The ABC (age, beginning, course) schizophrenia study was commenced in 1987 to generate and test hypotheses about pathogenic aspects of schizophrenia. One of the main branches of the study focused on how gender influences the age distribution of onset, symptomatology, illness behavior, and early course in schizophrenia. Proceeding from one of the rare, strikingly deviating, consistent findings--the gender difference in age at first admission--we launched a systematic search for explanations by generating and testing hypotheses in a series of substudies. We moved from the epidemiological to the neurobiological and finally to the clinical level. The present article is an attempt to provide a brief overview of the individual stages of the ABC study and the different levels of investigation involved in formulating and testing the estrogen hypothesis in animal experiments and in demonstrating its applicability to human schizophrenia. From these results, three hypotheses were formulated and tested on data from an ABC study sample of 232 first-episode cases of schizophrenia. The analyses described here represent the latest stages of the ABC study.

In the present study we compared the effects of the atypical neuroleptic zotepine to haloperidol and clozapine on stereotypies and locomotion induced in rats by the N-methyl-D-aspartate (NMDA) antagonist MK-801. Zotepine caused a dose-dependent reduction of MK-801-induced stereotypies and locomotion. Zotepine at a dosis of 2.5 mg/kg body weight showed a similar effect to 0.25 mg/kg haloperidol in reducing sterotypies and locomotion. Clozapine (5.0 mg/kg) reduced significantly locomotion and non-significantly stereotypies. These results add support to the assumption that MK-801-induced behavior provides an adequate animal model to test the potential efficacy of typical and atypical neuroleptics in the treatment of psychoses.

Chronic haloperidol treatment in rats results in behavioural supersensitivity to dopamine agonists. This mechanism has been suggested as a possible animal model for tardive dyskinesia. In the present study the simultaneous administration of vitamin E to chronic haloperidol treatment in rats prevented the development of behavioural supersensitivity to apomorphine. This finding suggest that the concomitant administration of vitamin E to neuroleptics might prevent the development of tardive dyskinesia in humans.

Central Institute of Mental Health, Unit Neurobiology of Functional Psychoses P. O. Box 12 21 20, D-6800 Mannheim 1, F. R. G.

For a systematic study of the influence of age and gender on symptomatology and early course of schizophrenia, we collected a representative sample of 392 first hospital admissions for schizophrenia (broad definition) from a population of 1.5 million. By using several operational definitions we assessed ‘true onset’ in a semistructured interview ‘IRAOS’. We were able to demonstrate that the mean age at onset 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 reach a peak in the age group 15-24, followed by a monotonous decrease. Females reach a lower first peak with a clear delay between 20 and 29. After the decrease a second smaller peak is observed consistently in females in the age group 45-49 and over. We hypothesized that the effect of dopaminol on the dopaminergic system enhances the vulnerability threshold, which is lowered again during menopause. We tested the hypothesis experimentally with animal models: estradiol treatment caused a significant reduction of both dopamine-agonist and -antagonist induced behavior showing a maximum in neonatal rats. The higher age at onset and the second peak after menopause in females may therefore be due to effects of estrogens. A comparison of early symptoms in the two sexes revealed only few significant differences, which are more likely to be attributed to illness behavior than to the disease. The same is true for the comparison over three age groups, which in negative symptoms showed no differences, whereas solely personality development accounted for the gender difference in positive symptoms. Patterns of early course of the psychosis also are surprisingly similar in the two sexes and over the three age groups. Unexpected is the prolonged course and the predominance of negative symptoms in the early states of schizophrenia in females compared to males.

We found in a representative sample of 392 first hospital admissions for schizophrenia a higher mean age at onset in females by 3.2 to 3.9 years, whereas the lifetime risk was equal for both sexes. In males the rates of onset show a steep increase reaching the maximum value in the age group 15-24 years, followed then 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 alternative explanations for this gender differences (for example, diagnosis artefacts, sociocultural factors), we hypothesized that the effect of oestradiol on the dopaminergic system enhances the vulnerability threshold for schizophrenia, which is lowered again during the menopause. Alternatively we assumed that testosterone reduces the vulnerability threshold and thus furthers the earlier onset of schizophrenia in males. We tested these hypotheses in animal models by investigating the effects of the gonadal hormones on haloperidol-induced catalepsy and on apomorphine-induced stereotypies in both neonatal and adult rats. Testosterone showed no clear influence on the tested dopamine-mediated behaviour. Oestradiol caused a significant reduction on both dopamine-agonist and dopamine-antagonist induced behaviour. These effects were stronger in neonatal animals. Since oestradiol caused a 2.8-fold reduction of dopamine receptor affinity for sulpiride, we assumed that the behavioural changes caused by oestradiol were accounted for by a down-regulation of the dopaminergic system.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of haloperidol and diazepam were investigated on stereotypies (wall contacts and turn rounds) induced by the non-competitive NMDA antagonist MK-801 in rats. Haloperidol (0.03, 0.10, 0.25 and 0.40 mg/kg body weight) caused a dose-dependent antagonism whereas diazepam (3.0 and 5.0 mg/kg) caused a dose-dependent agonism of the stereotypies induced by 0.30 mg/kg MK-801 (all drugs given intraperitoneal). Conversely, diazepam (5.0 mg/kg) given alone reduced significantly the number of spontaneous wall contacts and turn rounds. The paradoxial stimulation of MK-801 induced stereotypies by diazepam could be explained by a shift between positive and negative corticostriatothalamic feedback loops envolving GABAergic neurons in favour of the former.

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.