Clinical and theoretical implications of 5-HT2 and D-2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia

Objective: Dopamine D-2 receptor occupancy measurements provide a valid pre dictor of antipsychotic response, extrapyramidal side effects, and elevatio n of prolactin levels. The new antipsychotics clozapine, risperidone, and o lanzapine obtain antipsychotic response with few extrapyramidal side effect s 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 olanzapi ne, 5-60 mg/day; and 11 taking clozapine, 75-900 mg/day) had their D-2 and 5-HT2 occupancies determined with the use of [C-11]raclopride and [F-18]set operone, respectively, and positron emission tomography imaging. Results: C lozapine showed a much lower De occupancy (16%-68%) than risperidone (63%-8 9%) and olanzapine (43%-89%), Risperidone and olanzapine gave equal D-2 occ upancies at doses of 5 and 20 mg/day, respectively. All three drugs showed greater 5-HT2 than D-2 occupancy at all doses, although the difference was greatest for clozapine. Conclusions: Clozapine, at doses known to be effect ive in routine clinical settings, showed a D-2 occupancy clearly lower than that of typical antipsychotics, while risperidone and olanzapine at their usual clinical doses gave the same level of D-2 occupancy as low-dose typic al antipsychotics. The results also suggest that some previous clinical com parisons of antipsychotics may have been confounded by different levels of D-2 occupancy Clinical comparisons of these drugs, matching for De occupanc y, may provide a better measure of their true "atypicality" and will help i n understanding the contribution of non-D-2 receptors to antipsychotic effe cts.