Newer Antiseizure Medications and the Risk of Suicidality

The US Food and Drug Administration (FDA) has required a warning for increased risk of suicide for most antiseizure medications since 2008. The warning is based on a meta-analysis of randomized placebo-controlled trials for older medications. Newer antiseizure medications also carry this warning, although risk of suicidality for these drugs was not specifically studied. In this new study, Klein and colleagues conducted a meta-analysis of the risk of suicidality in patients with epilepsy from randomized clinical trials for newer antiseizure medications.

The studies included in the analysis were for antiseizure medications for treatment-resistant epilepsy that were approved after 2008. All were phase 2 or phase 3, randomized, double-blind, placebo-controlled clinical trials that evaluated suicidality prospectively.

The investigators found 5 new-molecule antiseizure medications approved by the FDA since 2008 that were tested in clinical trials that included prospective evaluations for suicidality: eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. They identified 17 studies for analysis. A total of 4000 patients from these 17 studies were treated with 1 of these 5 antiseizure medications and 1996 patients received placebo.

The investigators examined the studies for data on suicidal ideation, suicide attempts, and completed suicides. Suicidal ideation occurred in 12 (0.30%) patients taking antiseizure medications and 7 (0.35%) patients taking placebo (P = .74). In addition, 3 (0.08%) patients taking antiseizure medications and none taking placebo attempted suicide (P = .22). Finally, no completed suicides were reported in any of the 17 studies (P >.99).

Thus, the risk of total suicidality (ideation, attempts, and completed suicides combined) was not significantly different between participants who received antiseizure medications and those who received placebo. The researchers also did not find any significant differences between groups when the 5 antiseizure medications were evaluated individually.

The investigators contended that the 2008 FDA warning was based on a meta-analysis of studies that included retrospective reports, nonstandardized definitions of suicidality, both adjunctive and monotherapy designs, and varying diagnoses, and it did not account for suicidality at baseline. More recent trials, such as those analyzed in this meta-analysis, have had more consistent and standardized methodologies to evaluate suicidality compared with the trials included in the 2008 meta-analysis.

The researchers expressed concerns about the consequences of the FDA warning, such as the refusal of some patients to take antiseizure medications due to perceived risk of suicide, increased anxiety in patients taking antiseizure medications, exclusion of patients with suicide risks from clinical trials, and requirements for suicidality evaluations in clinical trials that have not been validated in cognitively impaired patients.

“The prominent ASM suicidality warning since 2008 may do more harm than benefit. Our analysis found no evidence to support such warning for the 5 new ASMs we evaluated,” the investigators concluded.

Source

Klein P, Devinsky O, French J, et al. Suicidality risk of newer antiseizure medications: a meta-analysis. JAMA Neurol. 2021;78(9):1118-1127.