Copyright Blackwell Munksgaard 2008

Bipolar Disorders 2008: 10: 215230

BIPOLAR DISORDERS

Review Article

Schizoaective disorder: diagnostic issues and

future recommendations
Malhi GS, Green M, Fagiolini A, Peselow ED, Kumari V.
Schizoaective disorder: diagnostic issues and future recommendations.
Bipolar Disord 2008: 10: 215230. Blackwell Munksgaard, 2008

Gin S Malhia, Melissa Greenb,

Andrea Fagiolinic, Eric D Peselowd
and Veena Kumarie
a

Objective: Diculties surrounding the classication of mixed psychotic

and aective syndromes continue to plague psychiatric nosology. This
paper addresses the controversy regarding the diagnostic validity of
schizoaective disorder (SAD), a diagnosis that is used in both DSM-IV
and ICD-10 and one that encroaches on both schizophrenia (SCZ) and
bipolar disorder (BD).
Methods: A systematic synthesis of clinical and empirical literature,
including evidence from cognitive, neurobiological, genetic, and
epidemiological research, was undertaken with the aim of evaluating the
utility of the SAD classication.

Northern Clinical School, University of Sydney,

School of Psychiatry, University of New South
Wales, Sydney, Australia, cUniversity of Pittsburgh
Medical Center, University of Pittsburgh,
Pittsburgh, PA, dNew York University School of
Medicine, Department of Veterans Affairs, New
York Harbor Healthcare System, New York, NY,
USA,eInstitute of Psychiatry, Kings College,
London, UK

Results: Distinctions between the diagnostic categories of SCZ, SAD

and BD are not clearly demarcated by ndings from neuropsychological,
neuroimaging, molecular neurobiology, or genetic epidemiology studies.
On the contrary, convergent evidence purports overlap across current
diagnostic boundaries in the heritability and pathophysiology of
psychotic and aective disorders. However, there are some disorderspecic ndings.
Conclusions: Schizoaective disorder is a prototypic boundary
condition that epitomizes the pitfalls of the current categorical
classication system. Future revisions to the DSM should consider the
implementation of one of two alternative models to account for
individuals presenting with mixed psychotic and aective symptoms.
These include the views that (i) SAD is a comorbid set of symptoms that
occur as a by-product of two separate disorders (SCZ and BD) or, that
(ii) SAD exists as the mid-point on a continuum between SCZ and BD,
such that the incorporation of these two disorders onto one dimension
may be a suitable alternative. Hence the category SAD should be omitted
in future revisions of DSM, allowing the development of meaningful
nomenclature that rests upon further rigorous investigation of
dierences and similarities between disorders.

Crude classications and false generalizations are

the curse of organized life.
George Bernard Shaw (18561950)
GSM has received funding for research from Pzer, AstraZeneca, Eli
Lilly & Co. and Wyeth; and serves on the advisory boards of Eli Lilly
& Co., Wyeth and AstraZeneca. AF serves on the speakers bureau
for Bristol-Myers Squibb, Pzer and Eli Lilly-Italy; and is a consultant
for Bristol-Myers Squibb, Pzer and Novartis. EDP serves on the
speakers bureau for Pzer and Forest. MG and VK have no reported
conict of interest.

Key words: bipolar disorder diagnosis

DSM-IV guidelines psychosis schizoaffective
disorder schizophrenia
Received 22 February 2007, revised and accepted
for publication 21 August 2007
Corresponding author: Professor Gin S. Malhi,
CADE Clinic, Department of Psychiatry, Level 5,
Building 36, Royal North Shore Hospital,
St Leonards, NSW 2006, Sydney, Australia.
Fax: +61 2 9926 7730;
e-mail: gmalhi@med.usyd.edu.au

A longstanding problem that plagues psychiatric

nosology concerns the variety of disorders that
present with an admixture of both aective and
psychotic symptoms. Over a century ago, the socalled Kraepelinian dichotomy was proposed as a
solution, by partitioning patients into two major
diagnostic categories: schizophrenia (SCZ) or
dementia praecox (an unremitting and progressively dementing illness) and bipolar disorder (BD)
or manic-depressive illness (an episodic, relapsing
and remitting illness). In practice, many cases fail
to qualify for either of these two diagnoses and

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Malhi et al.

clinically the distinction is of arguable signicance

(1).
The concept of schizoaective disorder (SAD)
was invoked in 1933 to describe acute schizoaffective psychosis (2) in which patients presented
with coterminous severe aective and psychotic
symptoms. Clinically, SAD became a rmly established diagnostic category that gained further
recognition upon inclusion as a subtype of SCZ
in the rst and subsequent versions of the Diagnostic and Statistical Manual for Mental Disorders
(DSM-I, DSM-II) (3, 4). In 1975, SAD was
redened as a separate category, with broad
criteria that allowed specication of a mostly
schizophrenic or mostly aective subtype. In
DSM-III (5), although SAD existed as a separate
category, no strict operational criteria were provided. Following revision, the DSM-III-R (6)
adopted the mostly schizophrenic category and
placed the mostly aective category under mood
disorder with mood-incongruent psychotic features. This diagnostic ux no doubt hampered
investigators engaged in studies attempting to
chart the course and prognosis of SAD and
determine its best management, and to date the
debate continues as to whether SAD is a form of
SCZ (7), a form of aective disorder (8), a
completely separate condition (9), or the mid-point
of a continuum between SCZ and BD (10).
The current DSM-IV paradoxically denes SAD
as distinct from SCZ and BD while maintaining,
there is no assumption that each category of
mental disorder is a completely discrete entity with
absolute boundaries dividing it from other mental
disorders or from no mental disorder. In clinical
practice the use of SAD often solves diagnostic
dilemmas associated with atypical presentation of
mood symptoms within the context of SCZ, but
may not serve the patient well with respect to
pharmacological or psychosocial management (7,
11). Clinicians understandably nd it dicult to
discriminate between SCZ and BD and perhaps by
virtue of personal bias diagnose one or the other,
or compromise and use the term SAD to defer
diagnostic exactness.
These inconsistencies undermine the usefulness
of diagnosis classication, and highlight the need
for careful deliberation of clinical and experimental
data in future revisions of the nomenclature.
With this in mind, it is of particular concern that
distinctions regarding the classication, clinical
features, course, and treatment of aective and
psychotic syndromes are not clearly demarcated by
genetic, neuropsychological, or neurophysiological
evidence (12). On the contrary, evidence from
brain imaging, molecular neurobiology, and genet-

216

ics purport overlap across diagnostic boundaries in

terms of both pathology and etiology, as well as the
existence of disorder-specic ndings. In this
paper, we synthesize empirical ndings pertinent
to the validity and utility of the SAD diagnosis,
focusing on evidence from cognitive, neurobiological, genetic, and epidemiological research that is
relevant to the lumping or splitting of psychotic
and aective symptoms into distinct diagnostic
categories. We outline putative alternatives for the
classication of patients that do not t neatly
within the criteria for SCZ or aective disorders,
including a comorbidity syndrome model, and a
continuum model of psychotic and aective symptoms (rather than syndromes), and discuss the
merits and problems inherent to each.

Classic diagnostic validators

Phenomenology

A clinical diagnosis of SAD is distinguished by the

simultaneous presentation of a combination of
psychotic symptoms such as hallucinations, delusions, or thought disorder and affective symptoms
(depressive or manic component). Specically,
both the DSM-IV-TR and ICD-10 criteria for
SAD include an uninterrupted period of illness
during which there is either (i) a major depressive
episode (MDE), (ii) a manic episode, or (iii) a
mixed episode concurrent with symptoms that
meet (iv) Criterion A for SCZ. However, it has
become increasingly apparent that an unequivocal
denition of SAD has not been attained across
standard international diagnostic criteria (see
Table 1); for example, DSM-IV and ICD-10 nominate dierent criteria regarding simultaneity and
temporal sequencing of symptoms (1), with more
variations apparent after translation to other
languages (13).
For example, ICD-10 conceptualizes SAD as
episodic, whereas DSM-IV denes SAD as an
uninterrupted illness in which the characteristic
symptoms of SCZ are present concurrently with a
depressive syndrome, a manic syndrome, or a
mixed episode. Furthermore, more than two weeks
of delusions or hallucinations in the absence of
prominent aective symptoms are required to set
SAD apart from psychotic depression or mania. In
addition, aective symptoms need to be present for
a substantial proportion of the total period of
illness so as to dierentiate it from SCZ, in which
mood symptoms are generally present only briey.
Such duration criteria regarding mood state
are dicult to quantify clinically, a diagnostic
complexity that is apparent in low inter-rater

Schizoaective disorder
Table 1. Diagnostic criteria for schizoaffective disorder (SAD)
Affective criteria

Schizophrenic criteria

Duration criteria

Simultaneity criteria

Additional criteria

DSM-IV

Major depressive,
manic or mixed
episode

Meeting Criterion A for

schizophrenia (two or
more of delusions,
hallucinations,
disorganized speech,
behavioural disturbances
or negative symptoms)
One symptom if
commenting or third
person voices, or
bizarre delusions

Major depressive
episode 2 weeks,
mixed or manic 1 week
Psychotic symptoms
1 month to meet
Criterion A for
schizophrenia

During the same

period of illness

Delusions or
hallucinations for
at least 2 weeks
without prominent
mood symptoms
Mood symptoms
as a substantial
portion of the total
duration of illness

ICD-10

Prominent manic,
depressive, or
mixed symptoms

One, preferably two of

(a) to (d) symptoms for
schizophrenia (does not
include symptoms of
speech)

Duration of the
affective episode
(manic at least
1 week, depressive
2 weeks)

Preferably
simultaneous,
at least within
a few days of
each other

reliabilities for single items as well as the entire

diagnostic category when using the DSM-IV denition (14) of SAD. Hence, the validity of the SAD
construct, as well as its division into depressive and
bipolar subtypes remains equivocal.
Gender

Schizoaective disorder appears to occur more

often in women than in men, and particularly in
married women. However, the age of onset for
women is later than men (15), and men with SAD are
more likely to manifest antisocial behaviour and
have either a at or inappropriate aect. The depressive subtype of SAD appears to be more common
in the elderly whereas the bipolar type appears to
predominate in younger patients, with depressive
symptoms more prevalent in females (16).
Differential diagnosis

General medical conditions and substance use can

present with a combination of psychotic and mood
symptoms. Psychotic disorder due to a general
medical condition, a delirium, or a dementia is
diagnosed when there is evidence from the history,
physical examination, or laboratory tests indicating that the symptoms are the direct physiological
consequence of a specic general medical condition. Substance-induced psychotic disorder and
substance-induced delirium are distinguished from
SAD by the fact that a substance (e.g., drug of
abuse, medication, or exposure to a toxin) is
judged to be causally related to the symptoms.
Distinguishing SAD from SCZ and from mood
disorder with psychotic features is often dicult.
In SAD, there must be a mood episode that is

concurrent with the active-phase symptoms of SCZ

with mood symptoms present for a substantial
portion of the total duration of the disturbance,
and delusions or hallucinations lasting at least
two weeks in the absence of prominent mood
symptoms. In contrast, mood symptoms in SCZ
either have a duration that is brief relative to the
total duration of the disturbance, occur only
during the prodromal or residual phases, or do
not meet full criteria for a mood episode. If
psychotic symptoms occur exclusively during periods of mood disturbance, the diagnosis is mood
disorder with psychotic features. In SAD, symptoms should not be counted toward a mood
episode if they are clearly the result of symptoms
of SCZ (e.g., diculty sleeping because of disturbing auditory hallucinations, weight loss because
food is considered poisoned, diculty concentrating because of psychotic disorganization). Loss of
interest or pleasure is common in non-aective
psychotic disorders and therefore, to satisfy the
necessary criteria for SAD, the MDE must include
pervasive depressed mood.
Because the relative proportion of mood to
psychotic symptoms may change over the course
of the disturbance, the appropriate diagnosis for an
individual episode of illness may change from SAD
to SCZ (e.g., a diagnosis of SAD for a severe and
prominent MDE lasting 3 months during the rst
6 months of a chronic psychotic illness would be
changed to SCZ if active psychotic or prominent
residual symptoms persist over several years without
a recurrence of another mood episode). The diagnosis may also change for dierent episodes of illness
separated by a period of recovery. For example, an
individual may have an episode of psychotic symptoms that meet Criterion A for SCZ during a MDE,

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Malhi et al.

recover fully from this episode, and then later

develop six weeks of delusions and hallucinations
without prominent mood symptoms. The diagnosis
in this instance would not be SAD because the
period of delusions and hallucinations was not
continuous with the initial period of disturbance.
Instead, the appropriate diagnoses for the rst
episode would be mood disorder with psychotic
features, in full remission and schizophreniform
disorder (provisional) for the current episode.
Depressive symptoms are ubiquitous throughout
all stages of SCZ, but are less well characterized
and often merge with the negative symptoms.
Similarly mood disturbances, especially depression,
commonly develop during the course of delusional
disorder. However, such presentations do not meet
criteria for SAD because the psychotic symptoms
in delusional disorder are restricted to non-bizarre
delusions and therefore do not meet Criterion A
for SAD. If there is insucient information concerning the relationship between psychotic and
mood symptoms, psychotic disorder not otherwise
specied may be the most appropriate diagnosis.
Epidemiology

Relatively little is known about the incidence,

prevalence, demographic factors, or risk factors
associated with SAD. This is in part a corollary of
the diering denitions of SAD used in various
studies. The prevalence of SAD has been estimated
to be <1% (0.50.8%) in the general population,
but the prevalence in patient populations is often
much higher, as in practice the clinician often
makes the diagnosis of SAD when he she is
uncertain. Overall, despite the lack of specic data
there is consensus that SAD is likely to be less
common than SCZ.
Objective signs

Comorbid depressive symptoms or syndromes

occur in 783% of people with SCZ (17, 18), with
a modal prevalence of 25% (19), and postpsychotic depression is often present before relapse
into an overt psychotic episode (20). Moreover,
recent epidemiological studies report depressive
symptoms and syndromes as common precursors
of the rst psychotic episode in adolescents later
diagnosed with SCZ (18).
With regard to psychotic symptoms in aective
disorders, it has been noted that the negative
symptoms of SCZ (aective attening, alogia
and or avolition) are typically evident in most if
not all moderately to severely depressed patients
(11). An estimated 58% of manic and 15% of

218

depressed patients report psychotic symptoms (21).

With regard to the characteristics of these psychotic symptoms, mood-incongruent delusions are
more commonly associated with SCZ and mood
disordered patients with psychotic features, while
mood-congruent delusions are more common in
BD (12). However, severe mood disorders with
psychotic symptoms can exhibit bizarre, moodincongruent hallucinations and delusions, akin to
SCZ. In practice, the distinction between SCZ with
comorbid major depression and SAD can be
dicult and there is little evidence to instruct
diagnostic separation. However, major depression
is usually recurrent and the frequency of aective
episodes may help partitioning.
Diagnostic stability

Whilst the majority of patients with an initial

diagnosis of SCZ or mood disorder receive the
same diagnosis on reassessment, the stability of the
SAD diagnosis has been particularly poor. For
example, one study has shown that only 36% of
those initially diagnosed with SAD received the
same diagnosis at a later time point (22); 42% of
these patients were diagnosed with SCZ at a 24month follow-up, with <1% diagnosed with BD.
In a more recent sample of 61 SAD patients, 37
patients (61%) were later diagnosed with BD (23);
the fact that less than half of these patients
diagnosed initially with SAD sustained the diagnosis in the long term suggests that current
diagnostic criteria are not serving a meaningful
purpose. Furthermore, a 10-year follow-up study
of the prognostic value of diagnoses on the SCZ
and aective spectrum suggest that patients with
mood disorder without psychotic features [i.e.,
unipolar depression (UD)] have the best prognosis,
while SCZ patients have the worst, with BD and
SAD patients having progressively worsening
intermediate courses, respectively (24). Individuals
with SAD often present with symptoms that
resemble those of individuals with SCZ (25), but
a course of illness that more closely resembles
individuals with BD (26).

Genetics

Twin, family and molecular genetic studies

Lifetime prevalence of both SCZ and BD are

estimated to be 1%, with heritability estimates for
these conditions ranging from 6085% for SCZ
(2729) and 4070% for BD (30, 31). Whilst
uctuating denitions of SAD make it dicult to
establish the lifetime prevalence of SAD, the

Schizoaective disorder
average estimate is 0.5% (29, 32, 33). At face value,
these prevalence and heritability estimates may be
taken to suggest that the low prevalence of SAD
represents the small number of cases that present
with an overlap of psychotic and aective symptoms, such that the SAD diagnosis may represent
random comorbidity of SCZ and BD diagnoses
(34, 35). However, such interpretations must be
considered with respect to the potential artifact of
comorbidity, as complex syndromes are divided
into smaller parts.
The pattern of heritability rates for specic
disorders may be important in delineating the
nature of clinical overlap. Indeed, shared genetic
liability across psychotic and aective disorders are
supported by large family studies (29, 33, 3638)
and several twin studies (28, 39). For example, an
excess of major depression and SAD has been
noted in the relatives of both BD and SCZ
probands (36, 40, 41), and studies from two large
family studies have reported higher rates of
psychotic mood disorder (BD) in rst-degree
relatives of schizophrenic probands, and vice-versa
(29, 33, 37, 38). However, comprehensive reviews
of heritability studies conducted prior to the mid1990s suggest a higher rate of mood disorders
among rst-degree relatives of SCZ probands than
SCZ in the rst-degree relatives of mood disorder
probands (with a mixture of both evident in
relatives of SAD probands) (42, 43).
In support of a continuum model of psychotic
mood disorders, Gershons Family Study (36)
reports lifetime prevalence of major aective disorder (including schizoaective) as 37%, 24%,
25%, 20% and 7% in relatives of probands with
schizoaective, bipolar I (BD I), bipolar II (BD II),
and UD, and normal controls, respectively. In this
model, schizoaective illness represents greatest
vulnerability, followed by BD I, BD II, then UD.
Taken together with ndings from the Roscommon Family Study (29), which reported SADdepressed type more commonly in rst-degree
relatives of SCZ probands, it has been suggested
that SAD-depressed type may be a milder version
of SCZ, while SAD-bipolar type is perhaps an
extreme version of BD (34, 44).
A recent review of the data from genetic epidemiology, linkage, association, cytogenetics and
gene expression studies in BD and SCZ concludes
that constellations of co-occurring mood and
psychotic symptoms are associated with putative
risk alleles in shared susceptibility genes (45). These
observations have very important nosological
implications as they demonstrate an overlap in
the biological basis of disorders that have been
classied as distinct entities for over 100 years (46).

Evidence from linkage studies in SCZ and BD

suggests at least four overlapping chromosomal
regions that may contain susceptibility genes
shared by the two disorders (4749). One example
is the gene encoding d-amino acid oxidase activator
(DAOA) on chromosome 13q (50). Another example is the gene Disrupted in Schizophrenia 1
(DISC1), with recent research suggesting that
SCZ, SAD and BD might be associated with
polymorphisms in this gene (50). There is also
recent evidence for shared genetic susceptibility
between SCZ, SAD and BD involving genes
related to the development of glutamate-signalling
pathways (51).
Endophenotypes

Given the dearth of studies focused on the elucidation of biological causal mechanisms of SAD as
distinct from SCZ or BD, this section will focus on
recent genetic linkage and association studies that
have paid increasing attention to neurocognitive
performance as a putative endophenotypic marker
of these disorders [see (52)]. A meta-analysis of
studies assessing cognitive functioning in these
disorders concludes that, despite similar impairments in some cognitive domains (e.g., executive
function, visual memory), SCZ patients demonstrate the most severe and stable neurocognitive
impairments, while BD patients perform better
overall (53), and there is some consensus that only
decits in attention remain stable over time in BD
(54, 55). Notably, most studies do not suggest a
signicant global cognitive impairment in BD, even
if the course of illness is severe and patients are
symptomatic (56) while SCZ is consistently associated with global as well as specic cognitive
impairments (57). These patterns of ndings may
also reect greater variability in neurocognitive
performance in BD, but not SCZ.
In the case of SCZ, impaired cognition and
executive function have been reported in both
patients and their unaected rst-degree relatives
(5860). In particular, neuropsychological measures of current, premorbid and verbal intellectual
functioning have been associated with SCZ
patients and their relatives, but not in the patients
or relatives of those with BD (61). There is also
evidence for abnormalities of memory in association with increased liability to either SCZ or BD,
suggesting that these memory decits may be
linked with the predisposition to psychosis in
general, but no neuropsychological impairment
was found to be specic to BD (61, 62). However,
other research suggests that executive function
(working memory) and verbal learning and

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Malhi et al.

memory (declarative memory) represent the most

viable endophenotypic markers of BD; decits in
these neurocognitive domains appear to be heritable, co-segregated within families, illness related,
and remain impaired during periods of symptomremission (52, 6264). In particular, spatial working memory performance clearly distinguishes
non-psychotic BD from patients with functional
(SCZ) psychosis (62). More specic investigation
of the putative executive decit in BD suggests
that impaired response inhibition associated with
ventral prefrontal cortex function is the more
likely candidate, rather than dorsolateral prefrontal function (e.g., rule attainment) (65). Finally, a
recent study by these authors suggests that
performance on a verbal uency task, representative of intact functioning of the fronto-temporal
regions in BD, may distinguish these patients from
SCZ (66). Only a few studies have directly
compared SCZ and SAD populations so far.
There are indications that patients with SCZ are
more impaired than patients with SAD in temporal lobe-dependent cognitive functions, such as
delayed recall (67). Some other cognitive functions
commonly found to be impaired in SCZ, such as
verbal working memory (in the presence of
impaired spatial working memory suggesting preserved articulatory rehearsal), may also be intact
in SAD (68).
In the psychophysiology literature, patients with
SCZ (6972) or schizotypal personality disorder
(73) are consistently reported to generate a high
percentage of error on anti-saccade performance
tasks than healthy individuals. There is considerable evidence for genetic transmission of this
abnormality in SCZ from family and twin studies
(74). The relatives of probands with abnormal antisaccade performance are also more likely to show
this abnormality than relatives of probands with
normal performance (7577). Furthermore, increased error rates are found in rst-, but not
second-degree relatives of SCZ patients (77). Some
studies have reported increased anti-saccade errors
in BD populations (7880), while others have not
(81). Interestingly, in a more recent study, antisaccade performance was reported to be temporally unstable in BD (with SCZ patients showing
reliable performance in the same study), suggesting
that this decit may be a state as opposed to trait
marker of BD (82). Increased anti-saccade errors
have also been noted in a mixed group of patients
with either major depression with psychotic features or BD with psychotic features (76). Erroneous anti-saccade performance seems to be
associated with the presence of psychotic features
across SCZ and aective disorders. Frontal lobe, in

220

particular dorsolateral prefrontal cortex (DLPFC),

activity is considered critical for successful antisaccade performance, which involves suppression
of a reexive saccade in favour of an anti-saccade
(83). Abnormalities of this region are generally
associated with SCZ (84). It is not yet established,
however, whether anti-saccade decits reect vulnerability to SCZ only, or to both BD and SCZ;
the existing data in BD patients seem to suggest
that it may not be associated with vulnerability to
BD. Another psychophysiological measure, prepulse inhibition (PPI) of the startle response,
reliably reveals inhibitory decits in patients with
SCZ (72, 85, 86) and in manic (87) but not
euthymic (88) patients with BD. PPI has also
emerged as a potential endophenotype of SCZ,
with observations of reduced PPI in relatives of
SCZ patients (89, 90) as well as in individuals with
schizotypal personality disorder (89). The potential
relevance for the genetics of BD remains to be
examined.

Longitudinal course

Age of onset

Epidemiological data regarding age of onset and

clinical course does not distinguish SCZ from BD,
as both have a similar age of onset, lifetime risk,
with comparable course of illness, worldwide
distribution, risk for suicide and genetic susceptibility (23, 47, 91).
Number of episodes and their duration

Whilst Kraepelins dementia praecox (SCZ) was

originally distinguished from manic-depressive
insanity (BD) on the basis of a progressively
deteriorating course, recent longitudinal studies
suggest that illness course does not pristinely
dierentiate SCZ and severe BD: the course of a
severe mood disorder can become non-responsive to
treatment, be chronic, lasting from over 2 years to
life without remissions, and with a progressive
deterioration [(11), p. 267].
The course of SAD is therefore ill-dened, with
recovery rates ranging widely (between 29% and
83%). Approximately 2030% of patients show a
deteriorating course with persistent psychotic
symptoms, whereas in another 10% of patients
the relative prominence of aective and schizophrenic symptoms may shift over time. In general,
the prognosis of patients with SAD is intermediate
between that of SCZ and that of aective disorder
patients. Predictors of poor outcome in SAD
include poor premorbid functioning, insidious

Schizoaective disorder
onset, absence of a precipitating factor, predominance of psychotic symptoms, early-age at onset,
poor inter-episode recovery, and a family history
of SCZ.
However, in general, patients with schizoaective
illness have a non-deteriorating course and respond
to lithium better than patients with SCZ but not as
well as patients with bipolar illness. Hence, the
prognosis for SAD is somewhat better than the
prognosis for SCZ, but considerably worse than
the prognosis for mood disorders as a whole.
Substantial occupational and social dysfunction is
common and the presence of precipitating events or
stressors is associated with better prognosis.
Prodromes

Attempts to dene prodromal features of individuals who will go on to develop a psychotic illness
have included the assessment of ultra-high risk
(UHR) states that have predominantly been
dened by the presence of attenuated positive
psychotic symptoms (92). It has recently been
argued that individuals reporting such symptoms
may represent a subgroup of individuals that are
most likely to manifest psychosis (93) such that
current conceptualizations of prodromal indicators
include cognitive impairment, aective symptoms,
social isolation and decline in social functioning
(94). The majority of research following these
UHR individuals has conrmed only those factors
contributing to the transition to psychosis, with
little available longitudinal data regarding the
diagnosis of these individuals with aective versus
non-aective psychotic disorders following their
initial psychotic episode. So far, there is evidence
from one study that reductions in the grey matter
volume of the posterior superior temporal gyrus
seen in rst episode psychosis is specic to patients
that go on to develop SCZ, and are not present in
individuals later diagnosed with aective psychosis, once again implicating temporal lobe abnormality specically in SCZ (95).
Treatment

The fact that lithium is comparatively more eective in aective disorders than in SCZ and typical
antipsychotics have relatively greater ecacy in
SCZ is supportive of a dichotomy. However,
valproate, a mood stabilizer, has been shown to
be useful as an adjunct in the treatment of SCZ (96)
suggesting that partitioning on the basis of treatment is not pristine. Unfortunately, systematic
pharmacological treatment studies of SAD are
lacking. Five open studies all yielded positive

results for risperidone in SAD, with an overall

65100% response noted in four of ve studies
involving a total of 183 patients (97). One doubleblind study found risperidone to be as eective as
haloperidol in the treatment of 13 patients with
SAD (98), while another reported that olanzapine
was superior to haloperidol over six weeks in 300
patients with SAD (99), and yet another noted that
when clozapine was compared with placebo in
SAD, 36% of the clozapine patients had a moderate marked response to clozapine (100). In addition, a review of 39 studies that presented data on
the treatment of SAD participants found that the
majority encouraged the use of lithium and carbamazepine in primarily aective patients, and clozapine for SCZ and schizoaective patients. Further,
it concluded that it is useful to subtype patients
according to an aective or schizophrenic symptom
bias, and that prospective and controlled studies
examining the long-term treatment of patients with
mixed psychotic and aective symptoms (i.e.,
currently dened as SAD) are warranted (101).
Patients with schizoaective disorder often
maintain complex pharmacological regimens as
clinicians attempt to target both psychotic and
aective symptoms. There is no clear evidence that
any one pharmacological strategy is superior to
any other, during acute or maintenance treatment
using: antipsychotic, mood stabilizer (lithium,
carbamazepine, sodium valproate), or antidepressant monotherapies, or combinations of these.
Acute treatment usually requires antipsychotics,
because most acutely ill patients have prominent
psychotic symptoms. With little evidence from
controlled studies, the choice of maintenance
strategy is often guided by the SAD subtype.
For example, mood stabilizers may be used in
patients with the bipolar subtype, antidepressants
in those with the depressive subtype, and antipsychotics in patients with persistent psychosis. In
practice, for SAD (bipolar subtype) often the
combination of a mood stabilizer plus an antipsychotic is prescribed whereas for the depressive
subtype, a mood stabilizer plus an antidepressant
is preferred. While the latter is frequently the
treatment given for psychotic depression, when
using an antidepressant in schizoaective illness it
is important to monitor for potential switching
from depression to mania and avoid precipitation
of rapid cycling (102). Further, in the bipolar
subtype, incomplete response to pharmacotherapy
might prompt consideration of electroconvulsive
therapy. Preliminary evidence suggests that atypical antipsychotics may have mood-stabilizing
properties (103), in which case this class may
provide the ideal monotherapy for patients with

221

Malhi et al.

schizoaective disorder. In patients where this and

other treatment strategies fail, a trial of clozapine
should be considered.
Neurobiology

Neuroimaging

With the increasing use of neuroimaging technologies there has been progress in the detection of
disease-specic changes in brain structure and
function relating to SCZ and BD, but to date
there is relatively little data available for SAD as a
distinct category. In brief, the SCZ literature points
to morphological abnormalities in fronto-temporal
regions (104) with the loss of frontal grey matter in
adolescence associated with the transition to SCZ
(105), and medial temporal volume loss following
the onset of frank psychotic illness (106). In BD,
loss of grey matter in frontal regions has been
specically identied in the subgenual prefrontal
cortex (107, 108) whereas in the anterior cingulate
cortex (ACC) patients with BD I have a larger
right ACC volume (109) and gyral abnormalities
(110). Juveniles with BD have been found to have
enlarged amygdalae (111113) as compared with
smaller amygdalae in adults with BD (107, 108).
Structural brain abnormalities common to SCZ
and BD I (i.e., not evident in depression without
psychotic features) include enlarged ventricles
(114), white matter volume reduction (115, 116),
signicant asymmetry of the posterior amygdalahippocampal complex (95), and high dopamine D2
receptor densities [Pearlson et al., 1996 cited by
(12)]. Quantitative assessments of neuroanatomical
structures in SAD as compared with BD patients
and healthy volunteers show that patients with
SAD exhibit striatal regional abnormalities that
resemble those seen in BD (117).
At the functional level, SCZ has most commonly
been associated with hypofrontality (reduced neuronal response) in the DLPFC during performance
of executive cognitive tasks [see (84, 118) for
reviews]. Some studies have also reported increased
DLPFC activation at low cognitive loads that may
indicate inecient use and limited availability of
prefrontal neural resources in SCZ [see (119, 120)
for a review]. Notably, non-psychotic siblings of
SCZ patients show increased task-related activity
while performing at a similar level to healthy
controls on working memory tasks (121, 122),
indicating lower neural eciency akin to that
noted in patients. Generally, the widespread activation abnormalities revealed with functional
imaging studies in patients with SCZ and their
biological relatives concur with the extent of

222

cognitive and emotional decits noted in the

neuropsychological literature and brain structural
abnormalities in the MRI literature, with genetic
vulnerability to SCZ broadly linked to a disruption
in fronto-thalamic-cerebellar networks (123).
Functional imaging studies in BD generally
point to hyperactivity in the striatal-thalamo-frontal networks (124, 125) and decreased activity in
the anterior cingulate (126) during working memory tasks. Euthymic BD patients also show
increased activity in the ventrolateral prefrontal
cortex (VLPFC) as well as in the limbic and
paralimbic regions during a task requiring sustained attention (127). Studies using cognitive
inhibition (e.g., Stroop) paradigms further demonstrate aberrant activity in the VLPFC but reduced
activity in the anterior cingulate and the temporal
cortex in euthymic BD patients (128). This is
consonant with recent functional imaging studies
that have examined emotional processing in euthymic bipolar patients that suggest an inability to
engage the prefrontal neural networks in cognitive
processing of emotional stimuli (129131).
The general pattern of ndings in SCZ and BD
in association with strong illness-specic symptoms
clearly points to dierential neural activation
decits in these two populations. There however
appears some commonality in the direction and
regional specicity of trait-like activation decits
across these two disorders. Unfortunately, functional brain activation studies of SCZ patients have
tended to include patients with SAD and no
functional imaging study to our knowledge has
directly compared SCZ and SAD patient groups.
It is possible that patients with SAD when
presenting with psychotic symptoms show functional brain decits similar to, but perhaps milder
than those found in SCZ in association with
psychotic symptoms.
Pathophysiology

Common ndings in SCZ and BD from the

Harvard Brain tissue resource centre include
decreased prefrontal cortex (PFC) neuronal size,
reduced ACC neuronal density, reduced PFC and
hippocampal synaptic and dendrite markers, and
glial cell reduction [Harrison, 2002, cited by Kempf
et al. (12)].
Summary and outstanding issues

SAD is a prototypic boundary condition that

highlights the disadvantages of a rigidly categorical
classication system. Given the diculty of demar-

Schizoaective disorder
to account for individuals presenting with mixed
psychotic and aective symptoms can be posited as
compatible with current data: (i) SAD as the midpoint on a continuum between SCZ and BD such
that SAD-depressed type may be a milder version
of SCZ, while SAD-bipolar type may be an
extreme version of BD (44), or (ii) SAD as a
comorbid set of symptoms that occur as a byproduct of two separate disorders (SCZ and BD)
(34). Clearly these two models have very dierent
clinical utility in terms of understanding the
etiology of each diagnosis, and with regard to
treatment. The possibility that SAD is a separate
distinct disorder is highly unlikely and is not
supported by the available evidence.

Model 1

Model 2

A
SA

Model 3

The dimensional approach to affective psychosis

SA

Fig. 1. Schematic representation of models for SAD. Model 1

depicts mood and psychotic symptoms within schizophrenia
and affective disorders, respectively, that are erroneously dened as SAD. Model 2 depicts an overlap of schizophrenia and
affective disorders with subsequent assignment to SAD. Model
3 depicts SAD as a separate nosological entity with a
distinct pathophysiology. S = schizophrenia schizophrenialike symptoms; A = affective disorders mood symptoms;
SAD = schizoaffective disorder. SAD is indicated by the
shaded areas.

cating psychotic and mood disorders, at least three

conceptual models (see Fig. 1) have been proposed
to explain the coexistence of schizophrenic and
aective symptoms in the same person: (i) SAD
patients comprise two groups of individuals: those
that have true SCZ with incidental aective
symptoms and those that have true aective
disorder with incidental SCZ symptoms; (ii) SAD
patients are the result of overlap between true
SCZ and true mood disorder patients and are
therefore a mixed group with genuine comorbidity
in which individuals have both SCZ and BD; and
(iii) SAD represents a distinct third psychotic
illness. The latter option is unlikely and SAD most
probably constitutes a heterogeneous group within
which some patients have SCZ and others have
mood disorders.
Whilst consensus is emerging on the need to
complement categorical classications of illness
with more informative and detailed information of
the clinical phenomena of psychopathology, there
remains the fundamental issue of how best to sort
these clinical descriptions. Two alternative models

The notion of a SCZ spectrum originates in the

observation that several dierent disorders tend to
cluster among biological relatives of individuals
with SCZ. For instance, the Roscommon Family
Study (42, 132) described a continuum of liability
that included: (i) typical SCZ; (ii) schizotypal and
paranoid personality disorders; (iii) SAD, depressed type; (iv) other non-aective psychotic
disorders (schizophreniform, atypical psychosis);
and (v) psychotic aective disorders. Indeed, a
recent review of empirical literature relevant to
categorical versus continuum denitions of psychotic and aective symptoms found that 133 of
260 studies relevant to the relationship of SAD
with SCZ and BD supported the placement of
SAD as lying on a continuum between SCZ and
BD (11), thus supporting a continuum of psychotic-aective disturbance. These authors thus
advised the re-evaluation of current DSM diagnostic categories of SCZ, SAD, BD and UD in line
with consolidating these diagnoses as dierent
points along a continuum of severity of a mood
disorder, with the potential to specify the presence
or absence, severity and type (e.g., mood congruent incongruent; paranoid, undierentiated or disorganized) of comorbid psychotic symptoms (11).
Lake and Hurwitzs (11) revised schema for
classifying psychotic mood disorders is based on
data generated from 260 studies of SCZ, BD and
SAD, in which the majority of these studies (133 of
260) support conceptualization of SAD along a
continuum of severity of mixed aective and
psychotic symptoms lying between SCZ (as the
most severe form of disorder) and BD I (which lies
above BD II and UD in terms of severity).
According to this model both SAD and SCZ
should be regarded as mood disorders, with the
most severe cases of mixed aective and psychotic

223

Malhi et al.

symptomatology (SCZ) reclassied as BD I with

psychotic features, and SAD reclassied as BD I or
BD II with or without mood congruent incongruent psychotic features. This model thus proposes
that both SCZ and SAD be removed from the
nomenclature, as previously suggested by others in
response to the questionable validity of the SAD
diagnosis (9, 44). Similar views on the construct of
SCZ are evident in recent decades (133, 134)
because of the inherent heterogeneity of its clinical
manifestation (and diagnostic criteria), alongside
the apparent failure of diagnostic criteria in terms
of elucidating biological causal mechanisms.
This dimensional view of SAD is consistent
with polygenetic models that assume interaction
between several genes and environmental factors
to eventuate as a disorder such as SCZ or SAD.
Given that multiple genes and multiple environmental risk factors are involved, it is possible for
people to inherit patterns of low, moderate, or
high doses of the risk factors that predispose to a
psychotic disorder (135). For instance, individuals
with very high doses would be at high risk for
SCZ, whereas people with moderate doses may
develop related conditions currently labelled
schizotypal personality disorder or SAD (136).
Furthermore, syndromes resembling SAD might
thus represent the product of inherited genes
predisposing to either SCZ or mood disorder (or
even genes for one type of disorder only, such as
SCZ) in association with exposure to environmental factors that are associated with the development of the other type of disorder (e.g., an
aective disorder).
Importantly, the dimensional perspective has
support from studies in brain imaging, molecular
neurobiology and genetics. This evidence is accumulating to suggest that overlap across diagnostic
boundaries in terms of both pathology and aetiology exists, but at this stage does not discount the
existence of disorder-specic factors (12). Thus, the
adoption of a dimensional approach to the symptoms of psychosis, mania and depression need not
result in a complete breakdown of current diagnostic categories. Instead, current diagnostic concepts of SCZ and aective disorders could either be
broadened to encompass multiple variations in
clinical presentation, or alternatively, jettisoned for
new diagnostic guidelines that treat psychotic and
aective symptoms as separate, but not mutually
exclusive, dimensions of psychotic illness.
There are, however, diculties with the dimensional approach. The most obvious relates to how
many dimensions suce, with the options ranging
from a single aective-psychotic dimension to
multidimensional conceptualizations along mutu-

224

ally exclusive (e.g., psychotic, aective, motivational) axes. If a multidimensional concept most
parsimoniously accounts for the clinical reality, a
problem for diagnoses will be in determining which
dimensions are of greater importance. Furthermore, it is unclear how to determine the relative
weight that should be assigned to the severity or
number of symptoms along a dimension. For
instance, is a delusion of greater salience and
hence severity than psychomotor slowing? Does
suicidal ideation, as a single symptom, confer the
same weight as the loss of appetite? In actuality
this is not a new problem and current categorical
classication faces the same diculty. However,
with a dimensional approach, where there is no
cut-o the problem is accentuated as rating along
a dimension is wholly dependent on such distinctions. Another limitation of a dimensional approach arises from a research perspective. When
investigating psychiatric patients the possible permutations of symptom patterns, as dened according to a continuum model, are likely to be limited
to a single individual at any one time and hence
will reect a natural category of symptoms with
clinical salience and relevance. However, generalizations from research of single cases would
obviously be limited. The grouping of symptoms
and symptom patterns along dimensions that do
not reect clinical practice may therefore limit the
utility of research ndings with respect to therapeutic application such that diagnoses may
emerge that are essentially theoretical and largely
serve research but have little use in treating
patients.
SAD as a comorbid syndrome (SCZ and BD)

The model of SAD as a comorbid diagnostic

category alongside SCZ or BD arguably nds
support in epidemiological studies reporting low
prevalence rates (35, 42). That is, SAD cases are
regarded as rare cases of individuals presenting
with comorbid SCZ and BD illnesses, such that
the diagnosis need not remain as a separate
category in the DSM, but could merely be viewed
as such and listed as a subtype of SCZ (comorbid
with BD).
Intuitively, this view of SAD as a comorbid
diagnostic category that arises from overlap
between SCZ and BD may be dicult to reconcile
with the already high degree of co-occurring
syndromes that are observed with use of the
current classication system. That is, would not a
further comorbidity phenomenon ultimately
question the validity of the current conguration
or clustering of symptoms? Indeed, the DSM has

Schizoaective disorder
been replete with dicult boundary disputes,
many of which could be the result of arbitrary categorical classications being incorrectly imposed
upon an underlying dimensional domain of psychiatry. In spite of this caveat, the utility of this
option may be combined with dimensional symptom rating options to provide a combination of
both categorical and dimensional aspects of
illness. As the generation of cut-o points for
categorical classication often involves implementing arbitrary constraints upon dimensional data
(such as perceptual experiences, neurocognitive, or
psychophysiological indices), such a system would
view categorical diagnosis and descriptions of
symptom dimensions as complementary, rather

than alternatives. Potentially this could see the

clinical use of popular dimensional scales commonly employed in research investigations [e.g.,
the Brief Psychiatric Rating Scale (137) or Positive
and Negative Syndrome Scale (138)], or the
construction of similar hybrids for use in the
DSM classication process.
Proposed Changes to DSM

This review of the extant literature suggests that

the current DSM-IV denition of SAD is impractical for research purposes and that it has limited
clinical salience. We therefore propose additional
speciers (see Table 2) for DSM-V that would

Table 2. Proposed use of subtype specifiers for schizophrenia (SCZ), bipolar disorder (BD) and major depression in future (DSM-V) diagnostic criteria
Diagnosis

Criterion A

Current DSM-IV specifiers

Proposed additional specifiers

Additional symptoms occurring
concurrently with active-phase
symptoms

Active-phase symptoms
SCZ

Two or more of delusions,

hallucinations, disorganized
speech, behavioural
disturbances or negative
symptoms (one if
commenting or third person
voices, or delusions are
bizarre) of at least one month
duration

Paranoid type
Disorganized type
Catatonic type
Undifferentiated type
Residual type

1. With symptoms meeting criteria

for mania or mixed features
2. With symptoms meeting criteria
for major depressive disorder

Bipolar I

One or more manic or

mixed episode

Can be applied to current

(or most recent) manic or
depressive episode
Severe without psychotic features
Severe with psychotic features
In partial remission
In full remission
Unspecified

During depressive manic phase:

Bipolar II

One of more MDE + at least

one hypomanic episode

No specifiers can be used

with this diagnosis in DSM-IV

1. With psychotic symptoms meeting

Criterion A for SCZ (i.e., 1 month)
and for at least 2 weeks without
prominent mood features
2. With psychotic symptoms meeting
Criterion A for SCZ with consistent
concurrent mood features
During depressive phase only:
1. With psychotic symptoms meeting
Criterion A for SCZ (i.e., 1 month)
and for at least 2 weeks without
prominent mood features
2. With psychotic symptoms meeting
Criterion A for SCZ with consistent
concurrent mood features

MDE

Five (or more) symptoms of

depression during same
two-week period with change
from previous functioning;
with at least one of the
symptoms either (i) depressed mood or (ii) loss
of interest or pleasure

Mild, moderate, severe

without psychotic features,
severe with psychotic features.
Chronic,
with catatonic features
with melancholic features
with atypical features
with post-partum onset

1. With psychotic symptoms meeting

Criterion A for SCZ (i.e., 1 month) and
for at least 2 weeks without prominent
mood features
2. With psychotic symptoms meeting
Criterion A for SCZ with consistent
concurrent mood features

MDE = Major Depressive Episode.

225

Malhi et al.

facilitate a better understanding of the overlap of

psychotic and mood symptoms. In brief, SCZ
should allow coding of symptoms for mania or
mixed features and symptoms of major depression.
Bipolar disorders should include speciers of
psychotic symptoms that meet Criterion A of
SCZ (in BD II this will apply largely only to the
depressive phase of the illness). Lastly, major
depression should also incorporate speciers for
psychotic symptoms that meet Criterion A of SCZ.
The removal of SAD and its substitution with a
diagnostic classication that allows nomination of
symptom speciers facilitates the adoption of a
data-based approach to tackling this dicult
nosological issue.
Conclusions

Schizoaective disorder has a tenuous existence on

the boundaries of psychotic and aective disorders
dened within a rigid categorical classication
system. There is increasing evidence for shared
genetic susceptibility that cuts across the Kraepelinian divide (46), and further advances in neurogenetics are necessary to delineate the nature of
psychosis and its various facets. Future revisions to
the DSM should consider the implementation of
one of two alternative models to account for
individuals presenting with mixed psychotic and
aective symptoms, in relation to current debate
surrounding the utility of the SAD diagnoses.
These include the views that (i) SAD exists as the
mid-point on a continuum between SCZ and BD,
such that the incorporation of these two disorders
onto one [possibly aective, see (11)] dimension
may be a suitable alternative, or (ii) SAD represents a comorbid set of symptoms that occur as a
by-product of two separate disorders (SCZ and
BD). Arguably the weight of evidence from a range
of investigations (cognition, genetics and neurobiology) already favours the former view of SAD as
a point on a continuum of aective-psychotic
psychopathology, such that it may not be premature to suggest that the SAD diagnostic category be duly jettisoned from the DSM. In addition,
making sucient allowance for specifying aective
or psychotic symptoms within psychotic and
aective disorders respectively might assist in
better understanding the characteristics of the
apparent overlap between mood disorders and
SCZ-like disorders (Table 2 illustrates the potential
use of speciers in this regard). Thus far the
absence of pathophysiological evidence in support
of a denitive answer as to whether SAD, SCZ and
aective disorders are the same illness has permitted the ongoing use of an ill-dened category.

226

Hence, future research is unlikely to yield novel

insights unless greater clarity and consensus with
respect to the denition of mixed states of psychotic and aective symptoms is achieved. To
attain this it is may be necessary to rst adopt a
statistical approach whereby the null hypothesis is
that there is no separate SAD entity and then based
on this assumption examine and interrogate the
evidence from combined samples of SCZ, BD and
(as currently dened) SAD. The data that emerges
from this process should help determine which
model best explains clinical reality. Therefore, akin
to the speciers currently used to dene the
depressive and bipolar subtypes of SAD, aective
and psychotic symptoms can be identied within
SCZ and aective disorders respectively. Furthermore, enriching the DSM nosology with the
potential to diagnose mixed symptom states on
dimensional axes could aid in solving some of the
shortcomings of the current diagnostic system and
assist progress towards a clinically useful and
scientically valid psychiatric nosology.
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