Are There Sex Differences in Neuropsychological Functions Among Patients With Schizophrenia?

Table 3 presents the multivariate test results for the overall effects of group and sex and their interaction. In addition, effect sizes were calculated, on the basis of univariate analyses of variance of the functions, for the effects of sex within group (table 3, columns 2 and 3) and group within sex (columns 5 and 6). Finally, univariate F tests are shown for the effects of sex (column 4), group (column 7), and their interaction (column 8) across functions. Figure 1 shows the standardized scores for each neuropsychological domain for male and female patients with schizophrenia and male and female comparison subjects.

Table 3 shows that the multivariate test (Wilks’s lambda) for an overall effect of group across all neuropsychological functions and the overall effect of sex were significant. The overall test of the interaction of group by sex was not significant.

When neuropsychological functions were compared by group within sex (table 3, columns 2–4, and figure 1), the results showed that the male schizophrenic patients performed significantly more poorly across all neuropsychological domains than the male comparison subjects. The female schizophrenic patients performed significantly more poorly than the female comparison subjects on attention, nonverbal memory, executive functions, and motor function. However, they were not significantly different from the female comparison subjects on language, verbal memory, and visual-spatial ability. In general, the effect sizes for the men, patients versus comparison subjects, were two to three times larger than the effect sizes among the women, except for nonverbal memory (table 3).

The sex effects within group showed that female and male normal comparison subjects did not significantly differ in performance on most of the neuropsychological domains, except visual-spatial ability (table 3, column 3); the male comparison subjects performed significantly better on visual-spatial ability and on motor speed than the females. In contrast, the male patients performed significantly more poorly than the female patients on attention, language, verbal memory, and executive functions (table 3, column 2). The male patients did not significantly differ from the female patients on nonverbal memory, visual-spatial ability, and motor speed because of poorer functioning among the men. The difference in effect sizes for men and women within groups was substantial (two- to eightfold), except for nonverbal memory (table 3, columns 2 and 3), even though the interaction of sex and group was not significant.

As is typical in schizophrenia, the patients showed significant decrements in neuropsychological performance across many functional domains. Although the overall interaction of sex by group was not significant, the effect sizes suggest that there are differences in deficits for male and female patients compared with normal subjects. Male patients were significantly impaired across all domains of functioning in comparison with male normal subjects. Female patients were significantly worse than female normal subjects on attention, executive functions, visual memory, and motor functions, with relatively preserved function in language, verbal memory, and visual-spatial ability. Further, male patients performed significantly worse than female patients on tasks of attention, verbal memory, and executive functions, three domains thought to be central in the neuropsychology of schizophrenia (21, 26, 27, 31, 33-35).

The results consistently showed medium to large differences in effect size between patients and comparison subjects within sex (table 3, columns 5 and 6) and between the sexes within groups (table 3, columns 2 and 3), suggesting that there is widespread dysfunction among male patients and greater preservation of functioning among female patients. Even for functions in which female patients showed deficits (i.e., executive functions or attention), the effect size for the deficits among male patients was twofold greater than that for female patients (table 3, columns 5 and 6).

Other studies examining neuropsychological functioning in schizophrenia have shown diffuse deficits among first-episode and chronic schizophrenic patients (13, 26, 33) and selective impairment in verbal memory (31). One possibility suggested by our work is that these findings apply primarily to male schizophrenic patients. In fact, the groups in these other studies (13, 26, 31, 33) included a majority of men (73%, 62%–87%, and 74%, respectively). Thus, it is possible that the effects were mainly accounted for by the men.

However, two recent studies, one of which (15) was specifically designed to study sex differences in neuropsychological functioning, reported no significant sex differences (11) or greater impairment in women (15). What could account for the inconsistency between our results and theirs? One possible methodological artifact may be that neither of the other studies matched schizophrenic and normal subjects within sex. This is important, since the variability of cognitive functions within sex in normal subjects is greater than the differences between the sexes (20). Thus, since sex effect sizes are small, it is important to control for as much extraneous variation as possible within sex-specific groups, such as using carefully matched normal comparison subjects within sex. Otherwise, the significance of the sex effects may not be detected, even with large study groups (11, 15).

Second, although one study (11) involved a large study group from three sources, it did not include normal comparison subjects. The absence of sex effects could potentially provide some insights into sex differences in particular cognitive functions in which normal subjects have been found to differ (20).

A third possibility is that there were sex differences in premorbid capacities among our subjects, which resulted in sex differences in cognitive performance after illness. In our schizophrenic group, the men had significantly lower reading scores and IQs than the normal comparison men, perhaps indicating that they were drawn from a population with lower intellectual capacity and thus exhibited lower cognitive performance as adults than the comparison men or schizophrenic women. This would suggest that our findings were due to sampling bias rather than to the effects of illness. We tested this by conducting additional analyses of covariance of the functions with group, sex, and their interaction, and statistically controlling for reading ability. We controlled for reading rather than IQ, since we and others have argued that IQ is more susceptible to illness effects than single-word oral reading (36, 37). Controlling for IQ would therefore “overadjust” by controlling for intellectual capacity and illness effects (36); thus, reading can be considered a better matching variable (36, 37). The results remained the same even when we controlled for reading. That is, the sex effects were still significant for language (when reading was dropped from the definition of the domain, since reading was used as a covariate), attention, verbal memory, and executive functions. Controlling for reading is a conservative test of our results, since it is possible that premorbid reading ability may also be subtly susceptible to illness effects early in the developmental course of the illness and more likely to be expressed by males (6, 7).

Our sample of women was not atypical of a large outpatient service network serving an extensive urban catchment area, since we systematically ascertained subjects by using a strict stratified-by-sex, random ascertainment procedure. The women were long-term, clinically stable outpatients, carefully matched to comparison subjects within sex. We did not initially design a study of sex differences that would include chronic patients, since we and others (16, 17) have argued that among chronic subjects, sex effects would be attenuated. Finding significant sex effects even among this chronic group of patients is meaningful, since the female patients had somewhat longer, although not significantly different, illnesses and more hospitalizations than the men and still functioned better in selective domains.

Given that the size of sex-specific groups was relatively small, the findings in this study must be replicated in larger groups with the use of similar methodological designs. However, we do not believe that group size accounted for the lack of significant differences in some functions among the women, since we found a differential effect among the men, and the male group sizes were similar to the females’. Further, we had excellent reliabilities on the functions, thus increasing the power to find significant effects even in small groups. Finally, although we had a small study group and thus low statistical power to detect significant interactions, differences in the effect sizes of the functions for sex within group and group within sex were substantial (two- to eightfold) and consistent. If we were to be conservative in our interpretation of the results because of the limitations of group size, then the results would still show that the differences in functions between female patients and female comparison subjects were much smaller than the differences between male patients and their comparison subjects, indicating that male patients are more impaired on specific functions than female patients. The lower, twofold difference in effect size for verbal memory may reflect sex differences in deficits in encoding (i.e., an executive function) or in verbal ability in general rather than memory deficits per se. Thus, it is important to investigate further the aspects of each overall domain in which men and women with schizophrenia differ.

Significant neuropsychological sex differences have been reported by other investigators as well. In fact, Hoff and colleagues (13) found a significant overall sex effect, although there was no significant result for any particular domain upon inspection of the univariate analysis. This may have been due to the small number of female patients compared with males (approximately 1:3). Further, these researchers controlled for education, which may have attenuated illness effects. Females, in general, in their study performed relatively better on verbal memory than males, and males, in general, performed better on visual-spatial ability, consistent with our results for female patients and male comparison subjects, respectively. Our findings are also consistent with previous studies of schizophrenic patients (7-9) and studies of high-risk offspring of schizophrenic parents (3–5), 21). These studies reported significant sex differences in neuropsychological performance, with males showing more deficits than females in particular areas, such as attention, language, and executive functions.

Our findings suggest that female schizophrenic patients may be less vulnerable to deficits involving verbal processing (e.g., language, verbal abstraction, and verbal memory) and visual-spatial ability. We believe this to be associated, in part, with normal sexual brain dimorphism (18, 20, 38) and normal sex differences in cognition (20) and brain physiology (39). Studies of cognition in normal subjects have reported that, on average, women perform better on tasks of verbal fluency and verbal memory, and men perform better on particular kinds of visual-spatial and mathematical reasoning tasks (20). Such normal cognitive differences may be associated with sex differences in brain structures. Preliminary magnetic resonance imaging (MRI) studies of small groups of normal subjects have reported that with adjustment for total brain volume, women had a larger hippocampus (40), dorsolateral prefrontal cortex, and superior temporal gyrus (40), 41) than men. Some MRI studies of schizophrenic patients have also indicated sex differences in brain volumes in areas such as the thalamus and ventricular system (42). The brain areas just mentioned contribute to long-term and working memory, sustained attention, abstract verbal reasoning, and language production. If these recent MRI findings are replicated, then women with schizophrenia may be less vulnerable to consequences from particular prenatal/perinatal or genetically determined insults that may differentially affect these areas of the brain in schizophrenia. Replication of our findings in this study is important, since the area of sex differences in neuropsychological functioning remains controversial.

Received June 2, 1997; revisions received Dec. 10, 1997, and March 23, 1998; accepted April 9, 1998. From the Harvard Institute of Psychiatric Epidemiology and Genetics, Laboratory of Neuropsychology, Department of Psychiatry, Harvard Medical School at Massachusetts Mental Health Center; the Department of Psychiatry, Harvard Medical School at Brockton VA Medical Center; the Department of Epidemiology, Harvard School of Public Health, Boston; and the Cognitive Neurology and Alzheimer’s Disease Center, Departments of Neurology and Psychiatry, Northwestern University Medical School, Chicago. Address reprint requests to Dr. Goldstein, Massachusetts Mental Health Center, 74 Fenwood Rd., Boston, MA 02115; [email protected] (e-mail). Supported initially by a Young Investigator Award to Dr. Goldstein from the National Alliance for Research on Schizophrenia and Depression and later by NIMH Scientist Development Award MH-00976 to Dr. Goldstein and NIMH Merit Award MH-43518 to Dr. Tsuang.