Genetic risk factors for behavioral adverse reactions in epileptic patients taking levetiracetam

Abstract

Levetiracetam (LEV) is an effective antiepileptic drug. Nevertheless, when the drug is used, its behavioral adverse drug reactions (ADRs), such as aggressivity, irritability, hyperexcitability, and anxiety, occur in almost 30% of cases. Recent studies show that personality traits can predispose to LEV-induced ARs.Objective: to establish genetic risk factors for behavioral ADRs in epileptic patients taking LEV. Patients and methods. Single nucleotide variants (SNVs) were chosen according to their importance for the development of impulsivity and aggressivity. At Stage 1, the dose-dependent effect of LEV, which was responsible for behavioral ADRs, was studied in 179 epileptic patients taking this drug, who were divided into four groups according to age and the presence of ADRs. Molecular genetic testing of SNVs DRD2 rs1800497 (DRD2/ANKK1 Taq1A), COMT rs4680, and DBH rs1611115 was done at Stage 2. Results and discussion. The ADR and non-ADR groups showed no statistically significant differences in the daily dose of LEV in both children (696.1 and 500.0 mg/day, respectively; p=0.087) and adults (750.9 and 750.9 mg/day, respectively; p=0.13). The similar data were obtained for blood LEV concentrations in children (31.6 and 27.3 μg/ml, p=0.12) and in adults (23.1 and 17.6 μg/ml, respectively; p=0.12). There was a statistically significant association between the carriage of the heterozygous CT genotype of SNV rs1611115 and the rate of both behavioral (OR, 3.38; 95% CI, 1.25–9.14; p=0.042) and CNS ADRs in general (OR, 3.29; 95% CI, 1.29–8.44; p=0.036). Higher impulsivity values were recorded in the carriers of the CT + TT genotypes of SNV rs1800497 (p<0.05) and rs1611115 (p<0.01) compared with those of the CC genotype. No statistically significant intergroup differences were obtained for SNV COMP rs4680. Conclusion. The dose-dependent effect of behavioral ADRs is absent in both pediatric and adult patients taking LEV. Increased impulsiveness in epileptic patients taking LEV is associated with the carriage of SNV rs1800497 and rs1611115. The LEV-induced behavioral ADRs are related to SNV DBH rs1611115 that can be considered as one of the potential genetic predictors for behavioral ADRs and impulsivity.