Rapid Release of Antipsychotic Drugs From Dopamine D₂ Receptors: An Explanation for Low Receptor Occupancy and Early Clinical Relapse Upon Withdrawal of Clozapine or Quetiapine

OBJECTIVE: In an attempt to understand the basis of early relapse after antipsychotic withdrawal, the objective of this study was to determine whether the low occupancy of dopamine D₂ receptors by clozapine and by quetiapine, as seen by brain imaging, could arise from a rapid release of some of the D₂-bound clozapine or quetiapine by the brain imaging compounds and by the action of a physiological concentration of dopamine. METHOD: Human cloned D₂ receptors were first pre-equilibrated with the [³H]antipsychotic drug, after which raclopride, iodobenzamide, or dopamine (at the physiological concentration in the synapse) was added, and the time course of release of the [³H]antipsychotic from the D₂ receptor was measured. RESULTS: Within 5 minutes, low concentrations of raclopride and iodobenzamide displaced appreciable amounts of [³H]clozapine and [³H]quetiapine from the D₂ receptors but, during the course of 1 hour, did not displace any of the other antipsychotic [^[3H]ligands. [³H]Clozapine and [³H]quetiapine, moreover, were displaced by dopamine (100 nM) at least 100 times faster than the other antipsychotic [³H]ligands. CONCLUSIONS: Clozapine and quetiapine are loosely bound to the D₂ receptor, and the injected radioactive ligand at its peak concentration may displace some of the D₂-bound antipsychotic drug, resulting in apparently low D₂ occupancies. Therefore, under clinical brain imaging conditions with [¹¹C]raclopride, D₂ occupancies by clozapine and by quetiapine may be higher than currently estimated. These considerations may result in high levels of the D₂ receptors being occupied by therapeutic doses of clozapine or quetiapine. The rapid release of clozapine and quetiapine from D₂ receptors by endogenous dopamine may contribute to low D₂ receptor occupancy and to early clinical relapse upon withdrawal of these medications.