Combination therapy or monotherapy for the depressed type of schizoaffective disorder.

Abstract

Several studies have demonstrated the effectiveness of adjunctive antidepressant drug therapy to improve the depressive or negative symptoms of schizoaffective disorder, however, monotherapy with atypical antipsychotics may be advantageous. We compared the efficacy and safety of risperidone monotherapy versus combination therapy of haloperidol with sertaline for the acute treatment of schizoaffective disorder, depressed type. This is an open label study of 52 female inpatients randomly assigned to risperidone alone (N = 26) or haloperidol in combination with sertraline (N = 26) for 12 weeks. The mean daily doses of medications were: risperidone: 3.75-3.29 mg/day, haloperidol: 5.35-4.15 mg/day, sertraline: 65.39-133.82 mg/day. Efficacy was measured using clinical rating scales of treatment, safety, and tolerability. Risperidone patients showed statistically significant greater improvement than haloperidol-sertraline patients on efficacy measures including Positive and Negative Syndrome Scale and Clinical Global Impressions rating. A higher number of risperidone patients dropped out of the study early. Fewer adverse events and lesser need for concomitant medications occurred in patients on risperidone. The risperidone group showed better psychological, social and occupational functioning (Global Assessment of Functioning) and higher quality of life (Heinrich's Quality of Life Scale). Risperidone has higher antipsychotic efficacy and tolerability compared with haloperidol-sertraline combination for the acute treatment of schizoaffective disorder, depressed type. Both treatments were comparable in terms of antidepressant efficacy.

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Neuropsychiatric Disease and Treatment 2009:5 91–101
91
O R I G I N A L R E S E A R C H
Combination therapy or monotherapy
for the depressed type of schizoaffective disorder
Lubomira Izáková1
Ivan Andre1
Angelos Halaris2
1Psychiatric Clinic, Faculty
of Medicine Comenius University
and Faculty Hospital, Bratislava,
Slovakia; 2Department of Psychiatry
and Behavioral Neurosciences, Loyola
University Medical Center, Maywood,
IL, USA
Correspondence: Angelos Halaris
Department of Psychiatry and Behavioral
Neurosciences, Loyola University Medical
Center, 2160 S. First Ave. Building 105
Room 1940 Maywood, IL 60153 USA
Tel +1 708 216 3275
Fax +1 708 216 5885
Email ahalaris@lumc.edu
Abstract: Several studies have demonstrated the effectiveness of adjunctive antidepressant
drug therapy to improve the depressive or negative symptoms of schizoaffective disorder,
however, monotherapy with atypical antipsychotics may be advantageous. We compared the
effi cacy and safety of risperidone monotherapy versus combination therapy of haloperidol with
sertaline for the acute treatment of schizoaffective disorder, depressed type. This is an open label
study of 52 female inpatients randomly assigned to risperidone alone (N = 26) or haloperidol in
combination with sertraline (N = 26) for 12 weeks. The mean daily doses of medications were:
risperidone: 3.75–3.29 mg/day, haloperidol: 5.35–4.15 mg/day, sertraline: 65.39–133.82 mg/day.
Effi cacy was measured using clinical rating scales of treatment, safety, and tolerability. Risperi-
done patients showed statistically signifi cant greater improvement than haloperidol-sertraline
patients on effi cacy measures including Positive and Negative Syndrome Scale and Clinical
Global Impressions rating. A higher number of risperidone patients dropped out of the study
early. Fewer adverse events and lesser need for concomitant medications occurred in patients
on risperidone. The risperidone group showed better psychological, social and occupational
functioning (Global Assessment of Functioning) and higher quality of life (Heinrich’s Quality
of Life Scale). Risperidone has higher antipsychotic effi cacy and tolerability compared with
haloperidol-sertraline combination for the acute treatment of schizoaffective disorder, depressed
type. Both treatments were comparable in terms of antidepressant effi cacy.
Keywords: schizoaffective disorder, depressed type, risperidone, haloperidol, sertraline
Introduction
The existence of schizoaffective disorder as a separate diagnostic entity has been
the subject of debate.1–3 It has often been considered to be the “waste” basket of a
diagnosis by exclusion. Nevertheless, the combination of schizophrenic and depres-
sive symptoms represents a clinical reality requiring accurate diagnosis and effective
management. The prognosis of schizoaffective disorder is usually more favorable
than for schizophrenia, but less positive in comparison to affective disorders.4 The
depressed type of schizoaffective disorder represents a challenge due to the chronic
and frequently deteriorating course of the illness with negative effects on all spheres
of social functioning. The net result is higher utilization of health care resources.5,6
A factor that can signifi cantly infl uence the prognosis for this disorder is the choice of
suitable therapeutic strategy, in the acute, as well as the continuation and maintenance
phases of treatment.
The pharmacotherapy of the acute phase of schizoaffective disorder involves
primarily antipsychotic and secondarily antidepressant drugs. However, to achieve
an optimal effect, patients with schizoaffective disorder, depressed type, require
targeted pharmacologic therapy aimed at improving the schizophrenic as well as
the affective components of the illness. Studies focusing on the pharmacotherapy of
schizoaffective disorder, depressed type, are limited. Most studies have focused on

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Izáková et al
the effi cacy and safety of antipsychotic monotherapy while
opinions regarding the appropriateness of combined anti-
psychotic–antidepressant therapy vary. Antidepressants are
especially useful when antipsychotic treatment improves the
psychotic symptoms only.7
Due to their effi cacy and safety profi le atypical antipsy-
chotics should result in improved long-term effi cacy, quality
of life, and patient compliance. Karow and colleagues8
found a subjective preference for atypical antipsychotics by
patients with schizophrenia and schizoaffective disorder,
who had received long-term antipsychotic medication. As
has been documented by Clark and colleagues,9 the use of
atypical antipsychotics in patients with schizophrenia and
schizoaffective disorder increased from 43% to 70% between
1995 and 1999. However, a surprising fi nding of this study
was that, in the era of new-generation antipsychotics with
broad-spectrum effi cacy, combination antipsychotic therapy
increased from 5.7% to 24.3%. In their meta-analysis of trials
aimed at comparing long-term treatment with typical and
atypical antipsychotics in patients with schizophrenia and
schizoaffective disorder published between 1994 and 2005,
Turner and Stewart10 observed a lower number of relapses,
fewer adverse events (AEs) and higher effi cacy of atypical
antipsychotics. Flynn and colleagues11 retrospectively studied
therapy in 70 hospitalized patients with schizoaffective dis-
order (depressive symptoms present in 53% patients): 90%
of patients received antipsychotics while the proportion of
atypical antipsychotics increased year-to-year; 87% patients
received an antipsychotic drug in combination with an anti-
depressant or mood stabilizer; only 6% of patients received
monotherapy with a typical or atypical antipsychotic drug.
There was a tendency to continue the antidepressant if the
patient was receiving such treatment before hospitalization
despite not currently experiencing depressive symptoms. The
presence of depressive symptoms at the time of hospitaliza-
tion rarely leads to the administration of an antidepressant.
Flynn and colleagues did not confi rm that monotherapy with
atypical antipsychotics is a widespread method in clinical
practice.
We had earlier conducted a retrospective pilot study to
obtain an overview of current treatment strategies in the acute
phase of treatment of schizoaffective disorder, depressed
type.12 We determined that the most prevalent pharmaco-
therapeutic strategy was the combination of antipsychotics
with antidepressants. The reasons for preferring such com-
bined treatment over monotherapy were: (a) low incidence
of AEs with selective serotonin reuptake inhibitors (SSRIs)
and serotonin–norepinephrine reuptake inhibitors (SNRIs),
(b) statistically signifi cant effect on reduction of depressed
symptoms, (c) decreased risk of relapse when changing the
antipsychotic medication. The treatment of schizoaffective
disorder in Slovakia was also studied by Dóci and colleagues13
In this study, the combination of antipsychotics with antide-
pressants also prevailed over monotherapy with an antipsy-
chotic drug, while atypical antipsychotics were preferred.
The present 12-week study was designed to compare the
effi cacy and safety of monotherapy with risperidone versus
combination therapy with haloperidol and sertraline in the
acute phase of schizoaffective disorder, depressed type.
Methods and materials
Study design
Open label, randomized, prospective, clinical study.
Inclusion and exclusion criteria
The study was meant to include men and women, aged 18–65,
hospitalized for schizoaffective disorder, depressed type,
diagnosed by ICD-10 criteria (The International Classifi ca-
tion of Diseases, 10th Revision) and DSM-IV (Diagnostic
and Statistical Manual of Mental Disorders, 4th Edition).
The nature of the episode was documented as fi rst or recur-
ring episode, relapse or gradual decompensation. The nega-
tive symptoms subscore had to be higher than the positive
symptoms subscore (Positive and Negative Syndrome Scale
[PANSS]) at the initial assessment. The total score on the
Calgary Depression Scale for Schizophrenia (CDSS) had to
be ?5 at the initial assessment. Patients previously receiving
a depot antipsychotic were included in the study only after
a minimum of one therapeutic interval had lapsed. Women
of reproductive age had to be practicing reliable contracep-
tion. The study was approved by the Institutional Ethics
Committee and all patients had to give written informed con-
sent before enrolling in the study. Exclusion criteria included
the presence of a mental disorder other than that specifi ed in
the inclusion criteria, the need for electroconvulsive therapy,
and a history of insuffi cient effi cacy of the study medication.
Patients with a serious or unstable medical condition were
excluded; however, patients with a chronic illness who were
stable on medication were allowed into the study.
Treatment
Risperidone monotherapy (Group R)
Risperidone was begun at 1 mg/day and subsequently titrated
according to the condition of the patient. The mean daily dose
of risperidone at week 1 was 3.75 mg/day (SD = 1.37) and at
the end of week 12 it was 3.29 mg/day (SD = 1.51).

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Therapy for the depressed type of schizoaffective disorder
Combined haloperidol and sertraline
therapy (Group HS)
The initial dose of haloperidol was determined on the basis
of the patient’s clinical condition. The initial dose of sertra-
line was 50 mg/day. The doses of combined therapy were
individually and fl exibly adjusted. A low dose of haloperidol
was preferred throughout the entire study. The mean daily
dose of haloperidol at week 1 was 5.35 mg/day (SD = 3.97)
and that of sertraline was 65.39 mg/day (SD = 23.53). At
week 12 the mean daily dose of haloperidol was 4.15 mg/day
(SD = 3.38) and the dose of sertraline was 133.82 mg/day
(SD = 38.47). Anticholinergics, benzodiazepines, and non-
benzodiazepine hypnotics were allowed at the discretion of
the physician and were recorded in the patient’s chart.
After obtaining informed consent, the patient’s eligibility
for inclusion in the study was assessed. The patient then
underwent an initial examination and was assigned a ran-
domized identifi cation code. A detailed record of previous
psychotropic and nonpsychotropic medications was obtained.
All psychotropic medications were discontinued and the
study medication was initiated.
Assessment of psychopathology and effi cacy and safety
of study medication were recorded at weeks 1, 2, and subse-
quently at two-week intervals. The fi nal assessment occurred
after 12 weeks, or in case of an early drop-out, at the time of
termination. All data were recorded in the patient’s chart. In
case of an early drop-out, the reason was recorded as well.
Instruments for assessment of therapeutic effi cacy
• Positive and Negative Syndromes Scale for Schizo-
phrenia (PANSS)14
• Calgary Depression Scale for Schizophrenia (CDSS)15,16
• Clinical Global Impression (CGI) (CGI-S; Severity of
Illness, CGI-I; Improvement)17
• Heinrich’s Quality of Life Scale (HQLS)18
• Global Assessment of Functioning Scale (GAF)19
• Drug Attitude Inventory (DAI)20
• Patient Preference Scale (PPS)21
Instruments for assessment of treatment safety
• Adverse events report (AER)
• Simpson–Angus Extrapyramidal Symptoms Rating
Scale (SAS)22
• Laboratory tests, vital signs, body weight
Statistical analyses
The demographic and clinical variables are described
based on characteristics of the study groups R and HS, and
reciprocally compared using the Mann–Whitney U test and
chi-square test. The characteristics of both groups were
assessed separately for the baseline (week 0), end of study
(week 12), and for the drop-out groups. The collected data
represent quantifi able differences of grouped median scores
of the assessment scales in respective assessed time points,
which were analyzed using the method of “Observed Cases.”
As the sets of patients are number-restricted, the statisti-
cal assessment applied nonparametric tests. For assessing
statistical signifi cance, we applied the signifi cance level of
at least 5% (p = 0.05). We placed emphasis on effect size,
calculated as the correlation rate of effect size of difference
between grouped medians (correlation rate rm). The correlation
rate (effect size) is standardized, and reaches values from 0
to 1. Its size will be interpreted as: 0.00–0.30 small, 0.30–0.50
medium, over 0.50 large.
In the statistical evaluation of variance in scores and
differences of scores in individual weeks in scales PANSS,
CDSS, CGI-I, CGI-S, PPS, HQLS, DAI within each group,
the Wilcoxon test (z) and the correlation rate of effect size
between grouped medians (rm) were applied. The statistical
evaluation of differences between individual groups and
statistical evaluation of score variances in individual weeks
used the Mann–Whitney U test and correlation rate of effect
size between grouped medians (rm). The two-way signifi cance
level (p) was evaluated. The interscale correlations within
both groups and between the groups were assessed using
correlation analysis. The primary indicator for evaluating
the tightness of relation of two quantitative variables was
determining the Spearman rank correlation coeffi cient rho.
The statistical software SPSS (SPSS Inc., Chicago, IL) and
Excel 2000 (Microsoft Corp., Redmond, WA) were used
for all analyses.
Results
Demographic and clinical characteristics
of patients
Two thousand four hundred sixty-six patients were screened
for the study. At the time of discharge from the hospital
207 patients (32.9% male, 67.1% female) were diagnosed
with schizoaffective disorder. Of these, 130 patients (62.8%)
were treated for schizoaffective disorder, depressed type, and
77 patients (37.2%) for manic type. None of the cases had
the mixed type of schizoaffective disorder. The sex distri-
bution of patients with schizoaffective disorder, depressed
type, was almost 4:1 in favour of females (78.5% female vs
21.5% male) (Table 1).
When patient enrolment into the study was completed,
54 patients (52 female) had met inclusion criteria. The only

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Izáková et al
two male patients who met inclusion criteria dropped out
at week 4, due to noncompliance with the study protocol.
They were not included in the statistical analysis. The subject
population included in the statistical analysis consisted of
52 female patients, representing 2.1% of the initial group.
The study patients were randomly assigned in a 1:1 ratio,
either to the risperidone monotherapy (Group R) or to the
haloperidol–sertraline combination therapy (Group HS).
The randomization codes were assigned using the method of
random number selection. The total duration of the study was
12 weeks. All patients were hospitalized at the beginning of
the study, and all were followed as outpatients after discharge
from the inpatient service. Two patients were enrolled in
the study at two different hospitalizations, after suffering a
relapse three years later. A solid remission in both of these
patients was obtained between hospitalizations. Since both
patients were randomized at their second hospitalization and
turned out to have been assigned to the other treatment group,
they were kept in the data analysis.
Demographic and clinical characteristics of Groups R
and HS at baseline are listed in Table 2. There were 14 drop-
outs in Group R and 9 dropouts in Group HS. There were
no statistically signifi cant differences in demographic and
clinical characteristics at weeks 0 and 12 (Mann–Whitney
U test, chi-square test). Groups R and HS differed at week
0 in living arrangement (rm = 0.47) and at week 12 in level
of education (rm = 0.30) (Table 2).
Evaluation of therapeutic effi cacy
Positive and Negative Syndromes Scale
for Schizophrenia
The subscore of positive and negative symptoms, the sub-
score of general psychopathology and the total PANSS score
in Groups R and HS improved signifi cantly from week 0
to week 12. In comparing Groups R and HS at week 0, a
statistical signifi cance (p = 0.004) and medium effect size
(rm = 0.39) was obtained only in the subscore of positive
symptoms in favour of group R. At weeks 2 and 6, no statisti-
cally signifi cant differences in the total score and the PANSS
subscores were obtained between the two Groups. At week
6, the effect size of the total PANSS score (rm = 0.30) and
the subscore of general psychopathology (rm = 0.32) suggest
a signifi cant difference in favour of Group R. These differ-
ences gain statistical signifi cance and a large effect size at
week 12 (rm = 0.47; rm = 0.56) (Figure 1).
Calgary Depression Scale for Schizophrenia
Improvement in depressive symptoms is demonstrated by the
reduction in CDSS scores between weeks 0 and 12 in both
groups. Group HS retained a higher CDSS score throughout
the entire study. At the beginning of the study, the Groups
differed signifi cantly (p = 0.001), refl ecting an effect of
randomization, and the effect size was medium (rm = 0.46).
To control for the signifi cant difference in baseline scores
between the two groups, we also compared scores in weeks
0–2, 2–6 and 6–12. During the course of the study the dif-
ference between Groups diminished slightly. At week 6, the
difference was no longer statistically signifi cant (p = 0.136;
rm = 0.23), however, it slightly increased again at week
12 (p = 0.047; rm = 0.32) (Figure 2).
Clinical Global Impression
The severity of illness, as assessed by the CGI-severity
(CGI-S) scale, decreased signifi cantly (p = 0.01) in both
groups with a large effect size (rm ? 0.60). The severity
of illness was comparable in both groups at the beginning
(grouped medians: Group R: 5.06; Group HS: 5.46 points).
At week 6, a statistically signifi cant difference (p = 0.048)
and a medium effect size (rm = 0.32) in favor of Group R
emerged, and from the perspective of effect size it persisted
until week 12 (rm = 0.33). Clinical improvement assessed
by CGI-I was statistically signifi cant with a large effect size
in the course of the study in both groups. Improvement was
more rapid during the fi rst six weeks.
Heinrich’s Quality of Life Scale
Both groups showed improvement in the quality of life
(grouped medians: Group R: 23.44 vs 34.67 points; Group
HS: 22.20 vs 31.33 points). There was no statistically sig-
nifi cant difference and no effect size at the beginning of the
study, however, Group HS achieved lower HQLS scores
throughout the study. At the end of week 12, a medium
Table 1 Population of patients with diagnosis F25.x according to
ICD-10
Population of inpatients
in years 2003–2006 (n)
Number
2466
with diagnosis F25.x (n/%)207/8.4%
F25.0 manic type (n/%)77/37.2%
Male40/51.9%
Female 37/48.1
F25.1 depressed type (n/%)130/62.8%
Male28/21.5%
Female102/78.5%
F25.2 mixed type (n/%)0/0.0%
Male 0/0.0%
Female 0/0.0%

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Therapy for the depressed type of schizoaffective disorder
effect size between Groups favoured Group R (r = 0.30)
(Figure 3).
Global Assessment of Functioning Scale
Overall functioning in both groups improved signifi cantly
during the study (p ? 0.001; rm ? 0.60). At week 0, groups
did not differ signifi cantly and there was no effect size.
The difference between groups grew during the study.
At week 12 the difference became statistically signifi cant
and there was a medium effect size in favor of Group R
(p = 0.044; rm = 0.38) (Figure 4).
Drug Attitude Inventory
Patients’ attitude towards therapy showed a positive change
during the study. In Group R, we noted an increase in DAI
score from −4.29 at week 1 to 6.67 points at week 12.
*
* *
**
90
80
70
60
50
40
30
20
10
0
Week 0 Week 2
Total score HS
Week 6Week12
Total score R
Negative subscore R
Negative subscore HS
General psychopathology R
Positive subscore HS
General psychopathology HS
Positive subscore R
Figure 1 The grouped medians of Positive and Negative Syndrome Scale total scores at weeks 0, 2, 6, 12.
Notes: R Group R; HS Group HS; *p ? 0.05; **p ? 0.001; †rm ? 0.3; ‡rm ? 0.5. Wilcoxon test (z) and effect size (rm): Group R: week 0–2: z = −4.281; p ? 0.001; rm = 0.65; week
0–6: z = −3.724; p ? 0.001; rm = 0.67; week 0–12: z = −3.062; p ? 0.001; rm = 0.68. Group HS: week 0–2: z = −4.398; p ? 0.001; rm = 0.66; week 0–6: z = −4.019; p ? 0.001;
rm = 0.67; week 0–12: z = −3.622; p ? 0.001; rm = 0.67. Mann–Whitney U test (Z) and effect size (rm): Group R vs Group HS; week 0: 320.50; Z = −0.320; p = 0.754; rm = 0.04;
week 2: 317.50; Z = −0.375; p = 713; rm = 0,05; week 6: 123.00; Z = −1.861; p = 0.063; rm = 0.30; week 12: 46.50; Z = −2.465; p = 0.012; rm = 0.47.
0
2
4
6
8
10
12
14
16
Week 12 Week 6Week 2
Week 0
Group RGroup HS
**
*
*
Figure 2 The grouped medians of Calgary Depression Scale for Schizophrenia score at weeks 0, 2, 6, 12.
Notes: *p ? 0.05; **p ? 0.001; †rm ? 0.3. Wilcoxon test (z) and effect size (rm): Group R: week 0–2: z = −3.868; p ? 0.001; rm = 0.61; week 0–6: z = −3.969; p ? 0.001;
rm = 0.66; week 0–12: z = −3.070; p ? 0.001; rm = 0.68. Group HS: week 0–2: z = −4.295; p ? 0.001; rm = 0.66; week 0–6: z = −4.021; p ? 0.001; rm = 0.67; t week 0–12:
z = −3.626; p ? 0.001; rm = 0.67. Mann–Whitney U test (Z) and effect size (rm): Group R vs Group HS: week 0: 158.50; Z = −3.303; p = 0.001; rm = 0.46; week 2: 207.50;
Z = −2.228; p = 0.025; rm = 0.32; week 6: 162.00; Z = –1.502; p = 0.136; rm = 0.23; week 12: 59.50; Z = −2.502; p = 0.047; rm = 0.32.