A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam

Abstract

Objective: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV.Methods: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122).Results: Univariate GWAS found no significant associations with either LEVassociated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. Significance:The polygenic burden for schizophrenia is a risk factor for LEVassociated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.

Levetiracetam vs Lamotrigine as First-Line Antiseizure Medication in Female Patients With Idiopathic Generalized Epilepsy

“…When considering the safety analysis, both ASMs were found to be well tolerated, with similar retention rates during the long-term follow-up in the entire cohort. A higher number of adverse effects was observed in the levetiracetam group, especially in terms of behavioral adverse effects and drowsiness, confirming previous literature findings . Accordingly, our data suggest that the use of lamotrigine may be preferable in absence epilepsy and GTCA in the presence of psychiatric comorbidities, based on the comparable effectiveness of lamotrigine and levetiracetam in these specific syndromes and their tolerability profile.…”

Levetiracetam-induced psychosis in a Filipino female diagnosed with anti-N-methyl-D-aspartate receptor encephalitis: a case report

“…17 The study of Campbell et al indicated that 1% of people exposed to LEV develop ADRs hence, they utilized a variety of approaches to assess the role of genetic variation in psychiatric and behavioral ADRs associated with LEV. 18 In their casecontrol study, they compared cases of LEV-associated behavioral disorder or psychotic reaction to LEV-exposed people without history of psychiatric ADRs and they showed that polygenic burden for schizophrenia is a risk factor for LEV-induced psychotic reaction. Their recommendation included the possibility of screening individuals with epilepsy to identify those at risk of developing ADRs and clinical knowledge on clinical risk factor such as history of depression and use of recreational drug.…”

“…Their recommendation included the possibility of screening individuals with epilepsy to identify those at risk of developing ADRs and clinical knowledge on clinical risk factor such as history of depression and use of recreational drug. 18 Though was commonly associated with a history of psychiatric disorder, the study by Molokwu et al deduced that there can be de novo presentation of this drug reaction. 19 Some studies showed that the higher risk for developing psychiatric symptoms from LEV can be attributed to a genetic predisposition.…”

A pharmacogenetic study of perampanel: association between rare variants of glutamate receptor genes and outcomes

“…Frontiers in Genetics frontiersin.org pharmacogenomic study of psychiatric ADR and levetiracetam revealed no association in either common or rare genetic variants (Campbell et al, 2022). However, Campbel et al utilized a hypothesis-free analysis that included a greater number of genes, and no statistically significant results were found after correction for multiple comparisons.…”