'No Justification' for Suicide Warning on All Antiseizure Meds

Megan Brooks

August 04, 2021

There is currently no evidence that newer antiseizure medications increase the risk for suicide among patients with epilepsy, new research shows.

"There appears to be no justification for the FDA [US Food and Drug Administration] to label every new antiseizure medication with a warning that it may increase risk of suicidality," study investigator Michael R. Sperling, MD, professor of neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, told Medscape Medical News.

"How many patients are afraid of their medication and do not take it because of the warning ― and are consequently at risk because of that? We do not know, but have anecdotal experience that this is certainly an issue," Sperling, who is director of the Jefferson Comprehensive Epilepsy Center, added.

The study was published online August 2 in JAMA Neurology.

Blanket Warning

In 2008, the FDA issued an alert stating that antiseizure medications (ASMs) increase suicidality. The alert was based on pooled data from placebo-controlled clinical trials that included 11 ASMs ― carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide.

The meta-analytic review showed that, compared with placebo, ASMs nearly doubled suicide risk among patients treated for epilepsy, psychiatric disorders, and other diseases.

As a result of the FDA study, all ASMs that have been approved since 2008 carry a warning for suicidality.

However, subsequent analyses did not show the same results, Sperling and colleagues note.

"Pivotal" ASM epilepsy trials since 2008 have evaluated suicidality prospectively. Since 2011, trials have included the validated Columbia Suicidality Severity Rating Scale, they note.

Sperling and colleagues conducted a meta-analysis of 17 randomized placebo-controlled epilepsy trials of five ASMs approved since 2008. These ASMs were eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. The trials involved 5996 patients, including 4000 who were treated with ASMs and 1996 who were treated with placebo.

Confining the analysis to epilepsy trials avoids potential confounders, such as possible differences in suicidality risks between different diseases, the researchers note.

They found no evidence of increased risk for suicidal ideation (overall risk ratio, ASMs vs placebo: 0.75; 95% CI: 0.35 – 1.60) or suicide attempt (risk ratio, 0.75; 95% CI: 0.30 – 1.87) overall or for any individual ASM.

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 who were treated with ASMs attempted suicide; no patients who were 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," the investigators write.

When prescribed for epilepsy, "evidence does not support the FDA's labelling practice of a blanket assumption of increased suicidality," said Sperling.

"Our findings indicate the nonspecific suicide warning for all epilepsy drugs is simply not justifiable," he said. "The results are not surprising. Different drugs affect cells in different ways. So there's no reason to expect that every drug would increase suicide risk for every patient," Sperling said in a statement.

"It's important to recognize that epilepsy has many causes ― perinatal injury, stroke, tumor, head trauma, developmental malformations, genetic causes, and others ― and these underlying etiologies may well contribute to the presence of depression and suicidality in this population," he told Medscape Medical News.

"Psychodynamic influences also may occur as a consequence of having seizures. This is a complicated area, and drugs are simply one piece of the puzzle," he added.

Sperling said the FDA has accomplished "one useful thing with its warning ― it highlighted that physicians and other healthcare providers must pay attention to their patients' psychological state, ask questions, and treat accordingly."

Medscape Medical News reached out to the FDA for comment but had not received a response by press time.

The study had no specific funding. Sperling has received grants from Eisai, Medtronic, Neurelis, SK Life Science, Sunovion, Takeda, Xenon, Cerevel Therapeutics, UCB Pharma, and Engage Pharma; personal fees from Neurelis, Medscape, Neurology Live, International Medical Press, UCB Pharma, Eisai, Oxford University Press, and Projects in Knowledge. He has also consulted for Medtronic outside the submitted work; payments went to Thomas Jefferson University. A complete list of authors disclosures is available with the original article.

JAMA Neurol. Published online August 2, 2021. Full text

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