Cognitive and behavioral effects of the anti-epileptic drug cenobamate (YKP3089) and underlying synaptic and cellular mechanisms

Song, Woo Seok; Cho, Young Seon; Oh, Sung Pyo; Yoon, Sang Ho; Kim, Young Sook; Kim, Myoung-Hwan

doi:10.1016/j.neuropharm.2022.109292

Cited by 9 publications

(5 citation statements)

References 46 publications

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“…13 In the same study, mice that received chronic treatment of 5 mg/kg (equivalent to 0.41 mg/kg in humans) after a period of adaption of 10 days showed impaired recognition and spatial learning performance. 13 Despite these interesting results, only one human study has examined this topic with a cognitive screening tool. The results showed that 72% of patients who took CNB doses that ranged from 50 to 250 mg/day for approximately 3 months (with a mean of 125 mg/day) had stable scores in the EpiTrack screening tool, while 16% of the patients even improved.…”

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 91%

“…To our knowledge, no studies have comprehensively addressed the effects of CNB on cognitive functioning in people with epilepsy. In animal models, a single administration of 10 and 30 mg/kg intraperitoneally CNB (corresponding to 0.81 and 2.44 mg/day in humans) has been found to have anxiolytic effects in the elevated zero maze and impaired recognition and object location memory 13 . In the same study, mice that received chronic treatment of 5 mg/kg (equivalent to 0.41 mg/kg in humans) after a period of adaption of 10 days showed impaired recognition and spatial learning performance 13 …”

Section: Introductionmentioning

confidence: 99%

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Prospective study of cenobamate on cognition, affectivity, and quality of life in focal epilepsy

Catalán‐Aguilar,

Hampel,

Cano‐López

et al. 2023

Epilepsia Open

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ObjectiveCenobamate is a recently approved antiseizure medication that proved to be safe and effective in randomized controlled trials. However, little is known about its impact on some areas frequently affected in epilepsy. For this reason, we explored the effects of cenobamate in cognitive performance, as well as on negative affectivity and quality of life in a sample of patients with drug‐resistant epilepsy.MethodsTwo prospective cohort studies were carried out. In Study 1, 32 patients (22 men and 10 women) underwent a baseline (T0) and a short‐term (T1) neuropsychological assessment after three months of cenobamate administration. In Study 2, 22 patients (16 men and 6 women) from the T1 sample also underwent a baseline and a follow‐up evaluation (T2) six months after T0.ResultsNo significant differences were found in cognitive variables, negative affectivity, and quality of life either in Study 1 or Study 2. Similarly, based on the reliable change index it was found that most patients showed no changes in these variables.SignificanceThese results suggest that cenobamate is a safe antiseizure medication in terms of cognition, negative affectivity, or quality of life since no adverse events have been found after three and six months of treatment.

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Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Prospective study of cenobamate on cognition, affectivity, and quality of life in focal epilepsy

Catalán‐Aguilar,

Hampel,

Cano‐López

et al. 2023

Epilepsia Open

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“…The authors showed that CNB influenced novel object recognition, object location memory, and Morris water maze performance in mice. Also, CNB suppressed hippocampal excitatory synaptic transmission by reducing the excitability of Schaffer collaterals and interfered with the induction of long-term potentiation [ 113 ]. Therefore, CNB can potentially affect cognitive function in animal models of epilepsy, but there was no report in the clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Cenobamate (YKP3089) and Drug-Resistant Epilepsy: A Review of the Literature

Rissardo,

Fornari Caprara

2023

Medicina

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Cenobamate (CNB), ([(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl], is a novel tetrazole alkyl carbamate derivative. In November 2019, the Food and Drug Administration approved Xcopri®, marketed by SK Life Science Inc., (Paramus, NJ, USA) for adult focal seizures. The European Medicines Agency approved Ontozry® by Arvelle Therapeutics Netherlands B.V.(Amsterdam, The Neatherlands) in March 2021. Cenobamate is a medication that could potentially change the perspectives regarding the management and prognosis of refractory epilepsy. In this way, this study aims to review the literature on CNB’s pharmacological properties, pharmacokinetics, efficacy, and safety. CNB is a highly effective drug in managing focal onset seizures, with more than twenty percent of individuals with drug-resistant epilepsy achieving seizure freedom. This finding is remarkable in the antiseizure medication literature. The mechanism of action of CNB is still poorly understood, but it is associated with transient and persistent sodium currents and GABAergic neurotransmission. In animal studies, CNB showed sustained efficacy and potency in the 6 Hz test regardless of the stimulus intensity. CNB was revealed to be the most cost-effective drug among different third-generation antiseizure medications. Also, CNB could have neuroprotective effects. However, there are still concerns regarding its potential for abuse and suicidality risk, which future studies should clearly assess, after which protocols should be changed. The major drawback of CNB therapy is the slow and complex titration and maintenance phases preventing the wide use of this new agent in clinical practice.

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“…We know that this ASM had an impact on mice's performance in the Morris water maze, novel object recognition, and object location memory, according to a recently published study on the behavioral, synaptic, and cellular actions of CNB. 31 …”

Section: Discussionmentioning

confidence: 99%

Cenobamate and Clobazam Combination as Personalized Medicine in Autoimmune-Associated Epilepsy With Anti-Gad65 Antibodies

Serrano-Castro,

Rodríguez-Uranga,

Cabezudo-García

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesAutoimmune-associated epilepsy (AAE) with antiglutamic acid decarboxylase 65 (GAD65) antibodies is considered a T-cell–mediated encephalitis that evolves to drug-resistant epilepsy. We do not have an effective therapeutic strategy for these patients. Because the GAD enzyme is primarily responsible for the conversion of glutamate to GABA, the mechanism of epileptogenesis in this condition predicts decreased levels of GABA content in synaptic vesicles. Cenobamate (CNB) acts as a positive allosteric modulator at synaptic and extra synaptic GABAA receptors, producing increased inhibitory neurotransmission in the brain. This mechanism could be especially beneficial in AAE with anti-GAD65 antibodies because it would be able to correct the imbalance due to the GABAergic stimulation deficit in postsynaptic neurons.MethodsWe recruit a retrospective multicentric consecutive case series of AAE with anti-GAD65 antibodies from 5 epilepsy units in Spain who have received treatment with CNB.ResultsA total of 8 patients were recruited. This cohort of highly refractory patients have failed a mean of 9.50 (SD = 3.20) ASM without control of seizures for sustained periods of time. The average number of seizures per month during the previous 3 months before CNB treatment was 19.63 (SD = 17.03). After the introduction of CNB improvement was achieved in all our patients, with a median reduction in the number of seizures of 92.22% (interquartile range [IQR]: 57.25–98.75). The mean follow-up was 156.75 days (SD = 68.23). In patients with concomitant treatment with clobazam (CLB), the median percentage of seizure reduction was higher than those not taking CLB: 94.72% (IQR: 87.25–100) vs 41.50% (p= 0.044) and also higher than the control group of patients with refractory epilepsy not related to anti-GAD65 treated with the same combination: 94.72% (IQR: 87.25–100) vs 45.00% (IQR: 25.00–87.00) (p= 0.019).DiscussionTreatment with the combination CNB + CLB could be a type of personalized medicine in patients with AAE with anti-GAD65. Our preliminary data will need to be endorsed with new prospective and controlled studies.

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Cognitive and behavioral effects of the anti-epileptic drug cenobamate (YKP3089) and underlying synaptic and cellular mechanisms

Cited by 9 publications

References 46 publications

Prospective study of cenobamate on cognition, affectivity, and quality of life in focal epilepsy

Prospective study of cenobamate on cognition, affectivity, and quality of life in focal epilepsy

Cenobamate (YKP3089) and Drug-Resistant Epilepsy: A Review of the Literature

Cenobamate and Clobazam Combination as Personalized Medicine in Autoimmune-Associated Epilepsy With Anti-Gad65 Antibodies

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