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.
Method: 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.