Real-World Challenges and the Role of Cenobamate in Epilepsy

Managing drug-resistant epilepsy presents considerable clinical hurdles for neurologists worldwide. Patients frequently require multiple antiseizure medications to achieve minimal seizure control. However, progressive polypharmacy significantly increases the cumulative drug burden, causing severe cognitive adverse effects and poor compliance. Therefore, clinicians actively seek modern therapeutic agents that provide superior efficacy while facilitating regimen simplification. The introduction of cenobamate in epilepsy care offers a promising strategy to overcome these persistent therapeutic roadblocks. Cenobamate possesses a unique dual mechanism of action that combines positive allosteric modulation of non-synaptic gamma-aminobutyric acid receptors with inhibition of the persistent sodium current. Consequently, this innovative molecule has demonstrated remarkable seizure reduction across clinical trials. The real-world European DECREASE study evaluated whether patients in Early Access Programs could successfully reduce their concomitant medication burden after initiating cenobamate. Ultimately, the investigators analyzed real-world registries to establish the effectiveness and tolerability of cenobamate during intensive medication tapering.

DECREASE Study Design and Patient Population Baseline

The DECREASE study pooled anonymized data from multicenter clinical registries across European cenobamate Early Access Programs. Investigators strictly defined inclusion criteria to isolate patients who achieved a meaningful reduction in their concomitant antiseizure drug load. Specifically, the cohort included patients who either transitioned completely to cenobamate monotherapy or reduced multi-drug regimens down to a single concomitant agent. Among the broader cohort of 694 patients enrolled in European early access registries, 75 individuals met these rigorous criteria. Furthermore, the mean age of this selected cohort was 39.5 years, spanning from 19 to 65 years. The baseline characteristics revealed an exceptionally treatment-resistant population with a median history of 10 prior antiseizure medications. Additionally, 61.3% of patients were taking two concomitant agents at baseline, while 30.7% were receiving three, and 8% were taking four concurrent medications. Thus, these baseline metrics illustrate a heavily pretreated group with longstanding refractory epilepsy.

Seizure Control and Long-Term Efficacy Outcomes

The clinical findings from the DECREASE study demonstrated robust and sustained seizure control following regimen simplification. Patients reached a median cenobamate dosage of 300 mg daily at their final evaluation, with an interquartile range of 200 to 350 mg. Moreover, the study maintained a substantial median follow-up period of 22 months, ensuring comprehensive long-term evaluation. In fact, 97% of patients completed at least one full year of follow-up, and only a single patient discontinued therapy at twelve months. Remarkably, 33.3% of the pooled cohort achieved complete seizure freedom at their last visit. Furthermore, 68% of patients achieved a greater than or equal to 50% reduction in baseline seizure frequency. These compelling outcomes confirm that tapering background medications does not compromise overall seizure control when cenobamate provides primary therapeutic coverage. Consequently, clinicians can achieve high rates of seizure suppression even while systematically decreasing concomitant medication burdens in refractory cases.

Impact of Regimen Simplification and Monotherapy Conversion

Tapering concomitant drugs allowed many patients to reach streamlined therapeutic regimens without losing seizure protection. By the final study visit, seven patients successfully converted to cenobamate monotherapy, representing 9.3% of the cohort. Meanwhile, the remaining 68 patients maintained stable disease control on cenobamate plus one concomitant antiseizure medication. Interestingly, patients who converted completely to monotherapy exhibited a numerically higher seizure-freedom rate of 57.1% compared to 30.9% in the dual-therapy group. Although this difference did not achieve statistical significance, it clearly underscores the viability of single-agent cenobamate therapy in selected individuals. Additionally, the researchers evaluated specific drug combinations to identify optimal partner agents. They observed that cenobamate combined with clobazam yielded the most effective clinical responses. Therefore, rational drug tapering strategies can reduce unnecessary polytherapy while optimizing complementary pharmacodynamic mechanisms.

Tolerability Profile and Pharmacokinetic Interactions

Safety and tolerability remain critical parameters when adjusting complex drug regimens in refractory epilepsy. Overall, adverse events occurred in 73.3% of patients during the observation period. The most frequently reported adverse effects included somnolence in 30.7%, dizziness or vertigo in 28%, and fatigue in 26.7% of individuals. Importantly, none of the reported adverse events led to permanent treatment discontinuation in this carefully monitored cohort. Concomitant drug reductions often helped mitigate central nervous system adverse effects, particularly when clinicians reduced clobazam or sodium channel blockers. Because cenobamate inhibits cytochrome P450 2C19 enzymes, it can elevate active metabolites of clobazam and provoke sedation. Thus, preemptive dose reductions of concomitant medications prevent severe toxicity and facilitate smoother titration schedules. Consequently, understanding these pharmacokinetic interactions enables clinicians to optimize tolerability while sustaining high therapeutic efficacy throughout long-term maintenance therapy.

Practical Clinical Strategies for Epilepsy Management

The findings from the DECREASE analysis provide actionable guidance for modern epileptology and clinical neurology practice. Clinicians managing refractory focal epilepsy should consider introducing cenobamate earlier in the treatment sequence rather than reserving it solely as a final option. When titrating cenobamate, neurologists must adopt a slow and structured dose-escalation schedule to minimize acute adverse events. In addition, practitioners should actively identify opportunities to deprescribe sedating or redundant concomitant antiseizure agents. Reducing background polypharmacy decreases the overall neurotoxic load, improves cognitive function, and enhances patient adherence to treatment. Furthermore, close clinical monitoring during the dose adjustment phase ensures that potential drug-drug interactions remain manageable. Ultimately, integrating cenobamate into structured deprescribing protocols allows clinicians to achieve meaningful seizure reduction while significantly simplifying overall daily treatment regimens.

What were the main findings of the DECREASE study regarding cenobamate?

The DECREASE study evaluated European Early Access Program patients with refractory epilepsy who significantly reduced concomitant antiseizure medications after starting cenobamate. Among 75 patients analyzed, one-third achieved complete seizure freedom and 68% experienced at least a 50% seizure reduction. Furthermore, 9.3% successfully transitioned to cenobamate monotherapy. Importantly, no patients discontinued cenobamate due to adverse events, demonstrating both high efficacy and favorable tolerability during medication reduction.

Which adverse events were most common during cenobamate treatment?

Adverse events occurred in 73.3% of the study cohort, but none prompted treatment discontinuation. The most frequent adverse events were somnolence in 30.7% of patients, dizziness or vertigo in 28%, and fatigue in 26.7%. These adverse reactions typically resolved or improved when clinicians reduced concomitant antiseizure medications. Preemptive dose reductions of partner medications like clobazam helped alleviate central nervous system side effects effectively.

Why is reducing concomitant antiseizure medications beneficial in refractory epilepsy?

Refractory epilepsy patients often take multiple antiseizure medications, which substantially increases the risk of cumulative cognitive impairment, chronic fatigue, and drug-drug interactions. By introducing an effective drug like cenobamate and systematically deprescribing unnecessary background agents, clinicians reduce overall pill burden and toxicity. This therapeutic simplification improves long-term compliance, minimizes adverse reactions, and enhances overall quality of life without sacrificing seizure control.

Disclaimer: This content is for informational and educational purposes only and is not intended as medical advice. Always consult a qualified healthcare professional regarding any medical condition or treatment. Refer to the latest local and national guidelines for clinical practice.

References

Villanueva V et al. DECREASE study: A European pool-analysis of patients with significant reductions in concomitant antiseizure medications in cenobamate Early Access Programs. Epilepsia Open. 2026 Aug 21. doi: 10.1002/epi4.70344. PMID: 42625556.

Roberti R et al. Real-world effectiveness and tolerability of cenobamate in drug-resistant epilepsy: A retrospective analysis of the patients included into the Early Access Programs (EAP) in Germany, France, and United Kingdom. Epilepsia. 2025;66(3):712-723.

Rosenfeld WE et al. Concomitant Antiseizure Medication Dose Reduction and Discontinuation After Starting Cenobamate: A Retrospective Review. Neurology. 2023;100(17 Suppl 2):P4-1.004.