Abstract

Comparative studies of the benzisoxazole derivative risperidone (R 64 766) were made with ritanserin, a selective centrally acting serotonin-S2 antagonist and with haloperidol, a selective centrally acting dopamine-D2 antagonist. Risperidone like ritanserin shows activity in all tests related to serotonin-S2 antagonism, but at even lower doses (peripheral S2-antagonism at 0.0011 mg/kg, central S2-antagonism at 0.014 mg/kg). Like haloperidol, risperidone shows activity in all tests related to dopamine-D2 antagonism; activity in rats for both compounds starts at 0.016 mg/kg, but some central nervous system controlled functions, including the induction of catalepsy, are relatively much less affected by risperidone. Qualitatively, risperidone is a mixed serotonin-dopamine antagonist. Quantitatively, its study in dogs reveals potent dopamine-D2 antagonistic activity with excellent p.o. bioavailability and a relatively long duration of action. From the obtained pharmacological data, risperidone could be expected to possess the complementary clinical effects of a ritanserin-like serotonin-S2 and an haloperidol-like dopamine-D2 antagonist. Serotonin-S2 antagonism may improve the quality of sleep, reduce negative and affective symptoms in schizophrenic patients and decrease extrapyramidal symptoms induced by classical neuroleptics. Because risperidone is a dopamine-D2 antagonist, antidelusional, antihallucinatory and antimanic actions are expected. The first clinical studies indicate that two additional therapeutic targets, which are not reached with classical neuroleptics, may be obtained with risperidone in the monotherapy of schizophrenia and related disorders: very important contact and mood-elevating properties and extrapyramidal symptoms-free maintenance therapy.