Some Anti-Seizure Drugs Associated with Higher Risk of Suicide

Some anti-seizure drugs used to treat epilepsy as well as depression, chronic pain, migraine, bipolar disorder, and other conditions are associated with a higher risk of suicide and violent death than other drugs in the same class, according to a new study. Experts caution that patients should not stop taking the drugs, which include gabapentin (Neurontin), lamotrigine (Lamictal), oxcarbazepine (Trileptal), tiagabine (Gabitril), and valproate (Depakote), without their doctor’s permission. Anne Harding of writes that it’s still not clear whether these risks are related to the drugs themselves or to underlying mood problems. Suicidal thinking and acts are “very, very rare,” says Carl Bazil, MD, a professor of clinical neurology and the director of the Columbia Comprehensive Epilepsy Center, in New York City. “The vast majority of patients do not have anything like that.” Dr. Bazil was not involved in the research. The study, published this week in the Journal of the American Medical Association, echoes a 2008 review by the U.S. Food and Drug Administration (FDA) that found that taking anticonvulsants (as this class of drugs is known) roughly doubled the risk of suicidal thoughts and suicide attempts, although the absolute risk remained small — less than half of 1 percent. According to the FDA analysis, which included 11 anticonvulsants, the risk that a person taking those drugs would exhibit suicidal behavior or have suicidal thoughts was about 1 in 230, compared to about 1 in 450 in people taking a placebo, the FDA found. As a result, the FDA required that the label of all anticonvulsants carry a warning about this increased risk. (The agency stopped short of requiring a so-called black box warning similar to those found on the labels of other antidepressant drugs, however.) The use of anticonvulsants has risen in recent years, among adults as well as children and teens. Doctors are increasingly prescribing the drugs off-label, meaning the drugs are not officially approved by the FDA for that condition. In the new study, a team of researchers led by Elisabetta Patorno, MD, a research fellow at Brigham and Women’s Hospital, in Boston, looked at prescription data for 13 different anticonvulsants from health plans across the country and compared them to federal death records and data on emergency room visits and hospitalizations. Of more than 2 million prescriptions filled in the five-year study period, the researchers looked at 297,620 new prescriptions. Among people who received the drugs, there were 801 suicide attempts, 26 suicides, and 41 violent deaths. (The researchers did not track suicidal thoughts, as did many of the trials considered by the FDA.) Unlike the FDA report, which looked at the class of drugs as a whole, Dr. Patorno and her colleagues analyzed the risk of suicidal behavior associated with specific drugs. They compared the drugs to one in the class — topiramate (Topamax) — because it is widely used and prescribed for a range of conditions. The risk of completed or attempted suicide among people taking tiagabine was 2.5 times greater than it was among those taking topiramate, while the risk among people taking oxcarbazepine was twice as great, the study found. The risk of completed or attempted suicide was also higher among people taking lamotrigine, valproate, or gabapentin, compared to topiramate. In all, 5 of the 12 drugs compared with topiramate were found to increase the risk of suicidal behavior. Although they are often considered as a class, anticonvulsants in fact have varied mechanisms and effects, says Andres M. Kanner, MD, a professor of neurological sciences and psychiatry at Rush Medical College, in Chicago. Valproate and lamotrigine tend to stabilize mood, for instance, while pregabalin (Lyrica) — which was not found to increase suicide risk in the study — has antianxiety effects, he says. “These drugs definitely are being used more and more by psychiatrists to treat patients with a variety of psychiatric disorders, but primarily mood and anxiety disorders,” says Dr. Kanner. Because having a mental illness such as bipolar disorder or depression is, by far, the biggest predictor of suicide, Dr. Patorno and her colleagues factored the patient’s diagnosis (and a range of other health variables) into their analysis. The results “argue that the risk was derived from the specific drug that the patient was taking and not their underlying conditions,” Dr. Patorno says. If she were taking one of the riskier medications herself, Dr. Patorno adds, she “would probably re-evaluate the therapy” in consultation with her physician. But the study has some important limitations, Dr. Kanner says. For one thing, he explains, topiramate — which is most commonly prescribed for migraine — is known to worsen some psychiatric conditions and many doctors won’t prescribe it to patients with a personal or family history of mental illness. Therefore, the comparison group may have already been at lower risk of suicidal thoughts or attempts, he says. Dr. Kanner also notes that health conditions such as depression and epilepsy, which sometimes overlap, can combine to affect suicide risk in ways that may have eluded the researchers’ models. “You’re dealing with a very complex interaction,” he says. “To just attribute [the increased risk] to antiepileptic medication doesn’t explain the facts properly.” Pinpointing whether anticonvulsants boost suicide risk in and of themselves will likely require a study that follows people over time, rather than one that looks back at previous treatment, as the current investigation did, Dr. Kanner adds. According to Dr. Bazil, another limitation of the study is that Dr. Patorno and her team used standardized insurance-billing codes to determine a patient’s diagnosis. These codes can be imprecise, Dr. Bazil says, and doctors who suspect that a patient has (or is at risk for) depression may decide to prescribe one anticonvulsant versus another for that reason, without necessarily listing the billing code for depression in the patient’s file. Dr. Kanner emphasizes that patients who are currently taking the drugs for any reason should not stop taking them without consulting their doctor, and that patients should also tell their doctor if they have a history of mental illness or if it runs in their family. “Very often clinicians will not inquire about these issues, and that’s where things get lost,” he says. People taking the drugs should tell their doctor if they begin to feel depressed, or have thoughts of suicide, says Dr. Bazil, but patients should not be overly alarmed by the study. “The main thing is to be cautious about the risks versus the benefits,” he says. “In my mind, you have to keep it in perspective. There may be an increased risk of suicidal ideation, [but] most of these patients have tremendous benefits from the drugs.” The study was funded by the Harvard School of Public Health and HealthCore, a research subsidiary of WellPoint, a health benefits company that serves the Blue Cross Blue Shield network.

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