Disclosures: Klein reports numerous relevant financial disclosures. Please see the study for his and all other authors’ relevant financial disclosures.
August 09, 2021
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'No evidence' newer antiseizure medications increase risk for suicidality

Disclosures: Klein reports numerous relevant financial disclosures. Please see the study for his and all other authors’ relevant financial disclosures.
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Five newer antiseizure medications approved since 2008 did not increase suicidality risk among people with epilepsy, according to results of a meta-analysis published in JAMA Neurology.

Pavel Klein

“The FDA has a class warning for all antiseizure medications that they increase the risk for suicidality based on a study the FDA did in 2008,” Pavel Klein, MD, FAAN, FAES, director of the Mid-Atlantic Epilepsy and Sleep Center in Maryland and clinical professor in the department of neurology at George Washington University, told Healio Neurology. “Since then, a number of newer antiseizure medications have been approved by the FDA, and they also carry this class warning; however, they have not been studied to see whether they increase suicidality risk, and yet the warning applies to them also. The suicidality warning for all antiseizure medications, as a class of drugs, is important, as it causes concern among a number of patients who may be reluctant to use the medications because of it.”

Klein noted that those who avoid taking antiseizure drugs over concerns related to the suicidality class label warning may then have less controlled or uncontrolled seizures. As a result, “paradoxically, the warning could potentially harm some patients,” he said.

In the current study, Klein and colleagues aimed to determine whether the newer antiseizure medications warrant this warning. They reviewed primary publications and secondary safety analyses in PubMed of all placebo-controlled phase 2 and 3 randomized trials of 10 antiseizure medications approved since 2008 to assess the risk for suicidality of these drugs compared with placebo. They used the keywords epilepsy, antiepileptic drugs, seizures, suicidality, suicidal ideation and the names of individuals drugs.

Klein and colleagues also reviewed articles for frequency of suicidality, which they categorized into ideation, attempts and completed suicides. When ascertaining mode of suicidality, they included treatment-emergent adverse event reports; Standardized Medical Dictionary for Regulatory Activities queries for events in prespecified categories, such as suicidal ideation and behavior; prospective collection of suicidality data as a prespecified safety outcome via the Columbia-Suicide Severity Rating Scale; and retrospective evaluation by blinded review via the Columbia-Classification Algorithm of Suicide Assessment. In the meta-analysis, they compared risk for drugs with that of placebo of each outcome for all drugs overall, as well as by individual drugs and trials.

After excluding studies that did not assess suicidality at all or did not do so prospectively, Klein and colleagues analyzed data from 17 randomized clinical trials that included the drugs eslicarbazepine, perampanel, brivaracetam, cannabidiol and cenobamate. The studies involved 5,996 total patients, of whom 4,000 were treated with antiseizure medications and 1,996 with placebo.

The researchers found no evidence of increased risk for suicidal ideation (drugs vs. placebo overall RR = 0.75; 95% CI, 0.35-1.6) or attempt (RR = 0.75; 95% CI, 0.3-1.87) overall or for any individual drug. A total of 12 of 4,000 patients (0.3%) treated with antiseizure medications had suicidal ideation compared with seven of 1,996 patients (0.35%) treated with placebo. Three patients treated with antiseizure medications and none treated with placebo attempted suicide. The researchers reported no completed suicides.

“There is no evidence that the newer antiseizure medications increased the risk for suicidality,” Klein said. “Patients and health care providers therefore do not need to be concerned about that possibility.”