ANTIPSYCHOTIC-DRUGS WHICH ELICIT LITTLE OR NO PARKINSONISM BIND MORE LOOSELY THAN DOPAMINE TO BRAIN D2 RECEPTORS, YET OCCUPY HIGH-LEVELS OFTHESE RECEPTORS

This review addresses two questions. First, why does clozapine apparen tly occupy low levels of dopamine D2 receptors in patients, in contras t to all other antipsychotic drugs which occupy 70-80% of brain dopami ne D2 receptors? Second, what is the receptor basis of action of antip sychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measu red in patients by a variety of radioligands. It has recently been fou nd, however, that the percent occupancy of a receptor by a drug depend s on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupa ncy is estimated to be of the order of 70-80% in the dopamine-rich reg ion of the human striatum, and even higher in the limbic DS-containing regions which are low in endogenous synaptic dopamine. This conclusio n arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissocia tion constants of the various radioligands at the D2 receptor. This re lation extrapolates to approximately 70-80% occupancy by clozapine whe n clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct di ssociation constant of the antipsychotic, thereby revealing that all a ntipsychotic drugs, including clozapine, occupy approximately 70-80% o f dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, a ntipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpro mazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which eli cit little or no Parkinsonism (melperone, seroquel, perlapine, clozapi ne, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind mo re loosely than dopamine to D2 receptors. Compared to the tightly boun d antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjust ment, but may dissociate from the D2 receptor more rapidly and could l ead to clinical relapse somewhat earlier than that found with the trad itional tightly bound antipsychotic drugs.