Improved irritability, mood, and quality of life following introduction of perampanel as late adjunctive treatment for epilepsy

Epilepsy & Behavior 104 (2020) 106883

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Improved irritability, mood, and quality of life following introduction of perampanel as late adjunctive treatment for epilepsy Johanna Sofia Moraes a,⁎, Graham Hepworth b, Sophia Ignatiadis a, Anita Dharan d, Ross Carne a, Udaya Seneviratne a,c, Mark J. Cook a, Wendyl Jude D'Souza a a

Department of Medicine, St Vincent's Hospital Melbourne, The University of Melbourne, Australia Statistical Consulting Centre, The University of Melbourne, Australia Department of Neurology, Monash Medical Centre, Melbourne, Australia d Melbourne School of Psychological Sciences, The University of Melbourne, Australia b c

a r t i c l e

i n f o

Article history: Received 10 August 2019 Revised 17 December 2019 Accepted 18 December 2019 Available online xxxx Keywords: Perampanel Efficacy and tolerability Mood and behavioral adverse events Quality of life

a b s t r a c t Objective: The objective of this study was to evaluate the efficacy and tolerability of perampanel (PER) in late adjunctive treatment of focal epilepsy. We assessed outcomes 1) according to patients' clinical profiles and the broad mechanism of action (MoA) of concomitant antiepileptic drugs (AEDs) and 2) the effects of PER on adverse events, irritability, mood, and quality of life (QOL). Methods: Consecutive patients commenced on PER at two epilepsy centers in Melbourne, Australia were identified. A nested cohort underwent detailed prospective assessment, while the remainder were retrospectively analyzed. Six- and 12-month efficacy endpoints were at least a 50% reduction in seizure frequency (responders) and complete seizure freedom. The prospective cohort underwent standardized validated questionnaires at 0, 1, 3, 6, and 12 months using the modified semi-structured seizure interview (SSI), Liverpool Adverse Events Profile (LAEP), Quality of Life in Epilepsy-Patient-Weighted (QOLIE-10-P), Neurological Disorders Depression Inventory Epilepsy (NDDI-E), and an Irritability Questionnaire. Results: One hundred sixty patients were followed for a median of 6 months: the mean number of prior AEDs was 6, 99% had drug-resistant epilepsy, and 72% had never experienced a prior seizure-free period of at least 6 months (=continuously refractory epilepsy). Perampanel was associated with responder and seizure freedom rates of 30.6% and 9.4% at 6 months and 19.4% and 4.4% (5.6% adjusted for the titration period) at 12 months. Having “continuously refractory epilepsy” was associated with a reduced likelihood of seizure freedom at 6 months (5% vs. 30%; p = 0.001) and 12 months (3% vs. 13%; p = 0.058). Quality of Life in Epilepsy-Patient-Weighted, irritability, and NDDI-E showed mean improvement at 6 months from baseline. Significance: Even when used as late add-on adjunctive therapy in patients with highly refractory focal epilepsy, PER can result in 12-month seizure freedom of 5.6%. The likelihood of seizure freedom was associated with prior “continuous medication refractoriness”. Six months after introduction of PER patients reported improved mood, QOL, and decreased irritability. © 2020 Elsevier Inc. All rights reserved.

1. Introduction Pharmacoresistant epilepsy remains an important problem with approximately one-third of patients with epilepsy refractory to treatment [1]. The ongoing development and introduction of newer antiepileptic drugs (AEDs) with novel mechanisms of action remain critical in trying

⁎ Corresponding author at: Department of Medicine, St Vincent Hospital Melbourne, 41 Victoria Pde, Fitzroy 3068, Australia. E-mail address: [email protected] (J.S. Moraes).

https://doi.org/10.1016/j.yebeh.2019.106883 1525-5050/© 2020 Elsevier Inc. All rights reserved.

to reduce seizure burden and quality of life (QOL) when patients do not achieve satisfactory seizure control from existing treatments. Perampanel (PER) is the first of its class, a highly selective, noncompetitive alpha-3-hydroxy-5-methyl-4-isoxaloeprononic acid (AMPA)type postsynaptic glutamate receptor antagonist [2]. The AMPA receptors are predominant mediators of excitatory transmission in the central nervous system (CNS) and critical to the spread of epileptic activity. By binding to postsynaptic AMPA receptors, PER reduces glutamate-induced excitatory neurotransmission. Perampanel has been licensed for use in epilepsy in more than 50 countries [3]. In Australia, PER was initially listed for reimbursement under the Federal Pharmaceutical Benefits Scheme (PBS) on November

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1st, 2014 as adjunctive therapy for focal seizures with or without focal seizures progressing to bilaterally tonic–clonic seizures (FBTCS) who have 1) previously failed at least one first-line AED and two secondline adjunctive AEDs and 2) currently treated with at least two AEDs including one second-line adjunctive AED. On the 1st of August 2018, this was extended for the adjunctive treatment of generalized tonic–clonic seizures in adult and adolescent patients from 12 years of age with idiopathic generalized epilepsy (IGE). Perampanel also has regulatory approval for use as monotherapy from 4 years of age in focal epilepsy in the United States. The efficacy and safety of PER as adjunctive treatment for focal seizures (±FBTCS) and generalised tonic-clonic seizure (GTCS) seizures have been established in four phase III randomized controlled trials (RCTs) and a long-term open-label extension study [4–8]. In patients with focal seizures (±FBTCS; n = 1478), adjunctive PER at 8 mg daily resulted in median percentage reduction in seizure frequency of 26.3%–30.8%, a ≥50% responder rate of 33.3%–37.6%, and seizure freedom of 2.2–4.8%. For GTCS seizures in patients with IGE (n = 162), corresponding results were 76.5%, 64.2%, and 30.9%. Several observational studies have looked at the use of adjunctive PER in real-world clinical practice. These studies generally support the efficacy and tolerability of PER as adjunctive therapy in refractory focal seizures across different populations [9–11]. However, they are typically retrospective medical record reviews estimating response, seizure freedom, and tolerability over relatively brief and sometimes discontinuous time windows. Behavioral adverse events (AEs) of antiepileptic medications are key rate-limiting manifestations affecting the choice of AED, patient QOL and long-term retention. Aggression, irritability, mood disturbance, and anxiety have all been reported with the use of PER [4,5,9,10,12]. The neurobiological basis of irritability and associated aggressive behavior is complex and has not yet been fully explained nor is there evidence for a single pharmacological mechanism by which PER may precipitate these effects. However, it is postulated that glutamate, via the AMPA receptor, plays a key role in mediating these manifestations [13,14] as well as strong evidence for the involvement of glutamate in the pathophysiology of depression [15]. We estimated efficacy and tolerability following initiation of adjunctive PER at two epilepsy centers in Melbourne, Australia in both a conventional retrospective design and a nested prospective cohort undergoing longitudinal assessments. This enriched prospective cohort enabled a more rigorous methodological design utilizing standardized validated prospective outcome estimates in an attempt to better understand adjunctive AED treatment in real-world settings. We focused on a more comprehensive evaluation of key-emergent behavioral, mood, irritability, and QOL factors. 2. Methods

2.1.2. Retrospective cohort Patients not included in the prospective cohort who had been prescribed PER were identified from public hospital and private practice clinics record databases (MC, RC, US, WD). Medical records were then reviewed from introduction of PER until the point at which patients were censored using a standardized proforma to extract clinical information. This involved recording the number of seizures and treatment emergent side effects from baseline at 3, 6, and 12 months to assess efficacy and adverse effects. 2.2. Perampanel treatment Participants were all treated with once daily PER at bedtime. Titration was in 2 mg increments to reach a target dose (4–12 mg) and occurred weekly to monthly depending on specialist preference and patient tolerability. 2.3. Data collection The following baseline variables were collected: age, gender, intellectual disability, psychiatric diagnosis, age of onset of epilepsy, presence of focal progressing to bilaterally tonic–clonic (FBTCS), presence of epileptogenic magnetic resonance imaging (MRI) lesions, or previous epilepsy surgery. The number of prior AEDs trialed and the specific AEDs prescribed at the time of PER commencement were also recorded. Two additional operational measures of the severity of the patient's epilepsy were documented, 1) drug-resistant epilepsy, defined as ongoing seizures despite trials of adequate doses of two appropriate AEDs [16] and 2) continuously refractory epilepsy, defined as having never experienced 6 months of seizure freedom from onset of epilepsy to commencement of PER [17]. Baseline seizure frequency was recorded at 3, 6, and 12 months prior to starting PER. Seizures were also categorized as either progressing to bilaterally tonic–clonic (=FBTCS) or those focal seizures with or without loss of awareness. Seizure frequencies were recorded separately at each time point. In the prospective cohort, seizure frequency was determined using “The modified semi-structured seizure interview (SSI)” [18] which was administered at 0, 1, 3, 6, and 12 months. In the retrospective cohort, seizure frequency was determined retrospectively from specialist clinical records. 2.4. Follow-up Patients were followed until the prespecified censor events: 1) PER cessation, 2) addition or up-titration of another AED, 3) epilepsy surgery, 4) death, or 5) the end of available follow-up. The total duration of follow-up was defined as the date of PER commencement to the first censor event.

2.1. Participants 2.5. Efficacy outcomes Participants commenced on PER between 2010 and Jan. 2017 by epilepsy specialists at St Vincent's Hospital Melbourne (SVHM) and Monash Medical Centre (MMC) were identified. Patients were included if they met the following criteria: 16 years of age or older, fulfilled PBS criteria for adjunctive use in drug-refractory focal epilepsy, and had at least one visit following commencement of PER. Patients were excluded if they had concomitant psychogenic nonepileptic seizures (PNES) or insufficient information was available. 2.1.1. Prospective cohort An unselected consecutive, nested cohort of patients (WD) was also recruited at the time of commencing PER and enrolled in the study. These patients underwent a more detailed prospective assessment of seizure frequency, AEs, mood, irritability, and QOL by standardized validated interviews.

Efficacy was determined at 6 and 12 months following the commencement of PER. Two efficacy outcomes were assessed at each time point, i) seizure freedom and ii) responder rate. A responder was defined as a participant who improved by at least 50% in seizure type (focal with or without altered awareness and Focal to bilateral tonicclonic seizure (FTBTCS)) and did not worsen in the other. Seizure freedom was defined as no documented seizures from the baseline time point to assessment time point for all seizure types. For 12-month seizure freedom, we also analyzed outcomes using a second definition of seizure freedom of no documented seizures for 12 months adjusting for the three-month titration period (i.e., at 15 months). Intention-to-treat (ITT) approach was undertaken, i.e., if a patient was enrolled in the study and started PER but did not reach an assessment time point, they were included in the analysis as a nonresponder.

J.S. Moraes et al. / Epilepsy & Behavior 104 (2020) 106883

2.6. Tolerability outcomes In the prospective cohort, data on AEs, QOL, mood, and behavior, following introduction of PER, were collected using the following validated questionnaires at 0, 1, 3, 6, and 12 months: the Liverpool Adverse Advents Profile (LAEP), Quality of Life in Epilepsy-Patient-Weighted (QOLIE-10-P), Neurological Disorders Inventory Epilepsy (NDDI-E), and a Patient and Carer Irritability Questionnaire (IRQ). In the retrospective cohort, AEs were collected by standardized proforma from the epilepsy specialist's consultation letters. The Liverpool Adverse Events Profile (LAEP) is used as a systematic measurement of adverse effects from AEDs [19]. It is a 19-item questionnaire that measures the occurrence and severity of AEs during the previous 4 weeks. We used the scale qualitatively to record AEs. Quality of Life in Epilepsy-Patient-Weighted is a 10-item questionnaire used to screen aspects of health-related QOL in persons with epilepsy [20]. An overall weighted score is calculated with higher scores representing better QOL. The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) screening tool is a 6-point questionnaire specifically designed to screen for depression in patients with epilepsy [21]. Scores N15 are considered positive for a major depressive episode, with a specificity of 90% and sensitivity of 81% and with a positive predictive value of 0.62. Currently, there are no generally accepted standardized measures of irritability in patients with epilepsy. We utilized ‘The Irritability Questionnaire’ developed for use in primary neuropsychiatric disorders [22]. This questionnaire consists of a self-rating component as well as a carer-rated component. The items cover a selection of subjective experiences, judgments, and behaviors thought to comprise the elements of irritability.

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In both retrospective and prospective cohorts, secondary tolerability outcomes were the cessation of PER because of side effects or censoring because of inefficacy. 2.7. Mechanism of action analysis The relationship between concomitant AED according to their mechanism of action (MoA) (e.g., PER plus at least one sodium channel blocker [SCB] AED) and efficacy outcomes was examined using our previously modified version of Margolis et al. [17,23]. 2.8. Statistical analysis The prospective and retrospective cohorts were combined to assess seizure responder, seizure freedom, PER retention, and frequency of AEs [17]. The association between each efficacy outcome and each categorical predictor variable was examined by a crosstable of frequencies and either Fisher's exact test (for binary predictors) or a chi-squared test (for predictors with more than two categories). The association with each continuous predictor was examined by calculating summary statistics of the predictor for both levels of the outcome. Independent sample t-tests were performed to indicate the strength of the association. It was planned to conduct logistic regression for the efficacy outcomes using all significant predictors together, but none of the outcomes had more than one significant predictor and some had none. Quality of life, mood, and irritability outcomes from the prospective data were examined by plotting each measure against time from baseline and fitting a nonparametric spline to indicate the trend. For each outcome, a linear mixed model was fitted with the patient as a random effect and time as a fixed effect to correct for missing data and compare

Fig. 1. Patient flow.

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each time with baseline using 95% confidence intervals (CIs) for the mean differences.

Table 1 Baseline characteristics (N = 160). Variable

n (%) or mean ± SD

N Gender (female) Age of epilepsy onset (years) Epilepsy duration (years) Age at initiation of perampanel (years) Drug-resistant epilepsy at initial perampanel Refractory epilepsy from onseta Previous VNS Epileptogenic MRI lesion Intellectual disability Previous psychiatric diagnosis Previous epilepsy surgery Focal seizures progressing to bilaterally tonic–clonic Mean prior AED Prior AED - b4 - 4–7 - N7 - Unknown Mean current AED Current AED -0 -1 -2 -3 -4 -5 -6 Focal seizures progressing to bilaterally tonic–clonic (previous 12 months) Focal seizures progressing to bilaterally tonic–clonic (previous 3 months) n = 87 0 1 2–6 7–12 N12 Focal seizures with or without loss of awareness (previous 3 months) n = 133 0 1 2–6 7–12 N12 Mechanism of action concomitant AEDs - SV2A inhibitor - SCB - GABA analog - MM AED Concomitant SCB AED -0 -1 -2 -3 -4

160 82 (51%) 18.6 ± 15.6 21.7 ± 14.8 40.4 ± 13.3 158 (99%) 115 (71%) 3 (2%) 64 (40%) 26 (16%) 55 (34%) 22 (14%) 132 (83%) 6 ± 2.7

3. Results One hundred ninety-one patients were identified and screened. Thirty-one patients were excluded from the final analysis (see Fig. 1), consisting of 3 patients who never commenced PER, 25 (24 retrospective, 1 prospective) without at least one review following medication initiation, one with subsequently diagnosed PNES, and two with insufficient available data. The remaining 160 patients met inclusion criteria and were followed up for a median of 6 months (range: 1–24); 68 had a baseline interview and first follow-up interview within one month and were classified as prospective with a detailed prospective assessment, while the remainder were retrospectively analyzed. Baseline characteristics are displayed in Table 1. One hundred fiftyeight (99%) patients had drug-resistant epilepsy; 72% never having experienced more than 6 months of seizure freedom; 37 (23%) of patients had more than seven previous AEDs, with 128 (80%) on more than two concomitant AEDs at PER initiation. Throughout the follow-up period, the peak daily dose of PER was 2–4 mg in 48 cases (30%), 6–8 mg in 58 cases (36%), and 10–12 mg in 37 cases (23%). At 6 and 12 months, the mean doses of PER were 6.1 mg and 7.5 mg, respectively. 3.1. Efficacy Using ITT analysis at 6 months (N = 111) following the commencement of PER, responder and seizure freedom rates were 30.6% and 9.4%, respectively. At 12 months (N = 82), this was 19.4% and 4.4%, respectively. When adjusted for the 3-month dose titration period, the 12month ITT seizure freedom was 5.6%, i.e., at 15 months. Of the 82 patients who completed 12 months of follow-up, seizure freedom was 8.5%, and 36% were responders. The responder and seizure freedom rates for FBTCS were 36.8% and 29.5% at 6 months and 27.6% and 19.3% at 12 months, respectively. 3.1.1. Factors associated with seizure outcome The baseline characteristics and concomitant AEDs at PER initiation were analyzed as explanatory variables for the outcome of being a responder or seizure freedom at 6 and 12 months. Having “Continuously refractory epilepsy” was associated with a reduced likelihood of becoming a 50% responder to PER at 6 months. Only 28% of patients with continuously refractory epilepsy showed a ≥ 50% response at six months compared with 53% of those without continuously refractory disease (p = 0.043). There were no significant associations of responding to PER at 12 months although the absence of epileptogenic lesion on MRI showed a nonsignificant association with seizure freedom at 12 months (p = 0.059). “Continuously refractory epilepsy” similarly was associated with a reduced chance of seizure freedom at 6 months (5% of continuously refractory patients vs. 30% without continuously refractory disease; p = 0.001) and 12 months (3% of continuously refractory patients vs. 13% without continuously refractory disease; p = 0.058). Duration of epilepsy at initiation of PER showed a nonsignificant association with seizure freedom at 12 months (p = 0.06). Fig. 2 shows the odds of achieving seizure freedom or response in patients who had previously experienced greater than 6 months of seizure freedom compared with patients with continuously refractory epilepsy. 3.1.2. Mechanism of action analysis A further analysis was undertaken to examine the individual influence of concomitant MoA AED on seizure freedom or responder, i.e., PER and at least one of a SCB, synaptic vesicle glycoprotein 2A (SV2A) inhibitor, gamma-Aminobutyric acid (GABA) analog, or AED with multiple mechanisms (MM) of action.

- 26 (16%) - 79 (49%) - 37 (23%) - 18 (11%) 2.6 ± 1.22 - 3 (2%) - 29 (18%) - 51 (32%) - 43 (27%) - 24 (15%) - 8 (5%) - 2 (1%) 86 (54%)

- 19 (22%) - 12 (14%) - 31 (36%) - 10 (11%) - 15 (17%)

- 21 (16%) - 7 (5%) - 17 (13%) - 16 (12%) - 72(54%) - 68 (43%) - 121 (76%) - 49 (31%) - 97 (61%) 39(24%) 45 (28%) 55 (34%) 20 (13%) 1 (1%)

ATL = anterior temporal lobectomy; VNS = vagal nerve stimulator; MoA = mechanism of action; SCB = sodium channel blocker; MM = multiple mechanisms; SV2A = synaptic vesicle glycoprotein 2A; AED = antiepileptic drug; PER = perampanel. a Refractory epilepsy from onset = never experienced at least 6 months of seizure freedom in lifetime.

Carbamazepine (CBZ) is known to reduce blood levels of PER. However, given only 22 (14%) of the 121 patients on a sodium channel blocker (SCB) who were on CBZ, this was unlikely to contribute individually to any potential SCBs MoA effect, and therefore, the CBZ + PER combination was only examined collectively with the other SCBs. No particular concomitant AED MoA was found to significantly influence either response or seizure freedom outcomes at 6 or 12 months. However, at 6 months, we observed a nonsignificant improved response when PER was combined with at least one GABA analog (41% vs. 26%; p = 0.074).

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Fig. 2. Predictors of efficacy - odds of achieving seizure freedom or 50% response in patients who had previously experienced greater than 6 months of seizure freedom compared with patients with continuously refractory epilepsy.* *Continuously refractory epilepsy = never having experienced N6 months seizure freedom. Nonrefractory vs. continuously refractory 6-month response (53% vs. 28%); 12-month response (12% vs. 22%); 6-month seizure freedom (30% vs. 5%); 12-month seizure freedom (13% vs. 3%); 15-month seizure freedom (13% vs. 4.3%).

3.2. Tolerability Patients were followed until the cessation of PER in 32 (20%), addition of another AED in 6 (3.75%), epilepsy surgery in two, or last clinic appointment in the remaining 120 (75%). Perampanel was stopped in 19 (11%) because of side effects, 11 (6.8%) because of lack of efficacy, and two for unspecified reasons. At 12 months, PER retention was 67.8% (82/121). Table 2a shows the cumulative frequency of treatment-emergent adverse effects across the follow-up period for the prospective cohort. Of the prospective cohort, 85% had treatment-emergent side effects with tiredness (37%) followed by irritability (31%) and unsteadiness (16%) or dizziness (15%), the most frequently reported adverse effects. Table 2b shows the cumulative frequency of treatment-emergent adverse effects across the follow-up period for the prospective cohort.

Table 2a Treatment-emergent adverse effectsa prospective (N = 68). Symptom CNS Tiredness Unsteadiness Dizziness Sleepiness Memory problems Difficulty concentrating Headache Disturbed sleep Shaky hands Double or blurred vision Behavioral Irritability Mood changes Depression Anger or aggression Nervousness/agitation Restlessness Gastrointestinal Weight gain Upset stomach Skin Hair loss Skin problems Other a

N

%

25 11 10 9 8 4 3 2 2 2

37 16 15 13 12 6 4 3 3 3

21 10 5 3 2 2

31 15 7 4 3 3

4 2

6 3

2 1 26

3 1 38

Thirty-two patients in the retrospective group had AEs recorded in their medical records (34.7%). The most frequently reported adverse effects in this group were mood changes (7.6%), depression (4.3%), and irritability (6.5%). Fig. 3 shows QOLIE-10-P, IRQ, and NDDI-E scores over time together with fitted splines to show trends. Over the course of the follow-up period, there was significant overall improvement in mean QOLIE-10-P (38.6 vs. 57.4; 95% CI for difference: 2.5, 35.1) and mean mood (NDDI-E scores: 13.9 vs. 11.0; 95% CI for difference: 1.0, 4.9) observed at 6 months and maintained thereafter. During the first month of treatment, there was an initial increase in patient-reported irritability, but over the course of the follow-up period, there was significant overall improvement in mean irritability scores (IRQ scores: 18.5 vs. 13.6; 95% CI for difference: 0.4, 9.3) at 6 months and maintained thereafter. There was no evidence that carers reported irritability change following initiation of PER.

Table 2b Treatment-emergent adverse effects retrospective cohort estimated by medical record review (N = 92). Symptom

Treatment-emergent = new adverse events from those observed at baseline.

CNS Tiredness Unsteadiness Dizziness Sleepiness Memory problems Difficulty concentrating Headache Disturbed sleep Shaky hands Double or blurred vision Behavioral Irritability Mood changes Depression Anger or aggression Nervousness/agitation Restlessness Gastrointestinal Weight gain Upset stomach Skin Hair loss Skin problems Other

N

%

1 5 2 3 2 1 0 0 0 1

1 5.4 2.2 3.3 2.2 1 0 0 0 1

6 7 4 2 3 0

6.5 7.6 4.3 2.2 3.3 0

2 0

2.2 0

2 0 4

2.2 0 4.3

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improvement from baseline to 6 months, with the exception of Quality of life in Epilepsy (QOLIE; analysis 2, for which the estimated means were 39.4 (at baseline) vs. 54.4 (at 6 months), with a 95% CI for the difference of (−0.7, 30.7)).

160 140 120

4. Discussion

QOLIE

100 80 60 40 20 0 0

5

10

15

20

25

15

20

25

15

20

25

Time

25

NDDI-E

20

15

10

5 0

5

10

Time

60

50

IRQ

40

30

20

10

0 0

5

10

Time

Fig. 3. Tolerability outcomes. QOLIE-10-P, NDDI-E and IRQ, and scores over time (months) together with fitted splines to show trends. There was significant overall improvement in mean QOLIE-10-P (38.6 vs. 57.4; 95% CI for difference 2.5, 35.1), mean mood (NDDI-E scores: 13.9 vs. 11.0; 95% CI for difference 1.0, 4.9), and patient-reported mean irritability (IRQ scores: 18.5 vs. 13.6; 95% CI for difference 0.4, 9.3) observed at 6 months compared with baseline and maintained thereafter. QOLIE = Quality of life in Epilepsy; NDDI-E = Neurological Disorders Depression Inventory Epilepsy; IRQ = Irritability Questionnaire.

We also ran the analysis of irritability, mood, and QOL again using last values carried forward up to 12 months. This was applied to patients in either of two ways, 1) those who did not reach a follow-up time point because of insufficient time (15 patients) or 2) those who withdrew for either efficacy or tolerability. We did a separate analysis for (1) and (2) to cover both possibilities. We did not extend this beyond 12 months as there were only a small number of observations at 18 and 24 months, resulting in considerably greater uncertainty if replacement values were inserted at these times. The results were very similar for all these scenarios to the original analysis. All showed a significant

In this real-world study, we assessed the efficacy and tolerability of adjunctive PER across two epilepsy centers in Melbourne, Australia by retrospective observations enriched with a prospective cohort with standardized evaluations of adverse effects, mood, irritability and QOL. Despite PER being initiated as late add-on treatment and 72% having continuously refractory epilepsy from disease onset, 5.6% experienced 12 months of continuous seizure freedom following PER titration. Seizure freedom was greater than four times more likely in patients without a prior history of continuous refractoriness suggesting that severity case-mix and how seizure freedom is classified are potentially important explanations of observed efficacy differences between real-world studies. Reassuringly, prospective patients report improved mood, QOL, and decreased irritability from six months of PER maintenance. We observed seizure freedom of 9.4% at 6 months and 4.4% at 12 months which increased marginally to 5.6% at 15 months after excluding seizures occurring during the three-month dose titration. This is similar to the 5% seizure freedom observed at 12 months for the preceding 6 months in a comparable cohort with N5 past ineffective AEDs [10] and higher than the 3.8% seizure freedom observed at 12 months for the preceding 3 months in a cohort with N 6 mean past ineffective AEDs [24]. It is also higher than the 3.1% seizure freedom observed at 12 months for the preceding ≥ 6 months in a large pooled European dataset with median prior number of AEDs of 6 [25]. Seizure freedom in observational studies of AEDs varies widely and is likely influenced by several factors including the underlying disease characteristics of the patients, highlighted by the chronicity of medication resistance. Patient populations with more severe disease identified by numerous prior treatment failures have been shown to have increasingly reduced chances of achieving 12 months of continuous seizure freedom following each successive ineffective AED [26]. In patients who have previously failed more than three AEDs, the probability of achieving seizure freedom can be as low as 2% [26]. Different epilepsy syndromes also show varying degrees of medication response with patients with IGE generally experiencing better efficacy outcomes compared with those with focal lesional or the epileptic encephalopathies [27,28]. Our cohort of patients could be considered a population with comparatively severe disease. To be eligible for Australian Federal government PER medication subsidy, patients with focal epilepsy must have previously failed at least two first-generation AEDs and one secondgeneration AED and be currently treated with at least two AEDs including one second-generation AED. This essentially results in PER only being used in Australian patients as late adjunctive treatment in highly refractory epilepsy. As well as disease severity, another influence on different efficacies observed between studies is the varying period of follow-up and operational definitions of seizure freedom used. Using a definition of “greater than six months seizure freedom at one year”, following commencement of PER studies has reported seizure freedom of 4.3% to 9.2% [10,29]. Defining seizure freedom less stringently as seizure-free for at least 3 months at the 12-month visit (“terminal remission”), other groups have observed similar rates following PER introduction of 6.9% to 9.1% [9,30]. These shorter discontinuous retrospective measures of seizure freedom, particularly with an open-label uncontrolled design, increase the chances that any postintervention observations may simply reflect “regression to the mean” [31]. Our patient cohort virtually all have drug-resistant epilepsy, with an average six past failed AEDs, 79% with currently more than two concomitant AEDs, and 71% never experiencing six months without seizures, i.e., “continuously refractory epilepsy”. Therefore, a prolonged continuous seizure freedom definition was employed after the dose titration period,

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until our primary outcome point 12 months later to increase the likelihood of capturing a more enduring drug effect [32]. Previous PER studies have found that predictors of seizure freedom include lower baseline seizure frequency, lower number of previous AEDs trialed, lower number of concomitant AEDs, and less use of concomitant enzyme-inducing AEDs [10,29,32]. We once again observed patients with “continuously refractory epilepsy” [17] to be strongly associated with a reduced likelihood of seizure freedom, with patients almost five times less likely to be seizure-free 12 months after commencing PER. This may be a more clinically useful intrinsic sign of disease severity/response than the greater number of previous failed AEDs as this can also potentially reflect pseudo-refractory epilepsy [33] or an underlying comorbid mood disorder [34]. Psychiatric and behavioral adverse reactions, including irritability, aggression, and depression, have been associated with the use of PER in both the pivotal trials [4–6] and real-world observational studies [9,12,29]. Irritability has been the most frequently reported psychiatric side effect with PER seen in 2.1% to 17.9% [4–6,10,11]. Irritability can be described as “a tendency to respond with negative affect in reaction to aversive stimuli or with hypersensitivity to aversive stimuli” [35]. Although the mechanism behind irritability and related aggressive behavior is not well understood, serotonin (5-HT), GABA, and especially glutamate (via the AMPA receptor) appear to play an important role [13,14]. Glutamate's effects on behavior are complex, and animal studies have demonstrated that blockade of AMPA receptors can lead to both increased and decreased aggressive behavior [36,37]. Our prospective observational arm of the study allowed us to estimate QOL, mood, and irritability using standardized validated survey instruments administered at fixed times. We administered our IRQ to patients and their spouse, carer, or parent to ensure reliable capture of this key symptom during dose titration and maintenance. Following introduction of PER, we found all three of these measures showed improvement after six months. Although numbers were small, medication response, seizure freedom, and medication intolerance did not explain these improvements. Notably, the overall rate of irritability reported across the course of the study was relatively high (31%). This, however, may be in part accounted for by the initial, transient increase in irritability as seen in IRQ scores during the first month of treatment. Psychiatric and behavioral manifestations are a key reason for medication discontinuation [38], and these improvements may explain our relatively high retention rate (68%) at 12 months compared with previous studies where oneyear retention have ranged from approximately 40% to 60% [10,29]. There were significantly lower rates of AEs in the retrospective compared with prospective cohorts particularly for irritability (6.5% vs. 31%) and mood changes (7.6% vs. 15%). This is likely due to two factors, 1) prospective cohort direct questioning reporting of symptoms when using the LAEP and 2) the inherent unreliability of estimating adverse advents from retrospective medical record review [39]. Depression occurs more frequently in patients with epilepsy than in the general population [40], with a prevalence of 23.1% in communitybased studies [41], and although more common in refractory disease, it is not well explained simply by seizure frequency [42]. Depression is a reported side effect of AEDs including PER [43] and may be induced or exacerbated with AED use particularly in patients with a personal or family history of a psychiatric disorder [14,15]. Depression was seen in 2.4% of patients taking 12 mg PER in the pivotal trials [44] and postlicensing studies observing rates of 1.3% to 6.4% [10,29,30,43]. Although these rates are relatively low and similar to the 2.6% to 5.9% depression seen in the general population [45], a number of anecdotal case reports [43,46] have raised the potential of PER causing severely disturbed mood including suicidality. There is strong evidence of the involvement of glutamate signaling pathways in the pathophysiology and treatment of mood disorders with the NMDA receptor antagonist ketamine mediating its antidepressant affects indirectly via activation of AMPA receptors [47]. This suggests that AMPA receptor blockade could theoretically account for the mood-related adverse effects of

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PER. Despite these theoretical concerns, the prospective arm of our study demonstrated a significant decrease in mean NDDI-E scores at 6-months postcommencement of PER. The QOL in epilepsy correlates with seizure frequency and severity [48], psychosocial functioning [48,49], and the presence of adverse effects of AEDs [50]. However, mood has been shown to be the single, most important factor affecting QOL above seizure frequency or severity [49], making the emergence of psychological and behavioral adverse reactions particularly important with regard to choice of AED. We observed significant improvement in QOLIE-10-P scores at six months compared with baseline. Given the improvements in irritability and mood observed, a parallel improvement in QOL is not surprising. The major limitation of this study is the imprecise estimation of seizures in the retrospective arm by medical record review and the prospective arm by patient self-report. The intrinsic nature of epileptic seizures affecting awareness makes the recording and accurate estimation by patient recall extremely challenging [51]. In our study, we attempted to mitigate this to some extent by interviewer-administered validated questionnaires at standardized time points. However, interviews are still subject to recall bias and participant fatigue when too frequent. Future studies with a more objective evaluation of seizures' outcomes with long-term prolonged ambulatory electroencephalogram (EEG) recordings or wearable devices hold exciting potential [52]. Subsidiary limitations to our study are the use of combined retrospective and prospective cohorts and our relatively short median time of exposure to PER of 6 months. To offset this, we have presented data that were not directly comparable such as tolerability outcomes separately for the two cohorts and presented outcomes at 6 months in addition to the more commonly cited 12-month efficacy endpoints. 5. Conclusions Our study is the first to show improved QOL, mood, and irritability following introduction and maintenance for at least six months on PER. The reasons behind these observations remain unexplained. Further larger prospective studies with mood and behavior specific endpoints are essential to verify if these results are replicable, including across different patient populations especially with earlier add-on less refractory disease. Ethics This study was approved by the SVHM and Monash Health Human Research Ethics Committee. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Declaration of competing interest This study was supported by an investigator-initiated grant from EISAI Australia Pty Limited. Eisai was not involved in the study design, the collection, analysis, and interpretation of the data gathered, the writing of the report, or the decision to submit the article for publication. References [1] French J. Refractory epilepsy: clinical overview. Epilepsia 2007;48(Suppl. 1):3–7. [2] Hanada T, Hashizume Y, Tokuhara N, Takenaka O, Kohmura N, Ogasawara A, et al. Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia 2011;52(7): 1331–40. [3] Tsai J, Wu T, Leung H, Desudchit T, Tiamkao S, Lim KS, et al. Perampanel, an AMPA receptor antagonist: from clinical research to practice in clinical settings. Acta Neurol Scand 2017:1–14. [4] French J, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, et al. Adjunctive perampanel for partial onset seizures: randomized phase III study 304. Neurology 2012;79:589–96.

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