Does evidence support the US Food and Drug Administration class warning of increased risk of suicidality for antiseizure medications approved since 2008?
In this meta-analysis of phase 2 and 3 randomized placebo-controlled epilepsy trials of antiseizure medications approved since 2008, suicidality was evaluated prospectively in trials of 5 antiseizure medications (eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate), including 17 trials involving 5996 patients, including 4000 patients treated with antiseizure medications and 1996 treated with placebo. There was no evidence of increased risk of suicidality (ideation or behavior) overall or for any individual drug.
There is no current evidence that newer antiseizure medications increase suicidality in epilepsy; therefore, a suicidality class warning is not warranted.
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.
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.
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.
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.
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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Klein P, Devinsky O, French J, et al. Suicidality Risk of Newer Antiseizure Medications: A Meta-analysis. JAMA Neurol. 2021;78(9):1118–1127. doi:10.1001/jamaneurol.2021.2480
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