Antiepileptic medications have been a mainstay in the treatment of bipolar illness since the use of valproate in the 1980’s.Since that time other anticonvulsants such as carbamazepine, lamotrigine, and oxcarbazepine have been added to the list that help control the mood fluctuations that occur in bipolar disorder. In January 2008, the FDA issued an alert about patients being treated with antiepileptics:
In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all at increased risk for suicidality when compared to placebo, and there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed. The relative risk for suicidality was higher in the patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.
The following is a list of antiepileptic drugs included in the analyses:
- Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
- Felbamate (marketed as Felbatol)
- Gabapentin (marketed as Neurontin)
- Lamotrigine (marketed as Lamictal)
- Levetiracetam (marketed as Keppra)
- Oxcarbazepine (marketed as Trileptal)
- Pregabalin (marketed as Lyrica)
- Tiagabine (marketed as Gabitril)
- Topiramate (marketed as Topamax)
- Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
- Zonisamide (marketed as Zonegran)
How did the FDA arrive at this conclusion?
According to their documents, the FDA began receiving reports of the increased risk of suicidality with the anticonvulsants and did a preliminary review that confirmed the possibility.So in 2005, the FDA began analyzing 199 placebo controlled trials of eleven different antiepileptic drugs. The conditions studied in these clinical trials included epilepsy, selected psychiatric illnesses, and other indications, including migraine and neuropathic pain syndromes. The analysis included 27,863 patients in drug treatment groups and 16,029 patients in placebo groups. Patients included in the analysis were five years of age or older. There were 4 completed suicides among patients in drug treatment groups and none among the patients in placebo groups. There were also 105 reports of suicidal symptoms in the drug treatment groups in comparison to 35 reports of suicidal symptoms in the placebo group.
Overall, 0.43% of the patients in drug treatment groups experienced suicidal behavior or ideation versus 0.22% of the patients in placebo groups, corresponding to an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation than in the placebo treatment groups. In comparison, the overall suicide risk in a treated bipolar population was found to be 3.66% in the STEP-BD study (Marangell, et al. Prospective Predictors of Suicide and Suicide Attempts, Bipolar Disorders 2006, 8: 566-575).In this analysis, the relative risk for suicidal thoughts or behavior was higher for patients with epilepsy compared to those patients with psychiatric or other disorders. The higher risk for suicidal behavior or suicidal ideation was observed at one week after starting a drug and continued to at least 24 weeks. The results were generally consistent among the drugs and were seen in all demographic subgroups. Specifically, there was no clear pattern of risk across age groups. (For more information please go to: http://www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm)
The Response
The FDA has placed a warning label on all antiepileptic drugs reflecting this increase risk of suicide, but it did not attach the dreaded black box warning.Since then, numerous groups have weighed in on the FDA’s findings.At a December 2008 meeting of the American Epilepsy Society, two researchers presented evidence that the findings are inconsistent and vary greatly by drug, region, and illness.Still other experts felt that this warning will do more harm than good and that it is too early to make such a broad statement without further research to substantiate the FDA’s claims. A noted psychiatrist, Dr. David Kahn of Columbia University, weighed in by commenting that the risk of suicide in bipolar disorder is far higher in an untreated patient than a treated one, and that both doctor and patient should be aware of the risk of suicidality in bipolar disorder.
What should you take from all of this?
It appears that antiepileptic drugs roughly double the risk of suicidality as compared with placebo. However, the absolute risks are small, and the effect appears more likely in patients treated for epilepsy than for patients with psychiatric illness (although the FDA has yet to publish all the data required to compare these two populations). In our daily practice, we as psychiatrists are always closely monitoring patients for any evidence of suicidality, so any signs and symptoms should be detected early and carefully evaluated.If it appears a medication is contributing to the increased suicidality, it should be discontinued.With this close monitoring of a given patient’s mood state and the small absolute risks found in the FDA’s analysis, we believe the risk associated with prescribing anticonvulsants in bipolar illness is extremely small.That being said, these findings should be discussed with any patient prior to initiating treatment with an antiepileptic medication, and more research is needed to understand the possible link between suicidality and antiepileptics.