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Effects of cenobamate on cognitive performance of epilepsy patients

Published:October 04, 2022DOI:https://doi.org/10.1016/j.seizure.2022.10.004

      Highlights

      • Assessment of cognition before and during adjunctive treatment with cenobamate.
      • Most patients showed stable or improved cognitive performance (EpiTrack).
      • Cognitive change was not associated with cenobamate dose.

      Abstract

      Purpose

      Cenobamate (CNB) is a new antiseizure medication (ASM) for the treatment of focal epilepsy in adults. While efficacy of CNB was confirmed in controlled clinical trials, its effects on cognition are unclear. Cognitive adverse effects of ASM affect quality of life and retention rate. Therefore, we investigated whether the adjunctive treatment with CNB is associated with changes in cognitive performance.

      Method

      Efficacy and tolerability of CNB were investigated in an observational study. Fifty patients with pharmacoresistant focal epilepsy aged 18 to 71 years (Mdn = 37.5 years) were tested before (T0) and after reaching the first target dose of CNB, usually after three months (T1). Cognitive performance was assessed using the EpiTrack©, a change-sensitive screening tool for attention and executive functions.

      Results

      The median CNB dose at T1 was 125 mg/day (range: 50 – 250 mg/day). Most patients received 2–3 concomitant ASMs. Individual test scores remained stable in 72%, significantly improved in 16%, and significantly deteriorated in 12% of the patients from T0 to T1. The total group showed a significant improvement in EpiTrack scores (p < .01). Changes in EpiTrack performance from T0 to T1 occurred independently of CNB dose, changes in the total drug load or reduction in seizure frequency.

      Conclusion

      Most of the patients showed stable or improved cognitive performance. Thus, there is preliminary evidence that adjunctive CNB is not associated with an increased risk of cognitive side effects for the majority of patients. These findings need to be confirmed in controlled trials encompassing higher doses.

      Keywords

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      References

        • Nakamura M.
        • Cho J.
        • Shin H.
        • Jang I.
        Effects of cenobamate (YKP3089), a newly developed anti-epileptic drug, on voltage-gated sodium channels in rat hippocampal CA3 neurons.
        Eur J Pharmacol. 2019; 855: 175-182https://doi.org/10.1016/j.ejphar.2019.05.007
        • Sharma R.
        • Nakamura M.
        • Neupane C.
        • Jeon B.H.
        • Shin H.
        • Melnick S.M.
        • et al.
        Positive allosteric modulation of GABAA receptors by a novel antiepileptic drug cenobamate.
        Eur J Pharmacol. 2020; 879173117https://doi.org/10.1016/j.ejphar.2020.173117
        • Chung S.S.
        • French J.A.
        • Kowalski J.
        • Krauss G.L.
        • Lee S.K.
        • Maciejowski M.
        • et al.
        Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures.
        Neurology. 2020; 94: e2311-e2322https://doi.org/10.1212/WNL.0000000000009530
        • Krauss G.L.
        • Klein P.
        • Brandt C.
        • Lee S.K.
        • Milanov I.
        • Milovanovic M.
        • et al.
        Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial.
        Lancet Neurol. 2020; 19: 38-48https://doi.org/10.1016/S1474-4422(19)30399-0
        • Lattanzi S.
        • Trinka E.
        • Zaccara G.
        • Striano P.
        • Del Giovane C.
        • Silvestrini M.
        • et al.
        Adjunctive Cenobamate for focal-onset seizures in adults: a systematic review and meta-analysis.
        CNS Drugs. 2020; 34: 1105-1120https://doi.org/10.1007/s40263-020-00759-9
        • Lattanzi S.
        • Trinka E.
        • Zaccara G.
        • Striano P.
        • Russo E.
        • Del Giovane C.
        • et al.
        Third-generation antiseizure medications for adjunctive treatment of focal-onset seizures in adults: a systematic review and network meta-analysis.
        Drugs. 2022; : 199-218https://doi.org/10.1007/s40265-021-01661-4
        • Steinhoff B.J.
        • Ben-Menachem E.
        • Brandt C.
        • García Morales I.
        • Rosenfeld W.E.
        • Santamarina E.
        • et al.
        Onset of efficacy and adverse events during cenobamate titration period.
        Acta Neurol Scand. 2022; https://doi.org/10.1111/ane.13659
        • Sankar R.
        • Holmes G.L.
        Mechanisms of action for the commonly used antiepileptic drugs: relevance to antiepileptic drug-associated neurobehavioral adverse effects.
        J Child Neurol. 2004; 19 (Suppl): S6-14https://doi.org/10.1177/088307380401900102
        • Witt J.
        • Elger C.E.
        • Helmstaedter C.
        Which drug-induced side effects would be tolerated in the prospect of seizure control?.
        Epilepsy Behav. 2013; 29: 141-143https://doi.org/10.1016/j.yebeh.2013.07.013
        • Bootsma H.P.
        • Ricker L.
        • Hekster Y.A.
        • Hulsman J.
        • Lambrechts D.
        • Majoie M.
        • et al.
        The impact of side effects on long-term retention in three new antiepileptic drugs.
        Seizure. 2009; 18: 327-331https://doi.org/10.1016/j.seizure.2008.11.006
        • Witt J.
        • Helmstaedter C.
        Monitoring the cognitive effects of antiepileptic pharmacotherapy-approaching the individual patient.
        Epilepsy Behav. 2013; 26: 450-456https://doi.org/10.1016/j.yebeh.2012.09.015
        • Krauss G.L.
        • Chung S.S.
        • Ferrari L.
        • Rosenfeld W.E.
        Cognitive and psychiatric adverse events during adjunctive cenobamate treatment in phase 2 and phase 3 clinical studies (P13-8.005).
        Neurology. 2022; 98 (18 Supplement)
        • Lutz M.T.
        • Helmstaedter C.
        EpiTrack: tracking cognitive side effects of medication on attention and executive functions in patients with epilepsy.
        Epilepsy Behav. 2005; 7: 708-714https://doi.org/10.1016/j.yebeh.2005.08.015
        • Helmstaedter C.
        • Witt J.
        The effects of levetiracetam on cognition: a non-interventional surveillance study.
        Epilepsy Behav. 2008; 13: 642-649https://doi.org/10.1016/j.yebeh.2008.07.012
        • Helmstaedter C.
        EpiTrack. Veränderungssensitives kognitives Screening zur Qualitäts-und Outcomekontrolle der medikamentösen Epilepsiebehandlung. 2nd ed. UCB-Pharma, Monheim2012
      1. WHO. ATC/DDD Index 2022, https://www.whocc.no/atc_ddd_index/; 2021 [accessed 14 March 2022].

        • Guy W.
        ECDEU assessment manual for psychopharmacology. US department of health, education, and welfare, Rockville, MD1976
        • R Core Team
        R: a language and environment for statistical computing.
        R Foundation for Statistical Computing, Vienna2021
        • Meschede C.
        • Witt J.
        • Brömling S.
        • Moskau-Hartmann S.
        • Rademacher M.
        • Surges R.
        • et al.
        Changes in cognition after introduction or withdrawal of zonisamide versus topiramate in epilepsy patients: a retrospective study using Bayes statistics.
        Epilepsia. 2020; 61: 1481-1490https://doi.org/10.1111/epi.16576
        • Crowe S.F.
        • Stranks E.K.
        The residual medium and long-term cognitive effects of benzodiazepine use: an updated meta-analysis.
        Arch Clin Neuropsychol. 2018; 33: 901-911https://doi.org/10.1093/arclin/acx120
        • Vingerhoets G.
        Cognitive effects of seizures.
        Seizure. 2006; 15: 221-226https://doi.org/10.1016/j.seizure.2006.02.012
        • Lv Y.
        • Wang Z.
        • Cui L.
        • Ma D.
        • Meng H.
        Cognitive correlates of interictal epileptiform discharges in adult patients with epilepsy in China.
        Epilepsy Behav. 2013; 29: 205-210https://doi.org/10.1016/j.yebeh.2013.07.014
        • Witt J.A.
        • Elger C.E.
        • Helmstaedter C.
        Adverse cognitive effects of antiepileptic pharmacotherapy: each additional drug matters.
        Eur Neuropsychopharmacol. 2015; 25: 1954-1959https://doi.org/10.1016/j.euroneuro.2015.07.027
        • Sperling M.R.
        • Klein P.
        • Aboumatar S.
        • Gelfand M.
        • Halford J.J.
        • Krauss G.L.
        • et al.
        Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study.
        Epilepsia. 2020; 61: 1099-1108https://doi.org/10.1111/epi.16525
        • Loring D.W.
        • Williamson D.J.
        • Meador K.J.
        • Wiegand F.
        • Hulihan J.
        Topiramate dose effects on cognition: a randomized double-blind study.
        Neurology. 2011; 76: 131-137https://doi.org/10.1212/WNL.0b013e318206ca02
        • Witt J.
        • Helmstaedter C.
        How can we overcome neuropsychological adverse effects of antiepileptic drugs?.
        Expert Opin Pharmacother. 2017; 18: 551-554https://doi.org/10.1080/14656566.2017.1309025
        • Thompson P.J.
        • Baxendale S.A.
        • Duncan J.S.
        • Sander J.W.
        Effects of topiramate on cognitive function.
        J Neurol Neurosurg Psychiatry. 2000; 69: 636-641https://doi.org/10.1136/jnnp.69.5.636
        • Meschede C.
        • Witt J.
        • Rademacher M.
        • von Wrede R.
        • Elger C.E.
        • Helmstaedter C.
        Evaluating the longer-term cognitive effects of adjunctive perampanel compared to lacosamide in a naturalistic outpatient setting.
        Seizure. 2018; 58: 141-146https://doi.org/10.1016/j.seizure.2018.04.015