Main risk factors for schizophrenia: increased familial loading and pre- and peri-natal complications antagonize the protective effect of oestrogen in women.

Women fall ill with schizophrenia 3 to 4 years later than men. The neurobiological mechanism, explaining the delay of onset in women until menopause, is presumably due to a sensitivity reducing effect of oestrogen on central d(2) receptors, as we have previously shown in animal experiments and in a controlled clinical study. The gender difference in age at onset seems to disappear in familial cases with schizophrenia, but it increases to highly significant values of 5 years or more in isolated cases according to a recent study by Albus and Maier (Schizophrenia Research 18:51-57, 1995). We tried to replicate these findings and to test the hypothesis of a functional antagonism between genetic predisposition to illness and the protective effect of oestrogen in a population-based sample of 232 first illness episodes of schizophrenia. In women with at least one first-degree relative suffering from schizophrenia, age at onset defined by first psychotic symptom was significantly reduced by several years and the difference with men disappeared. In sporadic female cases (no mental disorder in first-degree relatives) the age at onset was slightly increased compared with the total sample, which was in accordance with our hypothesis. In men with familial schizophrenia, but without a protective agent like oestrogen, the age at onset was only slightly and non-significantly reduced compared with the total group and with sporadic cases. This was in line with Albus and Maier and with our hypothesis that only the protective effect of oestrogen could be antagonized by a strong genetic disposition. The second main risk factor for schizophrenia is pre- and peri-natal complications. We compared men and women from our sample of first illness episodes with a history of pre- and peri-natal complications with those without a history of obstetric complications. In women the age at first psychotic symptom was markedly reduced, but due to small case numbers not significantly, compared with women without the risk factor and with the total group. Again, schizophrenic men with a history of pre- and peri-natal complications showed only a small, non-significant reduction of age at onset compared with the total and the group without the risk factor. Therefore, we concluded that the degree of genetically determined vulnerability and, presumably to a slightly lesser extent, the degree of pre- and peri-natal brain injury antagonizes the onset delaying effect of oestrogen in schizophrenia.