Dopamine receptor antagonism is a common mechanism underlying the therapeutic efficacy of all classical antipsychotic drugs. It is also thought to underlie the propensity of these agents to induce the movement disorder, tardive dyskinesia (TD), in one fifth of chronically exposed schizophrenia patients. We examined the polymorphic serine to glycine substitution in the first exon of the gene encoding the dopamine D3 receptor (DRD3) inn 53 schizophrenia patients with TD, 63 matched patients with similar antipsychotic exposure but no TD and 117 normal controls. There was a difference in allele frequency that was of borderline significance (P = 0.055), due to an excess of the DRD3 gly allele (allele 2) in the schizophrenia patients with TD. The difference in genotype distribution among the groups was highly significant ( The dopamine D3 receptor gene (DRD3) has been a focus of intense interest in psychiatric genetics for a number of years, primarily in relation to schizophrenia. This interest has not waned in spite of a discouraging disparity in the results obtained. The human DRD3 gene was localized to 3q13.3 by in situ hybridization.1 A polymorphic site in exon 1 of DRD3 gives rise to a serine to glycine substitution in the N terminal extracellular domain of the receptor protein. This creates a BalI (MscI) restriction enzyme site.2 Numerous groups have examined linkage and association of schizophrenia with DRD3. Linkage studies have been uniformly negative. Over 30 studies (mostly population-but also family-based) were included by Williams et al 3 in a meta-analysis that yielded evidence for a modest association with homozygosity for either Correspondence: Professor B Lerer,

These findings support a small but significant contribution of the HT2CR and DRD3 to susceptibility to TD, which is additive in nature.

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers.1 Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal effects profile of atypical antipsychotic drugs.2 We examined the association of three polymorphisms in the 5-HT2A receptor gene (HTR2A) with TD susceptibility-T102C 3 and his452tyr 4 in the coding region and A-1438G 5 in the promoter-in matched schizophrenia patients with (n = 59, SCZ-TD-Y) and without TD (n = 62, SCZ-TD-N) and normal control subjects (n = 96). The T102C and the A-1438G polymorphisms are in complete linkage disequilibrium but not his452tyr. Tardive dyskinesia (TD) is an idiopathic, often irreversible, involuntary movement disorder reported in 20% of patients following prolonged exposure to dopamine receptor antagonist drugs.1 The determinants of risk for TD remain largely undefined. A few studies provide indirect basic and clinical evidence implicating a genetic component in idiosyncratic extrapyramidal reactions to antipsychotic drugs. [7][8][9][10] We and others previously demonstrated an association between TD and a serine to glycine polymorphism (ser9gly) in exon 1 of the dopamine D3 receptor gene (DRD3). 11-14The 5-HT2A receptor is a site of action for atypical antipsychotic agents and has been implicated in their added efficacy as well as their reduced extrapyramidal side effects profile.2 Atypical antipsychotic agents such as clozapine 15,16 and olanzapine, 17 have been shown to induce much lower rates of TD than conventional antipsychotic drugs and this has been attributed to a protective effect of their high 5-HT2 receptor blocking activity relative to D2 receptor blockade. 17 The 5-HT2A receptor is distributed in striatal brain areas that modulate motor activity 18 and has been shown to interact with dopaminergic neurotransmission in brain regions relevant to antipsychotic drug action.19 Rodent studies suggest that high occupation of 5-HT2A receptors with lower D2 receptor occupancy might be involved in the absence of up-regulation of D2 receptors after treatment with atypical antipsychotic drugs. 20 This may be relevant to the documented lower rates of TD with atypical agents, given the classical hypothesis implicating D2 receptor supersensitivity with pathogenesis of druginduced TD.21 Furthermore, pretreatment with atypical antipsychotic agents has been shown to reduce repetitive jaw movements in a rat model for TD 22 and 5-HT2A receptor antagonists have been shown to attenuate apomorphine-induced stereotypic oral movements in rats. 23 Finally, long-term elevations in 5-HT2A receptor binding and mRNA expression in neostriatal regions have been documented in response to ontogenetic loss of dopamine neurons following 6 hydroxydopamine administration, 24

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal side effect profile of atypical antipsychotic drugs. We evaluated candidate dopamine and serotonin genes for association with drug-induced TD. We examined three polymorphisms in the dopamine D2 receptor gene (DRD2), two sites in the 3' region of the dopamine transporter (DAT) gene, two sites in the promoter and coding region of the dopamine D4 (DRD4) receptor gene, as well as polymorphic sites in the serotonin 6 receptor gene, the serotonin transporter gene and the tryptophan hydroxylase gene, for association with TD susceptibility. Schizophrenic patients with (n=59) and without TD (n=63), matched for antipsychotic drug exposure and other relevant variables, were studied. No significant associations were found. Within the limitations imposed by the size of the clinical sample, these findings suggest that the above polymorphic loci do not contribute significantly to risk for TD. Further examination of loci that yielded positive results at a trend level and investigation of other candidate genetic loci coding for antipsychotic drug targets is warranted.

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