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 D(4) receptors, serotonin 5-HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) 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 D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics.


METHODS
Positron emission tomography with the radioligands [(11)C]SCH23390 and [(11)C]raclopride was used to investigate D(1) and D(2) receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone.


RESULTS
Mean striatal D(1) occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D(2) occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D(1)/D(2) 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 D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.
Tauscher
Johannes
J
University of Toronto Department of Psychiatry, Schizophrenia Program. johannes.tauscher@meduniwien.ac.at
Hussain
Tabasum
T
Agid
Ofer
O
Verhoeff
N Paul L G
NP
Wilson
Alan A
AA
Houle
Sylvain
S
Remington
Gary
G
Zipursky
Robert B
RB
Kapur
Shitij
S
D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001552:Benzazepines / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000493:pharmacokinetics / Q000627:therapeutic use; D002250:Carbon Radioisotopes; D003024:Clozapine / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000378:metabolism*; D003987:Dibenzothiazepines / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011388:Prolactin / Q000097:blood; D011618:Psychotic Disorders / Q000188:drug therapy / Q000378:metabolism; D000069348:Quetiapine Fumarate; D020891:Raclopride / Q000493:pharmacokinetics; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D018967:Risperidone / Q000493:pharmacokinetics / Q000627:therapeutic use; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D014055:Tomography, Emission-Computed; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D001552:Benzazepines; D002250:Carbon Radioisotopes; D003987:Dibenzothiazepines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D020891:Raclopride; D011388:Prolactin; D003024:Clozapine; D018967:Risperidone; D000077152:Olanzapine