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Occupancy Is Not Just Antagonism

Gerhard Gründer, MD; Arvid Carlsson, MD, PhD; Dean F. Wong, MD, PhD

Arch Gen Psychiatry. 2003;60:974-977.

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.

From the Department of Psychiatry, University of Mainz, Mainz, Germany (Dr Gründer); Department of Pharmacology, University of Göteborg, Göteborg, Sweden (Dr Carlsson); and the Division of Nuclear Medicine, Departments of Radiology and Psychiatry, Johns Hopkins Medical Institutions, Baltimore, Md (Drs Gründer and Wong). Dr Gründer has served as a consultant for Bristol-Myers Squibb (New York, NY) and Otsuka (Rockville, Md). He has served on the speakers bureau of Bristol-Myers Squibb, Eli Lilly (Indianapolis, Ind), and Pfizer (New York, NY) and has received grant support from Pfizer and Sanofi-Synthélabo (Paris, France). Dr Wong has received grant support from Otsuka and travel support from Bristol-Myers Squibb.

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