1. ¹Department of Psychiatry, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA
2. ²Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA
3. ³Clinical Pharmacology and Discovery Medicine, Clinical Imaging Center, GlaxoSmithKline, London, UK

Correspondence: Dr LS Kegeles, Department of Psychiatry, Columbia University, 1051 Riverside Drive, Unit 31, New York, NY 10032, USA. Tel: +1 212 543 5497; Fax: +1 212 568 6171; E-mail: lsk5@columbia.edu

Received 19 October 2007; Revised 10 February 2008; Accepted 13 February 2008; Published online 16 April 2008.

Abstract

Positron emission tomography (PET) and the high affinity D_2/3 radiotracer [¹⁸F]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 D₂ 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 71.65.5% at 2 mg/day to 96.85.3% 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, D₂ 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.