This review addresses two questions. First, why does clozapine apparently occupy 
low levels of dopamine D2 receptors in patients, in contrast to all other 
antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, 
what is the receptor basis of action of antipsychotic drugs which elicit low 
levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 
50% of D2 receptors, as measured in patients by a variety of radioligands. It 
has recently been found, however, that the percent occupancy of a receptor by a 
drug depends 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 occupancy is estimated to 
be of the order of 70-80% in the dopamine-rich region of the human striatum, and 
even higher in the limbic D2-containing regions which are low in endogenous 
synaptic dopamine. This conclusion arises from two different approaches. One 
approach is to relate the reported clozapine occupancies in the human striatum 
with the dissociation constants of the various radioligands at the D2 receptor. 
This relation extrapolates to approximately 70-80% occupancy by clozapine when 
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 dissociation constant of the 
antipsychotic, thereby revealing that all antipsychotic drugs, including 
clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human 
striatum, and possibly higher in the limbic regions. As determined by the new 
dissociation constants, antipsychotic drugs which elicit Parkinsonism 
(trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, 
risperidone) bind more tightly than dopamine to D2, while those antipsychotic 
drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, 
clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more 
loosely than dopamine to D2 receptors. Compared to the tightly bound 
antipsychotic drugs, the more loosely bound antipsychotics generally require 
higher clinical doses, require fewer days for clinical adjustment, but may 
dissociate from the D2 receptor more rapidly and could lead to clinical relapse 
somewhat earlier than that found with the traditional tightly bound 
antipsychotic drugs.