Genetic variation in dopaminergic activity is associated with the risk for psychiatric side effects of levetiracetam
Genetic variation in dopaminergic activity is associated with the risk for psychiatric side effects of levetiracetam
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DOI：
10.1111/j.1528-1167.2012.03603.x
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发表时间：
2013-01-01
期刊：
影响因子：
5.6
通讯作者：
Hurlemann, Rene
中科院分区：
文献类型：
--
作者：
Helmstaedter, Christoph;Mihov, Yoan;Hurlemann, Rene
目的：左乙拉西坦是一种高效的抗癫痫药物。然而，LEV治疗的一个临床相关的精神并发症是易怒和攻击性的刺激。最近的行为研究表明，人格特征可能是这些副作用的易感因素。为了评估LEV不良精神症状的遗传基础，进行了一项基于候选基因的两阶段关联研究。方法：根据其与冲动性和反应性-冲动性攻击的相关性，先验地选择基因多态。基于两个阶段的数据，计算了Bonferroni校正的联合荟萃分析。主要发现：第一阶段分析包括290名癫痫患者，发现携带与多巴胺能活性降低相关的基因变异的患者中，LEV的不良精神副作用负荷较高：rs1611115(多巴胺-β-羟基酶，DBH)、rs4680(儿茶酚-O-甲基转移酶，COMT)和rs1800497(与多巴胺受体D2相关的ANKK1 Taq-1A)。包括100例癫痫患者的II期分析和联合荟萃分析证实了rs1800497基因多态的作用(Bonferroni联合荟萃分析的校正意义，p=0.0096)。意义：证实了从行为观察中得出的结论，即患者在接受LEV治疗的情况下可能容易发展为激怒和攻击性，这一发现首次提供了多巴胺能活动的遗传变异与LEV治疗的精神并发症风险之间存在关联的证据。需要重复和进一步的工作才能证明真正的因果关系。总体而言，行为副作用的药物基因组学方法可能会提供一种未来的工具来预测与抗癫痫药物相关的不良精神药物效应。
Purpose: Levetiracetam (LEV) is a highly effective antiepileptic agent. A clinically relevant psychiatric complication of LEV treatment, however, is the provocation of irritability and aggression. Recent behavioral research indicates that personality traits may predispose to these side effects. To assess the genetic basis of the adverse psychotropic profile of LEV, a candidate gene-based two-stage association study was conducted. Methods: Polymorphisms were a priori selected according to their relevance for impulsivity and reactive-impulsive aggression. Based on data from both stages, a Bonferroni-corrected joint meta-analysis was computed. Key Findings: Stage 1 analysis included 290 patients with epilepsy and revealed a higher load of adverse psychotropic side effects of LEV in patients carrying genetic variants associated with decreased dopaminergic activity: rs1611115 (dopamine-beta-hydroxylase, DBH), rs4680 (catechol-O-methyltransferase, COMT), and rs1800497 (dopamine receptor D2-associated ANKK1 TAQ-1A). Stage II analysis including 100 patients with epilepsy, and joint meta-analysis confirmed the effect of the rs1800497 polymorphism (Bonferroni corrected significance of the joint meta-analysis, p = 0.0096). Significance: Confirming the suggestion from behavioral observations that patients might be predisposed to develop irritation and aggression under treatment with LEV, the findings provide first evidence of an association of genetic variation in dopaminergic activity and the risk for psychiatric complications of LEV treatment. Replication and further work is required to prove a true causal relationship. Overall, the pharmacogenomic approach to behavioral side effects may provide a future tool to predict adverse psychotropic effects related to antiepileptic drugs.