title: Genetic variation in dopaminergic activity is associated with the risk for psychiatric side effects of levetiracetam.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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-β-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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Epileptology, University of Bonn, Bonn, Germany. c.helmstaedter@uni-bonn.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Helmstaedter
authors.forename: Yoan
authors.initials: Y
authors.lastname: Mihov
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Peter
authors.initials: P
authors.lastname: Nuernberg
authors.forename: Susanne
authors.initials: S
authors.lastname: Schoch
authors.forename: Rainer
authors.initials: R
authors.lastname: Surges
authors.forename: Christian E
authors.initials: CE
authors.lastname: Elger
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.forename: René
authors.initials: R
authors.lastname: Hurlemann
mesh_terms: D000328:Adult; D000374:Aggression / Q000187:drug effects*; D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D002394:Catechol O-Methyltransferase / Q000235:genetics; D004298:Dopamine / Q000235:genetics*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007508:Irritable Mood / Q000187:drug effects*; D000077287:Levetiracetam; D008297:Male; D010889:Piracetam / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D017448:Receptors, Dopamine D2 / Q000235:genetics; D012307:Risk Factors
chemical_list: D000927:Anticonvulsants; D017448:Receptors, Dopamine D2; D000077287:Levetiracetam; D004299:Dopamine beta-Hydroxylase; D002394:Catechol O-Methyltransferase; D004298:Dopamine; D010889:Piracetam