Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients

Objective: Multicenter trials with the novel antipsychotic risperidone have suggested a standard dose of 6 mg/day. However, a dose producing the highest response rate in fixed-dose studies is likely to exceed the minimal effective dose in most patients. The aim of this positron emission tomography (PET) study was to suggest a minimal effective dose of risperidone based on measurements of dopamine D-2 and serotonin 5-HT2A receptor occupancy. Method: Eight first-episode or drug-free schizophrenic patients were treated with risperidone, 6 mg/day, for 4 weeks and then 3 mg/day for 2 weeks. PET was performed after 4 and 6 weeks, with [C-11]raclopride to measure Dp receptor occupancy and [C-11]N-methylspiperone to measure 5-HT2A receptor occupancy. Results: Seven patients completed the study and responded to treatment with risperidone. No patient had extrapyramidal side effects at the time of inclusion in the study. At the 6-mg/day dose, mean D-2 receptor occupancy was 82% (range=79%-85%), 5-HT2A receptor occupancy was 95% (range=86%-109%), and six patients had developed extrapyramidal side effects. After dose reduction to 3 mg/day, D-2 receptor occupancy was 72% (range=53%-78%), and 5-HT2A receptor occupancy was 83% (range=65%-112%). Three patients had extrapyramidal side effects at this time. Conclusions: Treatment with risperidone, 6 mg/day, is likely to induce unnecessarily high D-2 receptor occupancy, with a consequent risk of extrapyramidal side effects. High 5-HT2A receptor occupancy did not prevent extrapyramidal side effects completely. The authors previously suggested an optimal interval for D-2 receptor occupancy of 70%-80%. To achieve this, risperidone, 4 mg/day, should be a suitable initial dose for antipsychotic effect with a minimal risk of extrapyramidal side effects in most patients.