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 D-2 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 D-2 and serotonin 5-HT2 receptors were assessed by using [C-11]raclopride and [F-18]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 D-2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D-2 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 D-2 occupancy at all doses. However, its D-2 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% D-2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.