The topic of the lead article could not be more provocative: sex and emotion! Not only is the Addington and others study, "Gender and Affect in Schizophrenia," (p 265-268) intriguing, but also it is theoretically important. In a methodologically well-designed study, the investigators fail to confirm previous reports of affective differences between men and women during the course of schizophrenia. Negative symptoms had previously been observed to occur more often in men; depressive symptoms, in women. This supposed difference has been variously interpreted.
Because schizophrenia appears to be more often familial in women than in men (1-4) and because affective psychosis is more heritable than schizophrenic psychosis, it has been suggested that some women diagnosed with schizophrenia by DSM-III-R criteria are really suffering from a schizoaffective psychosis more akin to depression than to schizophrenia. The Addington group meticulously excluded schizoaffective psychosis from their study sample, which may explain why, contrary to others (5-7), they did not see a sex difference in depressive symptoms in their schizophrenic population.
Negative symptoms may have been reported more often in the past among men (8) because men are frequently prescribed higher doses of neuroleptics (9,10), and negative symptom rating scales do not adequately distinguish primary and secondary deficit symptoms. In the Addington and others sample, the neuroleptic doses did not differ between men and women. Greater prevalence of substance abuse among male patients with schizophrenia relative to female patients may also contribute to differences reported in the literature. The gender gap in the extent of substance use is closing, however, and current inquiries into gender differences may no longer be plagued by this confound.
Inherent brain structure and function differences between the sexes (11,12), differential premorbid competencies (13), and birth complications (14) have all been invoked to explain symptom contrasts between men and women in schizophrenia. Whereas subtle differences between the sexes do exist in the above areas, systematic symptom differences are, as a result of the present data set, now thrown very much in doubt.
Other differences between men and women still hold. For instance, admission to hospital is delayed in women by a mean of 4 to 6 years (15-17), but this is only true (in sporadic schizophrenia) if the illness starts after puberty (18). Interestingly, it is not at all true in familial schizophrenia (19). Late onset (over the age of 35) is overwhelmingly more frequent in women than in men. The severity of illness expression in women is less debilitating than in men during the first decade following onset (7,20-24), but it worsens in subsequent years and eventually approximates that of men (25-27).
The neurodevelopmental hypothesis of schizophrenia proposes that the genes responsible for the disorder are expressed early in fetal life and act to impair neuronal migration, thus compromising the integrity of neural networks in adulthood. Furthermore, the hypothesis permits the subsequent influence of protective factors (fetal hormones, for instance) and/or aggravating factors (uterine infections, for instance), which accelerate or delay illness progression and raise or lower the threshold for the expression of symptoms. Male-female differences may result from sexual dimorphisms in schizophrenia-determining genes, but more likely evolve from subtle shifts in protective and aggravating influences. Hormonal and immune systems differ in men and women, and the pace of brain maturation differs as well. Any or all of these factors may be critical to the timing of onset and to the progression of disease.
In light of the differences in age of onset between men and women, it is tempting to speculate about the possible influence of gender on the height of the threshold for developing schizophrenia. There is some evidence that gendered behaviour, not only genetic sex, can influence brain morphology (12). If that is the case, it is certainly possible that the stress buffering that results from supportive families and protective social networks (more prevalent in young women than in young men) delays the onset of schizophrenia, promotes premorbid skill acquisition, and, consequently, assures a more favourable course of illness. The continuing study of sex differences may allow an exploration of such issues and may point the way toward effective early intervention.
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