AEDs and Suicide Risk

Do all Anti-Epileptic Drugs Increase the Risk of Suicide


In May 2008, the results of a meta-analysis conducted by the FDA showed an increased incidence of suicide in patients taking anti-epileptic drugs (AEDs). Specifically the analysis included carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. Not wanting to single out specific agents, the FDA added a black box warning to all AEDs for suicide risk.


The statement was immediately contested. The greatest point of criticism is that this blanket statement encompassed over 20 different medication which all have differences in affects on receptors and mechanisms of action. Additionally, patients with epilepsy have a higher risk of suicide than the general population, especially in the post-ictal phase of a seizure. Finally, the AEDs are life-saving medications. The statement put forth by the FDA was scrutinized due to concern that patients would stop taking the medications, which would lead to seizure and risk of death.


In 2007, an extensive review article discussing nuances between therapies was published in Drug Safety. Phenobarbital and phenytoin have established suicide risks, however, based on effects on serotonergic receptors, it is hypothesized that certain AEDs would have a protective effect. Author, Kalinin, proposed that carbamazepine, oxcarbazepine, valproate, and lamotrigine would prevent suicide secondary to improvements in cognitive function. In contrast, topiramate, tiagabine, vigabatrin, gabapentin, levetiracetam, and zonisamide all have negative effects on mood, though studies examining the clinical risk associated with most of these AEDs had not yet been conducted at the time of this review. Kalinin expressed that epilepsy itself comes with risks, and the negative effects of AEDs may be additive to existing problems with mood, more so than causative.

In addition to seizures, epilepsy does not come without risks. Patients with epilepsy have been found to have a significantly higher risk of suicide compared to the general population. Additionally, patients with epilepsy have an increased risk of depression, anxiety, psychoses, and high incidences of depression in the post-ictal phase after a seizure.


In the early 1990’s, observational studies showed that up to 1/3 of patients who commit violent suicide are deficient in folic acid. AEDs cause folate deficiency; which is acknowledged by heavy supplementation of folic acid during pregnancy, yet the majority of patients on an AED are not taking folic acid supplementation. Later studies have shown that low folate levels correlate to low levels of serotonin, which could lead to depression. Decreased folic acid levels in patients on an AED has not been proven to cause depression and there is very little available evidence.

In a study by Olesen et al published March 2010, researchers identified patients prescribed an AED between 1997-2006 with an epilepsy diagnosis and identified risk of suicide in comparison to suicide risk with carbamazepine treatment. This study also found an over-all risk of suicide, but risk was only significantly increased specifically with clonazepam, valproate, phenobarbital, lamotrigine, and levetiracetam.


The following month, a cohort study by Patorno et al was published in JAMA identified patients started on an AED between 2001-2006 and followed for 180 days. The risk of combined outcome of suicide, suicide attempt, or violent death was compared to that of topiramate as a baseline. Gabapentin, lamotrigine, oxcarbazepine and tiagabine all had increased risks of suicide in comparison to topiramate. However, patients in the study may have been taking the study medication for an indication other than epilepsy, so the results do not adequately reflect the correct patient population.


A nested case-control study published in Neurology in July 2010 divided AEDs into four categories: barbiturates, conventional AEDs, new AEDs with low risk of depression (oxcarbazepine, Lamotrigine, gabapentin, pregabalin) or new AEDs with high risk of depression (levetriacetam, tiagabine, topiramate, vigabatrin). The study showed that only new AEDs with high risk of depression were associated with increased risk of suicide.

While each of the three afore-mentioned studies was useful in showing only certain medications were associated with increased risks, the studies were not consistent in identification of higher risk medications. The studies also failed to analyze patients separately by psychiatric co-morbidities. A patient with depression has a higher risk of suicide compared to a patient without a psychiatric co-morbidity, yet the incidence of psychiatric co-morbidities were not identified in the previous studies.


The most recent study examining risk of suicide with AEDs was published in August 2010 in the New England Journal of Medicine. The study was a meta-analysis including over 5 million patients receiving any 10 of 11 AEDs included in the FDA meta-analysis (carbamazepine, gabapentin, Lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide with the exclusion of felbamate, not marketed in the UK). Patients were followed until end-point (suicide or suicide attempt) or until the end of the study period. Patients were categorized into having epilepsy, depression, bipolar disorder, a combination of disorders, or none of the three identified indications. There was an increased risk of suicide identified for patients taking an AED without depression, bipolar disorder, or epilepsy, however, for patients with one of these three indications, there was no increased risk.

The results of this study have prompted the FDA to plan to go back and review data on suicides with AEDs. Currently, the warning is still attached to all AEDs but patients should be counseled based on the medication that they are currently receiving. Levetiracetam and barbiturates have been consistently linked to mood changes and increased risk of suicide. Other medications such as gabapentin, topiramate, oxcarbazepine, lamotrigine, and valproate have shown increased risk in some studies, and in others, none.


The benefit that these medications provide to patients living with epilepsy far outweighs the risk. The risk of seizure and seizure complication is greater than the absolute risk of suicide. Additionally, patients suffered high risks of depression and suicide in the post-ictal phase of seizures, especially generalized and temporal front-lobe. Preventing seizures and post-ictal depression also prevents suicide. Patients should be warned of the risks, but also educated on the benefits. It is essential that patients with epilepsy maintain good adherence to their medication regimen and the black box warning for suicide may frighten patients into not taking their medication if they are not adequately counseled on prescription of the medication.


While this myth has not been fully “busted”, it will be interesting to see how the FDA and ILAE recommendations will change as a result of recent evidence.

References:


Kalinin VV. Suicidality and antiepileptic drugs: is there a link? Drug Safety 2007;30(2):123-142.


Bell GS et al. Suicide and epilepsy. Current Opinion in Neurology 2009;22:174-178.


Wolfersdorf M et al. Red-cell and serum folate levels in depressed inpatients who commit violent suicide: a comparison with control groups. Pharmacopsychiatry 1995;28(3):77-79.


Olesen JB et al. Antiepileptic drugs and risk of suicide: a nationwide study. Pharmacoepidemiology and Drug Safety 2010;19:518-524.


Patorno E et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA 2010;303(14):1401-1409.


Andersohn F et al. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicideal behavior. Neurology 2010;75:335-340.


Arana A et al. Suicide-related events in patients treated with antiepileptic drugs. NEJM 2010;363(6):542-552.