Asian Journal of Psychiatry 4 (2011) 60–64

Gender differences in Singaporean Chinese patients with schizophrenia

Jimmy Lee a,b,*, Jundong Jiang a,c, Kang Sim a, Jenny Tay a, Mythily Subramaniam a, Siow-Ann Chong a

a Institute of Mental Health, Singapore, Singaporeb Duke – NUS Graduate Medical School, Singapore, Singaporec National University of Singapore, Singapore, Singapore

A R T I C L E I N F O

Article history:

Received 8 March 2010

Received in revised form 23 November 2010

Accepted 27 November 2010

Keywords:

Schizophrenia

Gender differences

Chinese

Age of onset

Oestrogen

A B S T R A C T

The purpose of this study was to compare gender differences in age of onset of illness, clinical features

and prescription patterns in Chinese schizophrenia patients in Singapore. A cross-sectional study was

conducted which recruited 903 subjects diagnosed with schizophrenia from the Institute of Mental

Health between 2005 and 2008. Information on age of onset of schizophrenia, body mass index (BMI),

psychiatric family history and current medication was collected via a standardised collection form.

Symptom severity was assessed with Positive and Negative Syndrome Scale (PANSS). Differences in age

of onset of schizophrenia illness, clinical features and prescription patterns were compared between

gender groups. Among sporadic schizophrenia cases, female subjects demonstrated a bimodal

distribution in age of onset of illness, and had a significantly later age of illness onset compared

with male subjects. For subjects with family history of psychiatric disorder, no significant gender

differences were found in age of onset of illness. Female subjects had significantly higher BMI, higher

proportion of diabetes mellitus, lower negative symptom scores and were prescribed more atypical

antipsychotics and antidepressants compared with male subjects. Male subjects after age 50 were

prescribed a lower antipsychotic dose, but this difference was not observed in female subjects. In

conclusion, we found differences in age of onset of schizophrenia, severity of negative symptoms and

prescription patterns between the male and female gender groups in Chinese schizophrenia patients in

Singapore. These differences were consistent with findings from Caucasian population, and could

possibly be explained by influences of oestrogen.

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1. Introduction

Differences in the clinical course of schizophrenia may bepartially due to the biological state of being male or female –gender differences (Goldstein et al., 1989; Hafner, 2003; Hafneret al., 1998a; Leung and Chue, 2000; Pulver et al., 1990). It isbelieved that females have a more favourable clinical coursebecause of a later onset of illness, a more affective type ofpresentation and lower rates of co-morbid substance usedisorders. Recent meta-analyses have also suggested that maleshave a higher lifetime risk of developing schizophrenia (Alemanet al., 2003).

Studies from the Caucasian population reported a younger ageof onset of schizophrenia illness in males compared with females(Gureje and Bamidele, 1998; Hafner et al., 1998a). These studiesdescribed a difference in age of onset of up to 5 years betweenmales and females. The studies also reported a bimodal distribu-

* Corresponding author at: Institute of Mental Health, 10, Buangkok View,

Singapore 539747, Singapore. Tel.: +65 63892000; fax: +65 63855900.

E-mail address: jimmy_lee@imh.com.sg (J. Lee).

1876-2018/$ – see front matter � 2010 Elsevier B.V. All rights reserved.

doi:10.1016/j.ajp.2010.11.005

tion in the onset of illness in females, with the first peak betweenages 15 and 30, and a second smaller peak between ages 45 and 49(Hafner et al., 1998a,b). However, results from other studies in Asiaare mixed and did not support this finding of earlier age of onset inmales. Studies from Indian and Pakistani populations showed nodifferences in age of onset of illness between males and females(Murthy et al., 1998; Naqvi et al., 2005).

A single study on 542 Chinese inpatients in China revealed thatthe onset of illness in males was 5 years earlier than in females(Tang et al., 2007). However, this difference was no longersignificant if only cases with positive family history were selected.This finding was consistent with other reports that differences inage of onset of illness can only be observed in sporadic rather thanfamilial cases (Albus et al., 1994; Alda et al., 1996). This study alsoreported a significantly higher proportion of smokers, higherproportion of typical antipsychotic use and higher doses ofantipsychotics in male patients.

Studies showed that male patients with schizophrenia exhibitmore negative symptoms (Goldstein et al., 1990; Kay et al., 1987).Negative symptoms of schizophrenia present a managementchallenge to all clinicians and have been associated with poorerfunctional outcome. However, both male and female groups have

Table 1Comparison of demographic and clinical features between male and female groups.

Male

(N = 603)

Female

(N = 300)

P-value P-value

Mean (SD) Mean (SD) (unadjusted) (adjusted)

Age, years 49.4 (13.1) 50.0 (12.7) 0.499

Age of onset, years 27.4 (9.6) 29.0 (10.3) 0.022 0.017y

With family history 27.0 (8.6) 26.8 (8.9) 0.864

With no family history 27.5 (9.9) 29.8 (10.6) 0.006

Duration of

illness, years

21.9 (13.2) 20.9 (12.8) 0.270 0.945z

BMI (Kg/m2) 22.4 (4.2) 24.2 (5.1) <0.001 <0.001

PANSS score

Positive 9.9 (3.8) 10.1 (3.6) 0.558 0.633

Negative 12.3 (5.3) 11.3 (5.1) 0.007 0.002

General 21.2 (5.1) 21.4 (5.3) 0.546 0.687

n (%) n (%)

Family history of psychiatric disorder 0.112

Yes 134 (22.2) 81 (27.0)

No 469 (77.8) 219 (73.0)

Current smokers <0.001 <0.001

Yes 226 (37.5) 27 (9.0)

No 377 (62.5) 273 (91.0)

Diabetes mellitus 0.001 0.006

Yes 34 (5.6) 36 (12.0)

No 569 (94.4) 264 (88.0)

y Two-way ANOVA adjusting for family history.z ANCOVA adjusting for family history and age of onset of illness.

J. Lee et al. / Asian Journal of Psychiatry 4 (2011) 60–64 61

similar degrees of positive symptoms (Schultz et al., 1997).Treatment differences between males and females have also beenreported in the literature. Females were reported to require lowerdoses of antipsychotics until they became menopausal wheredoses of antipsychotics might increase. Females were also reportedto be more susceptible to extra-pyramidal side effects, and had ahigher prevalence of tardive dyskinesia (Seeman, 1986).

The Chinese ethnic group represents about a fifth of the world’spopulation but there is a paucity of related epidemiological studiesin the Chinese population. In the single reported Chinese study ongender differences in schizophrenia, the sample consisted of onlyinpatients that might not be representative of the overallschizophrenia population (Tang et al., 2007). Frequently, patientswith a more severe course of illness are more likely to requireinpatient management. Furthermore, the sample was obtainedfrom one of the major psychiatric hospitals, again not accuratelyreflecting community samples.

We hypothesized that there are differences between male andfemale gender groups in the age of onset of illness, clinical featuresand prescription patterns in the Singaporean Chinese patients withschizophrenia that might be similar to the Caucasian population.The aim of this cross-sectional study on Chinese inpatients andoutpatients with schizophrenia in Singapore was to investigategender differences in the age of onset of illness, clinical featuresand prescription patterns.

2. Materials and methods

2.1. Study design and setting

This cross-sectional study was conducted at the Institute ofMental Health (IMH) in Singapore. Singapore is an island countrywith a multi-ethnic population of about 4.8 million and a land areaof 710.2 sq km. The Chinese ethnic group forms about 77% of theresident population. The IMH is the only psychiatric hospital in thecountry and provides various levels of psychiatric services. Itprovides all levels of psychiatric care to approximately 1500inpatients and 15,000 outpatients with schizophrenia. A total of1515 patients from IMH were approached for the study but only1331 (87.9%) patients were eligible. Out of the eligible patients,903 (67.8%) consented to participate in the study during the period2005 to 2008. The study sample comprised of a mixture of bothinpatients and community dwelling patients (outpatients).Patients with a diagnosis of schizophrenia and of Chinese ethnicitywere eligible for this study. They were excluded if they had organicbrain disorders, epilepsy or mental retardation. Patients withschizophreniform disorder and schizoaffective disorder wereexcluded from this study.

This study was approved by the relevant ethics committees.Only patients who were capable of providing written informedconsent were recruited for this study.

2.2. Assessments

The diagnosis of schizophrenia was made using the StructuredClinical Interview for DSM-IV-TR Axis I Disorders, ResearchVersion, Patient Edition (SCID-I/P) by clinicians. Patients werealso assessed with the Positive and Negative Syndrome Scale(PANSS) to evaluate symptom severity (Kay et al., 1987).

A standardised data collection form was used in the gathering ofdata. Other than interviews with the patients, information was alsoextracted from their clinical charts. Information on gender, bodymass index (BMI), smoking and co-morbid physical illnesses wascollected. Data collected included age at onset of illness, defined asage at diagnosis, and age at first hospitalization. Information oncurrent treatment such as psychotropic medications used and their

doses was also collected. All antipsychotic doses were converted tototal chlorpromazine equivalent doses using standard guides(Lehman et al., 2004; Woods, 2003).

2.3. Statistical analyses

All statistical analyses were performed using Stata SE 10.0.Bivariate analyses were first performed to evaluate the differencesbetween variables of interest by gender. Chi-square tests wereused for categorical variables, and student’s t-test with equal orunequal variance was employed for continuous variables. Tocontrol potential confounders for continuous outcome variables,analysis of covariance (ANCOVA) or two-way analysis of variance(ANOVA) was used depending on whether the covariates werecontinuous or categorical. For categorical outcome variables,Mantel–Haenszel test was used to control for possible confoundingcovariates.

3. Results

A total of 903 patients were recruited for this study. The sampleincluded 300 (33.2%) females and 603 (66.8%) males. At time ofrecruitment, 378 (41.9%) patients were inpatients and 525 (58.1%)were outpatients. Of the 378 inpatients, 260 (68.8%) were malepatients and 118 (31.2%) were female patients. Of the 525outpatients, 343 (65.3%) were male patients and 182 (34.7%)were female patients. There was no difference in genderdistribution between inpatients or outpatients. Characteristics ofboth male and female groups are shown in Table 1. Of the 903recruited patients, 852 (94.4%) were hospitalized at least once intheir course of illness. There was a statistically significantdifference (P = 0.003) in mean age at first hospitalization betweenmale and female patients. The mean age at first hospitalization formale and female patients was 28.7 (SD 10.2) years and 31.0 (SD10.8) years respectively.

The average age of this study population was 49.6 years old. Apositive family history of a psychiatric disorder was present in23.8% of the study population. In general, female patients were 1.6years older than male patients at onset of illness. After stratifying

[()TD$FIG]

Fig. 1. Distribution of age of onset in male and female schizophrenia patients with P values computed from goodness of fit test (Pearson Chi-square test) for proportions of

multinomial population. (a) Group with family history of psychiatric disorder. (b) Group with no family history of psychiatric disorder.

J. Lee et al. / Asian Journal of Psychiatry 4 (2011) 60–6462

by family history of psychiatric disorder, there was no significantdifference in age of onset of illness between male and femalegroups in those with a positive family history of psychiatricdisorder. In the sub-group with no family history, the difference inage of onset of illness persisted. Male patients in the sub-groupwith no family history had a single large peak in age of onset ofillness from 21 to 25 (Fig. 1). Female patients in the sub-group withno family history had 2 peaks in age of onset of illness, a relativelyflat one from 16 to 35 and a second smaller peak in age of onset ofillness at about 46–50 years old (Fig. 1). After age 60, there was nodiscernible difference in age of onset between the 2 gender groups.

Compared with male patients, female patients had significantlyhigher BMI. 5.6% of males and 12.0% of females had a co-morbiddiagnosis of diabetes mellitus. There were no differences in thepositive and general psychopathology subscale scores. However,female patients had significantly lower PANSS negative subscalescores, even after adjusting for age, duration of illness, smokingstatus and family history.

The medication profiles for male and female patients are shownin Table 2. There was no significant difference in total dailychlorpromazine equivalent doses between male and femalepatients. The results were stratified by age, using age 50 as thecut-off point to indicate menopausal status in females. Malepatients more than 50 years old received a significantly lower doseof antipsychotic compared to male patients less than 50 years old.In female patients, there was no significant difference inantipsychotic dose between the 2 groups. These differences wereseen in total antipsychotic, typical as well as atypical antipsychoticcategories as demonstrated in Table 3.

There was a significantly higher proportion of typical antipsy-chotic drug prescribed in male patients (65.8%) when comparedwith female patients (58.0%). There was a significantly higherproportion of atypical antipsychotic drug prescribed in femalepatients (33.3%) compared to male patients (23.5%). Thesedifferences in prescription were more significant after adjustingfor age, duration of illness and total PANSS score. There was a

Table 2Comparison of medication between male and female schizophrenia patients.

Male (N = 603) Female (N = 300) P-value P-valuey

Mean (SD) Mean (SD) (unadjusted) (adjusted)

Cumulative antipsychotic exposure, year 18.1 (12.0) 17.7 (11.7) 0.641 0.559

Antipsychotic dose, mg per dayz 496.9 (528.1) 488.5 (492.2) 0.837 0.745

n (%) n (%)

Type of antipsychotic prescribed

Typical 0.021 0.012

User 397 (65.8) 174 (58.0)

Non user 206 (34.2) 126 (42.0)

Atypical 0.002 0.001

User 142 (23.5) 100 (33.3)

Non user 461 (76.5) 200 (66.7)

Antidepressants 0.001 0.002

User 96 (16.0) 75 (25.0)

Non user 507 (84.0) 225 (75.0)

Anticholinergics 0.580 0.348

User 413 (68.5) 200 (66.7)

Non user 190 (31.5) 100 (33.3)

Mood stabilizers 0.750 0.413

User 137 (22.7) 71 (23.7)

Non user 466 (77.3) 229 (76.3)

Benzodiazepine 0.721 0.858

User 169 (28.0) 88 (29.3)

Non user 433 (72.0) 212 (70.7)

y P-value after adjusting for age, duration of illness and total PANSS score.z The antipsychotics doses were converted to its equivalent chlorpromazine dose.

J. Lee et al. / Asian Journal of Psychiatry 4 (2011) 60–64 63

significant difference in antidepressant use, being higher in femalepatients (25%) than male patients (16%).

4. Discussion

In this study, we found differences in age at onset of illness,clinical course and prescription patterns between Chinese maleand female patients with schizophrenia in Singapore. On average,female patients present 1.6 years later than male patients, and hadtheir first hospitalization at a later age. Female patients with nofamily history of psychiatric disorder demonstrated a bimodaldistribution in age of onset of schizophrenia. At the point ofrecruitment, male patients had more negative symptoms, and 4times more smokers than female patients. Female patients hadhigher rates of atypical antipsychotic and antidepressant prescrip-tion, a higher BMI, and 2-fold higher rates of diabetes mellitus.

In addition, we also replicated the finding that only sporadiccases of schizophrenia demonstrated a difference in age of onsetbut not familial cases. When the familial cases were furtherstratified by gender groups, we found that male and female caseshad almost similar curves and no significant differences in age ofonset of schizophrenia. However, in the stratum of sporadic cases,there were visible differences between the gender groups withregards to the distribution of age of onset of schizophrenia. Malepatients with no family history of psychiatric disorder had a single

Table 3Comparison of antipsychotic dosage with in gender dichotomized at age 50.

Antipsychotic dose in

mg per dayyP-value

Age�50 Age>50

Total antipsychotic Male 574 408.7 <0.001

Female 487 490 0.958

Typical antipsychotic Male 508.6 370.4 0.006

Female 409.8 465.2 0.448

Atypical antipsychotic Male 367.5 272.9 0.016

Female 350.2 297.2 0.333

y The antipsychotics doses were converted to its equivalent chlorpromazine

dose.

prominent peak between the ages 21 and 25, and the rates reducedsharply from that point onwards. In the female group with nofamily history of psychiatric disorder, there was a bimodaldistribution in age of onset of schizophrenia. There was a lowerand broader peak between ages 16 and 35, followed by a smallersecond peak between ages 46 and 50.

These differences could have important implications in ourunderstanding of the schizophrenia illness. Firstly, the mechanismbehind the observed delay in onset of schizophrenia illness infemales needs to be further elucidated. One of the prominenthypotheses put forth involved oestrogen.

Oestrogen has been found to have effects on the developing brain(Rao and Kolsch, 2003). Brains of males with schizophrenia had beenshown to have more pronounced abnormalities. Male patients havesmaller temporal lobes and larger lateral ventricles (DeLisi et al.,1989). There are also sexually dimorphic differences in the brainsthat could explain the differential rates of development ofschizophrenia between the two sexes (Goldstein et al., 2002).Neuroprotective effects of oestrogen could explain the bimodaldistribution observed in female patients. The first peak in age ofonset of illness appeared attenuated and broad in female patientscompared to male patients and could be the result of oestrogenblunting the risk of early onset illness. In addition, a second smallerpeak in age of onset of illness was observed in female patientsbetween ages 46 and 50. This is traditionally the peri-menopausalperiod where oestrogen levels begin to fall, leading to a sudden lossof this neuroprotective effect, and a slight increase in cases.

In the stratum with family history of psychiatric disorder, therewere no observed differences between the ages of onset ofschizophrenia. In our study, we did not collect specific informationwith regards to diagnoses of affected family members. Neverthe-less, we observed similar findings as reported in other populations.This could be a result of the strong effects of genetic influence overenvironmental and hormonal influences (Olsen et al., 2008;Weickert et al., 2008).

Contrary to the earlier Chinese study, our study did not showthat female patients had higher positive and general psychopa-thology scores on the PANSS. Instead, we found that femalepatients had lower negative symptoms scores. Studies have

J. Lee et al. / Asian Journal of Psychiatry 4 (2011) 60–6464

suggested that the lesser negative symptoms observed in femalepatients with schizophrenia could be a result of oestrogen effectson the glutamatergic systems (Jelks et al., 2007). Other factors suchas medication dosage did not confound the results obtained in ourstudy as there were no differences in antipsychotic dosagesbetween the two gender groups. However, female patients wereprescribed a higher proportion of atypical antipsychotics andantidepressants, which could have reduced negative symptoms.

Prescription patterns were different between gender groups inour study. Contrary to studies from Caucasian populations andresults from China, we did not see a higher dosage of antipsychoticmedication prescribed in male patients. Instead, we observed that ahigher proportion of female patients received atypical antipsychoticand antidepressant medications. This could be due to female patientsbeing more prone to extrapyramidal side effects, or are more likely toreport symptoms of hyperprolactinemia, leading to a switch toatypical antipsychotic medication. A significant association with thisfinding was that female patients had higher BMI and were at 2 timeshigher risk of developing diabetes mellitus. Female patients havebeen reported to suffer from greater affective symptoms such asdysphoria, depression and irritability, and these could explain thehigher antidepressant usage (Goldstein et al., 1990).

In male patients, we observed a significantly lower antipsy-chotic dosage in the group more than 50 years old. Conversely, notonly did we not see a reduction in antipsychotic dosage in the olderage group female patients, we observe a trend towards a higherprescribed dose. This paradox could be due to the loss of protectiveeffects of oestrogen in the post-menopausal group of femalepatients, leading to a slightly elevated dose of antipsychoticmedication (Seeman, 1986).

One of the strengths of our study was the setting. The IMH is theonly psychiatric hospital in Singapore and responsible for the mentalhealth of almost all affected with serious mental illnesses. As a resultof the setting, we were able to recruit both inpatients as well asoutpatients into our study. Our study included only patients ofChinese ethnicity, and is one of the largest studies of this ethnic groupwith regards to gender differences. Diagnoses of schizophrenia weremade by clinicians with SCID-I/P to ensure accurate phenotyping.

One of the main limitations of this study lies in the cross-sectional study design. Measurements and medication informationcollected represent characteristics of patients at point of recruit-ment and did not reflect their longitudinal clinical or treatmentcourse. Therefore, attribution of higher BMI and rates of diabetesmellitus to atypical medication was not possible. We did not use astructured instrument such as the Interview for the RetrospectiveAssessment of the Onset of Schizophrenia (IRAOS) to establish theonset of schizophrenia; hence data collected retrospectively couldbe affected by bias (Hafner et al., 1992). Information on specificdiagnoses of affected family members in the family history was notavailable, and was collected as a dichotomous variable. Maritalstatuses of subjects were not collected and are believed to be aprotective factor that could confound gender differences.

In conclusion, our study showed that there are differences inclinical presentation, clinical course and prescription between thetwo gender groups in Chinese patients with schizophrenia. Most ofthese differences were consistent with findings from the Caucasianpopulation. Mechanisms responsible for gender differences inschizophrenia should be explored, especially the impact ofoestrogen on the schizophrenia illness, as they might provideinroads into molecular research that could aid in deconstructing thephenotype of schizophrenia or develop novel therapeutic strategies.

Acknowledgments

The authors acknowledge the National Medical Research Council,Singapore (NMRC/0834/2004) for providing the funding necessary

for this study; the NMRC had no further role in study design; in thecollection, analysis and interpretation of data; in the writing of thereport; and in the decision to submit the paper for publication.

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