A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone.
OBJECTIVE
Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT(2) receptors compared with dopamine D(2) receptors in vitro. The affinity of ziprasidone for these receptors in vivo in patients was examined in a positron emission tomography (PET) study.


METHODS
The authors conducted a PET study to evaluate D(2) occupancy (using [(11)C]raclopride) and 5-HT(2) occupancy (using [(18)F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12-16 hours after the last dose.


RESULTS
The mean 5-HT(2) receptor occupancy was significantly higher than the mean D(2) receptor occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT(2) receptor occupancy was almost four times lower than that for D(2) receptor occupancy.


CONCLUSIONS
These data affirm that ziprasidone is similar to other novel antipsychotics in having greater 5-HT(2) than D(2) receptor occupancy at therapeutic doses and suggest that the optimal effective dose of ziprasidone is closer to 120 mg/day than to the lower doses suggested by previous PET studies. The relatively high D(2) receptor occupancy, even at trough plasma levels, suggests that ziprasidone is more similar to risperidone and olanzapine in receptor occupancy profile than to clozapine and quetiapine. Since ziprasidone plasma levels show significant (more than twofold) variation within a single dose cycle, studies that are aimed at peak plasma levels (6 hours after the last dose) and that examine extrastriatal regions are required to fully characterize the in vivo occupancy profile of ziprasidone.
Mamo
David
D
Department of Psychiatry, University of Toronto, Montreal, Canada.
Kapur
Shitij
S
Shammi
C M
CM
Papatheodorou
George
G
Mann
Steve
S
Therrien
François
F
Remington
Gary
G
D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011618:Psychotic Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D011744:Pyrimidinones; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D044348:Receptors, Serotonin, 5-HT2 / Q000187:drug effects / Q000378:metabolism*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D013844:Thiazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014055:Tomography, Emission-Computed
D014150:Antipsychotic Agents; D010879:Piperazines; D011744:Pyrimidinones; D017448:Receptors, Dopamine D2; D044348:Receptors, Serotonin, 5-HT2; D013844:Thiazoles; D020891:Raclopride; C092292:ziprasidone; C045359:setoperone