Differential Effects of Aripiprazole on D ₂, 5-HT ₂, and 5-HT _1A Receptor Occupancy in Patients With Schizophrenia: A Triple Tracer PET Study

Objective: Aripiprazole has a unique pharmacological profile that includes partial agonism at D ₂ receptors, antagonism at 5-HT ₂ receptors, and partial agonism at 5-HT _1A receptors. The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D ₂, 5-HT ₂, and 5-HT _1A receptors in patients with schizophrenia or schizoaffective disorder. Method: Twelve patients who had previously received antipsychotic treatment were randomly assigned to receive 10 mg, 15 mg, 20 mg, or 30 mg of aripiprazole. After at least 14 days of treatment, participants underwent high-resolution PET scans using [ ¹¹ C]raclopride, [ ¹⁸ F]setoperone, and [ ¹¹ C]WAY100635. Results: Very high occupancy was observed at striatal D ₂ receptors (average putamen, 87%; caudate, 93%; and ventral striatum, 91%), lower occupancy at 5-HT ₂ receptors (54%–60%), and even lower occupancy at 5-HT _1A receptors (16%). D ₂ occupancy levels were significantly correlated with plasma drug concentrations, and even the lowest dose (10 mg) led to 85% D ₂ occupancy. Extrapyramidal side effects were seen only in two of the four participants with occupancies exceeding 90%. Conclusions: Aripiprazole exhibits a unique occupancy profile as compared with other conventional and atypical antipsychotics. The threshold for response appears to be higher than 60%, extrapyramidal side effects appear to be uncommon even at occupancies that exceed the conventional extrapyramidal side effects threshold of 80%, and 5-HT ₂ occupancy is lower than D ₂ occupancy. Implications for aripiprazole’s mechanism of action are discussed.