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Meta-Analysis
. 2021 Sep 1;78(9):1118-1127.
doi: 10.1001/jamaneurol.2021.2480.

Suicidality Risk of Newer Antiseizure Medications: A Meta-analysis

Pavel Klein  1 , Orrin Devinsky  2 , Jacqueline French  2 , Cynthia Harden  3 , Gregory L Krauss  4 , Robert McCarter  5 , Michael R Sperling  6
Affiliations
Meta-Analysis

Suicidality Risk of Newer Antiseizure Medications: A Meta-analysis

Pavel Klein et al. JAMA Neurol. .

Abstract

Importance: Most antiseizure medications (ASMs) carry a US Food and Drug Administration-mandated class label warning of increased suicidality risk, based on a meta-analysis comparing suicidality between individuals treated with medications vs placebo in randomized clinical trials done before 2008. ASMs approved since then carry this warning although they were not similarly studied.

Objective: To review all placebo-controlled phase 2 and 3 studies of 10 ASMs approved since 2008 to evaluate the risk of suicidality of these drugs compared with placebo.

Data sources: Primary publications and secondary safety analyses in PubMed of all phase 2 and 3 randomized placebo-controlled epilepsy trials of ASMs approved since 2008, using keywords epilepsy, antiepileptic drugs, seizures, suicidality, suicidal ideation, and the names of individual drugs.

Study selection: All phase 2 and 3 randomized clinical trials of adjunctive treatment of drug-resistant epilepsy and their secondary safety analyses.

Data extraction and synthesis: Articles were reviewed for frequency of suicidality (ideation, attempts, and completed suicides). Mode of suicidality ascertainment included treatment-emergent adverse event reports, Standardized Medical Dictionary for Regulatory Activities queries for events in prespecified categories including suicidal ideation and behavior, prospective collection of suicidality data as a prespecified safety outcome using the Columbia-Suicide Severity Rating Scale, and retrospective evaluation by blinded review using the Columbia-Classification Algorithm of Suicide Assessment. A meta-analysis compared risk for drugs vs placebo of each outcome for all drugs overall and by individual drugs and trials.

Main outcomes and measures: Suicidality (total and by ideation), attempts, and completed suicides.

Results: Excluding studies that did not evaluate suicidality (everolimus and fenfluramine) or did not evaluate it prospectively (lacosamide, ezogabine, and clobazam), 5 drugs were analyzed: eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. Suicidality was evaluated in 17 randomized clinical trials of these drugs, involving 5996 patients, of whom 4000 patients were treated with ASMs and 1996 with placebo. There was no evidence of increased risk of suicidal ideation (drugs vs placebo overall risk ratio, 0.75; 95% CI, 0.35-1.60) or attempt (risk ratio, 0.75; 95% CI, 0.30-1.87) overall or for any individual drug. Suicidal ideation occurred in 12 of 4000 patients treated with ASMs (0.30%) vs 7 of 1996 patients treated with placebo (0.35%) (P = .74). Three patients treated with ASMs and no patients treated with placebo attempted suicide (P = .22). There were no completed suicides.

Conclusions and relevance: There is no current evidence that the 5 ASMs evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Klein reports personal fees from Alliance-Stratus, Aquestive Therapeutics, Arvelle Therapeutics, Abbott, Biogen, Eisai, Engage Therapeutics, Greenwich Pharmaceuticals, Lundbeck, Neurelis, Sunovion, SK Life Science, and UCB Pharma outside the submitted work; grants from US Department of Defense/CURE and National Institutes of Health outside the submitted work; is CEO of PrevEp; and serves as a scientific board member of OB Pharma. Dr Devinsky has received consulting fees from Eisai, Zogenix, and Marinus Pharmaceuticals; grant support from National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, Multidisciplinary University Research Initiative, Centers for Disease Control and Prevention, and National Science Foundation; equity and/or compensation from Tilray, Receptor Life Sciences, Q-State Biosciences, Tevard Biosciences, Script Biosciences, Regel Biosciences, Ritrova, Empatica, Papa & Barkley, Rettco, SilverSpike, and California Cannabis Enterprises; and holds patents for the use of cannabidiol in treating neurological disorders that are owned by GW Pharmaceuticals (Dr Devinsky has waived any financial stake in these patents). Dr French reports grants from Epilepsy Research Foundation, Epilepsy Study Consortium, and National Institute of Neurological Disorders and Stroke during the conduct of the study; grants from Biogen, Cavion, Eisai, Engage, GW Pharmaceuticals, Lundbeck, Neurelis, Cerevel Therapeutics, Ovid Therapeutics, Pfizer, SK Life Sciences, Sunovion, UCB Pharma, Xenon, Zogenix, and grants from National Institute of Neurological Disorders and Stroke outside the submitted work; travel reimbursement from Epilepsy Study Consortium, Epilepsy Foundation, Adamas Pharmaceuticals, Arvelle Therapeutics, Axovant Gene Therapies, Biogen, Blackfynn, Cerevel Therapeutics, Crossject, CuroNZ, Engage Pharma, Eisai, Idorsia, Lundbeck, Neucyte, Neurelis, Novartis, Otsuka Pharmaceutical, Ovid Therapeutics, Pfizer, Redpin, Sage Therapeutics, SK Life Sciences, Sunovion, Takeda Pharmaceuticals, UCB Pharma, Xenon, and Zogenix, outside the submitted work; is on the editorial board of Lancet Neurology and Neurology Today; is chief medical/innovation officer for the Epilepsy Foundation for which NYU receives salary support; and consults and/or attends scientific advisory boards on behalf of the Epilepsy Study Consortium for Adamas Pharmaceuticals, Aeovian Pharmaceuticals, Alterity Therapeutics, Anavex Life Sciences, Arkin Holdings, Arvelle Therapeutics, Athenen Therapeutics/Carnot Pharma, Baergic Bio, Biogen, BioXcel Therapeutics, Cavion, Cerebral Therapeutics, Cerevel Therapeutics, Corlieve Therapeutics, Crossject, CuroNZ, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail Therapeutics, Epalex, Epihunter, Epiminder, Equilibre BioPharmaceuticals, Fortress Biotech, Greenwich Biosciences, GW Pharma, Janssen, Knopp Biosciences, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus, Mend Neuroscience, Merck, NeuCyte, Neurocrine, Neuropace, Otsuka Pharmaceutical Development, Ovid Therapeutics, Passage Bio, Praxis, PureTech LTY, Redpin, Sage, SK Life Science, Sofinnova, Stoke, Supernus, Synergia Medical, Takeda, UCB Pharma, West Therapeutic Development, Xenon, Xeris, Zogenix, and Zynerba. Dr Krauss reports grants from SK Life Science and UCB Pharma during the conduct of the study; has worked as an investigator for Eisai, SK Life Science, UCB Pharma, and has consulted for Arvelle Therapeutics and SK Life Science. Dr Sperling reports grants from Eisai, Medtronic, Neurelis, SK Life Science, Sunovion, Takeda, Xenon, Cerevel Therapeutics, UCB Pharma, and Engage Pharma; personal fees from Neurelis, Medscape, Neurology Live, International Medical Press, UCB Pharma, Eisai, Oxford University Press, and Projects in Knowledge; and consulted for Medtronic with all payments to Thomas Jefferson University outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Risk of Suicidal Ideation
RR indicates risk ratio.
Figure 2.
Figure 2.. Risk of Suicide Attempt
RR indicates risk ratio.
See this image and copyright information in PMC

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