11 - Genetic factors underlying drug-induced tardive dyskinesia

Summary

OVERVIEW

Tardive dyskinesia (TD) affects about one fifth of schizophrenia patients following chronic exposure to dopamine receptor antagonist drugs. Spontaneous dyskinesia has been reported in unmedicated schizophrenia patients and patients with TD have been reported to show distinct clinical features, suggesting a common underlying phenotype that may bear a distinct genetic predisposition. Drug- and patient-related risk factors for the development of TD have received much research attention but appear to predict only a minor part of the variance in the incidence of TD. Genetically determined individual variability in factors affecting drug levels, as well as compensatory responses to chronic dopaminergic antagonism, may account for a major portion of the variance in the incidence of TD. To-date, however, there has been a conspicuous lack of studies exploring a genetic predisposition to TD. Current data stem from sporadic clinical observations and from supportive, albeit indirect, evidence from rodent studies showing strain differences in behavioral and phamacodynamic models for drug-induced TD. Despite the lack of an established genetic contribution or mode of inheritance for vulnerability to develop TD, in recent years a number of groups have ventured to examine directly a possible contribution of specific candidate genes to TD, employing case-control association design in chronically medicated schizophrenia patients. Such studies report direct association of candidate polymorphic genes with drug-induced TD, providing further support for the existence of a genetic contribution and suggesting the likelihood of a polygenic, multifactorial inheritance for such vulnerability.