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Equivalent Occupancy of Dopamine D₁ and D₂ Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics

OBJECTIVE: Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D₄ receptors, serotonin 5-HT_2A receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D₂ receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine’s distinctiveness in refractory schizophrenia, the authors studied the in vivo D₁ and D₂ receptor profile of clozapine compared with other atypical antipsychotics. METHOD: Positron emission tomography with the radioligands [¹¹C]SCH23390 and [¹¹C]raclopride was used to investigate D₁ and D₂ receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone. RESULTS: Mean striatal D₁ occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D₂ occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D₁/D₂ occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31). CONCLUSIONS: Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D₁ and D₂ receptors. Whether its effect on D₁ receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D₁/D₂ receptors may be responsible for clozapine’s unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.

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