Gender effects are important to schizophrenia. Why is that so? First, they are important because of the many differences between men’s and women’s experience of schizophrenia. Clinicians need to learn to recognize these differences and to assess, treat, and, support men and women with schizophrenia in somewhat different ways to optimize the quality of their lives.  Researchers,  too,  need to study these differences to determine whether they offer clues to the etiology and pathogenesis of schizophrenia.

Genetics
Although a positive family history has been claimed in the past to be more common in women than in men patients with schizophrenia, there is no good evidence that this is the case. Genetic risk seems identical in the two sexes, which suggests that the expression of schizophrenia-prone genes is not affected by biological sex or steroid hormones. That being said, it is possible that in the future some schizophrenia risk genes may still be found that are transmitted at higher rates in one sex than in the other. The enzyme catechol-O- methyltransferase (COMT), for instance, has been the object of extensive investigations as a risk gene because of its major role in dopamine metabolism. In several older studies, a reported gender-specific association of COMT polymorphisms with schizophrenia had given rise to speculations on transmission ratio distortions, but the most recent studies have found no gender differences.

Environmental risk factors
Known environmental risk factors for schizophrenia, such as prenatal infection, obstetric complications, early rearing environments, and adolescent cannabis use impact the two genders differently and probably contribute to the reported differences in morbidity risk.

The association between prenatal exposure to influenza and later onset of schizophrenia is stronger in females, but obstetric complications have been reported to be more strongly associated with schizophrenia in men than in women (although this is controversial), whereas adolescent substance abuse,  particularly cannabis,  is more prevalent in the premorbid histories of males.

Because the pace of cerebral development is slower in males than in females, the male fetal brain is considered more susceptible to environmental adversity than the female brain, due at least in part to estrogen. By activating common intracellular signaling pathways and initiating “cross-talk” with neurotrophins, the female hormone estrogen is known to play an influential role in promoting neuronal survival after environmental insult. More symmetrical brain organization in females is also considered protective, in that the other side of a symmetrical brain can compensate for functions unilaterally disrupted. During adolescence, sex-specific (hormonally induced?) reductions in synaptic density may additionally contribute to the extra vulnerability of the male brain at that critical time.

Incidence rates
Recent meta-analyses of incidence risk report a mean ratio of 1.42 for men over women, an excess for males that is only slightly reduced when studies of lower quality are excluded.

This sex difference in incidence is significantly smaller in studies conducted prior to 1980.

This suggests that the broader diagnoses prevalent before 1980 (at that time, the diagnosis of schizophrenia would have included schizoaffective disorder and perhaps bipolar disorder with psychotic features) tended to flatten the sex ratio. No significant sex differences in incidence have been reported in studies from developing countries. The high death rate of vulnerable children and adolescents in developing countries might offer a partial explanation. Because more women than men first become ill with schizophrenia after age 55 (the frequent cutoff age for epidemiological studies), these older women may be lost to incidence analysis. But studies with an age cutoff of 64 years or older also yield a higher mean risk ratio for men (1.32). On the other hand, no sex differences have been found in prevalence rates of schizophrenia (whether point, period, lifetime, or lifetime morbid risk prevalences). The discrepancy between incidence and prevalence sex ratios could be accounted for by better male recovery (doubtful), higher rates of male incarceration (i.e., epidemiological unavailability) or higher male death rates, particularly from suicide.

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»  » Childhood development - Schizophrenia and Gender

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MARY V. SEEMAN
Mary V. Seeman, MDCM, FRCPC, FACP, is Professor and Tapscott Chair of Schizophrenia Studies at the University of Toronto and Centre for Addiction and Mental Health,Toronto, Ontario, Canada.

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REFERENCES

1. Aleman, A., Kahn, R. S., & Selten, J. P. (2003). Sex differences in the risk of schizophrenia: Evidence from meta-analysis. Archives of General Psychiatry, 60, 565–571.
2. Angermeyer, M. C., Kuhn, L., & Goldstein, J. M. (1990). Gender and the course of schizophrenia: Differences in treated outcomes. Schizophrenia Bulletin, 16, 293–307.
3. Cho, J. J., Iannucci, F. A., Fraile, M., Franco, J., Alesius, T. N., & Stefano, G. B. (2003). The role of the estrogen in neuroprotection: Implications for neurodegenerative diseases. Neuroendocrinology Letters, 24, 141–147.
4. Goldstein, J. M., Seidmann, L. J., O’Brien, L. M., Horton, N. J., Kennedy, D. N., Makris, H., et al. (2002). Impact of normal sexual dimorphisms on sex differences in structural brain abnormalities in schizophrenia assessed by magnetic resonance imaging. Archives of General Psychiatry, 15, 154–164.

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