Equivalent Occupancy of Dopamine D1 and D2 Receptors With Clozapine: Differentiation From Other Atypical Antipsychotics
Abstract
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-HT2A 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.