PET evidence that loxapine is an equipotent blocker of 5-HT2 and D-2 receptors: Implications for the therapeutics of schizophrenia

Objective: Loxapine, a dibenzoxazepine antipsychotic, is closely related to clozapine and shares clozapine's high affinity for binding to serotonin 5-HT2 and dopamine D-4 receptors. The purpose of this study was to document loxapine's 5-HT2 and D-2 receptor occupancy in vivo in patients with psychoses. Method: Ten patients who were taking loxapine (10-100 mg/day) had their D-2 and 5-HT2 receptors assessed by means of positron emission tomography with [C-11]raclopride and [F-18]setoperone, respectively. Results: The D-2 receptor occupancy ranged front 43% to 90%; 5-HT2 occupancy varied from 27% to near saturation. Statistical comparison of the results showed that loxapine was equipotent in blocking 5-HT2 and D-2 receptors. Conclusions: Loxapine differs from typical neuroleptics in demonstrating a high degree of 5-HT2 receptor occupancy. However, it is not ''atypical'' like clozapine and risperidone, since its 5-HT2 occupancy is not higher than its D-2 occupancy. The results demonstrate that a high level of 5-HT2 occupancy is not a sufficient condition for atypicality. If atypical antispychotic action is predicted on a combination of 5-HT2 and D-2 effects, then it requires >80% 5-HT2 occupancy in conjunction with <80% D-2 occupancy.