Schizoaffective Disorder 2011

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Schizoaffective Disorder
LESLIE CITROME
CNS Drugs
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CNS Drugs 2011; 25 (4): 317-331
1172-7047/11/0004-0317/$49.95/0
REVIEW ARTICLE
ª 2011 Adis Data Information BV. All rights reserved.
Schizoaffective Disorder
A Review of Current Research Themes and Pharmacological
Management
Joshua T. Kantrowitz1,2 and Leslie Citrome3
1 Schizophrenia Research Center, Nathan S. Kline Institute for Psychiatric Research, Orangeburg,
New York, USA
2 Department of Psychiatry, Columbia College of Physicians and Surgeons, New York, New York, USA
3 Department of Psychiatry, New York University School of Medicine, New York, New York, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. History and Diagnostic Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Diagnostic Uncertainty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Current Research Themes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2 Neurocognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1 Comparisons of Schizoaffective Disorder with Schizophrenia . . . . . . . . . . . . . . . . . . . . . . .
3.2.2 Comparisons of Schizoaffective Disorder with Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . .
3.3 Basic Sensory Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Medical Co-Morbidities and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1 Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Pharmacological Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1 Monotherapy with Antipsychotics or Mood Stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2 Combination Treatment with Antipsychotics, Mood Stabilizers and/or Antidepressants . . . . . . .
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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Despite a clear recognition of the existence of patients with co-morbid
psychotic and mood symptoms, many studies conclude that schizoaffective
disorder as a distinct diagnosis does not exist. Regardless of one’s opinion on
schizoaffective disorder, psychiatrists remain dependent on phenomenological descriptions for diagnosing psychiatric disorders, and these phenomenological criteria are also used for clinical trial entry. On the other hand,
many psychiatrists prescribe for specific target symptoms and do not always
rigidly follow diagnostic systems and, moreover, there have been very few
trials that have specifically studied schizoaffective disorder.
Despite recent intriguing work in epidemiology, genetics, neurocognition
and electrophysiology, the diagnosis of schizoaffective disorder remains controversial. Taken together, these studies suggest that even if schizoaffective
disorder exists as a separate diagnosis, it may not be useful clinically due to
considerable variation in the general use of this term. It is possible that diagnostic
criteria in the future will include genetic, imaging and electrophysiological
Kantrowitz & Citrome
318
components, and that this will allow for better differentiation of disease states
among the heterogeneous pool of patients currently believed to have schizophrenia, schizoaffective disorder or bipolar disorder.
Although it is likely that most, if not all, antipsychotics are effective for
schizoaffective disorder, given recent regulatory approval of a specific antipsychotic agent for the acute treatment of schizoaffective disorder, greater
attention is now being focused on the entity of schizoaffective disorder and
potential treatment decisions. However, based on the limited extant evidence,
it is not yet possible to make definitive treatment recommendations for schizoaffective disorder. Additional clinical trials that include other antipsychotics,
mood stabilizers and antidepressants are desirable and necessary before clear
and comprehensive evidence-based treatment recommendations can be made.
Few psychotic disorders are as controversial as
schizoaffective disorder. As currently formulated
in the DSM-IV-TR,[1] the fundamental feature of
schizoaffective disorder is a continuous period of
illness during which criteria for a major mood
disorder (e.g. a major depressive episode, a manic
episode or a mixed episode) coincide with the essential features of schizophrenia. Although mood
symptoms must represent a prominent part of the
illness episode, there must be psychotic symptoms
(delusions or hallucinations) without prominent
mood symptoms for at least 2 weeks.
No one denies that patients with co-morbid
psychotic and mood symptoms exist. Nevertheless, as reviewed in section 2, many researchers
conclude that schizoaffective disorder does not
exist as a distinct diagnosis. There is a lack of consensus regarding whether the disease represents
a distinct clinical entity, if the symptomatology
represents the presence of a co-occurrence of two
distinct mental disorders in a single patient, or
if the disease represents a state in the psychotic
continuum that extends from bipolar to schizophrenia. There are several extant reviews that
argue for and against the legitimacy of schizoaffective disorder.[2-4]
Regardless of one’s opinion on schizoaffective
disorder, psychiatrists remain dependent on phenomenological descriptions for diagnosing psychiatric disorders, and these phenomenological
criteria are also used for clinical trial entry. On
the other hand, many psychiatrists prescribe for
specific target symptoms and do not always rigidly follow diagnostic systems and, moreover, as
ª 2011 Adis Data Information BV. All rights reserved.
detailed in the section on pharmacological treatment (section 5), there have been very few trials that
have specifically studied schizoaffective disorder.
This review focuses primarily on the current
research themes of schizoaffective disorder, and
begins by tracing the history and diagnostic criteria
of the schizoaffective diagnosis, and then proceeds
to reviewing diagnostic reliability, and preliminary
findings in genetics, medical co-morbidities, neurocognitive functioning and early sensory processing,
before concluding with a review of pharmacological treatment studies. PubMed was searched up to
June 2010 using the keywords ‘schizoaffective disorder’ for all English-language articles. In addition,
we examined the reference lists of review articles for
other reports of interest that may have been missed
by our initial search. Since the primary focus of this
review is to educate the reader on current research
themes, we placed a particular focus on research
published since 2006.
1. History and Diagnostic Criteria
In his landmark 1919 work,[5] Kraepelin divided psychotic and mood disorders into distinct
nosological entities. This division continues to
be useful in determining the course of mental
illnesses. Even at the time, however, it was recognized that there were instances where the major
mental illnesses could not be so easily subdivided.
In 1933, Dr Jacob Kasanin coined the term
‘schizoaffective psychosis’ based on a case series
of nine patients.[6] This group was distinguished
by an acute onset of illness, prominent manic
CNS Drugs 2011; 25 (4)
Schizoaffective Disorder: Research Themes and Pharmacological Management
and/or depressive symptomatology, active social
and pre-morbid personalities, and relatively brief
periods of psychosis lasting weeks to a few months
and good recoveries. In the US, schizoaffective
disorder did not appear as a separate diagnosis
with operationalized criteria until DSM-III-R in
1987.[7]
Current diagnostic criteria for schizoaffective
disorder in DSM-IV-TR emphasize the need for
concurrent mood and psychotic symptoms (see
pages 319–23 in DSM-IV-TR[1]). According to
DSM-IV-TR, schizoaffective disorder is defined
as a period of uninterrupted illness that includes
psychotic and mood symptoms. More specifically, Criterion A states that, at some point in
their illness, schizoaffective disorder patients must
meet criteria for a major mood episode (i.e. a
major depressive, manic or mixed episode) coexisting with symptoms that meet criterion A for
schizophrenia (i.e. delusions, hallucinations, grossly
disorganized behaviour, catatonic behaviour or
negative symptoms). Criterion B states that,
during the same episode that met criterion A,
delusions or hallucinations persisted for at least
2 weeks without prominent mood symptoms, and
Criterion C specifies that the mood symptoms
must be present for a substantial portion of the
total duration of the illness. Criterion C exists
to minimize the over-diagnosis of schizoaffective
disorder in a psychotic patient with limited concurrent mood symptoms. Schizoaffective disorder
may be further subdivided into two subtypes:
bipolar type, if a manic episode or mixed episode
is part of the presentation, and a depressive type,
if only major depressive episodes are part of the
presentation.
Other diagnostic schemes for schizoaffective
disorder exist, including the Research Diagnostic
Criteria (RDC)[8] and the International Classification of Diseases (10th Edition) [ICD-10][9]
(table I). Similar to other diagnostic schemes,
RDC includes two main subtypes, manic and
depressed, but also argues for additional subdivisions, such as acute versus chronic, mainly
schizophrenic and mainly affective, for each subtype. ICD-10 differs from DSM-IV primarily by
requiring specific types of delusions or commenting auditory hallucinations, and being somewhat
ª 2011 Adis Data Information BV. All rights reserved.
319
looser on requiring simultaneous psychotic and
mood symptoms. Regardless of which set of diagnostic criteria is used, the duration criteria for
both the mood and psychotic subcriteria can be
difficult to assess. More so than for other psychiatric disorders, schizoaffective disorder requires
access to longitudinal clinical data, sometimes
over several years.
2. Diagnostic Uncertainty
Although the DSM-IV field trials[13] suggested
good reliability for the diagnosis of schizoaffective disorder, more recent trials have found a lack
of consensus. This can be summarized by a recent
meta-analysis,[14] which failed to find a clear distinction between schizoaffective and schizophrenia
or major depressive disorder in demographic characteristics, symptoms, neuroimaging examinations,
response to treatment, illness course and family
morbidity. These findings are consistent with several reports published since this particular metaanalysis was undertaken. In a study by a group
from Denmark,[15] 59 patients with hospital discharge diagnoses of schizoaffective disorder were
re-reviewed using explicit criteria, with no patients meeting DSM-IV-TR criteria and only six
patients meeting ICD-10 criteria. The majority of
these patients were better characterized by schizophrenia (n = 22) or a primary affective illness
(n = 6). In a strongly worded conclusion, the authors called for a moratorium on the clinical use
of the diagnosis of schizoaffective disorder. This
was supported by an analysis of the 2.5 million
person Denmark registry.[16] In this large analysis, a large degree of co-morbidity was found
between schizophrenia, bipolar and schizoaffective disorders. Taken together, these studies suggest that, even if schizoaffective disorder exists
as a separate diagnosis, it may not be clinically
useful due to considerable variation in the general
use of this term.
While it is often stated that the prognosis for
a patient with schizoaffective disorder is intermediate between that of chronic schizophrenia and
that of bipolar disorder, several recent studies[17,18]
have not revealed any clear distinctions between
these three disorders in terms of longitudinal
CNS Drugs 2011; 25 (4)
Kantrowitz & Citrome
320
Table I. Diagnostic criteria for schizoaffective disorder
Source
Criteria
DSM-III[10]
Included as a psychotic disorder not otherwise classified. Retained without diagnostic criteria for those instances in
which the clinician is unable to make a differential diagnosis with any degree of certainty between Affective Disorder
and either Schizophreniform Disorder or Schizophrenia
DSM-III-R[7]
A. A disturbance during which, at some time, there is either a Major Depressive or a Manic Syndrome concurrent
with symptoms that meet criterion A for Schizophrenia
B. During an episode of the disturbance, there have been delusions or hallucinations for at least 2 weeks,
but no prominent mood symptoms
C. Schizophrenia has been ruled out, i.e. the duration of all episodes of a mood syndrome has not been brief relative
to the total duration of the psychotic disturbance
D. It cannot be established that an organic factor initiated and maintained the disturbance
Subtypes: Bipolar (current or previous Manic Syndrome) or Depressive (no current or previous Manic Syndrome)
DSM-IV[11] and
DSM-IV-TR[1]
A. An uninterrupted period of illness during which, at some time, there is either a Major Depressive Episode, a Manic
Episode or a Mixed Episode concurrent with symptoms that meet Criterion A for Schizophrenia
Note: The Major Depressive Episode must include Criterion A1: depressed mood
B. During the same period of illness, there have been delusions or hallucinations for at least 2 weeks in the absence
of prominent mood symptoms
C. Symptoms that meet criteria for a mood episode are present for a substantial portion of the total duration of the active
and residual periods of the illness
D. The disturbance is not due to the direct physiological effects of a substance (e.g. a drug of abuse, a medication)
or a general medical condition
Subtypes: Bipolar, if the disturbance includes a Manic or a Mixed Episode (or a Manic or a Mixed Episode and Major
Depressive Episodes); Depressive, if the disturbance only includes Major Depressive Episodes
ICD-9[12]a
A psychosis in which pronounced manic or depressive features are intermingled with schizophrenic features and which
tends towards remission without permanent defect, but which is prone to recur. The diagnosis should be made only
when both the affective and schizophrenic symptoms are pronounced
ICD-10[9]a
G1. The disorder meets the criteria for one of the affective disorders of moderate or severe degree, as specified for
each category
G2. Symptoms from at least one of the groups listed below must be clearly present for most of the time during a period
of at least 2 weeks (these groups are almost the same as for schizophrenia):
1. thought echo, thought insertion or withdrawal, thought broadcasting
2. delusions of control, influence or passivity, clearly referred to body or limb movements or specific thoughts,
actions or sensations
3. hallucinatory voices giving a running commentary on the patient’s behaviour or discussing the patient among
themselves, or other types of hallucinatory voices coming from some part of the body
4. persistent delusions of other kinds that are culturally inappropriate and completely impossible, but not merely
grandiose or persecutory, e.g. has visited other worlds, can control the clouds by breathing in and out, can
communicate with plants or animals without speaking
5. grossly irrelevant or incoherent speech, or frequent use of neologisms
6. intermittent but frequent appearance of some forms of catatonic behaviour, such as posturing, waxy flexibility
and negativism
G3. Criteria G1 and G2 above must be met within the same episode of the disorder, and concurrently for at least part
of the episode. Symptoms from both G1 and G2 must be prominent in the clinical picture
G4. The disorder is not attributable to organic mental disorder, or to psychoactive substance-related intoxication,
dependence or withdrawal
RDC[8]
An episode of illness that fulfils the criteria for a full depressive or manic syndrome but also has at least one of the
symptoms suggesting Schizophrenia. Signs of the illness have lasted at least 1 week from the onset of a noticeable
change in the patient’s usual condition. The affective syndrome overlaps temporally to some degree with the active
period of schizophrenia-like symptoms
a
Although ICD-9 and -10 are also available in modified versions, noted as ‘Clinical Modification’ (CM), these versions have not resulted in
any textual changes to the criteria for schizoaffective disorder.
ICD-9 = International Classification of Diseases (9th Edition); ICD-10 = International Classification of Diseases (10th Edition); RDC = Research
Diagnostic Criteria.
ª 2011 Adis Data Information BV. All rights reserved.
CNS Drugs 2011; 25 (4)
Schizoaffective Disorder: Research Themes and Pharmacological Management
course. According to one study,[17] a family history
of chronic schizophrenia, the occurrence of symptoms of schizophrenia at some stage of the illness in
the absence of depression and an onset of the index
episode as an exacerbation of previous symptoms
were associated with a relatively poor outcome,
while a personal history of previous manic episodes
was associated with a relatively good outcome. As
recently reviewed,[18] other predictors of poor outcome in schizoaffective disorder include poor premorbid functioning, absence of a precipitating factor,
predominance of psychotic symptoms, early age
at onset and poor inter-episode recovery.
One recent study[19] supports the notion that
schizoaffective disorder can be reliably differentiated
from bipolar disorder. Twenty-one DSM-III-Rdiagnosed schizoaffective bipolar type patients
were compared with 87 bipolar patients at first
episode after 12 months of stability. Patients with
schizoaffective disorder had more first-degree relatives with schizophrenia and a lower pre-morbid
functional level, and were more symptomatic
both at baseline and at follow-up. This study was
limited by a relatively short follow-up duration
of 1 year.
In contrast, in a German study,[20] 241 firstepisode patients meeting ICD-10 criteria for
schizophrenia, schizoaffective or affective disorders were examined at the time of first hospitalization and then followed up after 15 years.
Despite a clear distinction in presentation from
affective disorders during the first hospitalization, at the 15-year follow-up patients with schizoaffective disorders had a prognosis similar to that
of patients with affective disorders. However, a
report[21] using an overlapping sample found that
patients with schizophrenia were more likely than
patients with schizoaffective or bipolar disorder
to have severe social disability. Another study[22]
suggests that pre-morbid adjustment can help differentiate DSM-IV schizophrenia from schizoaffective disorder. Pre-morbid adjustment was
evaluated with the Premorbid Adjustment Scale;[23]
patients with schizophrenia showed worse premorbid adjustment than the patients with schizoaffective disorder.
In summary, while some smaller studies suggest that schizoaffective disorder can be longiª 2011 Adis Data Information BV. All rights reserved.
321
tudinally differentiated from schizophrenia and
affective disorders, most studies have not revealed
any clear distinctions.
3. Current Research Themes
While phenomenological descriptions remain
the only realistic option at present for diagnosing
psychiatric disorders, novel research is being done
to attempt to distinguish schizoaffective disorder
from other disease states. Although this research
remains too preliminary to be used clinically at
present, it may be possible in the future to harness
genetic, neurocognitive or neurophysiological biomarkers to identify patients with schizoaffective
disorder who may benefit from specific treatments.
3.1 Genetics
The controversy surrounding schizoaffective
disorder extends to genetic linkage studies. As recently reviewed,[24] a complete genetic distinction
between affective and psychotic illnesses is not
supported by the data. However, there is preliminary evidence for a relatively specific genetic
susceptibility for DSM-IV- or RDC-defined schizoaffective disorder. As described below, the
various studies do not always show consistent
results for specific genes. These inconsistent findings may be due to false positives or the varying
diagnostic methodologies used. Further research
is clearly needed.
One of the first attempts to specifically search
for schizoaffective disorder linkages included a
small sample of families in which one patient had
DSM-IV schizoaffective disorder, bipolar type.[25]
A statistically significant signal was seen at chromosome 1q42, with suggestive trends seen for
chromosomes 22q11 and 19p13. While the same
group found no linkages in these regions among
their patients with schizophrenia or bipolar disorder, the chromosome 1 location was near to the
disrupted in schizophrenia 1 (DISC1) gene, which
has been associated with schizophrenia and bipolar disorder in other studies.[26] Chromosome
22q11 has also been associated with schizophrenia
in other studies,[27] but this was the first report of
an association with 19p13. In another study by a
CNS Drugs 2011; 25 (4)
Kantrowitz & Citrome
322
different research group,[28] the calreticulin gene
on chromosome 19 was identified as a possible
gene of interest. This finding awaits replication,
and is particularly intriguing because calreticulin
has been linked to the mechanism of action of
valproate and lithium.[29]
In a recent report[30] of a large sample from
the Wellcome Trust Case Control Consortium bipolar disorder genome-wide association data set
(1868 patients with bipolar disorder and 2938 controls, as defined by the Wellcome Trust Case Control Consortium[31]), RDC-defined schizoaffective
disorder, bipolar type (vs controls) showed multiple association signals, including a replication
of a previous association with GABAA receptor
genes for the bipolar phenotype.[32] The strongest
association signal occurred on chromosome 21
within the gene B3GALT5 (a member of the
b-1,3-galactosyltransferase gene family that encode type II membrane-bound glycoproteins with
diverse enzymatic functions), a gene that had not
been previously implicated in the pathophysiology
of mood or psychotic illnesses. Another strong
association was seen at chromosome 16p13.3
(A2BP1/FOX1 gene, encoding ataxin 2-binding
protein 1 isoform 4). Disruptions of this gene have
been associated with autism, mental retardation
and epilepsy. Other less strongly associated genes
include BSN, a gene essential in regulated neurotransmitter release from a subset of cerebral glutamatergic synapses; PTPRG, encoding a member of
the protein tyrosine phosphatase family; GRIK2,
encoding glutamate receptor 6; and CDH12, encoding cadherin 12, type 2, which is important for
mediating calcium-dependent cell-cell adhesion.
Another study[33] found evidence for a specific
linkage of the gene BDNF, which encodes brainderived neurotrophic factor, in schizoaffective
disorder. This gene has been more commonly
associated with mood, rather than psychotic disorders. In this study, which used DSM-IV criteria, individuals with mood disorders, as well as
schizoaffective disorder, were significantly more
likely to carry two copies of the most common
BDNF haplotype compared with healthy controls
or patients with schizophrenia.
In summary, these genetic studies indicate the
need for additional investigative work, but geª 2011 Adis Data Information BV. All rights reserved.
netic testing is not yet useful as a clinical tool for
characterizing schizoaffective disorder.
3.2 Neurocognition
The neurocognitive deficits associated with
schizophrenia often begin to develop in the years
immediately preceding the onset of frank psychotic symptoms, and represent a primary predictor of poor long-term outcome.[34,35] The
importance of cognitive dysfunction as a pharmacological target in schizophrenia has been
increasingly appreciated over recent years, as exemplified by National Institute of Mental Health
(NIMH)-initiated programmes such as MATRICS
(Measurement And Treatment Research to Improve Cognition in Schizophrenia) and TURNS
(Treatment Units for Research on Neurocognition
and Schizophrenia).[36,37] Although most studies
treat schizophrenia and schizoaffective disorder as
one group, a few studies have directly compared
schizoaffective disorder with schizophrenia or bipolar disorder.
3.2.1 Comparisons of Schizoaffective Disorder
with Schizophrenia
An initial attempt to examine differences in
neuropsychological functioning was conducted
in 1981,[38] finding few differences between RDCdiagnosed schizoaffective and affective patients
in performance on attentional tasks, but finding
that schizophrenia patients performed worse. Since
then, a number of studies have found conflicting
answers to the question of whether patients diagnosed with schizoaffective disorder can be distinguished from those with schizophrenia using
neuropsychological testing, as outlined below.
Studies Finding Superior Performance
in Schizoaffective Disorder
Using a more comprehensive cognitive battery, one study[39] found that RDC-diagnosed
schizoaffective disorder, depressed type patients
performed intermediately compared with patients
with unipolar depression or schizophrenia. These
results were further supported by findings with
DSM-III-R-diagnosed schizophrenia and schizoaffective disorder patients,[40] in which the schizoaffective and paranoid schizophrenia subjects
CNS Drugs 2011; 25 (4)
Schizoaffective Disorder: Research Themes and Pharmacological Management
tended to have fewer deficits, and perform at an
intermediate level between the healthy controls and
the subjects with schizophrenia subtypes, other
than paranoid. Schizoaffective disorder patients
may be particularly superior in temporal lobedependent cognitive functions, such as delayed
recall.[41]
Additional studies have found superior neurocognitive performance for schizoaffective disorder
patients compared with subjects with schizophrenia. One trial[42] compared 13 DSM-IV schizoaffective disorder patients with 44 schizophrenia
patients on several visuomotor tasks using the
Cambridge Neuropsychological Test Automated
Battery. The two groups were matched for symptom severity by the Positive and Negative Syndrome Scale (PANSS), and testing was repeated
after 2 years to test for divergence in performance
between the two groups. A significant divergence
was observed on visuospatial and visuomotor coordination abilities (e.g. paired associated learning and motor screening), with schizoaffective
patients performing better.
A 2005 study[43] compared 20 patients with
schizoaffective disorder with patients with paranoid (n = 20), undifferentiated (n = 29) and residual (n = 14) subtypes of schizophrenia, diagnosed
by DSM-III-R on a number of cognitive measures, including the Wechsler Adult Intelligence
Scale: 35% and 25% of the schizoaffective and
paranoid patients, respectively, were ‘‘neuropsychologically normal’’ on a cluster analysis. In
contrast, undifferentiated and residual subtype
patients performed significantly worse.
Finally, in a study of matched groups of schizophrenia patients, schizoaffective disorder patients
and healthy controls consisting of 14 subjects each,
patients with schizophrenia exhibited pronounced
impairments of both verbal and visuospatial working memory, whereas verbal working memory
performance was preserved in patients with schizoaffective disorder.[44] The findings of intact verbal
working memory in the presence of impaired spatial working memory suggested that schizoaffective
disorder patients may have preserved articulatory
rehearsal. This may represent a specific biomarker
for schizoaffective disorder, but would need to be
replicated in a larger sample.
ª 2011 Adis Data Information BV. All rights reserved.
323
Studies Finding Equivalent Performance
in Schizoaffective Disorder
In contrast, most larger studies have found few
differences between the disorders in terms of
neurocognitive testing.[45-48] A relatively large
2007 study[49] using DSM-IV criteria also found
schizoaffective disorder patients to perform statistically similarly to schizophrenia on most tasks.
In this study, 199 schizophrenia patients and
73 schizoaffective disorder patients were compared on measures of executive function, verbal
and nonverbal memory, and processing speed,
as well as two measures of social cognition
(the Hinting Task and the Bell Lysaker Emotion
Recognition Task). With the exception of the
Hinting Task, a measure of ‘Theory of Mind’,
schizoaffective patients did not differ significantly
on the cognitive measures. Another large study[50]
using DSM-IV criteria, included 103 outpatients
with a diagnosis of schizophrenia, 48 with schizoaffective disorder and 72 healthy controls from
the community who were tested on the Wechsler
Adult Intelligence Scale, the California Verbal
Learning Test, the Controlled Oral Word Association Test and the Reading subtest of the Wide
Range Achievement Test. Despite a finding of a
relative impairment for schizophrenia patients on
all cognitive measures, there was no statistical
evidence for the unique predictive validity of
any specific cognitive task. Group differences in
cognitive performance were considered to be insufficient to separate schizoaffective and schizophrenia patients. Finally, among the adolescents
with early-onset schizophrenia and schizoaffective disorder in the TEOSS (Treatment of Early
Onset Schizophrenia Spectrum) study,[51] both
groups had similar levels of neuropsychological
impairment.
Summary of Findings
Conflicting evidence has been presented in this
section, but it is notable that the studies that did
not find clear distinctions were considerably larger.
Given the different tests used, it is impractical to
directly and systematically compare the studies,
but at present there is little evidence to distinguish
schizophrenia from schizoaffective disorder on a
neuropsychological basis.
CNS Drugs 2011; 25 (4)
Kantrowitz & Citrome
324
3.2.2 Comparisons of Schizoaffective Disorder
with Bipolar Disorder
Patients with bipolar disorder have traditionally been thought of as being more cognitively
and functionally intact than patients with schizophrenia. This belief has been supported by some
meta-analyses that suggest that, despite similar
impairments in some cognitive domains (e.g. executive function, visual memory), patients with
schizophrenia demonstrate more severe and enduring impairments.[52] However, other, more recent meta-analyses[53,54] do not support such a
clear distinction.
Similar inconsistencies are found when schizoaffective disorder is directly compared with bipolar disorder. One older study[55] found no
significant differences in social and role functioning between DSM-III-R schizoaffective disorder, bipolar disorder and schizophrenia patients
who were otherwise comparable on dimensions
such as duration and severity of illness. A more
recent study[56] comparing 34 DSM-IV schizoaffective disorder patients with 41 bipolar disorder
patients without a history of psychosis and 35
healthy controls on several clinical, occupational
and neuropsychological variables found that patients with schizoaffective disorder demonstrated
greater impairment than that observed with controls and nonpsychotic bipolar disorder patients.
This was seen in several domains, including verbal
memory, executive function and attentional measures. Patients with bipolar disorder performed
similarly to the control group except for verbal
fluency. Similarly, in a study[57] of the Wisconsin
Card Sorting Test (WCST) and the Trail-Making
Test (TMT) using DSM-IV criteria, schizoaffective disorder patients performed at a level that was
intermediate between schizophrenia and bipolar
disorder patients in the number of perseverative
errors on the WCST, but on the TMT the patients
with schizoaffective disorder and schizophrenia
performed similarly. Most recently,[58] it was observed that euthymic schizoaffective patients had
similar cognitive functioning (declarative memory
and attention) to bipolar patients when demographic and clinical variables were controlled for.
Much like the comparisons with schizophrenia,
because of the conflicting studies it remains unª 2011 Adis Data Information BV. All rights reserved.
clear at present whether it is possible to distinguish patients with schizoaffective disorder from
those with bipolar disorder on the basis of neuropsychological testing.
3.3 Basic Sensory Processing
Impairments in neurocognition are often closely associated with deficits in early sensory processing and basic neurophysiology.[59] Because of
their high temporal resolution and non-invasive
nature, the EEG and event-related potentials are
excellent measures of the suspected neurophysiological dysfunction. Neurophysiological deficits
are often highly heritable, stable across time and
well validated across populations, and thus represent potential endophenotypes. For example,
deficits in basic auditory processing are well established in schizophrenia,[60,61] with robust effect
sizes across both studies. Basic sensory processing deficits have also been found in bipolar disorder.[62] It would therefore be expected that
some deficits would also be found in schizoaffective disorder, and a few studies have looked at
whether any basic sensory deficits are specific to
schizoaffective disorder. An early attempt to use
electrophysiology to differentiate schizoaffective
disorder (using ICD-10 criteria) found no clear
distinctive features from schizophrenia.[63] More
recently, some well validated measures, such as
P50 gating, the auditory steady-state response
(ASSR) and P300 have been specifically studied
in schizoaffective disorder.
P50 is an early auditory potential reflecting initial sensory activation. Gating refers to the decreased P50 amplitude to the second stimulus in
a paired click compared with the first, e.g. ‘gating
out’ of particular sensory information.[59] One
preliminary study[64] examined three endophenotypes (suppression of P50 auditory evoked responses, inhibition of leading saccades during
smooth pursuit eye movements and cancellation
of reflexive saccades in the antisaccade eye movement task) in patients with DSM-IV-TR schizophrenia (n = 29), bipolar disorder (n = 40) and
schizoaffective disorder, bipolar type (n = 18).
The schizophrenia and bipolar disorder groups
were clearly distinguishable, with the schizoCNS Drugs 2011; 25 (4)
Schizoaffective Disorder: Research Themes and Pharmacological Management
phrenia group more impaired. Six schizoaffective
disorder patients were classified as schizophrenialike and 12 were more similar to the bipolar disorder patients. The schizophrenia-like patients
were significantly younger at illness onset and
had higher symptom levels.
A smaller study[65] reviewed ASSR in schizoaffective disorder. ASSR is the response to auditory stimuli delivered at a repetition rate of 40 Hz.
Auditory stimulation at 40 Hz entrains the auditory neocortex at the stimulation rate[66] and may
be a biomarker of schizophrenia and impaired
cognition. In this preliminary study,[65] eight patients with DSM-IV-diagnosed schizoaffective disorder were found to have an ASSR that was similar
to healthy controls and dissimilar to schizophrenia
patients.
Finally, P300 reflects neurophysiological processes associated with processing infrequent target, novel or otherwise salient stimuli. In another
preliminary study,[67] 15 DSM-IV-diagnosed schizoaffective patients were compared with 22 healthy
controls and 22 schizophrenia patients. Schizoaffective patients exhibited normal P300 amplitudes
that were significantly larger than in schizophrenia
patients and indistinguishable from controls. The
differences between the two patient groups did not
appear to be accounted for by demographic or
symptomatic factors.
In conclusion, while remaining too preliminary for general clinical use at present, these findings, if replicated in larger studies, point towards
the potential for real differences in the neurophysiology and genetics of schizoaffective disorder.
4. Medical Co-Morbidities and Cancer
Schizophrenia has been associated with poor
physical health, including higher rates of obesity,
diabetes mellitus, hypertension, metabolic syndrome and cardiovascular disease.[68] This risk is
multifactorial, involving shared vulnerability, genetic factors and an unhealthy lifestyle, as well as
the potential impact of antipsychotics. In a review
of the literature,[69] patients with schizophrenia
had a higher prevalence of HIV infection and
hepatitis, osteoporosis, altered pain sensitivity,
sexual dysfunction, obstetric complications, cardioª 2011 Adis Data Information BV. All rights reserved.
325
vascular diseases, overweight, diabetes, dental problems and polydipsia than the general population.
Of interest, rheumatoid arthritis and cancer may
occur less frequently among patients with schizophrenia than in the general population. The question remains whether these characteristics are also
observed in patients with schizoaffective disorder.
4.1 Metabolic Syndrome
Cardiovascular disease and the metabolic syndrome are a particular problem among patients
with schizophrenia.[68] It appears that patients
with bipolar disorder and schizoaffective disorder are also at risk. These co-morbidities were
the focus of a database study[70] of 7529 male
patients (mean age 54.5 years) using ICD-9 criteria. Compared with patients with schizophrenia, those with bipolar disorder were 19%
more likely to have diabetes, 44% more likely to
have coronary artery disease and 18% more likely
to have dyslipidaemia, after controlling for age,
race and tobacco use with a multivariable logistic-regression. Patients diagnosed with schizoaffective disorder were 36% more likely than those
with schizophrenia to be diagnosed with dyslipidaemia and 30% more likely to be obese.
In a retrospective study of the medical records
of 243 older (aged 50–74 years) inpatients admitted to the University of Maryland Medical
Center (Baltimore, MD, USA) from January 1993
to July 1999, with DSM IV diagnoses of major depression, bipolar I disorder, schizoaffective disorder, schizophrenia or dementia, type 2 diabetes
rates were significantly higher in schizoaffective
disorder (50%) than in both bipolar I disorder
(26%) and schizophrenia (13%).[71] A logistic regression found that psychiatric diagnosis and
body mass index were the only significant and independent predictors of diabetes diagnosis. Type
of medication use was not a significant predictor.
Compared with national norms, diabetes rates
were significantly elevated only in bipolar I disorder and schizoaffective disorder patients.
4.2 Cancer
Compared with healthy controls, cancer may occur less frequently in patients with schizophrenia[72]
CNS Drugs 2011; 25 (4)
Kantrowitz & Citrome
326
and more frequently in those with bipolar disorder.[73] However, a recent study[74] suggests that,
compared with the general Jewish-Israeli population, patients with ICD-10 schizoaffective disorder
had no significant alteration in cancer risk. Factors
such as diet, smoking and medications were not
investigated. If confirmed, these findings could
further point to lifestyle or genetic differences between the populations.
In any event, studies that have co-mingled patients
with schizophrenia and schizoaffective disorder
are still mentioned in product labelling for several
second-generation antipsychotics. Additionally,
since schizoaffective disorder had been considered
a subtype of schizophrenia until the release of
DSM-III in 1980,[10] it is likely that studies used
as evidence to support the commercialization of
first-generation antipsychotics included patients
with schizoaffective disorder.
5. Pharmacological Treatment
The diverse array of symptoms encountered in
patients with schizoaffective disorder has led to
the use of potential treatment options from multiple pharmacological classes (e.g. antipsychotics,
mood stabilizers and antidepressants). Because of
difficulties with diagnostic uncertainty, there
have been few clinical trial reports focusing specifically on patients with schizoaffective disorder.
Those that do exist have generally been post hoc
subgroup analyses of larger schizophrenia trials
that included patients with schizoaffective disorder, bipolar type or schizoaffective disorder,
depressed type, or both. For studies published up
to and including 2007, we refer the reader to a
thorough narrative review by Jäger et al.[75] In
their search of MEDLINE, the Cochrane Database of Systematic Reviews, European Public
Assessment Reports (EPAs) and Drugs@fda,
only 33 articles were found that used widely accepted diagnostic criteria and reported separate
results for patients with schizoaffective disorder.
In a conclusion that aptly summarizes the inherent difficulties of the task, Jäger et al.[75] stated
that while ‘‘antipsychotics and mood stabilizers
appear to be effective y it is not possible to provide conclusive guidelines for clinical decision
making. Diagnostic confusion is likely to exacerbate therapeutic confusion.’’
The US FDA now considers schizoaffective
disorder as a bonafide diagnostic entity, and has
approved a specific agent, paliperidone, for its
pharmacological treatment.[76] Moreover, the FDA
has handled recent new drug approvals for antipsychotics by clearly separating schizophrenia
from schizoaffective disorder when both groups
have been included in the same registration trial.[77]
ª 2011 Adis Data Information BV. All rights reserved.
5.1 Monotherapy with Antipsychotics
or Mood Stabilizers
To further summarize Jäger et al.,[75] six
randomized, double-blind clinical trials of antipsychotics were found[78-83] that separately analysed patients with schizoaffective disorder. The
only analysable placebo-controlled trial involved
ziprasidone.[79] At a dosage of 160 mg/day, ziprasidone was more effective than placebo in improving mean Brief Psychiatric Rating Scale (BPRS)
total, several BPRS subfactors and the Clinical Global Impression-Severity (CGI-S) scale. At
120 mg/day, ziprasidone was significantly more
effective than placebo in improving mean CGI-S
scores as well. The other trials compared active
treatments, including comparisons of olanzapine
with haloperidol,[78,80,81] risperidone with haloperidol[82] and fluphenazine with lithium.[83]
Olanzapine[78,80,81] and fluphenazine[83] were statistically superior to haloperidol and lithium,
respectively. Risperidone appeared to have fewer
adverse effects than haloperidol, although there
was no obvious difference in efficacy outcomes.[82]
Two randomized trials that tested mood stabilizers were found, both evaluating maintenance
treatment. Only one was double-blind, the aforementioned trial in which fluphenazine was shown
to be superior to lithium.[83] The only other
randomized trial[84] found carbamazepine to be
superior to lithium in patients with RDC schizoaffective disorder depressive or non-classifiable
subtypes, but equivalent to lithium in RDC schizomanic disorders.
Only a few trials have been reported since the
Jäger et al.[75] review. Aripiprazole was recently
the subject of a pooled post hoc analysis, which
CNS Drugs 2011; 25 (4)
Schizoaffective Disorder: Research Themes and Pharmacological Management
suggested efficacy for schizoaffective disorder.[85]
The pooled analysis was from a subsample of
schizoaffective patients from two separate trials
comparing aripiprazole with placebo.[86,87] Much
like the original analysis of the full sample, a
significantly greater between-group improvement
was noted for aripiprazole versus placebo on
the PANSS Total score (-15.9 vs -3.4; p = 0.038)
and on the three-factor PANSS Positive subscale
(-4.6 vs -1.0; p = 0.027), but not on the threefactor Negative or General subscales. There were
no statistically significant differences between
groups in the mean change from baseline to endpoint in weight, glucose or total cholesterol levels,
or in extrapyramidal symptom scales. There was
a statistically significant decrease in prolactin levels
in subjects treated with aripiprazole compared
with placebo.
Most recently, paliperidone, the 9-hydroxy
metabolite of risperidone,[88-90] became the first
medication expressly approved by the FDA with
an indication for the acute treatment of schizoaffective disorder, both as monotherapy and as
an adjunct to mood stabilizers and/or antidepressants.[91] This indication is based on two randomized controlled trials.[92,93]
Although paliperidone was the first to be approved, it should be noted that all antipsychotics,
both typical and atypical, can reduce the intensity
and frequency of symptoms of schizophrenia.
Moreover, many, if not most, antipsychotics can
also reduce the symptoms of bipolar disorder.
Thus, the finding that paliperidone can be therapeutic for schizoaffective disorder is not a
surprise. It is probable that other first- and secondgeneration antipsychotics are also efficacious for
the treatment of schizoaffective disorder.
5.2 Combination Treatment with
Antipsychotics, Mood Stabilizers
and/or Antidepressants
Patients with bipolar disorder often receive
combination treatment with an antipsychotic and
a mood stabilizer. Several of these combinations
are FDA approved for the indication of bipolar
mania and/or bipolar maintenance. Hence, it
would not be surprising that patients with schizoª 2011 Adis Data Information BV. All rights reserved.
327
affective disorder would also receive combination treatments. However, only four double-blind
trials[94-97] were identified by Jäger et al.[75] that
focused on the acute treatment of schizoaffective
disorder. In one study, topiramate did not statistically separate from placebo as an add-on to
lithium, valproate or antipsychotics.[97] However,
lithium was superior to placebo in combination
with haloperidol[94] or antipsychotics in general.[95]
In a trial involving a combination approach with
an antidepressant medication, haloperidol combined with amitriptyline was superior to risperidone alone.[96] No relevant trials of combination
therapy have been published since the Jäger et al.[75]
review.
6. Conclusions
Despite recent intriguing work in genetics,
neurocognition and electrophysiology, the diagnosis of schizoaffective disorder remains controversial. Much of the controversy stems from the
limited specificity of current diagnostic schemes,
which rely on phenomenological anchors. Even
in the hands of well trained and conscientious
clinicians, it is often difficult to obtain the needed
records and history to make a precise diagnosis.
As reviewed, it is possible that diagnostic criteria
in the future will include genetic, imaging and
electrophysiological components, and that this
will allow for better differentiation of disease
states among the heterogeneous pool of patients
currently believed to have schizophrenia, schizoaffective disorder or bipolar disorder.
Beyond these diagnostic issues, the crucial issues
for clinicians treating patients with schizoaffective
disorder are treatment and prognosis. High vigilance
for coexisting medical problems is also important.
On average, it seems that a carefully diagnosed
patient with schizoaffective disorder may have a
prognosis that is intermediate between schizophrenia and bipolar disorder. A caveat is that
there is considerable variation in how the term
schizoaffective disorder is actually used outside
of research settings, and it behoves the clinician
to accurately characterize a patient’s past history.
Given the FDA’s approval of a specific antipsychotic agent for schizoaffective disorder, greater
CNS Drugs 2011; 25 (4)
Kantrowitz & Citrome
328
attention is currently being focused on the entity of
schizoaffective disorder and potential treatment decisions. At present, given the uncertainty surrounding the diagnosis, it is premature to recommend
particular agents as being specifically beneficial in
schizoaffective disorder. Additional clinical trials
that include other antipsychotics, mood stabilizers
and antidepressants are desirable and necessary
before definitive specific and comprehensive treatment recommendations can be made.
Acknowledgements
Joshua Kantrowitz has conducted clinical research supported by Roche, Sepracor, Jazz Pharmaceuticals, Novartis,
Pfizer and GlaxoSmithKline. He and/or his spouse own a
small number of shares of common stock in GlaxoSmithKline.
Leslie Citrome is a consultant for, has received honoraria
from or has conducted clinical research supported by Abbott
Laboratories, AstraZeneca Pharmaceuticals, Avanir Pharmaceuticals, Azur Pharma Inc., Barr Laboratories, BristolMyers Squibb, Eli Lilly and Company, Forest Research
Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz
Pharmaceuticals, Merck/Schering-Plough Corporation, Novartis,
Pfizer Inc., Sepracor and Vanda Pharmaceuticals. He and/or his
spouse own a small number of shares of common stock in BristolMyers Squibb, Cardinal Health Inc., Carefusion Corp., Eli Lilly
and Company, Johnson & Johnson, Pfizer Inc., Medco Health
Solutions and Merck.
No writing assistance or external financial support was
utilized in the production of this article.
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Correspondence: Dr Joshua T. Kantrowitz, Schizophrenia
Research Center, Nathan S. Kline Institute for Psychiatric
Research, 140 Old Orangeburg Road, Orangeburg, NY
10962, USA.
E-mail: [email protected]
CNS Drugs 2011; 25 (4)