5-HT₂ and D₂ Receptor Occupancy of Olanzapine in Schizophrenia: A PET Investigation

OBJECTIVE: Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia. The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT₂ and dopamine D₂ receptors in schizophrenic patients being treated with clinically relevant doses. METHOD: Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30–40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D₂ and serotonin 5-HT₂ receptors were assessed by using [¹¹C]raclopride and [¹⁸F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained. RESULTS: Olanzapine induced near saturation of the 5-HT₂ receptors, even at 5 mg/day. Its D₂ occupancy increased with dose: patients taking 5–20 mg/day showed 43%–80% D₂ occupancy, while patients taking 30–40 mg/day showed 83%–88%. CONCLUSIONS: Olanzapine is a potent 5-HT₂ blocker and shows a higher 5-HT₂ than D₂ occupancy at all doses. However, its D₂ occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10–20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D₂ occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects. (Am J Psychiatry 1998; 155:921–928)