pyrimidinones and Psychotic-Disorders

Aripiprazole has a unique pharmacological profile that includes partial agonism at D(2) receptors, antagonism at 5-HT(2) receptors, and partial agonism at 5-HT(1A) receptors. The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D(2), 5-HT(2), and 5-HT(1A) receptors in patients with schizophrenia or schizoaffective disorder.. Twelve patients who had previously received antipsychotic treatment were randomly assigned to receive 10 mg, 15 mg, 20 mg, or 30 mg of aripiprazole. After at least 14 days of treatment, participants underwent high-resolution PET scans using [(11)C]raclopride, [(18)F]setoperone, and [(11)C]WAY100635.. Very high occupancy was observed at striatal D(2) receptors (average putamen, 87%; caudate, 93%; and ventral striatum, 91%), lower occupancy at 5-HT(2) receptors (54%-60%), and even lower occupancy at 5-HT(1A) receptors (16%). D(2) occupancy levels were significantly correlated with plasma drug concentrations, and even the lowest dose (10 mg) led to 85% D(2) occupancy. Extrapyramidal side effects were seen only in two of the four participants with occupancies exceeding 90%.. Aripiprazole exhibits a unique occupancy profile as compared with other conventional and atypical antipsychotics. The threshold for response appears to be higher than 60%, extrapyramidal side effects appear to be uncommon even at occupancies that exceed the conventional extrapyramidal side effects threshold of 80%, and 5-HT(2) occupancy is lower than D(2) occupancy. Implications for aripiprazole's mechanism of action are discussed.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Basal Ganglia; Basal Ganglia Diseases; Carbon Radioisotopes; Caudate Nucleus; Cerebral Cortex; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorine Radioisotopes; Humans; Male; Piperazines; Positron-Emission Tomography; Psychotic Disorders; Putamen; Pyridines; Pyrimidinones; Quinolones; Raclopride; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine; Receptors, Dopamine D2; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Adult; Antipsychotic Agents; Brain; Corpus Striatum; Drug Administration Schedule; Female; Humans; Male; Piperazines; Psychotic Disorders; Pyrimidinones; Raclopride; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2; Schizophrenia; Thiazoles; Tomography, Emission-Computed