Genetic variation in dopaminergic activity is associated with the risk for psychiatric side effects of levetiracetam

Abstract

SUMMARYPurpose: 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-b-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.

Reflections on the Use of Perampanel in Epilepsy – Lessons from the Clinic and Real-world Evidence

“…53 Other factors may also have an impact on the risk of development of psychiatric or behavioural side effects. For example, genetic variation in dopaminergic activity is associated with the risk of psychiatric side effects with levetiracetam 54 and, although personalised therapy for…”

Implications of pharmacogenetics for the therapeutic use of antiepileptic drugs

“…: Plasma level [91] Chinese CYP2C9 PM : Plasma level [82] Indian NAT2*5A PM : t 1/2 , ; Cl [92] Indian MDR1 3435T and GABRG2588T : Plasma level, ; Brain level [116] ValproicAcid Chinese UGT1A3*5 ; Plasma level [94] Chinese UGT1A6 T19G, A541G, A552C ; Plasma level [117] -CYP2C9*2 ; Vmax [118] -CYP2C9*3 : Km [118] -CYP2C9*2/*3 ; Oxidative biotransformation [118] Chinese CYP2A6*4, CYP2B6, CYP2C9*3 : Plasma level [95] Zonisamide Japanese CYP2C19, CYP3A5 ; Cl [71] Levetiracetam -DRD2/ANKK1 TAQ-1A T+ -: Negative psychotropicside effects [69] Oxcarbazepine Han Chinese 72] Han Chinese HLA-BÃ1502 -MPE [86] Phenytoin European CYP2C9*2/*3 -: Toxicity [98] ADRs …”

“…Levetiracetam was reported to induce psychotropic side effects in up to 15% of patients [68]. The genetic basis of the adverse psychotropic profile of levetiracetam was demonstrated by the association between the dopamine receptor D2/ANKK1 TAQ-1A A+ genotype (the T allele of rs1800497) and the increased susceptibility to negative side effects [69]. However, replication and further work is required to prove a true causal relationship for these findings.…”

Comments on Ortinski P et al. Cognitive side effects of antiepileptic drugs. Epilepsy & Behavior 2004;5(Suppl. 1):S60–65.

“…As for the cognitive and behavioral side effects of AEDs, the future will show whether, apart from genetically driven treatment choices [34], a kind of rational pharmacotherapy can be established which takes side effects into consideration. A first approach into this direction had been made by Ketter and colleagues in 1999 by suggesting to prefer activating AEDs in already sedated patients, and vice versa [9].…”