Suicidality of Newer Antiseizure Medications: A Meta-Analysis

Abstract

Background: Most antiseizure medications (ASMs) carry an FDA-mandated class label warning of increased suicidality risk. This is based on an FDA meta-analysis comparing suicidality between ASM and placebo (PBO)-treated subjects in PBO-controlled randomized clinical trials (RCTs) done up to 2007. New ASMs approved since then carry this warning although they were not similarly evaluated. We review all PBO-controlled phase 2 and 3 studies of 10 ASMs approved since 2008 to compare suicidality between actively vs PBO-treated patients. Methods: We reviewed primary publications and secondary safety analyses of all phase 2 and 3 RCTs in patients with treatment-resistant epilepsy for ASMs approved since 2008 for the frequency of suicidality (ideation, attempts and completed suicides).A meta-analysis compared risk for ASM vs PBO of each outcome for all drugs overall and by individual ASMs and trials. Findings: Excluding RCTs of ASMs which did not evaluate suicidality (everolimus, fenfluramine),or did not evaluate it prospectively (lacosamide, ezogabine, clobazam) we analyzed five ASMs, eslicarbazepine, perampanel, brivaracetam, cannabidiol and cenobamate. Suicidality was evaluated in 17 RCTs of these five ASMs, involving 5996 patients,4,000 actively-treated and 1996 PBO-treated. Twelve of 4000 (0.3%) ASM-treated patients had suicidal ideation, compared with 7/1996 (0.35%) of PBO-treated patients (p=0.75).Three actively treated and no PBO-treated patients attempted suicide (p=0.22).There were no completed suicides. There was no evidence of increased risk of suicidal ideation (ASM versus PBO overall RR=0.75, 95% CI 0.35,1.60) or suicide attempt (RR=0.75, 95% CI 0.30,1.87) overall or for any individual drug. Risk ratios of suicidal ideation for individual drugs vs PBO were 0.76, 0.47, 0.88 and 1.22,respectively,for eslicarbazepine, perampanel, brivaracetam and cenobamate. No suicidalities were reported with cannabidiol. Interpretation: Newer antiseizure medications do not increase suicidality in epilepsy patients. The ASM suicidality class warning is not warranted. Suicidality risk should be evaluated for each medication using validated methods in prospective studies. Labeling should be based on data from such studies and individualized for each new ASM. Funding Statement: None. Declaration of Interests: PK receives grant support from CURE/department of defense. He has received consulting or speaker fees from, or been on advisory boards of Abbot, Aquestive, Eisai, Greenwich Pharmaceuticals, Neurelis, SK Life Science, Sunovion and UCB Pharma. He is on the Medical Advisory Board of Alliance-Stratus, is on Scentific Advisory Board of OB Pharma, and is the CEO of PrevEp, LLC. Orrin Devinsky receives grant support from NINDS, NIMH, MURI, CDC and NSF. He has equity and/or compensation from the following companies: Tilray, Receptor Life Sciences, Qstate Biosciences, Tevard Biosciences, Regel Biosciences, Script Biosciences, Empatica, Engage, Papa & Barkley, Rettco, SilverSpike, and California Cannabis Enterprises (CCE). He has received consulting fees from Eisai and Zogenix. J. French receives NYU salary support from the Epilepsy Foundation and for consulting work and/or attending Scientific Advisory Boards on behalf of the Epilepsy Study Consortium for Aeonian/Aeovian, Anavex, Arvelle Therapeutics, Inc., Athenen Therapeutics/Carnot Pharma, Axovant, Biogen, BioXcel Therapeutics, Blackfynn, Cerebral Therapeutics, Cerevel, Crossject, CuroNZ, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epiminder, Epitel, Fortress Biotech, Greenwich Biosciences, GW Pharma, Ionis, Janssen Pharmaceutica, Knopp Biosciences, Lundbeck, Marinus, Mend NeuroscienceMerck, NeuCyte, Inc., Neurocrine, Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Passage Bio, Pfizer, Praxis, Redpin, Sage, SK Life Sciences, Sofinnova, Stoke, Sunovion, Supernus, Takeda, UCB Inc., Xenon, Xeris, Zogenix. J. French has also received research grants from Biogen, Cavion, Eisai, Engage, GW Pharma, Lundbeck, Neurelis, Ovid, Pfizer, SK Life Sciences, Sunovion, UCB, Xenon and Zogenix as well as grants from the Epilepsy Research Foundation, Epilepsy Study Consortium, and NINDS. She is on the editorial board of Lancet Neurology and Neurology Today. She is Chief Medical/Innovation Officer for the Epilepsy Foundation for which NYU receives salary support. She has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Arvelle Therapeutics, Inc., Biogen, Cerevel, Engage, Lundbeck, NeuCyte, Inc., Otsuka, Sage, UCB, Xenon, Zogenix. Cynthia Harden is employed by Xenon Pharmaceuticals Inc. Gregory Krauss has worked as an investigator for Cerevel Therapeutics, Eisai Labs, EpiWatch, Inc. SK Life Sciences, UCB Pharma, and as a consultant for Arvelle Therapeutics, NeuroCyte, Inc. Pled Pharma, and SK Life Science. He is a director of and owns equity in EpiWatch, Inc. Robert McCarter receives grant support from CHF/O’Malley Foundation and from NIH, and receives research support from Johns Hopkins University. Michael Sperling receives research grant and contracts from NIH, UCB Pharma, SK Life Sciences, Takeda, Neurelis, Engage Therapeutics, Medtronic, Eisai, Cavion, Cerevel, and Xenon. He has consulted for the Medtronic and the Epilepsy Study Consortium. He has received speaker fees from Eisai, Medscape, NeurologyLive, UCB Pharma, Projects in Knowledge.