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Schizophrenia Research
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a r t i c l e
i n f o
Article history:
Received 22 August 2015
Received in revised form 2 October 2015
Accepted 6 October 2015
Available online xxxx
Keywords:
First-episode schizophrenia
Treatment response
Antipsychotics
Gender differences
a b s t r a c t
Gender differences in the response to antipsychotic treatment have been detected in the past, but not studied in
great detail. The results of the European First-Episode Schizophrenia Trial (EUFEST) were analyzed with a focus
on gender differences in the response to randomized treatment of rst-episode schizophrenia. A total of 498 patients (298 men and 200 women) were randomly assigned by a web-based online system to open-label treatment with haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone. Treatment response was
evaluated using the positive and negative syndrome scale (PANSS). Data were collected at baseline and then prospectively for one year. Baseline characteristics (age and proportion of patients assigned to individual antipsychotics) were the same between the male and female patients with the exception of ziprasidone: signicantly
fewer men, proportionately, were prescribed ziprasidone. There was no signicant difference between genders
between the initial total PANSS and subscale scores. A signicant interaction between time and gender was
found, with more robust PPANSS and TPANSS score improvement in women during the course of treatment.
Of all of the antipsychotics used, only olanzapine led to signicantly greater improvement in the total PANSS
score in women during the follow-up period. Gender differences should be given more attention in research
and clinical practice. Their causes require clarication, and future strategies for dealing with them may be considered in early intervention programs and guidelines.
2015 Elsevier B.V. All rights reserved.
1. Introduction
Gender differences in psychotic disorders have been observed in
terms of illness onset and course. Clinical studies that examine outcomes separately for men and women can help determine whether
treatment has differential effectiveness or distinct side effects according
to gender. The issue of gender-specic responses to medication interventions addresses an understudied area. For many years, researchers
omitted women from clinical trials to avoid the difculty of assessing
the potentially interfering effects of female hormones and the bias menstrual cycles might mean for study results.
Many studies have tried to determine the role of gender in schizophrenia, but mainly in terms of epidemiology, clinical symptoms, and
course of illness. Gender differences in antipsychotic responses have
been less systematically pursued. However, gender-related effects
Corresponding author at: Department of Psychiatry, Faculty Hospital Brno, Jihlavska
102, Brno-Bohunice 625 00, Czech Republic.
E-mail address: eva.ceskova@gmail.com (E. Ceskova).
http://dx.doi.org/10.1016/j.schres.2015.10.013
0920-9964/ 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Ceskova, E., et al., Gender differences in the treatment of rst-episode schizophrenia: Results from the European First
Episode Schizophrenia Trial, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.10.013
2. Methods
2.1. Study design
Data from EUFEST were used for the present study. The EUFEST rationale, design, and methods were published elsewhere (Fleischhacker
et al., 2005 Kahn et al., 2008). The subjects were 1840 years of age,
met the Diagnostic and Statistical Manual of Mental Disorders fourth
edition (DSM IV) criteria for schizophrenia, schizophreniform disorder,
or schizoaffective disorder. The rst episode of schizophrenia in a partially antipsychotic-naive study population must not have lasted more
than two years since the rst onset of symptoms. The use of any antipsychotic drug had to be shorter than two weeks in the previous year and
must not have exceeded six weeks cumulatively. All participants, or
their legal representatives, provided written informed consent. The
trial complied with the Declaration of Helsinki and was approved by
the ethics committees at the participating centers. The study is registered as an International Standard Randomized Controlled Trial, number ISRCTN68736636.
2.2. Treatment
Patients were randomly assigned by a dedicated web-based online
system to a daily regimen of haloperidol (14 mg), amisulpride (200
800 mg), olanzapine (520 mg), quetiapine (200750 mg), or
ziprasidone (40160 mg). Patients and their treating physicians were
not blinded to the assigned treatment. All study drugs were given orally,
within the above dose ranges, at the treating psychiatrist's discretion.
The use of mood stabilizers, benzodiazepines, antidepressants, and anticholinergic drugs was allowed, and documented (Kahn et al., 2008).
2.3. Assessment
To evaluate gender differences in response to antipsychotics, positive and negative syndrome scale (PANSS, Kay et al., 1987) scores
were applied. For a more detailed analysis, the total PANSS and all subscales (positive PPANSS, negative NPANSS, and general GPANSS) scores
were used.
2.4. Data analysis
Demographic, clinical, and treatment-related data were collected at
baseline and then prospectively for 12 months. We analyzed the baseline data and data collected after 1, 3, 6, 9, and 12 months. We compared
the men and women in terms of mean PANSS total and all subscales
scores.
Standard descriptive statistics were applied in the analysis: absolute
and relative frequencies for categorical variables and mean supplemented by a 95% condence interval for continuous variables and
scores.
The statistical signicance of differences between men and women
was tested using Fisher's exact test for categorical variables and an unpaired t-test for continuous variables and scores. The statistical signicance of gender, treatment, and their overall interaction was
computed using generalized estimating equations (GEE) with time as
a within-subject variable. Bonferroni correction was applied for multiple testing; = 0.05 was taken as the level of statistical signicance
in all analyses. Statistical analysis was computed using SPSS 22 (IBM
Corporation, 2013).
3. Results
3.1. Demographic data
Descriptive data for patients in the EUFEST trial have been published.
The data can be summarized as follows: The study was performed at 50
sites in 14 countries. A total of 498 patients (298 men and 200 women)
were randomly assigned by a web-based online system to haloperidol
(14 mg per day, n 103: 64 men, 39 women), amisulpride (200
800 mg per day, n 104: 58 men, 46 women), olanzapine (520 mg per
day, n 105: 67 men, 38 women), quetiapine (200750 mg per day, n
104. 68 men, 36 women), or ziprasidone (40160 mg per day, n 82:
41 men, 41 women) follow-up visits were continued for one year
(Kahn et al., 2008).
3.2. Baseline characteristics comparison between men and women
Baseline characteristics (age and proportion of patients assigned to
individual antipsychotics) were the same between men and women
with the exception of ziprasidone: signicantly fewer men, proportionately, were randomly assigned to ziprasidone. The initial total PANSS
and all PANSS subscales scores did not differ between groups (Table 1).
3.3. Psychopathology change comparison between men and women
After three months of treatment, a signicantly greater improvement in the total PANSS and all PANSS subscales scores, was seen in
women. However, after Bonferroni correction was applied, only
PPANS and total PANSS score remained signicant. After six months,
the women had improved signicantly more in the total PANSS and
the PPANSS subscale, but only in the PPANSS subscale after Bonferroni
correction. After nine months, signicantly more pronounced improvement was seen in women in the total PANSS and all the PANSS subscale
scores, with the exception of the NPANSS. After Bonferroni correction
only PPANSS subscale and the total PANSS scores in women was significant see Table 2.
Using GEE, a signicant interaction between time and gender was
found, with a more robust PPANSS and TPANSS score improvement in
women over the course of treatment see Table 4, model 1, and Table 2.
3.4. Psychopathology change comparison between men and women in
response to all given antipsychotics
Among all antipsychotics randomized to EUFEST participants at the
admission to the trial, only olanzapine led to signicantly greater improvement in all domains of psychopathology, e.g. the total PANSS
Table 1
Comparison of male and female baseline characteristics.
Results
Whole
sample
N = 498
Men
N = 298
Women
N = 200
P
value
26.0
(25.526.5)
25.6
(25.026.2)
26.5
(25.727.3)
0.069
64 (21.5%)
58 (19.5%)
67 (22.5%)
68 (22.8%)
41 (13.8%)
39 (19.5%)
46 (23.0%)
38 (19.0%)
36 (18.0%)
41 (20.5%)
0.652
0.369
0.372
0.217
0.050
22.9
(22.223.6)
21.3
(20.422.2)
43.6
(42.444.8)
87.8
(85.490.2)
40.1
(38.541.7)
23.5
(22.624.3)
21.2
(20.122.2)
44.9
(43.446.5)
89.6
(86.792.5)
40.0
(38.241.8)
0.346
23.1
(22.623.7)
21.2
(20.621.9)
44.1
(43.245.1)
88.5
(86.790.4)
40.0
(38.841.2)
0.870
0.179
0.344
0.941
PPANSS: positive PANSS subscale score; NPANSS: negative PANSS subscale score; GPANSS:
general PANSS: subscale score; TPANSS: total PANSS score; CI: condence interval; significant results are shown in bold.
Please cite this article as: Ceskova, E., et al., Gender differences in the treatment of rst-episode schizophrenia: Results from the European First
Episode Schizophrenia Trial, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.10.013
Table 2
PANSS score changes from baseline (95% CI) comparison of men and women.
Results
All subjects
N = 498
Men
N = 298
Women
N = 200
P value
P value
Bonferroni corr.
N = 452
7.2 (7.8; 6.6)
3.1 (3.6; 2.5)
9.3 (10.2; 8.3)
19.5 (21.2; 17.7)
N = 267
6.9 (7.6; 6.1)
2.7 (3.4; 2.0)
8.6 (9.7; 7.5)
18.2 (20.3; 16.0)
N = 185
7.7 (8.6; 6.8)
3.6 (4.5; 2.7)
10.2 (11.7; 8.6)
21.3 (24.2; 18.4)
0.136
0.120
0.109
0.084
0.680
0.600
0.545
0.420
N = 406
11.1 (11.8; 10.5)
5.4 (6.1; 4.8)
15.2 (16.3; 14.1)
31.8 (33.9; 29.7)
N = 234
10.3 (11.2; 9.5)
4.8 (5.7; 3.9)
14.1 (15.6; 12.6)
29.3 (32.1; 26.4)
N = 172
12.2 (13.2; 11.3)
6.3 (7.3; 5.2)
16.7 (18.3; 15.2)
35.2 (38.1; 32.3)
0.003
0.042
0.020
0.004
0.015
0.210
0.100
0.020
N = 363
12.0 (12.7; 11.3)
6.1 (6.8; 5.3)
16.9 (18.2; 15.7)
35.1 (37.4; 32.8)
N = 209
11.2 (12.2; 10.3)
5.6 (6.6; 4.7)
16.1 (17.8; 14.4)
33.0 (36.2; 29.9)
N = 154
13.1 (14.1; 12.1)
6.6 (7.7; 5.5)
18.0 (19.8; 16.3)
37.9 (41.1; 34.6)
0.007
0.211
0.130
0.038
0.035
0.995
0.650
0.190
N = 340
12.8 (13.5; 12.0)
6.7 (7.5; 5.8)
17.9 (19.2; 16.6)
37.3 (39.8; 34.9)
N = 194
11.9 (13.0; 10.9)
6.0 (7.1; 4.9)
16.6 (18.4; 14.8)
34.6 (38.0; 31.2)
N = 146
13.9 (14.9; 12.9)
7.5 (8.8; 6.2)
19.6 (21.4; 17.7)
40.9 (44.4; 37.5)
0.008
0.085
0.026
0.011
0.040
0425
0.131
0.055
N = 341
13.1 (13.9; 12.3)
7.1 (7.9; 6.2)
19.0 (20.4; 17.7)
39.3 (41.9; 36.8)
N = 194
12.6 (13.6; 11.6)
6.7 (7.8; 5.5)
18.3 (20.1; 16.5)
37.7 (41.2; 34.2)
N = 147
13.7 (14.9; 12.6)
7.6 (8.9; 6.4)
20.1 (21.9; 18.2)
41.6 (45.2; 38.0)
0.159
0.275
0.182
0.130
0.795
0.995
0.910
0.650
PPANSS: positive PANSS subscale score; NPANSS: negative PANSS subscale score; GPANSS: general PANSS subscale score; TPANSS: total PANSS score; signicant results are shown in bold.
and all the PANSS subscale scores in women. However, only an improvement in the total PANSS remained signicant after Bonferroni correction see Table 3.
Based on the GEE analysis, no signicant interaction between treatment and gender was found see Table 4, model 2.
4. Discussion
The primary outcome measure of the EUFEST was all-cause treatment discontinuation, which was substantially lower in patients on
second-generation antipsychotic drugs than in those taking haloperidol.
The differences between the treatment groups and the interaction between treatment and time were not signicant. Further, there were no
signicant differences between the treatment groups for the depression
score and adherence (Kahn et al., 2008). However the proportion of response and remission was higher for most second-generation antipsychotics than for haloperidol (Boter et al., 2009). Subgroup analysis for
gender did not show statistically signicant differences in all-cause
treatment discontinuation between patients on haloperidol and those
taking second-generation antipsychotic drugs (Kahn et al., 2008).
In the present study, we evaluated gender differences in the treatment response to rst (haloperidol) and second-generation antipsychotics (amisulpride, olanzapine, quetiapine, ziprasidone). We found
that the change of psychopathology, especially positive and total
Table 3
PANSS score changes after 12 months from baseline (mean) comparison of men and women in response to individual antipsychotics.
Amisulpride
PPANSSa
NPANSSa
GPANSSa
TPANSSa
a
b
Haloperidol
Olanzapine
Quetiapine
Ziprasidone
M
N = 37
W
N = 33
M
N = 41
W
N = 26
M
N = 49
W
N = 34
M
N = 43
W
N = 27
M
N = 24
W
N = 28
13.1 (6.2)
7.2 (7.7)
18.1 (10.6)
38.4 (20.6)
14.2 (6.5)
7.3 (8.2)
20.1 (10.8)
41.6 (20.3)
12.6 (6.6)
6.6 (8.4)
19.5 (12.7)
38.7 (24.5)
9.8 (7.6)
4.6 (6.7)
15.4 (12.4)
30.5 (24.5)
11.4 (8.0)
5.4 (7.3)
16.0 (13.9)
32.9 (26.0)
15.4 (6.7)
9.1 (7.2)
22.5 (10.9)
47.0 (20.0)b
13.3 (8.1)
6.6 (9.9)
19.6 (14.4)
40.0 (28.1)
13.2 (7.9)
9.1 (7.3)
20.3 (9.6)
42.3 (21.0)
13.2 (5.4)
8.6 (8.8)
18.7 (11.5)
40.5 (22.3)
15.1 (6.2)
7.6 (9.7)
21.0 (12.9)
43.8 (24.1)
Please cite this article as: Ceskova, E., et al., Gender differences in the treatment of rst-episode schizophrenia: Results from the European First
Episode Schizophrenia Trial, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.10.013
Table 4
Sources of variability of PANSS score.
Variability sourcea
PPANS
% expl. var
NPANSS
% expl. var
GPANSS
% expl. var
TPANSS
% expl. var
Model 1
Gender
Time
Gender Time
0.3%
99.0%
0.7%
0.028
b0.001
0.033
1.8%
96.6%
1.6%
0.013
b0.001
0.331
0.1%
99.0%
0.9%
0.232
b0.001
0.084
0.3%
98.8%
0.9%
0.036
b0.001
0.037
Model 2
Gender
Time
Gender Time
Treatment
Gender Treatment
0.2%
98.6%
0.8%
0.4%
0.1%
0.049
b0.001
0.030
0.209
0.795
1.7%
92.9%
1.6%
1.5%
2.3%
0.013
b0.001
0.307
0.230
0.077
0.1%
98.0%
0.9%
0.5%
0.4%
0.276
b0.001
0.077
0.233
0.360
0.3%
97.9%
0.9%
0.5%
0.4%
0.045
b0.001
0.033
0.120
0.304
Analysis based on generalized estimating equations with time as a within-subject variable; signicant results are shown in bold.
antidepressants. We have analyzed the differences in co-medication between both sexes post-hoc. Only patients with co-medication were
taken into consideration. Women more frequently received adjunctive
treatment with specic serotonin reuptake inhibitors (42/221, 19% vs.
45/146, 30.8%, p = 0.012). However, no signicant differences between
men and women were detected in the use of antidepressants in the
groups on different randomized antipsychotics in the study, including
olanzapine.
Our results are subject to the limitations related to the original protocol. The EUFEST study was a pragmatic study, powered and aimed at
the measurement of effectiveness, and it did not focus on the detection
of gender differences. Further, there was not a reliable measurement of
adherence (i.e., plasma levels monitoring) only the self-report compliance scale.
5. Conclusion
The ndings support the assumption of gender differences in the decrease of psychopathology in response to treatment with different antipsychotic drugs in rst-episode schizophrenia. The gender differences
should be further researched. No treatment guidelines refer to gender
as a potentially important factor in the choice of antipsychotics. This
analysis supports the notion that they should be taken into consideration. Sensitivity to gender differences can serve specic needs of patients and perhaps improve treatment outcomes.
Contributors
All authors participated in the conception and design of the study and in the critical
revision of the manuscript, and all authors gave their nal approval for publication.
Ceskova analyzed and interpreted the data and drafted the manuscript. Svancara and
Jarkovsky performed the statistical analysis.
Conict of interest
EC received a speaker's honoraria from Janssen-Cilag and Angelini CR and fees for the
advisory board from Janssen-Cilag, CR.
RP, JL, JS and JJ report no conicts of interest.
Acknowledgments
This study was supported by the project CEITEC Central European Institute of Technology (CZ.1.05/1.1.00/02.0068) from the European Regional Development Fund. The project had no role in the study design, in the data collection, in the writing of the paper, or in
the decision to submit the paper.
We are grateful to Wolfgang Fleischhacker and Ren Kahn for providing all the
EUFEST data and for their inspiring remarks.
Please cite this article as: Ceskova, E., et al., Gender differences in the treatment of rst-episode schizophrenia: Results from the European First
Episode Schizophrenia Trial, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.10.013
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Please cite this article as: Ceskova, E., et al., Gender differences in the treatment of rst-episode schizophrenia: Results from the European First
Episode Schizophrenia Trial, Schizophr. Res. (2015), http://dx.doi.org/10.1016/j.schres.2015.10.013