title: Dose-occupancy study of striatal and extrastriatal dopamine D2 receptors by aripiprazole in schizophrenia with PET and [18F]fallypride.
abstract: Positron emission tomography (PET) and the high affinity D(2/3) radiotracer [(18)F]fallypride allow the assessment of D(2/3) receptor occupancy of antipsychotic drugs in striatal and extrastriatal brain regions. We measured regional occupancy attained across a range of clinical dosing by the partial D(2) agonist aripiprazole using these methods. Twenty-eight PET scans were acquired on the ECAT EXACT HR+ camera in 19 patients with schizophrenia or schizoaffective disorder. Daily aripiprazole doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Mean regional occupancies, a model-independent estimate of aripiprazole effect on pituitary binding, and PANSS ratings changes were evaluated. Occupancy levels were high across regions of interest, ranging from 71.6+/-5.5% at 2 mg/day to 96.8+/-5.3% at 40 mg/day. Occupancy levels were higher in extrastriatal than striatal regions. Pituitary measures of aripiprazole effect correlated with doses and were unrelated to prolactin levels, which remained within the normal range under medication. PANSS positive (but not negative) symptom improvement correlated with striatal but not extrastriatal occupancies. These data show, for the first time, D(2) occupancy by aripiprazole in treated patients with schizophrenia in extrastriatal as well as striatal regions, with high occupancy for all doses. We discuss possible explanations for higher extrastriatal than striatal occupancy. Correlations of ratings of clinical improvement with regional occupancy suggest that aripiprazole, as do other antipsychotics, benefits positive symptoms of schizophrenia most directly through its modulation of striatal rather than cortical or other extrastriatal dopamine activity.
authors.affiliation: Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA. lsk5@columbia.edu
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kegeles
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: W Gordon
authors.initials: WG
authors.lastname: Frankle
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hackett
authors.forename: Sung-A
authors.initials: SA
authors.lastname: Bae
authors.forename: Robyn
authors.initials: R
authors.lastname: Gonzales
authors.forename: Jong-Hoon
authors.initials: JH
authors.lastname: Kim
authors.forename: Beatriz
authors.initials: B
authors.lastname: Alvarez
authors.forename: Roberto
authors.initials: R
authors.lastname: Gil
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
authors.forename: Anissa
authors.initials: A
authors.lastname: Abi-Dargham
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology; D000068180:Aripiprazole; D001549:Benzamides; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D049268:Positron-Emission Tomography; D011759:Pyrrolidines; D015363:Quinolones / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D012559:Schizophrenia / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; C094948:N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2,3-dimethoxybenzamide; D010879:Piperazines; D011759:Pyrrolidines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D000068180:Aripiprazole; D004298:Dopamine