Are there gender differences in neuropsychological performance in patients with first-episode schizophrenia?

Schizophrenia Research 28 (1997) 39–50

Are there gender differences in neuropsychological performance in patients with first-episode schizophrenia? Margot Albus *, Werner Hubmann, Fritz Mohr, Josef Scherer, Norbert Sobizack, Ute Franz, Susanne Hecht, Margitta Borrmann, Christine Wahlheim State Mental Hospital Haar, Vockestrasse 72, D 85540 Haar, Germany Received 26 August 1996; accepted 7 July 1997

Abstract To investigate gender differences in neuropsychological (NP) functioning in first episode (FE) schizophrenia, consecutively recruited patients with FE schizophrenia (37 males, 29 females) and a subsample of these patients (20 males, 20 females), individually matched for gender, age, and education to healthy controls (20 males, 20 females) were compared on a battery of standardized neuropsychological tests. Women performed better than men in tests of verbal memory and learning, and men performed better than women in spatial organization. However, no differences were present between schizophrenic patients and controls, except that male and female schizophrenic patients showed the most pronounced impairment in visual motor processing, attention and verbal memory and learning. Our data suggest that gender does not appear markedly to modify the cognitive impairment characteristic of schizophrenia. However, they underline the necessity of controlling confounding factors on NP performance such as gender and education. © 1997 Elsevier Science B.V. Keywords: First episode schizophrenia; Gender differences; Matching procedures; Neuropsychological testing

1. Introduction Gender differences in schizophrenia have been reported for several domains. The best replicated gender difference in schizophrenia is the tendency for males to manifest the disease at an earlier age (Angermeyer and Ku¨hn, 1988; Gorwood et al., 1993; Ha¨fner et al., 1994). Also, much of the evidence indicates that schizophrenic men may have a poorer premorbid history, worse response to antipsychotic medications, worse outcome, and * Corresponding author. Tel: +49 89 4562 3236; Fax: +49 89 4562 3211. 0920-9964/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PII S 09 2 0 -9 9 6 4 ( 9 7 ) 0 0 0 91 - 1

more structural brain abnormalities (Andreasen et al., 1990; Goldstein et al., 1990; Lewine et al., 1995). Based on these findings and reports that schizophrenic men are at a greater risk for exhibiting a history of developmental problems in childhood (Goldstein et al., 1994) than schizophenic women, one might expect a milder disease form in female schizophrenics and probably less cognitive impairment in female compared to male schizophrenics (Goldberg et al., 1995). Although there is a considerable number of studies on NP performance in schizophrenia, the issue of sex differences in neurocognitive function among schizophrenic patients has only been

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addressed by a few studies, and the results have been mixed. Some studies have suggested that schizophrenic men tend to manifest greater neurocognitive impairment than schizophrenic women in several domains of function (Goldstein et al., 1994, 1995; Hoff et al., 1995; Seidman et al., 1996). However, other studies have indicated either no differences (Scottish Schizophrenia Research Group, 1987; Hoff et al., 1992; Andia et al., 1995; Goldberg et al., 1995) or even greater abnormalities among women (Perlick et al., 1992; Lewine et al., 1996). The samples investigated comprised first-episode schizophrenics (Scottish Schizophrenia Research Group, 1987; Hoff et al., 1992) as well as chronic schizophrenics (Perlick et al., 1992; Andia et al., 1995; Goldberg et al., 1995; Lewine et al., 1996). At least some of these inconsistencies may be attributable to sampling biases like investigating females with an atypically early age of onset relative to males (Perlick et al., 1992; Goldberg et al., 1995) or comparing patients with a chronic course of the illness (Perlick et al., 1992; Andia et al., 1995; Goldberg et al., 1995; Lewine et al., 1996), thus being biased by the different outcomes and age of onset distributions of schizophrenic men and women, as well as from inadequately matched controls ( Walker and Lewine, 1993). Other problems in comparing male and female schizophrenic patients stem from the fact that fairly reliable gender differences have been observed in cognitive function for at least three decades ( Kimura, 1992). Several studies suggest that females tend to have better verbal skills, in particular, verbal fluency and verbal memory ( Kramer et al., 1988; Collaer and Hines, 1995) and perform better than men in perceptual speed, whereas men tend to have better visual spatial and mathematical reasoning skills ( Kimura, 1992). With regard to some frequently administered neuropsychological tests, Kramer et al. (1988) reported that healthy females performed better in verbal learning and memory as measured by the California verbal learning test (CVLT, Delis et al., 1987). This finding was replicated by Reite et al. (1993) who additionally found that males perfomed better on the block design, a subtest of the Wechsler Adult Intelligence Scale, revised

( WAIS-R, Wechsler, 1981), which depends upon complex visuo-constructional integration skills and on the visual reproduction subtest of the Wechsler Memory Scale—Revised ( WMS-R, Wechsler, 1987). Effects of age and education on the performance of healthy controls have been reported for the Wisconsin Card Sorting Test (Boone et al., 1993; Heaton et al., 1986, 1994), for the paired associate learning subtest of the Wechsler-Memory-Scale-R ( Wechsler, 1987; Des Rosiers and Ivison, 1988) and for the Color-Word-Interference-Test (Stroop, 1989; Houx et al., 1993). These studies highlight the importance of interpreting neuropsychological performance within the context of subjects’ gender, education and age. To address the question of gender differences in neuropsychological functioning in schizophrenic patients, the present study tries to control the following confounding variables, not adequately dealt with in the studies published so far: (1) To avoid the bias of different outcome distribution with the reported worse outcome in schizophrenic men (Goldstein, 1988), potentially afflicting NP performance as well as the effect of long-term medication on NP performance, only patients experiencing their first episode ( FE ) of schizophrenia were investigated. (2) To take into account the different age of onset distributions with an earlier age of onset in schizophrenic men (Angermeyer and Ku¨hn, 1988; Ha¨fner et al., 1994) as well as the bias of investigating females with an atypically early age of onset, two samples were compared. The first sample consisted of all consecutively admitted male and female FE schizophrenics with female schizophrenic patients being 4.4 years older than male schizophrenics, ruling out the bias of investigating females with an atypically early age of onset. The second sample, a subsample of the first sample, comprised male and female FE schizophrenics individually matched with regard to age, gender and education, thus ruling out different age of onset distributions, education and age effects on NP performance but including female schizophrenics with a

M. Albus et al. / Schizophrenia Research 28 (1997) 39–50

potentially atypically early age at onset relative to males. (3) Since the sex differences in cognitive function found among schizophrenic patients generally parallel the kinds of differences that have been noted in the general population (Pearlson and Pulver, 1994; Lewine et al., 1995), sex differences in schizophrenia can be properly assessed only by comparing same-sex patients with same-sex controls on the neuropsychological areas of function investigated. Also, the data on the impact of age and education on several NP tests point to the necessity of same-sex demographic similarity between patients and controls (Goldstein et al., 1995). Therefore, in the matched sample of the present study, the control group was individually matched with regard to relevant demographic characteristics such as gender, age and education. (4) Finally, to prevent potentially confounding effects of an acute psychotic disorganization on complex tests, we carried out the investigation at the time of the best possible remission after treatment with NLs during the index admission in male and female FE schizophrenics. The best possible remission was defined as a reduction in BPRS-total score of at least 50% compared to index admission and a rating no higher than 12 in the subscores Anxiety/Depression, Anergia, Thought Disturbance and a rating no higher than 9 in the subscores Activation and HostileSuspiciousness. To avoid the bias of differential effects of the different neuroleptics on NP performance, all patients were treated with butyrophenones (80.9% with haloperidol, 13.2% with benperidol, and 5.9% with bromperidol ).

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from acutely admitted inpatients of the State Mental Hospital Haar, a facility that provides primary psychiatric care in Upper Bavaria. Of this sample, 20 male and 20 female FE schizophrenics were drawn (Sample 2), and the 40 normal control subjects were pairwise matched to this group of schizophrenics with regard to gender, age and education. All subjects were screened with a medical history questionnaire to exclude the following: history of moderate or severe head trauma or other neurological disorders, current alcohol or other substance abuse and systemic medical diseases that are likely to affect central nervous system functions. With reference to another first onset study (Lieberman et al., 1993), the following inclusion criteria for FE schizophrenic patients were applied: FE schizophrenics meeting DSM-III-R criteria for schizophrenia or schizophreniform disorder with no cumulative lifetime treatment with neuroleptics (NLs) for longer than 12 weeks prior to admission.

2.2. Procedures: assessment of psychopathology The diagnosis of schizophrenia was assigned on the basis of a structured interview based on DSMIII-R criteria (SCID, Spitzer et al., 1987). Symptom severity was evaluated by trained and experienced raters through a semistructured interview that was videotaped to control for inter-rater reliability and assessed with the Brief Psychiatric Rating Scale (BPRS, Overall and Gorham, 1988) and the Scales for the Assessment of Positive and Negative symptoms (PANSS, Kay et al., 1988) and Negative Symptoms (SANS; Andreasen, 1983). Depressive symptoms were rated by means of the original 18-item scale of the Hamilton Rating Scale for Depression (Hamilton, 1976). Raters were blind with regard to diagnoses, medication and neuropsychological performance.

2. Methods 2.1. Participants Sixty-eight patients with first-episode schizophrenia or schizophreniform disorder (37 males, 29 females, sample 1) were consecutively recruited

2.2.1. Neuropsychological assessment All the subjects underwent a battery of neuropsychological tests designed to tap a broad range of functions in a standardized fashion by two trained and experienced psychometrists. In select-

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ing the neuropsychological tests, we focussed on the NP ability areas that are regarded to be relevant in studies of schizophrenia (Saykin et al., 1994): verbal intelligence and language, spatial organization, verbal memory and learning, visual memory, short-term memory, visual–motor-processing and attention, information processing and attention, and abstraction/flexibility (see Table 1). Verbal intelligence and language ( VBL) were measured by the two subtests, ‘Information’ and ‘Similarities’, of the HAWIE-R, the German version of the WAIS-R ( Wechsler, 1981). To test verbal fluency, a lexicographic subtest of the LPS (Horn, 1983) and the semantic Supermarket-Test (Genzel, 1991), which is adopted from the Dementia Rating Scale (Mattis, 1976), were administered. Spatial organization (SPT ), used in measuring non-verbal intelligence, was assessed

with the Block Design and Picture Completion tests, both subtests of the HAWIE-R. Verbal memory and learning ( VBM ) were evaluated by the ‘Logical memory’ Test (immediate and delayed recall ) and the ‘Paired Associate Learning Test’, both subtests of the revised Wechsler-MemoryScale ( WMS-R, Wechsler, 1987), and the California Verbal Learning Test (CVLT, Delis et al., 1987). Visual memory ( VIM ) was evaluated by the ‘Visual reproduction’ subtest (immediate and delayed recall ) of the revised WechslerMemory Scale ( WMS-R). Short-term memory (STM ) was assessed by the ‘Digit-span’ subtest of the WAIS-R and a reading span test. The ColorWord-Interference test (Stroop, 1989), a test of selective attention, the Trailmaking Test ( TMT; Reitan, 1958) as well as the Digit Symbol Test, a subtest of the HAWIE-R, are considered to test

Table 1 Neuropsychological functions and groups of tests that measure each function Verbal intelligence and language ( VBL) Information, Similarities Verbal-Fluency-Tests Spatial Organization (SPT ) Picture Completion, Block Design Verbal memory and learning ( VBM ) Logical-Memory-Passages—immediate —delayed Paired Associate Learning Test Sum of Trial 1–5 Visual Memory ( VIM ) Visual reproduction—immediate —delayed Short-term Memory (STM ) Digit-span Reading-Span Visual-Motor-Processing and Attention ( VSM ) Parts A and B Digit-Symbol-Test Color-Word-Interference Information-Processing and Attention d∞ False alarm Percentage correct three-letter-version Percentage correct eight-letter-version Abstraction-Flexibility (ABS ) Categories, Perseverative Responses

WAIS-R (HAWIE-R) Supermarket-Test Leistungs–Pru¨f-System (LPS) WAIS-R (HAWIE-R) Wechsler-Memory-Scale-R Wechsler-Memory-Scale-R California-Verbal-Learning-Test Wechsler-Memory-Scale-R

WAIS-R (HAWIE-R) Reading-Span-Test Trail-Making-Test WAIS-R (HAWIE-R) Stroop-Color-Word-Test Continuous Performance Test (CPT ) Span of Apprehension Test (SAT ) Wisconsin-Card-Sorting Test ( WCST )

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accelerated visual-motor processing and attention ( VSM ). Techniques used to measure informationprocessing and attention were the Continuous Performance Test (CPT, Rosvold et al., 1956) and the Span of Apprehension Test (SAT, Neale, 1971). Abstraction and conceptual flexibility (ABS) were assessed using the modified WCST (Heaton, 1981), a test version of 48 response cards. The total battery of tests usually took 3–4 h to complete and was generally administered by two trained psychometrists on two occasions to an individual patient over a period of 2–3 days.

well as for the matched subgroup (Sample 2: 20 male and 20 female FE schizophrenics and 20 male and 20 female controls) with diagnosis (FE schizophrenics, controls) and gender (male, female) as the between-group factor. In a second step, univariate analyses of variance were carried out for each neuropsychological function. These univariate analyses of variance should be considered as exploratory, not as a confirmatory analysis. In significance testing of the contrasts, the Bonferroni procedure was employed.

2.3. Data analysis All raw test scores were converted to Z-scores (standard equivalents) based on the means and standard deviations of the control group which was individually matched with regard to age, gender, and education to the schizophrenic subsample (Sample 2). Rarely occurring deviant Zscores were truncated at Z=-6. Then Z-scores were grouped by function (mean scores). Multivariate analysis of variance (MANOVA) was carried out for the consecutively recruited patient group and the healthy comparison subjects (Sample 1: 37 male and 29 female FE schizophrenics and 20 male and 20 female controls) as

3. Results 3.1. Demographic and clinical data There were no statistically significant gender differences between the groups with regard to age, education and parental socio-economic status (see Table 2). In the total sample, there were no significant differences between males and females in total scores obtained on the SANS, PANSS, BPRS and HAMD. In the matched subsample (sample 2) of FE schizophrenics, schizophrenic males scored higher in the PANSS positive score (see Table 3).

Table 2 Demographic data for the total sample of first episode schizophrenics as well as for the matched subsample Education Element school

Parental SES High school

Middle class

Gender

Age

College

Lower class

Upper middle class

12 8 12 7 df=2; x2=0.93; p=0.63

17 10

10 17 10 7 16 6 df=2; x2=0.60; p=0.74

37 28.8+7.1 29 33.2+11.2 df=1,65; F=3.57; p=0.06

5 5 5 5 df=2; x2=0.00; p=1.00

10 10

7 7 6 3 11 6 df=2; x2=2.49; p=0.28

20 29.4+7.3 20 29.4+7.3 df=1,39; F=0.00; p=1.0

5 5 5 5 df=2; x2=0.00; p=1.00

10 10

4 7 9 5 4 11 df=2; x2=1.13; p=0.57

20 29.4+7.3 20 29.3+7.3 df=1,39; F=0.00; p=0.98

FE schizophrenics Total sample Male Female Matched sample Male Female Controls Male Female

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Table 3 Ratings of psychopathology, illness onset and medication in male and female first episode schizophrenic patients (means and s.d.) Total sample—schizophrenics

SANS composite score PANSS-negative PANSS—positive BPRS—total (18 items) HAMD—total (18 items) Duration between first signs and index-admission (years) Duration between index-admission and testing (weeks) Chlorpromazin-equivalents

Matched sample—schizophrenics

Males

Females

df

T

p

Males

Females

df

T

p

34.3+18 12.4+5.0 11.1+4.1 27.5+7.4 4.5+4.3 5.6+5.9

32.9+21 11.9+6.0 10.2+4.3 26.3+7.3 6.7+5.1 6.4+5.9

57 57 57 57 57 57

0.28 0.38 0.86 0.62 −1.8 0.73

ns ns ns ns ns ns

38.3+19 12.7+4.6 10.8+3.7 27.4+7.3 4.6+4.0 5.4+5.8

32.5+22 11.5+5.9 8.5+2.9 24.7+8.0 7.4+5.4 6.1+5.7

33 33 33 33 33 33

0.84 0.64 2.1 1.06 −1.7 0.74

ns ns <0.05 ns ns ns

4.9+3.9

5.6+3.1

57

0.19

ns

5.3+3.7

5.5+2.9

33

0.14

ns

653+467

440+427

57

1.8

ns

637+490

431+443

33

1.3

ns

SANS, Scale for the Assessment of Negative Symptoms; PANSS, Scale for the Assessment of Positive and Negative Symptoms; BPRS, Brief Pschiatric Rating Scale; HAMD, Hamilton Depression Scale.

3.2. Correlations between age, education and parental socio-economic status and neuropsychological test performance

3.3. Neuropsychological performance

As can be seen from Table 4, education showed a high impact on neuropsychological performance in FE schizophrenic patients as well as in healthy comparison subjects, whereas age and parental socio-economic status did not considerably influence neuropsychological functioning.

All differences are considered to be significant on a significance level of at least p<0.05 after Bonferroni-correction (see Fig. 1 and Table 5). 3.4. Total group (Sample 1)

(1) Comparison between FE schizophrenic (37

Table 4 Correlations between age, education, and parental socio-economic status and neuropsychological test performance: total sample of FE schizophrenics (N=66) and normal controls (N=40) Function

VBL SPT VBM VIM STM VSM CPT SAT ABS Profile mean

Agea

Educationb

Parental SESb

Schizophrenic

Controls

Schizophrenic

Controls

Schizophrenic

Controls

0.024 0.062 −0.051 −0.001 0.118 −0.160 0.017 −0.130 0.113 −0.009

0.275 −0.133 −0.121 −0.038 0.194 −0.350 0.308* −0.097 −0.274 −0.050

0.543** 0.376** 0.398** 0.258* 0.173 0.065 −0.041 0.212 0.329** 0.430**

0.468** 0.212 0.312* 0.320* 0.314* 0.055 0.250 0.208 0.127 0.388**

0.105 0.097 0.098 0.057 −0.035 0.013 −0.213 −0.206 −0.011 −0.033

0.211 0.280 0.313* 0.088 0.205 0.247 0.220 0.165 −0.077 0.332*

*p<0.05. **p<0.01. aPearson correlation. bSpearman rank correlation.

M. Albus et al. / Schizophrenia Research 28 (1997) 39–50

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Fig. 1. Neuropsychological profile for the consecutively enrolled sample of male (N=37) and female (N=29) patients with first episode (FE) schizophrenia relative to male (N=20) and female (N=20) healthy controls, whose performance is set to zero. Functions are verbal intelligence and learning ( VBL), spatial organization (SPT ), verbal memory and learning ( VBM ), visual memory ( VIM ), short-term memory (STM ), visual motor processing and attention ( VSM ), information processing and attention (Span of Apprehension Test, SAT, Continuous Performance Test, CPT ) and abstraction/flexibility (ABS).

males and 29 females) and controls (20 males and 20 females) (1) Multivariate analysis of variance: There was a significant effect for group (df=10; F= 13.76; p<0.05) and for gender (df=10; F= 4.53; p<0.05), but no significant group–gender interaction (df=11; F=1.39; p=ns). (2) Univariate comparisons: FE schizophrenics differed significantly from controls in VSM (df=1,102; F=103.1; p<0.05), in VBM (df= 1, 102; F=60.89; p<0.05), in VBL (df=1,102; F=25.53, p<0.05), in CPT (df=1,102; F= 20.05; p<0.05), in VIM (df=1,102; F=19.17; p<0.05), in SPT (df=1,102; F=18.02; p<0.05), in STM (df=1,102; F=15.66,

p<0.05), in SAT (df=1,102; F=9.66; p<0.05) and in profile mean (df=1,102; F=58.28; p<0.05). A significant gender difference was found for SPT (df=1,102; F=5.82; p<0.05) and VBM (df=1,102; F=5.11; p<0.05) (see Fig. 1). (3) Comparison between the matched groups (Sample 2) (1) Multivariate analysis of variance: Again, the MANOVA showed a significant effect for group (df=10; F=9.83; p<0.05) and for gender (df=10; F=4.39; p<0.05), but no significant group–gender interaction (df=10; F=.436; p=ns)

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Table 5 Z-scores (mean and s.d.) of the three groups (controls, total sample and matched subsample of schizophrenic patients) investigated in nine areas of neuropsychological functioning and profile mean based on the test performance of the total control group (N=40) Controls

Male N=20 Verbal intelligence and language ( VBL) Spatial organization (SPT ) Verbal memory and learning ( VBM ) Visual memory ( VIM ) Short-term memory (STM ) Visual-motor processing and attention ( VSM ) Information processing and attention (CPT ) (SAT ) Abstraction/flexibility (ABS ) Profile mean

Schizophrenia: Total sample Female N=20

Schizophrenia: Matched subsample

Male N=37

Female N=29

Male N=20

Female N=20

0.00+0.59

0.00+0.63

−0.50+0.78

−0.91+0.68

−0.52+0.84

−0.71+0.67

0.06+0.65 −0.17+0.63

−0.06+0.54 0.17+0.66

−0.40+0.79 −1.62+0.73

−1.04+0.72 −1.43+0.72

−0.52+0.86 −1.59+0.76

−0.89+0.72 −1.24+0.75

−0.10+1.0 0.02+0.82 −0.24+0.69

0.10+0.88 −0.02+0.86 0.24+0.73

−0.52+1.44 −0.51+0.78 −1.73+1.00

−1.33+2.13 −0.73+0.67 −1.90+0.96

−0.56+1.62 −0.64+0.80 −1.93+1.02

−0.62+1.79 −0.58+0.70 −1.85+1.10

−0.07+0.94

0.07+0.85

−0.55+0.83

−1.19+1.18

−0.75+1.05

−1.43+1.28

0.12+0.88 −0.02+0.94 −0.05+0.58

−0.12+0.88 0.02+0.94 0.04+0.46

−0.74+1.40 −0.35+1.42 −0.77+0.66

−0.70+1.12 −0.64+1.31 −1.10+0.65

−0.82+1.67 −0.63+1.87 −0.88+0.79

−0.75+1.30 −0.69+1.50 −0.97+0.70

(2) Univariate analysis: There were significant differences between the groups in VSM (df= 1,38; F=74.89; p<0.05), in VBM (df=1,38; F=54.15; p<0.05), in SPT (df=1,38; F= 28.83; p<0.05), in CPT (df=1,38; F=18.68; p<0.05), in VBL (df=1,38; F=15.61; p<0.05) and in profile mean (df=1,38; F= 69.47; p<0.05). Significant gender differences were found in VBM (df=1,38; F=9.51; p<0.05) (see Fig. 2).

4. Discussion To our knowledge, this is the first study to examine gender differences in neuropsychological function in FE schizophrenia and individually matched healthy controls taking into account influences of age, education, gender and, at least partially, parental socio-economic status on NP performance, e.g. factors that have been shown to be confounding variables on NP performance (Des Rosiers and Ivison, 1988; Boone et al., 1993; Houx et al., 1993). As expected, sex played a modulating role in NP performance in the healthy control sample as well as in the group of FE schizo-

phrenics. Our findings on gender differences are in concordance with reports in the literature on better performance of females in verbal learning and memory ( Kramer et al., 1988; Reite et al., 1993; Collaer and Hines, 1995) and men showing better visual spatial skills ( Kimura, 1992; Reite et al., 1993). Since the control sample showed consistency with typical trends in the general population regarding cognitive function, our healthy comparison subjects can be considered as representative for the general population. In addition, our sample of male and female first episode schizophrenics can be considered as representative. The findings of gender differences of 4.4 years at first admission with males having an earlier age at onset together with the duration between the occurence of first signs of the illness and first index admission are in line with the data reported by Ha¨fner et al. (1994) of the Danish and Mannheim case registers. Also, the age at first admission in FE females lies in the range that would be expected in a representative sample of schizophrenic women (Angermeyer and Ku¨hn, 1988). The higher number of male FE schizophrenics compared to females in our consecutively recruited sample has also been reported by other

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Fig. 2. Neuropsychological profile for the matched sample of male (N=20) and female (N=20) patients with FE episode schizophrenia relative to male (N=20) and female (N=20) healthy controls whose performance is set to zero. Functions are verbal intelligence and learning ( VBL), spatial organization (SPT ), verbal memory and learning ( VBM ), visual memory ( VIM ), short-term memory (STM ), visual motor processing and attention ( VSM ), information processing and attention (Span of Apprehension Test, SAT, Continuous Performance Test, CPT ), and abstraction/Flexibility (ABS).

authors (Hoff et al., 1992; Lieberman et al., 1993; Goldberg et al., 1995) despite different samples and methodologies. This supports, although somewhat controversially, the assumption of a gender disparity with higher rates of schizophrenia in men than in women (Cooper et al., 1987; Castle and Murray, 1991) at least in inpatient samples. The major finding of this study that compared individually matched representative FE schizophrenics and controls is that female schizophrenics did not differ from male schizophrenics compared to female and male controls on a comprehensive group of neuroposychological tests when controlling for the effects of age, sex, education and, at least partially, parental socio-economic status. This supports the assumption that the differences in NP performance found in male and female FE

schizophrenics are not different than the gender differences that are reported in the general population. This finding contrasts some of the previous literature suggesting a worse performance in males (Goldstein et al., 1994; Hoff et al., 1995; Seidman et al., 1996) or a worse performance in females (Perlick et al., 1992; Lewine et al., 1996). In concordance with our results, Goldberg et al. (1995) reported, in one of the first studies that contrasted performance of male and female schizophrenic patients on a wide but conceptually overlapping series of clinical neuropsychological test, that in an overwhelming number of comparisons, no significant differences between groups were found. It also suggests that the milder form of illness in schizophrenia in females (Goldstein, 1988; Goldstein et al., 1990) does not appear to

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be associated with better neuropsychological performance. Therefore, in our study, gender did not appear markedly to modify the cognitive impairment characteristic of schizophrenia. Our data are consistent with the notion that milder courses of schizophrenia in women may be, at least in part, an epiphenomenon (Andia et al., 1995). Women may have psychological, sociological and biological protective factors that result in easier management of their disorder. However, there is no a priori reason to believe that these protective factors in women would have a significant impact on the many and marked cognitive impairments of schizophrenia. Our results suggest that in FE schizophrenic patients, men and women perform similarly on a wide variety of neurocognitive tests compared to males and females found in the general population. One other possible explanation for our results might be that psychopathology accounts for differences in neuropsychological performance among the groups. However, there were no significant differences in the total sample with regard to either positive or negative symptoms, whereas in the matched subsample, men scored higher than females only in PANSS positive score. Assuming that higher ratings in the PANSS positive score would influence NP, test results would be in favor of a better performance in female FE schizophrenics and additionally support our finding that female FE schizophrenic patients do not perform better than male FE schizophrenic patients. A second methodological issue is that of medication status. Since patients in our study were tested under neuroleptics (NLs) to control for state related factors such as cognitive derailment and acute psychotic disorganization, effects of NLs on test performance cannot be excluded. However, several studies suggest either no influence or even improvement after treatment with classical NLs in some attentional functions, IQ-test performance and CPT (Sweeney et al., 1991; Verdoux et al., 1995; Epstein et al., 1996). Also, anticholinergic properties inherent to butyrophenones are quite small, so that a negative impact on memory function seems neglectible (see Gold et al., 1991). Even when conceding a negative impact of NLs on NP test performance, a more pronounced negative

impact on the performance of male FE schizophrenics should be expected, since they are treated with higher doses of NLs. This again underlines the validity of the finding of no better neuropsychological performance of female FE schizophrenics. Both groups performed significantly worse compared to healthy controls matched for age, gender, and education in several areas of NP functioning. When focussing on the most pronounced deficits, performances in VSM and VBM were the most impaired functions in male and female FE schizophrenics. Taking into consideration the fact that VSM has been shown to reveal the most pronounced deficits in male and female FE schizophrenics as well as in chronic schizophrenics (Albus et al., 1996), these data tentatively suggest that impairment in VSM is a stable underlying trait of patients with schizophrenia and is largely unaffected by gender and the course of illness.Finally, our results underline the impact of matching procedures on NP test performance that most likely account for a considerable amount of the discrepant findings on gender differences in schizophrenic patients published so far (Perlick et al., 1992; Goldstein et al., 1994, 1995; Hoff et al., 1995; Goldberg et al., 1995; Lewine et al., 1996; Seidman et al., 1996). Of the demographic characteristics taken into account, education has by far the most important impact on neuropsychological performance. In contrast, age and parental socio-economic status seem to be of minor importance or even neglectible. Therefore, our data strongly support the necessity of controlling for gender and education when addressing the question of neuropsychological impairment in schizophrenia.

Acknowledgment We wish to thank Mrs P. Hinterberger-Weber and Mrs R. Po¨tsch for their invaluable assistance during this project. This study was supported by a grant from the German Research Foundation (Al 230/3-1).

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