Two years ago the FDA issued a warning to physicians that antiepileptic drugs (AEDs) may increase thoughts of suicide or acts. The federal response came after clinical trials data and a subsequent meta-analysis of the clinical trials with 11 AEDs showed a two-fold higher risk of developing suicidal behavior or ideation in patients taking these medications compared to those taking a placebo. The risk increased right after the treatment started and remained high throughout the 24-week study periods and seemed high regardless of why the medicine was prescribed.
Now, two new studies have looked at the problem using observational data and report that the risk may be due to the conditions that underlie the drug use.
In a study published Aug. 5 in the New England Journal of Medicine, investigators from Spain studied data collected from medical records from patients in England derived from the Health Improvement Network (THIN) database, which is representative of the general population in the United Kingdom and includes more than 6.7 million patients. The data, which are based on daily records from general practitioners, include anonymous demographic, medical, and prescription information on individual patients.
The investigators identified 66,925 patients with epilepsy — 24 percent of whom did not have a diagnosis of depression or bipolar disorder and did not take AEDs; 435,790 patients with depression and 3,814 with bipolar disorder only did not take AEDs, and 77,319 patients received AEDs but did not have epilepsy depression, or bipolar disorder.
Alejandro Arana, MD, and colleagues at the Risk MR Pharmacovigilance Services and the Hospital Universitario de la Princesa in Madrid, reported that the overall incidence of suicide-related events per 100,000 person-years was 15 for patients without epilepsy, depression or bipolar disorder; 38.2 for those with epilepsy who did not take AEDs; and 48.2 for patients with epilepsy who were taking AEDs. [All had a confidence interval of 95 percent.]
Among patients with depression alone, the incidence rate of suicide-related events was 129.1 per 1,000,000 person-years for those who were not receiving AEDs and 177.3 per 100,000 person-years for those who received AEDs.
In adjusted analyses, antiepileptic drug use was not associated with higher risk of suicidality in patients with epilepsy (odds ratio 0.58; 95%CI 0.35—0.98) or bipolar disorder (1.13; 95%CI 0.35-3.61), but was significantly associated with higher risk in patients with depression (1.65; 95% CI 1.24-2.19) and in patients without epilepsy, depression or bipolar disorder (2.57; 95% CI 1.78-3.71).
“Observational studies are the only way to address the unintentional effects of these medications,” said Dr. Arana. He said that it was not clear if the results from the FDA meta-analysis would be replicated in clinical practice.
“The assessment of suicidality in the clinical trials included in the FDA meta-analysis was subject to several limitations such as the lack of systematic or standardized language to define suicidal ideation and behavior across clinical trials,” he said.
“Neurologists informing their patients about the benefits and risks of medications do not have to worry patients about an increased risk of suicidal thoughts,” he said, “but can help them understand their disease and treatment.”
DO RISKS VARY BY AED CLASS?
Another study that was published in the July 27 issue of Neurology hoped to determine whether the suicide risk was increased among all the different classes of AEDs or higher in those medications thought to carry a greater risk for depression.
Frank Andersohn, MD, and his colleagues at the Institute for Social Medicine, Epidemiology and Health Economics at the of Charité University Medical Center in Berlin, Germany, used a nested case-control study of 44,300 patients with epilepsy who were treated with AEDs derived from the United Kingdom General Practice Research Database. Patients had at least one prescription for an epilepsy drug from 1989 through 2005, and had been followed for an average of five years.
They viewed prospective data on patients who reported self-harm or suicidal behavior — 453 cases — and compared them to 8,962 age-matched controls who had not harmed themselves or committed suicide. They classified the medications into four groups: barbiturates, conventional anti-epileptic medicines and the newer drugs that carry a low risk (lamotrigine, gabapentin, pregabalin, and oxcarbazepine) and a high risk (levetiracetam, tiagabine, topiramate, and vigabitrin) for causing depression.
The investigators reported that the current use of the newer AEDs with a high risk for depression was associated with a three-fold increased risk for suicidal behavior and/or action. There was no increased risk in any of the other groups of medications. Six of the 453 people, or 1.3 percent, who harmed themselves or attempted suicide were taking the newer drugs with the higher risk of depression, compared to 45 of the 8,962 people, or 0.5 percent, of those who did not harm themselves.
“These results may be helpful for doctors and people with epilepsy as they decide which drugs to use,” said Dr. Andersohn. “An earlier analysis of data by the FDA grouped all of the epilepsy drugs together and found an increased risk of suicidal thoughts and behavior, but could not address the question of whether there were differences among the various classes of epilepsy drugs.”
In an editorial in the same issue of Neurology, Josemir Sander, MD, PhD, of the University College London in the United Kingdom and the Epilepsy Institute of the Netherlands Foundation and Marco Mula, MD, PhD, of the University Hospital Maggiore della Carità in Novara, Italy, said that some researchers have been concerned that patients may refuse taking these medicines because of the concern for the potential for triggering thoughts of suicide.
The FDA warning has “caused some problems as people with epilepsy became reluctant to take the drugs when advised,” said Dr. Sander. “The meta-analysis had a number of methodological problems which did not take into account that the populations in whom antiepileptics are usually used.” Dr. Sander is interested in premature mortality in people with epilepsy and one of the culprits of this increase mortality is suicide.
Still, his recommendation is that the “risk from having uncontrolled epileptic seizures is much greater than the risk of suicide from the drugs so people should not make hasty decisions.” He added that the mental state of any person who is advised to start an anti-epileptic medication or for whom a change in medication is considered should be screened prior to starting the medication and the drug choice taken into account.
Arana A, Wentworth CE, Arellano FM, et al. Suicide-related events in patients treated with antiepileptic drugs. N Engl J Med 2010;363: 542-551.
Andersohn F, Schade R, Garbe E, et al. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology
2010; 75: 335-340.
Mula M, Sander JW. Editorial: Antiepileptic drugs and suicidality: Much ado about very little? Neurology 2010;75:300-301.