The dopamine D4 receptor structurally and pharmacologically resembles the dopamine D2 and D3 receptors. Clozapine, an atypical antipsychotic that is relatively free of the adverse effects of drug-induced parkinsonism and tardive dyskinesia, binds to the D4 receptor with an affinity 10 times higher than to the D2 and D3 receptors. This may explain clozapine's atypical properties. Here we report the existence of at least three polymorphic variations in the coding sequence of the human D4 receptor. A 48-base-pair sequence in the putative third cytoplasmic loop of this receptor exists either as a direct-repeat sequence (D4.2), as a fourfold repeat (D4.4) or as a sevenfold repeat (D4.7). Two more variant alleles were detected in humans. Expression of the complementary DNA for the three cloned receptor variants showed different properties for the long form (D4.7) and the shorter forms (D4.2, D4.4) with respect to clozapine and spiperone binding. To our knowledge, this is the first report of a receptor in the catecholamine receptor family that displays polymorphic variation in the human population. Such variation among humans may underlie individual differences in susceptibility to neuropsychiatric disease and in responsiveness to antipsychotic medication.

Several studies have shown that depressed patients have significantly lower catechol-o-methyltransferase (COMT) activity than healthy controls. Two COMT genes coding for low activity, COMTL, and high activity, COMTH have been identified. We undertook an association study on 75 depressive disorder patients, 40 bipolar disorder patients and 135 healthy controls. All the subjects were Japanese. Patients with depressive disorders exhibited a significantly higher rate of genotypes with the COMTL allele than healthy controls (p = 0.012), which was not the case in patients with bipolar disorders. The presence of the COMTL allele was significantly associated with depressive disorders (odds ratio 2.19, 95% CI 1.19-4.03). Our results suggest the COMTL allele contributed to the etiologies of depressive disorders.

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