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

Table 3

Studies reporting psychiatric and behavioral adverse reactions to perampanel.

Study	Study design	Study population	Main findings
Biro et al. 2015 [35]	Case-control, weeks–18 months	(mean age: 10.5 years) treated with PER	Aggression in 8 patients (13.8%).
Chung et al. 2017 [43]	Case-control, –142 weeks	patients (≥12 years) with epilepsy using PER in monotherapy or with LEV and/or TPM	PER with increased risk of PBAR (incl. aggression, hostility, irritability, and anger). Occurrence of hostility and aggression independent of cotreatment with LEV or TPM.
Coyle et al. 2014 [74]	Case-control, months	patients with epilepsy (mean age: 31 years)	PBAR most common reason for discontinuation (aggression: ; suicidal ideation ; both combined: ).
De Liso et al. 2016 [44]	Case-control, months	children/adolescents (mean age: 14.2 years) using PER as add-on	PBAR in 19 patients (30.6%), including irritability (; 11.3%) and aggression (; 4.8%).
Dolton and Choudry 2014 [75]	Case report, months	1 patient (37 years) with epilepsy, Tourette’s, moderately reduced cognitive function and demanding behavior	Add-on treatment with 8 mg PER improved seizure control but worsened aggressive behavior which resulted in institutionalization of the patient.
Ettinger et al. 2015 [34]	Review of safety in phase I, II, and III clinical studies	(12–>65 years) with epilepsy, Parkinson’s, pain, MS, or migraine who received either PER or placebo	Higher incidence of aggression and hostility for PER vs. placebo in “narrow” and “broad” questionnaires (narrow: PER 3.0% vs. placebo 0.7%; broad: 11.8% vs. 5.7%), but not increased in non-epilepsy disorders.
French et al. 2015 [76]	RCT, –54 weeks	patients (man age: 28.4 years) with generalized epilepsy, of which PER: 81 and placebo: 81	Irritability was the only individual adverse reaction with incidence ≥5% (PER: 11.1% vs. placebo 3.7%). Combined incidence of hostility and aggression: PER 18.5% vs. placebo 4.9%.
Huber and Schmid 2017 [37]	Case-control, years	patients (mean age: 30 years) with epilepsy and cognitive impairment of various degrees	PBAR in 50%, incl. irritability, aggression, increased sensitivity, and suicidal ideation/acts. This was also the main reason for discontinuation of PER.
Krauss et al. 2014 [77]	RCT, –>2 years	patients (≥12 years) with epilepsy, using 1–3 AEDs and PER as add-on	Irritability in 11.5% and aggression in 5.1%, leading to discontinuation of PER in 1.3% and 0.4%, respectively. 3.9% had ≥1 serious PBAR, of which 0.2% agitation, 0.2% abnormal behavior, and 1% aggression.
Lagae et al. 2016 [78]	RCT, weeks	(12–17 years) with epilepsy (PER: 85 and placebo: 48)	No difference in total score (behavior and competence) between PER and placebo, but aggression and hostility in 15 patients (17.6%) on PER vs. 2 (4.2%) on placebo.
Rosenfeld et al. 2015 [45]	RCT, –29 weeks	(12–17 years) with epilepsy of which PER: 98 and placebo: 45	Aggression in 8.2% (vs. 0% on placebo). Aggression was one of the most common reasons (6.6%) for dose changes or discontinuation of PER
Rugg-Gunn 2014 [46]	Review article, weeks	patients of which 1008 on PER and 442 on placebo	Higher frequency of PBAR with PER, particularly irritability and aggression. Frequency of serious PBAR reported as low, but 3 cases of aggression and 1 of suicidal ideation.
Snoeijen-Schouwenaars et al. 2017 [36]	Case-control, months	patients (mean age: 27.4 years) with epilepsy and intellectual disability	Behavioral adverse reactions in 40.3%. Most common: aggression, agitation, disturbing behavior, and mood symptoms.
Steinhoff et al. 2013 [47]	RCT, weeks	of which PER: 1038 (mean age: 34.8 years) or placebo: 442 (mean age: 34.3 years)	Irritability in 11.8% on 12 mg PER (vs. 2.9% on placebo and 3.9–6.7% on 2–8 mg PER). Aggression in 3% on 12 mg PER (vs. 1% on placebo, 1% on 4 mg PER, and 2% on 8 mg PER). Hostility or aggression in 5% (4 mg), 12% (8 mg), and 20% (12 mg) on PER, vs. 6% on placebo
Steinhoff et al. 2014 [79]	Cohort study, months	patients (≥12 years) with focal seizures	Aggression in 2.8%, irritability in 2.1%.
Wehner et al. 2017 [80]	Cohort study, –42 months	patients (≥17 years) using PER as add-on	Negative effect on mental health in 137 patients (36%), incl. worsened mood, increased irritability and demanding behavior
Zaccara et al. 2013 [48]	Meta-analysis	patients with epilepsy or Parkinson’s, of which 2627 used PER in a total of 9 RCTs	Irritability and aggression with a PER dose of 12 mg/day.; Overall tolerability was better in epilepsy compared to Parkinson’s, but patients with Parkinson’s were older.

RCT: randomized controlled trial, t: observation time; PBAR: psychiatric and/or behavioral adverse reactions; LEV: levetiracetam; PER: perampanel; TPM: topiramate.