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

Table 2

Studies reporting psychiatric and behavioral adverse reactions to levetiracetam.

Study	Study design	Study population	Main findings
Brodtkorb et al. 2004 [57]	Cohort study, months	adults (mean age: 34.7 years), of which 56 have intellectual disability	PBAR (aggression, irritability, mood swings, anxiety, restlessness, and psychotic symptoms) were among the most frequent adverse reactions. More frequent in patients with intellectual disability (23% vs. 10%).
Chen et al. 2017 [19]	Case-control, –15 years	(2–18 years) with epilepsy; mono- or polytherapy	PBAR in 13.8%, leading to dose reduction or discontinuation in 11.2%. LEV with the highest frequency of PBAR (16.2%), leading to dose reduction or discontinuation in 6.7%.
Chen et al. 2017 [18]	Case-control, months	adults (mean age 41 years) with epilepsy; mono- or polytherapy of which LEV: 1890	PBAR in 17.2%, leading to dose reduction or discontinuation in 13.8%. LEV with the highest frequency of these adverse reactions (22.1%), leading to dose reduction in 17.7%.
Chung et al. 2007 [50]	Cohort study, years	adults (mean age 38.5 years) (LEV: 196; LTG: 251; OXC: 97; TPM: 156; ZNS: 128)	Discontinuation due to PBAR in 19% using LEV (vs. 2–7% with LTG, OXC, TPM, and ZNS).
Ciesielski et al. 2006 [58]	Cohort study, weeks	(22–52 years) with epilepsy (LEV: 10, PGB: 10)	No difference in neuropsychological tests after short-term treatment with LEV or PGB.
Cramer et al. 2003 [32]	Review article, years	Total adults (epilepsy, cognitive disorders, and anxiety) of which LEV: 2871, placebo: 1308	PBAR in 25.4% of 1393 patients using LEV (vs. 6.2% with placebo), including agitation (1.6% vs. 0.2%), emotional instability (3.0% vs. 0.2%), hostility (3.3% vs. 0.9%), and nervousness (7.3% vs. 1.8%). PBAR more common in epilepsy compared to non-epilepsy (cognition/anxiety) ().
de la Loge et al. 2010 [59]	RCT, weeks	(4–16 years), of which 64 used LEV as add-on and 34 used placebo	Significant difference in total problem score between LEV (worsened) vs. placebo (improved). Significant worsening of aggression (LEV vs. placebo; ). Based on questionnaires.
Dinkelacker et al. 2003 [30]	Case series, months	adults with epilepsy	33 patients that experienced irritability or aggression (representing 3.5% of all patients treated with LEV, vs. <1% not on LEV). 24 patients: moderate or transient irritability, of which 10 had to reduce dose or discontinue. Nine (8 males) had severe aggressive symptoms; two of them required acute psychiatric intervention.
French et al. 2001 [60]	Review article, years	adults (healthy subjects and patients with epilepsy or anxiety)	PBAR in 13% of 769 patients with epilepsy using LEV in placebo-controlled studies (placebo: 6%). 6% (placebo: 4.1%) of elderly and 5.1% (placebo: 5.5%) of patients with anxiety reported PBAR.
Guilfoyle et al. 2017 [61]	Case-control, months	children (mean age: 8.9 years) with newly diagnosed epilepsy, of which 37% started with LEV	Increased frequency of PBAR with any AED. LEV among those AEDs with the highest frequency.
Halma et al. 2014 [62]	Meta-analysis	(1 month–18 years) with epilepsy using LEV as monotherapy or add-on. 13 studies in total	Three RCTs: hostility (7.3%), nervousness (6.1%), and aggression (4.9%). Significantly increased risk for these adverse reactions (relative risk: 2.2 vs. placebo; 95% KI: 1.4–3.4). Ten observational studies: worsened and improved behavior with LEV. Add-on therapy associated with irritability (4.7%), hyperexcitability (4.4%), and aggression (2.7%); monotherapy associated with general behavior problems (19%) and irritability (2.6%).
Helmstaedter et al. 2008 [63]	Interview-based, –5 years	, of which 288 used LEV (men age: 38 years), 135 relatives, and 43 controls (using different AEDs)	37% reported a negative behavior change, of which aggression was most frequent.
Kanemura et al. 2014 [64]	Cohort study, months	children (mean age: 10.3 years) with epilepsy and pervasive developmental disorder	Of eight patients with improved seizure control, six had >50% reduction in panic episodes or aggression.
Kang et al. 2013 [51]	Case-control, months	(mean age: 33 years) using LEV in mono- or polytherapy	Behavioral adverse reactions in up to 24%, of which irritability was most frequent.
Kowski et al. 2016 [65]	Case-control, years	patients with epilepsy (mean age: 44.7 years), of which 438 used monotherapy (different AEDs)	LEV with the highest frequency of anger, aggression, nervousness, and agitation
Labiner et al. 2009 [39]	RCT, weeks	patients with epilepsy (>16 years) of which 132 used LTG and 136 used LEV as add-on	Patients on LEV: worsened anger-aggression subscore, while patients on LTG improved each week.
Lee et al. 2011 [33]	Cohort study, weeks	patients with epilepsy (mean age: 35.4 years)	Improvement of anxiety symptoms with LEV, but five patients (6.5%) discontinued LEV due to PBAR (nervousness, irritability, anxiety, hostility, depression, suicidal ideation, and attempted suicide).
Mbizvo et al. 2014 [66]	Meta-analysis	children and adults, 11 studies in total	Agitation in 0.82% on LEV vs. 0.14% on placebo. Irritability in 0.46% vs. 0% on placebo.
Mula et al. 2003 [52]	Cohort study, months	patients (mean age: 35.6 years) using LEV as add-on	PBAR in 10%, of which aggression was most frequent (3.5%).
Mula et al. 2004 [31]	Cohort study, months	patients with epilepsy and learning disabilities (mean age: 30.6 years)	PBAR in 15 patients (12.7%). Aggression most common (9 patients; 7,6%). Two patients (1.7%) experienced agitation, anger, and hostility.
Mula et al. 2007 [67]	Case-control, years	patients with epilepsy (mean age: 37.9 years) using LEV and TPM (not simultaneously)	PBAR in 13%.
Mula et al. 2015 [68]	Case-control, interview	(mean age: 42 years)	9.8% reported that aggressive behavior «always» was a problem.
Schiemann-Delgado et al. 2012 [69]	RCT, weeks	(4–16 years) of which 80 were from the de la Loge et al. (2010) study	No difference in score for behavior/aggression (LEV vs. placebo). Aggression occurred in 7.8%, irritability in 7.8% [sic], abnormal behavior in 3.9%.
Schoenberg et al. 2017 [70]	RCT, weeks	healthy elderly subjects, (mean age: 72.4 years) of which LEV: 9 and placebo: 11	LEV well tolerated regarding cognition, mood, and balance, but increased general tendency to feeling irritated ( vs. placebo).
Shukla et al. 2016 [71]	Case-control, years	patients with epilepsy (mean age: 21 years) using LEV (114), OXC (151), or VPA (134), of which 292 were included	PBAR in 43 patients (irritability, compulsive symptoms, aggression, psychosis). 23 (20.2%) used LEV. LEV discontinued in 10 patients (9%).
Tekgul et al. 2016 [49]	Case-control,; months	(6 months–18 years: mean age: 9.9 years) using LEV in monotherapy	PBAR in 87%. Irritability (67%), hyperactivity (8%), and disturbed behavior (5%) were most common.
Weintraub et al. 2007 [27]	Case-control, months	of which 521 patients (mean age: 43 years) used LEV	LEV with highest incidence (16%) of PBAR, leading to a discontinuation in 8%. Irritability in 9%, disturbed behavior in 3.5%.
White et al. 2003 [53]	Case-control, months	(mean age: 41.4 years)	7% discontinued LEV due to PBAR, mainly depression, and irritability. 1.8% were evaluated as a potential threat for themselves or others.
Wieshmann and Baker 2013 [72]	Case-control, interview	(mean age: 41.6 years) of which 418 have epilepsy and 41 controls. 158 used LEV in monotherapy or add-on, 260 used other AEDs	49% of LEV users reported anger as a problem, vs. 3% using other AEDs, and 7% of controls.
Wieshmann and Baker 2017 [73]	Case-control, interview	of which 329 (mean age: 39.8 years) have epilepsy using CBZ, VPA, LTG, or LEV in monotherapy, and 51 healthy controls	CNS-related adverse reactions more common with CBZ, VPA, LTG, and LEV vs. controls. Anger significantly more frequent with LEV (54% vs. 34% on CBZ, 33% on VPA, 31% on LTG, and 6% in controls).

RCT: randomized controlled trial, t: observation time; PBAR: psychiatric and/or behavioral adverse reactions; CBZ: carbamazepine; LEV: levetiracetam; LTG: lamotrigine; OXC: oxcarbazepine; PGB: pregabalin; TPM: topiramate; VPA: valproate; ZNS: zonisamide.