OBJECTIVES: Risperidone, an atypical antipsychitics which blocks both dopaminergic and serotonergic receptors, have a good response to the negative symptoms as well as positive symptoms, and improve cognitive dysfunction of schizophrenic patients. Furthermore, it has few extrapyramidal side effects and tardive dyskinesia. Although it had been reported that the atypical antipsychotics have less effect on prolactin(PRL) than the classical antipsychotics, we could experience PRL-associated symptoms such as amenorrhea, galactorrhea and hyperprolactinemia in practice. Therefore we tried to identify the sex differences of risperidone-induced hyperprolactinemia, to evaluate factors affecting PRL levels, and to know the association between cognitive disorders and PRL. METHODS: The baseline levels of PRL and TSH prior th risperidone administration were measured by enzyme immunoassay method for 50 patients (25 males and 25 females) admitted with schizophrenia, schizoaffective disorder or schizophreniform disorder according to the DSM-IV classification, and the measurements of PRL were repeated on the 2nd and the 4th wks of risperidone administration. Concomitantly, the severity of psychotic symptoms using CGI, BPRS and PANSS, and the cognitive dysfunction using PANSS-CF were assessed prior to, on the 2nd and the 4th wks of risperidone administration. The PRL and TSH levels of 54 healthy controls(29 males and 25 females) who had no medical, neurological and psychiatric illnesses were also evaluated. Furthermore, the correlation with the psychiatric diagnosis, education, age, sex, duration of illnesses, risperidone dosage, duration of risperdone administration, TSH concentration, cognitive function, severity of psychotic symptoms were also identified. RESULTS: 1) The baseline PRL levels of female schizophrenics(74.3+/-49.6ng/ml) were significantly(p<0.005) higher than those of males(36.3+/-24.6ng/ml), which wee significantly(p<0.0001 respectively) higher than those of controls(females 16.9+/-6.1ng/ml, males 13.3+/-4.9ng/ml). The PRL levels measured on the 2nd wks(females 133.7+/-47.8ng/ml, males 56.9+/-23.6ng/ml) and on the 4th wks(females 146.1+/-45.9ng/ml, males 70.0+/-31.5ng/ml) after risperidone administration were significantly(p<0.0001 respectively) higher in females. The mean dosages of risperidone on the 2nd wks were 3.8+/-1.7mg(2-6mg) for the females and 4.0+/-1.6mg(2-6mg) fore the males, and on the 4th wks were 4.5+/-2.1mg(2-8mg) fore the females and 5.4+/-2.2mg(2-8mg) for the males. 2) The rise of PRL levels were positively correlated with increased risperidone dosage in males(y=0.307 on the 2nd wks and y=0.280 on the 4th wks), while they were not correlated with dosages in females. For the females, the PRL levels were negatively correlated(y=-0.320) with decrease of TSH concentration. The baseline PRL levels were not correlated with age, education, duration of illnesses, psychopathology, cognitive disorders in both males and females, while it was negatively correlated with TSH levels only in females(y=-0.320). 3) The cognitive dysfunction was correlated with PRL levels in males, while PANSS-CF scores were negatively correlated with PRL levels(y=-0.220 on the 2nd wks and y=-0.366 on the 4th wks) in females. The psychopathology was positively correlated with cognitive dysfunction in both males and females. Therefore, the risperdone-induced cognitive improvement seemed to be correlated with improvement of psychopathology in both males and females, and with increase in PRL levels only in females. CONCLUSIONS: The fact that the serum PRL levels of schizophrenics were higher than those of controls, especially in females suggested that it could be related with risperidone dosage in males and with primary pathological process in females. The risperidone-associated cognitive improvement seemed to be related with general improvement of psychopathology as well as the rise of PRL levels especially in females. The facts that the effect of risperidone-induced hyperprolactinemia and the cognitive function were more in females suggested that somewhat different mechanisms could be exerted on them.