Suggested Minimal Effective Dose of Risperidone Based on PET-Measured D₂ and 5-HT_2A 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 D₂ and serotonin 5-HT_2A 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 [¹¹C]raclopride to measure D₂ receptor occupancy and [¹¹C]N-methyl­spiperone to measure 5-HT_2A 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 D₂ receptor occupancy was 82% (range=79%–85%), 5-HT_2A receptor occupancy was 95% (range=86%–109%), and six patients had developed extrapyramidal side effects. After dose reduction to 3 mg/day, D₂ receptor occupancy was 72% (range=53%–78%), and 5-HT_2A 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 D₂ receptor occupancy, with a consequent risk of extrapyramidal side effects. High 5-HT_2A receptor occupancy did not prevent extrapyramidal side effects completely. The authors previously suggested an optimal interval for D₂ 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.