Pharmacologic treatment of impulsive aggression with antiepileptic drugs

Abstract

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.

Brain γ‐aminobutyric acid: a neglected role in impulsivity

“…Forchetti & Meek, ; Nishikawa & Scatton, ; Gocho et al ., ), and this may be an important contributory mechanism in these disorders. Indeed, antiepileptic drugs, which act through GABA‐related mechanisms, are effective in impulsive aggression but interestingly not premeditated aggression (Stanford et al ., ). Moreover, genetic studies in suicide completers, with and without depression, have identified altered expression and epigenetic regulation of genes related to GABAergic neurotransmission in the PFC (Poulter et al ., ; Klempan et al ., ; Sequeira et al ., ).…”

“…Interestingly, however, a subset of three young children with ADHD responded positively when treated with the indirect GABA agonist valproate but not when treated with methylphenidate (Miyazaki et al ., ). Anti‐epileptic drugs, which act directly or indirectly to affect GABA transmission, are also effective in treating individuals with impulsive aggression (see Stanford et al ., ; for a summary of studies). Moreover, as noted above, GABA levels are reduced in the sensorimotor cortex of children with ADHD relative to age‐matched controls (Edden et al ., ).…”

Neuroimaging and Neurocognitive Correlates of Aggression and Violence in Schizophrenia

“…Accumulating evidence points towards an important role of several neurotransmitters such as serotonin, dopamine, and noradrenalin in impulsive behavior, and recent findings also implicate glutamate and cannabinoid neurotransmission in impulsivity (for a review, see Pattij and Vanderschuren [131]). Therefore, impulsive behavior may be responsive to pharmacological treatment, and several studies could show that agents with serotonergic-enhancing properties such as serotonin-reuptake inhibitors [132–134] as well as antiepileptic dugs may reduce incidences of impulsive aggression, but not premediated aggression (for reviews, see Huband et al [135] and Stanford et al [136]). …”

Epilepsy and brain injury: A case report of a dramatic neuropsychiatric vicious circle

“…Valproate, for example, significantly reduced destructive and aggressive behaviour in patients with acquired brain injury [31]. Topiramate is useful in both focal and generalized epilepsy [36], reducing seizure frequency and impulsivity and having a mood-stabilizing effect [37]. Phenobarbital may cause dose-related hyperactivity and behavioural disorders [38] and its discontinuation may result in decreased impulsiveness and hyperactivity [39].…”