Suicide and Epilepsy: The Role of Antiseizure Medications

Mental health disorders are common among the 50 million people worldwide living with epilepsy, who also face a substantially higher risk for suicide compared with those without the condition.^2,3

“Patients with epilepsy face a 2 to 3 times higher baseline risk of suicide than the general population, even before treatment is initiated,” said Abrahim “Abe” Razzak, MD, a resident physician in the division of internal medicine at the University of California, San Diego.^3,4 The higher risk in this population is “due to neurobiological differences – limbic dysfunction, [hypothalamic-pituitary-adrenal] axis abnormalities, and serotonergic pathway differences – alongside psychosocial burden.”^2,5,6

Earlier research linking antiseizure medications (ASMs) with suicidality led to a class-wide safety warning on ASMs.^7,8 However, subsequent studies have provided a more nuanced understanding.

Antiseizure Medications and Suicidality

In 2008, the US Food and Drug Administration (FDA) published a meta-analysis of 199 randomized clinical trials to assess the risk of suicidality – defined as suicidal ideation or behavior – associated with 11 ASMs among 43,892 patients with epilepsy, psychiatric disease, pain disorders, or other diseases.⁷

Among those with epilepsy, ASMs were associated with suicidality rates of 3.4 per 1000 patients, compared with 1.0 per 1000 patients with placebo. Based on these results, the FDA required all ASMs approved thereafter to include a safety warning regarding the associated risk of suicidality.⁸

Subsequent studies have sought to clarify the suicide risk associated with various ASMs. In a 2021 meta-analysis, Klein et al examined this risk by analyzing 17 randomized clinical trials focused on 5 newer ASMs – eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. The researchers found no significant increase in the risk for suicidal ideation (risk ratio [RR], 0.75; 95% CI, 0.35-1.60) or suicide attempts (RR, 0.75; 95% CI, 0.30-1.87) when these ASMs were compared with placebo.⁸ The researchers concluded, “There is no current evidence that the 5 ASMs evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning.”⁸

Among other research on the topic, “Observational data is mixed, with some studies suggesting increased risk with gabapentin, lamotrigine, or tiagabine, while others show no association,” Dr Razzak explained.⁹

Dr Razzak and his colleagues also conducted an analysis of ASMs in the FDA Adverse Event Reporting System (FAERS). The study, which examined 25 ASMs, identified “signals for suicidal/self-injurious behavior with diazepam, pregabalin, brivaracetam, gabapentin, clonazepam, zonisamide, lacosamide, and levetiracetam, and the first 4 of these were ‘likely true’ signals by multiple metrics,” Dr Razzak said.¹ “Of note, FAERS data cannot establish causality or incidence but highlight drugs and contexts that merit attention.”

Elucidating Risk and the Need for FDA Warning

Danielle Becker, MD, MS, director of the epilepsy division and associate professor of neurology at The Ohio State University Wexner Medical Center in Columbus, and Dr Razzak both agree that the increased risk for suicidality in patients with epilepsy is largely driven by the disease itself.

Dysregulation and abnormal electrical activity in parts of the brain that regulate mood can contribute to the risk, Dr Becker explained. “I also think the core foundation of what epilepsy takes from patients’ lives – including their independence, livelihood, ability to work or pursue education, and ability to drive – leads to increased risk of depression and suicidality as well.”¹⁰

An estimated 20% of individuals with epilepsy have been diagnosed with anxiety disorders, and 25% have been diagnosed with depression.³

“I believe that the FDA warning does more harm than good for patients with epilepsy,” Dr Becker stated. “We want to prescribe them medications to control their seizures and ultimately improve their life, but have to warn them that these medications may also worsen their mood and cause suicidal ideation.”

“This adds increased stress, confusion, and emotional burden and makes the decision to try new medications, which could be life-changing, much more difficult and scarier, and could potentially reduce adherence,” she continued.

While the suicidality risk associated with ASMs overall may not merit the current class-wide safety warning, some “pharmacovigilance analyses, including ours, did identify drug-specific signals that deserve monitoring,” Dr Razzak noted.¹ “Thus, the best approach is refinement, not removal: Labeling should acknowledge the elevated baseline risk in epilepsy, stress the importance of structured screening, and note that not all ASMs share the same risks.”

Mental Health Screening and Support

Dr Becker and Dr Razzak recommend that providers routinely screen for changes in mood and suicidal ideation in all patients with epilepsy, regardless of which medication they take.

“I recommend screening for depression and anxiety, two of the most common morbidities associated with epilepsy, which often go underdiagnosed and undertreated,” Dr Becker said.

In a study published in 2025 in Epilepsia, Gandy et al found that only 66% of epilepsy care facilities, including clinics and inpatient settings, routinely administered mental health screenings.¹¹ The most frequently used screening tools reported in the study were the Neurological Disorders Depression Inventory for Epilepsy (NDDI‐E) and the Generalized Anxiety Disorder–7.

“The NDDI-E is a specialized screening tool designed to help identify depressive symptoms specifically in individuals with epilepsy,” Dr Becker explained. “The NDDI-E focuses on depressive symptoms while aiming to differentiate them from the potential side effects of ASMs or other epilepsy-related cognitive effects.” 

Along with screening for depression and anxiety, routine screening for suicidality is essential in patients with epilepsy, given the elevated baseline risk in this population, Dr Razzak advised.

“The [Columbia-Suicide Severity Rating Scale] can be used for structured suicidality assessment, and screening should occur at baseline, after starting or adjusting an ASM, and periodically thereafter,” he said.⁸ “When suicidality is suspected, clinicians should assess the acuity of the situation and establish a safety plan. For active suicidal intent, hospitalization must be considered.”

Dr Razzak added that researchers have increased the use of structured suicidality assessments in clinical trials investigating ASMs, per FDA recommendations.^8,14

“By screening patients, encouraging supportive social relationships, and referring patients to cognitive behavioral therapy and mental health services, as well as introducing evidence-based epilepsy self-management programs, we can help reduce epilepsy stigma and improve quality of life for these individuals,” according to Dr Becker.^12,13

Clinicians should aim to optimize each patient’s ASMs while considering psychiatric comorbidity, Dr Razzak said. “[Selective serotonin reuptake inhibitors] and [Serotonin-norepinephrine reuptake inhibitors] are generally safe in epilepsy^15,16 and should be initiated if depression is confirmed, with close follow-up 2 to 4 weeks following medication initiation.”

He emphasized the need to educate patients and families “that epilepsy alone increases risks and that most patients tolerate ASMs safely,” and to encourage medication adherence to reduce withdrawals. He also recommended that clinicians provide additional resources, including information about crisis lines such as 988.*

Looking Ahead: Research and Care Priorities

Along with the ongoing need for routine mental health screenings among all patients with epilepsy, Dr Razzak pointed to several remaining needs regarding the risk for suicidality in this population. These include “standardized suicidality stratification by ASM for epilepsy-specific cohorts, high-quality registry and claims linkage studies to understand absolute risks for treatment initiation and titration, and biomechanistic studies to understand how ASMs interact with suicidality pathways.”

In the meantime, “Recognizing that the risk of suicidal ideation and worsened behavior are part of the epilepsy disease state itself, and not necessarily related to the ASMs, helps diagnose these disorders, provide education, and identify resources to get patients better, necessary care sooner,” Dr Becker said.

*If you or someone you know is struggling or in crisis, help is available. Please call or text the 988 Suicide and Crisis Lifeline at 988, visit 988lifeline.org for crisis chat services, or contact the Crisis Text Line by texting HOME to 741741. Veterans can dial 988 and press 1 to access the Veterans Crisis Line or visit veterancrisisline.net for crisis chat services.