Clozapine can induce high dopamine D₂ receptor occupancy in vivo

Abstract.

Rationale: Clozapine is a unique antipsychotic with very low propensity to cause motor side effects. In contrast to most other antipsychotics that block more than 70% of dopamine D₂ receptors at therapeutic doses, clozapine occupies less than 70%. Furthermore, even at maximum occupancy, 70% is not exceeded. Several mechanisms have been proposed as explanations for this low D₂ receptor occupancy, but clear evidence is limited. Objectives: In patient studies the data are limited by the dose-range that can be safely used; therefore, the aims of this study were to examine the maximum occupancy of dopamine D₂ receptors with up to 5.0 mg/kg of bolus injection of clozapine to non-human primates and to measure the time course of occupancy. Methods: PET examination with [¹¹C]raclopride was performed to measure the dopamine D₂ receptor occupancy in the striatum of two monkeys after the bolus injection of 0.2–5.0 mg/kg clozapine. [¹¹C]raclopride was injected sequentially to follow the time course of occupancy up to 7 h after the clozapine injection. Results: Dopamine D₂ receptor occupancy reached up to 83% after 5.0 mg/kg clozapine injection. Occupancy decreased with a half-life of 7.22 h after 5.0 mg/kg clozapine and 5.25 h after 1.0 and 2.0 mg/kg clozapine. Conclusions: Clozapine could occupy a high proportion of dopamine D₂ receptors. The time course of occupancy was relatively fast, with a half-life of several hours.