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PET Evidence That Loxapine Is an Equipotent Blocker of 5-HT₂ and D₂ 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 D₄ receptors. The purpose of this study was to document loxapine's 5-HT₂ and D₂ receptor occupancy in vivo in patients with psychoses. METHOD: Ten patients who were taking loxapine (10–100 mg/day) had their D₂ and 5-HT₂ receptors assessed by means of positron emission tomography with [¹¹C]raclopride and [¹⁸F]setoperone, respectively. RESULTS: The D₂ receptor occupancy ranged from 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 D₂ 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 D₂ occupancy. The results demonstrate that a high level of 5-HT₂ occupancy is not a sufficient condition for atypicality. If atypical antispychotic action is predicated on a combination of 5-HT₂ and D₂ effects, then it requires >80% 5-HT₂ occupancy in conjunction with <80% D₂ occupancy. (Am J Psychiatry 1997; 154:1525–1529)

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