Dose-finding study of paliperidone ER based on striatal and extrastriatal dopamine D₂ receptor occupancy in patients with schizophrenia

Rationale: Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects. Objectives: In this study, we measured striatal and extrastriatal dopamine D₂ receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose. Materials and methods: Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [¹¹C]raclopride and one with [¹¹C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D₂ receptor occupancy was calculated. Results: The dopamine D₂ receptor occupancies in the striatum measured with [ ¹¹C]raclopride and the temporal cortex measured with [ ¹¹C]FLB 457 were 54.2-85.5% and 34.5-87.3%, respectively. ED ₅₀ values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D ₂ receptor occupancy between the striatum and the temporal cortex. Conclusions: The data from this study suggest that paliperidone ER at 6-9 mg provides an estimated level of dopamine D₂ receptor occupancy between 70-80% and that the magnitude of dopamine D₂ receptor occupancy is similar between the striatum and temporal cortex.