Lack of association between serotonin-2A receptor gene (HTR2A) polymorphisms and tardive dyskinesia in schizophrenia

Tardive dyskinesia (TD) is a disabling neurological side effect associated with long-term treatment with typical antipsychotics. Family studies and an imal models lend evidence for hereditary predisposition to TD. The newer at ypical antipsychotics pose a minimal risk for Tn which is in part attribute d to their ability to block the serotonin-2A (5-HT2A) receptor. 5-HT2A rece ptors were also identified in the basal ganglia; a brain region that plays a critical role In antipsychotic-induced movement disorders. We tested the significance of variation in the 5-HT2A receptor gene (HTR2A) in relation t o the Tn phenotype. Three polymorphisms in HTR2A, one silent (C102T), one t hat alters the amino acid sequence (his452tyr) and one in the promoter regi on (A-1437G) were investigated in 136 patients refractory or intolerant to treatment with typical antipsychotics and with a DSM-IIIR diagnosis of schi zophrenia. We did not find any significant difference in allele, genotype o r haplotype frequencies of polymorphisms in HTR2A among patients with or wi thout TD (P > 0.05). Further analysis using the ANCOVA statistic with a con tinuous measure of the TD phenotype (Abnormal involuntary Movement Scale (A IMS) score) found that the AIMS scores were not significantly influenced by HTR2A polymorphisms, despite controlling for potential confounders such as age, gender and ethnicity (P > 0.05). Theoretically, central serotonergic function can be subject to genetic control at various other mechanistic lev els including the rate of serotonin synthesis (tryptophane hydroxylase gene ), release, reuptake (serotonin transporter gene) and degradation (monoamin e oxidase gene). Analyses of these other serotonergic genes are indicated, In summary, polymorphisms in HTR2A do not appear to influence the risk for TD. Further studies evaluating in tandem multiple candidate genes relevant for the serotonergic system are warranted to dissect the genetic basis of t he complex TD phenotype.