AES 2008: Panel Disputes FDA Finding on Antiepileptics and Risk for Suicide

Allison Gandey

December 08, 2008

December 8, 2008 (Seattle, Washington) — Epilepsy experts are concerned that a recent finding by the US Food and Drug Administration (FDA) that antiepileptic drugs (AEDs) increase the risk for suicide will have dire consequences for patients with epilepsy and potentially the future of antiepileptic drug trials. The group raised its objections at a forum discussion late Friday at AES 2008: American Epilepsy Society 62nd Annual Meeting.

Drs. Andres Kanner, John Barry, Rochelle Caplan, and Jacqueline French among the speakers.

"The concern the FDA has raised has to be looked at with a very strong grain of salt, given the analysis of the data demonstrates methodological problems," session moderator Andres Kanner, MD, from Rush University Medical Center, in Chicago, Illinois, told Medscape Neurology & Neurosurgery.

Results from a recent FDA meta-analysis suggest that patients taking AEDs are significantly more likely to become suicidal. To investigate this issue, the agency looked at 199 placebo-controlled clinical studies including more than 43,000 patients.

The study involved 11 AEDs and found that treated patients had more suicidal thoughts or behavior than patients on placebo (0.43% vs 0.22%, or 2:1 per 1000 patients; 95% CI, 0.7 – 4.2). The study also found the relative risk was higher in patients treated for epilepsy than for selected psychiatric illnesses (3.6 vs 1.6).

But experts presenting at the forum discussion here during the meeting dispute these findings. Dale Hesdorffer, PhD, from Columbia University, in New York, and Anne Berg, PhD, from Northern Illinois University, in DeKalb, argue that the data do not support the FDA conclusions.

After crunching the numbers, Drs. Hesdorffer and Berg told meeting attendees that the study findings are inconsistent across the 11 drugs. The results are also inconsistent by indication and vary greatly between epilepsy and other psychiatric disorders, they said. In addition, the findings are inconsistent by region.

"The increased risk of suicide was not seen in all drugs, and there is no explanation as to why," Dr. Berg said. "This is a bureaucratic, not scientific, decision."

"There is the potential for a lot of damage here," said presenter Rochelle Caplan, MD, a pediatric and adolescent psychiatrist from the University of California, Los Angeles. "Parents are not going to want their children on these medications if they are concerned about an increased risk of suicide. It is unfortunate that the FDA released this information before there are data to substantiate it."

Negative Consequences for Clinical Trials

Presenter Jacqueline French, MD, from New York University Medical Center, said that the FDA decision could also have negative consequences on future clinical trials.

She pointed out there are currently no epilepsy-specific depression scales and many patients are likely suffering from undiagnosed psychiatric comorbidities. She speculated that these patients and others already having suicidal thoughts may be excluded from future trials.

Dr. French points out this could affect sample sizes. "And if these patients are excluded from trials, how will we identify whether there is a suicide signal?" Before adding depression or suicide scales to trials, Dr. French recommends that a pilot study be conducted to determine how these scales will affect the trials.

Despite the panel'sconcerns about the FDA finding, Dr. Kanner emphasized to Medscape Neurology & Neurosurgery that clinicians should remain vigilant in assessing the mental health of patients.

Patients With Epilepsy Have 3-Fold Higher Risk for Suicide

"This doesn't mean that we shouldn't be attentive to the suicidal potential of patients," Dr. Kanner said. "Studies have shown that people with epilepsy have a 3-fold higher risk of suicide. All clinicians have to look for mood and anxiety disorders as part of their evaluation, and if they don't feel comfortable treating patients for this kind of condition, they should refer to a mental health professional."

Dr. Kanner says the impact of comorbid conditions like depression and anxiety on quality of life can be worse than the effect of epilepsy. He recommends the following 3 tools to determine comorbidities:

  • The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E).

  • The Generalized Anxiety Disorder Scale (GAD-7).

  • The module on suicide from the Mini International Neuropsychiatric Instrument (MINI).

Dr. Kanner says 4 key questions can help clinicians assess whether a patient is suicidal:

  • Have you ever thought about committing suicide?

  • If yes, what stops you from doing it?

  • Have you ever tried to kill yourself?

  • Has anyone in your family ever tried to commit suicide?

Certain AEDs Should Be Avoided

John Barry, MD, a psychiatrist at the Stanford University School of Medicine, in California, said that while experts are determining whether AEDs increase the risk for suicide, there are some drugs that appear to be more problematic than others.

Dr. Kanner said he agreed and that barbiturates should be avoided in patients with epilepsy and mental health comorbidities. Drugs such as lamotrigine and topiramate already carry labeling suggesting such risks, he added.

Dr. Kanner concluded, "We need more well-done prospective studies to determine whether AEDs have an impact on the risk of suicide."

Session moderator Dr. Kanner and presenter Dr. French report having financial ties to AED manufacturers. The remaining panelists report no relevant financial relationships.

AES 2008: American Epilepsy Society 62nd Annual Meeting. Presented December 5, 2008.

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