No Evidence of Suicidality Observed With New Antiseizure Medication Use


There was no evidence of increased risk of suicidal ideation or attempt overall or for any individual antiseizure medication in a meta-analysis of 5 newer ASMs.

Pavel Klein, MD

Pavel Klein, MD

A recently conducted meta-analysis of 5 antiseizure medications (ASMs) approved since 2008 showed no evidence of increased suicidality in patients with refractory epilepsy who don’t have a history of suicidality. Investigators concluded that the FDA-mandated suicidality class warning for these drugs is not warranted.1

The study was led by Pavel Klein, MD, director, Mid-Atlantic Epilepsy and Sleep Center, and featured numerous other notable names within the space, including Orrin Devinsky, MD, director, Comprehensive Epilepsy Center, NYU Langone, and Jacqueline French, MD, director, Translational Research and Clinical Trials in Epilepsy, NYU Grossman School of Medicine.

The investigators reviewed publications in PubMed from all phase 2 and 3 randomized clinical trials of eslicarbazepine (Aptiom; Sunovion), perampanel (Fycompa; Eisai), brivaracetam (Briviact; UCB Pharma), cannabidiol (Epidiolex; GW Pharmaceuticals), and cenobamate (Xcopri; SK Life Science) since 2008, using epilepsy, antiepileptic drugs, seizures, suicidality, suicidal ideation, and the names of individual drugs as keywords. Other ASMs including lacosamade (Vimpat; UCB), ezogabine (Potiga; GlaxoSmithKline), clobazam (Sympazan; Aquestive Therapeutics), everolimus (Afinitor Disperz; Novartis), and fenfluramine (Fintepla; Zogenix) were originally included, but later excluded because they did not evaluate suicidality or did not evaluate it prospectively.

Studies were evaluated for mode of suicidality ascertainment, categorized as reporting treatment-emergent adverse event (TEAE), using 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-Classification Suicide Severity Rating Scale, and retrospective evaluation by blinded review using the Columbia-Classification Algorithm of Suicide Assessment.

READ MORE: NYU Langone’s Comprehensive Epilepsy Center Elevates Care Standards, Drug Development

The final analysis included 17 studies of 5 ASMs involving 5996 patients, including 4000 patients treated with ASMs and 1996 treated with placebo. In total, 12 patients (0.30%) treated with ASM had suicidal ideation, compared with 7 of 1996 patients (0.35%) treated with placebo (X2 = 0.108; P = .74). Additionally, 3 patients who received active treatment and no patients treated with placebo attempted suicide (X2 = 1.498; P = .22). Notably, there were no completed suicides.

Investigators not only concluded that the suicidality class warning is no longer warranted, but that “determination and labeling of suicidality risk should be based on evidence from randomized clinical trials and individualized for each new ASM.”

Findings from the meta-analysis also indicated that there is no overall evidence of statistically significantly increased risk of suicidal ideation (overall risk ratio, 0.75 [95% CI, 0.35-1.60]) or suicide attempt (risk ratio, 0.75 [95% CI, 0.30-1.87]) in participants randomized to receive study ASM vs placebo. Risk ratios of suicidal ideation for individual drugs vs placebo were 0.88 for brivaracetam, 1.22 for cenobamate, 0.76 for eslicarbazepine, and 0.47 for perampanel. There were no suicidalities reported with cannabidiol.

The findings from this study provide clarity to an alert issued by the FDA in 2008.2 At the time, a meta-analysis indicated a 1.80-fold increase of suicidality for patients who were on ASMs compared with placebo. The pivotal study included 11 ASMs among 43,892 patients treated for epilepsy, psychiatric diseases, and other diseases. Following the findings, the FDA advisory board concluded that all ASMs “pose an increased risk of suicidality (defined as suicidal ideation and behavior), and prescriptions should be accompanied by a patient medication guide describing this risk.” All ASMs were required to have a warning for suicidality following that announcement.

Klein et al wrote that the recommendations made by the FDA have greatly influenced prescribing and developing new ASMs, with suicidality prominently listed among ASM-related adverse events. With that, patients may be less willing to take ASMs, potentially reducing adherence, a major driver of seizure recurrence, which is associated with increased risk of injury and death.

1. Klein P, Devinsky O, French J, et al. Suicidality risk of newer antiseizure medications. JAMA Neurol. Published online August 2, 2021. doi: 10.1001/jamaneurol.2021.2480.
2. Statistical review and evaluation: antiepileptic drugs and suicidality. US Department of Health and Human Services. News release. Published May 23, 2008. Accessed August 5, 2021.
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