Certain Anticonvulsants Linked to Increased Risk for Suicide, Violent Death

Pauline Anderson

April 20, 2010

April 20, 2010 — A new study has found a link between certain anticonvulsant medications and increased risk for attempted or completed suicide or violent death.

In this exploratory analysis, researchers report that compared with topiramate as a reference drug, use of gabapentin, lamotrigine, oxcarbazepine, and tiagabine was associated with an increased risk for suicidal acts or violent death.

The hope is that the study results may help guide physician-prescribing habits and encourage them to weigh more closely the risks and benefits of prescribing anticonvulsant agents, said lead study author, Elisabetta Patorno, MD, MPH, from the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

"The main purpose of the study was to try to find some differences among the various anticonvulsive agents in order to provide physicians with additional knowledge and information on what kind of medication to prescribe according to the specific diseases of their patients," Dr. Patorno said.

The study is published in the April 14 issue of the Journal of the American Medical Association.

Consistent With FDA Report

The study results are consistent with those of a 2008 US Food and Drug Administration (FDA) meta-analysis that found patients taking anticonvulsant drugs had about twice the risk for suicidal behavior or ideation vs patients receiving placebo. After publication of that study, the FDA required new labeling.

Although the FDA study provided a general statement about a class of medications, this current analysis found differences among specific drugs, said Dr. Patorno.

The message we would like to send out is that physicians should balance the risks and benefits of a specific medication.

However, these new study results "absolutely" do not mean that physicians should cease prescribing certain anticonvulsants, said Dr. Patorno. "These are well-established medications, and they have lot of benefits. The message we would like to send out is that physicians should balance the risks and benefits of a specific medication. They should decide what is the medication that best fits the needs of a specific patient, according to the disease they're treating."

She pointed out that these agents are used not just for epilepsy but for a wide range of other conditions, including severe pain syndromes. In the case of a patient desperate for pain relief, Dr. Patorno said she would tell physicians, again, to weigh the risks and benefits of prescribing a specific anticonvulsant agent.

Of course, these risks and benefits should be part of the discussion with the patient, added Dr. Patorno. She recommends that physicians inform a patient of possible risks at the time of initiating a new prescription and then closely monitor the patient for early symptoms that could be linked to the drug. "They should be looking for any change in mood, any change in terms of new depressive symptoms, or new anxiety symptoms," she said.

Topiramate Reference Drug

The cohort study compared the risk for suicidal acts or violent death in patients 15 years or older who started taking an anticonvulsant medication between July 2001 and December 2006 with the risk in patients who started taking a reference anticonvulsant drug. Topiramate was chosen as the primary reference drug because it is the second most commonly used agent in the study population and is used for a wide range of indications but is not commonly used as a first-line therapeutic approach in epilepsy.

Anticonvulsant drugs considered included the following: carbamazepine, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, tiagabine, topiramate, valproate, and zonisamide.

Anticonvulsant drugs are the main therapeutic agents used to treat epilepsy, but they are also used for bipolar disorder, mania, neuralgia, migraine, and neuropathic pain. Off-label use is increasing, the study authors note.

Data included medical and pharmacy claims from the HealthCore Integrated Research Database (HIRD), which represents all filled prescriptions and clinical encounters from health plans in the Southeastern, Mid-Atlantic, Central, and Western regions of the United States.

Identifying Suicides

Researchers identified suicide attempts through emergency department visits and hospitalizations. They cross-checked HIRD with the US Social Security Administration Master Death Index to determine which members of the HIRD had died. Suicides are reliably documented on death certificates.

The researchers identified 297,620 new treatment episodes of anticonvulsant medications. The most frequently prescribed medications were gabapentin (48.0%) followed by topiramate (19.4%), lamotrigine (7.5%), and valproate (6.2%).

Patients beginning to take topiramate were more likely to be female, to have had a diagnosis of migraine, and to have used antimigraine medication in the previous 6 months. New users of other anticonvulsants were more likely to have had diagnoses of epilepsy, neuropathic pain, depression, manic depressive disorder, or anxiety and to have used antidepressant, antipsychotic, and analgesic medications.

The study uncovered 827 attempted or completed suicides and 868 combined attempted or completed suicides or violent deaths within 180 days after initiation of any anticonvulsant medication. The risk for attempted or completed suicide was increased for gabapentin, lamotrigine, oxcarbazepine, tiagabine, and valproate.

Table. Risk for Attempted or Completed Suicide by Treatment vs Topiramate

Drug HR (95% CI)
Gabapentin 1.42 (1.11 – 1.80)
Lamotrigine 1.84 (1.43 – 2.37)
Oxcarbazepine 2.07 (1.52 – 2.80)
Tiagabine 2.41 (1.65 – 3.52)
Valproate 1.65 (1.25 – 2.19)

CI = confidence interval; HR = hazard ratio

Extending the follow-up to 360 days yielded no substantive differences.

A secondary analysis confirmed the increased risk and identified an excess of 5.6 cases of attempted or completed suicide among new users of gabapentin, 10.0 cases among new users of oxcarbazepine, and 14.1 cases among new users of tiagabine compared with topiramate — all per 1000 person-years.

The risk remained increased for gabapentin in subgroups of younger and older patients, patients with mood disorder, and patients with epilepsy or seizure disorder.

Dr. Patorno and her colleagues found an increased risk for suicidal acts beginning within the first 14 days after treatment initiation, suggesting that anticonvulsant medication could induce behavior effects before the achievement of their full therapeutic effectiveness.

Methods Questioned

Reached for a comment, Andres M. Kanner, MD, professor of neurological sciences at Rush Medical College and associate director of the Section of Epilepsy and Rush Epilepsy Center at Rush University Medical Center, Chicago, Illinois, questioned the methods used by the study authors.

It might not have been the drugs themselves but the conditions for which they were prescribed that accounted for the increased suicide risk, he suggests. Most of the drugs linked to increased suicidality in the study were used to treat mood or other psychiatric disorders, whereas the comparison drug, topiramate, was used to treat migraines, said Dr. Kanner.

"It's a well-established fact that patients with a prior psychiatric history exposed to topiramate have an increased risk of having psychiatric adverse events," Dr. Kanner told Medscape Neurology. "It's very possible that in this study, patients with migraines who had a previous psychiatric history were not assigned to topiramate because of its known negative psychotropic properties.

"If you're using topiramate only for people with migraines, you're going to have less chance that they’ll have psychiatric adverse events," he noted.

Dr. Kanner has served as coordinator of a psychiatry special interest group for the American Epilepsy Society and has expressed doubts that the FDA warning, based on the previous meta-analysis, should apply to all such drugs.

He added that it would have been helpful in this study to see a multivariate analysis that demonstrated the degree to which each indication contributed to the variance in the risk for suicide.

In response to Dr. Kanner’s comments, Dr. Patorno said the primary analysis adjusted for an exhaustive list of anticonvulsant medication indications that may be associated with increased risk for suicidal acts, including preexisting psychiatric disorders. And a secondary analysis, which used a high-dimension propensity score that allows adjusting for large numbers of baseline covariates, including preexisting psychiatric diagnoses, confirmed these results.

Furthermore, said Dr. Patorno, although new recipients of lamotrigine, oxcarbazepine, and tiagabine had a higher proportion of diagnosis and treatment for depressive and manic depressive disorders than topiramate recipients at baseline, this pattern was not identifiable for gabapentin.

She reiterated that the FDA meta-analysis, which included data from 199 placebo-controlled clinical trials, had results compatible with her own.

Still, Dr. Kanner maintains that the only way to establish the real increased risk for suicide in patients taking anticonvulsant agents is through a prospective study in which people with epilepsy, mood disorders, migraine, or other pain syndromes are randomly assigned to one of these drugs irrespective of their prior psychiatric profile.

"We did evaluate the increased risk of suicidal acts associated with anticonvulsant drugs prospectively by identifying suicidal events following the initiation of anticonvulsant treatment in a population of anticonvulsants new initiators," Dr. Patorno responded. "Prevalent users of anticonvulsant medications were not included in our study."

The mechanism by which these medications act is very complex, Dr. Patorno added. "These agents have some psychotropic effects in the sense of mood modification, but it's hard to hypothesize something more solid than that right now," she said. Further investigation to learn the exact mechanism would be "very helpful," she added.

In past research, gabapentin and lamotrigine have been linked to behavioral problems, such as aggression and hyperactivity, particularly in children and adults with learning disabilities and cognitive impairment. Tiagabine has been found to produce nervousness and depressive mood.

The study was supported by the HealthCore Fellowship in Pharmacoepidemiology and the Pharmacoepidemiology Research and Training Fund of the Harvard School of Public Health. Study coauthors Rhonda L. Bohn, MPH, ScD, and Peter M. Wahl, MLA, MS, reported being employed by HealthCore Inc, a subsidiary of WellPoint, through the study execution. Dr Bohn reported that she has recently left the company and works as an independent consultant. Sebastian Schneeweiss, MD, ScD, reported being a paid member of the scientific safety advisory boards of HealthCore Inc and ii4sm; being a paid consultant to HealthCore, World Health Information Science Consultants, and RTI International; and having received an investigator-initiated research grant on the safety of nonsteroidal anti-inflammatory drugs from Pfizer. No other disclosures were reported. Dr. Kanner is an uncompensated member of the editorial advisory board of Medscape Neurology. He reports that he has received research grants from GlaxoSmithKline, and Novartis Pharmaceuticals Corporation. Dr. Kanner has also disclosed that he has served on the advisory boards of GlaxoSmithKline, UCB Pharma Inc, and Ortho-McNeil Inc. Dr. Kanner has also disclosed he has served on the speaker's bureaus of GlaxoSmithKline, UCB Pharma Inc, Pfizer Inc, and Ortho-McNeil Inc.

JAMA. 2010;303:1401-1409.

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