Polymorphisms of the dopamine D4 receptor and response to antipsychotic drugs

The dopamine D₄ receptor may be a site through which the clinical effects of antipsychotic drugs are mediated. Polymorphisms of a 48 base pair repeat in the third exon of the DRD4 gene code for different length segments in the third intracytoplasmic loop of the D₄ receptor. The most common long (seven repeat) form of the D₄ receptor has been shown in both physiologic and pharmacologic experiments to respond differently to dopamine agonists and antagonists than do shorter forms of D₄. Thus, variants of D₄ may partly determine patient response to antipsychotic drugs and, in particular, response to typical neuroleptics, which have a relatively low affinity for the D₄ receptor, as compared to clozapine, which has a relatively high affinity for D₄. DRD4 polymorphisms in the third intron were characterized in 28 patients with chronic psychosis who responded well to typical neuroleptics, 32 patients who responded well to clozapine, and 57 healthy comparison subjects. Patients responding to typical neuroleptics carried the allele for the long (seven repeat) form of the D₄ receptor (allele frequency 8.9%) less frequently than patients responding to clozapine (allele frequency 23.4%, P = 0.046) or healthy comparison subjects (allele frequency 26.3%, P = 0.004). The results of this study suggest that inherited variants of D₄ may explain some of the interindividual variation seen in patient response to different classes of antipsychotic medication. Received: 10 October 1997/Final version: 20 May 1998