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.