Suicidality Risk of Newer Antiseizure Medications

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.

Pharmacokinetics and safety of cenobamate, a novel antiseizure medication, in healthy Japanese, and an ethnic comparison with healthy non‐Japanese

“…However, these results are thought to be meaningful in evaluating the drug‐related effects for exploratory purposes, and it has recently been reported that there is no clear evidence of an increased risk of suicidality with cenobamate. 31 The safety results from this study indicate that cenobamate may become an alternative ASM with reasonable exposure and tolerability profiles in Japanese.…”

Critical Appraisal of Cenobamate as Adjunctive Treatment of Focal Seizures in Adults

“…There is a suspect that all ASMs, as a class and across all ranges of indications, may be associated with a small increment of suicidal thoughts or behaviour 32 even though a more recent analysis failed to confirm this finding. 33 In the open-label CNB study, 16 [34][35][36][37][38] are still not available. Hence, we do not know how many drug-resistant patients with focal epilepsies that achieved seizure freedom over few months in the randomized, double-blind studies will keep on without seizures over the years.…”

Suicidality: Once Again, Don’t Blame the Drug Class

“…Is it possible that there is a systematic difference in suicidality effects between the drugs considered in the FDA report 2 and the newer drugs considered in the Klein et al publication? 1 That is unlikely. No excess risks of suicide attempt nor completed suicide were discovered among patients taking ASMs, including many patients taking one of the same 5 newer ASMs, in an analysis of medical records in the United Kingdom (“suicidality” could not be measured from these medical records).…”

“…Klein and coauthors have reported a metanalysis of suicidality associated with the use of 5 newer antiseizure medications (ASMs) using data from the randomized clinical trials (RCTs), and have concluded that there was no statistical association of any of these drugs with suicidality. 1 They were able to do so with confidence because all clinical trials of ASMs after 2008 were required to measure suicidality specifically and prospectively, usually with the Columbia suicidality risk scale. Many earlier RCTs included no specific measurements of suicidality before or after drug assignment, and suicidality was thus detectable only from open-ended enquiry about side effects.…”

“…Warnings were then added to the labeling of all ASMs, for example, this wording from a package insert: “ Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation” . This FDA report has been critiqued in detail in this journal and others, 3 - 6 but it is important to review the main objections in order to understand the results from Klein et al 1 A central criticism of the FDA report is that it was illogical to combine results from trials of drugs of very different chemical classes and mechanisms of action. Other criticisms were based on perceived statistical flaws.…”