Pharmacologic treatment of impulsive aggression with antiepileptic drugs

Aggressive behavior is a major concern in mental health and criminal justice settings. Although pharmacotherapy is often used in the treatment of the violent individual, no medication is presently approved by the US Food and Drug Administration specifically for such use. In recent years, antiepileptic drugs (AEDs) have become increasingly popular for the management of impulsive (reactive) aggressive behavior. The research literature has implicated several neurobiologic deficits associated with impulsive aggression, including reduced central serotonergic functioning, executive dysfunction, and prefrontal deficits. It has been suggested that the neurobiologic deficits specific to impulsive aggressive behavior may serve as indicators of an ineffective behavioral control system. A review of the literature finds that AEDs, particularly those that block sodium channels and/or have GABA-related mechanisms of action, are effective in reducing the frequency and intensity of impulsive aggressive outbursts both when used as the primary agent of treatment and as an adjunct to ongoing pharmacotherapy. Strong evidence for efficacy in impulsive aggression exists from randomized controlled trials for most of the common AEDs (phenytoin, carbamazepine, oxcarbazepine, lamotrigine, valproate/ divalproex sodium, topiramate). Additional controlled studies are needed for tiagabine and gabapentin. Of the common AEDs, only levetiracetam has been shown to be ineffective in the treatment of impulsive aggression. It is important to note that the anti-aggressive effects seen with the AEDs appear to be specific to the impulsive form of aggression. Individuals who display premeditated aggression do not seem to benefit from this type of treatment. Clinically, we recommend phenytoin (initial dose 100 mg three times daily) as the AED of first choice for the treatment of impulsive aggressive outbursts. This recommendation is based on this drug's limited side effect profile (compared with the other AEDs) and the large amount of empiric data supporting its clinical efficacy in impulsive aggression. In the event that the impulsive aggressive individual does not respond to pharmacotherapy with phenytoin, carbamazepine (initial dose 150 mg three times daily) and valproate/divalproex sodium (initial dose 250 mg three times daily) have both proved to be effective secondary options.