Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study.
OBJECTIVE
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.


METHODS
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.


RESULTS
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%.


CONCLUSIONS
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.
Mamo
David
D
Department of Psychiatry, University of Toronto, Toronto, Canada. david_mamo@camh.net
Graff
Ariel
A
Mizrahi
Romina
R
Shammi
C M
CM
Romeyer
Françoise
F
Kapur
Shitij
S
D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D000068180:Aripiprazole; D001479:Basal Ganglia / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000453:epidemiology / Q000378:metabolism; D002250:Carbon Radioisotopes; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D010879:Piperazines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D011618:Psychotic Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D011699:Putamen / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines; D011744:Pyrimidinones; D015363:Quinolones / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D020891:Raclopride; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D012559:Schizophrenia / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D065127:Dopamine D2 Receptor Antagonists; D005462:Fluorine Radioisotopes; D010879:Piperazines; D011725:Pyridines; D011744:Pyrimidinones; D015363:Quinolones; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D020891:Raclopride; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000068180:Aripiprazole; C045359:setoperone