You are on page 1of 16

Drugs

DOI 10.1007/s40265-016-0551-x

REVIEW ARTICLE

Antipsychotic Management of Schizoaffective Disorder: A Review


Jean-Pierre Lindenmayer1,2,3 Amandeep Kaur1

Springer International Publishing Switzerland 2016

Abstract Schizoaffective disorder (SAD) is an incapac- supportive data exist, it is possible that other atypical
itating illness that presents clinicians with challenges in antipsychotics may have similar efficacy to the two men-
terms of both its diagnosis and its psychopharmacological tioned above. We conclude with a number of research
management. Most studies conducted on the psychophar- recommendations for the study of treatment options for
macological treatment of SAD also include patients with patients with SAD. First, there is a need for studies with
schizophrenia or other psychotic illnesses, thereby pro- patients specifically diagnosed with SAD for both the acute
viding an unspecific view to the clinician as to the best way and the maintenance phase. The sample size needs to be
of treating patients with SAD. The objective of this article adequate to allow a primary analysis of efficacy and to
is to review studies on evidence-based treatment of patients allow for analysis of the SAD subtypes: depressed and
with SAD. We conducted a systematic literature search in bipolar. Another recommendation is the need for studies of
MEDLINE/PubMed for full-text studies in the English patients with SAD stratified into patients with and without
language using the terms Schizoaffective and treatment mood stabilizers or antidepressants to allow the examina-
or antipsychotic schizoaffective. Our review found rela- tion of the adjunctive role of these psychotropic medica-
tively few studies with either an active comparator or tions. A third recommendation is to focus on specific co-
placebo that examined the efficacy of antipsychotics for morbid aspects of patients with SAD, such as suicidality
patients with SAD without an admixture of patients with and substance use disorders. Data from such studies will fill
schizophrenia. Only oral paliperidone extended release the gap of evidence-based treatment approaches and help
(ER), paliperidone long-acting injection (LAI), and clinicians in making important treatment decisions for
risperidone have been shown to be effective and safe in patients with this complex condition.
reducing psychotic as well as affective components in
acutely ill SAD patients in controlled studies. Paliperidone
ER and LAI have also been shown to be efficacious in the
Key Points
maintenance treatment phase of SAD patients. While no
Few controlled studies have been performed on the
use of antipsychotics for the treatment of patients
with schizoaffective disorder.
Only risperidone and paliperidone (as an extended-
& Jean-Pierre Lindenmayer
release oral and a long-acting injectable formulation)
lindenmayer@nki.rfmh.org
have been shown to have efficacy against both
1
Psychopharmacology Research Department, Manhattan psychotic and mood symptoms.
Psychiatric Center, Wards Island, NY 10035, USA
2
The efficacy of adjunctive antidepressants or mood
New York University Medical Center, New York, NY, USA
stabilizers has not been tested in controlled samples
3
Nathan S. Kline Institute for Psychiatric Research, of patients with schizoaffective disorder.
Orangeburg, NY, USA
J.-P. Lindenmayer, A. Kaur

1 Introduction Psychopharmacological treatment studies conducted in


SAD are few compared with those in schizophrenia and
The earliest classification of mental illness by Kraepelin in bipolar disorder [15], thus providing little guidance to assist
1919 [1] as due to either thought disturbance or mood dis- clinicians in deciding the management of SAD based on
ruption (Kraepelinian dichotomy) continues to be debated clinical trials [17]. Most studies used by clinicians for the
to this day [2]. Kraepelin classified psychosis with thought management of SAD are extrapolations of studies in
disturbance as dementia praecox and psychosis with mood schizophrenia patients or based on results of the few studies
disruption as manicdepressive insanity [1]. This classi- that have conducted an analysis of the SAD patient sub-
fication did initiate the polarizing dichotomy of two sepa- sample by using an affect rating scale [18]. Since antipsy-
rable psychopathological entities without an in-between chotics are the mainstay of management for SAD, this paper
diagnostic entity. Jacob Kasanin [3] coined the term focuses on evidence-based antipsychotic treatment studies
schizoaffective disorder to integrate the additional finding of patients with SAD by including studies carried out in the
of disturbances in affect in his patients presenting with last ten years. While mood stabilizers and antidepressants
dementia praecox. Schizoaffective disorder (SAD) was are also frequently used, either alone or in combination with
eventually categorized in 1987 by the American Psychiatric antipsychotics in clinical settings, no controlled studies
Association as an independent disorder in the Diagnostic have been conducted with these agents in pure SAD sam-
and statistical manual of mental disorders, third edition, ples. Studies are found with these agents either within
revised (DSM-III-R) [4]. The SAD diagnosis was main- bipolar samples or within samples of schizophrenia patients
tained in subsequent editions of the DSM. During the without sub-analyses. Hence, the specific aim of this article
deliberations for DSM-V, significant debate focused on is to review evidence-based antipsychotic treatment trials of
possibly removing the diagnostic concept of this disorder. both the acute and the maintenance pharmacological man-
However, the diagnosis was maintained, and final diag- agement of patients with SAD. Since there is little evidence
nostic criteria stated by DSM-V include the following: (1) for a differential pharmacological response for the bipolar
the presence of major mood disturbance along with criteria or depressive type, we review the efficacy of antipsychotic
A of Schizophrenia; (2) The psychotic component, i.e., therapy for SAD without subtyping.
delusions and hallucinations, should be present for 2 or
more weeks in the absence of major mood disturbance; (3)
Major mood disturbance should be present for a significant 2 Methods
period of time during both active and residual phases of
illness. SAD is further specified as bipolar type or depres- We conducted a systematic literature search in MEDLINE/
sive type, with or without catatonia [5]. The disorder is PubMed for full-text studies in the English language using
characterized by mixed symptoms of schizophrenia and the terms Schizoaffective and treatment or antipsychotic
affective disorder. SAD is estimated to be about one-third schizoaffective.
less common than schizophrenia, with an estimated lifetime We included studies that (1) used DSM-IV, DSM-IV-
prevalence of 0.3 % [6, 7]. Like schizophrenia, the onset of text revision (TR) or International statistical classification
SAD is typically in early adulthood; however, it usually of diseases and related health problems, 10th edition (ICD-
takes several years for patients to receive a SAD diagnosis, 10) diagnostic criteria; (2) included C20 participants; (3)
after having been diagnosed with another initial psychiatric was published within the last 10 years; (4) included studies
illness [8]. Patients with SAD experience significant func- exclusively in SAD patients; (5) if they combined SAD and
tional impairments and exhibit higher rates of hospitaliza- schizophrenia patients, used affective disorder rating scales
tion, suicidality, and substance abuse [10, 11] than patients such as the Young Mania Rating Scale (YMRS), Calgary
with schizophrenia. According to one study, patients with Depression Scale for Schizophrenia (CDSS), Hamilton
SAD represent one-quarter of admissions in acute psychi- Depression Scale (HDRS-21/HAM-D) or the analysis of
atric units [12]. The overall prognosis of SAD appears to be the SAD patients sub-samples was conducted separately;
intermediate to that of schizophrenia and affective disorders (6) included participants aged C18 years; (7) provided data
[9, 13], and the disorder requires long-term treatment. Few derived from standardized rating scales, were of at least
specific treatment guidelines exist for the psychopharma- 4 weeks duration and included information on study
cological treatment of SAD. It is generally treated with design, sample description, inclusion/exclusion criteria,
complex pharmacologic regimens that include antipsy- and descriptions of study arms of drugs and outcome
chotics, mood stabilizers, and antidepressants [14, 15], measures. Studies conducted exclusively in patients with
which increases the potential side-effect burden and renders schizophrenia or with samples of both patients with SAD
the clinical decision-making process more difficult [16]. and those with bipolar disorder were excluded.
Treatment of Schizoaffective Disorder

While the diagnostic criteria in DSM-IV and ICD-10 duration of schizophrenic and affective symptoms. In
identify the same groups of patients overall, cases may be contrast, the DSM-IV requires that (1) delusions or hal-
defined as schizoaffective in one that would not qualify lucinations occur for at least 2 weeks in the absence of
for that diagnosis in the other system. The ICD-10 and prominent mood symptoms; and (2) that the mood
DSM-IV definitions are similar in that they both require symptoms are present for a substantial portion of the total
periods of significant mood symptoms (i.e., that the full duration of the illness [19].
criteria be met for a mood episode) and significant Our search yielded 2931 results. The majority of the
schizophrenia-like psychotic symptoms, which must occur studies were discarded, as they included antipsychotic
concurrently during the same episode of the disorder. treatment trials without specifying a subsample analysis of
However, the definitions differ significantly with respect SAD patients or were conducted to establish the role of
to the required relationship between the mood and psy- non-pharmacological treatments such as Cognitive
chotic symptoms. The ICD-10 diagnosis depends on an Behavior Therapy (CBT) with SAD patients or were case
approximate balance between the number, severity, and series reports (see Fig. 1).

Records obtained through Addional record idened through


database searching other sources

(n= 2931) (n=5)

Records aer duplicates removed

(n =2098)

Records screened Records excluded

(n = 2098) Based on Inc./Excl. criteria

(n = 2052)

Full-text arcles assessed for


eligibility Full-text arcles excluded, due to:

(n= 46) -Studies that failed to use any aect


rang scale (n=10)

-Sample size of <10 (n=10)

Studies included in -Studies done on both SAD and SCH


qualitave analysis subjects that did not specify the subject
number (n=5)
(n= 14)
-Studies that failed to measure the
ecacy of anpsychoc medicaons (n=
3)

-Studies that failed to do separate sub-


analysis on SAD paents (n=3)

-Study with primary outcome being


metabolic (n= 1)

Fig. 1 Flowchart showing study selection process. SAD schizoaffective disorder, SCH schizophrenia
J.-P. Lindenmayer, A. Kaur

3 Results An 8-week, randomized (1:1:1), double-blind, fixed-


dose study was conducted in inpatients with schizophrenia
We included 14 studies that investigated the effects of or SAD to find the dose-relationship of standard-dose
antipsychotic drug treatment in SAD patient populations olanzapine (10 mg/day) versus high-dose olanzapine
(Table 1). Nine were double-blind randomized controlled (20 mg/day, 40 mg/day). The study patients included
trials (RCTs) [20, 21, 2325, 27, 28, 30, 33]; five were showed suboptimal response to their previous antipsychotic
open-label studies [22, 26, 29, 31, 32]. All studies used medication, but were not treatment resistant. There was no
DSM-IV; only one study also used ICD-10. The few significant group difference in the number of patients who
studies conducted in purely SAD patient populations and were receiving concomitant mood stabilizers and antide-
the heterogeneity of the study populations precluded a pressants, or in those who completed treatment and in the
formal meta-analysis. time-to-treatment discontinuation. The study found no
significant difference in dose-response relationship
3.1 Acute Antipsychotic Pharmacotherapy between the three dose groups. There was significant
improvement in total PANSS score at the endpoint in all
A 4-week, randomized (1:1), double-blind study in hospi- three dose groups. No significant relation was seen in dose-
talized patients with schizophrenia or SAD evaluated the response relationships for all three dose groups for CGI-S,
efficacy and safety of ziprasidone (80160 mg/day) versus CGI-Global Improvement scale (CGI-I), Montgomery
aripiprazole (1030 mg/day). A total of 68.0 and 69.5 % of Asberg Depression Rating Scale (MADRS), quality of life
subjects completed the study in the ziprasidone and arip- (QOL), or Global Assessment of Functioning (GAF). A
iprazole groups, respectively. The main reasons for discon- post hoc analysis showed a significant relation between
tinuation in the ziprasidone versus aripiprazole groups were, baseline PANSS total score and the dose of olanzapine.
respectively, lack of efficacy (4.8 vs. 7.0 %) and treatment- Patients who had a higher baseline PANSS total score
emergent adverse events (7.2 vs. 3.1 %). The Clinical Glo- ([111) and were receiving atypical antipsychotics had a
bal Impression-Severity scale (CGI-S) score improved in better treatment response to higher-dose olanzapine. The
both groups. No improvement was seen on the Brief Psy- most common adverse effect in all three groups was dry
chosis Rating Scale-derived [BPRSd; total score derived mouth. The incidence of fatigue (p = 0.016) and dizziness
from the Positive and Negative Syndrome Scale (PANSS)]. (p = 0.025) was reported more in the olanzapine 40-mg
Both treatment groups showed significant improvement on dose group. The 10-mg dose olanzapine group was asso-
PANSS total score at endpoint. No statistically significant ciated with an increase in suicidal ideation (p = 0.024). A
difference was found between treatment groups on the statistically significant dose-response relationship was seen
CDSS score, hospital discharge eligibility rates, weight, in the mean change of weight (p = 0.003) and prolactin
metabolic parameters, prolactin levels (decreased in both (p \ 0.001). Patients receiving higher-dose olanzapine
groups), Simpson Angus Scale (SAS) total score, and Barnes significantly gained more weight than those in other
Akathisia Rating Scale (BARS) score. However, at day 4, groups. There was no in-group difference in the number of
ziprasidone was shown to have a significant better total patients in each group with a significant increase in weight.
score on the BPRSd scale compared with aripiprazole, a Patients receiving baseline atypical antipsychotics showed
finding that needs to be investigated in future studies. a significant mean change in weight, which was not seen in
Somnolence (26.4 vs. 13.3 %), extrapyramidal symptoms patients receiving baseline typical antipsychotics or with-
(EPS) (8.8 vs. 5.5 %), and agitation (11.2 vs. 9.4 %) were out the use of antipsychotics at baseline. Some of the study
found more commonly in the ziprasidone group, whereas limitations included lack of a placebo group, failure to
dyspepsia (18.0 vs. 9.6 %), nausea (15.6 vs. 6.4 %), head- complete the study by a relatively high number of patients
ache (17.2 vs. 12.0 %), and akathisia (7.0 vs. 5.6 %) were because of reasons other than efficacy and tolerability, and
more frequently seen in the aripiprazole group. A total of 15 use of only fixed doses versus flexible dosing. Also, since
patients in the ziprasidone and 13 patients in the aripiprazole the study was conducted in stable patients with residual
groups discontinued treatment due to adverse events or lack symptoms, the study results cannot be extrapolated to
of efficacy. The use of stringent inclusion criteria in a small acutely hospitalized patients. This study shows that
and heterogeneous study population might be the reason severely ill patients benefit from olanzapine 20 or
behind the lack of difference seen in BPRSd rating scale 40 mg/day doses, especially if they were previously
between the two groups. It appears that both treatments receiving atypical antipsychotics; however, the depression
were, overall, equally efficacious, and that neither treatment measure used in this study did not show any differential
had a differential impact on the depressive component of dose effect. Hence, few data from this study can be applied
SAD [20]. to the management of SAD patients [21].
Table 1 Acute antipsychotic management of schizoaffective disorder
Study Sample [diagnostic criteria] Study period Study type Study arms Outcome measures Results

Zimbroff et al. Total = 253; SAD = 59 4 wk, acute ran, db ZIP (80160 mg/day) vs. CGI-S, BPRSd, ZIP was non-inferior to ARI on CGI-S score
2007 [20] [DSM-IV] therapy ARI (1030 mg/day) PANSS, CDSS (p = 0.007) and PANSS total score (p \ 0.0001)
at endpoint. No significant between-group
difference on PANSS total score (p = 0.30) and
subscales scores (p = 0.16 for positive symptoms,
p = 0.71 for negative symptoms, p = 0.42 for
excitement item), CDSS score (p = 0.92) and
BPRSd score (p = 0.248)
Kinon et al. 2008 Total SCH ? SAD = 599; 8 wk, acute mc, db, ran, OLA standard vs. higher PANSS (total and All three doses failed to show any statistically
Treatment of Schizoaffective Disorder

[21] SAD pts on 10 mg/day therapy pg, fixed- dose (10, 20, or subscales), CGI-S, significant doseresponse relationship for total
= 63; SAD pts on dose 40 mg/day) CGI-I, MADRS, PANSS (p = 0.295), CGI-I (p = 0.256), CGI-S
20 mg/day = 63; SAD pts GAF, QLS (p = 0.487), MADRS (p = 0.514), QLS
on 40 mg/day = 61 (p = 0.314), and GAF (p = 0.532) scores
[DSM-IV]
Izakova et al. SAD, depressed type = 52 12 wk, acute ol pro, ran RIS mono (3.753.29) vs. PANSS, GAF, Statistically significant improvement on PANSS
2009 [22] [DSM-IV, ICD-10] therapy combined HAL HQLS, CDSS, total (p = 0.012), CDSS (p = 0.047) GAF
(5.344.5 mg/day) and CGI-I, DAI, PPS (p = 0.044), and CGI-S (p = 0.048) scores in RIS
SER mono group vs. HAL-SER therapy group. RIS
(65.39133.82 mg/day) mono performed better in HQLS score
(p = 0.012). No significant difference in DAI,
PPS, or duration of hospital stay
Glick et al. 2009 SAD pts = 179 (bipolar Two 9 4 wk, ran, db, pg, Study 1: ARI (15, 20, PANSS positive, Significant improvement on total PANSS score
[23] type = 96, depressive acute therapy fixed-dose, 30 mg/day) vs. PL with negative and (-15.9 in tx group vs. -3.4 in PL; p = 0.038),
type = 83) [DSM-IV] pc, pooled, HAL (10 mg/day) arm as general PANSS positive subscale (-4.6 vs. -1.0;
post hoc active control psychopathology, p = 0.027), mean CGI-S (-0.6 vs. -0.2;
analysis Study 2: RIS (6 mg) as CGI-S, CGI- I p = 0.06). No statistically significant change in
active control PANSS negative subscale score (-3.7 vs. -1.2;
p = 0.15) or PANSS general psychopathology
subscale score (-8.3 vs. -3.1; p = 0.06).
Statistically significant change in prolactin level
vs. PL (-5.6 vs. -1.3; p \ 0.001). Response rate
significantly higher for ARI group vs. PL
(p = 0.14). No separate sub-analysis for HAL or
RIS sub-arm
Canuso et al. Total = 311 (depressed 6 wk, acute ran, db, pc, pg PAL ER 6 mg/day vs. PL PANSS, YMRS, PANSS score at endpoint in PAL group -20.0 vs.
2010 [24] type = 95; bipolar therapy HDRS-21, CGI-S- -10.6 in PL (p = 0.0001); YMRS score -10.6 in
type = 209) [DSM-IV] SCA, CGI-C-SCA PAL vs. -5.7 in PL group (p = 0.0013); HRSD-
21 score of -10.2 in PAL vs. -6.2 in PL
(p = 0.0026); change in CGI-S-SCA score in PAL
-1.2 vs. -0.7 in PL (p = 0.0026)
Table 1 continued
Study Sample [diagnostic criteria] Study period Study type Study arms Outcome measures Results

Canuso et al. Total = 316 (69.1 % 6 wk, acute ran, db, pg pc PAL ER (lower dose or PANSS, CGI-S- Mean PANSS increased statistically significantly in
2010 [25] bipolar type, 30.9 % therapy higher dose: 6 mg or SCA, CGI-C- higher dose PAL ER vs. PL (p = 0.003). No
depressive type); lower 12 mg/day, respectively) SCA, YMRS, significant change in lower dose PAL vs. PL
dose = 109; higher vs. PL HDRS-21 (p = 0.187). Significant improvement in higher-
dose = 100; PL = 107 dose PAL ER but not with lower-dose PAL ER vs.
[DSM-IV] PL for positive symptoms (p = 0.001),
disorganized thoughts (p = 0.004), and
uncontrolled hostility/excitement (p \ 0.001) on
PANSS subscales. Higher-dose but not lower-dose
PAL ER associated with greater improvement in
mean CGI-S-SCA total score (p \ 0.001), CGI-S-
SCA positive (p \ 0.001), negative (p = 0.038),
and manic (p \ 0.001) domain scores. Significant
improvement on YMRS score (p \ 0.001) in
higher-dose vs. lower-dose and PL. Significant
improvement in HDRS-21 in both lower- and
higher-dose PAL ER (p \ 0.05) but not in PL
Di Fiorino et al. QUE XR: SCH = 59; 12 wk, ran, ol, pg, QUE XR CDSS, PANSS, Statistically significate effect in PANSS total score
2014 [32] SAD = 48. RIS: maintenance flexible-dose (400800 mg/day) vs. HAM-D, CGI-S, (p = 0.0002), CDSS score (1.8 times; p \ 0.05),
SCH = 51; SAD = 52 therapy RIS (46 mg/day) DAI and HAM-D score (p \ 0.0001) in QUE XR group
[DSM-IV] vs. RIS. Significant improvement in CGI-S scores
(p = 0.9) and DAI-10 scores (p = 0.2) in both
groups, not statistically significant
ARI aripiprazole, BPRSd Brief Psychosis Rating Scale-derived, CDSS Calgary Depression Scale for Schizophrenia, CGI-C-SCA CGI-S for Schizoaffective Disorder, CGI-I CGI-Global
Improvement scale, CGI-S Clinical Global Impression-Severity scale, DAI Drug Attitude Inventory, db double-blind, DSM Diagnostic and Statistical Manual of Mental Disorders, GAF Global
Assessment of Functioning, HAL haloperidol, HAM-D Hamilton Depression Scale, HQLS/QLS Heinrichs Quality of Life Scale, HDRS Hamilton Depression Scale, ICD-10 International
Statistical Classification of Diseases and Related Health Problems, 10th edition, MADRS Montgomery Asberg Depression Rating Scale, mc multicenter, mono monotherapy, ol open-label, OLA
olanzapine, PAL paliperidone, PAL ER paliperidone extended release, PANSS Positive and Negative Syndrome Scale, pc placebo-controlled, pg parallel-group, PL placebo, PPS Patient
Preference Scale, pro prospective, pt(s) patient(s), QOL quality of life, QUE XR quetiapine extended release, ran randomized, RIS risperidone, SAD schizoaffective disorder, SCH
schizophrenia, SER sertraline, wk week, YMRS Young Mania Rating Scale, ZIP ziprasidone
J.-P. Lindenmayer, A. Kaur
Treatment of Schizoaffective Disorder

A 12-week, open-label, randomized, prospective clinical insufficient improvement of clinical symptoms (aripipra-
study was conducted to assess the efficacy of risperidone zole 13 %; placebo 18 %). The most common side effects
monotherapy versus the combination of haloperidol and were (for aripiprazole vs. placebo in each case) headache
sertraline in acutely ill patients with SAD-depressed type. (36.9 vs. 45.5 %), agitation (33.6 vs. 38.2 %), insomnia
The authors found a statistically significant difference in (27.9 vs. 30.9 %), anxiety (27.0 vs. 25.5 %), dyspepsia
the total PANSS score favoring risperidone monotherapy at (15.6 vs. 18.2 %), nausea (18.0 vs. 20.0 %), psychotic
endpoint. No statistically significant change was found in disorder (14.8 vs. 21.8 %). EPS-related side effects did not
depression as measured by the CDSS, although the com- statistically differ from placebo in terms of SAS, BARS,
bination haloperidol plus sertraline group had higher CDSS and Abnormal Involuntary Movement Scale (AIMS)
scores throughout the study. The change in CGI-S scale scores. No significant adverse metabolic effects were seen
was significant in both groups, with no difference between between the groups in weight, total cholesterol, or glucose,
the groups. However, improvement in GAF and Heinrichs but the study was only conducted for 4 weeks, which limits
Quality of Life Scale (HQLS) score were statistically sig- the degree of drug exposure, and therefore the under-
nificant in the risperidone group, and not in the haloperidol standing of the metabolic profile of aripiprazole. The
plus sertraline group. Thus, risperidone monotherapy was original studies did not use affective rating scales, and no
shown to be superior to combined haloperidol plus sertra- separate analysis was conducted to investigate the effect of
line therapy in many areas, but was not superior in aripiprazole in depressive and bipolar SAD types. While
depressive symptomatology. The only adverse effects aripiprazole was clearly more effective than placebo in this
mentioned in the study were EPS, which were mild. EPS- large sample of patients with acute SAD, we do not know
related adverse effects were more frequently associated how aripiprazole affected the depressed and manic features
with the haloperidolsertraline group than with risperidone. of this disorder. Regarding metabolic and prolactin effects,
The limitations of the study were the small sample size and aripiprazoles effects were comparable to those of placebo.
open-label study design. The study subjects were pre- Hence, it may be a good choice for patients with SAD with
dominantly females. The authors stated that the high metabolic risk factors and drug-induced increases in pro-
prevalence of SAD in females compared with males was lactin levels [23].
the reason for the gender disparity observed in the study A 6-week, double-blind, placebo-controlled, parallel-
population. Despite the limitations, the study is informa- group international study was conducted to examine the
tive, as it focused on the management of patients with SAD efficacy and safety of oral paliperidone extended-release
(depressed type), a group in which very few studies have (ER) in patients diagnosed with acute SAD. Patients were
been conducted so far [24]. In addition, an antipsychotic is acutely psychotic, with a mean PANSS score in the low to
frequently combined with an antidepressant and did not mid 90s and a mean CGI-S for Schizoaffective Disorder
offer any advantage over risperidone monotherapy [22]. (CGI-S-SCA) score of 4.6. Screening included a washout
A post hoc analysis was carried out by extracting data period, in which the use of all other anti-psychotic medi-
for patients with SAD from two original studies that cations was terminated. Concomitant use of mood stabi-
included hospitalized patients with schizophrenia or SAD lizers or antidepressants versus no use was included as a
presenting with an acute relapse. Both studies were basis for randomization (1:1:1) in the three groups: lower
4-week, randomized, parallel-group studies. In study 1, the dose of paliperidone ER (6 mg/day, could be reduced to
fixed dose of aripiprazole was 15 mg or 30 mg/day versus 3 mg/day), higher dose of paliperidone ER (12 mg/day;
placebo. A third arm of haloperidol 10 mg/day was also could be decreased to 9 mg/day), or placebo. The study
added as an active control [34]. In study 2, the fixed dosage found a significant improvement on PANSS total score
of aripiprazole was 20 mg or 30 mg/day versus placebo with high-dose paliperidone ER versus placebo, but not
with risperidone 6 mg/day as active arm [35]. Neither with low-dose paliperidone ER as compared with placebo
study compared the results between study medication and at endpoint. Significant improvement was also seen on
active treatment arms. This post hoc analysis found a PANSS positive factor, disorganized thoughts, and
greater mean change in favor of aripiprazole for the uncontrolled hostility/excitement factors for the high-dose
PANSS total score, a mean change in the PANSS positive paliperidone ER group as compared with the placebo
score, and a non-significant mean change in the CGI-S at group, but not for the low-dose paliperidone ER group.
endpoint. The improvement in PANSS negative score was High-dose paliperidone ER was associated with significant
not statistically significant. A total of 55 % of patients in improvement in CGI-S-SCA total score, CGI-S-SCA pos-
the aripiprazole group and 41 % of patients in the placebo itive, CGI-S-SCA negative, and CGI-S-SCA manic
group completed the treatment. Withdrawal from the study domains score and the YMRS score. Both groups showed
mainly occurred during the first 2 weeks due to reports of significant improvement in HDRS-21 score versus placebo.
side effects (aripiprazole 11 %; placebo 18 %) and The results were comparable for the groups with or without
J.-P. Lindenmayer, A. Kaur

adjunctive mood stabilizers or antidepressants, although then discontinued), or 1-week taper (full dose of antipsy-
the study was not powered to answer this question directly. chotic was continued from day 13, after which the dose
The most frequent adverse effects were headache, nausea, was reduced to 50 % on days 47, and then discontinued)
insomnia, tremor, akathisia and hypertonia. Of note, a high depending upon the choice of the treating psychiatrists.
placebo response was seen in the study, which might have Immediate switching was the favored method of switching
confounded the results for low-dose paliperidone ER with the antipsychotic for efficacy or tolerability reasons. A total
respect to the mean change of the PANSS score. The of 80 patients failed to complete the study; ziprasidone-
authors speculate that this may have been due to the short induced side effects were the cardinal factor leading to
trial period, which may have increased the possibility of study discontinuation. The degree of compliance, as judged
the small difference between drug and placebo [36]. This by treating psychiatrists, was high throughout the study
study laid the foundation for the US FDA approval for (C94 %). Ziprasidone was associated with significant
paliperidone ER in patients with SAD [24]. improvement in BPRS total score, especially in the first
A second 6-week, randomized, double-blind, placebo- 2 weeks of the treatment and in subjects switched from the
controlled, parallel-group study was conducted to compare haloperidol or risperidone groups but not for those in the
the efficacy and tolerability of flexible dosing of paliperi- olanzapine group. Significant improvements were also seen
done ER 312 mg/day, either as monotherapy or as adjunct in all pre-switch groups for CGI-S; PANSS total, positive,
to mood stabilizers/antidepressants in acutely ill SAD and negative; MADRS scores; GAF; and Drug Attitude
patients or in those with a recent exacerbation. Paliperi- Inventory (DAI) upon switching to ziprasidone, with the
done ER was started at a dose of 6 mg/day. The dose could exception of the olanzapine group on the MADRS score
be altered in 3 mg/day steps (range of 312 mg/day) until and DAI. Improvement on AIMS, BARS, and modified
the 15th day of the study. A total of 158 (52 %) subjects SAS (m-SAS) was seen in all three groups at endpoint,
were concomitantly using mood stabilizers or antidepres- with statistically significant improvement seen in the
sants at baseline. The mean PANSS total score, YMRS haloperidol and risperidone groups, but not in the olanza-
score, and HDRS-21/HAM-D-21 scores at baseline were pine group. Significant mean weight loss was seen in the
92.1, 23.1, and 20.2, respectively. The mean dose of pre-switch olanzapine group. Non-significant mean
paliperidone ER was 8.19 mg/day. The study showed sig- decrease and increase in mean body weight was seen in the
nificant improvement in all outcome measures (PANSS, risperidone and haloperidol group, respectively. Ziprasi-
CGI-S-SCA, YMRS, HDRS-21/HAM-D-21) and on a done switch showed a neutral effect on metabolic param-
composite response measure, both as monotherapy and as eters and prolactin. The most common adverse effect was
an adjunct to mood stabilizers/antidepressants. The somnolence in all three pre-switch groups. This study
improvement in PANSS started from day 4. Of subjects supports the switching to ziprasidone (80120 mg/day with
receiving treatment with paliperidone ER, 40.5 % attained food), with a better response and with fewer adverse effects
a composite response as compared with 28.0 % of the compared with haloperidol, olanzapine, or risperidone
placebo group (p = 0.046). The most common treatment- therapy [29]. However, given that there was no separate
emergent adverse effects were headache (15 %), dizziness analysis for the patients with SAD, and that the SAD sub-
(8.4 %), insomnia (6.5 %), dyspepsia (5.6 %), akathisia group was quite small, no clear conclusion can be drawn
(6.1 %), hypertonia (4.7 %), weight gain (7.5 %), and for the treatment of patients with SAD.
mean increase in prolactin levels (2.8 %). Unlike its sister A 12-week, randomized (1:1), open-label, parallel-
study mentioned above, no significant placebo effect was group, flexible-dose study examined the efficacy and safety
seen in this study. Again, results did not change when of quetiapine extended release (XR) in both patients with
comparing patients treated adjunctively with mood stabi- schizophrenia and those with SAD (400800 mg/day)
lizers or with antidepressants versus paliperidone ER versus risperidone (46 mg/day). The inclusion criteria
monotherapy. This study, along with the similar study consisted of having a minimum HAM-D score of 20 at
mentioned above, was part of a first registration program baseline and HAM-D item 1 score of minimum 2, pointing
for paliperidone ER in patient populations with SAD [25]. to the inclusion of depressed patients. A total of 18 patients
A 12-week, open-label, single-treatment, flexible-dose discontinued treatment from the quetiapine ER group
switch study compared the efficacy and different switch (eight due to adverse effects) and 26 patients in the
strategies versus oral ziprasidone (80160 mg/day) in risperidone group (ten due to lack of interest in the study).
stable patients with SAD and schizophrenia with subopti- Some patients also received antidepressants during the
mal efficacy or intolerable adverse effects to haloperidol, study: 14.0 % in the quetiapine XR group and 16.5 % in
olanzapine, or risperidone. Patients were switched by either the risperidone group. Greater improvement was seen on
immediate switching, 500 % taper (antipsychotic dose the PANSS total score, CDSS score, and HAM-D score in
was given in a dose of 50 % of the baseline for 1 week, the quetiapine XR group versus the risperidone group. A
Treatment of Schizoaffective Disorder

sub-analysis was also conducted on patients with Reports of sexual dysfunction, hormonal adverse effects,
schizophrenia and depressive symptoms; results indicated glucose intolerance, or discomfort at injection site were
that quetiapine XR was equally as efficacious as risperi- low. While the study was open-label and failed to include
done in improving depressive symptoms. Ten patients any affective rating scale to measure changes in mood, it
receiving quetiapine XR and seven receiving risperidone demonstrated that risperidone monotherapy was effective
discontinued treatment due to adverse effects. The most in about 50 % of participants, ameliorating the anxiety/
common side effects in the quetiapine XR group were depression and the uncontrolled hostility/excitement
somnolence (5.6 %), sedation (4.7 %), and hypotension aspects of SAD, while close to half of patients had either
(3.7 %). In the risperidone group, the most common side antidepressants or mood stabilizers added to their
effects were hyperprolactinemia (9.7 %), anxiety (4.9 %), risperidone monotherapy [26].
and insomnia (3.9 %). A small reduction in SAS total score A randomized, double-blind, parallel, fixed-dose,
was seen for quetiapine XR; this is in contrast with the 24-week study was conducted in schizophrenia and SAD
risperidone group, which showed a small increase. No patients with depressive symptoms in an outpatient setting
significant change was seen on metabolic parameters. This to evaluate the efficacy of olanzapine 10 mg, 15 mg, or
study supported the efficacy of once-daily quetiapine XR in 20 mg/day versus ziprasidone 80 mg, 120 mg, or
improving depressive symptoms, both in patients with 160 mg/day. Some patients were receiving antidepressant
schizophrenia and in those with SAD [32]. medications at baseline: 51.1 % of those receiving olan-
zapine and 54.7 % of those receiving ziprasidone. A sig-
3.2 Maintenance Treatment of Schizoaffective nificant number of patients completed the study in the
Disorder (SAD) olanzapine group. The number of patients discontinuing
treatment in the first 2 weeks of the study did not differ
A 6-month, open-label, non-randomized, uncontrolled, between the two groups, with the median time for dis-
single-arm European study examined the efficacy and continuation being 163 (olanzapine) and 73 (ziprasidone)
safety of risperidone long-acting injectable (RLAI) days (p \ 0.001). The discontinuation rates were as fol-
(2550 mg/2 weeks) in patients with stable SAD (inpa- lows: ziprasidone 80 mg/day (72.1 %), 120 mg/day
tients or outpatients) and a low mean PANSS score of (67.2 %), and 160 mg/day (71.6 %), and olanzapine
69.4 (20.7) and a GAF score of 59.4 (15.6) at base- 10 mg/day (50.0 %), 15 mg/day (64.4 %), and 20 mg/day
line. Most subjects were started on RLAI directly (with- (52.1 %). Poor responses to treatment or worsening of
out giving oral risperidone), and most patients (80 %) symptoms were significantly higher in the ziprasidone
were receiving antipsychotic monotherapy. The most group as compared with the olanzapine group, particularly
common reason for discontinuation from the study was the worsening of psychosis. Significant improvement was
withdrawal of consent (11 %), adverse effects (4 %), lack seen on CDSS score in both groups at 8 weeks; however,
of efficacy (4 %), and treatment non-adherence (3 %). At the treatment group difference was not significant. At
some point during the study, 19 % of the subjects 24 weeks, the olanzapine group showed significant
required additional therapy with oral risperidone (median improvement on the CDSS total score by last observation
modal dose = 3 mg), 48 % initiated treatment with carried forward (LOCF) analysis, but not by mixed effect
antidepressants, 47 % with anti-epileptic mood stabilizers, model repeat measurement (MMRM) analysis. Significant
and 14 % with lithium. Significant improvement in total improvement on the MADRS total score change was seen
PANSS score and subscale scores were found, starting in both groups using both MMRM and LOCF analysis. No
from week 4. There was a significant improvement in the significant treatment difference was seen on the PANSS
PANSS anxiety/depression and uncontrolled hostility/ex- total score using MMRM analysis; however, using LOCF
citement factors. Statistically significant positive changes analysis, the olanzapine group showed significant
were also seen in other outcome measures, i.e., CGI-S, improvement on the PANSS total score as compared with
total EPS Rating Scale (ESRS) score, and patient satis- the ziprasidone group. Greater improvement was seen in
faction. Marked improvement was seen in the social the GAF score in the olanzapine group versus the ziprasi-
functioning, emotional, and mental health parts of the done group at endpoint. Increase in weight gain, appetite,
36-item Short Form (SF-36) questionnaire. A total of and peripheral edema were reported in the olanzapine
66 % of the patients reported treatment-emergent adverse group, whereas psychosis, decrease in appetite, influenza,
effects; the most common side effects ([5 %) were and migraine were reported in the ziprasidone group. No
anxiety (11 %), insomnia, headache and worsening of significant difference was found in the levels of triglyc-
SAD symptoms (all 6 %). A significant increase in mean erides, prolactin, glycated hemoglobin (HbA1c), fasting
body weight and body mass index (BMI) was seen. glucose, cholesterol, or in QTc interval. In this study, dif-
J.-P. Lindenmayer, A. Kaur

ferences were more significant on MADRS score than on receiving aripiprazole versus placebo in SAD patients
CDSS score [27]. Overall, olanzapine appeared to be more compared with schizophrenia patients, although the result
effective at protecting patients from relapse and showed was not statistically significant. No significant difference
superiority in treating depression as compared with was found in the Brief Assessment of Cognition in
ziprasidone, pointing to an effect of olanzapine on mood. Schizophrenia (BACS), AIMS, BARS, SAS scores, or
A randomized (1:1), double-blind, 6-month study eval- metabolic parameters, comparable with the schizophrenia
uated the efficacy of olanzapine (1020 mg/day with 5-mg group. This study inadvertently supports the notion that
increments) versus quetiapine (300700 mg/day with antipsychotic polypharmacy may not be more effective
100-mg increments) in stable outpatients with schizophre- than monotherapy in patients with schizophrenia. Separate
nia and with SAD with predominant negative symptoms sub-analysis in subjects with SAD indicated that adjunctive
and poor functioning (mean baseline GAF score = 43). aripiprazole leads to a non-significant enhanced improve-
Significant improvement was seen in the olanzapine group ment on mean PANSS score as compared with
on most of the assessment measures compared with the schizophrenia patients. The failure to show any advantage
quetiapine group. The study was completed by 52.6 % of adjunctive aripiprazole in this study may be due to the
(olanzapine group) and 37.7 % (quetiapine) of patients, failure to require a minimum PANSS score criteria, a lack
while 32.0 and 12.9 % patients in the quetiapine group of a prospective treatment phase, or the use of a low dose
discontinued the study due to poor response or worsening of aripiprazole [30].
of symptoms, respectively. Headache and somnolence were A 2-year open-label, randomized, active-controlled
the most common side effects seen in both groups. Psy- study examined the efficacy in long-term remission and
chosis, pain, and anorexia were reported significantly in the safety of RLAI and oral quetiapine in both schizophrenia
quetiapine group as compared with the olanzapine group. and SAD patients. Clinically stable patients treated with
No significant difference was seen in weight gain, BMI, or oral risperidone, olanzapine, or oral antipsychotics were
treatment-emergent-movement disorder [28]. As in the switched to RLAI or oral quetiapine. Risperidone and
study above, olanzapine appeared to be superior on most quetiapine non-responders were excluded from the study.
outcome measures as compared with quetiapine in The reasons for study discontinuation were patients choice
stable outpatients. However, little information can be in the risperidone and quetiapine groups (18 %), side
derived specifically for patients with SAD. effects in the quetiapine group (15 %), and other reasons
A large randomized (1:1), double-blind, placebo-con- not specified in the risperidone (14 %) and quetiapine
trolled 16-week study examined the efficacy of adjunctive (20 %) groups. A significant difference between the two
oral aripiprazole (215 mg/day) to quetiapine groups was seen in patients who completed the study
(400800 mg/day) or risperidone (48 mg/day) in chronic, (n = 151 in the RLAI group vs. n = 120 in the quetiapine
stable outpatients with SAD and schizophrenia. Patients group) favoring RLAI. A higher number of patients met
were randomized to the aripiprazole group (n = 168) or remission criteria in the RLAI group than in the quetiapine
the placebo adjunctive group (n = 155), and 115 patients group. Significant differences were seen in CGI-Change
in the adjunctive aripiprazole group and 107 patients in the (CGI-C) score, MADRS total score, and MADRS apparent
adjunctive placebo group completed the treatment. Sub- sadness score favoring RLAI, but not in the MADRS
jects discontinued treatment for various reasons (aripipra- reported sadness score. Most common treatment-emergent
zole vs. placebo group): adverse effects (5.4 vs. 10.3 %), adverse effects were psychiatric symptoms (43.2 % RLAI;
withdrawing consent (8.9 vs. 5.8 %), lost to follow-up (7.1 43.0 % quetiapine), nervous system disorders (18.8 %
vs. 7.7 %), noncompliance (7.1 vs. 3.2 %), lack of efficacy RLAI; 27.6 % quetiapine), and somnolence (1.8 % RLAI,
(0.6 vs. 0 %), and other reasons not specified (2.4 vs. 11.3 % quetiapine). While this study clearly found RLAI to
3.9 %). The mean dose at endpoint of aripiprazole was be superior over quetiapine in both remission rates and in
10.3 mg/day, while the mean dose of quetiapine was improvements in depression symptoms, it is not clear
516 mg/day and 513 mg/day in the placebo and the arip- whether these improvements were due to more consistent
iprazole groups, respectively. The mean dose at endpoint of antipsychotic exposure in the depot administration group
risperidone was 4.8 mg/day and 4.6 mg/day in the placebo versus the oral group [31].
and aripiprazole groups, respectively. The mean baseline A randomized, double-blind, placebo-controlled inter-
PANSS total score was 75. No difference was found in the national study evaluated the efficacy of paliperidone LAI
mean total PANSS score, CGI-S, PANSS positive, PANSS once monthly injectable for both acute and maintenance
negative, CGI-I, CDSS, Subjective Well-Being under treatment (78234 mg/month) either as monotherapy or
Neuroleptic (SWN), and Arizona Sexual Experience Scale adjunctively to mood stabilizers or antidepressants in only
(ASEX) score. A sub-analysis of the SAD group found that SAD patients. While this study included an acute phase,
the mean total PANSS score improved with patients we elected to discuss this study in our maintenance
Treatment of Schizoaffective Disorder

treatment section given its long-term design. The study 4 Discussion


consisted of three phases: a 13-week open-label, flexible-
dose, lead-in-period, followed by 12-week fixed-dose 4.1 Acute Therapy Studies
stabilization period, followed by a 15-month, double-
blind, relapse-prevention phase. Paliperidone palmitate The only antipsychotics examined for their respective
LAI was administered at the initial dose of 234 mg on efficacy in appropriate samples of well-defined patients
day 1 and 156 mg on day 8. Flexible doses were given with SAD have been aripiprazole, ziprasidone, risperidone
thereafter (117234 mg in week 5; 78234 mg in weeks 9 oral or LAI, and paliperidone ER oral or LAI. In fact, the
and 13). The mean dose given in the double-blind phase only studies with adequate sample size and specifically
was 146.25 mg. A total of 24.6 % patients experienced restricted to patients with SAD have been three studies
relapse, 49.4 % completed the study, and 26.0 % dis- with paliperidone, which led to the FDA approval for this
continued the study (withdrawal of consent being the compound for the acute and maintenance treatment of
most common cause). The number of patients in the open- patients with SAD. For acutely ill hospitalized patients
label phase receiving concomitant antidepressants and with both prominent psychotic and affective symptoms, a
mood stabilizers was 161 and 186, respectively. In the higher dose of paliperidone ER (12 mg/day) either as
double-blind phase of the study, 78 and 105 patients were monotherapy or as adjunct to mood stabilizers or antide-
receiving concomitant antidepressants and mood stabiliz- pressants was effective and safe [24, 25, 33]. Risperidone
ers, respectively. Significant differences were found for monotherapy was also found to be more efficacious in
all-cause discontinuations and time to all-cause discon- reducing the symptoms and severity of patients with SAD,
tinuations in favor of the paliperidone ER group versus depressed type, compared with the combination of
the placebo group. The study found significant delay in haloperidol and sertraline [22]. This finding is not sur-
time to relapse, with relapse rates of 15.2 and 33.5 % in prising in the light of the study by Canuso and colleagues
the paliperidone LAI and placebo group, respectively. In [24, 25] with paliperidone ER, which showed that
the double-blind phase, the rate of relapse was 2.49 times paliperidone ER was effective in patients with SAD, since
higher for placebo than for paliperidone LAI. More this compound is an active metabolite of the parent com-
patients experienced relapse in the placebo group in both pound risperidone. Also, the need for concomitant medi-
monotherapy and adjunctive therapy versus paliperidone cations for anxiety and insomnia was much less in the
LAI. A number of subjects were hospitalized due to risperidone group than in the haloperidol and sertraline
worsening of SAD symptoms: 3.0 % (paliperidone LAI groups. This provides an economical advantage to patients.
group) and 7.1 % (placebo group). Significant improve- However, we do not know the specific efficacy of other
ments in the paliperidone LAI group versus placebo were second-generation antipsychotics in patients with SAD, as
observed in Personal and Social Performance Scale (PSP), these compounds have not been tested in pure populations
YMRS scores, PANSS total scores, and CGI-S-SCA of SAD patients. Given their similarity in D2 antagonism,
scores. The most common side effects in both treatment one can expect that these compounds may be similarly as
groups were as follows (paliperidone LAI vs. placebo): effective in patients with SAD as they are in patients with
SAD symptoms (5.9 vs. 3.0 %), weight gain (4.7 vs. schizophrenia. One exception is most likely clozapine,
8.5 %), nasopharyngitis (3.5 vs. 5.5 %), headache (3.5 vs. which has a very complex mechanism of action and effi-
5.5 %), and insomnia (7.1 vs. 4.9 %). EPS-related adverse cacy cannot be extrapolated from studies with
effects were experienced in the paliperidone LAI group schizophrenia patients to patients with SAD.
(8.5 %) and the placebo group (7.1 %) as follows One of the few studies comparing two antipsychotics in
(paliperidone LAI vs. placebo): hyperkinesia (3.7 vs. patients with SAD found ziprasidone (80160 mg/day)
2.9 %), Parkinsonism (3.0 vs. 1.8 %), tremor (1.2 vs. versus aripiprazole (1030 mg/day) to be equally as
2.4 %), dyskinesia (0.6 vs. 1.8 %), dystonia (0 vs. 1.2 %). effective as ziprasidone in reducing psychotic symptoms in
Prolactin-related adverse effects (paliperidone LAI vs. acutely ill patients with SAD, improving overall func-
placebo) were experienced by 13.9 versus 5.8 % of tioning and affect. The only advantage of ziprasidone was
women and 7.1 versus 1.2 % of men. More subjects to show an early positive effect starting from day 4 of the
reported weight gain (C7 %) in the paliperidone LAI treatment, which was not seen in the aripiprazole group.
(13.0 %) than the placebo (6.0 %) groups. In total, this However, no such distinct advantage existed beyond the
trial supports the monthly use of paliperidone LAI in initial phase of treatment [20].
preventing the relapse of psychotic, manic, and depressive While several other studies of patients with acute
symptoms in the schizoaffective population in patients schizophrenia and acute SAD are available, none have
willing to accept an LAI preparation [33] (Table 2). analyzed their sample of patients with SAD separately, nor
Table 2 Studies on maintenance treatment of schizoaffective disorder
Study Sample [diagnostic Study period Study type Study arms Outcome Results
criteria] measures

Mohl et al. N = 249 [DSM-IV] 6 mo, maintenance tx Non-ran, single- RLAI (2575 mg/2 wk) PANSS, CGI-S, Total PANSS score, positive symptom, negative
2005 [26] arm, ol GAF, SF-36, symptom, and general psychopathology subscale
ESRS scores statistically significantly improved from BL
(p \ 0.001). Mean GAF score improved significantly
(p \ 0.001). CGI-S score reduced significantly
(p \ 0.001). Total ESRS score reduced progressively
at 4 wk and after (p \ 0.001). SF-36 score reduced
significantly (p \ 0.01). Most pts satisfied with tx
(p \ 0.001). Statistically significant (p \ 0.001)
increase in body weight and BMI at endpoint
Kinon et al. SAD and SCH pts 24 wk, maintenance ran, db, fixed- OLA (1020 mg/day) vs. CDSS, MADRS, At 8 wk, significant improvement was seen on CDSS
2006 [27] with prominent therapy dose, parallel, ZIP (80160 mg/day) PANSS, GAF score but no in-between group difference seen
depressive mc (p = 0.497, LOCF; p = 0.0493, MMRM). At 24 wk,
symptom = 394 OLA group showed significantly more improvement on
[DSM-IV] depressive symptoms and GAF (p \ 0.017) scores.
Significant improvement seen on CDSS score by
LOCF (p = 0.017) but not by MMRM (p = 0.105)
analysis. On MADRS scale, significant improvement
observed by both MMRM (p = 0.010) and LOCF
(p = 0.003) analysis. Significantly more OLA pts
adhered to the study (p \ 0.001)
Kinon et al. OLA = 171 6 mo, maintenance mc, db, ran OLA (1020 mg/day) vs. SANS, PANSS, Significant improvement on SANS total score was seen
2006 [28] QUE = 175 therapy QUE (300700 mg/day) Illness factors in both groups with no statistically significant
subscale of difference (p = 0.09). OLA group showed significantly
SAD pts on CMRS?, PFQ, more improvement on PANSS positive symptoms (p =
OLA = 113 CDSS 0.022), CGI severity scale (p = 0.020), CGI
SAD pts on improvement scale (p \ 0.001), CMRS?illness
QUE = 117 factors (p = 0.021), GAF score (p = 0.01), Instrumental
[DSM-IV] Role domain of QLS (p = 0.029) and PFQ - level of
effort (p = 0.014) as compared to QUE. CDS total
score was statistically significantly improved in both
groups (p \ 0.001). More OLZ groups patients
completed the study (p = 0.007).
Alptekin et al. SAD = 45, 12 wk, maintenance ol, non-ran, ZIP (80160 mg/day) vs. BPRS, CGI-S, Statistically significant change in BPRS in ZIP group
2009 [29] total = 285 therapy BL-controlled, OLA, RIS, and HAL. All PANSS, (p \ 0.0001). Significant improvement in CGI-S
[DSM-IV] single-tx three drugs given within MADRS, GAF (p \ 0.001), PANSS (p \ 0.001), and MADRS score
flexible-dose 25 % of RDD per package in all three groups switched to ZIP (p \ 0.05) except in
study OLA group on MADRS scale. Significant
improvement was seen on GAF (p \ or = 0.002) at
wk 12 in all three pre-switch groups; significant
improvement seen on DAI in HAL and RIS pre-switch
groups (p \ 0.05) but not in OLA pre-switch group
J.-P. Lindenmayer, A. Kaur
Table 2 continued
Study Sample [diagnostic Study period Study type Study arms Outcome Results
criteria] measures

Kane et al. 2009 SAD = 71, 16 wk, maintenance mc, db, pc, ran ARI (215 mg/day) vs. PANSS, CGI-S, Both tx well tolerated and efficacious. No statistically
[30] SCH = 252 therapy PL ? stable dosage of CDSS, ASEX, significant difference from BL to endpoint in CGI-S
[DSM-IV-TR] QUE (400800 mg/day) or FSI, BACS, scores (p = 0.689), PANSS positive (p = 0.279) or
RIS (48 mg/day) SWN, CGI-I negative scores (p = 0.836), SWN scores (p = 0.466),
mean CGI-I scores (p = 0.545), CDSS scores
(p = 0.927), ASEX scores (p = 0.275), FSI scores
(p = 0.650) and BACS scores
Smeraldi et al. SAD = 118, 2 y, maintenance therapy ran (1:1), active- RLAI (33.6 10.1 mg/2 Rate of remission, More subjects on RLAI completed tx vs. QUE
2013 [31] SCH = 548 control, ol wk) vs. QUE (mean mode PANSS, (p = 0.0074). 101/151 pts on RLAI and 72/120 pts on
Treatment of Schizoaffective Disorder

[DSM-IV] dose = 413 159.2 mg) MADRS, CGI- QUE in remission at endpoint. Significant
C scores improvements seen on MADRS total (p = 0.004) and
apparent sadness score (p = 0.003) and CGI-C score
(p \ 0.0001) favored RLAI over QUE. No significant
change seen on MADRS reported sadness score
(p = 177).
Fu et al. 2015 [33] Total = 334, [DSM- 13-wk ol flexible-dose ran, db, pc, int PAL (78, 117, 156, PANSS, PSP, Monthly PAL statistically significantly delays time to
IV; 95 % of pts phase; 12-wk fixed-dose 234 mg/month) vs. PL YMRS, CGI-S- relapse for psychotic, depressive, and manic symptoms
met diagnostic stabilization period; SCA, HDRS-21, vs. PL (p \ 0.001). For mono, relapse risk was 3.38
criteria of DSM- 15-mo db, relapse- MSQ, PSP greater than PL (p = 0.002); for adjunctive tx, relapse
V] prevention phase risk was 2.03 greater than PL (p = 0.021). PAL
superior on PSP scale (p = 0.014) vs. PL. Statistically
significant improvement in total PANSS (p \ 0.001),
CGI-S-SCA (p \ 0.001), HDRS-21 (p \ 0.001),
YMRS (p \ 0.001), and MSQ (p \ 0.001) scores.
Mean change on PSP from BL favored PAL monthly
over PL (p = 0.014)

ARI aripiprazole, ASEX Arizona Sexual Experience Scale, BACS Brief Assessment of Cognition in Schizophrenia, BL baseline, BMI body mass index, BPRSd Brief Psychosis Rating Scale - derived, CDSS/
CDS Calgary Depression Scale for Schizophrenia, CGI-C CGI-Change, CGI-C-SCA CGI-S for Schizoaffective Disorder, CGI-I CGI-Global Improvement scale, CGI-S Clinical Global Impression-Severity
scale, CMRS? Case Manager Rating Scale-Plus, DAI Drug Attitude Inventory, db double-blind, DSM Diagnostic and Statistical Manual of Mental Disorders, ESRS Extrapyramidal Symptoms Rating Scale,
GAF Global Assessment of Functioning, HAL haloperidol, HDRS Hamilton Depression Scale, LOCF last observation carried forward, MADRS Montgomery Asberg Depression Rating Scale, mc
multicenter, MMRM mixed effect model repeat measurement, mo month, mono monotherapy, MSQ Medication Satisfaction Questionnaire, ol open-label, OLA olanzapine, PAL paliperidone, PANSS
Positive and Negative Syndrome Scale, pc placebo-controlled, PFQ Patient Functioning Questionnaire, PL placebo, PPS Patient Preference Scale, pt(s) patient(s), QOL quality of life, QUE XR quetiapine
extended release, ran randomized, RDD recommended daily dose, RIS risperidone, RLAI risperidone long-acting injectable, SAD schizoaffective disorder, SCH schizophrenia, SF-36 36-item short-form
health questionnaire, SWN Subjective Well-Being under Neuroleptic, tx treatment, wk week, YMRS Young Mania Rating Scale, ZIP ziprasidone
J.-P. Lindenmayer, A. Kaur

were they powered enough to allow clear conclusions from In contrast, RLAI (33 10 mg) as compared with oral
such a sub-analysis. Clinicians are left to expand the quetiapine (413 159 mg) has been shown to be more
findings for acute patients with schizophrenia to acute effective in sustaining remission as well as improving
patients with SAD regarding the efficacy of the different overall functioning and affect in clinically stable patients
antipsychotics tested. A preliminary and cautious conclu- with SAD, most likely due to better assured adherence with
sion would be that all atypical antipsychotics, which have RLAI [31]. It is well known that long-term adherence to
been successfully tested in patients with schizophrenia, daily oral antipsychotic treatment regimens is often diffi-
would also be efficacious in patients with SAD. The cult to achieve due to challenges in patients adherence [37,
additional open question is what the adjunctive mood sta- 38]. Lack of adherence will contribute to suboptimal out-
bilizers or antidepressants added to the effects of antipsy- comes and psychotic and mood relapses [39]. In contrast,
chotics would bring, particularly in patients with high regular dosing via injection eliminates the burden of daily
levels of depression or mania. One such study, albeit rare, oral medication intake and facilitates monitoring of treat-
was a study with risperidone monotherapy, which was ment adherence by the physician [41, 42]. LAI therapies,
found to be more efficacious in reducing the symptoms and such as once-monthly paliperidone palmitate, have
severity of SAD, depressed type, than the combination of demonstrated improvement in long-term outcomes in
haloperidol and sertraline [22]. This points to the possi- schizophrenia patients compared with placebo [40].
bility that adjunctive antidepressants may not always be
necessary in the acute treatment of patients with SAD, 4.3 Is Monotherapy with Antipsychotic Medication
whereby patients with concomitant mood stabilizers or Adequate in the Management of SAD?
antidepressants may respond in a manner similar to patients
receiving antipsychotic monotherapy. Finally, the question Several clinical trials have indicated that atypical antipsy-
whether polypharmacy with two antipsychotics may be chotics without adjunctive mood stabilizers or antidepres-
more efficacious than monotherapy was also addressed in sants may be as effective as adjunctive antidepressant or
one study. The use of aripiprazole (215 mg/day) as an mood stabilizer regimens for both acute and maintenance
adjunctive treatment to quetiapine (400800 mg/day) or treatment of SAD [31, 33]. In particular, studies conducted
risperidone (48 mg/day) was well tolerated and generally with paliperidone ER and paliperidone LAI support that
safe, but failed to find any distinct advantage on psychotic atypical antipsychotics are as effective as monotherapy in
and affective SAD symptoms [30]. the treatment of both psychotic and affective components
of the disorder [24, 25, 33]; however, the trials were not
4.2 Maintenance/Relapse-Prevention Studies powered enough to allow statistical sub-analysis of patients
receiving mood stabilizers or antidepressants compared
There also have been few studies examining the long-term with patients receiving monotherapy. Another result sup-
efficacy and tolerability of antipsychotic maintenance porting this possibility of antipsychotic monotherapy for
treatment for patients with SAD. Most available mainte- SAD patients is provided by the use of risperidone
nance studies include both patients with schizophrenia and monotherapy showing advantages over the combined
those with SAD, without sub-analyses for the SAD sub- treatment of haloperidol with sertraline in SAD, depressive
samples. As with the acute studies, the clinician must type.
extrapolate from results of studies with mixed More studies need to be conducted in SAD patient
schizophrenia and SAD diagnostic groups. One of the few populations, and should be adequately powered and
longer-term studies specifically with SAD patients specifically comparing SAD patients receiving monother-
demonstrated the effectiveness of risperidone for treating apy and SAD patients receiving mood stabilizers or
not only psychotic symptoms but also anxiety/depression antidepressants to have a clearer idea of the benefit of
symptoms and uncontrolled hostility/excitement aspects of antipsychotics as monotherapy in SAD patient populations.
SAD [26]. In terms of other specific antipsychotics, both This is particularly important for clinicians who frequently
olanzapine (1020 mg/day) and ziprasidone use these adjunctive treatments for patients with SAD.
(80160 mg/day) have shown effective improvement in Another related question is whether adjunctive mood sta-
depressive symptoms, besides improving overall function- bilizers or antidepressants may be specifically helpful in
ing in SAD patients. However, olanzapine was associated patients with high measures of mania and/or depression.
with greater effects on weight and metabolic parameters Finally, there are no studies on the preventive anti-suicidal
[27]. Both quetiapine XR (400800 mg/day) and risperi- effects of antipsychotics in patients with SAD. This issue is
done (46 mg/day) have shown comparable maintenance crucial, as patients with SAD have a high level of suicidal
effects on depressive symptoms as measured by CDSS and behavior, which often leads to psychiatric admissions.
HAM-D [32].
Treatment of Schizoaffective Disorder

5 Conclusion 2. Raymond Lake C. Disorders of thought are severe mood disor-


ders: the selective attention defect in mania challenges the
Kraepelinian dichotomy. A review. Schizophr Bull.
Our review found there are relatively few studies with 2008;34(1):10917. doi:10.1093/schbul/sbm035.
either an active comparator or placebo that examine the 3. Kasanin J. The acute schizoaffective psychoses. Am J Psychiatry.
efficacy of antipsychotics for patients with SAD without an 1933;13(97126):4.
4. American Psychiatric Association. Diagnostic and statistical
admixture of patients with schizophrenia. While many
manual of mental disorders, third edition text revised (DSM-III-
antipsychotic studies for patients with schizophrenia also TR). Washington DC: APA; 1987.
include SAD patients, no sub-analyses are conducted tar- 5. American Psychiatric Association. Diagnostic and statistical
geting this subgroup, most likely due to the under-powered manual of mental disorders. 5th ed. Arlington, VA: American
Psychiatric Association; 2013.
designs. Therefore, the only conclusion that can be drawn
6. Olfson M, Marcus SC, Wan GJ. Treatment patterns for
from these studies is that antipsychotics may be as effica- schizoaffective disorder and schizophrenia among Medicaid
cious and tolerable in SAD patients as they are in patients patients. Psychiatr Serv. 2009;60(2):2106. doi:10.1176/appi.ps.
with schizophrenia. 60.2.210.
7. Perala J, Suvisaari J, Saarni SI, et al. Lifetime prevalence of
Only oral paliperidone ER and LAI and risperidone have
psychotic and bipolar I disorders in a general population. Arch
been shown to be effective and safe in reducing psychotic Gen Psychiatry. 2007;64(1):1928. doi:10.1001/archpsyc.64.1.
as well as affective components of SAD in controlled 19.
studies of patients with SAD. Both paliperidone ER and 8. Abrams DJ, Rojas DC, Arciniegas DB. Is schizoaffective disorder
a distinct categorical diagnosis? A critical review of the literature.
LAI appear to be efficacious both in acutely ill patients
Neuropsychiatr Dis Treat. 2008;4(6):1089109. doi:10.2147/
with prominent affective symptoms and in the maintenance NDT.S4120.
treatment phase of patients with SAD. While there are no 9. Harrow M, Grossman LS, Herbener ES, Davies EW. Ten-year
supporting data, it is possible that other atypical antipsy- outcome: patients with schizoaffective disorders, schizophrenia,
affective disorders and mood-incongruent psychotic symptoms.
chotics may have similar efficacy in patients with SAD as
Br J Psychiatry. 2000;177:4216.
the two compounds mentioned above. 10. DeFrances CJ, Cullen KA, Kozak LJ. National Hospital Dis-
We conclude with a number of research recommendations charge Survey: 2005 annual summary with detailed diagnosis and
for the study of treatment options for patients with SAD. procedure data. Vital Health Stat. 2007;165:1209.
11. Cheniaux E, Landeira-Fernandez J, Lessa Telles L, et al. Does
First, there is a need for studies with patients specifically
schizoaffective disorder really exist? A systematic review of the
diagnosed with SAD for both the acute and the maintenance studies that compared schizoaffective disorder with schizophrenia
phase. The sample size needs to be adequate to allow a pri- or mood disorders. J Affect Disord. 2008;106(3):20917. doi:10.
mary analysis of efficacy and to allow for analysis of the 1016/j.jad.2007.07.009.
12. Kent S, Fogarty M, Yellowlees P. Heavy utilization of inpatient
SAD subtypes, depressed and bipolar. A second recom-
and outpatient services in a public mental health service. Psy-
mendation concerns the need for studies of patients with chiatr Serv. 1995;46(12):12547.
SAD stratified into patients with and without mood stabi- 13. Azorin JM, Kaladjian A, Fakra E. Current issues on schizoaf-
lizers or antidepressants to allow the examination of the fective disorder. Encephale. 2005;31(3):35965 [in French].
14. Keck PE Jr, McElroy SL, Strakowski SM, West SA. Pharmaco-
adjunctive role of these psychotropic medications. A third
logic treatment of schizoaffective disorder. Psychopharmacology
recommendation is the need to focus on specific co-morbid (Berl). 1994;114(4):52938. doi:10.1007/BF02244982.
aspects of patients with SAD, such as suicidality and sub- 15. Murru A, Pacchiarotti I, Nivoli AM, Grande I, Colom F, Vieta E.
stance use disorders. Data from such studies will fill the gap What we know and what we dont know about the treatment of
schizoaffective disorder. Eur Neuropsychopharmacol.
of evidence-based treatment approaches and help clinicians
2011;21(9):68090. doi:10.1016/j.euroneuro.2011.03.001.
in important treatment decisions for these complex patients. 16. Levinson DF, Umapathy C, Musthaq M. Treatment of schizoaf-
fective disorder andschizophrenia with mood symptoms. Am J
Compliance with Ethical Standards Psychiatry. 1999;156(8):113848.
17. Cascade E, Kalali AH, Buckley P. Treatment of schizoaffective
Conflicts of interest J.-P. Lindenmayer, MD, has received research disorder. Psychiatry (Edgmont). 2009;6(3):157.
grant support in the last 2 years from Envivo, Pfizer, Alkermes, 18. Jager M, Becker T, Weinmann S, Frasch K. Treatment of
Neurocrine, Roche, and Avanir. A. Kaur, MD, has no conflicts of schizoaffective disorder: a challenge for evidence-based psychi-
interest to report. atry. Acta Psychiatr Scand. 2010;121(1):2232. doi:10.1111/j.
1600-0447.2009.01424.x.
Funding No sources of funding were used to assist with the 19. First MB. Towards harmonization: an annotated guide to differ-
preparation of this review. ences in the DSM-IV and ICD-10 definitions of mental disorders.
2007: p. 24 [online]. Available from: http://bjp.rcpsych.org/
content/bjprcpsych/suppl/2009/11/02/195.5.382.DC1/bjp_195_
References ds382.pdf. Accessed 18 Sept 2015.
20. Zimbroff D, Warrington L, Loebel A, Yang R, Siu C. Compar-
ison of ziprasidone and aripiprazole in acutely ill patients with
1. Kraepelin E. Dementia praecox and paraphrenia. Edinburgh: schizophrenia or schizoaffective disorder: a randomized, double-
Livingston; 1919.
J.-P. Lindenmayer, A. Kaur

blind, 4-week study. Int Clin Psychopharmacol. 31. Smeraldi E, Cavallaro R, Folnegovic-Smalc V, Bidzan L, Emin
2007;22(6):36370. Ceylan M, Schreiner A. Long-term remission in schizophrenia
21. Kinon BJ, Volavka J, Stauffer V, Edwards SE, Liu-Seifert H, and schizoaffective disorder: results from the risperidone long-
Chen L, Adams DH, Lindenmayer JP, McEvoy JP, Buckley PF, acting injectable versus quetiapine relapse prevention trial
Lieberman JA, Meltzer HY, Wilson DR, Citrome L. Standard and (ConstaTRE). Ther Adv Psychopharmacol. 2013;3(4):1919. doi:
higher dose of olanzapine in patients with schizophrenia or 10.1177/2045125313479127.
schizoaffective disorder: a randomized, double-blind, fixed-dose 32. Di Fiorino M, Montagnani G, Trespi G, Kasper S. Extended-
study. J Clin Psychopharmacol. 2008;28(4):392400. doi:10. release quetiapine fumarate (quetiapine XR) versus risperidone in
1097/JCP.0b013e31817e63a5. the treatment of depressive symptoms in patients with schizoaf-
22. Izakova L, Andre I, Halaris A. Combination therapy or fective disorder or schizophrenia: a randomized, open-label,
monotherapy for the depressed type of schizoaffective disorder. parallel-group, flexible-dose study. Int Clin Psychopharmacol.
Neuropsychiatr Dis Treat. 2009;5:91101. 2014;29(3):16676. doi:10.1097/YIC.0000000000000017.
23. Glick ID, Mankoski R, Eudicone JM, Marcus RN, Tran QV, 33. Fu DJ, Turkoz I, Simonson RB, Walling DP, Schooler NR,
Assuncao-Talbott S. Theefficacy, safety, and tolerability of Lindenmayer JP, Canuso CM, Alphs L. Paliperidone palmitate
aripiprazole for the treatment of schizoaffective disorder: results once-monthly reduces risk of relapse of psychotic, depressive,
from a pooled analysis of a sub-population of subjects from two and manic symptoms and maintains functioning in a double-
randomized, double-blind, placebo-controlled, pivotal trials. blind, randomized study of schizoaffective disorder. J Clin Psy-
J Affect Disord. 2009;115(12):1826. doi:10.1016/j.jad.2008. chiatry. 2015;76(3):25362. doi:10.4088/JCP.14m09416.
12.017. 34. Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG,
24. Canuso CM, Lindenmayer JP, Kosik-Gonzalez C, Turkoz I, Zimbroff DL, Ali MW. Efficacy and safety of aripiprazole and
Carothers J, Bossie CA, Schooler NR. A randomized, double- haloperidol versus placebo in patients with schizophrenia and
blind, placebo-controlled study of 2 dose ranges of paliperidone schizoaffective disorder. J Clin Psychiatry. 2002;63(9):76371.
extended-release in the treatment of subjects with schizoaffective 35. Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E,
disorder. J Clin Psychiatry. 2010;71(5):58798. doi:10.4088/JCP. Stringfellow J, Ingenito G, Marder SR. Aripiprazole, an
09m05564yel. antipsychotic with a novel mechanism of action, and risperidone
25. Canuso CM, Schooler N, Carothers J, Turkoz I, Kosik-Gonzalez vs placebo in patients with schizophrenia and schizoaffective
C, Bossie CA, Walling D, Lindenmayer JP. Paliperidone exten- disorder. Arch Gen Psychiatry. 2003;60(7):68190.
ded-release in schizoaffective disorder: a randomized, controlled 36. Kemp AS, Schooler NR, Kalali AH, Alphs L, Anand R, Awad G,
study comparing a flexible dose with placebo in patients treated Davidson M, Dube S, Ereshefsky L, Gharabawi G, Leon AC,
with and without antidepressants and/or mood stabilizers. J Clin Lepine JP, Potkin SG, Vermeulen A. What is causing the reduced
Psychopharmacol. 2010;30(5):48795. doi:10.1097/JCP. drug-placebo difference in recent schizophrenia clinical trials and
0b013e3181eeb600. what can be done about it? Schizophr Bull. 2010;36(3):5049.
26. Mohl A, Westlye K, Opjordsmoen S, Lex A, Schreiner A, Benoit doi:10.1093/schbul/sbn110 (Epub 2008 Aug 22).
M, Braunig P, Medori R. Long-acting risperidone in stable pa- 37. Murru A, Pacchiarotti I, Nivoli AM, Bonnin CM, Patrizi B,
tients with schizoaffective disorder. J Psychopharmacol. Amann B, Vieta E, Colom F. Rates and clinical correlates of
2005;19(5 Suppl):2231. treatment non-adherence in schizoaffective bipolar patients. Acta
27. Kinon BJ, Lipkovich I, Edwards SB, Adams DH, Ascher-Svanum Psychiatr Scand. 2012;125(5):4128. doi:10.1111/j.1600-0447.
H, Siris SG. A 24-week randomized study of olanzapine versus 2012.01837.x.
ziprasidone in the treatment of schizophrenia or schizoaffective 38. Murru A, Pacchiarotti I, Amann BL, Nivoli AM, Vieta E, Colom
disorder in patients with prominent depressive symptoms. J Clin F. Treatment adherence in bipolar I and schizoaffective disorder,
Psychopharmacol. 2006;26(2):15762. bipolar type. J Affect Disord. 2013;151(3):10038. doi:10.1016/j.
28. Kinon BJ, Noordsy DL, Liu-Seifert H, Gulliver AH, Ascher- jad.2013.08.026.
Svanum H, Kollack-Walker S. Randomized, double-blind 39. Lindenmayer JP, Liu-Seifert H, Kulkarni PM, Kinon BJ, Stauffer
6-month comparison of olanzapine and quetiapine in patients V, Edwards SE, Chen L, Adams DH, Ascher-Svanum H, Buckley
with schizophrenia or schizoaffective disorder with prominent PF, Citrome L, Volavka J. Medication nonadherence and treat-
negative symptoms and poor functioning. J Clin Psychopharma- ment outcome in patients with schizophrenia or schizoaffective
col. 2006;26(5):45361 (Erratum in: J Clin Psychopharmacol. disorder with suboptimal prior response. J Clin Psychiatry.
2009 Apr;29(2):169). 2009;70(7):9906. doi:10.4088/JCP.08m04221.
29. Alptekin K, Hafez J, Brook S, Akkaya C, Tzebelikos E, Ucok A, 40. Pandina G, Lane R, Gopal S, Gassmann-Mayer C, Hough D,
El Tallawy H, Danaci AE, Lowe W, Karayal ON. Efficacy and Remmerie B, Simpson G. A double-blind study of paliperidone
tolerability of switching to ziprasidone from olanzapine, risperi- palmitate and risperidone long-acting injectable in adults with
done or haloperidol: an international, multicenter study. Int Clin schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry.
Psychopharmacol. 2009;24(5):22938. doi:10.1097/YIC. 2011;35(1):21826. doi:10.1016/j.pnpbp.2010.11.008.
0b013e32832c2624. 41. Kane JM, Eerdekens M, Lindenmayer JP, Keith SJ, Lesem M,
30. Kane JM, Correll CU, Goff DC, Kirkpatrick B, Marder SR, Karcher K. Long-acting injectable risperidone: efficacy and
Vester-Blokland E, Sun W, Carson WH, Pikalov A, Assuncao- safety of the first long-acting atypical antipsychotic. Am J Psy-
Talbott S. A multicenter, randomized, double-blind, placebo- chiatry. 2003;160(6):112532.
controlled, 16-week study of adjunctive aripiprazole for 42. Nasrallah HA. The case for long-acting antipsychotic agents in
schizophrenia or schizoaffective disorder inadequately treated the post-CATIE era. Acta Psychiatr Scand. 2007;115(4):2607.
with quetiapine or risperidone monotherapy. J Clin Psychiatry.
2009;70(10):134857. doi:10.4088/JCP.09m05154yel.