The Adverse Effects of Commonly Prescribed Antiseizure Medications in Adults With Newly Diagnosed Focal Epilepsy
Abstract
Background and Objectives
Systematic screening can help identify antiseizure medication (ASM)-associated adverse events (AEs) that may preclude patients from reaching effective doses or completing adequate trial periods. The Adverse Event Profile (AEP) is a self-completed instrument to identify the frequency of common AEs associated with ASM use. This study aimed to compare the AE profile of commonly used ASMs in adults with newly diagnosed focal epilepsy.
Methods
The Human Epilepsy Project is a prospective, international, observational study investigating markers of treatment response in newly diagnosed focal epilepsy. Participants were enrolled within 4 months of treatment initiation. Adult participants on levetiracetam, lamotrigine, carbamazepine, or oxcarbazepine monotherapy who completed the AEP and Mini International Neuropsychiatric Interview at enrollment were included. Multivariable generalized linear and penalized logistic regression models assessed differences in total and itemized marginal AEP scores and dichotomized responses (“never/rarely” vs “sometimes/always”).
Results
A total of 225 adults initiated on levetiracetam (n = 132, 59%), lamotrigine (n = 55, 24%), carbamazepine (n = 19, 8.4%), or oxcarbazepine (n = 19, 8.4%) were included. There were no significant differences in AEP total scores between ASMs. Patients with depression (adjusted marginal score ratio [aMSR] 1.23, 95% CI 1.09–1.39, p = 0.001) and anxiety (aMSR 1.15, 95% CI 1.04–1.26, p = 0.007) had worse AEP total scores than those without. After adjusting for depression and anxiety, levetiracetam users were >3 times more likely to report feelings of aggression (adjusted odds ratio [aOR] 3.38, 95% CI 1.07–10.7, p = 0.038) and almost half as likely to experience unsteadiness (aOR 0.45, 95% CI 0.21–0.99, p = 0.047) than lamotrigine users. Carbamazepine and oxcarbazepine had the highest rates of discontinuation (42.1%, each), followed by levetiracetam (34.8%) and lamotrigine (16.4%). Levetiracetam users had the highest proportion of discontinuations because of AEs alone (18%), and lamotrigine had the lowest (5%).
Discussion
Systematic screening for AEs in adults with newly diagnosed focal epilepsy on ASM monotherapy showed that those with comorbid psychiatric conditions report greater AEs overall, irrespective of ASM. Levetiracetam was associated with >3-fold risk of psychiatric AEs and half the risk of experiencing unsteadiness than lamotrigine. Levetiracetam had the highest proportion of discontinuations because of AEs alone, while lamotrigine had the lowest.
Introduction
The selection of a first antiseizure medication (ASM) is a critically important step in optimizing care for people with epilepsy. Treatment selection requires careful consideration of clinical and patient-related factors.1,2 Adverse events (AEs) are common and can preclude patients with epilepsy from reaching effective therapeutic doses or completing adequate trial periods and may increase the risk of developing drug resistance.3-6 Although over 20 ASMs are currently available for focal epilepsy, not all are considered appropriate for initial monotherapy. Levetiracetam is currently the most commonly prescribed first-line ASM in newly diagnosed epilepsy in industrialized countries.7,8 Sodium channel modulators lamotrigine, carbamazepine, and oxcarbazepine are considered “first-line therapy” for focal epilepsy, and there is strong evidence that lamotrigine is associated with a lower incidence of side effects and significantly greater 12-month seizure remission rates than levetiracetam or zonisamide in people with focal epilepsy.9 Investigating the rate and severity of AEs reported on commonly prescribed ASMs for newly diagnosed focal epilepsy using systematic screening tools can help to better inform ASM choices in early treatment phases.
The Adverse Event Profile
The Adverse Event Profile (AEP) (eFigure 1) is a commonly used 19-item screening instrument validated for assessing and quantifying the burden of ASM-associated AEs in people with epilepsy.10-12 The AEP items assess subjective experiences suggestive of ASM toxicity across different domains: cognition/coordination (unsteadiness, double or blurred vision, difficulty in concentrating, shaky hands, dizziness, and memory problems), mood/emotion (feelings of aggression, nervousness or agitation, and depression), sleep (tiredness, restlessness, upset stomach, sleepiness, and disturbed sleep), weight/cephalgia (weight gain and headache), and tegument/mucosa (hair loss, problems with skin, and trouble with mouth or gums).13 Each AEP item is rated as occurring “never,” “rarely,” “sometimes,” or “always” in the preceding 28 days. Several studies using the AEP have shown that current or previous psychiatric disorders, in particular depression or anxiety, increase the likelihood of experiencing AEs,11,14-18 even where mood disturbance is subsyndromic.19 ASM drug load, seizure frequency, age, and sex can also influence AEP ratings.11,14-16
Aims and Hypotheses
Using data from the Human Epilepsy Project (HEP), we aimed to compare adverse subjective experiences as measured by the AEP between common first-line agents prescribed to adults with newly diagnosed focal epilepsy. Because levetiracetam is used most commonly7,8 and lamotrigine has been suggested as a preferred ASM in focal epilepsy,9 particular emphasis on differences between levetiracetam and lamotrigine were made.
Methods
Study Design
The HEP20 is a multicenter, observational 3–6-year prospective study that enrolled patients between 2012 and 2020. The HEP was designed to collect and evaluate potential clinical and biological markers predictive of disease outcome, progression, and treatment response in people with newly diagnosed focal epilepsy. The study was approved centrally by the New York University Institutional Review Board and locally by each participating sites' institutional research ethics board.
Participants
Participants were recruited across 37 major tertiary epilepsy centers across the United States, Australia, and Europe within 4 months of initiating ASM treatment of newly diagnosed focal epilepsy. The HEP was advertised with posters and pamphlets at participating sites. Potential participants were identified by treating neurologists or by direct expressions of interest on the HEP website. Study eligibility was determined according to the inclusion/exclusion criteria as outlined in previous publications.21 A total of 448 participants were eligible and enrolled in the HEP. Inclusion for analysis in this study required participants to have completed the AEP and Mini International Neuropsychiatric Interview (MINI) (eFigure 2) within 28 days of enrollment and to be on ASM monotherapy at the time of completion. At the time of AEP completion, participants could have trialed more than 1 ASM, as long as the first ASM was initiated within 4 months of enrollment. Because the AEP asks about side effects in the 28 days before its completion, participants on sequential ASM monotherapy or ASM polytherapy in the 28 days before completion of the AEP were excluded. As the MINI is only administered to adults, participants younger than 18 years at the time of enrollment were not included in this analysis.
Data Collection
Baseline data on participant demographics, epilepsy characteristics, and ASM use were collected on enrollment using case report forms (CRFs). CRFs were designed and finalized a priori and standardized across sites. Data collected through CRFs were then entered by recruiting sites into a centrally managed RedCap database. Quality and time lines of CRF and survey completion were monitored centrally by a project director and actioned by site coordinators. Collected data included age at enrollment, sex, race, employment status, epilepsy type/syndrome, etiology, age at onset, and lifetime history of seizure frequency before diagnosis. Detailed information of prescribed ASMs, dates of initiation and discontinuation (if applicable), and doses were also collected. ASMs reported as prescribed but never initiated were not included in the study. Adherence to ASMs was monitored during the study at annual visits.
Participants completed the AEP and MINI at enrollment (eFigures 1 and 2). The MINI is a short, structured diagnostic interview that assesses for current and lifetime presence of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-International Classification of Diseases, 10th Revision–coded psychiatric disorders in adults. In this study, the MINI was used to identify current and past history of depressive (major depressive episodes, with and without melancholia, dysthymia) and anxiety (generalized anxiety disorder, panic disorder, phobias, and agoraphobia) disorders.22-24 The MINI was administered by staff personnel at study visits, and the AEP questionnaires were completed online either at home or on-site during a participants' study visit using provided computers.
Statistical Analysis
Characteristics of the study population were expressed as medians and interquartile ranges (IQRs) for continuous data that were not approximately normally distributed and as counts and percentages for categorical data. Each AEP item was scored on a 1–4 Likert scale (1 = never; 2 = rarely; 3 = sometimes; 4 = always). For each individual patient, the AEP total score was calculated by summating scores of all AEP items, except for the items of depression and anxiety (excluded to avoid overlapping with MINI depression or anxiety diagnoses), resulting in a maximum score of 68. We also dichotomized the individual AEP items into never or rarely vs sometimes or always to compare clinically relevant frequencies of occurrence of AEs across ASM monotherapies.
Univariable logistic regression was performed to assess the associations between ASMs and MINI depression and anxiety, respectively. To compare total AEP scores across ASM groups, a multivariable generalized linear model with a Poisson distribution, log link function, and robust variance was used. ASM groups were included as the independent variable, along with MINI depression diagnosis, MINI anxiety diagnosis, total ASM drug load, seizure frequency in the 28 days before AEP completion, age, and sex as covariates. Age, sex, and seizure frequency are known confounders that affect both the selection of antiseizure medication in clinical practice and AEP reporting. MINI anxiety and depression diagnoses are prognostic factors that only affect AEP ratings and are considered control variables. ASM drug load is considered a mediator because its effects on AEP ratings is affected by the choice of antiseizure medication. The theoretical relationships between ASM, AEP, and covariates are shown in eFigure 3. ASM drug load was calculated as the ratio of ASM daily dosage at enrollment to World Health Organization Defined Daily Doses (eTable 1).25
For each of the 19 AEP items, a penalized logistic model was used to assess the associations between different ASMs or non-ASM factors and dichotomized individual AEP items. The same variables as stated above were included in the models. Sensitivity analysis was performed by removing the 2 covariates MINI depression and anxiety diagnoses to assess their impact on the comparisons between LEV and LTG. For AEP items where female sex were associated with an increased risk, the differences between ASMs in women were further examined in post hoc analysis by adding an interaction term of sex and ASM into the multivariable penalized logistic models.
The results were expressed as marginal score ratios (MSRs) for AEP scores, which are ratios of expected AEP scores, and odds ratios (ORs) for dichotomized AEP items, with 95% CIs. The adjusted results reflect associations between ASMs and AEP outcomes that are independent of the influence of the covariates. Statistical significance was set at p < 0.05 unless otherwise stated. The Benjamini-Hochberg procedure26 was used to calculate a q-value and control for a 10% false discovery rate (i.e., q < 0.1) in multiple comparisons across ASMs or AEP items, where applicable. All statistical tests were performed using Stata version 16.1 (StataCorp., College Station, TX).
Data Availability
All data generated or analyzed in this study are included in this published article and its additional files. Requests for material should be made to the corresponding authors.
Results
Characteristics of the Study Sample
Of the 448 participants enrolled in the HEP, 225 met criteria for inclusion in this analysis (eFigure 4). Participants were mostly prescribed levetiracetam (n = 132, 59%), followed by lamotrigine (n = 55, 24%), and carbamazepine, and oxcarbazepine (n = 19, 8.4% each). Most of the participants were on their first ASM at the time of AEP completion (n = 194, 86%), followed by 29 on their second (13%) and 2 on their third (0.9%) ASM. The median time from initiation of the first ASM to AEP completion was 82 days (IQR 44–130). Of the 31 participants not on their first ASM, 15 (48%) were previously on levetiracetam, 5 (16%) on lamotrigine, 2 (7%) on oxcarbazepine, 0 (0%) on carbamazepine, and 9 (29%) on “other” (valproate, lorazepam, phenytoin, clonazepam). For those who were not on their first ASM when completing the AEP, the reasons for discontinuing previous ASMs are detailed in eTable 2.
The median age at enrollment was 36 years (IQR 27–46, range 18–64). Most participants were female (61%), and distributions of sex were similar for each ASM, except for lamotrigine, where 75% of users were female compared with 47%–58% in other ASM groups. Most participants identified as White (78%), and most were employed full-time (64%). Seizures in the 28 days before enrollment ranged from 0 to 5, with 135 (60%) participants having no seizures, 60 (27%) having 1–4 seizures, and 30 (13%) having 5 or more seizures. Clinical and demographic characteristics of these groups are listed in Table 1.
| CBZ | LTG | LEV | OXC | Total | |
|---|---|---|---|---|---|
| n (%) | 19 (8.4) | 55 (24) | 132 (59) | 19 (8.4) | 225 (100) |
| Age at enrollment, y, median (IQR) | 43 (30–54) | 34 (25–45) | 36 (27–45) | 38 (27–49) | 36 (27–46) |
| Age of epilepsy onset, y, median (IQR) | 38 (24–50) | 31 (19–43) | 34 (24.5–43) | 31 (21–45) | 33 (23–43) |
| Sex, n (%) | |||||
| Female | 9 (47) | 41 (75) | 77 (58) | 11 (58) | 138 (61) |
| Male | 10 (53) | 14 (25) | 55 (42) | 8 (42) | 87 (39) |
| Race, n (%) | |||||
| Black or African American | 1 (5.3) | 5 (9.1) | 20 (15) | 1 (5.3) | 27 (12) |
| Asian | 0 (0) | 3 (5.5) | 5 (3.8) | 0 (0) | 8 (3.6) |
| White | 17 (89) | 45 (82) | 99 (75) | 15 (79) | 176 (78) |
| American Indian or Alaska Native | 0 (0) | 0 (0) | 0 (0) | 1 (5.3) | 1 (0.4) |
| Mixed | 0 (0) | 1 (1.8) | 3 (2.3) | 0 (0) | 4 (1.8) |
| Unknown | 1 (5.3) | 1 (1.8) | 5 (3.8) | 2 (11) | 9 (4.0) |
| Employment, n (%) | |||||
| Full-time | 11 (58) | 29 (53) | 89 (67) | 14 (74) | 143 (64) |
| Full-time homemaker | 0 (0) | 2 (3.6) | 8 (6.1) | 0 (0) | 10 (4.4) |
| Part-time | 2 (11) | 9 (16) | 9 (6.8) | 2 (11) | 22 (10) |
| Student (not currently employed) | 1 (5.3) | 6 (11) | 14 (11) | 1 (5.3) | 22 (10) |
| Unemployed | 4 (21) | 8 (15) | 10 (7.6) | 2 (11) | 24 (11) |
| Unknown | 1 (5.3) | 1 (1.8) | 2 (1.5) | 0 (0) | 4 (1.8) |
| Total seizure count in previous 28 d, median (IQR) | 0 (0–2) | 0 (0–1) | 0 (0–3) | 1 (0–5) | 0 (0–2) |
| ASM total daily dose, mg, median (IQR) | 400 (400–600) | 150 (100–200) | 1,500 (1,000–2,000) | 1,050 (900–1,200) | — |
| Drug load,25 median (IQR) | 0.40 (0.40–0.60) | 0.50 (0.33–0.67) | 1.00 (0.67–1.33) | 1.05 (0.90–1.20) | 0.67 (0.50–1.00) |
Abbreviations: ASM = antiseizure medication; CBZ = carbamazepine; drug load = expressed as a ratio of World Health Organization Defined Daily Dose for average adult maintenance dose by oral administration; IQR = interquartile range; LEV = levetiracetam; LTG = lamotrigine; MDE = major depressive episode; MINI = Mini International Psychiatric Interview; OXC = oxcarbazepine.
Psychiatric Disorders Assessed With the MINI
The results of the MINI are displayed in Table 2. Twenty-five percent of participants had a psychiatric disorder. Most of these had solely an anxiety-related disorder (16% of entire sample), a minority (2.7%) had exclusively a major depressive episode or dysthymia, and 6.7% had both anxiety and a major depressive episode or dysthymia. The proportion of participants with anxiety-related disorders alone, or a combination of depression and anxiety disorders, were highest among lamotrigine users. The prevalence of a major depressive episode or dysthymia alone was highest among oxcarbazepine users. However, no significant differences were found between ASM monotherapies in the risk of major depressive episode/dysthymia or anxiety-related disorders as detected by the MINI (Table 3). Psychiatric characteristics by subcategories of the MINI are presented in eTable 3.
| CBZ | LTG | LEV | OXC | Total | |
|---|---|---|---|---|---|
| n (%) | 19 (8.4) | 55 (24) | 132 (59) | 19 (8.4) | 225 (100) |
| Only MDE/dysthymia | 0 (0) | 1 (1.8) | 4 (3.0) | 1 (5.3) | 6 (2.7) |
| Only anxiety-related disorder | 3 (16) | 11 (20) | 21 (16) | 1 (5.3) | 36 (16) |
| Both MDE/dysthymia and anxiety-related disorder | 1 (5.3) | 6 (11) | 7 (5.3) | 1 (5.3) | 15 (6.7) |
| Total patients with any psychiatric disorder | 4 (21) | 18 (33) | 32 (24) | 3 (16) | 57 (25) |
Abbreviations: ASM = antiseizure medication; CBZ = carbamazepine; LEV = levetiracetam; LTG = lamotrigine; MDE = major depressive episode; MINI = Mini International Psychiatric Interview; OXC = oxcarbazepine.
| Depression | Anxiety | |||
|---|---|---|---|---|
| OR (95% CI) | p Value | OR (95% CI) | p Value | |
| LEV vs LTG | 0.62 (0.23–1.70) | 0.36 | 0.60 (0.30–1.22) | 0.16 |
| LTG vs CBZ | 2.63 (0.30–22.9) | 0.38 | 1.68 (0.48–5.81) | 0.41 |
| LEV vs CBZ | 1.64 (0.20–13.4) | 0.65 | 1.01 (0.31–3.28) | 0.99 |
| OXC vs CBZ | 2.12 (0.18–25.5) | 0.56 | 0.44 (0.07–2.76) | 0.38 |
| OXC vs LTG | 0.81 (0.15–4.27) | 0.80 | 0.26 (0.05–1.27) | 0.096 |
| OXC vs LEV | 1.29 (0.26–6.35) | 0.75 | 0.44 (0.10–2.00) | 0.29 |
Abbreviations: ASM = antiseizure medication; CBZ = carbamazepine; LEV = levetiracetam; LTG = lamotrigine; MINI = Mini International Psychiatric Interview; OR = odds ratio; OXC = oxcarbazepine.
Factors Significantly Associated With AEP Items
Associations between non-ASM factors and individual AEP items are shown in eTable 4. Being female was associated with a 2 to 3-fold increased risk of tiredness, double vision, or headache. The effect was similar across different ASMs (eTable 5). Having the presence, or a history of, a major depressive episode or dysthymia was associated with a 3 to 11-fold increased risk of a number of AEP items, from nervousness and/or anxiousness to restlessness, trouble with mouth or gums, shaky hands, and depression. Having comorbid anxiety was associated with a 2 to 3-fold increased risk of several AEP items, comprising restlessness, feelings of aggression, nervousness and/or anxiousness, difficulty concentrating, dizziness, and depression. Pretreatment seizure frequency was associated with a modest (i.e., 1%) yet significant increased risk of experiencing feelings of aggression.
AEPs of ASM Monotherapies
After removing depression and anxiety from the total AEP score and controlling for seizure frequency, drug load, sex and age, depression, and anxiety, the mean total AEP score was 28.9 (n = 225, 95% CI 27.7–30.1). The average AEP total score for levetiracetam (28.5, 95% CI 27.0–29.9) was similar to that of sodium-modulating ASMs (carbamazepine 30.7, 95% CI 25.9–35.4; lamotrigine 29.3, 95% CI 26.9–31.6; oxcarbazepine 28.6, 95% CI 24.4–30.0). A diagnosis of depression was associated with a 23% higher (worse) total AEP score than those without depression (adjusted MSR [aMSR] 1.23, 95% CI 1.09–1.39, p = 0.001), and a diagnosis of anxiety was associated with a 15% higher (worse) total AEP score than those without anxiety (aMSR 1.15, 95% CI 1.04–1.26, p = 0.007).
Levetiracetam vs Lamotrigine
Proportions of levetiracetam and lamotrigine users' who responded to each AEP item dichotomized as sometimes or always (vs never or rarely) are shown in Figure 1. This figure shows comparable proportions of individuals who reported experiencing sometimes or always on AEP items between levetiracetam and lamotrigine users. The exceptions were feelings of aggression (more prevalent among levetiracetam users) as well as shaky hands and double or blurred vision (more prevalent among lamotrigine users). The data were further stratified by sex and shown in eFigure 5.
AEP = Adverse Event Profile.
After adjusting for seizure frequency, drug load, sex, and age (but not depression and anxiety), comparison of dichotomized responses to AEP items between levetiracetam and lamotrigine users found no significant differences between the ASMs, except for unsteadiness, where levetiracetam users were half as likely to experience feelings of unsteadiness sometimes or always than those on lamotrigine (aOR 0.44; 95% CI 0.20–0.96, p = 0.039) (Figure 2A). This difference was not statistically significant after accounting for multiple comparisons (q = 0.45). There was also a noteworthy, though not statistically significant, finding that suggests levetiracetam users might be more likely to experience feelings of aggression than lamotrigine users (aOR 2.99; 95% CI 0.98–9.17, p = 0.055). After additional adjustments for depression and anxiety (Figure 2B), levetiracetam users were more than 3 times as likely to report sometimes or always experiencing feelings of aggression compared with those on lamotrigine (aOR 3.38, 95% CI 1.07–10.7, p = 0.038) and about half as likely to experience unsteadiness (aOR 0.45, 95% CI 0.21–0.99, p = 0.047). These differences were not significant after accounting for multiple comparisons (q = 0.45).
(A) Pairwise comparisons of those reporting rarely or never vs sometimes or always on Adverse Event Profile items between levetiracetam and lamotrigine users. ^Odds of experiencing the underlying event sometimes to always. Adjusted for seizure frequency, drug load, age, and sex. #Benjamini-Hochberg procedure. False discovery rate cutoff at 0.10. (B) The same comparison after making additional adjustments for depression and/or anxiety on the MINI. ^Odds of experiencing the underlying event sometimes to always. Adjusted for dichotomized MINI depression (no depression; major depressive episode or dysthymia) and anxiety (no anxiety; panic disorder, agoraphobia, social phobia, or generalized anxiety disorder), seizure frequency, drug load, age, and sex. #Benjamini-Hochberg procedure. False discovery rate cutoff at 0.10. LEV = levetiracetam; LTG = lamotrigine; MINI = Mini International Psychiatric Interview.
Other ASM Comparisons
Levetiracetam users were less likely to report sometimes or always experiencing unsteadiness (aOR 0.29, 95% CI 0.10–0.86, p = 0.025), difficulty concentrating (aOR 0.27, 95% CI 0.09–0.77, p = 0.014), and weight gain (aOR 0.27, 95% CI 0.08–0.93, p = 0.039) than carbamazepine users. Lamotrigine users were less likely to report sometimes or always experiencing tiredness (aOR 0.25, 95% CI 0.07–0.84, p = 0.025) and weight gain (aOR 0.22, 95% CI 0.05–0.89, p = 0.033) than carbamazepine users. These findings were not retained after adjusting for multiple comparisons. No other between-group differences were identified (eTable 6).
ASM Retention
The proportions of participants who continued vs those who discontinued their ASM monotherapy, with participant-reported reason(s) for discontinuation, are shown in Figure 3. Lamotrigine had the highest rate of retention, with 84% of users remaining on the drug, followed by levetiracetam (65%) then carbamazepine (58%) and oxcarbazepine (58%). The highest proportion of discontinuations because of AEs alone was seen among levetiracetam users (18%) while carbamazepine and oxcarbazepine had the highest proportion of discontinuations because of AEs ± safety concerns ± poor seizure control (32%). The median maximum daily dose reached at the time of discontinuation was 400 mg for carbamazepine (n = 8, IQR 400–650 mg), 200 mg for lamotrigine (n = 9, IQR 75–400 mg), 1,000 mg for levetiracetam (n = 46, IQR 500–2,000 mg), and 600 mg for oxcarbazepine (n = 8, IQR 225–900 mg). The median maximum daily dose reached for those who continued their ASM was 400 mg for carbamazepine (n = 11, IQR 400–800 mg), 300 mg for lamotrigine (n = 46, IQR 200–400 mg), 1,500 mg for levetiracetam (n = 86, IQR 1,000–2,000 mg), and 1,500 mg for oxcarbazepine (n = 11, IQR 1,050–1,800 mg).
ASM = antiseizure medication; CBZ = carbamazepine; LEV = levetiracetam; LTG = lamotrigine; OXC = oxcarbazepine.
Discussion
Our study systematically screened for AEs in adults commenced on commonly prescribed ASMs after a new diagnosis of focal epilepsy. Consistent with documented prescribing patterns, most of our cohort were on levetiracetam monotherapy (59%), followed by lamotrigine (24%). As expected,11,14-18 psychiatric disorders of depression and anxiety were significantly associated with increased total AEP scores. There were no significant differences in the total AEP scores between ASMs, after controlling for depression, anxiety, ASM load, seizure frequency, age, and sex.
Despite the known psychiatric AEs of levetiracetam being routinely discussed before commencing the drug and its avoidance in those at increased risk of developing psychiatric AEs in current practice,27-33 we found that levetiracetam users were still more than 3 times as likely to experience feelings of aggression than lamotrigine users. This is particularly salient in this group because recruiting sites in the HEP were largely tertiary sites with epilepsy specialists well versed in the nuances of adverse effects of ASMs. One explanation for this may be that many patients first initiated on ASM therapy are not necessarily treated in a specialist epilepsy tertiary center but rather in a setting associated with first presentation of seizures (emergency department, general neurology, or general practice). Patients may then only be referred to specialist epilepsy centers, such as those in the HEP, when they are not achieving adequate seizure control or are experiencing AEs on their initial ASM. We also found that levetiracetam had a relatively higher rate of discontinuations because of side effects compared with lamotrigine and other common sodium channel-modulating ASMs, suggesting that these psychiatric AEs continue to account for a considerable proportion of levetiracetam discontinuations. We note this finding was only evident after adjustments for depression and anxiety were made, although there was a nonsignificant trend before adjustment (p = 0.055). This may be explained by the higher proportion of pretreatment comorbid psychiatric disorders in lamotrigine users. Higher numbers of psychiatric disorders in lamotrigine users may be reflective of preferential prescribing of lamotrigine for its mood-stabilizing effects34 and avoidance of levetiracetam because of its psychiatric adverse effects in people with comorbid psychiatric illness.27 In comparison with other ASMs, levetiracetam fared better than carbamazepine on a number of AEP items (unsteadiness, difficulty concentrating, and weight gain), but not better than other sodium channel modulators.
By contrast, we found lamotrigine users were over twice as likely to report experiencing unsteadiness than levetiracetam users. We also saw a trend of lamotrigine users to experience more AEs related to blurry or double vision compared with levetiracetam users. This is in keeping with clinical trial evidence that coordination abnormalities are among the most commonly observed AEs with lamotrigine monotherapy.34 However, there were no significant differences in the reporting of unsteadiness between lamotrigine and other ASMs in our analysis. Discontinuation rates for lamotrigine also remained the lowest among the ASMs assessed in our study. When compared with other ASMs, lamotrigine outperformed carbamazepine on items of tiredness and weight gain, in addition to levetiracetam on feelings of aggression, suggesting a relatively favorable tolerability profile overall. Nevertheless, the risk of coordination disturbances with lamotrigine should be kept in mind given that lamotrigine is an often preferred first-line therapy for people with newly diagnosed focal epilepsy.9
We also note that women were more likely to report feeling tired, having headaches, or experiencing double vision, irrespective of ASM type, which may be possibly related to sex differences in average weight (dose/kg) or ASM metabolism.35 Women were also over-represented among those prescribed lamotrigine. Higher rates of lamotrigine use among women is reflective of current prescribing practices, with its preference over other agents, likely related to its favorable teratogenic risk profile.36 Our study also showed that one-quarter of our cohort had a comorbid psychiatric illness around the time of treatment initiation and that having a comorbid psychiatric disorder puts these patients at a greater risk of experiencing and reporting adverse effects on any ASM. Being female and having a comorbid psychiatric disorder are important considerations when choosing an ASM with the best chance of being well tolerated.
This study has several strengths. Our prospective observational cohort study facilitated recruitment of 448 participants with newly diagnosed focal epilepsy across 37 epilepsy tertiary referral sites worldwide. Although most of the sites were in the United States, the mix of international and cross-continental recruiting sites helped to minimize potential bias for differences in clinical populations, prescribing practices, languages, and practitioner beliefs around ASM tolerability. The HEP study design also facilitated real-world observations of the trajectories of individuals with newly diagnosed focal epilepsy whose condition may have been initially managed in the community but subsequently managed in tertiary centers. Participants were recruited and enrolled within 4 months of treatment initiation to capture AEs in early treatment phases. Factors related to AE reporting (seizure frequency, depression and anxiety, drug dose, age, and sex) were assessed at the same time as the AEP and later controlled for in analyses. Comorbid diagnoses of depression and/or anxiety disorders were made using the MINI, a validated diagnostic tool to quantify lifetime presence of neuropsychiatric conditions, allowing us to assess the impact of a history of these conditions before commencing ASMs and completing the AEP. Notably, systematic screening with the AEP enabled a cross-sectional assessment of AEs in all participants, providing a more accurate picture of ASM tolerability than what may be achieved when measured by spontaneous reporting alone.37,38
There are also limitations. First, having only included individuals with newly diagnosed focal epilepsy, our findings may not be generalizable to those with other epilepsies. Second, because the AEP asks for “problems or side effects” of an ASM, the AEP may be interpreted by users to reflect both baseline/preexisting issues and true ASM-related AE issues. Although we cannot address this limitation directly, we attempted to control for this potential confounder by controlling for baseline characteristics and psychiatric comorbidities. Third, as mentioned earlier, patients were likely to be counseled for the behavioral and mood disturbance effects of levetiracetam, particularly in tertiary centers such as those in the HEP, and therefore, the AEs reported could be in part explained by a nocebo effect. Our multisite, international study design may have reduced the potential for this bias to some extent by recruiting from different providers across different health systems and countries. Fourth, given the well-known psychiatric AEs of levetiracetam and mood-stabilizing benefits of lamotrigine, those with baseline issues with aggression were probably less likely to be prescribed levetiracetam and/or more likely to be prescribed lamotrigine in our cohort, and this was evident in our data. We addressed this by controlling for depression and anxiety in our analyses. Of note, not included in this analysis was the role of bipolar affective disorders (as we had too few numbers to include in the analyses) and as a similarly related mood disturbance with syndromic overlap with depression and anxiety, bipolar affective disorder may also alter AEP reporting. Fifth, we had a relatively small number of individuals on carbamazepine and oxcarbazepine, limiting the statistical power to detect differences between each of these 2 subgroups and other monotherapies. Larger studies including more patients on carbamazepine and oxcarbazepine are thus warranted for adequately powered between-group comparisons. Sixth, this analysis did not assess how AEs changed over time, across subsequent ASMs or how they are related to time to treatment failure; furthermore, AEs remain subjective to experiences. Finally, all findings were not significant after accounting for multiple comparisons. However, because this is a real-world observation (rather than a stochastic simulation), adjusting for multiple comparisons may not be required for controlling false discovery and are unlikely to alter our results.
Our study shows that despite the common avoidance of levetiracetam in people with preexisting psychiatric comorbidities because of its negative psychotropic properties, psychiatric AEs remain a common occurrence (over 3-fold increased risk compared with lamotrigine) and likely still account for early discontinuations of levetiracetam. Our study also showed that lamotrigine users were over twice as likely to report feelings of unsteadiness than those on levetiracetam. The risk of this AE is significant and should be taken into consideration when choosing an ASM in the context of the overall favorable tolerability profile of lamotrigine. These AEs seem to occur early in treatment initiation, and systematic screening for AEs during the early phases of initiating ASMs may predict subsequent treatment failure.5,6 Patients who report frequent AEs on any ASM may also benefit from screening for neuropsychiatric conditions irrespective of existing psychiatric diagnoses, given participants with depression and/or anxiety are more likely to report AEs on the AEP. Future research should investigate the role of other factors in AE reporting, including treatments of psychiatric comorbidities, which can ultimately better guide clinical practice in optimizing first-line ASM choices in people with newly diagnosed focal epilepsy.
Glossary
- AE
- adverse event
- AEP
- Adverse Event Profile
- aMSR
- adjusted marginal score ratio
- aOR
- adjusted odds ratio
- ASM
- antiseizure medication
- CRF
- case report form
- HEP
- Human Epilepsy Project
- IQR
- interquartile range
- MINI
- Mini International Neuropsychiatric Interview
- OR
- odds ratio
Appendix 1 Authors
| Name | Location | Contribution |
|---|---|---|
| Sarah N. Barnard, MD, MIPH | Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Department of Neurology, Alfred Health, Melbourne, Australia; Department of Neurology, New York University Grossman School of Medicine, New York | Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data |
| Zhibin Chen, PhD, MBiostat, BSc(Hons), BCom-Accg | Department of Neuroscience, Central Clinical School, Monash University; Department of Neurology, Alfred Health; Clinical Epidemiology, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Andres M. Kanner, MD | Department of Neurology, University of Miami, Miller School of Medicine, FL | Drafting/revision of the manuscript for content, including medical writing for content; study concept or design |
| Manisha G. Holmes, MD | Department of Neurology, Westchester Medical Center Health, Valhalla, NY | Drafting/revision of the manuscript for content, including medical writing for content; study concept or design |
| Pavel Klein, MB, BChir | Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD; Department of Neurology, The George Washington University, DC | Drafting/revision of the manuscript for content, including medical writing for content; study concept or design |
| Bassel W. Abou-Khalil, MD | Department of Neurology, Vanderbilt University Medical Center, Nashville, TN | Drafting/revision of the manuscript for content, including medical writing for content; study concept or design |
| Barry E. Gidal, PharmD | School of Pharmacy, University of Wisconsin, Madison | Drafting/revision of the manuscript for content, including medical writing for content; study concept or design |
| Jacqueline French, MD | Department of Neurology, New York University Grossman School of Medicine, New York | Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data |
| Piero Perucca, MD, PhD | Department of Neuroscience, Central Clinical School, Monash University; Department of Neurology, Alfred Health; Department of Neurology, The Royal Melbourne Hospital; Department of Medicine, Austin Health, The University of Melbourne; Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, Heidelberg, Australia | Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data |
Appendix 2 Coinvestigators
| Coinvestigators are listed at Neurology.org. |
Supplementary Material
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Information & Authors
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© 2024 American Academy of Neurology.
Publication History
Received: April 9, 2024
Accepted: July 16, 2024
Published online: September 13, 2024
Published in print: October 8, 2024
Disclosure
S.N. Barnard receives salary support from the Epilepsy Study Consortium (Funded by Andrews Foundation, Eisai, Engage, Lundbeck, Pfizer, SK Life Science, Sunovion, UCB, Vogelstein Foundation) for ongoing work on the Human Epilepsy Project (1). Z. Chen is supported by the National Health and Medical Research Council (NHMRC) of Australia (GNT1156444) and Monash University. He/his institution has received consultancy fees and/or research grants from Arvelle Therapeutics and UCB Pharma, outside the submitted work. A.M. Kanner has received honoraria from the Epilepsy Foundation of America for serving as co-editor-in-chief of its official publication, Epilepsy.com; and has received honoraria from Neurelis and Angelini Pharma for participation in advisory boards and from Jazz Pharmaceutical for giving a lecture on Psychiatric Aspects of Epilepsy. M.G. Holmes reports no relevant disclosures. P. Klein has served as a consultant, advisory board member or speaker for Abbott, Angelini, Aquestive, Arvelle Therapeutics, Aucta Pharmaceuticals, Dr. Reddy's, Eisai, Jazz Pharmaceuticals, Neurelis, Neurona, SK Life Science, Sunovion, UCB Pharma, UNEEG, and UniQure, is a member of the medical advisory board of Stratus and of the scientific advisory board of OB Pharma, is the CEO of PrevEp, Inc., and has received research support from CURE/Department of Defense and from the NIH/SBIR. B.W. Abou-Khalil has received research grant support from Cerevel, Otsuka, SK Life Science Inc., UCB Pharma, Xenon, and Neuroelectrics, paid to the author's institution. B.W. Gidal has received honoraria from SK Life Science (consulting/speaking), Jazz (consulting/speaking), Aquestive (consulting), Azurity (consulting), and Catalyst (speaking). J. French receives salary support from the Epilepsy Foundation and for consulting work and/or attending scientific advisory boards on behalf of the Epilepsy Study Consortium for Aeonian/Aeovian, Agrithera, Inc., Alterity Therapeutics Limited, Anavex, Angelini Pharma S.p.A, Arkin Holdings, Arvelle Therapeutics, Inc., Athenen Therapeutics/Carnot Pharma, Autifony Therapeutics Limited, Baergic Bio, Beacon Biosignals Inc., Biogen, Biohaven Pharmaceuticals, BioMarin Pharmaceutical Inc., BioXcel Therapeutics, Bloom Science Inc., BridgeBio Pharma Inc., Camp4 Therapeutics Corporation, Cerebral Therapeutics, Cerevel, Clinical Education Alliance, Coda Biotherapeutics, Cognizance Biomarkers, Corlieve Therapeutics, Crossject, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Epitel Inc., Equilibre BioPharmaceuticals, Genentech Inc., Greenwich Biosciences, Grin Therapeutics, GW Pharma, Janssen Pharmaceutica, Jazz Pharmaceuticals, and Knopp. P. Perucca is supported by the Australian National Health and Medical Research Council (APP1163708), the Epilepsy Foundation, the University of Melbourne, Monash University, Brain Australia, and the Weary Dunlop Medical Research Foundation, has received speaker honoraria or consultancy fees to his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, the Limbic, and UCB Pharma (outside the submitted work), and is an Associate Editor for Epilepsia Open. Go to Neurology.org/N for full disclosures.
Study Funding
There was no targeted funding for this study. Creation of the HEP was sponsored by the Epilepsy Study Consortium. Funding for the HEP was received from industry, philanthropy, and foundations (UCB Pharma, Eisai, Pfizer, Lundbeck, Sunovion, the Andrews Foundation, the Vogelstein Foundation, Finding a Cure for Epilepsy and Seizures [FACES], and Friends of Faces). The funders of the HEP had no role in the design or conduct of this study; collection, management, analysis, or interpretation of the data; preparation of the manuscript; or decision to submit the manuscript for publication.
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