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Mechanism of New Antipsychotic Medications:  Occupancy Is Not Just Antagonism

Gerhard Gründer, MD; Arvid Carlsson, MD, PhD; Dean F. Wong, MD, PhD
Arch Gen Psychiatry. 2003;60(10):974-977. doi:10.1001/archpsyc.60.10.974.
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  Antagonism of D2-like dopamine receptors is the putative mechanism underlying the antipsychotic efficacy of psychotropic drugs. Positron emission tomographic studies suggest that the antipsychotic effect of dopamine receptor antagonists occurs within a therapeutic window between 60% and 80%(striatal) D2 receptor occupancy. The incidence of extrapyramidal side effects increases above the 80% threshold. However, the novel atypical antipsychotic drug, aripiprazole, occupies up to 95% of striatal D2-like dopamine receptors at clinical doses, and the incidence of extrapyramidal side effects with aripiprazole is no higher than with placebo. The most likely explanation for this finding is aripiprazole's weak partial agonism at D2-like dopamine receptors. This particular pharmacologic feature characterizes a new class of atypical antipsychotics that does not match the original concept of a therapeutic occupancy window for antagonist antipsychotics. When not involving pure antagonists, it implies a need to adjust the expected receptor occupancy (measured using positron emission tomography) for the therapeutic window.

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Relationship between aripiprazole daily dose, D2 and D3 receptor occupancy in the putamen, and clinically expected and used aripiprazole doses. Mean receptor occupancy values in the putamen at a given dose were adapted from Yokoi et al18 and fit to a simple Emax model using nonlinear regression and assuming a 1-site saturation. Horizontal lines indicate the hypothesized therapeutic window between 60% and 80% striatal D2 receptor occupancy suggested by Farde et al.4,5 The light-shaded area designates the dose range that should lead to receptor occupancy within this therapeutic window, whereas the dark-shaded area indicates the dose range that has proved to have antipsychotic efficacy.

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