abuse, anxiety disorders, obesity, eating disorders, and
general medical disorders. All illnesses should be addressed
individually when a treatment plan is developed. Depending on the relationship among the comorbid diagnoses,
the successful treatment of one disorder may lead to improvement in the others. Nevertheless, this is not always
the case, and the goal should always be full remission of
951
NOTES
1. Feltner et al., 2003; Pande et al., 2003; Pohl et al., 2005; Rickels
et al., 2005.
2. Of these two atypical agents, ziprasidone is less likely to be associated with weight gain.
25
Lithium . . . is the lightest of the solid elements and it is perhaps not surprising that it should in
consequence possess certain modest magical qualities.
G. P. Hartigan (1959)
Manic-depressive illness carries the risk of suicide throughout its course (see Chapter 8). The precise timing of suicide
cannot be predicted, but there are almost always warning
signs in the preceding days to weeks. The challenge for clinicians is to discern, from a complex and fluctuating clinical picture, suicidal intent in a patient, and to assess the
presence of various risk factors for suicide, which may
manifest as symptoms, stressful situations, and/or comorbidities. Specifically, treatment of manic-depressive patients to prevent suicide has three key elements: (1) clinical
assessment of intent and overall suicide risk; (2) intensive
treatment of those acute symptoms associated with an increased risk of suicide; and (3) careful clinical follow-up of
patients with suicide risk factors, with renewed attention
to treating the patients underlying affective disorder and
comorbidities. While no approach is foolproof, treatment
in a maximally supportive clinical environment can reduce
the risk of suicide and save lives (Rucci et al., 2002; Knox et
al., 2003; Bruce et al., 2004).
In 1999, the U.S. Surgeon General declared that suicide
is a preventable public health problem (U.S. Public Health
Service, 1999). This embracing of a public health perspective on suicide was prompted by compelling evidence that
(1) mental illness was undiagnosed in about 50 percent of
suicides (see Chapter 8), (2) inadequate treatment characterized the majority of those individuals who had been
diagnosed (Isometsa et al., 1994; Isacsson et al., 1997;
Oquendo et al., 1999), and (3) the majority of those who
killed themselves had had some type of contact with the
health care system in the months leading up to their death.
In the final month before the act alone, according to results
of more than 40 studies, nearly 45 percent of suicide victims had had contact with a primary care physician and
another 20 percent with a specialist (Luoma et al., 2002).
954
Treatment
955
BOX 252. Questions That May be Helpful in Inquiring about Specific Aspects of Suicidal Thoughts,
Plans, and Behaviors
Begin with questions that address the patients feelings
about living:
Have you ever felt that life was not worth living?
Did you ever wish you could go to sleep and not wake up?
Follow up with specific questions that ask about thoughts
of death, self-harm, or suicide:
Is death something youve thought about recently?
Have things ever reached the point that youve thought
of harming yourself?
For individuals who have thoughts of self-harm or suicide,
ask:
How often have those thoughts occurred (including frequency,
persistence, obsessional quality, controllability)?
How likely do you think it is that you will act on them in the future?
What do you envision happening if you actually killed yourself
(e.g., escape, reunion with significant other, rebirth, reactions of
others)?
Have you made a specific plan to harm or kill yourself? (If so,
what does the plan include?)
For individuals who have attempted suicide or engaged in
self-damaging actions, questions parallel to those in the
previous section can address the prior attempts.
Additional questions can be asked in general terms or can
refer to the specific method used and may include the
following:
Can you describe what happened (e.g., circumstances, precipitants, view of future, use of alcohol or other substances,
method, intent, seriousness of injury)?
What did you think would happen (e.g., going to sleep versus injury versus dying, getting a reaction out of a particular person)?
How did you feel about surviving the attempt? Relieved? Disappointed? Indifferent?
Did you receive treatment afterward (e.g., medical versus psychiatric, emergency department versus inpatient versus outpatient)?
For individuals with repeated suicidal thoughts or attempts,
ask:
About how often have you tried to harm (or kill) yourself?
When was the most recent time?
Can you describe your thoughts at the time you were thinking
most seriously about suicide?
For individuals with psychosis, ask specifically about hallucinations and delusions:
Have you ever done what the voices ask you to do? (What led
you to obey the voices? If you tried to resist them, what made it
difficult?)
Have there been times when the voices told you to hurt or kill
yourself? (How often? What happened?)
Are there things that youve been feeling guilty about or blaming yourself for?
Consider assessing the patients potential to harm others
in addition to himself or herself:
Are there others who you think may be responsible for what
youre experiencing (e.g., persecutory ideas, passivity experiences)? Are you having any thought of harming them?
Are there other people you would like to die with you?
Are there others who you think would be unable to go
on without you?
Source: Questions are selected from Table 3 of the American Psychiatric Associations Practice Guideline for the Assessment and Treatment of Patients
with Suicidal Behaviors. See that table for additional questions. Reproduced with permission from the American Psychiatric Association.
Suicide assessment is not without its limitations. Research has failed to yield a set of criteria that predicts suicide risk in an individual patient.1 Nor has any method of
suicide assessment been adequately evaluated prospectively,
in part because suicide is a statistically rare event (IOM,
2002). Assessment instruments are available, but no set of
criteria can be sensitive enough to detect every patient at
high risk while also avoiding a high false-positive identification rate. The current understanding of risk factors for
suicide depends mainly on retrospective studies that lacked
control groups and standardized measures of symptoms
and behaviors; these studies may also suffer from bias introduced by the knowledge that a suicide occurred. Yet regardless of how imperfect clinical assessment may be, it can
help prevent many suicides, and its imperfections cannot
justify inattention or inaction on the part of the clinician.
956
Treatment
Note: Most factors come from clinical experience rather than a strong
evidence base, because very little research has addressed the specific factors that might be protective in manic-depressive iIllness.
Sources: Goodwin and Jamison, 1990; Malone et al., 2000; Jacobs et al.,
2003.
Table 251. Acute and Chronic Risk Factors for Suicide among Patients
with Affective Disorder Who Committed Suicide (N = 25)
versus Patients Who Did Not Commit Suicide (N = 929)
Acute Risk Factor
(p Value)a
Hopelessness
.463
.007
Alcohol abuse
.029
.372
.005
.223
.012
.879
.613
.041
Suicide attempts
.815
.086
Obsessive-compulsive features
.063
.303
Indecisiveness
.085
.062
Diminished concentration
.028
.078
Global insomnia
.011
.765
Symptom
957
Note: Acute refers to suicide occurring within 1 year of assessment; chronic refers to suicide
occurring within 210 years of assessment.
a
Probability values for Mann-Whitney U statistics.
Source: Fawcett et al., 1990. Reproduced with permission from the American Psychiatric Association.
958
Treatment
Protective Factors
Minimum pathology in a suicidal person bereft of
strengths may be lethal, while severe pathology in a person with unusual strengths may constitute only
a moderate risk. (Motto, 1975, p. 239)
CLINICAL MANAGEMENT
The seriously suicidal person with manic-depressive illness,
whether bipolar or recurrent unipolar, requires intensive
clinical care. Suicide is prevented most effectively by a combination of immediate strategies to keep the patient safe by
ameliorating acute risk factors, and long-term strategies to
stabilize the patients underlying illness and thereby prevent
recurrences of potentially life-threatening affective episodes.
The clinician may need to change or add medications, modify psychotherapeutic practices, and enlist support from the
patients family members and friends. A suicidal crisis while
a patient is under psychiatric care often provides the opportunity and impetus to reappraise previous assumptions
about diagnosis, psychiatric history, treatment response, and
involvement in the treatment process of family members
and other individuals of significance to the patient.
The immediate priorities with a suicidal patient are (1)
to keep the patient safe by precluding or reducing access to
common methods of suicide, such as firearms and medication overdose; (2) to establish a therapeutic alliance; and
(3) to treat acute risk symptoms that can be clinically modified (e.g., recurrent severe anxiety/panic, mixed states, agitation, impulsivity, global insomnia, and substance abuse).
The second priority is to develop and implement a systematic treatment plan for preventing future episodes of suicidal
depression, mania, and mixed states. Chronic-risk patients
959
Figure 251. Overall approach to manic-depressive patients with acute and chronic risk factors
for suicide.
If risk is acute
If risk is chronic
960
Treatment
used, particularly in the United States, because of the presence of obstructive legal and bureaucratic pressures that
make the treatment difficult and cumbersome to employ;
the risk of litigation by a small minority of patients; the
availability of alternative antidepressant treatments; the influence of negative publicity from outside the medical field;
and, within the psychiatric field, a relative lack of awareness
of ECTs advantages in treating the acutely suicidal patient.
ECT has several advantages over pharmacotherapy: the
antidepressant response is more rapid, thereby decreasing
the immediate risk of suicide; there is less potential for
worsening the course of the illness; and the interruption of
the depressive episode allows time for the prophylactic effect of a mood stabilizer to take hold (Prudic and Sackeim,
1999). At the same time, however, some caveats are in order. First, ECT does not always relieve these symptoms
quickly. Moreover, there may be delays in scheduling or accomplishing required medical tests and examinations, and
during this period, the symptomatic patient remains at
risk. Finally, ECT may be no more effective than other
short-term treatments (see the later discussion).
Therapeutic Style
Most clinicians agree that psychodynamic psychotherapy
is contraindicated for suicidal patients, especially those
who have bipolar disorder (Winokur et al., 1969; Hankoff,
1982). Clinical experience suggests that a direct and involved
approach is the most effective and compassionate. The
therapist should be willing to take more initiative with severely depressed patients than might be appropriate with
others. Directness with a suicidal patient is imperative, because the gravity of the situation demands immediate action, and the patients paralysis of will necessitates active
intervention. Also, most suicidal bipolar patients are hyperalert and hypersensitive, as well as guarded and suspicious, and they often possess an uncanny ability to sense
fear, irritation, and evasiveness in their therapists. Directness on the part of the clinician can help allay unnecessary
anxiety and unwarranted speculation, decrease a pervasive
sense of hopelessness, and establish a basis for trust that
can extend into other aspects of clinical care. Along with
directness, the therapist must demonstrate an ability to
understand complex and painful feelings.
Because manic-depressive illness has biological roots,
psychotherapeutically oriented clinicians often refer suicidal manic-depressive patients to psychopharmacologists,
some of whom may not have the time, interest, or skill
to provide psychotherapy and thus may tend to rely too
961
heavily on medication. Conversely, clinicians who are primarily psychotherapists may tend to place too little emphasis on the importance of medication in alleviating shortterm risk factors as well as treating the long-term course
of the illness. This clinical problem is especially significant
for suicidal patients, who have a particular need for integrated medical and psychotherapeutic care.
Suicide-Oriented Therapies
Contemporary randomized controlled trials of the longterm efficacy of psychotherapy in manic-depressive illness
have focused on the bipolar subgroup (see Chapter 22).
Disappointingly few of these studies have tested the efficacy of specific suicide-oriented therapies, and none have
focused on decreasing suicide, or even suicidality, per se.
Indeed, most clinical trials that address suicidal behaviors
have been directed at personality disorders or have grouped
together patients with very different diagnoses (Brown
et al., 2005). Further, the outcome measure has usually been
deliberate self-harm, which encompasses both nonlethal
and lethal intent and varying degrees of planning; it is an
imperfect proxy for suicide. The primary problem is that
most trials are underpowered to detect a decrease in suicide because of its relative rarity.
Systematic reviews of the efficacy and methodology of
suicide-oriented clinical trials are available.4 The types
of therapies examined in such trials include particular
cognitive-behavioral therapies (e.g., dialectical behavioral
therapy for borderline personality disorder), psychodynamic interpersonal therapy, emergency cards (which allow emergency admission or contact with a physician),
and problem-solving therapy. Recently, Miklowitz and Taylor (2006) proposed an adaptation of family-focused therapy for suicidal bipolar patients that holds promise for
helping this at-risk group of patients. Given the limitations
of the literature, clinical experience suggests that with suicidal bipolar patients, the quality of the relationship between therapist and patient is more important than any
particular type of psychotherapy.
Providing Reassurance
The liberal and intelligent use of reassurance, an integral
part of the treatment of manic-depressive illness, is particularly important when the patient is suicidal. Indeed, it is
reasonable to offer hope when dealing with a generally treatable and spontaneously remitting illness. Winokur and colleagues (1969) suggested frequently reassuring patients and
families first, that depression is an illness; second, that it is
time-limited; and third, that the clinician is familiar with
this kind of problem. While depressed, suicidal patients are
unlikely to acknowledge that such reassurance is helpful,
although after they have recovered, they often remark on
962
Treatment
Communicating Information
Explicit information about both the bipolar and recurrent
unipolar forms of manic-depressive illness, their treatment, and their association with suicide is particularly important when dealing with suicidal patients, who may feel
profound hopelessness and be severely cognitively impaired. Whenever feasible, information should be provided
to such patients in both oral and written form. One of the
first messages that must be clearly communicated concerns
the limits on confidentiality between suicidal patients and
their therapists. This message becomes highly significant
for patients who are paranoid, irritable, and hostile or are
experiencing mixed states and rapidly fluctuating moods.
Other information for the patient and, where appropriate,
for the family are listed in Box 256.
It is important to communicate consistently that although manic-depressive illness is serious, it can be treated
successfully in the great majority of cases. Left untreated,
however, particularly early in its course, it not infrequently
results in suicide. The clinician must explain to both patient and family that denial of the possibility of recurrence
is common, but it can also be dangerous. Such an explanation predicts thoughts and feelings and thereby lends credence to the clinicians recommendations.
The patient must be strongly and persuasively encouraged to take lithium or other medications as prescribed. In
the case of lithium, the patient should be informed that the
drug has been demonstrated to have a strong antisuicidal
effect and that it can sometimes work as effectively against
depression as it does against mania, but that it usually takes
Medication Issues
Worsen sleep
Decrease impulse control and judgment
Potentiate or interfere with prescribed medications
Worsen course of illness
Increase the likelihood of mixed states
Recovery Issues
Medication Monitoring
The importance of prescribing only limited amounts of potentially lethal medications to suicidal patients cannot be
overstated. Growing reliance on SSRI antidepressants has
reduced the likelihood of lethal overdose because they are
less toxic than monoamine oxidase inhibitors (MAOIs)
and tricyclic antidepressants. In the pre-SSRI era, Murphy
(1975) concluded that half of patients who killed themselves
through an overdose had obtained their lethal antidepressant
dose in a single prescription. Lithium is also potentially lethal
and should be monitored accordingly (see Chapter 20).
Instructions regarding medicationsdosages, timing,
side effects, potentially dangerous adverse reactions, and
potentiation/interference by alcohol and other drugs
should be explicit and in writing. If possible, another concerned individual (family member or friend) should become involved in monitoring the medications prescribed
for a suicidal patient because confusion, hopelessness, and
ambivalence about taking drugs can make depressed patients particularly susceptible to errors in taking medications. Plastic pill boxes with separate sections for each day
of the week are helpful to many patients, particularly those
who are confused as a result of their depression or are taking more than one medication.
963
Availability of Clinician
When patients are suicidal, they should be seen and contacted more frequently than usual. If financial or scheduling
problems exist, the clinician should attempt to see the patient for shorter periods of time but more often. It may
help to establish a time each day, or every few days, for a
brief telephone conversation. Because the slowed anergic
quality of bipolar depression often makes telephoning a
difficult task for the patient, we find it helpful to initiate
these contacts, asking the patient frequently and regularly
to give his own assessment of suicidal ideation and obtaining as much information as possible from family members
about the patients behavior and suicidal intent.
The clinicians accessibility to the patient and the patients understanding and acceptance of his alliance with
the clinician are dimensions of care that are crucial to keeping the patient alive through the worst times. The patient
must be told clearly how to reach the clinician in an emergency or during an acute exacerbation of suicidal thoughts
and feelings. Directions for dealing with answering services, on-call systems, and coverage by other clinicians
should be explicit and conveyed both orally and in writing. Depressive confusional states, as well as guilt or fear
about overburdening and alienating clinicians, often prevent patients from indicating that they do not fully understand such practical details. Putting this information in
writing, along with Do not hesitate to call, can be both
concrete and reassuring. The clinician needs to have a clear
agreement with all suicidal patients stipulating that they
will call if they are in danger of losing control of their feelings or actions, become acutely suicidal, or feel the need
for immediate care. It generally is prudent as well to share
this information with the closest family member or friend.
Clinician Attitudes
Therapists should always be sensitive to the feelings,
thoughts, and actions engendered in them by a patient (see
Chapter 22), but this is especially so when the patient is
suicidal. The therapists reactions often reflect the added
stress, responsibility, and time commitments involved in
treating a suicidal patient, who is frequently irritable and
who conveys a sense of contagious hopelessness. The tendency for some therapists to overidentify with patients
professionally successful ones in particularcan increase
the therapists own psychological distress and lead to denial or overprotectiveness. The serious possibility of suicide reminds most therapists of their own limitations. As
Cassem (1978, pp. 595596) noted:
The need to balance consideration for the patients safety
with the goal that he live his life independently . . . reminds
964
Treatment
To facilitate communication, relatively new legal instruments, known as psychiatric advance directives, can be used
by patients, when well, to document their instructions for
care in times of suicidal crisis, including preferences for
medication, hospitalization, and ECT and the designation
of an individual authorized to make health care decisions
on their behalf. More than 20 states have passed specific
statutes for psychiatric advance directives. Forms can be
downloaded through various gateway Web sites (e.g., Duke
University, 2005) and through patient advocacy groups
(see the suggested guidelines of the Depressive and Bipolar
Support Alliance given in Box 221 in Chapter 22).
Hospitalization
The decision to admit a suicidal patient to a psychiatric
hospital is often straightforward and reassuring. On the
other hand, when a patient equates hospitalization with
failure or symbolic defeat or when the stigma of hospitalization may have a severe and negative effect on work or
personal relationships, the decision becomes more complicated. The psychological, social, financial, and clinical disadvantages to the patient must be weighed not only against
the risk of suicide, but also against the pragmatic and emotional costs to the family and the clinician if the patient remains out of the hospital.
Hospitalization, although decreasing the risk of suicide,
does not eliminate it. Robins and colleagues (1959) found
that 7 percent of patients in their sample had committed
suicide while in a psychiatric hospital. Weeke (1979) reported an even higher rate: 27 percent of manic-depressive
patients killed themselves while under hospital care, although half of them were on a pass or had absconded.
Weeke emphasized the need for special precautions to supplement hospitalization and the careful observation of such
patients even when they appear substantially improved or
recovered (see also Winokur et al., 1969; Roose et al., 1983).
These measures are not always effective in preventing suicide, however. Busch and colleagues (2003) examined 76
cases of inpatient suicide and found that 42 percent had
been on orders for suicide checks every 15 minutes or had
been seen by staff within 15 minutes of their suicide. This
finding underscores the potential inadequacy of one of the
most commonly used precautions for those at acute risk of
suicide.
Motto (1975) and Hawton and Catalan (1982) provided
specific examples of ways to document evidence and improve communication among hospital staff members to
prevent suicide:
The degree of suicide risk should be carefully assessed
and should be stated explicitly (for example, low, moderate, or high).
The measures to be taken in dealing with the acutely suicidal patient should be stated in clear, specific terms.
Most hospitals have devised suicide observation procedures that include detailed instructions to nurses and
physicians.
Nursing staff should be required to document on the patients chart that the suicide prevention measures have
been carried out.
It is especially important to specify whether the risk of
suicide for a patient is acute or chronic. Once acute risk has
been determined, efforts must be made to reduce that risk,
such as by aggressively treating insomnia, agitation, and
anxiety symptoms and providing the patient with one-onone observation until the acute-risk state has ended.
Other factors important to preventing suicide in hospitalized patients are a high staff/patient ratio, a reduced
number of exits on the ward or a locked ward, and an
awareness that increased risk occurs during a change in
nursing shifts and when a crisis on one part of the ward
distracts staff attention from the suicidal patient (Hawton
and Catalan, 1982). It is essential, when possible, to ask the
patients family members about expressed suicide intent
since, as noted earlier, patients more often confide in family members than in their doctors.
Follow-Up Care
The chronic, recurrent, and serious nature of manicdepressive illness makes careful monitoring during the recovery period an essential part of treatment. Even in the
early nineteenth century, Benjamin Rush (1812, p. 239)
called attention to the danger of this period:
We should be careful to distinguish between a return of
reason and a certain cunning, which enables mad people
to talk and behave correctly for a short time, and thereby
to deceive their attendants, so as to obtain a premature
discharge from their place of confinement. To prevent the
evils that might arise from a mistake of this kind, they
should be narrowly watched during their convalescence,
nor should they be discharged until their recovery. . . .
Three instances of suicide have occurred in patients soon
after they left the Pennsylvania Hospital, and while they
were receiving the congratulations of their friends upon
their recovery.
965
966
Treatment
Benzodiazepines
Results of several clinical trials suggest that adequate, regularly administered doses of benzodiazepines, such as clonazepam or lorazepam, can act fairly rapidly to reverse severe anxiety, panic attacks, and agitated states. Smith and
colleagues (2002) presented data showing more rapid improvement in depression when clonazepam was added to
fluvoxamine. Londborg and colleagues (2000) found over
the first 3 weeks of treatment that fluoxetine plus clonazepam at night, versus fluoxetine plus placebo, worked
better in reducing total Hamilton Rating Scale for Depression (HAM-D) scores, anxiety, and sleep disturbance.
Treatment-emergent anxiety was reported for 25 percent of
placebo but only 7 percent of cotherapy patients. An extension study assigned patients to the same dose (20 mg) of
fluoxetine or an increased dose (40 mg) at 6 weeks (Smith
et al., 2002). One week later, cotherapy (fluoxetine with
clonazepam) was found to be superior to fluoxetine with
placebo with respect to HAM-D and Clinical Global Impressions (CGI) ratings; response rates were 32 and 4 percent, respectively. Cotherapy with benzodiazepines was
also found to be useful for rapid treatment of anxiety and
insomnia.
There are caveats, however. The effects of benzodiazepines wear off rapidly, necessitating supervised use until
basic antidepressant and/or mood-stabilizing treatment
with medications or ECThas reduced the severity of depressive symptoms. Although giving one or two doses of
anxiolytic medication can result in dramatic improvement
in the acute state and thereby potentially lower acute suicidal risk, failure to repeat the dosage on a regular schedule
until the underlying affective disorder has improved may
967
The sleep disturbances that often accompany severe anxiety and panic and that represent an independent risk factor for suicide should be treated aggressively with sedative
hypnotics, sedating atypical antipsychotics, or sedating and
anxiolytic anticonvulsants, such as valproate or gabapentin.
Anticonvulsants and antipsychotics can be used to
treat those patients who display disinhibition or outbursts
of anger in response to fast-acting benzodiazepines. In
these circumstances, anticonvulsants such as divalproex
(Schatzberg, 1998), atypical antipsychotics, or sedating
typical antipsychotics, such as thioridazine, may be useful,
particularly in reducing agitation and anxiety. Indeed,
these treatments can be life-saving in some high-risk patients. All of these medications are relatively safe if used
skillfully and with the necessary amount of supervision
and follow-up. It is important that they be given in sufficient doses, even if temporary sedation results, until the
suicidal crisis has been brought under control. The atypical antipsychotics merit special mention because, as discussed later, the atypical clozapine is the only drug other
than lithium for which there is replicated evidence of a reduction in suicide risk. (See Chapter 19 for discussion of
the use of anticonvulsants and atypical antipsychotics in
the treatment of bipolar depression.)
Electroconvulsive Therapy
Lithium
Several meta-analyses encompassing dozens of studies
have shown that lithium is a powerful antisuicide agent.
Tondo and Baldessarini (2000) analyzed 22 long-term investigations of lithium therapy published from 1974 to 1998.
In the more than 5,600 patients studied (representing nearly
968
Treatment
Figure 252. Rates of suicide and suicide attempts among patients with major affective disorders, without (Off ) and with (On) long-term lithium maintenance treatment, and estimated rates in the general
population. Rates are in terms of suicidal acts per 100 patient-years (% per year). Note that the suicide attempt rates for patients treated with lithium versus the general population do not differ significantly, but
the rate for suicide among treated patients is 10 times higher than that among the general population.
(Source: Baldessarini et al., 2006b. Reproduced with permission from the New York Academy of Sciences.)
4.5
Suicides
Attempts
0.8
0.7
3.5
0.6
0.5
2.5
Rate
Rate
0.9
0.4
0.3
1.5
0.2
0.1
0.5
Off
On
General
Off
On
General
Pooled RR
(4.91)
0.01
0.1
1
10
RR (95% Cl)
100
1000
Figure 253. Overall random-effects meta-analysis of 31 studies of the risk of suicide and/or
suicide attempts with and without lithium treatment. The risk ratio (RR) and 95 percent confidence interval (CI) for each study are shown (squares are proportional to study weight). The
computed pooled RR (diamond) is 4.91 (95 percent CI = 3.826.31; z = 12.5, p <.0001). The vertical solid line represents the null hypothesis (RR = 100). Asterisks (*) denote randomized controlled trials. (Source: Baldessarini et al., 2006b. Reproduced with permission from the New
York Academy of Sciences.)
969
970
Treatment
Table 252. Summary of Meta-Analyses: Lithium Treatment vs. Risk for Suicide
No. of
Studies
Risk Ratio
(95% CI)
p Value
31
4.91
(3.826.31)
12.5
<.0001
30
5.34
(4.276.68)
14.7
<.0001
Suicides only
23
4.86
(3.367.02)
8.42
<.0001
Attempts only
17
4.98
(3.566.96)
9.42
<.0001
Bipolar disorderc
14
5.34
(3.597.93)
8.28
<.0001
17
4.66
(3.436.33)
9.82
<.0001
16
3.92
(2.945.23)
9.33
<.0001
15
5.56
(3.987.76)
10.1
<.0001
Condition
patients treated in two large health maintenance organizations. A regression analysis, which controlled for age, gender, health plan, year of diagnosis, concomitant use of other
psychotropic medications (e.g., antidepressants, antipsychotics), and comorbid diagnoses indicated that suicide was
2.7 times more likely among patients on divalproex versus
lithium. Suicide attempts resulting in hospitalization or
emergency department visits were 1.7 times more likely for
those taking divalproex than among those on lithium. By
far the primary determinant of which stabilizer was being
used was the year of initial treatment: at the beginning of
the period studied, 1994, more than 80 percent of the patients were prescribed lithium, but by 2001, about half were
being given divalproex and half lithium, reflecting the
trend in prescribing patterns in the United States during the
1990s (see Chapter 20). Taken together, the role of when patients entered treatment, along with the fact that comorbid
diagnoses and coexisting medications were equivalent in
the two groups, suggest that, any clinical differences in the
patients chosen to receive the two drugs are unlikely to have
contributed significantly to the differing suicide rates found.
Another recent meta-analysis that was restricted to randomized controlled trials found similar, albeit somewhat different, outcomes. Cipriani and colleagues (2005) analyzed
32 such trials comparing lithium with placebo (n = 1,389
The authors, like Wolf and colleagues (1996) a decade earlier, emphasized the importance of taking into consideration the duration of lithium treatment given not only their
own findings, but also those of earlier studies showing
higher mortality rates when lithium treatment lasted only
2 to 5 years (Norton and Whalley, 1984; Vestergaard and
Aagaard, 1991; Brodersen et al., 2000) versus 5 to 10 years
(Coppen et al., 1990, 1991; Muller-Oerlinghausen et al.,
1992a). The benefits of prolonged lithium treatment to
some extent reflect a selection bias, of course: patients who
respond better to lithium may be more likely to continue
taking it, while those who respond less well or who otherwise are at increased risk for nonadherence (e.g., patients
with substance abuse or personality disorder) may be
more likely to stop taking their medication.
Adherence to lithium is key. In a recent 16-year follow-up
study of lithium-treated patients with major affective disorders (who met the criterion of two to three affective
episodes in a 5-year period), those who adhered to lithium
had a standardized mortality ratio (SMR) of 8, while nonadherent patients had an SMR of 31, indicating that adherence
reduced the risk of suicide about four-fold (Brodersen et al.,
2000). Most of the suicides occurred among the atypical
patients enrolled in the study (those with schizoaffective
disorder, bipolar-II disorder, mixed episodes, and/or rapid
cycling). The authors observed that the rate of nonadherence was about 40 percent in the first 2 years of treatment in
this sample, but subsequently dropped to 5 to 10 percent.
This finding calls for more clinical attention to adherence,
especially during the early years of treatment (see Chapter
21). Adherence is particularly important for another reason,
alluded to above. There is strong evidence that suicide and
suicide attempts sharply increase after discontinuation of
lithium, especially abrupt discontinuation (Baldessarini
et al., 1999; Tondo and Baldessarini, 2000), as do episodes of
affective illness (Faedda et al., 1993; Baldessarini et al., 1999;
Baldessarini et al., 2003). Baldessarini and colleagues (1999,
p. 81) concluded that the first months after discontinuation
of lithium may carry a particularly high risk of suicidal behavior and included multiple attempts and fatalities, sometimes in persons without previous suicidal acts. Moreover,
the fatality rate due to suicide was 1.27 per 100 patient-years
after discontinuation of lithium compared with 0.101 during
lithium maintenancean alarming 12.6-fold increase.
Lithium also has been studied in combination with
other medications. Angst and colleagues (2002) provided
evidence that a combination of lithium and antidepressant
medications taken over a 6-month period can result in a
significant reduction in the incidence of suicide in patients
with recurrent affective disorders, especially those with
bipolar disorder. This study is discussed in detail in the
section on antidepressants.
971
Antidepressants
Antidepressants are efficacious for treating major depression and anxiety, but controversy exists as to whether they
prevent suicide or can, under some circumstances, trigger
it, and if the latter, in what age group and with what diagnosis or illness severity. We first consider the benefits of
antidepressants for suicide prevention and then the possibility that suicide or suicidal behaviors may be precipitated
by SSRI antidepressants in a small subgroup of particularly vulnerable individuals.
Most clinical trials of antidepressants have not meaningfully addressed potential efficacy in preventing suicide
because they have expressly excluded suicidal patients or
those with a history of suicide attempts, selected against
severe forms of depression, and because they are of insufficient duration to detect a relatively rare event; they have
relied instead on reports of suicidal ideation or attempts.
Given the exclusion of high-risk patients, it is not surprising that adequately powered meta-analyses of clinical trials
have found no significant difference in rates of suicide between antidepressant and placebo treatment (Khan et al.,
2000a, 2003; Storosum et al., 2002). The absence of an observed antisuicide effect may also reflect the failure of antidepressants to reduce acute suicide risk over a relatively
short period of treatment (1 to 8 weeks); the drugs may be
more effective at reducing long-term risk. Results of epidemiological studies, on the other hand, reveal that suicide
rates have been declining since the late 1980s, a time during
which the prescribing of SSRIs for both adults and adolescents has risen dramatically.7 Much of this increased prescribing has occurred in primary care settings (Pirraglia et
al., 2003). A recent analysis of county-level U.S. vital statistics found that SSRIs were associated with lower rates of
suicide, whereas tricyclic antidepressants were associated
with higher rates (Gibbons et al., 2005). This finding reflects, at least in part, the toxicity of tricyclics when an
overdose is taken. It may also reflect the fact that patients
who were prescribed tricyclics almost certainly represented a more clinically ill population; the SSRIs have been
972
Treatment
Table 253. Standardized Mortality Ratio (SMR) for Untreated vs. Treateda
Unipolar (n = 147) and Bipolar (n = 158) Patients
Condition
Unipolar suicide
Unipolar total mortality
Bipolar suicide
Bipolar total mortality
a
Untreated SMR
Treated SMR
Untreated vs.
Treated p Value
38.07
11.86
0.001b
1.67
1.56
0.001c
29.19
6.43
0.001c
2.18
1.33
0.001c
Treated with antidepressants, antipsychotics, and/or lithium over at least a 6-mo period or for
the entire period between two episodes.
b
Significant.
c
With p < .05 (two-tailed) different from 1.0 (Poisson distribution).
Source: Angst et al., 2002.
Figure 254. Antidepressant use at the time of suicide. An asterisk (*) indicates that no information
is available about adequacy of dosage. (Source: Adapted from Jamison, 1999.)
USA,
1978
USA,
1980
Switzerland,
1985
Hungary,
1990*
Finland,
1994
USA,
1994*
Antidepressant
prescribed and/or
present at autopsy
USA,
1997*
10
20
973
30
40
50
60
974
Treatment
Atypical Antipsychotics
Several studies have found that clozapine reduces rates of
suicide or attempted suicide in patients with schizophrenia
or schizoaffective disorder. The first such study to be published was of 183 neuroleptic-resistant patients who had
been consecutively hospitalized. After being prescribed
clozapine, they were followed for periods of 6 months to 7
years. The number of suicide attempts with high lethality
was reduced from five before the index hospitalization to
zero afterward (Meltzer and Okayli, 1995). Walker and colleagues (1997) found a significant decrease in death rates
from suicide in an epidemiologic sample of 67,072 users of
clozapine. Likewise, Reid and colleagues (1998), comparing
rates of suicide in a subset of patients treated with clozapine (n = 1,310) in a group of 30,000 schizophrenic patients
treated in the Texas mental health system, found a marked
reduction in the clozapine-treated group. More recently,
Modestin and colleagues (2005) found that clozapine diminished the frequency of serious suicidal acts in a sample
of 75 patients with schizophrenia, 14 with schizoaffective
disorder, and 5 with affective illness. On the other hand,
Sernyak and colleagues (2001), retrospectively studying a
group of 1,415 schizophrenic patients treated with clozapine, found no reduction in suicide compared with a schizophrenic control group not treated with the drug.
There is some evidence that olanzapine, another atypical antipsychotic, also reduces suicide attempts. Olanzapine, as compared with haloperidol, was associated with a
significant decrease in rates of attempted suicide in schizophrenic patients treated over 1 year (this study included
schizoaffective patients) (Glazer, 1997). In a post hoc
analysis of a randomized clinical trial, olanzapine given
over a period of 28 weeks was found to be superior to
risperidone in reducing suicide attempts (Tran et al., 1998).
These findings suggest that olanzapine may have effects
similar to those of clozapine in reducing suicide in schizophrenia. More recently, Houston and colleagues (2006)
found that the addition of olanzapine (versus placebo) to
lithium or divalproex monotherapy significantly reduced
suicidal ideation (as measured by HAM-D-3 scores) in 58
bipolar-I mixed-state patients.
975
CONCLUSIONS
The seriously suicidal person with manic-depressive illness,
whether bipolar or recurrent unipolar, requires intensive
clinical care. Suicidal behavior is treated and prevented
most effectively by a combination of immediate and longterm strategies. The immediate strategy is to keep the suicidal patient safe by ameliorating acute risk factors, such as
global insomnia, agitation, and severe anxiety. The longterm strategy is to stabilize the patients underlying illness,
particularly recurrent depressive or mixed episodes. When
bipolar or recurrent unipolar patients at chronic risk for
suicide are maintained on lithium, alone or in combination with other mood stabilizers and/or atypical antipsychotics, the incidence of suicide can be significantly reduced. Lithiums antisuicidal effect has been demonstrated
by meta-analyses of more than 30 studies that reveal an
approximately five-fold reduction in suicide risk among
patients treated with versus those not treated with lithium.
Careful treatment with antidepressants may also reduce
the risk of suicide, but for bipolar patients antidepressants
should generally be preceded by a mood stabilizer, preferably lithium because of its demonstrated antisuicidal effect. When administered alone, antidepressants may induce
mood cycling or mixed states, which may in turn heighten
the risk of suicide. Bipolar patients prescribed antidepressants, particularly children and adolescents, should be
carefully monitored, and they and their family members
advised to be alert to possible agitation and precipitous
switches in mood.
976
Treatment
NOTES
1. MacKinnon and Farberow, 1976; Pokorny, 1983, 1991; Murphy
et al., 1984; Goldstein et al., 1991; IOM, 2002.
2. Anne Sexton, probably 1977. Dr. Orne file, restricted collection. Cited in Middlebrook (1991, p. 36).
3. A very large percentage of adolescent-onset depression is
bipolar (see Chapter 6), and psychiatrists initially misdiagnose
40 to 60 percent of bipolar patients as unipolar; primary care
physicians and pediatricians miss an even larger percentage
(see Chapter 3).
4. Hawton et al., 1998, 2000; IOM, 2002; Jacobs et al., 2003;
Hepp et al., 2004; Soomro, 2004; Miklowitz and Taylor,
2006.
Appendix
Bipolar Kids
http://www.geocities.com/enchantedforest/1068/
Bipolar News
http://www.bipolarnews.org/
978
Appendix
Appendix
Phone: 781-239-0071
Fax: 781-431-7447
www.nmisp.org
Stanley Medical Research Institute
8401 Connecticut Avenue, Suite 200
Chevy Chase, MD 20815
Phone: 301-571-0760
Fax: 301-571-0769
http://www.stanleyresearch.org/
Substance Abuse and Mental Health Services
Administration
1 Choke Cherry Road
Rockville, MD 20857
Phone: 800-273-8255
www.samhsa.gov
Suicide Awareness Voices of Education
9001 E. Bloomington Freeway, Suite 150
Bloomington, MN 55420
Phone: 952-946-7998
www.save.org
Suicide Prevention Action Network USA (SPAN USA)
1025 Vermont Avenue, N.W., Suite 1066
Washington, DC 20005
Phone: 202-449-3600
Fax: 202-449-3601
www.spanusa.org
Surgeon General of the United States
www.surgeongeneral.gov
Systemic Enhancement Program for Bipolar
Disorder (STEP-BD)
http://www.stepbd.org/
979
980
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