Pharmacogenetics of antipsychotic induced weight gain and tardive dyskinesia

Typical antips/ychotics induce movement side-effects including tardive dyskinesia (TD). Although atypical antipsychotics have a lower incidence of motor side-effects, their use is hindered by side-effects such as weight gain. The variability in side-effect outcomes across patients is determined by a combination of genetic and environmental factors. We investigated genetic factors in patient risk to develop typical antipsychotic-induced TD and clozapineinduced weight gain. 112 typical antipsychotic treatment-resistant schizophrenia patients were assessed for TD severity using the AIMS upon entry into a structured clozapine trial. During clozapine treatment, weight was assessed at baseline, 6 week and 6 months. ANCOVA analyses correcting for covariates were utilized to detect differences among genotypes at candidate gene loci for both mean AIMS score and mean change in weight while on clozapine. The dopamine D3 receptor gene was found to be associated with TD (F[2,951=8.25, p<0.0005). The cytochrome P450 1A2 gene also revealed a significant association withTD (F12,99]=11.37, p=0.0007). Preliminary studies have not shown associations between 5HT2C genotypes and change in weight following 6 weeks (F[2,75]=0.63, p=0.54) and 6 months (F[2,42|=0.13, p=0.88) of clozapine treatment. Although replication is necessary, this study supports a role for both DRD3 and CYP1A2 in the pathogenesis of TD.