Although the US Food and Drug Administration (FDA) mandates class label warnings of increased suicidality risk for many antiseizure medications, a recent meta-analysis suggests there is no current evidence that eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate increase suicidality risk in patients with epilepsy. Findings from this study were published in JAMA Neurology.

In 2008, the FDA issued a warning regarding antiseizure drugs.  The agency stated these drugs may lead to an increased suicidality risk, which includes suicidal thoughts and behavior. The warning came after analysis data of about 200 trials involving 11 antiseizure drugs found these drugs were associated with an increased risk of suicide compared to their placebo counterparts.

Now, researchers believe it’s time to revisit the FDA-mandated suicidality risk warnings as epilepsy practice and new antiseizure drug development has been impacted.


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The recent meta-analysis included 17 phase 2 and 3 randomized controlled trials which evaluated antiseizure medications in epilepsy. All trials investigated medications that have been approved since 2008, and each trial was required to report on suicidality and/or suicidal ideation to be eligible for inclusion in the meta-analysis.

The analysis included a pooled cohort of 4000 patients assigned to an antiseizure medication and 1996 assigned to placebo. Antiseizure medications included in the analysis were eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate.

Approximately 0.30% (n=12) of the pooled cohort treated with an antiseizure medication had suicidal ideation vs 0.35% (n=7) of people assigned to placebo (χ2 = 0.108; P =.74). There was no difference between the number of patients who received an active therapy vs those who received placebo in regard suicide attempts (χ2 = 1.498; P =.22). No completed suicides were reported.

The meta-analysis revealed no significantly increased risk of suicidal ideation (overall risk ratio [RR], 0.75; 95% CI, 0.35-1.60) or suicide attempt (RR, 0.75; 95% CI, 0.30-1.87) with antiseizure medications vs placebo. When comparing individual drugs to placebo, the RRs of suicidal ideation were 0.88 for brivaracetam, 1.22 for cenobamate, 0.76 for eslicarbazepine, and 0.47 for perampanel.

No suicidalities were reported with cannabidiol. There was a greater number of suicidal ideation reports in patients who received placebo (n=4) compared with those treated with perampanel (n=3), but this was not statistically significant (χ2 = 2.063; P =.15).

Studies in this meta-analysis conducted before 2011 included non-standardized suicidality questionnaires, which the researchers suggest may have limited the “accurate assessment of risk” for these drugs in the meta-analysis.

The researchers add that based on the current level of evidence, the “FDA-mandated suicidality class warning for these drugs is not warranted,” but the “determination and labeling of suicidality risk should be based on evidence from randomized clinical trials and individualized for each new” antiseizure drug.

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.

Reference

Klein P, Devinsky O, French J, et al. Suicidality risk of newer antiseizure medications: A meta-analysis. JAMA Neurol. Published online August 2, 2021. doi:10.1001/jamaneurol.2021.2480 US Department of Health and Human Services. Statistical review and evaluation: antiepileptic drugs and suicidality. Published May 23, 2008. Accessed September 9, 2021.