A PET Study Evaluating Dopamine D₂ Receptor Occupancy for Long-Acting Injectable Risperidone

OBJECTIVE: Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D₂ binding profile at doses of 25, 50, or 75 mg administered every 2 weeks. METHOD: After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [¹¹C]raclopride PET to measure D₂ occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone. RESULTS: Mean post- and preinjection D₂ occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D₂ occupancy (ED₅₀) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D₂ occupancy. CONCLUSIONS: All three doses of injectable risperidone showed peak D₂ occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.