P.3.c.050 Interaction between polymorphisms of oxidative enzymes and susceptibility to tardive dyskinesia in psychiatric patients

Abstract

Tardive dyskinesia (TD) is a severe and potentially irreversible antipsychotic-induced movement disorder that has been and continues to be a significant problem associated with long-term use of antipsychotics [1]. About 30% of patients chronically exposed to neuroleptics may exhibit tardive dyskinesia. Neuronal degeneration due to oxidative stress has been proposed as a mechanism for the pathogenesis of tardive dyskinesia [2]. Several studies have examined the pharmacogenetics of TD and oxidative-stress enzymes in various ethnic groups, but not in Russians. Purpose: To investigate the possible effects of three missense polymorphisms (Ile105Val, Ala9Val, and Pro197Leu) in three oxidative-stress enzymes (GSTP1, SOD2, and GPX1, respectively) on orofaciolingual (TDof) and limb-truncal (TDlt) dyskinesias in Russian psychiatric inpatients from Siberia. Methods: After approval of the study protocol by the institutional bioethics committee, subjects were included from two psychiatric departments in Tomsk, Siberia. DNA extraction and TaqMan genotyping were conducted according to standard protocols and blind to the clinical status of the subjects. Subjects were characterized either as carriers or non-carriers of an allele. The sum of the first 7 items of the Abnormal Involuntary Movement Scale was utilized as a proxy for the severity of TD (TDsum). Multivariate parametric regression and two-part models were performed to identify the effect of different variables (allelecarriership status, age, gender, type of psychiatric department, use of anticholinergic and antipsychotic medication) on TD. Results: In total 146 Russian Caucasian patients (91 males, 55 females) with an age of 46.8±17.6 years (sample mean±SD) met the inclusion criteria. Seventy-nine (54%) subjects were included from a psychiatric department for permanently hospitalized, severely ill patients. The remaining 46% were less-severely ill inpatients from a psychiatric department for temporal hospitalization. About 95% of the patients had clinically-established schizophrenia (n = 138) and only 5% had schizotypical disorder (n = 8). The genotype distributions of Ile105Val (79 Ile/Ile, 53 Ile/Val, and 11 Val/Val), Ala9Val (37 Ala/Ala, 62 Ala/Val, and 42 Val/Val) and Pro197Leu (72 Pro/Pro, 60 Pro/Leu, and 11 Leu/Leu) were in consistency with the Hardy-Weinberg equilibrium. Our analyses do not suggest that Pro197Leu polymorphism (GPX1) is associated with TD. However, our analyses suggest that the 105Val-allele of Ile105Val (GSTP1) may be associated with a lower risk and a severity of TDof and TDlt and that Ile105Val pharmacogenetics may be different in Slavonic Caucasians from that in American Caucasians. This finding is plausible, since it has been suggested that Ile105Val polymorphism is functional with the 105Val-allele leading to a decreased enzymatic activity and detoxification capacity. Furthermore, we found evidence for an association between Ala9Val polymorphism (SOD2) and TDof, but not TDlt. Conclusions: This is the first study on the pharmacogenetics of TD and oxidative stress enzymes in Russian psychiatric subjects. Our findings extend the available knowledge on the pharmacogenetics of TD and oxidative stress.