J Nucl Med. 2007; 48 (Supplement 2):112P
Neurosciences: Psychiatry
Psychiatry II |
Dose-occupancy study of striatal and extrastriatal dopamine D2 receptors by aripiprazole in schizophrenia measured with [18F]fallypride PET
Lawrence Kegeles1,
W. Gordon Frankle2,
Mark Slifstein1,
Elizabeth Hackett1,
Jennifer Bae1,
Robyn Gonzales1,
Jong-Hoon Kim1,
Beatriz Alvarez1,
Roberto Gil1 and
Anissa Abi-Dargham1
1 Psychiatry, Columbia University, New York, New York; ;
2 Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Objectives: Site of action of antipsychotic medications is an area of active interest, and the partial agonist mechanism of aripiprazole (APZ) raises the possibility of unique properties of this agent. We measured its regional D2 receptor occupancy across a range of clinical doses in patients with schizophrenia using PET and [18F]fallypride. Methods: 28 PET scans were acquired in 19 patients with DSM-IV schizophrenia or schizoaffective disorder (ages 29.2 ± 10.1 years, 4F, 15M). 9 patients (group A) were studied at baseline (at least 21 days medication-free) and on APZ (18 scans); 8 (group B) were studied on APZ only, and 2 (group C) at baseline only. Daily APZ doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Scans were acquired on an ECAT EXACT HR+, and ROIs were drawn on each subject’s coregistered MRI. V3" was determined using SRTM with cerebellum as reference region. D2 occupancy (n=17) was computed for each ROI as 100%*(1-V3" apz/ V3" bsl), where "bsl" refers to the individual’s scan off APZ for group A, and to the mean of the n=11 off-APZ scans for group B. APZ plasma levels were obtained at scan time and correlated well with dose but were only available for 15 subjects, hence dose was analyzed. ED50 was determined from the dose-occupancy curve for each ROI. Several extrastriatal ROIs were excluded from analysis because of low V3" values or dose-occupancy goodness-of-fit criteria. ED50 and mean occupancies were computed for 5 striatal subregions and 3 extrastriatal regions. Results: Occupancy levels were high across ROIs, ranging from 64.9 ± 6.8% at 2 mg to 93.2 ± 2.5% at 40 mg. ED50 values were comparable across the 5 striatal subregions (1.93 ± 0.12 mg) and the orbital prefrontal cortex (2.13 mg), and slightly lower for thalamus (1.51 mg) and medial temporal lobe (1.40 mg), although 95% confidence intervals for these two regions included the striatal values. Conclusions: These data suggest an absence of differential occupancy of D2 receptors by APZ between striatal and extrastriatal regions, all of which show high occupancy across a wide dosing range. Correlations of clinical ratings of treatment effects with occupancy will be examined to further assess localization of drug action.
Research Support (if any): Bristol-Myers Squibb
