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Generating and testing a causal explanation of the gender difference in age at first onset of schizophrenia

Published online by Cambridge University Press:  09 July 2009

H. Häfner ,
A. Riecher-Rössler ,
W. An Der Heiden ,
K. Maurer ,
B. Fätkenheuer  and
W. Löffler
H. Häfner*
Affiliation:
Schizophrenia Research Unit, Central Institute of Mental Health, Mannheim, Germany
A. Riecher-Rössler
Affiliation:
Schizophrenia Research Unit, Central Institute of Mental Health, Mannheim, Germany
W. An Der Heiden
Affiliation:
Schizophrenia Research Unit, Central Institute of Mental Health, Mannheim, Germany
K. Maurer
Affiliation:
Schizophrenia Research Unit, Central Institute of Mental Health, Mannheim, Germany
B. Fätkenheuer
Affiliation:
Schizophrenia Research Unit, Central Institute of Mental Health, Mannheim, Germany
W. Löffler
Affiliation:
Schizophrenia Research Unit, Central Institute of Mental Health, Mannheim, Germany
*
1Address for correspondence: Professor H. Häfner, Central Institute of Mental Health, P.O. Box 12 21 20, D-68072 Mannheim 1, Germany.
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Synopsis

Motivated by the lack of knowledge of the pathophysiological processes underlying the manifestation of symptoms in schizophrenia, we have worked out a systematic search strategy. Since epidemiological distribution patterns consistently deviating from expected values provide valuable indications of causal relationships, we chose the higher age of females at first admission for schizophrenia, first reported by Kraepelin and since then confirmed in over 50 studies, as the basis for our study. This unexplained epidemiological finding was replicated on Danish and Mannheim case-register data by systematically controlling for selection and diagnostic artefacts and by testing alternative explanations at the individual stage of the study. To check whether the difference in age at first admission was determined by a difference in age at onset, 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) designed for this purpose. Any of the definitions of first-ever onset applied – first sign of mental disorder, first psychotic symptom, first acute 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 showed 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 plausibility of psychosocial versus biological explanations we hypothesized that due to the effect of oestrogens the vulnerability threshold for schizophrenia is elevated in females until the menopause. Animal experiments and post mortem analyses showed that chronic oestrogen applications significantly shortened dopamine-induced behaviour and reduced D2 receptor sensitivity in the brain. The applicability of this pathophysiological mechanism to human schizophrenia was tested on acutely schizophrenic females with normal menstrual cycles. A significant negative correlation was found between measures of symptomatology and plasma oestrogen levels. The manifestation of symptoms in schizophrenia appears to be influenced by a sufficiently sensitive D2 receptor system in the brain, blocked by neuroleptics and modulated by oestrogens.

Type
Original Articles
Information
Psychological Medicine , Volume 23 , Issue 4 , November 1993 , pp. 925 - 940
Copyright
Copyright © Cambridge University Press 1993

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