Supplementum No. 317. Vol. 71.

1985

The longitudinal course of

recurrent affective illness:
Life chart data from
research patients at the NIMH
Peter Roy-Byrne, M.D., Robert M. Post, M.D, Thomas W. Uhde, M.D.,
Theodora Porcu, B.A., and Debra Davis, Ph.D.

Acta
Psvchiatrica J

Scandinavica
MUNKSGAARDCOPENHAGEN
ISBN: 87 -16-06292-2
ISSN: 0065-1591
Authors and Affiliations:
Peter P. Roy-Byrne, M.D.
Senior Staff Fellow
Unit on Anxiety and Affective Disorders
Biological Psychiatry Branch
National Institute of Mental Health
Bethesda, Maryland
Robert M. Post, M.D.
Chief
Biological Psychiatry Branch
National Institute of Mental Health
Bethesda, Maryland
Thomas W. Uhde, M.D.
Chief
Unit on Anxiety and Affective Disorders
Biological Psychiatry Branch
National Institute of Mental Health
Bethesda, Maryland
Theodora Porcu, B.A.
Biological Psychiatry Branch
National Institute of Mental Health
Bethesda, Maryland
Debra Davis, Ph.D.
Biological Psychiatry Branch
National Institute of Mental Health
Bethesda, Maryland
Acknowledgements
We gratefully acknowledge John Bartko,
Ph.D., who provided statistical consultation;
Kathleen Squillace, B.S., Margaret Erwin-
Gorwin, B.S., K. Sue Bell, M.S.W., Robert
Savard, M.S.W., Sandra Rucker and Harriet
Brightman, who provided clinical and tech-
nical assistance; and the 3-West nursing staff
and staff psychiatrists who assisted in the life
charting process and provided excellent on-
going clinical care for the patients during their
stay on the unit.
Summary
Using data gathered in a naturalistic study of
95 research patients at the NIMH, a
retrospective method of documenting the life
course of recurrent affective illness is
presented, along with a partial prospective
validation of this method. In these patients, the
severity, frequency, and duration of manic and
depressive episodes, as well as their pattern
and distribution, are characterized. These
variables are examined in different patients
subgrouped according to gender and age of
onset, polarity, and rapidity of cycling of
illness. The findings are compared with data
on the life course of affective illness found in
studies from the pre-pharmacologic era.
3
The longitudinal course of recurrent affective illness:
Life chart data from research patients at the NIMH
Kraepelin [ 11 initially documented in great
detail the qualitative and quantitative aspects
of not only acute manic and depressive
episodes, but also the longitudinal and at times
progressive course of affective illness. Since his
pioneering work, a number of studies using
relatively large samples in both the pre- and
post-psychopharmacological eras have ex-
amined the issues of frequency of recurrence of
episodes over time, and related phenomena
regarding the patterns of manic-depressive
episodes [2-IS]. Most recently, the systematic
efforts of Grof and associates [ 14-16],based on
longitudinal data of patients in Europe and in
Canada, have added greatly to this detailed life
approach. Goodwin and Jamison 1191 have
reviewed the literature and presented data on
the course of affective illness.
In this paper we attempt to further examine
several issues regarding the life course of
affective illness in another series of patients
studied at NIMH for several reasons. First, in
this current era of psychopharmacology and
other somatic treatments of affective illness, an
appreciation of the precise characteristics of
the prior course of episodes is essential for
assessing not only the efficacy of acute
treatment, but for investigating the degree of
prophylactic efficacy of accepted modalities
such as lithium and tricyclics, as well as new
treatments such as carbamazepine [20].
Without this information, one cannot know if
an apparent response to acute treatment is
merely an expected spontaneous remission, or
if the subsequent course of illness during
prophylactic treatment truly represents an
improvement over the course of illness
preceding it.
Secondly, most of the data and hypotheses
regarding affective illness have been based on
acute and state-related consideration of the
illness and its treatment rather than its
longitudinal and, at times, progressive course.
W e would hope that attention to the detailed
course of the illness will help to refocus
attention on possible biological and psycho-
logical processes that could account for its
recurrent nature and the long-term changes in
function that may occur concomitantly with
the illness and may underlie aspects of it [21].
It is possible that individual variations in
course of illness represent a hidden source of
variance in studies of state-related biologic
parameters. For example, the wide range of
values of C S F monoamine metabolites
obtained in the depressed state, and the
significant overlap of these values with those
obtained in the normal state in many studies,
might be, in part, a function of individual
variations in course of illness. Some
preliminary analyses of how course of illness
relates to underlying biochemical and
physiological parameters has been presented
elsewhere [22].
Thirdly, in many of the attempts to
categorize episodes of affective illness, manic
and depressive episodes have not been counted
separately. This leads to a possible confound-
ing of interpretations of the data or at least an
inability to distinguish the course of manic and
depressive episodes independently. In addition,
many previous studies did not analyze their
data separately for unipolar and bipolar
patients. In the present study we examined
manic and depressive phases as separate
episodes, and unipolar and bipolar patients as
separate groups.
Fourthly, charting of the prior course of
illness may help uncover critical variables
related to the onset or offset of episodes and
thus may ultimately enhance the clinical
management of patients from both somatic
a n d psychosocial perspectives. Critical
variables might include seasonal changes,
holidays, anniversaries, menstrual-cycle
changes, east-west travel, medical illness,
5
various drug therapies, both psychotropic and
other, and significant life events. Furthermore,
presenting a patient with a schematic and
pictorial representation of the entire course of
illness allows for a more global view of the
illness and may combat compliance problems
due to denial either of illness or of the role of
relevant variables (i.e., drug noncompliance,
psychosocial stressors) in illness.
Finally, our clinical impression of the use of
life charting procedures is that the casual
estimates of illness recurrence utilized in many
clinical settings are inaccurate, since estimates
based on number of hospitalizations do not
adequately reflect the course or severity of
illness. There is currently n o generally
accepted systematic approach to record-
keeping on the course of episodes of affective
illness. It is a secondary hope of this paper that,
in addition to presenting data of relevance to
the course of manic-depressive illness, the
study will stimulate efforts to better
systematize patient and physician record-
keeping of affective episodes and longitudinal
course of illness. Improved record-keeping on
a routine clinical basis might allow incorpora-
tion of more detailed descriptions of prior
course of illness into diagnostic subclassifi-
cations. This might be of heuristic value since
the simple unipolar-bipolar distinction
currently represents the only subclassification
scheme based on course of illness.
In this paper we discuss the methods of
collecting detailed accounts of the life course
of illness in a population of largely treatment-
resistant manic-depressive patients hospitalized
on a research ward at NIMH and present
preliminary data on course of illness so
derived. We compare and contrast how
retrospectively-collected data compare with
prospective detailed, twice-daily observations
by nurses and physicians collected over
periods of NIMH hospitalization. Data are
presented in a naturalistic fashion without
consideration of the variety of treatments
offered individual patients in the past, although
these treatments, including drug types,
6
dosages, and durations have been recorded
and will be considered in future analyses of the
data. Because the data are based on a select
population biased by the tertiary referral
process to a clinical research unit, we present it
largely for heuristic reasons: that is, to suggest
a way of thinking about affective illness, to
illustrate the kinds of analyses of course of
illness data that are possible, and to
demonstrate the kinds a n d patterns of
interrelationships among different variables
that can emerge. Large-scale epidemiologic
studies would be required to make definitive
statements about the nature and variabililty of
the course of recurrent affective illness in the
post-drug era.
SUBJECTS AND METHODS
Subjects
Subjects were 95 patients consecutively
admitted over a six-year period to the 3-west
clinical research ward of the Biological
Psychiatry Branch at the NIMH. All patients
in this study met RDC criteria for primary
affective illness according to the guidelines of
Spitzer and associates [23] and would meet the
less stringent DSM-111 criteria [24] as well.
Patients ranged in age from 19 to 69 with an
identical mean and median age of 39. Fifty-six
were female and 39 were male. Seventy-one
had the bipolar form of the illness and 24 the
unipolar form. The majority of patients had
been resistant to some conventional pharma-
cologic and psychologic therapies and some
had been referred to the NIMH often as a “last
resort” for more intensive evaluation and
experimental pharmacologic treatments.
Because patients had to be willing and able to
participate in research protocols in order to be
accepted, no patient had a chronic medical
illness or required ongoing drug treatment for
a medical condition (i.e., hypertension,
diabetes). Seventy-nine patients stayed longer
than 12 weeks with the majority of these
remaining at least six months. Most patients
had received conventional somatic treatments
prior to their NIMH admission, with the
particular type of intervention varying
according to the time of the episode (i.e.,
patients rarely received lithium prior to 1970
or antidepressantdantipsychotics prior to the
mid-1 950s).
Definitions
The major difficulty in the study was the
acquisition of accurate data regarding past
affective episodes which did not reach a
sufficient severity to require hospitalization. In
an attempt to proceed toward this goal, and in
keeping with the spirit of the RDC, we defined
affective episodes based on a functional
incapacity criterion in the hope that this would
allow reliable information to be collected and
cross-validated from several sources. Only
three severities of affective episodes were so
categorized.
1) Mild depression was defined as one
involving only subjective distress on the part of
the patient, which may or may not have been
noted by friends and relatives, but was of
sufficient intensity and duration to be clearly
differentiated from one’s normal state.
2 ) Moderate depression was one defined as
having the appropriate clinical characteristics
of mood dysregulation (consistent with RDC
criteria) that resulted in a clearcut impairment
in the patient’s functioning. That is, the patient
would continue to be able to function at work,
home or school, but only with the greatest
difficulty. There would also be objective signs
of this difficulty, such as job absences,
marginal performance at school, difficulties in
maintaining grades, and similar difficulties in
performance at home.
3) Severe depresion was arbitrarily defined
as one requiring hospitalization or otherwise
essentially incapacitating the patient; he would
no longer be able to carry out his usual
professional and social functions.
Mild, moderate and severe mania were
defined in a roughly similar fashion according
to severity of functional incapacity, with one
exception. Mild mania was based not only on
the patients’ subjective sense of being in a
clearly differentiable state from their usual
selves (most often demonstrating a decreased
need for sleep, an increase in energy, activity,
spending of money, etc.), but reports from
friends, family members and physicians were
more highly utilized in the assessment of this
category because of an increased tendency for
manic patients to “overlook” or deny these
periods. The moderate and severe categories
were based on the same functional incapacity
rating described above; ‘moderate’ reflected
dysfunction in social and employment areas,
while ‘severe’ reflected complete incapacity or
hospitalization. Fig. 1 illustrates the way in
which we graphically represented our data.
In order to be conservative about what
constituted a discrete depressive episode, an
episode of depression was only counted if it
reached sufficient intensity to meet the criteria
for moderate severity. The episode was
considered ended when the patient: 1 )
returned to a baseline non-affectively disturbed
state; 2) returned to a chronic baseline of mild
subjective distress which lasted more than one
year; or, 3) with the onset of a manic episode.
The one year period was selected to distinguish
patients with chronic depressions who might
have more severe acute episodes superimposed
(so-called “double depressions”) [25] from
those whose chronic baseline might represent
the waning stages of an acute episode. The
only exception to this rule was that mild
depressions bounded immediately on either
side by a mania and lasting less than one year
were counted as episodes because of their
natural part of a bipolar cycle. Mild manic
episodes, in contrast to mild depressive
episodes, were included in the frequency count
as discrete episodes. This appeared to be a
conservative cut-off because of reluctance on
the part of patients and their families to label
manic-like behavior as distinctly abnormal.
The offset of a manic episode was described in
a similar fashion as a return to a normal
functional baseline or by the onset of the next
depressive episode.
7
 SCHEMA FOR GRAPHING COURSE OF
AFFECTIVE ILLNESS
DEC. 1983
In
0
.-cm
0
._
zz
- //////////////-
DatLEvent
11 LJan 1 Event
Dec 1 6 . Event
Figure 1
Episode durations were derived from these
criteria. Mild depressive symptoms were
included in the duration of the episode only if
they were immediately contiguous with more
severe depressive symptoms or a mania, by
themselves lasted less than one year, and
always returned t o a non-symptomatic
baseline or another mania. If a person had
chronic levels of subjective distress throughout
much of his life, interspersed between more
severe depression (i.e., "double depression",
see [ 2 5 ] ) , these periods of time would not be
included in the duration of a depressive
episode. Fig. 2 contains several examples of
individual life course of illness derived by this
retrospective method.
Age of onset of illness was defined in three
ways: first subjective symptoms, first
psychological or psychopharmacological
treatment, and first hospitalization. In
addition, onset of illness was dichotomized
into early onset (before age 30) and late onset
8
= Lithium Carbonate
Neuroleptic
- Minor Tranquilizer
_ _ _ _ _ Tricyclic
.. .. .. MA01
X X X ECT
July
Zalion
20-23
(age 30 or after). Duration of illness was also
calculated from the three points above.
Numbers of hospitalizations for depression and
mania were assessed in the usual fashion with
the exception that if a patient was directly
transferred from one facility to another, or had
only several intervening days as an outpatient
without symptom remission, the t w o
hospitalizations would be counted as one.
In addition to the retrospective data, more
precise estimates of manic and depressive
episodes based o n twice-daily nursing
observations during the course of NIMH
hospitalization were utilized. Individual
depressive episodes were defined as depression
ratings greater than or equal to seven on the
15-point Bunney-Hamburg global depression
scale [26] and lasting for at least a period of
one week, unless they were delimited by a
manic episode or represented an abrupt three
point or greater jump from the previous days'
depression ratings, in which case they could
 LIFE COURSE OF ILLNESS IN AFFECTIVE DISORDER

I L J
Bipolar I
1940 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 1978
1 . , . , . 1 . , . 1 . , . , . , . , . 1 ~ 1 . 1 . 1 ~ 1 ~ , ' ~ ' 1 ' 1 ' 1 '

%W M

133MS M

152% F

Bipolar II
1944 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 1980
m T - - T - T - m l I T I 1 I 1 ' I I I 1
1-

AGE 83

137LN M AGE18 I , i n *33 __

161 FC F
_ _ ~

Unipolar
1954 56 58 60 62 64 66 68 70 72 74 76 1978
t
PATIEM AGE OF ON= AGE OF ADMISSION TO NIH
93 sc

66% AGE23

I
111 SP

104 WE

Figure 2

9
last less than 7 days. An episode was admission of the patient to the unit, detailed
considered terminated with the onset of a historical data were collected from patient and
manic episode following the return of family members by a physician and a social
depression ratings below five for at least five worker. Previous hospital records (which were
days, or if depression ratings dropped abruptly often difficult to obtain because of privacy
by 3 points and stayed down. A manic episode regulations) and physicians’ clinical notes were
was defined as mania ratings greater than two also utilized. A special weekly “life charting
on the global rating scale and lasting for at meeting” was routinely held in which nursing
least three days; one- or two-day manias were staff and research assistants helped patients
considered an episode only if mania was more organize themselves around discrete tasks
severe (greater than 4) and erupted from a related to the construction of their own life
stable depressed baseline. In this fashion we charts. Tasks depended partly on the patient’s
were able to obtain a precise measure of the clinical state and varied from providing
number of manic episodes, depressive chronologies of geographical moves, jobs,
episodes, and total episodes at NIMH, as well schools, etc. to obtaining and systematically
as the number of days of mania, depression examining old diaries, calendars, and photo
and total days in either type of episode. We albums. Significant life events were identified,
further derived a theoretical measure of along with birthdays, anniversaries, and
cycling frequency based on the expected important holidays to serve as anchor points
number of episodes per yeaT. Fig. 3 illustrates and facilitate accurate dating of episodes. It
the course of illness during NIMH hospitali- was surprising to note that in many cases
zation for four patients derived by the above patients’ spouses had kept detailed records
criteria. without having been specifically requested to
do so by former physicians. Data from all
Methods sources were collated, visually displayed and
The collection of the retrospective data finalized with the patient present in a euthymic
proceeded in several stages. Following phase in order to minimize the problem of

PATTERNS OF RHYTHMIC ALTERATIONS IN MANIC ~ DEPRESSIVE ILLNESS

- LlTIllUM
................................. _ _ ......
... *NEVROLEPTICS
wwrmwE
PlRleEDlL

*IN,*
IDEPRESSION

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PITllN, yl,B ............
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10
state-dependent recall [27]. Only episodes
distinctly remembered by the patient and
documented by at least one outside source
(i.e., hospital records, physician notes, family
member) were included in the life charting and
in the final episode count.
Analysis
A total of 70 patients (46 bipolar and 24
unipolar) had their life course of affective
illness completed in this fashion while another
25 patients received a shorter version based
largely on past records that did not allow for
measurement of number and duration of
Table 1
episodes or hospitalizations. Retrospectively
derived variables fell into four categories (age
of onset, duration of illness, episodes, and
hospitalizations) while prospectively derived
NIMH variables dealt only with episode-
related measures (see Table 1).
In addition to the above variables dealing
with quantitative aspects of prior course of
illness, for bipolar patients with sufficient
information (n = 46), we derived from the
respective data several variables dealing with
the pattern and distribution of episodes (see
Table 2). For each patient, we recorded the
type of first episode (mania or depression) and

RETROSPECTIVELY-DERIVED VARIABLES X S.D.

Age 39.8 13.4
Age of onset, from first symptoms 25.5 11.2
from first treatment 28.0 11.65
from first hospitalization 30.0 12.1

Duration of illness, from first symptoms (years) 14.4 10.9

from first treatment 11.8 10.6
from first hospitalization 10.2 10.6

Hospitalizations, for mania 1.8 3.3

for depression 3.5 3.7
total 5.3 4.3
total per year ill since first hosp. 0.76 0.86
total weeks hospitalized 50.6 120.5
total weeks hospitalized per year ill 5.0 8.4

Episodes, of mania 10.0 22.4

of depression 12.6 24.5
total 22.6 46.0
total per year since first symptoms 1.7 2.4
total weeks ill 226.0 180.9
total weeks ill per year since first symptoms 22.2 17.5

Episodes, the year before NIMH 3.5 4.6

Weeks ill, the year before NIMH 37.0 15.6

PROSPECTIVELY-DERIVED (at NIMH) VARIABLES

Manias 1.6 3.1
Depressions 2.0 3.0
Total Episodes 3.6 5.8
Days Manic 37.2 87.3
Days Depressed 101.0 93.5
Total Days Ill 138.2 130.0
Episodes, per year at NIMH 6.25 7.15
Weeks ill, per year at NIMH 33.9 15.7

11
 Table 2

Patterns of Illness Variables (for Bipolar Patients Only) X -t SD

Percent of episodes that were depressions 53.6 k 16.2
Percent of illness periods with only a single episode (no switches) 60.0 F 23.6
Percent of polyphasic illness periods where depression precedes mania 44.0 k 34.0
Duration of mania/duration of depression (average) 2.23 i I .8
Duration of “first episode” (weeks) 17.9 k 21.8
Duration of “first interval” (following first episode) (weeks) 188.0 * 304.0

whether the first period of illness (before a
remission) was uniphasic (one episode type; no
phase switches) or polyphasic (several
episodes of alternating polarity without an
intervening well interval). For each patient we
also recorded the proportion of each episode
type (percentage of episodes that were manic
or depressive); the proportion of single versus
polyphasic periods of illness; the proportion of
polyphasic illness periods in which depressions
preceded manias (as opposed to the opposite
pattern); the relative durations of each episode
type expressed as a ratio (average duration of
mania/average duration of depression); the
duration of the first episode; and the interval of
time after the first episode before a relapse
occurred. Since, in cases of immediate cycling
from one phase to another, a zero interval was
recorded, any patient with a n initial
polyphasic period of illness (n = 20)
technically would have a “first interval” of
zero. Therefore, in patients with initial
biphasic illness periods (n = 12), the “first
interval” was defined as that following both
phases (technically the second interval)
although the “duration of first episode” was
still taken as the duration of the first phase.
When the initial period of illness was more
than biphasic, the “first interval” was recorded
as zero and the “duration of first episode” as
that of the first phase of the illness period. All
of these patients (n = 8), following their initial
polyphasic illness period, relapsed again within
8 weeks so that, in a sense, they were similar to
patients described by Kukopulos et al (1980)
as “continuously cycling”.
12
Finally, several measures of episode
frequency a n d patterns of cycling were
recorded. For each patient, the pattern of
successive intervals over time was graphically
displayed and the resulting series of graphs
were sorted into two clusters: in one (the
sensitization type), the initial well intervals
(11-14) were longest and all subsequent ones
were shorter with the pattern resembling that
seen in various sensitization paradigms [21]; in
the other (no pattern), the longest well
intervals occurred randomly throughout the
course of illness and were not confined to the
initial stages (fig. 4). Bipolar patients were also
defined as rapid cyclers (those with four or
more episodes the year before NIMH
admission) and non-rapid cyclers.
In addition to presenting data on the
distribution of all these variables in the patient
population, we chose to address several
questions about course of illness. Since few
life-course of illness studies have been done,
a n d thus little data exists to generate
hypotheses, only a few questions were
designed to test prior findings, with most
questions designed to generate hypotheses. For
this reason, an overall alpha (type 1) level of
0.10 was used. Individual significance levels
for each test were then 0.1O/K where K is the
number of tests. This is an appropriate
Bonferroni correction when multiple tests are
performed on the same data set (28).
Otherwise, p values of .05 were used. For
questions involving the entire patient sample,
analyses were done separately for unipolar and
bipolar patient groups unless otherwise
 DURATION OF WELL INTERVAL BETWEEN SUCCESSIVE
EPISODES IN BIPOLAR PATIENTS

* Sensitization Pattern (n=24)

.--a No Sensitization Pattern (n=22)

d3
n

A
I.

7
1S t 2nd 3rd 4th 5th 6th 7th 8th 9th 10th
WELL INTERVAL
Figure 4

indicated. The following questions were 2. Do gross measures of course of illness,

addressed
1. How valid is our retrospective method of
measuring episodes? This was assessed in part
by performing a series of multiple linear
regressions to see which of the retrospective
variables in Table 1 was able to significantly
predict any of the seven prospectively-
measured NIMH episode-related variables
(corrected p value = 0.014). In addition, we
specifically checked to see whether the average
durations of each episode type (depression and
mania) in the retrospective and prospective
data correlated with one another. Pearson r
correlations (p value .05) were used to answer
this.
such as duration of illness, hospitalization
number or total time hospitalized, bear any
predictive relation to the more precisely
assessed individual episodes of mania and
depression (i.e., how well do they represent
course of illness)? This was assessed by
performing eight multiple linear regression
analyses with the eight episode-related
variables in Table 1 as dependent variables
and the other variables in Table 1 as
independent variables (corrected p value =
0.0125).
3. How does pattern of illness relate to
other aspects of course of illness in bipolar
patients? Does pattern of illness predict how
13
long or how frequently patients are ill? The
variables in Table 2 were used to predict
retrospectively and prospectively derived
episode variables via a series of multiple linear
regression analyses (corrected p values 0.0 12
and 0.014, respectively). Conversely, can a
particular pattern of illness be predicted by
other patterns or course of illness variables?
Again, a series of six multiple linear regressions
were performed to predict each variable in
Table 2 with age of onset, the episode
variables in Table 1, and the other pattern-of-
illness variables as independent variables
(corrected p value = 0.016).Finally, two linear
discriminant functions were performed using
the same independent variables as above to
differentiate the subgroups of patients with first
episode mania vs. depression and first period
of illness uniphasic vs. polyphasic. A chi
square analysis was also performed (p value
.05) to determine if there was any relation
between these two pairs of subgroups.
4. In bipolar patients, is there a parallelism
in the frequency of opposite mood phases in
both the retrospectively and prospectively
derived episodes or in hospitalizations for
manias and depressions? Is there a parallelism
in the average duration of manias and
depressions in retrospectively and pro-
spectively derived episodes? Finally, for
patients with initial depressive episodes, what
is the cumulative probability of bipolarity
revealing itself with each successive episode?
5. What is the relationship between the
subgroups of bipolar patients with and without
rapid cycling and those with (“sensitization”
subgroup) and without a steady increase in
cycling over time. Is there a male/female
difference in either of these pairs of subgroups?
Chi square analysis was used to answer these
questions (p value .05). Finally, can course of
illness or pattern of episodes differentiate either
of these two pair of subgroups? Four separate
linear discriminant function analyses (two for
the variables in Table 1 and two for the
variables in Table 2) were performed to see
which variables in each of the two data sets
14
differentiated the two pair of subgroups. Since
“episodes the year before N I M H was used to
define the rapid cycler group, it was eliminated
from the discriminant function analyses used
to differentiate that group from other bipolar
patients.
6. What is the frequency distribution of age
of onset in the overall group? Is there any
evidence of bimodality, especially if male and
female subgroups are compared [19]? How
well do the three different measures of age of
onset correlate? Because previous data exist on
this subject [29] and thus a hypothesis exists to
be tested, we used p values of 0.05 and
employed a series of Pearson r correlations.
Does age of onset determine subsequent
course or pattern of illness? We used data from
the regression analyses done as part of
questions 1-3 above to determine if age of
onset predicts course or pattern of illness.
Next, we performed two linear discriminant
functions to see if any of the variables in
Tables 1 or 2 (excluding age of onset) could
differentiate bipolar patients with early and
late onset of illness (the unipolar group was
too small to subdivide and analyze by
regression techniques).
7. Is course of illness different in bipolar
and unipolar patients? Is course or pattern of
illness different in males and females (again
only bipolar patients were used). A series of
linear discriminant function analyses were
performed using retrospective and prospective
variables separately to differentiate unipolar
from bipolar patients (excluding, as in-
dependent variables, manic episodes and
hospitalizations) and using these two sets of
variables and variables in Table 2 to
differentiate bipolar males and females. In
addition, a series of t-tests were also performed
between bipolar and unipolar patients, and
between males and females, using the
retrospective variables in table 1 (p value <
.05).
For all analyses, the percentage of the
variance accounted for by a significant
variable is denoted by r2, and the direction of
the relationship is positive unless the word
“inverse” accompanies the r2 value.
RESULTS
Validity of the Life Charting Process
Each patient in the euthymic state viewed
his or her own final life chart and felt the chart
accurately represented the course of their
illness, indicating that these charts have some
face validity. Their validity is further
reinforced by the fact they were derived from
a n d checked by multiple sources of
information. Another source of validation is
their ability to predict future course of illness at
NIMH (predictive validity), although this is
obviously complicated by the inherent
variability as opposed to predictability in the
course of illness. Table 3 indicates that, in the
bipolar patient group, retrospectively-
determined episode measures were the best
predictors of the various prospectively-
determined episode measures. In particular,
episodes in t h e year prior t o N I M H
hospitalization were most strongly predictive
of course of illness at NIMH. Duration of
illness and various measures of hospitalization
were infrequent predictors and even when they

Table 3

Retrospective Predictors of NIMH Episode Variables

(Bipolar Patients Only)

Dependent Variable r’ Direction

Significant Predictors (p < .14)
NUMBER OF MANIAS
Episodes the year before NIH .40 +
Episodes depression .55 +
Duration of Illness since first hospitalization .65

NUMBER OF DEPRESSIONS
Episodes the year before NIH .44 +
TOTAL NUMBER OF EPISODES
Episodes the year before NIH .48 +
Episodes of depression .58 +
Duration of illness from first treatment 67
Weeks hospitalized, per year .73
Total hospitalizations .77 +
DAYS MANIC
Weeks hospitalized per year .55 +
DAYS DEPRESSED
No predictors
TOTAL DAYS ILL
Episodes of depression .45 +
EPISODES, PER YEAR AT NIMH
Episodes, the year before NIMH .48 L

WEEKS ILL, PER YEAR AT NIMH

No predictors

r2 = cumulative percent of variance accounted for with each added predictor variable

15
were, they contributed little to the variance. In
addition, there was a robust correlation
between the average duration of depressive
episodes retrospectively determined and the
average duration of depressive episodes at
NIMH for bipolar patients (r = .45,p < .008)
although the average duration of manic
episodes in the past and at NIMH were not
significantly correlated (r = .26, p = .16).
Furthermore, in the 23 bipolar patients having
both types of episodes during NIMH
hospitalization, the relative duration of
depressive compared to manic episodes in the
past was correlated at a trend significancelevel
(r = .39, p = .057) with the same data gathered
prospectively during NIMH hospitalization.
LONGER RELATIVE DURATION OF DEPRESSIVE COMPARED
TO MANIC EPISODES IN BIPOLAR PATIENTS
MANIA >3
- 3
- 2
- 1.2
- 1
DEPRESSION 1 1 1 1
LONGER
- EQUAL
Figure 5
16
Figs. 5 & 6 show that the distribution of
relative episode durations prior to NIMH
hospitalization is similar to the distribution of
relative episode durations occurring during
NIMH hospitalizations. In contrast to these
numerous validating correlations, in unipolar
patients no retrospective variables predicted
course of illness at NIMH.
Relationships Among Retrospective
Course of Illness Variables
Table 4 indicates that in bipolar patients
total weeks hospitalized was the best predictor
of frequency of episodes and total time ill and
was a weaker predictor of episodes the year
- 1
- 1
- 1
-
1.2 2 3 >3
EPISODE
DURATIONS
DEPRESSIONS
LONGER
 RELATIVE LONGER DURATION OF DEPRESSIVE COMPARED
TO MANIC EPISODES DURING NIMH HOSPJTALJZATJON
N = 23 BIPOLAR PATIENTS

51

Mania - -
Depression 1 1
MANIAS
LONGER - EQUAL
EPISODE
DURATIONS

Figure 6
- DEPRESSIONS
LONGER
. -

before NIMH. Number of hospitalizations
bore no predictive relationship to actual
episodes! Duration of illness was a relatively
poor predictor of episodes in this group. In
contract, in unipolar patients, duration of
illness was the best predictor of total episodes,
accounting for 76%of the variance, and weeks
ill per year ill accounting for 46% of the
variance.
Pattern of Illness
Pattern of illness did not predict episode
variables (total episodes, episodes/year,
episodes the year before NIMH hospitali-
zation), but the length of the interval between
first and second episodes and the percentage of
illness periods without a phase switch (i,e.,
‘single episodes’), did predict total time ill. The
percentage of illness periods with only a
“single episode” was the only predictor of total
weeks ill (inverse r2 = .13) and the second best
predictor of weeks ill/year ill (inverse
additional r2 = .lo). The length of the first
illness-free interval was the best predictor of
total weeks ill (inverse, r2 = .28). Fig. 7 shows
the distribution of interval length following
first episode. It can be seen that close to 80%of
17
 Table 4
Prediction of Episode-Related Variables by Other Variables

Bipolar Unipolar
2 Direction r’ Direction
Dependent Variable
Significant Predictors (p < ,0125)

EPISODES O F MANIA
Weeks hospitalized .80 +
Episodes before NIMH .86 +
Hospitalizations for depression .88

EPISODES O F DEPRESSION
Weeks hospitalized .58 +
Episodes the year before NIMH .66 +
Duration of illness from first symptoms .72 +
Duration of illness from first hospitalization .76 +
TOTAL NUMBER OF EPISODES
Weeks hospitalized .76 +
Episodes the year before NIMH .84 +
Duration of illness from first hospitalization 76

EPISODES PER YEAR

Weeks hospitalized per year .68 + none
Episodes the year before NIMH .74 +
Duration of illness from first symptoms .7Y

WEEKS ILL
Weeks hospitalized .3 I +
Hospitalizations for depression .38

WEEKS ILL PER YEAR

Duration of illness from first symptoms .29 .46
Weeks hospitalized per year .64

EPISODES BEFORE NIMH

Total episodes .24 + none
Weeks ill .3Y +
Weeks hospitalized SO
WEEKS BEFORE NIH none none

r’ = cumulative percent of variance accounted for with each added predictor variable

patients relapsed in five years. Overall, the
mean and median length of the first interval
were 189 and 100 weeks. In the entire group
of bipolar patients of 648 periods of illness,
385 (60%)consisted of a single episode.
No pattern or course of illness variable
significantly predicted other pattern of illness
variables in Table 2. However, the subgroup of
18
patients whose first episode was a depression
(28 of 46 or 60%) was differentiated from
those with a first episode of mania (18 of 46 or
40%) by a lower percentage of manias before
depressions (r2 = .27) and a higher percentage
of depressive episodes (additional r2 = .07).
They also were more often likely to become
rapid cyclers (Chi-square X = 5.26, p = 0.02).
 DURATION OF WELL INTERVAL FOLLOWING
FIRST EPISODE IN BIPOLAR PATIENTS
(n=46)
Percent Relapsing within Each Year

-
0Cumulative Percent Having Relapsed Up to and
Including a Given Year I

I-
5 -
g
w
20
L

The subgroup of patients whose first illness
period was polyphasic was differentiated from
those with a uniphasic first illness period by
more total weeks ill (r2 = .18) and a higher
percentage of manias preceding depressions
(additional r2 = .07). Finally, patients with a
first episode of mania were more likely to have
a first period of illness that was polyphasic
(Chi-square - X = 6.45, p = 0.01).
In the entire group of bipolar patients, of
371 polyphasic periods of illness, 271 (73%)
had a sequence type where mania preceded
depression. However, this is considerably
skewed by one patient with a large number of
illness periods of this type. If this patient is
eliminated, the percentage of manias preceding
depression is 94 of 191 or 49%. In individual
patients, the proportion of each type of
sequence was wide ranging and appeared to be
similar in bipolar I and bipolar I1 patients (fig.
8). In the entire group, there were slightly more
patients with greater numbers of depressive
than manic episodes (see fig. 9) although this
may be due to a greater proportion of females
in the group (see fig. 10 and discussion
following). ’
There was a high correlation between the
number of manic and depressive episodes
reported in the retrospective data (r = .90, p <
.OOOl) and between the two types of episodes
observed prospectively during NIMH hospital-
ization (r = .91, p < .0001).Conversely, there
was no significant correlation between the
number of prior hospitalizations for depression
and mania. There was also a significant
correlation between the relative durations of
manic and depressive episodes in the
retrospective data (r = .40, p = 0.005) but no
correlation between the durations of each
episode type during NIMH hospitalization.
Depressive episodes tended to last longer than
manic episodes in most patients both prior (fig.
5 ) and during (fig. 6) NIMH hospitalization.
Fig. 11 shows the cumulative probability of
19
 TYPE OF EPISODE BEGINNING
POLYPHAS IC ILLNESS PER I0DS

(n=46)
12 0 BP II = 12
B P I = 34

10
v)
I-
Gb 8
Q
Q
U
0
5
rn
E
3
2
6

4
n
2

100% >8O% >60% >6O% >8O% 100%

MANIA DEPRESSION
PRECEDES -EQUAL- PRECEDES
DEPRESSION MANIA
PERCENT OF POLYPHASIC
ILLNESS PERIODS
Figure 8

a manic episode occurring over time in bipolar
patients with initial episodes of depression (n =
23). After three episodes, eight of 23 (34%)of
these patients still had not had a manic
episode. However, after six episodes, all but
two (92%)had had a manic episode.
Episode Frequency
Fig. 12 shows for the entire group of
20
patients that the mean interval length between
episodes decreases over time with each
successive episode. Taken in conjunction with
the fact that the mean duration of consecutive
episodes over time is similar and even
decreases slightly (fig. 13), this implies an
overall increase in cycling with time. However,
when the length of successive intervals for each
individual patient is considered, 24 of 46
 RELATIVE PREDOMINANCE OF MANIC OR DEPRESSED
EPISODES IN INDIVIDUAL BIPOLAR PATIENTS

l4 r
12

10
v,
I-

CT
w 6
m
2
3
z
4

0
>3:1
MANIA
<3:1

PREDOMINATES
<2:1

-- Q EQUAL <2:1 <3:1

DEPRESSION
>3:1

PR E D 0 M I NATES
Figure 9

patients (52%) show progressively shorter
intervals during the course of their illness (a
pattern resembling that seen in various
sensitization paradigms) while 22 of 46 (48%)
show n o particular pattern with longer
intervals randomly distributed throughout the
course of the illness (fig. 4). Interestingly,
successive episode durations are similar in
these two groups (fig. 12). As previously
mentioned, bipolar patients were also
subdivided according to cycling frequency. Of
note, the only variable capable of differenti-
ating rapid cyclers from other bipolar patients
at NIMH was number of episodes, thereby
partially validating the rapid cycling group.
There was no significant relationship between
these two different pairs of subgroupings, i.e.,
those defined as rapid cyclers were not
disproportionately represented among those
with steady overall increase in cycling with
time. Also, there was n o male/female
difference in either of these subgroups.
T h e only course of illness variable
differentiating the rapid cyclers from other
21
 EFFECT OF SEX ON RELATIVE PREDOMINANCE
OF EPISODE TYPE IN BIPOLAR PATIENTS
6
r
4

m
c o
>3:1 <3:1 <2:1 EQUAL <2:1 <3:1
z
w
c-
h
a
u-
0
MANIA
PR ED0 M1 NATES
- EQUAL-
DEPRESSION
PREDOMINATES

r r 8
W
m

0 L >3:1
I
1

<3:1 <2:1 - EQUAL <2:1 <3: 1 >3: 1

Figure 10

bipolar patients was their greater number of
weeks ill the year before NIMH (r2 = .12) and
more hospitalization for depression (additional
r2 = .07), while the only discriminating pattern
of illness variable was the tendency for rapid
22
cyclers to more often have first episodes of
depression.
In contrast, a large number of factors were
capable of differentiating the group of patients
with a progressive increase in cycling with
 NUMBER OF SUCCESSIVE DEPRESSIONS
BEFORE A MANIA IN BIPOLAR PATIENTS

n=28 Patients with First Episode Depression

=Percent at Each Episode

0Cumulative Percent
-

I I

rn
2 3 4 5 6 7 8 17
EPISODE NUMBER
Figure 11

time from those without this pattern (see Table
5). Basically, the sensitization group had more
hospitalizations for depression, more episodes
the year before NIMH, a higher percentage of
depressions and single episodes, a longer
period before relapse following their initial
episode, fewer weeks ill/year, and fewer
episodes per year.
Age of Onset
Three measures of age of onset of illness,
figured from first symptoms, first treatment,
and first hospitalization were all highly
intercorrelated in both unipolar and bipolar
patients ( p < . O O O l ) . Fig. 14 shows
simultaneous frequency distributions for these
three variables for all patients. Frequency
distributions in the male/female subgroups
were similar with female distribution failing to
show the age 20 and age 40 bimodal pattern of
onset previously described [ 191. All distribu-
tions show a modal age of onset between ages
16 and 20. Age of onset was not significantly
different in unipolar and bipolar patients.
Age of onset did not predict any episode-
related variable in bipolar or unipolar patients,
or any pattern of illness variable in bipolar
patients. In bipolar patients, no variable in
Table 1 differentiated patients with early and
late onset of illness. However, later onset
patients had longer first episodes (r2 = .14).
Males vs. Females
Bipolar males had more weeks illlyear ill
(r2 = .21) and more hospitalizations for mania
(additional r2 = .08). Bipolar females had a
higher percentage of episodes that were
depressive (r2 = .13). Fig. 10 illustrates this
23
 DECREASING DURATION OF WELL INTERVAL BETWEEN
SUCCESSIVE EPISODES IN BIPOLAR PATIENTS

NIMH 1984
(means)
--a Kraepelin 1921

1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th
WELL INTERVAL

Figure 12

latter aspect via frequency distribution. Results
of the univariate analysis (mean k SEM)
indicated that bipolar females were ill longer
from first treatment (15.2 5 1.9 vs. 7.9 k 1.4
years, p < .Ol), had more hospitalizations for
depression (3.3 f 0.58 vs. 1.3 f 0.55, p <
.05), and had more episodes the year before
*
NIH admission (5.8 1.14 vs. 2.7 3Z 4.7, p <
.05).
Unipolar vs. Bipolar Patients
No prospectively-derived variables differ-
entiated bipolar from unipolar patients. Table
6 lists the retrospectively-derived course of
illness variables that differentiated the two
groups. Using combinations of factors in a
multivariate analysis, bipolar patients had
more episodes the year before NIMH, more
24
total weeks ill, and more hospitalizations/year,
while unipolar patients had had more
hospitalizations for depression, more weeks ill
the year before NIMH and more weeks
ill/years ill. Univariate analysis revealed that
bipolar patients had more total episodes (3 1.6
i7.6 vs. 4.0 f 0.83, p < .02), more episodes
of depression (14.6 3Z 3.4 vs. 4.0 f 0.83, p <
.05), and more episodes per year ill (2.15 f
0.38 vs. 0.64 k 0.16, p < .01) than unipolar
patients (fig. 15) despite having similar total
time ill (20.9 f vs. 17.0 k 2.4 wks, p = NS)
(fig. 16). Total time ill per year ill was actually
greater in unipolar patients (29.2 f 5.3 VS.
19.2 wks ill per year ill, p < .05).
DISCUSSION
Despite the acknowledged difficulty in
 DURATION OF SUCCESSIVE AFFECTIVE EPISODES IN BIPOLAR PATIENTS

25
I

ln
Y

f
1 20
Ah.
-'*..

8 IB
8 0
0

k~ 15at
/

-
2
0
4n
3
lo-
All (N = 46)
0--0 Sensitization (N = 24)

5t
.----A No Pattern (N = 22)

I I I I I I I I 1
O: 2 3 4 5 6 7 8 9 10
EPISODE NUMBER
Figure 13

retrospectively reconstructing prior course of predictors of NIMH episodes, (see Table 3)

illness, the robust correlations noted in bipolar
patients between episode number the year
prior to NIMH hospitalization, and prospec-
tively measured episode number at NIMH,
suggest a high degree of reliability between
two totally independent sources of information
and, hence, partial validation of o u r
methodology. Although one could argue that
this relationship merely indicates that the most
recent cycling frequency predicts future
cycling frequency, there also remains a
significant correlation between number of
prior depressive episodes and number of
episodes a t NIMH. Furthermore, neither
number of hospitalizations nor various
measures of duration of illness was a
significant predictor of number of prior
episodes or episodes in the year prior to NIMH
hospitalization. Although several non-episode
course of illness variables were significant
they accounted for little of the variance of
these measures.
Thus, these data emphasize the importance
of collecting longitudinal data on the course of
affective illness in bipolar patients, utilizing
episodes rather than the more gross measures
of number of times hospitalized or overall
duration of illness. Without such measures, it
appears that the most robust predictors of
future course of illness may be obscured or
missed altogether. The fact that, in bipolar
patients, total weeks hospitalized was a much
better predictor of episode frequency than total
weeks ill is curious. It may be that since time
hospitalized is partially a measure of illness
severity, this implies that more severely ill
patients also have a more unstable form of
illness that switches on and off more
frequently.
In the unipolar patients the relationships
25
 Table 5
Variables Discriminating Between Cycling Patterns
(“Sensitization,” i.e., increasing episode frequency vs. No Pattern)
Course of Illness Variables
Weeks per year ill
Episodes per year ill
Hospitalized for depression
Episodes the year before NIMH
Patterns of Illness Variable
First Interval
Percent depression
Percent single illness period
* + signifies greater in sensitization group
- signifies greater in no pattern group
were substantially different from those
observed in the bipolar cohort. No retro-
spectively derived variables predicted
prospective course and, in contrast to the
bipolar group, duration of illness was a good
predictor of number of episodes, and number
of hospitalizations was a fair predictor of total
weeks ill. There are a number of possible
explanations for this contrast. First, from a
statistical point of view, the fact that unipolar
patients had far fewer episodes means that the
range of values for episode number is
truncated and, hence, there is less likelihood of
significant correlation between retrospectively
and prospectively measured episode frequency.
Secondly, the unipolar patient group is
probably more heterogeneous than the bipolar
group a n d this mixture may obscure
correlations among subgroups of unipolar
patients. Third, there are only half as many
unipolar as bipolar patients in this study and,
hence, the probability of failing to find
correlates that might, in fact, exist (i.e., type 2
statistical error) is much higher. Finally,
however, it is possible that this contrast
represents a bona-fide difference between
bipolar and unipolar patients.
In individual bipolar patients, there was a
symmetry both in the frequency of occurrence
26
2 Direction*
,146 -
,206 -
,259 +
,335 +
,229 +
,294 +
,346 +
of manic and depressive episodes (determined
retrospectively and prospectively), and in the
average durations of manic and depressive
episodes (determined retrospectively, but not
prospectively). This suggests a similarity in
factors triggering both types of episodes and
probably also a similarity in those factors
sustaining each type of episode once they have
begun. The failure to find that the durations of
each episode type at NIMH were also
correlated may be due to differences in the
rapidity with which treatment was instituted
for the different phases (i.e., manias often were
more quickly treated), to differences in the
offset criteria used to measure the two phases
at NIMH, or to the variable efficacy of the
more recently developed treatments admin-
istered at NIMH [20] which may have
influenced the durations of each episode type
differently.
In the bipolar patient group as a whole,
depressions tended to last longer than manias
in most patients. Although this fact has been
reported in numerous older studies [ 191, Angst
[lo], in a more recent study (in which patients
received acute but not prophylactic treatment),
found that manias lasted slightly longer than
depressions, Again, this discrepancy may
reflect the effects of prophylactic treatment in
 AGE OF ONSET IN MAJOR AFFECTIVE
DISORDER BY THREE CRITERIA

30
(n=95)
-
*--o
From First Symptoms
From First Treatment
0. - .o From First Hospitalization

25
v)
t- ..9
z
-
W
20
t-
a
a
U
0
K 15
w

3
z 10
0''
.- 9
-*

1 I I
6-10 16-20 26-30 3640 46-50 56-60
1-5 11-15 21-25 31-35 41-45 51-55 61-65

AGE OF ONSET
Figure 14

our patients,
, although our population was
largely treatment-resistant. Our failure to find
that the relative durations of each episode type
were in any way related to other aspects of
course or pattern of illness (other than overall
duration of time ill) suggests that factors that
trigger episodes may be quite different from
those that sustain them. Finally, our finding
that duration of individual episodes over time
remains fairly constant, with perhaps just a
slight decrease (see fig. 12), is similar to Grof s
[ 141 finding.
During a given period of illness, the
tendency to switch phases (i.e., have a lower
proportion of 'single episodes') predicted more
total time ill and total time Wyear. This
27
 Table 6
Variables Discriminating Between Bipolar and Unipolar Patients
(+ signifies greater in bipolar, - signifies greater in unipolar)
Episodes before NlMH
Total Weeks Ill the Year before NlMH
Total Weeks Ill
Hospitalization for Depression
Total Weeks 111 per Year
Hospitalization per Year 111
finding may just reflect the fact that polyphasic
illness periods last longer but also could imply
that an essentially unstable form of illness (i.e.,
more phase switches) is more enduring and
severe. The corollary finding that the subgroup
of patients whose first illness period was
polyphasic could be differentiated from those
with an initial uniphasic illness period by their
greater subsequent time ill implies that an
illness that is initially unstable also may turn
out to be more enduring. Our finding that
about 60% of the illness periods in our
population were uniphasic is only slightly
lower than the 70% reported by Angst [12].
This slightly greater incidence of polyphasic
illness periods may reflect the treatment-
resistant nature of our population.
The majority of our patients (60%) had a
first episode of depression. This is somewhat
higher than the average of numerous studies
[19] (around 50%), many of which required
that, to be counted, an episode had to result in
either hospitalization or treatment. Because
our life charting method counted any episode
meeting symptomatic a n d dysfunctional
criteria, regardless of treatment or hospitali-
zation, we may have been able to identify
more early untreated depressive episodes. Our
finding that patients with a first manic episode
tend to have a higher proportion of subsequent
manias is in agreement with the findings of
Peris [l 11. Although Lundquist [6] noted a
greater tendency to relapse and Swift [2] noted
a poorer prognosis in patients whose initial
episodes were manias, we failed to find any
28
______~ _____ ~
.I 1 +
21
28 +
.34
37
41 +
difference in frequency of episodes or total
time ill between patients with initial manic
versus initial depressive episodes. However,
neither of these authors specified whether these
manias were single episodes or part of an
initial polyphasic illness period. Since we
found an association between initial manias
and initial polyphasic illness periods (the latter
associated with more subsequent time ill), it is
possible that this earlier finding was confined
to initial polyphasic illness periods that begin
with a mania.
In our population, polyphasic illness periods
had roughly equal proportions of each type of
episode-phase sequence (eliminating the one
patient previously mentioned). This is in line
with the similar frequency of each type of
sequence found by Kukopulos [ 171and differs
only a bit from the slightly greater frequency of
depressions preceding mania found by Angst
[ 121. Unlike Kukopulos [ 171, we failed to find
that bipolar I1 patients had a predominance of
depressions preceding manias, with bipolar I
patients showing the opposite pattern, since
each subdiagnosis had a similar distribution of
sequences among patients (fig. 6). T h e
association of first episodes of depression, and
first illness periods that are uniphasic, with
subsequent polyphasic illness periods charac-
terized by a sequence of depressions preceding
manias, has not been previously reported.
Finally, our finding that over a third of our
patients with an initial depression had not yet
suffered a mania after three episodes is in
agreement with Angst [13] but at variance
 FREQUENCY OF EPISODES IN BIPOLAR
AND UNIPOLAR PATIENTS

12
o--+ Unipolar n=23

10 M Bipolar n=51
v)
t-
z
Lu
t-8
a
a
LL
0
[
I:
Lu 6
m
2
3
2
4

1-2 5-6 9-10 13-14 17-18 21-30

0 3-4 7-8 11-12 15-16 19-20 >30

NUMBER OF EPISODES
Figure 15

with several other reports (30, 31) that note
that the majority of bipolar patients (84%and
90% in these two reports) can be so classified
(i.e., have their first manias) by the time of the
third episode.
Course and pattern-of-illness variables were
far more capable of distinguishing patients
divided according to increasing episode
frequency over time as opposed to those
divided according to a high number of recent
episodes (i.e., rapid cyclers). The latter division
produced two very similar subgroups differing
only in the amount of time ill in the last year (a
partial derivative of the rapid cycler group
being defined as having a high number of
episodes in the past year) and the number of
29
 SIMILAR TOTAL TIME ILL IN BIPOLAR AND UNIPOLAR PATIENTS

Bipolar n = 48
* + Unipolar n = 23

30

20

10

TOTAL WEEKS ILL

Figure 16

lifetime hospitalizations for depression
(possibly also a contaminant of the greater
number of episodes in the past year).
In contrast, using a multivariate analysis,
patients with an increasing frequency of
episodes over time (sensitization pattern) could
be distinguished from other bipolar patients by
seven different variables (Table 5). Although
overall these patients had fewer episodes per
year ill, less total time ill per year ill, and fewer
polyphasic periods of illness, they had more
episodes in the year prior to NIMH admission
when these previous variables were controlled.
Thus, while their illness initially was less
severe than in the other subgroup (no pattern),
it seemed to evolve over time until it became
more severe. Furthermore, although the
progressive shortening of interval length in
these patients decelerated after the third or
fourth episode, it did not level off but
30
continued to shorten at a slower rate (fig. 3).
Although examination of these two subgroups
in terms of underlying biological correlates
and medication responsivity should prove
interesting, contrasting the sensitization
subgroup with a group of patients having a less
chronic form of affective illness than that seen
in all our patients (i.e., successive intervals
each of long duration) would prove more
helpful in testing and validating sensitization
models of affective illness [21].
Our finding that only 20%of our patients
with recurrent episodes had not relapsed five
years after the first episode differs from Angst’s
data [lo] showing that 50% of his bipolar
patients had not relapsed by 7% years. In our
study in particular, the sensitization subgroup
(partly as an artifact of our original definition)
took longer to relapse following their initial
episode (Table 5). Coupled with the fact that
they ended up more severely ill just prior to
NIMH hospitalization, this suggests that
patients with longer periods of time to relapse
after the first episode do not necessarily have a
more benign course of illness. Achte [32] has
also described a similar phenomenon where
patients with long, symptom-free intervals
following relatively short first episodes relapse
into a chronic state of illness.
Unlike Zis et a1 [I61 and Keller et a1 [33],
we failed to find a relation between the length
of the first interval and the age of onset in our
patients. However, Dunner et a1 [34] also
failed to find such a relationship in his patients.
Both our samples as well as Keller’s consisted
of patients who were treated according to
community standards in a naturalistic design,
with treatment frequently continuing between
episodes. In contrast, Dunner’s [34] sample,
like Zis’ [ 161, was medication-free between
acute episodes. Therefore, it is doubtful that
treatment accounts for the different results.
Instead, it is more likely due to sampling
differences, since both Dunner’s and our
sample were smaller and possibly more biased,
coming from a special research unit and a
lithium clinic, respectively.
The only variable able to distinguish early
from late onset bipolar patients was the longer
duration of first episode in late onset patients.
This is in keeping with the findings of some
authors that episode duration seems longer in
older patients, especially first episode duration
[6,32]. We did not find a greater proportion of
manic episodes in our older patients, in
contrast to Taylor [35]. Furthermore, our
failure to find other differentiating variables is
in keeping with numerous studies that have
failed to find other differences in course of
illness between early and late onset patients
[35-371.
Bipolar males and females were found to
differ on several parameters. The higher
proportion of depressions in females has been
noted by others [12, 381. The greater number
of weeks ill/year ill and of hospitalizations for
mania in males imply that, at least in this
population, males are more severely ill. This
may again be a selection artifact, since
participation in the research program usually
required consent for an extended hospitali-
zation (often four to six months) and such a
commitment poses greater financial burdens
on families when the typically male head of
the household is involved. Hence, males may
have had to be sicker to agree to such a
program. Additionally, Angst [12] has noted
that males tend to have more severe manias,
which may partially explain the greater
number of hospitalizations for mania. Results
of the univariate analysis indicate that females
were cycling faster prior to admission which is
consistent with earlier reports that females are
more frequently rapid cyclers [39].
Finally, a combination of several variables
were capable of differentiating the subgroups
of bipolar and unipolar patients. However, the
individual t-test analyses showing a far greater
number of episodes and yet a similar total time
ill in bipolar compared with unipolar patients
perhaps best epitomize the difference between
bipolar illness (many episodes switching on
and off) and unipolar illness (fewer, longer-
lasting episodes). Although total episodes
failed to be a significant predictor variable
differentiating the two subgroups once
episodes the year before NIMH were factored
out, whereas total time ill was a significant
variable when taken in combination with
other variables, these findings are a function of
the multivariate nature of the analyses, which
can alter univariate relationships. It should be
noted that age of onset in both groups was not
significantly different, despite the fact that it
has been noted to be so by others [40].
In conclusion, we have demonstrated a
number of aspects of course of illness in a
more modern population receiving naturalistic
treatment and compared these with prior
findings from the pre-pharmacology era. This
preliminary analysis suggests that many
patients continue to have sustained disability
in spite of the availabililty of somatic
treatments, and that many of the interrelation-
31
ships among course or pattern of illness
variables, described years earlier, continue to
recur seemingly unaffected by various
treatments. These results further suggest that,
despite the plethora of available psychoactive
drugs, there is a need for newer treatments
with a different spectrum of action to alter and
ameliorate the course of illness in such
patients. Currently, carbamazepine is emerging
as one such alternative [20]. We have also
shown that our specific retrospective method
32
for documenting the prior course of affective
illness has some predictive validity. Although
prospective studies are devoid of the numerous
biases present in retrospective studies and are
clearly more valid, retrospective studies may
serve a useful purpose in generating testable
hypotheses that might not otherwise be
pursued. Therefore, while prospective studies
on the course of affective illness continue [41],
retrospective methodologies similar to ours
should be further utilized.
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