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GENETIC RISK FACTORS FOR THE DEVELOPMENT OF BEHAVIORAL ADVERSE DRUG REACTIONS IN PATIENTS WITH EPILEPSY TAKING LEVETIRACETAM

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Abstract

Levetiracetam (LEV) is a highly effective antiepileptic drug (AED). However, unwanted behavioral adverse drug reactions (ADR), such as aggression, irritability, hyperexcitability, and anxiety occur in almost 30% of cases. Recent researches have shown that personality traits may predispose to the emergence of LEV-induced ADR.

Purpose: To determine the genetic risk factors for the development of behavioral ADR in patients with epilepsy, taking LEV.

Materials and methods: Single nucleotide variants (SNVs) were chosen according to their importance for the development of impulsivity and aggression. At stage I, the investigation of dose-dependent effect for behavioral ADRs development was performed in 179 patients with epilepsy, taking LEV, which were divided into 4 groups depending on age and the presence of ADRs. At stage II, molecular genetic research of SNVs rs1800497 of DRD2 gene (DRD2/ANKK1 Taq1A), rs4680 of COMT gene, and rs1611115 of DBH gene was done.

Results: No statistically significant differences in LEV daily dose in patients with and without ADRs both in 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) were found. The same data were obtained for blood LEV concentration (31.6 and 27.3 mg/ml, p = 0.12 in children; 23.1 and 17.6 mg/ml, p = 0.12 in adults, respectively). Statistically significant association was shown between heterozygous CT genotype of SNV rs1611115 and the frequency of both behavioral ADRs (p = 0.042; OR 3.38; 95% CI 1.25-9.14) and CNS associated ADRs in general (p = 0.036; OR 3.29; 95% CI 1.29-8.44). Higher impulsivity indicators were determined in carriers of (CT + TT) genotypes of SNVs rs1800497 (p<0.05) and rs1611115 (p<0.01) in comparison with carriers of CC genotype. No statistically significant intergroup differences were found for rs4680 SNV of COMT gene.

Conclusion: The dose-dependent effect of behavioral ADRs development is absent both in children and adults taking LEV. Increased impulsiveness in patients with epilepsy taking LEV was associated with SNVs rs1800497 and rs1611115.

Behavioral ADRs are associated with SNV rs1611115 of DBH gene, which can be considered as one of the potential genetic predictors of behavioral ADRs and impulsivity.

About the Authors

A. A. Usoltseva
V. F. Voyno-Yasenetsky Krasnoyarsk State Medical University of the Ministry of Health of Russian Federation
Russian Federation


D. V. Dmitrenko
V. F. Voyno-Yasenetsky Krasnoyarsk State Medical University of the Ministry of Health of Russian Federation
Russian Federation


S. N. Zobova
V. F. Voyno-Yasenetsky Krasnoyarsk State Medical University of the Ministry of Health of Russian Federation, Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences , the Separate Division "Research Institute of Medical Problems of the North"
Russian Federation


E. N. Bochanova
V. F. Voyno-Yasenetsky Krasnoyarsk State Medical University of the Ministry of Health of Russian Federation
Russian Federation


N. A. Shnayder
V. F. Voyno-Yasenetsky Krasnoyarsk State Medical University of the Ministry of Health of Russian Federation, V.M. Bechterev National Medical Research Center of Psychiatry and Neurology of the Ministry of Health of Russian Federation
Russian Federation


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For citation:


Usoltseva A.A., Dmitrenko D.V., Zobova S.N., Bochanova E.N., Shnayder N.A. GENETIC RISK FACTORS FOR THE DEVELOPMENT OF BEHAVIORAL ADVERSE DRUG REACTIONS IN PATIENTS WITH EPILEPSY TAKING LEVETIRACETAM. Neurology, Neuropsychiatry, Psychosomatics. 0;. (In Russ.)

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ISSN 2074-2711 (Print)
ISSN 2310-1342 (Online)