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Peter A. Rao, MD; David Pickar, MD; Pablo V. Gejman, MD; Anca Ram, MD; Elliot S. Gershon, MD; Joel Gelernter, MD

Arch Gen Psychiatry. 1994;51(11):912-917.

Abstract
Objective
To test the hypothesis that interindividual differences in response to clozapine therapy might be attributable to the D₄ dopamine receptor (DRD4) alleles they carry. Different alleles of the D₄ dopamine receptor, coded by the DRD4 gene, differ in the affinity with which they bind the atypical antipsychotic drug clozapine in vitro. This may have physiologic implications. Clinical response to clozapine therapy varies among patients. The observation that, in vitro, clozapine binds the protein products of different DRD4 alleles with differing affinity characteristics suggested this hypothesis.

Method
The region of the DRD4 gene that encodes the putative third cytoplasmic loop of the D₄ receptor contains a 48—base pair sequence repeated a variable number of times. With use of polymerase chain reaction amplification, we assessed this variable number of tandem repeats polymorphism in a series of schizophrenic and schizoaffective subjects who had been treated with clozapine, and related genotype with treatment response, to test the hypothesis that DRD4 alleles lead to varying response to clozapine.

Results
Allelic variation at the DRD4 locus does not predict clinical response to clozapine relative to either fluphenazine hydrochloride or placebo in subjects with treatment-refractory schizophrenia or schizoaffective disorder.

Conclusions
DRD4 alleles do not predict therapeutic response to clozapine in schizophrenic and schizoaffective patients. There are implications from these data for the pathophysiology of schizophrenia and the machanism of clozapine's therapeutic effect are discussed.

Author Affiliations
From the Department of Psychiatry, West Haven (Conn) Veterans Affairs Medical Center (Drs Rao and Gelernter); the Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, Conn (Drs Rao and Gelernter); the Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, Md (Dr Pickar); and the Clinical Neurogenetics Branch, National Institute of Mental Health, Bethesda, Md (Drs Gejman, Ram, and Gershon). Dr Rao is now at the Department of Psychiatry, Columbia University, New York, NY.

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