Mid-Atlantic Epilepsy and Sleep Center, Bethesda, Maryland.
NYU Langone School of Medicine, Department of Neurology, New York, New York.
JAMA Neurol. 2021 Sep 1;78(9):1118-1127. doi: 10.1001/jamaneurol.2021.2480.
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.
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.
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.
There is no current evidence that the 5 ASMs evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning.
大多数抗癫痫药物 (ASM) 根据 2008 年前进行的随机临床试验中比较药物治疗与安慰剂治疗个体之间的自杀率的荟萃分析，带有美国食品和药物管理局规定的增加自杀风险的类别标签警告。此后批准的 ASM 虽然没有进行类似的研究，但仍带有此警告。
回顾自 2008 年以来批准的 10 种 ASM 的所有安慰剂对照 2 期和 3 期研究，以评估这些药物与安慰剂相比的自杀风险。
使用“癫痫、抗癫痫药物、癫痫发作、自杀、自杀意念”和个别药物名称等关键词，在 PubMed 中对所有自 2008 年以来批准的 ASM 的 2 期和 3 期随机安慰剂对照癫痫试验的主要出版物和二次安全分析进行了搜索。
所有辅助治疗耐药性癫痫的 2 期和 3 期随机临床试验及其二次安全分析。
文章对自杀意念（意念、尝试和完成自杀）的频率进行了评估。自杀意念确定的方式包括治疗后出现的不良事件报告、对包括自杀意念和行为在内的预定类别事件的标准化医学词典监管活动查询、使用哥伦比亚自杀严重程度评定量表作为预定安全性结局前瞻性收集自杀意念数据，以及使用哥伦比亚分类算法对自杀评估进行盲法回顾。荟萃分析比较了所有药物以及个别药物和试验中药物与安慰剂的每种结局的风险。
自杀意念（总体和通过意念）、尝试和完成自杀。
排除了未评估自杀意念的研究（everolimus 和 fenfluramine）或未前瞻性评估自杀意念的研究（lacosamide、ezogabine 和 clobazam），分析了 5 种药物：eslicarbazepine、perampanel、brivaracetam、大麻二酚和 cenobamate。对这些药物的 17 项随机临床试验进行了自杀评估，涉及 5996 名患者，其中 4000 名患者接受 ASM 治疗，1996 名患者接受安慰剂治疗。没有证据表明自杀意念（总体药物与安慰剂的风险比，0.75；95%CI，0.35-1.60）或尝试（风险比，0.75；95%CI，0.30-1.87）的风险增加，也没有任何个别药物的风险增加。接受 ASM 治疗的 4000 名患者中有 12 名（0.30%）出现自杀意念，接受安慰剂治疗的 1996 名患者中有 7 名（0.35%）（P=0.74）。3 名接受 ASM 治疗的患者试图自杀，没有接受安慰剂治疗的患者试图自杀（P=0.22）。没有完成自杀。
目前没有证据表明本研究评估的 5 种 ASM 会增加癫痫患者的自杀率，因此不需要进行自杀风险类别警告。
