Oestradiol enhances the vulnerability threshold for schizophrenia in women by an early effect on dopaminergic neurotransmission

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Summary

In a representative sample of 392 first hospital admissions for schizophrenia from a population of 1.5 million we assessed the “true” age of onset by a semistandardized interview “IRAOS”. We demonstrated that the mean age at onset of the disease is 3–4 years higher in females than in males, with the lifetime risk being exactly equal. In males, the rates of onset show a steep increase — starting from school age and reaching their maximum value in the age group 15–24 years — followed by a steady decrease. Females reach the first peak with a clear delay between 20 and 29 years. After the decrease, a second smaller peak is observed consistently in females within the age group 45–49 years and over. After having excluded competing explanations, we hypothesized that the effect of oestradiol on the dopaminergic system enhances the vulnerability threshold, which is lowered again during the menopause. Alternatively, we assumed that testosterone reduces the vulnerability threshold and thus furthers the earlier onset of the disease in males. We tested the hypotheses in three animal models by examining the effect of gonadal hormones on haloperidol-induced catalepsy and on apomorphine-induced stereotypies in both neonatal and adult rats. No clear influence by testosterone was shown. Oestradiol caused a significant reduction of both dopamine-agonist and dopamine-antagonist induced behaviour. The effects were stronger in neonatal rats. Since oestradiol caused the dopamine (DA) receptor affinity for sulpiride to be reduced by a factor of 2.8, we assumed that the behavioural changes due to oestradiol were accounted for by a down-regulation of DA receptor sensitivity. The higher age at onset and the second peak of onsets after menopause in females may therefore be due to a functional effect and possibly also to an additional structural effect of oestrogens already exerted on the development of the brain.