Pharmacogenetics of antipsychotic-induced extrapyramidal symptoms

Abstract

Objective: To identify genetic variants that confer susceptibility to or protection against extrapyramidal symptoms (EPS) induced by antipsychotic drugs, specifically antipsychotic induced parkinsonism (AIP) and tardive dyskinesia (TD). Methods: 1) Candidate gene studies of patients acutely treated with antipsychotics with replication of positive findings in an independent sample; 2) Genome wide association study of patients treated with antipsychotics (CATIE trial) with replication in an independent sample; 3) Functional studies in genetically modified mice to determine the role of genes associated with AIP or TD susceptibility or protection in human studies. Results: 1) In studies of candidate genes implicated in dopamine receptor signaling, we found significant evidence for association of RGS2 with AIP, a regulatory SNP, rs4606, associated with reduced expression conferring protection. Originally demonstrated in an Israeli sample (Greenbaum et al. 2007), this finding was confirmed in an independent US sample (Greenbaum et al. 2009). 2) The CATIEGWAS for AIP yielded 15 SNPs that were significant at P<1 x 10-4 (Alkelai et al. 2009). Of these, association of the intronic SNP, rs12678719, in the ZFPM2 (multiple zinc finger protein) gene, was replicated in our US sample after correction for multiple testing (p<0.008). 3) Studies with RGS2 knockout (KO) mice are underway employing mice wild type, heterozygous or homozygous for the RGS2 KO mutation. Thus far we have observed a clear inverse relationship between level of RGS2 expression of and D1 agonist induced locomotor activity. Studies on the effect of chronic antipsychotic drug administration are under way. Conclusion: If validated and applied in the clinic, findings such as these could permit a priori identification of patients at increased or reduced risk for AIP and facilitate rational selection of candidates for treatment with first (FGA) and second generation antipsychotics (SGA) which have different adverse effect profiles.