Clinical and Theoretical Implications of 5-HT₂ and D₂ Receptor Occupancy of Clozapine, Risperidone, and Olanzapine in Schizophrenia

OBJECTIVE: Dopamine D₂ receptor occupancy measurements provide a valid predictor of antipsychotic response, extrapyramidal side effects, and elevation of prolactin levels. The new antipsychotics clozapine, risperidone, and olanzapine obtain antipsychotic response with few extrapyramidal side effects and little prolactin elevation. The purpose of this study was to compare the D₂ and serotonin 5-HT₂ receptor occupancies of these drugs in patients receiving multiple-dose, steady-state regimens. METHOD: Forty-four patients with schizophrenia (16 taking risperidone, 2–12 mg/day; 17 taking olanzapine, 5–60 mg/day; and 11 taking clozapine, 75–900 mg/day) had their D₂ and 5-HT₂ occupancies determined with the use of [¹¹C]raclopride and [¹⁸F]setoperone, respectively, and positron emission tomography imaging. RESULTS: Clozapine showed a much lower D₂ occupancy (16%–68%) than risperidone (63%–89%) and olanzapine (43%–89%). Risperidone and olanzapine gave equal D₂ occupancies at doses of 5 and 20 mg/day, respectively. All three drugs showed greater 5-HT₂ than D₂ occupancy at all doses, although the difference was greatest for clozapine. CONCLUSIONS: Clozapine, at doses known to be effective in routine clinical settings, showed a D₂ occupancy clearly lower than that of typical antipsychotics, while risperidone and olanzapine at their usual clinical doses gave the same level of D₂ occupancy as low-dose typical antipsychotics. The results also suggest that some previous clinical comparisons of antipsychotics may have been confounded by different levels of D₂ occupancy. Clinical comparisons of these drugs, matching for D₂ occupancy, may provide a better measure of their true “atypicality” and will help in understanding the contribution of non-D₂ receptors to antipsychotic effects.