European Neuropsychopharmacology (2011) 21, 680690

www.elsevier.com/locate/euroneuro

REVIEW

What we know and what we don't know about the

treatment of schizoaffective disorder
A. Murru, I. Pacchiarotti, A.M.A. Nivoli, I. Grande, F. Colom, E. Vieta
Bipolar Disorders Programme, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain

Received 29 October 2010; received in revised form 24 February 2011; accepted 2 March 2011

KEYWORDS
Schizoaffective disorder;
Treatment;
Clinical trials;
Antipsychotics;
Mood stabilizers;
Mania;
Depression

Abstract
Schizoaffective disorder (SAD) is a chronic, severe and disabling illness consisting on the concurrent
presentation of symptoms of schizophrenia and affective disorders (depression and/or mania).
Evidence for the treatment of SAD mostly derives from studies based on mixed samples (i.e.
schizophrenic and schizoaffective patients) or on extrapolations from studies on schizophrenia or
bipolar disorder. The objective of the present review is to systematically consider and summarize the
best evidence-based approaches to the treatment of SAD and extensively point out the gap between
treatment research and clinical practice of this disorder. The complex problem of controlling the
pleomorphic presentation of SAD's syndromic construct is reflected in the lack of evidence on key
topics, including: diagnostic consistency, pharmacological approaches (mood stabilizers, antidepressants, both in acute and maintenance treatment as well as their possible combination), and the
adjunctive role of psychosocial and biophysical interventions. Finally, treatment strategies for SAD,
both unipolar and bipolar type, are proposed.
2011 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction
Schizoaffective disorder (SAD) is a chronic, severe and
disabling illness consisting on the concurrent presentation
of symptoms of schizophrenia and affective disorders. The
occurrence of a full major depressive, manic or mixed

Corresponding author. Tel.: +34 932275400; fax: +34 932275795.

E-mail address: evieta@clinic.ub.es (E. Vieta).

episode with symptoms that meet criteria for schizophrenia

and the persistence of delusions or hallucinations for at least
2 weeks during the euthymic phase are the diagnostic
features of SAD according to DSM-IV-TR (APA, 2000).
During the early stages of the illness, or when considering
only cross-sectional clinical criteria, the differential diagnosis
of psychoses is more complex than was formerly thought
(Gonzlez-Pinto et al., 1998). From a longitudinal perspective,
SAD presents as an intermediate form of psychotic disorder
between schizophrenia and bipolar disorder (Benabarre et al.,
2001), but it may account for up to one-quarter of admissions
to acute units (Kent et al., 1995).

0924-977X/$ - see front matter 2011 Elsevier B.V. and ECNP. All rights reserved.
doi:10.1016/j.euroneuro.2011.03.001

What we know and what we don't know about the treatment of schizoaffective disorder
The lack of conclusive specific data on the biology and
course of SAD bears therapeutic consequences. Treatment
guidelines which consider SAD subgroups mostly reflect the
inclusion of SAD patients in studies designed for schizophrenic
samples, being a treatment with antipsychotic, alone or in
combination with mood stabilizers or antidepressants, the most
common treatment strategy (Cascade et al., 2000). An optimal
treatment management should be based on specifically tailored
studies, but at present state it is only rarely possible to base
clinical practice on standalone or adjunctive trials, placebocontrolled or comparative, or on pooled- and sub-analyses of
schizoaffective samples extracted from wider studies. More
frequently data come from mixed samples (generally schizophrenia plus schizoaffective), or from indirect evidence,
extrapolated from the data of trials on schizophrenic (Levinson
et al., 1999; RANZCP, 2005) and bipolar samples (Mensink and
Slooff, 2004). Large observational studies also exist (Vieta et al.,
2001). On the other hand, there is an absolute absence of
specific treatment guidelines, which reflects a substantial
scarcity of diagnosis-specific evidence-based treatment. Most
of the studies produced so far on SAD treatment suffer from high
heterogeneity of the samples included, reflecting a different
diagnostic criteria used, as reported in a past systematic review
(Jger et al., 2010a,b).
Being so difficult to establish a syndrome-based treatment
plan, clinicians usually find themselves focusing on symptoms,
ending up managing both the psychotic and affective dimensions
with complex therapies (Levinson et al., 1999) based on the
combination of antipsychotics and mood stabilizers (Olfson
et al., 2009).
The main goal of the present review is to critically
consider and summarize the best evidence-based approaches
to the treatment of SAD. According to the results of the
review, we propose treatment strategies for SAD, both for
bipolar and unipolar type.

681

2. Methods
Systematic review on randomized, double blind, placebo-controlled
trials specifically tailored for the treatment of SAD. Post-hoc pooledor sub-analyses on the data concerning SAD patients in randomized,
double blind, placebo-controlled trials originally designed for the
treatment of schizophrenic or bipolar populations were also
reviewed.

2.1. Study samples

Based on the contrast between the great amount of indirect evidence
from studies on different populations (i.e. schizophrenia, psychosis,
psychotic first episodes and bipolar disorder), and its lack of clear
evaluation of the schizoaffective populations, the authors divided the
sources of potential interests according to the scheme presented in
Fig. 1. Subsequently, the authors decided to consider for review only
double blind, randomized, controlled trials (RCTs) based exclusively on a
schizoaffective population: standalone trials or post-hoc pooled- and
sub- analyses on schizoaffective samples from different studies. All RCTs
on acute or maintenance treatment that investigated the efficacy and/
or tolerability of any drug treatment tested for SAD populations were
eligible for reviewing. Non-RCT studies were excluded from this review.
Only English-language articles having undergone peer review were
considered in the present report. Duplicated publications of trials were
identified, so that only data from a single study were included in the
present review.

2.2. Literature search

A systematic search concerning RCTs was performed using MEDLINe/
PubMed/Index Medicus, PsycINFO/PsycLIT, Excerpta Medica/EMBASE,
considering a time period ending on 15th of June, 2010. A cross-check
between references obtained was done. A further search was performed
in the site www.clinicaltrials.gov and www.clinicaltrialsresults.org to
check the literature results and to get information on eventually started,
ongoing, or concluded trials on SAD samples yet to be finished.

Figure 1 Evidence base from randomized control trials on the treatment of schizoaffective disorder. RCTs = Randomized Controlled
Trials; Post-Hoc = pooled or sub-analyses, from trials including schizoaffective and not-schizoaffective patients, considering
schizoaffective patients only; PBO = Placebo; Mono = monotherapy; Adj = adjunctive therapy; and Tot = total.

682
-Literature search. The authors searched for placebo-controlled
trials as well as for studies with an active comparator. To find studies
with SAD patients included in the samples, potentially leading to
published pooled analyses, authors used the keywords schizoaffective
disorder combining with treatment, using 3 search limits in the type
of article section: controlled trial, meta-analysis, and randomized controlled trial. To find standalone trials the specifier [title] was
used following the keywords schizoaffective disorder.
Crosscheck with CLINICAL TRIALS. Keywords were
schizoaffective disorder.
-Crosscheck with CLINICAL TRIAL RESULTS. Study indication
specifiers were: schizophrenia and schizoaffective disorder,
schizophrenia or schizoaffective disorder, and schizoaffective
disorder, schizophrenia, and schizophreniform disorder.

2.3. Data extraction

The first step was to decide, on the basis of the abstract or full text,
whether the article was a RCT on the treatment of SAD or not. The
paper should report details on design, sample description, inclusion/
exclusion criteria, outcome measures, and adverse events. Each
citation was individually reviewed to identify further possible RCTs
of interest. Data were classified in three groups: 1. Data of interest,
2. Duplicated data and 3. Data of no interest, according to the
previously described criteria. RCT were then classified into those
concerning standalone trials and pooled analyses. In the CLINICAL
TRIALS literature search, authors found a study specifically tailored
on SAD-diagnosed patients on the use of mifepristone (study ID:
NCT00725270, last updated on June 2009), but no access to the data
was granted, so that it was not considered for reviewing.

3. Results and discussion

3.1. Systematic search results
The search returned 2387 papers concerning RCTs on samples
in which SAD patients were included. The great majority of
them had to be excluded as they were opinion or review
papers, observational and open studies. At last, only a small
minority of papers fulfilled our inclusion criteria and could be
considered as RCTs on lithium monotherapy in maintenance
treatment for bipolar disorder. The final selection included 6
studies, namely: 3 standalone trials (Janicak et al., 2001;
Chengappa et al., 2007; Canuso et al., 2010), and 3 pooled
analyses on SAD patients (Tran et al., 1999; Keck et al., 2001;
Glick et al., 2009a).
Crosscheck with CLINICAL TRIALS search: it returned 385
articles, which underwent further examination.
Crosscheck with CLINICAL TRIAL RESULTS search: it
returned a total of 14 trials, 3 phase IV, 9 phase III, 2 phase
II. None of them considered separate SAD diagnosed patients
in the samples.
Final literature results are summarized in Table 1.

3.2. Results
3.2.1. What we know
All analyzed studies were recent multicenter, parallel group
RCTs, which assessed the efficacy and tolerability of sponsored
drugs in a schizoaffective sample. Drugs tested include
olanzapine (Tran et al., 1999), ziprasidone (Keck et al., 2001),
risperidone, (Janicak et al., 2001), topiramate adjunctive to
lithium or valproate (Janicak et al., 2001), aripiprazole (Glick

A. Murru et al.
et al., 2009a), and paliperidone extended release (Canuso et al.,
2010). All studies are placebo-controlled trials apart from the
risperidone one. Haloperidol was used as an active comparator
in the Tran's and Janicak's studies (see Table 1).
Totally, 665 acutely ill SAD patients were evaluated
during 48 week trials. A subgroup of patients from Tran's
study (1999) consisting of 85 patients was evaluated in the
long term, for 1 year. DSM-IV or DSM-IV-TR criteria were used
in all but Tran's and Keck's study, which respectively followed
DSM-III and DSM-III-R criteria (see Table 2).
In the oldest study considered (Tran et al., 1999), olanzapine
superiority to haloperidol was tested in a sub sample of 300 SAD
patients participating in a larger study on schizophrenic
patients. Among SAD patients 196 (71 bipolar type and 39
depressed type) were allocated to olanzapine 520 mg/day, in
6-weeks. A statistically significant greater percentage of
olanzapine-treated (55.1%) than haloperidol-treated (33.7%)
patients completed this study (pb 0.001). The change from
baseline to end-point was used as the outcome variable. In both
the overall patient population and the bipolar subtype group,
olanzapine-treated patients were found to show a statistically
significant greater improvement in mean scores from baseline
than did haloperidol-treated patients on four of five efficacy
measures (BPRS total, PANSS total, PANSS negative, and MADRS
total). Among depressed subtype groups, the difference in mean
improvement from baseline to end-point failed to reach
statistical significance on any of the efficacy measures. A
statistically significant greater percentage of olanzapinetreated vs. haloperidol-treated patients showed a reduction in
BPRS total score of at least 40% from baseline, regardless type of
diagnosis (p=0.001). In the overall patient population, in the
depressive group, but not in the bipolar one, the mean changes
from baseline to end-point in MADRS total score were
statistically significantly different favouring olanzapine (overall: p=0.045 and depressive: p=0.047).
A comparative study evaluated the efficacy and tolerability of risperidone vs. haloperidol within 6 weeks (Janicak
et al., 2001) in a sample of 62 SAD patients, allocated to two
treatment arms: risperidone, up to 10 mg/day (n = 30 and 18
bipolar type) and haloperidol, up to 20 mg/day (n = 32 and 15
bipolar type). Both treatment groups improved, but the
study failed to find significant differences regarding the main
outcomes considered (total PANSS or CARS-M, or in the CARSM Mania subscale mean change scores, in the CGI, on the
basis of treatment assignment). A sub-analysis on the
diagnostic subtype showed that subtype had no effect on
the medication response.
Treatment with different doses of ziprasidone was tested
in a pooled analysis of 215 SAD patients with data derived
from the two separate double blind, placebo-controlled
studies that assessed a larger cohort and included patients
with schizophrenia (Keck et al., 2001). Schizoaffective
subpopulations were separately presented only in one of
the two studies included in the post-hoc analysis, so that
subgroups information was lost. After combination of the
data from both studies significant linear, dose-related
improvements in all primary efficacy variable scores and in
BPRS Manic Item scores were observed (p = 0.01). Ziprasidone
120 mg/day was significantly more effective than placebo in
improving mean CGI-S scores (p = 0.05).
Chengappa et al. (2007) compared the efficacy and
tolerability of topiramate vs. placebo as adjunctive

What we know and what we don't know about the treatment of schizoaffective disorder
Table 1

683

Studies considered and their designs.

References

Study characteristics
Study type

Study design

Treatment Primary aim

tested

Arms

Concomitant
medication

Tran et al., 1999

PAS, 6 weeks/1 year

study

Double blind, RCT, OLZ

FtF, and mono

OLZ superiority over

Hal in SAD

2:1
OLZ:Hal

none

Janicak et al.,
2001

SA, 6 weeks study

Double blind, RCT, RSP

FtF, and mono

Efficacy and safety of

1:1
none
risperidone vs. haloperidol RSP (10 mg):
Hal (20 mg)
in the treatment of SAD

Keck et al., 2001

PAP, 4 week +6 week

studies

Double blind, RCT, ZIP

PBO, mono

Efficacy of ziprasidone in
the treatment of SAD

1:1:1:1:1
none
ZIP 40 mg:
ZIP 80 mg:
ZIP 120 mg:
ZIP 160 mg:
PBO

Chengappa et al., SA, 8-weeks (+8 weeks in Double blind, RCT, TPM (adj) Efficacy and safety of
2007
continuation), study
PBO, adj
adjunctive TPM in SAD

2:1
TPMPBO

-Valproate,
Lithium,
Lithium
+Valproate,
antipsychotics

Glick et al., 2009a PAP, two 4-week studies Double blind, RCT, ARP
Post-hoc analysis of
PBO, and mono
2 studies

Efficacy and safety of

ARP in the treatment
of patients hospitalized
for an acute relapse of
SAD compared to PBO

1:1

none

Canuso et al.,
2010

Efficacy and tolerabilityy

of PAL extended release
in SAD

1:1:1
AD or MS
PAL 6 mg: (except for
PAL 12 mg: CBZ)
PBO

SA, 6 weeks study

Double blind, RCT, PAL

PBO, and mono

ARP:PBO

Notes: SAD = Schizoaffective Disorder; SA = standalone trial; PAS = post-hoc sub-analysis; PAP = post-hoc pooled-analysis; RCT = randomized
controlled trial; FtF = Face to Face; mono = monotherapy; adj = adjunctive treatment; PAL = paliperidone; TPM = topiramate; ARP = aripiprazole;
RSP = risperidone; ZIP = ziprasidone; OLZ = olanzapine; TPM = topiramate; PBO = placebo; AD = antidepressants; MS = mood stabilisers; CBZ =
carbamazepine.

treatment to lithium or divalproex. The trial lasted 8 weeks

and the sample consisted of 48 SAD patients, 32 assigned to
the adjunctive topiramate arm. Similar reductions in PANSS
total scores were observed in each treatment group. The
results were very similar for all the PANSS subscale scores,
and for scores on the YMRS, CGI-S, MADRS and the DAI
subscales. Treatment discontinuations were not significantly
different between treatment groups at 8 weeks.
Glick et al. (2009a) conducted a pooled analysis of the two
trials testing the efficacy and tolerability of fixed doses of
aripiprazole (15 and 30 mg/day, 20 and 30 mg/day) vs.
placebo on schizoaffective and schizophrenic patients in
4 weeks. A total of 171 SAD patients were included, and 117
of them entered the aripiprazole arm. PANSS Total score was
significantly greater with aripiprazole than with placebo at
Weeks 3 and 4 (aripiprazole, 15.9 2.6 vs. placebo, 3.4
5.4; and p = 0.038). The original studies (Kane et al., 2002;
Potkin et al., 2003) presented a fourth arm of treatment with
comparative drugs (respectively haloperidol and risperi-

done), but were not powered to make a comparison to

aripiprazole. The mean change in the PANSS Positive
subscale score from baseline to Week 4 was also significantly
greater in the aripiprazole group (p = 0.027), while not
statistically significant improvement compared with placebo
was found in the PANSS Negative score. Endpoint CGI-I scores
were significantly better with aripiprazole than placebo
( p=0.023), and while CGI-S only showed a trend to significance
favouring aripiprazole Response rates were significantly greater
in the aripiprazole group than the placebo group (32.5% vs.
20.4%, and p=0.14).
The last RCT included in the present review was carried out
by Canuso et al. (2010) and was aimed at evaluating the efficacy
and tolerability of 2 dose ranges (612 mg/day) of paliperidone
ER as monotherapy in the treatment of 316 acute SAD patients
within 6 weeks. This is the only trial primarily and specifically
designed to test the efficacy and safety of a psychotropic drug in
the treatment of schizoaffective disorder in a placebocontrolled paradigm. There was a significant improvement

684
Table 2

A. Murru et al.
Inclusion criteria, sample sizes and allocations.

References

Patients Selection

Sample

Diagnosis/Clinical criteria

Rating scales

General
size (n.)

Drug tested arm

size (n)

Tran et al., 1999

DSM-III

Janicak et al., 2001

SAD DSM-IV

Acute 300
Maintenance 110
62

Acute 196
Maintenance 85
30

Keck et al., 2001

DSM-III-R
Hospitalization 3-4 weeks before

Acute: BPRS 18
Maintenance CGI 3
PANSS 50
CARS-M 16
(bipolar type)
HDRS 22
BPRS 37 (study 1)
PANSS 60 (study 2)
CGI-I 3

115

Chengappa et al., 2007

SAD bipolar type DSM-IVTR

ZIP 40 mg (16)
ZIP 80 mg (22)
ZIP 120 mg (18)
ZIP 160 mg (25)
32

Glick et al., 2009a

Canuso et al., 2010

SAD DSM-IV
SAD DSM-IV

PANSS 60
CGI-S 4
Stable mood stabilizers levels
PANSS 60
PANSS 60
YMRS and/or HDRS 16

48

171
316

117
PAL 6 mg (109)
PAL 12 mg (100)

Abbreviations: SAD = Schizoaffective Disorder; PANSS = Positive and Negative Symptom Scale; BPRS = Brief Psychiatric Rating Scale; HDRS =
Hamilton Rating Scale for Depression; CGI-S = Clinical Global Impression Severity of Illness; PAL = paliperidone; ZIP = ziprasidone; PBO = placebo.

with higher-dose paliperidone ER compared to placebo in PANSS

total score at week 6 end point (p=0.003), while the lower-dose
group did not separate from placebo. The higher-dose, but not
the lower-dose, paliperidone ER group exhibited the significant
improvements vs. placebo in mean CGI-SSCA total score
(pb 0.001), as well as CGI-SSCA positive (pb 0,001), negative
(pb 0.038), and manic (p b 0.001) domain scores. Subjects with
prominent manic symptoms at baseline and treated with higherdose paliperidone ER showed a significant improvement vs.
placebo in the total YMRS (pb 0.001). Those with predominant
depressive symptoms at baseline had a statistically significant
improvement in total HDRS-21 scores, both in high and low
paliperidone ER doses (p b 0.05).
All efficacy outcomes, together with significant tolerability outcomes, are presented in Table 3.

4. Discussion
4.1. What we don't know
The aim of the present review was to consider the best
evidence-based approaches to the treatment of SAD. Based
on this evidence, we planned suggesting some treatment
strategies for SAD, bipolar and unipolar types. However, lack
of clarity on some crucial issues makes this task complex.
4.1.1. Diagnosis
The first critical point may be the diagnostic assessment of
schizoaffective disorder, complicated by its poor diagnostic
definition. A study found a total absence of SAD diagnosis
congruence between DSM-IV and ICD-10 (Vollmer-Larsen et al.,
2006). Another study found that congruence rates between DSMIV and ICD-10 are high for bipolar disorder diagnosis, reasonable
for schizophrenia and unipolar depression, but low for SAD

(Cheniaux et al., 2009). Moreover, in the McLeanHarvard First

Episode Project (Salvatore et al., 2009), SAD showed a poor
diagnostic stability, as 22.4% of SAD-diagnosed patients had it
changed after 2 years. In contrast with these data, a retrospective study from Brenner et al. (2010) found a diagnostic stability
of 73.1% for the diagnosis of Schizoaffective Disorder in a sample
of 123 patients: diagnostic stability was higher for the bipolar
type subgroup of patients. The diagnostic boundary between
affective and psychotic disorder is often difficult to detect, as
distinguishing between these two dimensions does not seem
always possible (Marneros et al., 2008), and some voices have
been raised against the consistency of the diagnosis (Swartz,
2002; Vollmer-Larsen et al., 2006; Lake and Hurwitz, 2007;
Ghaemi et al., 2008; Jger et al., 2010a,b). The debate on the
clinical consistency of SAD diagnostic category is still open (Vieta
& Phillips, 2007), and diagnostic limitations may play an
important role in the design of the treatment trials by biasing
the samples with a heterogeneous population. Moreover,
current distinction between SAD bipolar type and unipolar
type should be further investigated. As it was pointed out
before, while there is some evidence on the characterization of
SAD-bipolar type as an intermediate form between schizophrenia and bipolar disorder, the definition of unipolar SAD should be
better assessed. The current nosology contemplates the not
uncommon comorbidity between schizophrenia and major
depression (Buckley et al., 2009), so that its distinction from
unipolar SAD should be clearly assessed to avoid the risk of
misdiagnosing unipolar SAD, should a difference between these
conditions ever be ruled out.
4.1.2. Prognostic factors
Besides the heterogeneity derived from the poor consistency of the diagnostic construct, differences in the
subpopulations of schizoaffective patients should be pointed
out and investigated, so that specific treatment options may

What we know and what we don't know about the treatment of schizoaffective disorder
Table 3

685

Efficacy and tolerability outcomes.

References Efficacy endpoints

Primary outcome
definition

Outcomes
Secondary outcome
definition

Primary results

Secondary
results

Safety outcomes

Drug vs comparator
(p value)

Drug vs comparator
(p value)

Drug vs
comparator

Drug vs
comparator

Tran et al., Change in BPRS,

1999
PANSS, and MADRS

Not specified

Acute:

All outcomes p N 0,05;

maintenance: MADRS
p = 0,047

Janicak et
al., 2001
Keck et al.,
2001

Not specified

Acute
Increase in
weight (p = 0,001)
Less worsening
on SAS (p = 0,001)
Less parkinsonism
(p b 0,001)
Less akathisia
(p b 0,001)
Maintenance
Less worsening on
SAS (p = 0,016)
Less EPS
(p b 0,001)
Weight gain
(p b 0,032)
Less EPS (p = 0,03)

ZIP 160 mg:

BPRS manic
(p 0,01);

General pain,
somnolence
p N 0,05

Change in PANSS,
CARS-M, HDRS scores
Change in BPRS, CGI-S,
CGI-I (BPRS derived
from PANSS in study 2)

PANSS, CARS-M,
HDRS N 0,05
BPRS Depressive/
ZIP 160 mg:
BPRS, CGI-S
manic items
(p 0,01);
Subscales (study 1)
ZIP 120 mg:
MADRS and BPRS
manic subscale (study 2) CGI-S (p 0,05);

Chengappa Change in PANSS

et al.,
total score
2007

Change from baseline in: p N 0,05;

1. YMRS;
2. MADRS;
3. CGI-S
4. DAI
5. BAS
6. SAS

p N 0,05

Constipation p = 0,04

Glick et al., Change in PANSS total

2009a
score

Changes from baseline in: 0.038

1. PANSS negative and
positive scales
2. CGI-S and CGI-I scores
and response rate
Change from baseline in: PAL 12 mg = 0.003
1. 5 PANSS scales
PAL 6 mg = 0.187
2.CGI-S-SCA
3. CGI-C-SCA
4.composite response,
5.time to first response
to treatment
6. YMRS and HDRS-21
scores

PANS
positive:0.027
CGI-I:0,023
CGI-S:0,06

EPS: 30,3% vs. 25,

and 5%
Akathisia-related:
16,4% vs. 10, and 9%
p N 0,05
(12 mg, 6 mg, and
PBO)
At least 1 event:
69,4%, 72,2%, 57,
and 0%
EPS: 22,4%; 23,1%;
12, and 1%
N 7% body weight:
7,1%; 2,9%, and 0,9%

Canuso et Change in PANSS total

al., 2010 score

12 and 6 mg:
composite
response
(0.001;0.008)
HDRS (b 0.05)
12 mg only:
PANSS
subscales
CGI-S-SCA
(0.001)
YMRS (b 0.001)

Notes: PANS = Positive and Negative Symptom Scale; BPRS = Brief Psychiatric Rating Scale; MADRS = Montgomery-Asberg Depression Rating Scale;
YMRS = Young Mania Rating Scale; CARS-M = Clinician-Administered Rating Scale for Mania; CGI-S = Clinical Global Inventory Severity; CGI-I =
Clinical Global Inventory Improvement; SAS = Simpson-Angus Scale; DAI = Drug Attitude Inventory; EPS = Extra-Pyramidal Symptoms; BAS = Barnes
Akhatisia Rating Scale; ZIP = Ziprasidone; PAL = Paliperidone; and PBO = Placebo.

686
be tailored. Persistent psychotic symptoms worsen the
prognosis of schizoaffective patients (Marneros et al.,
1993). These symptoms which are core features in SAD
positively relate cognitive impairment and have been found
to be related to poor treatment adherence in bipolar
disorder (Martinez-Aran et al., 2009). Moreover, cognitive
impairment is known to be related to poorer outcome in
schizophrenia (Palmer et al., 2009) and in bipolar patients,
even euthymic (Bonnn et al., 2010) and is usually more
severe in schizoaffective patients (Torrent et al., 2007;
Studentkowski et al., 2010). These deficits may influence,
for instance, the extent to which schizoaffective patients
may benefit from specifically developed psychosocial interventions. Also, the number of previous episodes may
influence the possibility of full recovery from an acute
episode (Marneros et al., 1993), but there is no evidence if it
can affect response to treatment in SAD.
4.1.3. Treatment
The specific treatment of SAD remains a largely unexplored
topic. Schizoaffective patients are usually included as a milder
sub-sample of studies on schizophrenic patients (Lerma-Carrillo
et al., 2008; Stip and Tourjman, 2010) or, more recently, as a
more severe sub-sample of studies designed for bipolar patients
(Vieta et al., 2008). This brings to a substantial lack of trials
specifically aimed at the treatment of SAD and, thus, to a
clinical practice based on indirect evidence. The most
immediate consequence is that most of the therapies used for
SAD, including mood stabilizers, atypical antipsychotics and
benzodiazepines, have at best shown a not-specifically measured effectiveness in SAD, or have been shown to present
beneficial effects for bipolar disorder or schizophrenia and are
only supposedly useful in the treatment of SAD, on the basis of
extrapolations into clinical practice.
4.1.4. Antipsychotics
Among all drugs, antipsychotics are the best studied in
SAD (see What we know section). However, there are still
important gaps in the evidence base with these compounds.
Only paliperidone has been specifically assessed in SAD in a
standalone, placebo-controlled trial. The evidence is very
limited for drugs such as clozapine, amisulpride, and
quetiapine. Evidence so far produced for olanzapine and
risperidone would benefit from further studies, on specific
schizoaffective populations samples, assessing the efficacy
and tolerability of these drugs vs placebo.
4.1.5. Classical mood stabilizers
A great emphasis has been given on the treatment with
antipsychotic drugs in SAD, while there is no high-quality
evidence (randomized placebo-controlled or head-to-head
trials following modern diagnostic criteria) is given for the
role of classical mood stabilizers (namely, lithium and
anticonvulsants), despite their use in the daily clinical
practice. Solid, high quality scientific evidence for the use
of classical mood stabilizers is urged, and its lack seems at
odds with the theoretical construct of this disorder, at least
in the bipolar type, in which affective symptoms are so
intense as to fulfil diagnostic criteria for manic, hypomanic,
and mixed or depressed episode. Despite the well-known
tendency of clinicians to prescribe mood stabilizers for
schizoaffective patients, extrapolations from studies on

A. Murru et al.
other population samples should be done with caution, as
extrapolation from bipolar disorder studies could support the
use of a drug, i.e. lithium, while evidence on the role of the
same drug in schizophrenia seems negative (Leucht et al.,
2007), even if less strongly in augmentation (Leucht et al.,
2004). Thus, it is still to ascertain to which of the two poles of
psychosis (i.e. schizophrenia and bipolar disorder) SAD is to
be placed near. Moreover, this is not a trivial question if we
think of the therapeutic implications, and the role of mood
stabilizers should be assessed with dedicated studies on this
population. As for valproate, past reports on its possible use
in SAD exist (Hayes, 1989). However, as in a previous study
conducted by McElroy et al. (1987), the response to
valproate by patients with SAD seems worse than that
observed in patients with affective disorders. A retrospective chart review, although limited by an uncontrolled and
retrospective design, suggested that divalproex is welltolerated and may be effective for the treatment of SAD,
bipolar type, even at modest mean dosages and serum levels
(Bogan et al., 2000). On the other hand, a double blind
randomized trial of augmentation therapy with mood
stabilizers (valproate and lamotrigine) in a small sample of
schizophrenic and schizoaffective patients did not show
substantial benefits (Glick et al., 2009b), although, again, no
specific evaluation on the schizoaffective subpopulation is
given. Lamotrigine could have a place: even if schizophrenic
patients with residual symptoms showed no benefits from
adjunctive lamotrigine in two double blind randomized
placebo-controlled multicenter studies (Goff et al., 2007),
specific evidence of lamotrigine effectiveness in SAD is
positive but only anecdotal, and would need further
investigation (Erfurth et al., 1998).
4.1.6. Antidepressants
Antidepressant treatment in SAD also presents a gap
between evidence in the literature and clinical practice. In
the preliminary presentation of their naturalistic study on
the treatment of schizoaffective patients acutely hospitalized, Grieger et al. (2001) outlined that patients are treated
with antidepressant or antimanic agents on the basis of a
history of prior mood symptoms, regardless of whether mood
symptoms are evident on admission. Flynn et al. (2002)
reported a tendency to continue antidepressant treatment if
the patient was receiving such treatment before hospitalization despite not currently experiencing depressive symptoms. In schizophrenia, antidepressants are especially useful
when antipsychotic treatment improves the psychotic
symptoms only (Siris, 2000). Data on the use of antidepressants in acutely schizoaffective depressed patients is almost
absolute, but in a double blind, placebo-controlled trial
conducted on a mixed schizophreniaschizoaffective sample, citalopram has shown to be effective as adjunctive
treatment to antipsychotics for reducing sub-syndromal
depressive symptoms (Zisook et al., 2009). The same group
examined the effects of citalopram augmentation of antipsychotics on suicidal ideation (Zisook et al., 2010).
Treatment-emergent suicidal ideation was no more common
with citalopram than placebo and, in those patients with
baseline suicidal ideation, the SSRI used reduced suicidal
ideation, especially in those whose depressive symptoms
responded to the treatment. However, results from pure
schizophrenic samples in methodologically solid trials in

What we know and what we don't know about the treatment of schizoaffective disorder
antidepressant use have failed to show the significant improvements with different SSRIs as citalopram, fluoxetine, and
sertraline (respectively Salokangas et al., 1996; Buchanan
et al., 1996; Addington et al., 2002).
4.1.7. Combination therapies
Combination therapy seems a likely therapeutic possibility in
SAD for its course of illness, the lack of a drug that addresses the
whole range of symptom dimensions, and largely following
analogies with the major disposability of data on bipolar
disorder and schizophrenia. To date, the best evidence for the
treatment of SAD patients has been presented and published for
atypical antipsychotics as paliperidone ER (Canuso et al., 2010)
and risperidone (Janicak et al., 2001) which presents the only
standalone trials for SAD, aripiprazole (Glick et al., 2009a),
olanzapine (Tran et al., 1999), ziprasidone (Keck et al., 2001).
On the other hand, a recent review on clinical practice data
shows that the most common treatment prescribed for
schizoaffective disorder is antipsychotic alone (22%), followed
closely by antipsychotic plus classic mood stabilizer (20%);
antipsychotic plus antidepressant (19%); and antipsychotic plus
classic mood stabilizer plus antidepressant (18%) (Cascade
et al., 2000). Combination therapy, which thus seems common
in everyday practice, has been evaluated in a randomized
clinical trial only by the negative adjunctive topiramate study by
Chengappa et al. (2007), and it should be more extensively
investigated, especially as far as the combinations of an
antipsychotic and a mood-stabilizer are concerned.
4.1.8. Maintenance treatment
Apart from the extension of the study on olanzapine, no RCT
has investigated the maintenance treatment in SAD. This gap
between research and clinical practice appears especially
problematic, as the construct of the disorder implies a severe
chronic condition characterized by relapses/recurrences. A
recent randomized, open label study investigated the effectiveness in relapse prevention of risperidone long-acting
injectable (RLAI) compared to oral quetiapine in a sample of
mixed schizophrenic and schizoaffective patients within two
years (Gaebel et al., 2010). RLAI proved to be significantly
(pb 0.0001) more effective than quetiapine and equally well
tolerated, but no specific outcomes on schizoaffective patients
were furnished. In an open-label, multicentric open study,
patients with SAD, considered stable on their antipsychotic
medication at study entry, experienced additional significant
clinical improvements while on treatment with RLAI in a 50week study period (Lasser et al., 2004). This data, combined
with the rates of poor adherence to treatment in schizoaffective
patients (Murru et al., 2010) seems to encourage the use of long
acting antipsychotic treatment in this very group of patients.
The efficacy in recurrence prevention of agents tested in
acute episodes should be assessed with strong methodologicalbuilt studies. Meanwhile, clinical practice appears to be guided
by extrapolation from the practice on schizophrenic and bipolar
patients. The extent to which maintenance treatment with
mono- or combination therapy represent an option in SAD should
also be evaluated.
4.1.9. Psychosocial interventions
There is a predictable lack of evidence for the possible use of
psychotherapeutic interventions in SAD. As for bipolar disorder
(Colom et al., 2003), schizoaffective disorder, bipolar type

687

patients could benefit from a psychoeducative intervention,

adapted and specifically tailored to the persistent psychotic
symptoms (Marneros et al., 1993) and the more severe cognitive
impairment (Torrent et al., 2007). Similarly, a post-hoc analysis
of a psychotic unipolar depressed sample showed an improvement in the inpatients who received adjunctive treatment with
Acceptance and Commitments Therapy, a cognitive-based
intervention (Gaudiano et al., 2007). Cognitive-oriented therapy for Early Psychosis showed some efficacy in a 12-months
study (Jackson et al., 1998, 2001, 2005), but it was lost in
subsequent 1-year- and 4-years- follow-up. On the other hand, a
recent meta-analysis on psychoeducative interventions for
schizophrenia pointed out a moderate effect on relapses and
re-hospitalizations in the short term and no significant effect in
the long term for patients psychoeducation, while interventions
on care-givers have shown to be more effective in reducing
symptoms by the end of treatment and preventing relapse at 7
12 month follow-up (Lincoln et al., 2007). Again, the extent to
which these interventions may improve the outcome of SAD
should be tested in specific samples. Psychological treatments
(i.e. psychoeducation) could play a role as adjunctive treatment
to relatively compensated patients, but should probably be
somewhat adapted to the more severe cognitive impairments in
schizoaffective population.
4.1.10. Biophysical interventions
Apart from pharmacological and psychological interventions, biophysical treatments should be specifically tested in
schizoaffective samples. A recent, positive retrospective
chart review (Lvy-Rueff et al., 2010) supports maintenance
electroconvulsive therapy (ECT) combined with medication
as an efficient alternative to pharmacological treatment
alone. Similarly, ECT has been reported to be useful even in
SAD with comorbid obsessive-compulsive disorder (Hanisch
et al., 2009), so that there seems to be room for ECT in the
maintenance treatment of SAD, even if in another case series
these patients seem to respond somewhat worse than their
purely affective counterparts (Swoboda et al., 2001). The
already documented paucity of data on SAD is pushed even
forward in the case of ECT, which represents a therapeutic
option which is traditionally neglected by clinical research.

4.2. Filling the gap

The need for moving from scientific evidence to day-to-day
clinical practice brings clinicians to look for a control of
symptoms based on risky extrapolations from the data on
other disorders.
To this moment, solid evidence for the use of some of the
available atypical antipsychotics (see Results section) has
been produced. However, speculations on similitudes and
differences with the two extremes of the psychotic dimension
(i.e. schizophrenia and bipolar disorder) seem unavoidable in
order to obtain, if not a specific treatment, at least a control
over the cluster of symptoms generally presented by schizoaffective patients.
For SAD, unipolar type, the presence of psychotic symptoms
combined with the null risk for manic symptoms could justify a
treatment with the combination of an atypical antipsychotic
with an antidepressant. The latter class of compounds has been
enriched with drugs different from the SSRI that would deserve

688
careful evaluation. Antidepressant as a whole should be further
investigated on specific schizoaffective populations.
As for SAD, bipolar type, the use of antidepressant should
likely be avoided because of the risk of treatment emergent
affective switches. Due to the overall acceptable control of
manic symptoms and manic recurrences prevention shown by
most atypical antipsychotic and following Ketter and Calabrese
(2002) classification of mood stabilizers, clinical research on the
treatment of SAD, bipolar type, should likely focus on from
below profile agents (i.e. quetiapine and lamotrigine), to be
supposedly used in combination with from above atypical
antipsychotics, in order to prevent recurrences of both
polarities.
In conclusion, pharmacological studies usually do not focus
on SAD alone. Limited, specific solid evidence of efficacy and
tolerability exists for just a few atypical antipsychotics as
monotherapy (namely, paliperidone, and risperidone). Apart
from these few studies, other specific information may be
gathered from analyses of large trials in patients with
schizophrenia that have included a subset of patients with SAD
(the aripiprazole, olanzapine, and ziprasidone trials). Beyond
that, the practical clinical need of properly treating SAD
patients may be supported by analogies with studies on the
treatment of the psychotic and affective dimensions alone.
Combination treatment, already frequent in bipolar disorder,
seems inevitable in SAD due to its very nature and to the
exigency to treat different symptom dimensions, both in
unipolar and bipolar types. Summing up all these considerations,
in the present review we propose two different treatment
patterns that may act as a compass for the generic management
of SAD. Apart from pharmacological treatment, biophysical
treatments (i.e. electroconvulsive therapy) should be tested as
an option for treatment-resistant patients.

Role of the funding source

The authors of this study would like to thank the support of the
Generalitat de Catalunya to the Bipolar Disorders Group (2009 SGR
1022). Francesc Colom would like to thank the support and funding
of the Spanish Ministry of Health, Instituto de Salud Carlos III,
CIBERSAM. Dr Colom is also funded by the Spanish Ministry of Science
and Innovation, Instituto Carlos III, through a Miguel Servet
postdoctoral contract (CP08/00140) and a FIS (PS09/01044).

Contributors
AM. Wrote the manuscript, took part in the literature search,
review, and discussion of results.
I.P. and A.M.A.N. Reviewed and double checked results of the
literature search.
I.G. took part in the literature search.
F.C. and E.V. coordinated the work, discussed the results and the
conclusion of the manuscript.

Conflict of interests
A.M. has served as consultant for Bristol-Myers-Squibb. I.P. declares no
conflict of interest. A.M.A.N. has served as consultant for Bristol-MyersSquibb. I.G. declares no conflict of interest. F.C. has served as advisory
or speaker for the following companies: Astra Zeneca, Bristol-Myers,
Pfizer Inc, Glaxo-Smith-Kline, Eli-Lilly, M.S.D. Merck, Sanofi-Aventis,
Otsuka, andTecnifar & Shire. E.V. has received grants and served as a

A. Murru et al.
consultant, adviser, or speaker for the following entities: Almirall,
AstraZeneca, Bristol-Myers Squibb, Eli Lilly, the Forest Research
Institute, GlaxoSmithKline, Janssen-Cilag, Jazz, Lundbeck, Merck,
Novartis, Organon, Otsuka, Pfizer, Sanofi-Aventis, Servier, SheringPlough, the Spanish Ministry of Science and Innovation (CIBERSAM), the
Seventh European Framework Programme (European Network of Bipolar
Research Expert Centres), the Stanley Medical Research Institute,
United Biosource Corporation, and Wyeth.

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