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.

Imaging the competition between D(2/3) radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D(2) receptor exists in a high (D(2)(high)) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D(2)(high) only. [(11)C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D(2/3) agonist radioligand for positron emission tomography (PET) imaging in humans. Since [(11)C]-(+)-PHNO is expected to bind preferentially to D(2)(high), it should be particularly vulnerable to competition with endogenous dopamine. Nine healthy subjects participated in two PET scans, one after administration of d-amphetamine and one after placebo. [(11)C]-(+)-PHNO PET test re-test variability was determined in 11 healthy subjects. Binding potentials (BPs) were calculated for caudate, putamen, ventral striatum, and globus pallidus. d-Amphetamine led to a significant decrease of [(11)C]-(+)-PHNO BPs in caudate (-13.2%), putamen (-20.8%), and ventral striatum (-24.9%), but not in globus pallidus (-6.5%). d-Amphetamine-induced displacement correlated with serum d-amphetamine levels in all regions but caudate. This is the first report on competition between endogenous dopamine and a D(2/3) agonist radioligand in humans. [(11)C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D(2/3) antagonist radioligands.

The kinetic modeling of [ 11 C]-( + )-PHNO binding to the dopamine D 2/3 receptors in six human volunteers using positron emission tomography (PET) is described. [ 11 C]-( + )-PHNO is the first agonist radioligand for the D 2/3 in humans and as expected showed high uptake in caudate, putamen, globus pallidus (GP) and ventral striatum, and low uptake in cerebellum. A two-tissue compartment model (2CM) with four parameters was necessary to adequately fit time-activity data in all regions. Although a 2CM provided an excellent estimation of total distribution volumes, which were highly correlated with those obtained with the invasive Logan approach, it provided a poor identification of the k 3 /k 4 ratios. Coupling K 1 /k 2 between brain regions (Method C) or fixing K 1 /k 2 to the value obtained in cerebellum (Method D) enabled more stable estimates of k 3 /k 4 as compared with an unconstrained 2CM. The k 3 /k 4 obtained with Method D ranged from 0.1260.03 in cerebellum to 3.9360.77 in GP and were similar to those obtained when coupling K 1 /k 2 . Binding potentials (BPs) obtained using the simplified reference tissue model (BP SRTM ) ranged from 2.0860.34 in caudate to 3.5560.78 in GP and were highly correlated with k 3 /k 4 estimates obtained with Method D (r = 0.98). However, BP SRTM were 11%65% lower than values obtained with Method D. BPs derived using the noninvasive Logan approach were slightly lower but not significantly different than BP SRTM . This study demonstrates that [ 11 C]-( + )-PHNO can be used for the quantitative measurement of D 2/3 densities and should enable further studies of potential D 2/3 dysregulation in several important psychiatric and neurologic illnesses.

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Antipsychotic drugs produce unpleasant subjective experiences, which have been associated with high levels of dopamine D2 receptor occupancy. Aripiprazole is a partial agonist antipsychotic, which is hypothesized to produce a different subjective experience profile compared to standard D2 antagonist antipsychotics. The aim of this study was to compare the effect of D2 occupancy produced by a partial agonist antipsychotic (aripiprazole) to that of antagonist antipsychotics (risperidone or olanzapine) on the subjective well-being of patients. Subjective well-being was measured using the Subjective Well-being under Neuroleptics Scale (SWN) and was related to dopamine D2 receptor occupancy using [11C]raclopride PET. Patients that were switched to aripiprazole showed improvement in their subjective well-being from 79.80 (S.D.=16.08) to 89.90 (S.D.=15.33), an effect that was sustained for 6 months. This sustained improvement was observed despite very high levels of DA D2 occupancy (82-99%), in contrast to the effects of antagonist antipsychotics on subjective well-being.

Higher D(2) receptor occupancy is associated with negative subjective experience in patients taking risperidone or olanzapine. These negative subjective effects may be related to the high discontinuation rates seen in usual practice. Understanding the neurobiological mechanism of these negative subjective experiences and developing antipsychotics with novel (i.e., non D(2)) mechanisms may be critical in improving the treatment of psychosis.