Medicine That Can Induce Violence: The Case Of Antiepileptic Drugs (AEDs)

by James O’Hanlon, Ph.D., Psychopharmacologist

Most people know that alcohol and certain illicit drugs can promote feelings of hostility leading to impulsive aggression. Less well known is that many medicinal drugs from numerous therapeutic classes can do the same in susceptible individuals. The class of drugs for controlling seizures in epilepsy (anti-epileptic drugs, AEDs) is used to illustrate the point. The choice was not because AEDs are collectively the worst in this respect but rather because the individuals who must use them did not generally suffer from a mental disorder that predisposed them to aggressive behavior before starting the medication. Another reason is that epilepsy often accompanies developmental disorders and if severe, is sufficient by itself to qualify an individual for Regional Center services.

The aggression inducing properties of antiepileptics was brought into sharp focus by an FDA “black-box” warning attached to the 2012 approval of perampanel (Fycompa) for treating epilepsy:

Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger and homicidal ideation and threats have been reported in patients taking FYCOMPA…FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening.

Perampanel followed the standard testing procedure for an AED headed for approval. In the culminating clinical trials, perampanel in different daily doses or placebo were added, double-blind, to whatever AEDs epileptic patients had been taking in unsuccessful attempts to control their seizures. Individual trials were scheduled for 6 months. During this period, anger-related side effects emerged in 12% and 20% of the patients receiving the lowest and highest maintenance doses as compared to only 6% of those receiving placebo. More disturbingly, 3 of 4,368 patients in all trials expressed homicidal ideation and/or threats, which FDA viewed as life-threatening. Yet perampanel has proven to be one of the most effective AEDs and for that reason entered the market in 2013 and remains there today. This is in accord with neurologists’ belief that seizure control is primary.  A sound principle: self-perpetuating seizures can be lethal and even self-terminating seizures can be brain-damaging if frequent and severe. Neurologists are therefore willing to accept considerable risk for adequate seizure control. Besides, perampanel is only one of many AEDs that can produce life-threatening reactions. The implementation of prudent safeguards minimizes the respective risks while not eliminating them entirely.

FDA’s late recognition of the seriousness of AED-induced aggression naturally raised the question of whether any of the previously approved AEDs possess this property. To answer the question, neurologists specializing in treatment of epilepsy undertook the first retrospective survey of psychiatric and behavioral side-effects of 18 AEDs approved in the USA before perampanel.¹   They reviewed the records of 4,085 patients whose seizures started at the age of 18 or older and who took one or more of these AEDs from the year 2000 to 2014. The purpose was to compare rates of psychiatric and behavioral side effects associated with different AEDs. Rates of “Psychiatric” side effects – depression, psychosis, anxiety and suicidal ideation – were relatively low and are not the topic of this article. “Behavioral” side-effects were more prevalent and largely (84%) related to expressions of anger: i.e. irritability – generally negative mood with a tendency to lose temper easily; tantrum – sudden outburst of anger out of proportion to stressor; and aggression – behavior aimed at causing harm to self or others. The investigators further distinguished between “intolerable” side effects that led to dose reduction or discontinuation of the AEDs supposed to be causing them and those that did not.

Sixteen AEDs were associated with low rates of anger-related side effects; i.e., < 4%. The two exceptions were tiagabine (Gabatril) and levetiracetam (Keppra) . Tiagabine was associated with a 10.9% rate of irritability but the group taking it was by far the smallest (46) and the data may be unreliable. The same cannot be said for levetiracetam: the group taking levetiracetam was the second largest (1,890) in the survey. The first table below shows the overall rate of anger-related side effects among patients taking levetiracetam in comparison with the average rate of side effects in patients taking any of the other AEDs. The second table is similarly constructed for comparing rates of intolerable anger-related side effects.

Overall Rates of Side Effects (%)

Rates of Intolerable Side Effects (%)

* Statistically significant difference: Levetiracetam rate higher than average rate of other AEDs

The rates of anger-related side effects were significantly greater for patients taking levetiracetam than any combination of AEDs without levetiracetam. Other studies have indicated that the rates are even higher in children and individuals with intellectual disability than typically developing adults. Levetiracetam, which otherwise has a benign side effect profile, resembles perampanel in respect to its tendency to induce aggressive behavior. That is not to say that either highly efficacious AED should be avoided. But it does indicate that neurologists prescribing them should inform patients and care providers of the possible anger-related side effects and if informed of their emergence, consider substituting another AED.

¹ Chen B, Choi H, Hirsch LJet al. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy & Behavior 2017; 76: 24-31.