A CHAPTER OF SYSTEMATIC SCHIZOPHRENIA RES EARCH - SEARCH FOR CAUSAL EXPLANATIONS OF THE SEX DIFFERENCE IN AGE AT 1ST ONSET

With the aim of detecting causal processes contributing to the onset o f schizophrenic symptoms a systematic search strategy was worked out. One of the few epidemiological findings on schizophrenia consistently diverging from expected values, the sex difference in age at first adm ission, was taken as a basis and replicated on data from the Danish an d the Mannheim case registers by controlling for selection and diagnos tic artefacts. Danish psychiatrists turned out to have underdiagnosed schizophrenia to a considerable extent at least in 1976, the year from which the analysed case-register data dated. After the exclusion of a lternative explanations, the time when symptoms appeared for the first time and the first acute episode occurred was determined for a repres entative sample of 267 first-admitted cases with a diagnosis of non-af fective functional disorder by using the IRAOS interview designed for this purpose. At any of the definitions of first onset applied the mea n age of females was significantly higher than that of males, the diff erence ranging from 3.2 to 4.1 years. The distribution of onsets acros s the female life cycle showed a clearly delayed increase at young age and a second, lower peak of onsets at the age of 45-54, whereas the c umulative incidence up to the age of 60 years was equal for males and females. On assessing the plausibility of psychosocial versus biologic al explanations it was hypothesized that due to the effect of estrogen s the vulnerability threshold for schizophrenia is raised in females u ntil the menopause. Animal experiments and postmortem analysis showed that chronic estrogen applications significantly shortened dopmaine-in duced behaviour and reduced D2 receptor sensitivity in the brain. The applicability of this pathophysiological mechanism on human schizophre nia was tested on acutely schizophrenic females with normal menstrual cycles. A significant negative correlation was found between measures of symptomatology and plasma estrogen levels. Apparently, manifestatio n of schizophrenic symptoms is influenced by a sufficiently sensitive D2 receptor system in the brain, blocked by neuroleptics and modulated by estrogens.