Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications

Wolking, Stefan; Campbell, Ciarán; Stapleton, Caragh; McCormack, Mark; Delanty, Norman; Depondt, Chantal; Johnson, Michael R.; Koeleman, Bobby P. C.; Krause, Roland; Kunz, Wolfram S.; Marson, Anthony G; Sander, Josemir W.; Sills, Graeme J.; Striano, Pasquale; Zara, Federico; Sisodiya, Sanjay M.; Cavalleri, Gianpiero L.; Lerche, Holger

doi:10.3389/fphar.2021.688386

Cited by 12 publications

(7 citation statements)

References 32 publications

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“…It will perform a genome-wide association study (GWAS) on individuals responding to specific ASMs or functionally related groups of ASMs, using non-responders as controls. It will also identify several potential regions of interest, but this will not detect relevant genome-wide loci for the ASM-specific response [ 143 ]. GWAS studies did not show a predictive value of common genetic variants for ASM response status.…”

Section: Currently Used Antiepileptic Drugsmentioning

confidence: 99%

Pharmacogenetics of Drug-Resistant Epilepsy (Review of Literature)

Smolarz

Makowska

Romanowicz

2021

IJMS

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Pharmacogenomic studies in epilepsy are justified by the high prevalence rate of this disease and the high cost of its treatment, frequent drug resistance, different response to the drug, the possibility of using reliable methods to assess the control of seizures and side effects of antiepileptic drugs. Candidate genes encode proteins involved in pharmacokinetic processes (drug transporters, metabolizing enzymes), pharmacodynamic processes (receptors, ion channels, enzymes, regulatory proteins, secondary messengers) and drug hypersensitivity (immune factors). This article provides an overview of the literature on the influence of genetic factors on treatment in epilepsy.

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Section: Currently Used Antiepileptic Drugsmentioning

confidence: 99%

Pharmacogenetics of Drug-Resistant Epilepsy (Review of Literature)

Smolarz

Makowska

Romanowicz

2021

IJMS

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“…Studies are trying to elicit the answers to these questions. For example, the area of pharmacogenomics is growing with the aim of personalising therapies based on an individual’s genetic profile with regard to variants that affect response and AEs [ 307 ]. With this in mind, the HLA-A*11:01 allele has been identified as possibly being associated with LEV-induced psychiatric AEs [ 308 ].…”

Section: Discussionmentioning

confidence: 99%

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

Strzelczyk

Schubert‐Bast

2022

CNS Drugs

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The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and significant neurodevelopmental comorbidities. The latter include intellectual disability, developmental delay, behavioural problems including attention-deficit hyperactivity disorder and autism spectrum disorder, psychiatric problems including anxiety and depression, speech impairment and sleep problems. Classical examples of developmental and epileptic encephalopathies include Dravet syndrome, Lennox–Gastaut syndrome and tuberous sclerosis complex. The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep. We have performed a targeted literature review of ASMs commonly used in the treatment of developmental and epileptic encephalopathies to discuss the latest evidence on their effects on behaviour, mood, cognition, sedation and sleep. The ASMs include valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) and everolimus. Bromide, felbamate and other sodium channel ASMs are discussed briefly. Overall, the current evidence suggest that LEV, PER and to a lesser extent BRV are associated with psychobehavioural adverse events including aggressiveness and irritability; TPM and to a lesser extent ZNS are associated with language impairment and cognitive dulling/memory problems. Patients with a history of behavioural and psychiatric comorbidities may be more at risk of developing psychobehavioural adverse events. Topiramate and ZNS may be associated with negative effects in some aspects of cognition; CBD, FFA, LEV, BRV and LTG may have some positive effects, while the remaining ASMs do not appear to have a detrimental effect. All the ASMs are associated with sedation to a certain extent, which is pronounced during uptitration. Cannabidiol, PER and pregabalin may be associated with improvements in sleep, LTG is associated with insomnia, while VPA, TPM, LEV, ZNS and LCM do not appear to have detrimental effects. There was variability in the extent of evidence for each ASM: for many first-generation and some second-generation ASMs, there is scant documented evidence; however, their extensive use suggests favourable tolerability and safety (e.g. VPA); second-generation and some third-generation ASMs tend to have the most robust evidence documented over several years of use (TPM, LEV, PER, ZNS, BRV), while evidence is still being generated for newer ASMs such as CBD and FFA. Finally, we discuss how a variety of factors can affect mood, behaviour and cognition, and untangling the associations between the effects of the underlying syndrome and those of the ASMs can be challenging. In particular, there is enormous h...

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“…Several candidate rare genetic variants were found in the exome-based research of patients with non-familial non-acquired focal epilepsy and DEPDC5 was regarded as a potential risk factor for drug resistance ( 31 ). For the specific drug response, common genetic variants were not significantly associated with common ASMs in a study containing 3,649 individuals with focal epilepsy or generalized genetic epilepsy ( 32 ). However, an exome-based study targeting rare genetic variants revealed an increased burden of damaging variants in gene groups associated with pharmacokinetics or targeting in patients resistant to valproic acid or levetiracetam ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Current trends and hotspots in drug-resistant epilepsy research: Insights from a bibliometric analysis

Zhong

Liu

et al. 2022

Front. Neurol.

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BackgroundDrug-resistance is a significant clinical issue in persons with epilepsy. In the past few years, many studies have been published investigating the management of drug-resistant epilepsy (DRE); however, no systematic and quantitative evaluation of this research has been performed. Therefore, a bibliometric analysis was conducted to demonstrate the current status of DRE research and to reflect the trends and hotspots within the field.MethodsWe retrieved publications on DRE published between 2011 and 2021 from the Science Citation Index Expanded of the Web of Science Core Collection. All articles related to DRE were included in this study. VOSviewer, R software, and CiteSpace were used to perform bibliometric research.ResultsA total of 3,088 original articles were included in this study. The number of publications on DRE has continued to increase over the past 11 years. The USA published the most papers with the highest number of citations and H-index. The National Institutes of Health and the University of Toronto were the most prolific funding agency and affiliation, respectively. Epilepsy & Behavior and Epilepsia ranked first as the most prolific and co-cited journals, respectively. The keywords “cannabidiol”, “neuromodulation”, “seeg” and “perampanel” revealed recent research hotspots. The top 100 most cited papers were classified into eight main topics, of which pharmacotherapy, disease mechanisms/pathophysiology, and neuromodulation were the three most important topics.ConclusionsThis analysis of bibliometric data demonstrated that DRE has always been a topical area of research. The mechanisms of epilepsy and therapies have been the focus of DRE research, and innovative antiseizure medications and surgical approaches are fast-developing research trends.

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Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications

Cited by 12 publications

References 32 publications

Pharmacogenetics of Drug-Resistant Epilepsy (Review of Literature)

Pharmacogenetics of Drug-Resistant Epilepsy (Review of Literature)

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

Current trends and hotspots in drug-resistant epilepsy research: Insights from a bibliometric analysis

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