New Evidence of Suicidal Thinking and Behavior In Patients Using Anti-Epileptic Drugs

In July 2008, a committee of independent experts advised the Food and Drug Administration (FDA) to review new evidence concerning increased risk of suicidal thinking and behavior in patients using anti-epileptic drugs (AEDs).

The committee recommended a warning be placed in the “Warnings” section of all AED labels, and that a guide for patients, called a Medication Guide, be developed. However, they wrongly opposed adding a black-box warning (the FDA’s most prominent warning) to the label of all AEDs notifying consumers of this association between the drugs and suicidal behavior.

Many AEDs are used to treat epilepsy, but they are also used to treat pain and as mood stabilizers in people with manic-depressive disorders.

Meta-analysis of AED studies leads to discovery of suicidal behavior

Early in 2005, the manufacturer of an AED alerted the FDA of an increased incidence in suicide-related events in a placebo-controlled trial of its drug. In response, the FDA asked other sponsors of AEDs to provide data from their clinical trials comparing AEDs to placebo. 

The FDA received data on 199 randomized trials, involving over 43,000 subjects, in which patients got either one of these drugs or a placebo. The studies represented 11 AEDs (out of about 43 drugs currently approved for epilepsy): carbamazepine (TEGRETOL, EPITOL, CARBATROL, TERIL), divalproex sodium (DEPAKOTE), felbamate (FELBATOL), gabapentin (NEURONTIN), lamotrigine (LAMICTAL), levetiracetam (KEP- PRA), oxcarbazepine (TRILEPTAL), pregabalin (LYRICA), tiagabine (GABITRIL), topiramate (TOPA- MAX) and zonisamide (ZONE- GRAN). Notably, phenytoin (DI- LANTIN), a commonly prescribed anti-epileptic, was not among the drugs studied.  

One-third of the trials were for the treatment of epilepsy; the rest were for psychiatric or other uses such as chronic pain or fibromyalgia. When the trials were combined statistically, a technique called meta-analysis, only four completed suicides were reported — all in the AED group, but not enough to be statistically significant. However, an analysis focused on suicidal behavior or ideation revealed a statistically significant doubling of the risk: 0.37% of patients in the AED group experienced suicide-related events, compared to 0.22% of patients taking placebo. Among patients taking AEDs for epilepsy, the risk was 3.5 times greater compared to placebo. With this analysis in hand, the FDA released an alert in January 2008, and convened an advisory committee in July to address the need for further measures.

Although many committee members had reservations regarding the methods used to collect the data, they agreed with the FDA’s analysis and decided that the findings should apply to all AEDs — not just those studied.

Recommendations not strong enough

The committee also agreed that consumers had to be alerted to the small yet potentially fatal side effect. But citing fears that a black-box warning could lead to changes or discontinuation of medication, with deleterious consequences for patients, the committee voted against a blackbox warning in favor of a notification in the drug label and a patient-friendly Medication Guide.

Unfortunately, the committee’s actions fall short of the intended goal of adequately warning patients of the increased risk of suicide-related events. If enough concern existed for them to vote for the other two measures, a black-box warning should have been added to all AEDs, and the FDA should have required that a letter be sent to physicians urging them to speak with their patients about these risks as soon as possible. 

What You Can Do

These drugs may increase the risk of suicidal behaviors and actions. The following are recommendations from the FDA:

• Do not make any medication regimen changes without consulting your provider. Unsupervised sudden changes in prescription drugs can have dangerous adverse effects.

• Be mindful of any day-to-day changes in mood, behavior or actions.

• Pay attention to common warning signs that may indicate an increased risk of suicide, including: talking or thinking about hurting oneself or ending one’s life; withdrawal from family and friends; worsening depression; increased preoccupation with death and dying; giving away prized possessions.

• If you see or experience any of these warning signs, contact your provider immediately.