- Email: [email protected]
Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study
YEBEH-106658; No of Pages 5 Epilepsy & Behavior 102 (2020) 106658
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study Sang-Ahm Lee ⁎, Ji Ye Jeon, Hyun-Woo Kim Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 2 October 2019 Accepted 25 October 2019 Available online xxxx Keywords: Epilepsy Refractory focal seizures Aggression Depression Perampanel Topiramate
a b s t r a c t Purpose: Clinical trials have demonstrated the efficacy of perampanel for the treatment of epilepsy. However, patients treated with this and other antiepileptic drugs often exhibit aggressive behaviors. We investigated the clinical factors contributing to aggression in patients with refractory focal epilepsy during 6 months of adjunctive perampanel treatment. Methods: This was a single-center longitudinal study involving patients treated with perampanel (starting dose, 2 mg/day; maximal dose, 12 mg/day). Patients were assessed with an aggression questionnaire (Korean version of Aggression Questionnaire [AQ-K]) and the hospital anxiety depression scale (HADS) at the beginning of the study and after receiving treatment for 6 months. Paired t-tests were used to compare AQ-K and HADS scores at the beginning of the study with those recorded at the end, and stepwise linear regression models were applied to identify predictive factors. Results: Thirty-two patients (mean age, 42.4 ± 10.3 years) successfully completed the 6-month study. The AQ-K and HADS scores increased after 6 months of adjunctive perampanel treatment (p b .1). The HADS scores related to depression at baseline predicted changes in total AQ-K scores, whereas the change in this HADS score was a predictor of physical and verbal aggression. A perampanel dose of ≥8 mg was a predictive factor for changes in anger and HADS scores related to depression after 6 months. Unexpectedly, concomitant use of topiramate had protective effects on AQ-K scores (including for verbal aggression and anger) in patients receiving perampanel. Conclusion: Depressive symptoms and a high dose of perampanel are potential predictors for aggression, whereas concomitant use of topiramate is protective against aggression in patients receiving perampanel for focal epilepsy. © 2019 Elsevier Inc. All rights reserved.
1. Introduction Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, is a novel antiepileptic drug (AED) with a broad spectrum of anticonvulsant activities [1]. Phase III randomized controlled trials have established the clinical efficacy and safety of perampanel as adjunctive treatment for partial onset seizures with or without secondary generalization [2–4] as well as for primary generalized tonic–clonic seizures [5]. However, similarly to other AEDs, perampanel can contribute to psychiatric and behavioral symptoms such as aggression, depression, and suicidal ideation in persons with epilepsy (PWE) [6]. An analysis of data pooled from three phase III studies [2–4] revealed that 2.8% and 6.3% of patients with partial onset seizures given 8-mg and 12-mg perampanel, respectively,
exhibited aggressive behavior compared with only 0.7% of those given a placebo [6]. Aggression in PWE may thus be a problem with the use of perampanel in everyday clinical practice, and particular care should be taken when prescribing perampanel for patients with a high risk of aggression. A recent posthoc analysis of data pooled from four phase III trials [2–5] found that concomitant administration of levetiracetam and/or topiramate, both of which are shown to induce aggressive behavior in PWE [7], did not increase the risk of aggression-related adverse effects in patients receiving perampanel [8]. However, the clinical factors that predict the development or aggravation of aggression with adjunctive perampanel treatment are not known. To begin to address this, we examined changes in aggression over 6 months in patients with refractory focal epilepsy treated with perampanel.
⁎ Corresponding author at: Department of Neurology, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. E-mail address: [email protected] (S.-A. Lee).
https://doi.org/10.1016/j.yebeh.2019.106658 1525-5050/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: S.-A. Lee, J.Y. Jeon and H.-W. Kim, Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study, Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.106658
2
S.-A. Lee et al. / Epilepsy & Behavior 102 (2020) 106658
2. Methods 2.1. Subjects Patients with intractable epilepsy who visited Asan Medical Center from October 2016 to April 2017 and agreed to use perampanel as adjunctive therapy were recruited for this study. Patients eligible for inclusion in the study were between 19 and 65 years of age, had refractory focal seizures (defined as recurring focal or focal-to-bilateral generalized tonic–clonic seizures monthly, even when at least two AEDs were administered), and completed the 6-month follow-up. The new International League Against Epilepsy classifications of seizures and epilepsy were applied in this study [9,10]. Patients were excluded if they had a seizure 72 h prior to study enrollment or if they had difficulty with conversation or written communication. 2.2. Study design This was a single-center 6-month longitudinal study investigating the changes in aggression in patients with refractory focal seizures following adjunctive therapy with perampanel. The study consisted of two treatment periods: a 12-week titration period and a 12-week maintenance period. During the titration period, the dose of perampanel was initially 2 mg once daily at bedtime and then was increased by 2 mg/day at ≥2-week intervals to a maximum of 12 mg/day. If participants experienced intolerable adverse events, the dose of perampanel was decreased. The final dose at the end of the titration period was used for the maintenance period unless the seizures were not adequately controlled; in these cases, the dose was increased to a maximum of 12 mg/day. Doses of concomitant AEDs were decreased as needed but not withdrawn. Seizure reduction was assessed via 50% responder rates, defined as the proportion of participants who had ≥50% reduction in total seizure frequency during the maintenance period. Patients completed a set of questionnaires assessing aggression, depression, and anxiety at the beginning and at the end of the study. Written informed consent was obtained from all subjects. The study design was approved by the Institutional Review Board of Asan Medical Center. 2.3. Measures The aggression questionnaire (AQ) comprises 29 items from four categories: physical aggression (nine items), verbal aggression (five items), anger (seven items), and hostility (eight items) [11]. Each item is rated on a 5-point Likert scale, with a score of 0 for “never” and a score of 4 for “always.” Scores for each item are then summed to obtain a total score, with higher scores representing higher levels of aggression. In this study, the validated Korean version of the Aggression Questionnaire (AQ) (AQ-K) was used [12], in which two of the original items from the anger category (“Some of my friends think I'm a hothead” and “Sometimes I fly off the handle for no good reason”) were omitted because they related more to verbal aggression and hostility than to anger. Thus, 27 items were represented for the evaluation of aggression, with a maximal possible score of 108 [12]. Symptoms of anxiety and depression were measured using the Korean version of the hospital anxiety depression scale (HADS). This tool comprises 14 items: seven related to anxiety (HADS-A) and seven related to depression (HADS-D) [13]. Items are scored on a scale from 0 (no distress) to 3 (significant distress), generating a maximum possible score of 21 for each portion, with higher scores representing higher levels of depression and anxiety.
for nominal variables. Paired t-tests were used to determine whether scores from the AQ-K, HADS-A, and HADS-D at the time of study enrollment (i.e., baseline) were significantly different from those at the end of the study. A stepwise linear regression analysis, with a p-value of N 0.1 as an exit criterion and a p-value of b0.05 as an entry criterion, was used to identify factors predicting changes in scores after 6 months of adjunctive treatment with perampanel. The dependent variables were the score differences (baseline score minus score at the end of the study), such that a negative score was indicative of an aggravation of aggression. The independent variables included age, sex, and psychological, epilepsy-related, and AED-related variables. Specifically, psychological variables included baseline and difference scores for the HADS and AQ-K. Epilepsy-related variables were age at seizure onset, duration of epilepsy, seizure frequency (monthly vs. weekly) during the 3 months prior to study enrollment, and recurrence of focal-to-bilateral tonic– clonic seizures during the 3 months prior to study enrollment. The AED-related variables were the speed of perampanel titration (2 or 3 weeks vs. 4 weeks), the maintenance dose of perampanel (4 mg vs. 6 mg vs. ≥8 mg), a ≥50% seizure reduction during the maintenance period, the number of concomitant AEDs, and the prescription of a concomitant AED in more than 25% of the participants. Univariate linear regression was used for univariate analyses, from which variables with a p-value of b 0.1 were entered into a stepwise linear regression model. Collinearity was determined for all multiple linear regression models by calculating the variance inflation factor; regression models with a variance inflation factor of N5 were excluded because of significant collinearity. All statistical tests were two tailed, and a p-value of b0.05 was considered significant. Data were analyzed using the Statistical Package for the Social Sciences version 21.0 (IBM Corp., Armonk, NY, USA). 3. Results 3.1. Subjects Of the 42 patients enrolled, ten were excluded from the study because of dizziness and/or falling (n = 5), aggressive behaviors (n = 1), suicidal ideation (n = 1), hypersomnia (n = 1), aggravation of seizures (n = 1), and withdrawal of consent after judging the effect of perampanel to be insufficient (n = 1). Thus, 32 participants (19 male, 13 female; mean age, 42.4 ± 10.3 years) successfully completed the 6month study (Table 1). All the participants except one had focal epilepsy. Approximately 70% of participants had one or more seizures per month, and the remaining participants had one or more seizures per week. The average number of concomitant AEDs was 3.2 (SD, 0.9). Levetiracetam was the most frequent concomitant AED (65.6%), followed by valproic acid (53.1%), carbamazepine (53.1%), and topiramate (50.0%). At the end of the study period, the average daily dose of perampanel was 6.0 mg (SD, 1.8 mg), and 37.5% of patients had a ≥ 50% reduction in the frequency of seizures. 3.2. Changes in aggression, anxiety, and depressive symptoms The total AQ-K scores were higher at the end of the 6-month study period but were not statistically different from baseline (p = .066) (Table 2). This trend was noted for both physical aggression and anger (p = .069 and p = .073, respectively) but not for verbal aggression or hostility (Table 2). The HADS-A scores after 6 months were also not statistically different from baseline, but HADS-D scores were slightly higher at the end of the 6-month period (p = .098) (Table 2). 3.3. Factors contributing to changes in AQ-K scores
2.4. Statistical analysis Data are presented as means and standard deviations (SDs) or standard errors (SEs) for numeric variables, and numbers and percentages
Univariate analyses revealed that differences in total AQ-K scores were significantly related to HADS-D scores at baseline (p = .033) and to concomitant use of topiramate (p = .037) (Table 3). In addition,
Please cite this article as: S.-A. Lee, J.Y. Jeon and H.-W. Kim, Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study, Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.106658
S.-A. Lee et al. / Epilepsy & Behavior 102 (2020) 106658
3
3.4. Factors contributing to changes in scores for AQ-K categories
Table 1 Subject characteristics (n = 32). Age, years, mean (SD) Men, n (%) Age at seizure onset, years, mean (SD) Duration of epilepsy, years, mean (SD) Etiology of epilepsy, n (%) Central nervous system infection Hippocampal sclerosis Malformation of cortical development Traumatic Vascular Perinatal Unknown Epilepsy type, n (%) Focal Unknown Seizure type, n (%) Focal aware Focal impaired awareness Seizure frequency in the last 3 months, n (%) 1 or more per month 1 or more per week Presence of FBTCS in the last 3 months, n (%) Number of AEDs, mean (SD) Concomitant AEDs, n (%) Levetiracetam Valproic acid Carbamazepine Topiramate Pregabalin Oxcarbazepine Othersa Histories of psychiatric disorders, n (%) HADS-A scores ≥8, n (%) HADS-D scores ≥8, n (%) Perampanel, maintenance dose, mean (SD) Perampanel, maintenance dose, n (%) 4 mg 6 mg 8 mg 10 mg Titration speed of perampanel, n (%) 2 weeks 3 weeks 4 weeks 50% seizure responder rates of perampanel, n (%)
42.4 (10.3) 19 (59.4) 20.5 (12.6) 21.9 (10.1) 4 (12.5) 2 (6.3) 2 (6.3) 1 (3.1) 1 (3.1) 1 (3.1) 21 (65.6) 31 (96.9) 1 (3.1) 1 (3.1) 31 (96.9) 22 (68.8) 10 (31.3) 25 (78.1) 3.2 (0.9) 21 (65.6) 17 (53.1) 17 (53.1) 16 (50.0) 14 (43.8) 9 (28.1) 10 (31.3) 4 (12.5) 14 (43.8) 12 (37.5) 6.0 (1.8) 11 (34.4) 11 (34.4) 9 (28.1) 1 (3.1) 9 (28.1) 4 (12.5) 19 (59.4) 12 (37.5)
AED, antiepileptic drug; HADS-A, Hospital Anxiety Depression Scale-Anxiety; HADS-D, Hospital Anxiety Depression Scale-Depression; n, number; SD, standard deviation; FBTCS, focal to bilateral tonic–clonic seizures. a Zonisamide, lamotrigine, phenytoin, lacosamide, clobazam, and lorazepam were prescribed individually less than 10%.
baseline HADS-A scores were related to differences in total AQ-K scores (p = .064). A stepwise linear regression model identified HADS-D scores at baseline (B, − 1.461; SE, 0.665; p = .036) and concomitant use of topiramate (B, 10.491; SE, 4.409; p = .024) as independent factors associated with changes in total AQ-K scores (Table 4). Unexpectedly, the concomitant use of topiramate was protective against the increased aggression at the end of the 6-month study period. This model explained 28.3% of the variance in total AQ-K scores.
Variables with p-values of b0.1 in the univariate analyses are shown in Table 3, and these were applied to the stepwise linear regression model for individual categories of the AQ-K (Table 4). The differences between baseline and endpoint HADS-D scores were identified as independent factors for increases in physical aggression (B, 0.810; SE, 0.289; p = .009) and verbal aggression (B, 0.661; SE, 0.188; p = .001) (Table 4). Concomitant use of topiramate was identified as a protective factor against increases in verbal aggression (B, 2.914; SE, 1.111; p = .014) and anger (B, 2.375; SE, 1.027; p = .028). A perampanel dose of ≥8 mg at 6 months was identified as an independent factor for an increase in anger (B, −4.091; SE, 1.108; p = .001). These models for physical aggression, verbal aggression, and anger explained 20.7%, 38.3%, and 39.6% of the variance, respectively, in the individual categories of the AQ-K. For hostility, there were no factors significantly associated with differences from baseline. 3.5. Factors contributing to changes in HADS-D scores Univariate analyses revealed that a dose of perampanel of ≥8 mg at 6 months (p = .078), weekly seizure recurrence (p = .077), and concomitant use of pregabalin (p = .052) were related to differences in HADS-D scores (Table 5). A stepwise linear regression model identified a perampanel dose of ≥8 mg as an independent factor associated with an aggravation of depressive symptoms (B, − 2.318; SE, 1.087; p = .041) (Table 5). This model explained 13.2% of the variance in differences in HADS-D scores. 4. Discussion The aim of this study was to identify the clinical factors that contribute to aggression in patients with refractory focal epilepsy receiving perampanel. Our analyses identified the presence of depressive symptoms, an increase in these depressive symptoms after 6 months of adjunctive perampanel treatment, and a higher dose of perampanel (≥8 mg) as significant predictors of aggression. By contrast, concomitant use of topiramate was protective against increased aggression in these patients. Two patients (4.8%) dropped out of the study because of severe psychiatric adverse effects (1 each for aggression and suicidal ideation). This rate is comparable to that reported from an analysis of data pooled from three phase III studies [2–4], in which 2.5% of participants in the perampanel group dropped out of the study because of aggression, anger, and anxiety [14]. Similarly, a recent 3-month prospective study of perampanel conducted in Japan found that 3.9% of the patients discontinued perampanel because of psychiatric adverse effects [15]. The 50% responder rate in our study was 37.5%, which is also comparable to rates from the analysis of the three phase III studies for adjunctive perampanel for refractory focal seizures (4 mg, 28.5%; 8 mg, 35.3%; 12 mg, 35.0%) [14]. In the present study, we found that aggression (physical aggression and anger) and depressive symptoms were aggravated after 6 months
Table 2 Differences in scores of the AQ-K, HADS-A, and HADS-D over a 6-month period of the perampanel study.
AQ-K scores Physical aggression Verbal aggression Anger Hostility HADS-A scores HADS-D scores
At the baseline, mean (SD)
At the 6 months, mean (SD)
Differences between two measures, mean (SD)
p value
54.1 (14.0) 16.0 (5.9) 11.1 (3.4) 11.8 (3.4) 15.5 (5.4) 7.0 (4.0) 6.5 (3.4)
58.9 (21.3) 17.8 (6.9) 11.9 (4.6) 12.9 (4.2) 16.6 (11.0) 6.9 (4.9) 7.4 (4.8)
−4.8 (14.2) −1.8 (5.4) −0.8 (3.9) −1.2 (3.6) −1.1 (9.2) 0.1 (3.5) −0.9 (3.0)
0.066 0.069 0.280 0.073 0.517 0.882 0.098
AQ-K, Korean version of Aggression Questionnaire; HADS-A, Hospital Anxiety Depression Scale-Anxiety; HADS-D, Hospital Anxiety Depression Scale-Depression; SD, standard deviation.
Please cite this article as: S.-A. Lee, J.Y. Jeon and H.-W. Kim, Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study, Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.106658
4
S.-A. Lee et al. / Epilepsy & Behavior 102 (2020) 106658
Table 3 Univariate linear regression showing factors with p b .1 in association with differences in scores of the AQ-K and its subscales over a 6-month period of the perampanel study in patients with intractable epilepsy (n = 32). Differences in measures (at baseline minus at 6 months) Total AQ-K scores
HADS-A at baseline HADS-D at baseline Changes in HADS-Da Age, year Age at seizure onset, year Seizure recurrence, weekly Use of levetiracetam Use of topiramate Use of pregabalin Perampanel titration speed Perampanel dose ≥8mgb
Physical aggression
Verbal aggression
Anger
Hostility
B
SE
B
SE
B
SE
B
SE
B
SE
−1.136 −1.595⁎
0.622 0.712
– – – – 11.313⁎ – – –
– – – – 4.665 – – –
– – 0.810⁎⁎ 0.187⁎ 0.128 −3.809 −3.268 – – – –
– – 0.289 0.088 0.074 1.957 1.937 – – – –
– −0.406⁎ 0.624⁎⁎ – – – – 2.625 −3.365⁎ −2.429 –
– 0.196 0.205 – – – – 1.302 1.256 1.341 –
−0.322⁎ – 0.447⁎ 0.115 0.098 −2.927⁎ – 2.375 – – −5.182⁎⁎⁎
0.156 – 0.203 0.060 0.049 1.295 – 1.224 – – 1.317
– – −0.922 – – – – – – – –
– – 0.531 – – – – – – – –
AQ-K, Korean version of Aggression Questionnaire; B, unstandardized coefficients; beta, standardized coefficients; HADS-A, Hospital Anxiety Depression Scale-Anxiety; HADS-D, Hospital Anxiety Depression Scale-Depression; SE, standard error. a Differences in HADS-D scores over a 6-month period (at baseline minus at 6 months). b Reference: peramapanel dose 4 mg. ⁎ p b .05. ⁎⁎ p b .01. ⁎⁎⁎ p b .001.
of perampanel treatment. However, the small sample size in this study may have prevented these from reaching statistical significance. Indeed, p-values just above the conventional cutoff value of 0.05 in studies with small population sizes do not confirm a lack of an effect but rather indicate that “there is some evidence of an effect, but the result has just missed statistical significance” [16,17]. In a Japanese study with a larger sample size (n = 59), perampanel administration significantly aggravated both aggression and depressed mood over a 3-month period as measured using the AQ and the Neurological Disorders Depression Inventory for Epilepsy, respectively [15]. In the present study, the presence of depressive symptoms before patients received perampanel was predictive of overall aggression, and an increase in depressive symptoms after receiving perampanel was predictive of physical and verbal aggression. The link between depression and aggressive behavior is well documented in the literature. For example, a recent longitudinal study based on a population without epilepsy conducted in Sweden found an association between a diagnosis of depression and violent crime, independent of potential confounding variables such as familial, sociodemographic, and individual factors [18]. A large multicenter study of Italian patients with epilepsy also found an association between psychiatric disturbances and aggression (i.e., AQ score) after adjusting for age and sex [19]. A Korean study using the AQ reported that depressive symptoms along with perceived stigma and anxiety were associated with aggression in PWE [20].
It is well known that perampanel-induced aggression is dose dependent. In addition to the effect reported by Ettlinger et al. [6], Chung et al. [8] showed that the frequency of aggressive behavior nearly doubled in patients receiving 6-mg perampanel compared with that in patients given 2- or 4-mg perampanel or a placebo. Although a statistically significant increase in aggression was not observed in the patients receiving ≥8 mg of perampanel in the present study, depressive symptoms became worse in these patients, and an increase in depressive symptoms at 6 months was significantly associated with increased physical and verbal aggression. Therefore, a high dose of perampanel may influence aggression directly and/or indirectly through an increase in depressive symptoms. The posthoc analysis of clinical trials reported by Chung et al. [8] indicates that topiramate and/or levetiracetam does not influence aggression-related adverse effects in patients receiving perampanel, and the longitudinal study conducted in Japan similarly found no impact of concomitant AEDs [15]. Unexpectedly, we found that concomitant use of topiramate was protective against increased aggression, particularly verbal aggression and anger. By contrast, topiramate is also associated with adverse psychiatric effects. In a prospective study in the United Kingdom, 7.6% of patients discontinued adjunctive topiramate treatment because of intolerable psychiatric effects, with 7.4% discontinuing zonisamide and 6.8% discontinuing levetiracetam, whereas only 1.9% of patients discontinued sodium channel-blocking AEDs, such as,
Table 4 Stepwise linear regression showing factors associated with differences in scores of the AQ-K and its subscales over a 6-month period of the perampanel study in patients with intractable epilepsy (n = 32). Differences in measures (at baseline minus at 6 months) Total scores of the AQ-K
HADS-D at baseline Changes in HADS-Da Use of topiramate Perampanel dose ≥8 mgb
Physical aggression
Verbal aggression
Anger
B
SE
beta
B
SE
beta
B
SE
beta
B
SE
beta
−1.461⁎ – 10.491⁎ –
0.665 – 4.409 –
−0.347 – 0.375 –
0.810⁎⁎ – –
0.289 – –
0.455 – –
0.661⁎⁎ 2.914⁎ –
0.188 1.111 –
0.515 0.383 –
– 2.375⁎ −4.091⁎⁎⁎
– 1.027 1.108
– 0.334 −0.533
AQ-K, Korean version of Aggression Questionnaire; B, unstandardized coefficients; beta, standardized coefficients; HADS-D, Hospital Anxiety Depression Scale-Depression; SE, standard error. a Differences in HADS-D scores over a 6-month period (at baseline minus at 6 months). b Reference: peramapanel dose 4 mg. ⁎ p b .05. ⁎⁎ p b .01. ⁎⁎⁎ p b .001.
Please cite this article as: S.-A. Lee, J.Y. Jeon and H.-W. Kim, Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study, Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.106658
S.-A. Lee et al. / Epilepsy & Behavior 102 (2020) 106658 Table 5 Linear regression showing factors associated with differences in scores of the HADS-D over a 6-month period of the perampanel study in patients with intractable epilepsy (n = 32). Differences in scores of the HADS-D (at baseline minus at 6 months) Univariate linear regression
Perampanel dose ≥8 mga Seizure recurrence, weekly Use of pregabalin
Stepwise linear regression
B
SE
p value
B
SE
p value
−2.318 −2.027 −2.071
1.267 1.106 1.022
0.078 0.077 0.052
−2.318 – –
1.087 – –
0.041 – –
B, unstandardized coefficients; beta, standardized coefficients; HADS-D, Hospital Anxiety Depression Scale-Depression; SE, standard error. a Reference: peramapanel dose 4 mg.
lacosamide and eslicarbazepine [21]. However, a recent study in the United States found a slightly lower discontinuation rate for topiramate (4.7%) and a much higher rate for levetiracetam (17.7%), as a result of intolerable psychiatric behavioral side effects (the rate for discontinuation of zonisamide at 7.9% is comparable to that of other studies) [22]. However, the behavioral effects of topiramate were not worse than those of carbamazepine in patients with benign Rolandic epilepsy [23], and positive behavioral effects were noted in PWE with intellectual disability [24]. Topiramate is often used as an adjunctive for treating behavioral problems in patients with neurological and psychiatric disorders. A randomized controlled trial of patients with Alzheimer's dementia found that low-dose topiramate (25–50 mg/day) was as effective as risperidone for controlling behavioral disturbances [25]. A recent comprehensive meta-analysis of randomized controlled trials in patients with schizophrenia and related diseases showed that the addition of topiramate was superior to antipsychotic monotherapy for treating overall, positive, and negative symptoms [26]. Furthermore, topiramate decreased aggressive behavior in patients with borderline personality disorder in three randomized controlled trials [27] and was also shown to reduce impulsive or addictive behaviors, such as, alcohol and cocaine use [28,29] and binge eating [30]. Therefore, larger confirmatory studies are needed to clarify the behavioral effects of topiramate, including the protection against aggressive behaviors in PWE reported here. Limitations should be noted when interpreting the results of the present study. First, the sample size in this study was relatively small (n = 32), making it more difficult to distinguish real effects from random variation [16]. Second, intelligence was not assessed, and information about the participants' education was not collected, although we did exclude those who were unable to read or understand the questionnaire. Low intelligence and a low level of education are considered risk factors for aggressive behaviors in PWE [19]. Patients with epilepsy who have graduated from high school reportedly have larger cognitive reserves and more adequate behavior than those with fewer years of formal education [31]. Lastly, the proportion of patients who discontinued the study was relatively high (23.8%) compared with discontinuation rates (8.1% and 14.6% for 4-mg and 8-mg perampanel, respectively) in a pooled analysis of phase III studies [14], which may have introduced bias. However, the proportion of patients who dropped out because of severe psychiatric adverse reactions was comparable to that reported in the pooled analysis [14]. In summary, the results from this study identify depressive symptoms and a high dose (≥8 mg) of perampanel as predictors for aggression in patients with refractory focal epilepsy receiving perampanel. By contrast, concomitant use of topiramate had protective effects on aggression in these patients. Additional studies comprising larger sample sizes and longer treatment durations are needed to confirm these effects. Nevertheless, these findings suggest that depressive symptoms should be evaluated in PWE before beginning regimens that involve concomitant perampanel.
5
Declaration of competing interest We declare no conflicts of interest in relation to this study. Acknowledgments This research was not supported by funding from agencies in the public, commercial, or not-for-profit sectors. References [1] Patsalos PN. The clinical pharmacology profile of the new antiepileptic drug perampanel: a novel noncompetitive AMPA receptor antagonist. Epilepsia 2015; 56:12–27. [2] French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology 2012;79:589–96. [3] French JA, Krauss GL, Steinhoff BJ, Squillacote D, Yang H, Kumar D, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia 2013;54:117–25. [4] Krauss GL, Serratosa JM, Villanueva V, Endziniene M, Hong Z, French J, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;78:1408–15. [5] French JA, Krauss GL, Wechsler RT, Wang XF, DiVentura B, Brandt C, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: a randomized trial. Neurology 2015;85:950–7. [6] Ettinger AB, LoPresti A, Yang H, Williams B, Zhou S, Fain R, et al. Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel. Epilepsia 2015;56:1252–63. [7] Hansen CC, Ljung H, Brodtkorb E, Reimers A. Mechanisms underlying aggressive behavior induced by antiepileptic drugs: focus on topiramate, levetiracetam, and perampanel. Behav Neurol 2018;15:2064027. [8] Chung S, Williams B, Dobrinsky C, Patten A, Yang H, Laurenza A. Perampanel with concomitant levetiracetam and topiramate: post hoc analysis of adverse events related to hostility and aggression. Epilepsy Behav 2017;75:79–85. [9] Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE commission for classification and terminology. Epilepsia 2017; 58:522–30. [10] Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia 2017;58:512–21. [11] Buss AH, Perry M. The aggression questionnaire. J Pers Soc Psychol 1992;63:452–9. [12] Seo SG, Kwon SM. Validation study of the Korean version of the Aggression Questionnaire. Korean J Clin Psychol 2002;21:487–501. [13] Oh SM, Min KJ, Park DB. A study of the standardization of the Hospital Anxiety and Depression Scale for Koreans — a comparison of normal, depressed and anxious groups. J Korean Neuropsychiatr Assoc 1999;38:289–96. [14] Steinhoff BJ, Ben-Menachem E, Ryvlin P, Shorvon S, Kramer L, Satlin A, et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia 2013;54:1481–9. [15] Goji H, Kanemoto K. The effect of perampanel on aggression and depression in patients with epilepsy: a short-term prospective study. Seizure 2019;67:1–4. [16] Hackshaw A. Small studies: strengths and limitations. Eur Respir J 2008;32:1141–3. [17] Altman DG, Bland JM. Absence of evidence is not evidence of absence. BMJ 1995; 311:485. [18] Fazel S, Wolf A, Chang Z, Larsson H, Goodwin GM, Lichtenstein P. Depression and violence: a Swedish population study. Lancet Psychiatry 2015;2:224–32. [19] Piazzini A, Bravi F, Edefonti V, Turner K, Vignoli A, Ferraroni M, et al. Aggressive behavior and epilepsy: a multicenter study. Epilepsia 2012;53:174–9. [20] Seo JG, Kim JM, Park SP. Perceived stigma is a critical factor for interictal aggression in people with epilepsy. Seizure 2015;26:26–31. [21] Stephen LJ, Wishart A, Brodie MJ. Psychiatric side effects and antiepileptic drugs: observations from prospective audits. Epilepsy Behav 2017;71:73–8. [22] Chen B, Choi H, Hirsch LJ, Katz A, Legge A, Buchsbaum R, et al. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy Behav 2017; 76:24–31. [23] Kang HC, Eun BL, Lee CW, Moon HK, Kim JS, Kim DW, et al. Korean Pediatric Topiramate Study Group. The effects on cognitive function and behavioral problems of topiramate compared to carbamazepine as monotherapy for children with benign rolandic epilepsy. Epilepsia 2007;48:1716–23. [24] Martin P, Schreiner A, Rettig K, Schäuble B. Topiramate in patients with epilepsy and intellectual disability. Epilepsy Behav 2009;14:496–502. [25] Mowla A, Pani A. Comparison of topiramate and risperidone for the treatment of behavioral disturbances of patients with Alzheimer disease: a double-blind, randomized clinical trial. J Clin Psychopharmacol 2010;30:40–3. [26] Zheng W, Xiang YT, Xiang YQ, Li XB, Ungvari GS, Chiu HF, Correll CU. Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand 2016;134:385–38. [27] Comai S, Tau M, Pavlovic Z, Gobbi G. The psychopharmacology of aggressive behavior: a translational approach: part 2: clinical studies using atypical antipsychotics, anticonvulsants, and lithium. J Clin Psychopharmacol 2012;32:237–60.
Please cite this article as: S.-A. Lee, J.Y. Jeon and H.-W. Kim, Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study, Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.106658
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study Sang-Ahm Lee ⁎, Ji Ye Jeon, Hyun-Woo Kim Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 2 October 2019 Accepted 25 October 2019 Available online xxxx Keywords: Epilepsy Refractory focal seizures Aggression Depression Perampanel Topiramate
a b s t r a c t Purpose: Clinical trials have demonstrated the efficacy of perampanel for the treatment of epilepsy. However, patients treated with this and other antiepileptic drugs often exhibit aggressive behaviors. We investigated the clinical factors contributing to aggression in patients with refractory focal epilepsy during 6 months of adjunctive perampanel treatment. Methods: This was a single-center longitudinal study involving patients treated with perampanel (starting dose, 2 mg/day; maximal dose, 12 mg/day). Patients were assessed with an aggression questionnaire (Korean version of Aggression Questionnaire [AQ-K]) and the hospital anxiety depression scale (HADS) at the beginning of the study and after receiving treatment for 6 months. Paired t-tests were used to compare AQ-K and HADS scores at the beginning of the study with those recorded at the end, and stepwise linear regression models were applied to identify predictive factors. Results: Thirty-two patients (mean age, 42.4 ± 10.3 years) successfully completed the 6-month study. The AQ-K and HADS scores increased after 6 months of adjunctive perampanel treatment (p b .1). The HADS scores related to depression at baseline predicted changes in total AQ-K scores, whereas the change in this HADS score was a predictor of physical and verbal aggression. A perampanel dose of ≥8 mg was a predictive factor for changes in anger and HADS scores related to depression after 6 months. Unexpectedly, concomitant use of topiramate had protective effects on AQ-K scores (including for verbal aggression and anger) in patients receiving perampanel. Conclusion: Depressive symptoms and a high dose of perampanel are potential predictors for aggression, whereas concomitant use of topiramate is protective against aggression in patients receiving perampanel for focal epilepsy. © 2019 Elsevier Inc. All rights reserved.
1. Introduction Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, is a novel antiepileptic drug (AED) with a broad spectrum of anticonvulsant activities [1]. Phase III randomized controlled trials have established the clinical efficacy and safety of perampanel as adjunctive treatment for partial onset seizures with or without secondary generalization [2–4] as well as for primary generalized tonic–clonic seizures [5]. However, similarly to other AEDs, perampanel can contribute to psychiatric and behavioral symptoms such as aggression, depression, and suicidal ideation in persons with epilepsy (PWE) [6]. An analysis of data pooled from three phase III studies [2–4] revealed that 2.8% and 6.3% of patients with partial onset seizures given 8-mg and 12-mg perampanel, respectively,
exhibited aggressive behavior compared with only 0.7% of those given a placebo [6]. Aggression in PWE may thus be a problem with the use of perampanel in everyday clinical practice, and particular care should be taken when prescribing perampanel for patients with a high risk of aggression. A recent posthoc analysis of data pooled from four phase III trials [2–5] found that concomitant administration of levetiracetam and/or topiramate, both of which are shown to induce aggressive behavior in PWE [7], did not increase the risk of aggression-related adverse effects in patients receiving perampanel [8]. However, the clinical factors that predict the development or aggravation of aggression with adjunctive perampanel treatment are not known. To begin to address this, we examined changes in aggression over 6 months in patients with refractory focal epilepsy treated with perampanel.
⁎ Corresponding author at: Department of Neurology, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. E-mail address: [email protected] (S.-A. Lee).
https://doi.org/10.1016/j.yebeh.2019.106658 1525-5050/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: S.-A. Lee, J.Y. Jeon and H.-W. Kim, Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study, Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.106658
2
S.-A. Lee et al. / Epilepsy & Behavior 102 (2020) 106658
2. Methods 2.1. Subjects Patients with intractable epilepsy who visited Asan Medical Center from October 2016 to April 2017 and agreed to use perampanel as adjunctive therapy were recruited for this study. Patients eligible for inclusion in the study were between 19 and 65 years of age, had refractory focal seizures (defined as recurring focal or focal-to-bilateral generalized tonic–clonic seizures monthly, even when at least two AEDs were administered), and completed the 6-month follow-up. The new International League Against Epilepsy classifications of seizures and epilepsy were applied in this study [9,10]. Patients were excluded if they had a seizure 72 h prior to study enrollment or if they had difficulty with conversation or written communication. 2.2. Study design This was a single-center 6-month longitudinal study investigating the changes in aggression in patients with refractory focal seizures following adjunctive therapy with perampanel. The study consisted of two treatment periods: a 12-week titration period and a 12-week maintenance period. During the titration period, the dose of perampanel was initially 2 mg once daily at bedtime and then was increased by 2 mg/day at ≥2-week intervals to a maximum of 12 mg/day. If participants experienced intolerable adverse events, the dose of perampanel was decreased. The final dose at the end of the titration period was used for the maintenance period unless the seizures were not adequately controlled; in these cases, the dose was increased to a maximum of 12 mg/day. Doses of concomitant AEDs were decreased as needed but not withdrawn. Seizure reduction was assessed via 50% responder rates, defined as the proportion of participants who had ≥50% reduction in total seizure frequency during the maintenance period. Patients completed a set of questionnaires assessing aggression, depression, and anxiety at the beginning and at the end of the study. Written informed consent was obtained from all subjects. The study design was approved by the Institutional Review Board of Asan Medical Center. 2.3. Measures The aggression questionnaire (AQ) comprises 29 items from four categories: physical aggression (nine items), verbal aggression (five items), anger (seven items), and hostility (eight items) [11]. Each item is rated on a 5-point Likert scale, with a score of 0 for “never” and a score of 4 for “always.” Scores for each item are then summed to obtain a total score, with higher scores representing higher levels of aggression. In this study, the validated Korean version of the Aggression Questionnaire (AQ) (AQ-K) was used [12], in which two of the original items from the anger category (“Some of my friends think I'm a hothead” and “Sometimes I fly off the handle for no good reason”) were omitted because they related more to verbal aggression and hostility than to anger. Thus, 27 items were represented for the evaluation of aggression, with a maximal possible score of 108 [12]. Symptoms of anxiety and depression were measured using the Korean version of the hospital anxiety depression scale (HADS). This tool comprises 14 items: seven related to anxiety (HADS-A) and seven related to depression (HADS-D) [13]. Items are scored on a scale from 0 (no distress) to 3 (significant distress), generating a maximum possible score of 21 for each portion, with higher scores representing higher levels of depression and anxiety.
for nominal variables. Paired t-tests were used to determine whether scores from the AQ-K, HADS-A, and HADS-D at the time of study enrollment (i.e., baseline) were significantly different from those at the end of the study. A stepwise linear regression analysis, with a p-value of N 0.1 as an exit criterion and a p-value of b0.05 as an entry criterion, was used to identify factors predicting changes in scores after 6 months of adjunctive treatment with perampanel. The dependent variables were the score differences (baseline score minus score at the end of the study), such that a negative score was indicative of an aggravation of aggression. The independent variables included age, sex, and psychological, epilepsy-related, and AED-related variables. Specifically, psychological variables included baseline and difference scores for the HADS and AQ-K. Epilepsy-related variables were age at seizure onset, duration of epilepsy, seizure frequency (monthly vs. weekly) during the 3 months prior to study enrollment, and recurrence of focal-to-bilateral tonic– clonic seizures during the 3 months prior to study enrollment. The AED-related variables were the speed of perampanel titration (2 or 3 weeks vs. 4 weeks), the maintenance dose of perampanel (4 mg vs. 6 mg vs. ≥8 mg), a ≥50% seizure reduction during the maintenance period, the number of concomitant AEDs, and the prescription of a concomitant AED in more than 25% of the participants. Univariate linear regression was used for univariate analyses, from which variables with a p-value of b 0.1 were entered into a stepwise linear regression model. Collinearity was determined for all multiple linear regression models by calculating the variance inflation factor; regression models with a variance inflation factor of N5 were excluded because of significant collinearity. All statistical tests were two tailed, and a p-value of b0.05 was considered significant. Data were analyzed using the Statistical Package for the Social Sciences version 21.0 (IBM Corp., Armonk, NY, USA). 3. Results 3.1. Subjects Of the 42 patients enrolled, ten were excluded from the study because of dizziness and/or falling (n = 5), aggressive behaviors (n = 1), suicidal ideation (n = 1), hypersomnia (n = 1), aggravation of seizures (n = 1), and withdrawal of consent after judging the effect of perampanel to be insufficient (n = 1). Thus, 32 participants (19 male, 13 female; mean age, 42.4 ± 10.3 years) successfully completed the 6month study (Table 1). All the participants except one had focal epilepsy. Approximately 70% of participants had one or more seizures per month, and the remaining participants had one or more seizures per week. The average number of concomitant AEDs was 3.2 (SD, 0.9). Levetiracetam was the most frequent concomitant AED (65.6%), followed by valproic acid (53.1%), carbamazepine (53.1%), and topiramate (50.0%). At the end of the study period, the average daily dose of perampanel was 6.0 mg (SD, 1.8 mg), and 37.5% of patients had a ≥ 50% reduction in the frequency of seizures. 3.2. Changes in aggression, anxiety, and depressive symptoms The total AQ-K scores were higher at the end of the 6-month study period but were not statistically different from baseline (p = .066) (Table 2). This trend was noted for both physical aggression and anger (p = .069 and p = .073, respectively) but not for verbal aggression or hostility (Table 2). The HADS-A scores after 6 months were also not statistically different from baseline, but HADS-D scores were slightly higher at the end of the 6-month period (p = .098) (Table 2). 3.3. Factors contributing to changes in AQ-K scores
2.4. Statistical analysis Data are presented as means and standard deviations (SDs) or standard errors (SEs) for numeric variables, and numbers and percentages
Univariate analyses revealed that differences in total AQ-K scores were significantly related to HADS-D scores at baseline (p = .033) and to concomitant use of topiramate (p = .037) (Table 3). In addition,
Please cite this article as: S.-A. Lee, J.Y. Jeon and H.-W. Kim, Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study, Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.106658
S.-A. Lee et al. / Epilepsy & Behavior 102 (2020) 106658
3
3.4. Factors contributing to changes in scores for AQ-K categories
Table 1 Subject characteristics (n = 32). Age, years, mean (SD) Men, n (%) Age at seizure onset, years, mean (SD) Duration of epilepsy, years, mean (SD) Etiology of epilepsy, n (%) Central nervous system infection Hippocampal sclerosis Malformation of cortical development Traumatic Vascular Perinatal Unknown Epilepsy type, n (%) Focal Unknown Seizure type, n (%) Focal aware Focal impaired awareness Seizure frequency in the last 3 months, n (%) 1 or more per month 1 or more per week Presence of FBTCS in the last 3 months, n (%) Number of AEDs, mean (SD) Concomitant AEDs, n (%) Levetiracetam Valproic acid Carbamazepine Topiramate Pregabalin Oxcarbazepine Othersa Histories of psychiatric disorders, n (%) HADS-A scores ≥8, n (%) HADS-D scores ≥8, n (%) Perampanel, maintenance dose, mean (SD) Perampanel, maintenance dose, n (%) 4 mg 6 mg 8 mg 10 mg Titration speed of perampanel, n (%) 2 weeks 3 weeks 4 weeks 50% seizure responder rates of perampanel, n (%)
42.4 (10.3) 19 (59.4) 20.5 (12.6) 21.9 (10.1) 4 (12.5) 2 (6.3) 2 (6.3) 1 (3.1) 1 (3.1) 1 (3.1) 21 (65.6) 31 (96.9) 1 (3.1) 1 (3.1) 31 (96.9) 22 (68.8) 10 (31.3) 25 (78.1) 3.2 (0.9) 21 (65.6) 17 (53.1) 17 (53.1) 16 (50.0) 14 (43.8) 9 (28.1) 10 (31.3) 4 (12.5) 14 (43.8) 12 (37.5) 6.0 (1.8) 11 (34.4) 11 (34.4) 9 (28.1) 1 (3.1) 9 (28.1) 4 (12.5) 19 (59.4) 12 (37.5)
AED, antiepileptic drug; HADS-A, Hospital Anxiety Depression Scale-Anxiety; HADS-D, Hospital Anxiety Depression Scale-Depression; n, number; SD, standard deviation; FBTCS, focal to bilateral tonic–clonic seizures. a Zonisamide, lamotrigine, phenytoin, lacosamide, clobazam, and lorazepam were prescribed individually less than 10%.
baseline HADS-A scores were related to differences in total AQ-K scores (p = .064). A stepwise linear regression model identified HADS-D scores at baseline (B, − 1.461; SE, 0.665; p = .036) and concomitant use of topiramate (B, 10.491; SE, 4.409; p = .024) as independent factors associated with changes in total AQ-K scores (Table 4). Unexpectedly, the concomitant use of topiramate was protective against the increased aggression at the end of the 6-month study period. This model explained 28.3% of the variance in total AQ-K scores.
Variables with p-values of b0.1 in the univariate analyses are shown in Table 3, and these were applied to the stepwise linear regression model for individual categories of the AQ-K (Table 4). The differences between baseline and endpoint HADS-D scores were identified as independent factors for increases in physical aggression (B, 0.810; SE, 0.289; p = .009) and verbal aggression (B, 0.661; SE, 0.188; p = .001) (Table 4). Concomitant use of topiramate was identified as a protective factor against increases in verbal aggression (B, 2.914; SE, 1.111; p = .014) and anger (B, 2.375; SE, 1.027; p = .028). A perampanel dose of ≥8 mg at 6 months was identified as an independent factor for an increase in anger (B, −4.091; SE, 1.108; p = .001). These models for physical aggression, verbal aggression, and anger explained 20.7%, 38.3%, and 39.6% of the variance, respectively, in the individual categories of the AQ-K. For hostility, there were no factors significantly associated with differences from baseline. 3.5. Factors contributing to changes in HADS-D scores Univariate analyses revealed that a dose of perampanel of ≥8 mg at 6 months (p = .078), weekly seizure recurrence (p = .077), and concomitant use of pregabalin (p = .052) were related to differences in HADS-D scores (Table 5). A stepwise linear regression model identified a perampanel dose of ≥8 mg as an independent factor associated with an aggravation of depressive symptoms (B, − 2.318; SE, 1.087; p = .041) (Table 5). This model explained 13.2% of the variance in differences in HADS-D scores. 4. Discussion The aim of this study was to identify the clinical factors that contribute to aggression in patients with refractory focal epilepsy receiving perampanel. Our analyses identified the presence of depressive symptoms, an increase in these depressive symptoms after 6 months of adjunctive perampanel treatment, and a higher dose of perampanel (≥8 mg) as significant predictors of aggression. By contrast, concomitant use of topiramate was protective against increased aggression in these patients. Two patients (4.8%) dropped out of the study because of severe psychiatric adverse effects (1 each for aggression and suicidal ideation). This rate is comparable to that reported from an analysis of data pooled from three phase III studies [2–4], in which 2.5% of participants in the perampanel group dropped out of the study because of aggression, anger, and anxiety [14]. Similarly, a recent 3-month prospective study of perampanel conducted in Japan found that 3.9% of the patients discontinued perampanel because of psychiatric adverse effects [15]. The 50% responder rate in our study was 37.5%, which is also comparable to rates from the analysis of the three phase III studies for adjunctive perampanel for refractory focal seizures (4 mg, 28.5%; 8 mg, 35.3%; 12 mg, 35.0%) [14]. In the present study, we found that aggression (physical aggression and anger) and depressive symptoms were aggravated after 6 months
Table 2 Differences in scores of the AQ-K, HADS-A, and HADS-D over a 6-month period of the perampanel study.
AQ-K scores Physical aggression Verbal aggression Anger Hostility HADS-A scores HADS-D scores
At the baseline, mean (SD)
At the 6 months, mean (SD)
Differences between two measures, mean (SD)
p value
54.1 (14.0) 16.0 (5.9) 11.1 (3.4) 11.8 (3.4) 15.5 (5.4) 7.0 (4.0) 6.5 (3.4)
58.9 (21.3) 17.8 (6.9) 11.9 (4.6) 12.9 (4.2) 16.6 (11.0) 6.9 (4.9) 7.4 (4.8)
−4.8 (14.2) −1.8 (5.4) −0.8 (3.9) −1.2 (3.6) −1.1 (9.2) 0.1 (3.5) −0.9 (3.0)
0.066 0.069 0.280 0.073 0.517 0.882 0.098
AQ-K, Korean version of Aggression Questionnaire; HADS-A, Hospital Anxiety Depression Scale-Anxiety; HADS-D, Hospital Anxiety Depression Scale-Depression; SD, standard deviation.
Please cite this article as: S.-A. Lee, J.Y. Jeon and H.-W. Kim, Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study, Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.106658
4
S.-A. Lee et al. / Epilepsy & Behavior 102 (2020) 106658
Table 3 Univariate linear regression showing factors with p b .1 in association with differences in scores of the AQ-K and its subscales over a 6-month period of the perampanel study in patients with intractable epilepsy (n = 32). Differences in measures (at baseline minus at 6 months) Total AQ-K scores
HADS-A at baseline HADS-D at baseline Changes in HADS-Da Age, year Age at seizure onset, year Seizure recurrence, weekly Use of levetiracetam Use of topiramate Use of pregabalin Perampanel titration speed Perampanel dose ≥8mgb
Physical aggression
Verbal aggression
Anger
Hostility
B
SE
B
SE
B
SE
B
SE
B
SE
−1.136 −1.595⁎
0.622 0.712
– – – – 11.313⁎ – – –
– – – – 4.665 – – –
– – 0.810⁎⁎ 0.187⁎ 0.128 −3.809 −3.268 – – – –
– – 0.289 0.088 0.074 1.957 1.937 – – – –
– −0.406⁎ 0.624⁎⁎ – – – – 2.625 −3.365⁎ −2.429 –
– 0.196 0.205 – – – – 1.302 1.256 1.341 –
−0.322⁎ – 0.447⁎ 0.115 0.098 −2.927⁎ – 2.375 – – −5.182⁎⁎⁎
0.156 – 0.203 0.060 0.049 1.295 – 1.224 – – 1.317
– – −0.922 – – – – – – – –
– – 0.531 – – – – – – – –
AQ-K, Korean version of Aggression Questionnaire; B, unstandardized coefficients; beta, standardized coefficients; HADS-A, Hospital Anxiety Depression Scale-Anxiety; HADS-D, Hospital Anxiety Depression Scale-Depression; SE, standard error. a Differences in HADS-D scores over a 6-month period (at baseline minus at 6 months). b Reference: peramapanel dose 4 mg. ⁎ p b .05. ⁎⁎ p b .01. ⁎⁎⁎ p b .001.
of perampanel treatment. However, the small sample size in this study may have prevented these from reaching statistical significance. Indeed, p-values just above the conventional cutoff value of 0.05 in studies with small population sizes do not confirm a lack of an effect but rather indicate that “there is some evidence of an effect, but the result has just missed statistical significance” [16,17]. In a Japanese study with a larger sample size (n = 59), perampanel administration significantly aggravated both aggression and depressed mood over a 3-month period as measured using the AQ and the Neurological Disorders Depression Inventory for Epilepsy, respectively [15]. In the present study, the presence of depressive symptoms before patients received perampanel was predictive of overall aggression, and an increase in depressive symptoms after receiving perampanel was predictive of physical and verbal aggression. The link between depression and aggressive behavior is well documented in the literature. For example, a recent longitudinal study based on a population without epilepsy conducted in Sweden found an association between a diagnosis of depression and violent crime, independent of potential confounding variables such as familial, sociodemographic, and individual factors [18]. A large multicenter study of Italian patients with epilepsy also found an association between psychiatric disturbances and aggression (i.e., AQ score) after adjusting for age and sex [19]. A Korean study using the AQ reported that depressive symptoms along with perceived stigma and anxiety were associated with aggression in PWE [20].
It is well known that perampanel-induced aggression is dose dependent. In addition to the effect reported by Ettlinger et al. [6], Chung et al. [8] showed that the frequency of aggressive behavior nearly doubled in patients receiving 6-mg perampanel compared with that in patients given 2- or 4-mg perampanel or a placebo. Although a statistically significant increase in aggression was not observed in the patients receiving ≥8 mg of perampanel in the present study, depressive symptoms became worse in these patients, and an increase in depressive symptoms at 6 months was significantly associated with increased physical and verbal aggression. Therefore, a high dose of perampanel may influence aggression directly and/or indirectly through an increase in depressive symptoms. The posthoc analysis of clinical trials reported by Chung et al. [8] indicates that topiramate and/or levetiracetam does not influence aggression-related adverse effects in patients receiving perampanel, and the longitudinal study conducted in Japan similarly found no impact of concomitant AEDs [15]. Unexpectedly, we found that concomitant use of topiramate was protective against increased aggression, particularly verbal aggression and anger. By contrast, topiramate is also associated with adverse psychiatric effects. In a prospective study in the United Kingdom, 7.6% of patients discontinued adjunctive topiramate treatment because of intolerable psychiatric effects, with 7.4% discontinuing zonisamide and 6.8% discontinuing levetiracetam, whereas only 1.9% of patients discontinued sodium channel-blocking AEDs, such as,
Table 4 Stepwise linear regression showing factors associated with differences in scores of the AQ-K and its subscales over a 6-month period of the perampanel study in patients with intractable epilepsy (n = 32). Differences in measures (at baseline minus at 6 months) Total scores of the AQ-K
HADS-D at baseline Changes in HADS-Da Use of topiramate Perampanel dose ≥8 mgb
Physical aggression
Verbal aggression
Anger
B
SE
beta
B
SE
beta
B
SE
beta
B
SE
beta
−1.461⁎ – 10.491⁎ –
0.665 – 4.409 –
−0.347 – 0.375 –
0.810⁎⁎ – –
0.289 – –
0.455 – –
0.661⁎⁎ 2.914⁎ –
0.188 1.111 –
0.515 0.383 –
– 2.375⁎ −4.091⁎⁎⁎
– 1.027 1.108
– 0.334 −0.533
AQ-K, Korean version of Aggression Questionnaire; B, unstandardized coefficients; beta, standardized coefficients; HADS-D, Hospital Anxiety Depression Scale-Depression; SE, standard error. a Differences in HADS-D scores over a 6-month period (at baseline minus at 6 months). b Reference: peramapanel dose 4 mg. ⁎ p b .05. ⁎⁎ p b .01. ⁎⁎⁎ p b .001.
Please cite this article as: S.-A. Lee, J.Y. Jeon and H.-W. Kim, Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study, Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.106658
S.-A. Lee et al. / Epilepsy & Behavior 102 (2020) 106658 Table 5 Linear regression showing factors associated with differences in scores of the HADS-D over a 6-month period of the perampanel study in patients with intractable epilepsy (n = 32). Differences in scores of the HADS-D (at baseline minus at 6 months) Univariate linear regression
Perampanel dose ≥8 mga Seizure recurrence, weekly Use of pregabalin
Stepwise linear regression
B
SE
p value
B
SE
p value
−2.318 −2.027 −2.071
1.267 1.106 1.022
0.078 0.077 0.052
−2.318 – –
1.087 – –
0.041 – –
B, unstandardized coefficients; beta, standardized coefficients; HADS-D, Hospital Anxiety Depression Scale-Depression; SE, standard error. a Reference: peramapanel dose 4 mg.
lacosamide and eslicarbazepine [21]. However, a recent study in the United States found a slightly lower discontinuation rate for topiramate (4.7%) and a much higher rate for levetiracetam (17.7%), as a result of intolerable psychiatric behavioral side effects (the rate for discontinuation of zonisamide at 7.9% is comparable to that of other studies) [22]. However, the behavioral effects of topiramate were not worse than those of carbamazepine in patients with benign Rolandic epilepsy [23], and positive behavioral effects were noted in PWE with intellectual disability [24]. Topiramate is often used as an adjunctive for treating behavioral problems in patients with neurological and psychiatric disorders. A randomized controlled trial of patients with Alzheimer's dementia found that low-dose topiramate (25–50 mg/day) was as effective as risperidone for controlling behavioral disturbances [25]. A recent comprehensive meta-analysis of randomized controlled trials in patients with schizophrenia and related diseases showed that the addition of topiramate was superior to antipsychotic monotherapy for treating overall, positive, and negative symptoms [26]. Furthermore, topiramate decreased aggressive behavior in patients with borderline personality disorder in three randomized controlled trials [27] and was also shown to reduce impulsive or addictive behaviors, such as, alcohol and cocaine use [28,29] and binge eating [30]. Therefore, larger confirmatory studies are needed to clarify the behavioral effects of topiramate, including the protection against aggressive behaviors in PWE reported here. Limitations should be noted when interpreting the results of the present study. First, the sample size in this study was relatively small (n = 32), making it more difficult to distinguish real effects from random variation [16]. Second, intelligence was not assessed, and information about the participants' education was not collected, although we did exclude those who were unable to read or understand the questionnaire. Low intelligence and a low level of education are considered risk factors for aggressive behaviors in PWE [19]. Patients with epilepsy who have graduated from high school reportedly have larger cognitive reserves and more adequate behavior than those with fewer years of formal education [31]. Lastly, the proportion of patients who discontinued the study was relatively high (23.8%) compared with discontinuation rates (8.1% and 14.6% for 4-mg and 8-mg perampanel, respectively) in a pooled analysis of phase III studies [14], which may have introduced bias. However, the proportion of patients who dropped out because of severe psychiatric adverse reactions was comparable to that reported in the pooled analysis [14]. In summary, the results from this study identify depressive symptoms and a high dose (≥8 mg) of perampanel as predictors for aggression in patients with refractory focal epilepsy receiving perampanel. By contrast, concomitant use of topiramate had protective effects on aggression in these patients. Additional studies comprising larger sample sizes and longer treatment durations are needed to confirm these effects. Nevertheless, these findings suggest that depressive symptoms should be evaluated in PWE before beginning regimens that involve concomitant perampanel.
5
Declaration of competing interest We declare no conflicts of interest in relation to this study. Acknowledgments This research was not supported by funding from agencies in the public, commercial, or not-for-profit sectors. References [1] Patsalos PN. The clinical pharmacology profile of the new antiepileptic drug perampanel: a novel noncompetitive AMPA receptor antagonist. Epilepsia 2015; 56:12–27. [2] French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology 2012;79:589–96. [3] French JA, Krauss GL, Steinhoff BJ, Squillacote D, Yang H, Kumar D, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia 2013;54:117–25. [4] Krauss GL, Serratosa JM, Villanueva V, Endziniene M, Hong Z, French J, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;78:1408–15. [5] French JA, Krauss GL, Wechsler RT, Wang XF, DiVentura B, Brandt C, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: a randomized trial. Neurology 2015;85:950–7. [6] Ettinger AB, LoPresti A, Yang H, Williams B, Zhou S, Fain R, et al. Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel. Epilepsia 2015;56:1252–63. [7] Hansen CC, Ljung H, Brodtkorb E, Reimers A. Mechanisms underlying aggressive behavior induced by antiepileptic drugs: focus on topiramate, levetiracetam, and perampanel. Behav Neurol 2018;15:2064027. [8] Chung S, Williams B, Dobrinsky C, Patten A, Yang H, Laurenza A. Perampanel with concomitant levetiracetam and topiramate: post hoc analysis of adverse events related to hostility and aggression. Epilepsy Behav 2017;75:79–85. [9] Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE commission for classification and terminology. Epilepsia 2017; 58:522–30. [10] Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia 2017;58:512–21. [11] Buss AH, Perry M. The aggression questionnaire. J Pers Soc Psychol 1992;63:452–9. [12] Seo SG, Kwon SM. Validation study of the Korean version of the Aggression Questionnaire. Korean J Clin Psychol 2002;21:487–501. [13] Oh SM, Min KJ, Park DB. A study of the standardization of the Hospital Anxiety and Depression Scale for Koreans — a comparison of normal, depressed and anxious groups. J Korean Neuropsychiatr Assoc 1999;38:289–96. [14] Steinhoff BJ, Ben-Menachem E, Ryvlin P, Shorvon S, Kramer L, Satlin A, et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia 2013;54:1481–9. [15] Goji H, Kanemoto K. The effect of perampanel on aggression and depression in patients with epilepsy: a short-term prospective study. Seizure 2019;67:1–4. [16] Hackshaw A. Small studies: strengths and limitations. Eur Respir J 2008;32:1141–3. [17] Altman DG, Bland JM. Absence of evidence is not evidence of absence. BMJ 1995; 311:485. [18] Fazel S, Wolf A, Chang Z, Larsson H, Goodwin GM, Lichtenstein P. Depression and violence: a Swedish population study. Lancet Psychiatry 2015;2:224–32. [19] Piazzini A, Bravi F, Edefonti V, Turner K, Vignoli A, Ferraroni M, et al. Aggressive behavior and epilepsy: a multicenter study. Epilepsia 2012;53:174–9. [20] Seo JG, Kim JM, Park SP. Perceived stigma is a critical factor for interictal aggression in people with epilepsy. Seizure 2015;26:26–31. [21] Stephen LJ, Wishart A, Brodie MJ. Psychiatric side effects and antiepileptic drugs: observations from prospective audits. Epilepsy Behav 2017;71:73–8. [22] Chen B, Choi H, Hirsch LJ, Katz A, Legge A, Buchsbaum R, et al. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy Behav 2017; 76:24–31. [23] Kang HC, Eun BL, Lee CW, Moon HK, Kim JS, Kim DW, et al. Korean Pediatric Topiramate Study Group. The effects on cognitive function and behavioral problems of topiramate compared to carbamazepine as monotherapy for children with benign rolandic epilepsy. Epilepsia 2007;48:1716–23. [24] Martin P, Schreiner A, Rettig K, Schäuble B. Topiramate in patients with epilepsy and intellectual disability. Epilepsy Behav 2009;14:496–502. [25] Mowla A, Pani A. Comparison of topiramate and risperidone for the treatment of behavioral disturbances of patients with Alzheimer disease: a double-blind, randomized clinical trial. J Clin Psychopharmacol 2010;30:40–3. [26] Zheng W, Xiang YT, Xiang YQ, Li XB, Ungvari GS, Chiu HF, Correll CU. Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand 2016;134:385–38. [27] Comai S, Tau M, Pavlovic Z, Gobbi G. The psychopharmacology of aggressive behavior: a translational approach: part 2: clinical studies using atypical antipsychotics, anticonvulsants, and lithium. J Clin Psychopharmacol 2012;32:237–60.
Please cite this article as: S.-A. Lee, J.Y. Jeon and H.-W. Kim, Effect of perampanel on aggression in patients with refractory focal epilepsy: A 6-month longitudinal study, Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.106658