A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone.

Abstract

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.

• Authors: David Mamo, Shitij Kapur, C M Shammi, George Papatheodorou, Steve Mann, François Therrien, Gary Remington
• Journal: The American journal of psychiatry (Am J Psychiatry) Vol. 161 Issue 5 Pg. 818-25 (May 2004) ISSN: 0002-953X [Print] United States
• PMID: 15121646 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antipsychotic Agents
• Piperazines
• Pyrimidinones
• Receptors, Dopamine D2
• Receptors, Serotonin, 5-HT2
• Thiazoles
• Raclopride
• ziprasidone
• setoperone

Topics

• Adult
• Antipsychotic Agents (blood, pharmacokinetics, therapeutic use)
• Brain (diagnostic imaging, drug effects, metabolism)
• Corpus Striatum (diagnostic imaging, drug effects, metabolism)
• Drug Administration Schedule
• Female
• Humans
• Male
• Piperazines (pharmacokinetics, therapeutic use)
• Psychotic Disorders (diagnostic imaging, drug therapy, metabolism)
• Pyrimidinones
• Raclopride
• Receptors, Dopamine D2 (drug effects, metabolism)
• Receptors, Serotonin, 5-HT2 (drug effects, metabolism)
• Schizophrenia (diagnostic imaging, drug therapy, metabolism)
• Thiazoles (pharmacokinetics, therapeutic use)
• Tomography, Emission-Computed