Mechanisms Underlying Aggressive Behavior Induced by Antiepileptic Drugs: Focus on Topiramate, Levetiracetam, and Perampanel

Abstract

Antiepileptic drugs (AEDs) are effective against seizures, but their use is often limited by adverse effects, among them psychiatric and behavioral ones including aggressive behavior (AB). Knowledge of the incidence, risk factors, and the underlying mechanisms of AB induced by AEDs may help to facilitate management and reduce the risk of such side effects. The exact incidence of AB as an adverse effect of AEDs is difficult to estimate, but frequencies up to 16% have been reported. Primarily, levetiracetam (LEV), perampanel (PER), and topiramate (TPM), which have diverse mechanisms of action, have been associated with AB. Currently, there is no evidence for a specific pharmacological mechanism solely explaining the increased incidence of AB with LEV, PER, and TPM. Serotonin (5-HT) and GABA, and particularly glutamate (via the AMPA receptor), seem to play key roles. Other mechanisms involve hormones, epigenetics, and “alternative psychosis” and related phenomena. Increased individual susceptibility due to an underlying neurological and/or a mental health disorder may further explain why people with epilepsy are at an increased risk of AB when using AEDs. Remarkably, AB may occur with a delay of weeks or months after start of treatment. Information to patients, relatives, and caregivers, as well as sufficient clinical follow-up, is crucial, and there is a need for further research to understand the complex relationship between AED mechanisms of action and the induction/worsening of AB.

Home-cage monitoring ascertains signatures of ictal and interictal behavior in mouse models of generalized seizures

“…Future studies that incorporate home-cage monitoring may help dissect the various determinants of spontaneous interictal behavior, including factors such as type of seizure onset (focal Vs generalized), spontaneous seizure or spike frequency/recency, and the pleiotropic role of an underlying genetic etiology (if present). Finally, this technology may also help discern why certain anticonvulsants, regardless of epilepsy type or seizure frequency, are themselves associated with high rates of adverse behavioral side effects [73, 74].…”

Brivaracetam: First Canadian Experience in an Intractable Epilepsy Population

“…However, in our study, psychiatric side effects were more frequent with BRV therapy than that described in other studies with LEV therapy (15-30%). [5][6] This suggests that psychiatric AEs may be higher with BRV than it was previously demonstrated in clinical trials. Our study also contrasts with the study by Yates et al, 25 a small open-label prospective trial where 29 patients experiencing psychiatric AEs with LEV were switched to BRV.…”

“…Brivaracetam (BRV) is the latest AED approved for focal epilepsy and is characterized by its high affinity for selectively binding to synaptic vesicule protein 2A (SV2A), 15-to 30-fold than its analogue levetiracetam (LEV). 4 LEV is known to cause psychiatric side effects in 15-30% of patients, 5,6 presumably by its negative modulating effect on AMPA receptors. 5 BRV does not share inhibitory activity on high-voltage Ca 2+ channels and AMPA receptors, which could explain a lower incidence of psychiatric AEs than with LEV.…”

“…4 LEV is known to cause psychiatric side effects in 15-30% of patients, 5,6 presumably by its negative modulating effect on AMPA receptors. 5 BRV does not share inhibitory activity on high-voltage Ca 2+ channels and AMPA receptors, which could explain a lower incidence of psychiatric AEs than with LEV. 4 Randomized controlled studies demonstrated that BRV can successfully reduce seizure frequency.…”

Home-cage Monitoring Ascertains Signatures of Ictal and Interictal Behavior In Mouse Models of Generalized Seizures

“…Future studies that incorporate home-cage monitoring may help dissect how interictal behavior is modulated by seizure onset (focal Vs generalized), spontaneous seizure or spike frequency, as well as discern why certain anticonvulsants, regardless of epilepsy type or seizure frequency, are themselves associated with high rates of adverse behavioral side effects (66,67).…”