By Pegah Afra, MD
Associate Professor of Neurology, Weill Cornell Medical College; Associate Attending Neurologist; NewYork-Presbyterian Hospital; Adjunct Associate Professor, University of Utah
SYNOPSIS: This study reports data that refutes the U.S. Food and Drug Administration’s class warning regarding suicidality risk in patients with epilepsy who are taking the newer antiepileptics, approved since 2008. The class warning should be reconsidered.
SOURCE: Klein P, Devinsky O, French J, et al. Suicidality risk of newer antiseizure medications: A meta-analysis. JAMA Neurol 2021;78:1118-1127.
The U.S. Food and Drug Administration (FDA) issued a class warning for antiseizure medications (ASMs) in 2008 regarding their increased suicidality risk (1.80-fold). This was based on meta-analysis of pooled data from 199 randomized, placebo-controlled clinical trials involving 11 ASMs: carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. There were a total of 43,892 patients in these 199 randomized placebo-controlled trials: 16,029 in the pooled placebo arm and 27,863 patients in the pooled drug arm (including 10,942 patients with epilepsy, 11,796 patients with psychiatric disorders, and 21,154 with other disorders [mainly pain]).1
Suicidality occurred in 4.3/1,000 patients in the pooled drug arm compared with 2.2/1,000 patients in the pooled placebo arm, with a risk difference of 2.1 per 1,000. In patients with epilepsy, suicidality rates were 3.4/1,000 with ASM treatment vs. 1/1,000 with placebo. Additionally, there were four completed suicides, all in the pooled drug arm (two patients with epilepsy and two patients with psychiatric disorders). 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.”2 These recommendations have resulted in an FDA-mandated warning for suicidality in ASMs developed after 2008.2 This class warning has influenced clinical practice as well as ASM investigational trial designs after 2008, including systematic and standardized assessment of suicidality done in clinical trials after 2011.
In this study by Klein et al, the risk of suicidality of newer ASMs (vs. placebo) was evaluated by reviewing all Phase II and III placebo-controlled adjunctive treatment trials of 10 ASMs approved after 2008. Primary articles were obtained and reviewed for frequency of suicidality, in total as well as in subcategories (frequency of suicidal ideation, attempts, and completed suicides). Studies that did not evaluate suicidality (everolimus and fenfluramine) or did not evaluate it prospectively (lacosamide, ezogabine, and clobazam) were excluded. Therefore, five ASMs were included: eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate.
These five ASMs were evaluated in 19 studies (16 pivotal [Phase II or III studies] and three nonpivotal studies and included three eslicarbazepine, four perampanel, six brivaracetam, four cannabidiol, and two cenobamate studies. Two of the four cannabidol studies were excluded because of the absence of suicidality evaluation, leaving 17 studies included. These 17 studies had 5,996 patients, and suicidality was evaluated in 4,000 patients treated with ASMs vs. 1,996 patients treated with placebo in the following subcategories:
- Suicidal ideation: Present in 12/4,000 (0.30%) patients treated with ASM compared with 7/1,996 (0.35%) patients treated with placebo (χ2 = 0.108; P = 0.74);
- Suicidal attempts: Present in 3/4,000 (0.075%) patients treated with ASM compared with no patients treated with placebo attempted suicide (χ2 = 1.498; P = 0.22);
- Completed suicide: There were no completed suicides in either group.
There was no evidence of bias or heterogeneity between the placebo and treatment groups. The study found no evidence that the five ASMs (eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate) evaluated in this study increase suicidality in patients with epilepsy and, therefore, the FDA’s suicidality class warning for these five ASMs does not seem to be warranted.
The FDA suicidality class warning issued in 2008 has affected both clinical management of epilepsy and ASM drug development. The FDA pooled analysis of 199 trials that was the basis of the suicidality class warning had its own methodological limitations, which are outside the scope of this commentary.3 Overall, the 2008 issued class warning can influence clinical practice by affecting a patient’s decision to start or adhere to ASMs (potentially increasing the risk of sudden unexpected death in epilepsy [SUDEP]). The risk of uncontrolled seizures may be higher than the risk of suicidality from the ASMs.
It also has altered clinical trials. Since 2013, all Phase I-III clinical trials have excluded patients with suicidal risk. The risk is higher in patients with uncontrolled epilepsy, resulting in a significant proportion of patients with uncontrolled epilepsy being excluded from these trials. It also makes it impossible to evaluate whether ASMs affect suicidality in these high-risk patients. As a result of mandating suicidality evaluations, many of the ASM clinical trials done after 2008 evaluate suicidality in a prospective manner. More specifically, studies conducted between 2008 and 2011 did not assess suicidality in systematic and standardized ways, while studies conducted in 2011 and thereafter did.
Pooling this prospective suicidality data for the five ASMs listed earlier, the authors did not find any evidence to support the FDA’s original class ruling for suicidality. This important finding may affect future development of ASM clinical trials, as well as clinical practice.
- U.S. Department of Health and Human Services. Statistical review and evaluation: Antiepileptic drugs and suicidality. https://www.fda.gov/files/drugs/published/Statistical-Review-and-Evaluation--Antiepileptic-Drugs-and-Suicidality.pdf
- Busko M. FDA advisory members agree antiepileptics pose suicidality risk, nix need for black-box warning. Medscape. Published July 11, 2008. https://www.medscape.com/viewarticle/577432
- Hesdorffer DC, Kanner AM. The FDA alert on suicidality and antiepileptic drugs: Fire or false alarm? Epilepsia 2009;50:978-986.