GENERATING AND TESTING A CAUSAL EXPLANATION OF THE GENDER DIFFERENCE IN AGE AT 1ST ONSET OF SCHIZOPHRENIA

Motivated by the lack of knowledge of the pathophysiological processes underlying the manifestation of symptoms in schizophrenia, we have wo rked out a systematic search strategy. Since epidemiological distribut ion patterns consistently deviating from expected values provide valua ble indications of causal relationships, we chose the higher age of fe males at first admission for schizophrenia, first reported by Kraepeli n and since then confirmed in over 50 studies, as the basis for our st udy. This unexplained epidemiological finding was replicated on Danish and Mannheim case-register data by systematically controlling for sel ection and diagnostic artefacts and by testing alternative explanation s at the individual stage of the study. To check whether the differenc e in age at first admission was determined by a difference in age at o nset, a representative sample of 267 first-admitted patients with non- affective functional psychosis was examined by using an interview for the retrospective assessment of the onset of schizophrenia (IRAOS) des igned for this purpose. Any of the definitions of first-ever onset app lied - first sign of mental disorder, first psychotic symptom, first a cute episode - led to a significant age difference of 3.2 to 4.1 years between the sexes. The distribution of onsets across the life cycle s howed a later increase and a second, lower peak between the ages of 45 and 54 years among females compared with males. The lifetime risk for schizophrenia was equal for males and females. After testing the plau sibility of psychosocial versus biological explanations we hypothesize d that due to the effect of oestrogens the vulnerability threshold for schizophrenia is elevated in females until the menopause. Animal expe riments and post mortem analyses showed that chronic oestrogen applica tions significantly shortened dopamine-induced behaviour and reduced D 2 receptor sensitivity in the brain. The applicability of this pathoph ysiological mechanism to human schizophrenia was tested on acutely sch izophrenic females with normal menstrual cycles. A significant negativ e correlation was found between measures of symptomatology and plasma oestrogen levels. The manifestation of symptoms in schizophrenia appea rs to be influenced by a sufficiently sensitive D2 receptor system in the brain, blocked by neuroleptics and modulated by oestrogens.