Topiramate Versus Naltrexone for Alcohol Use Disorder: A Genotype-Stratified Double-Blind Randomized Controlled Trial.

OBJECTIVE: There have been no well-controlled and well-powered comparative trials of topiramate with other pharmacotherapies for alcohol use disorder (AUD), such as naltrexone. Moreover, the literature is mixed on the effects of two polymorphisms-rs2832407 (in GRIK1) and rs1799971 (in OPRM1)-on response to topiramate and naltrexone, respectively. The authors sought to examine the comparative effectiveness of topiramate and naltrexone in improving outcomes in AUD and to examine the role of the rs2832407 and rs1799971 polymorphisms, respectively, on response to these medications. METHODS: In a 12-week, double-blind, placebo-controlled, randomized, multisite, genotype-stratified (rs2832407 and rs1799971) clinical trial comparing topiramate and naltrexone in treating AUD, 147 patients with AUD were randomly assigned to treatment with topiramate or naltrexone, stratified by genotype (rs2832407*CC and *AC/AA genotypes and rs1799971*AA and *AG/GG genotypes). The predefined primary outcome was number of heavy drinking days per week. Predefined secondary outcomes included standard drinks per drinking day per week, body mass index (BMI), craving, markers of liver injury, mood, and adverse events. RESULTS: For the number of heavy drinking days per week, there was a near-significant time-by-treatment interaction. For the number of standard drinks per drinking day per week, there was a significant time-by-treatment interaction, which favored topiramate. There were significant time-by-treatment effects, with greater reductions observed with topiramate than naltrexone for BMI, craving, and gamma-glutamyltransferase level. Withdrawal due to side effects occurred in 8% and 5% of the topiramate and naltrexone groups, respectively. Neither polymorphism showed an effect on treatment response. CONCLUSIONS: Topiramate is at least as effective and safe as the first-line medication, naltrexone, in reducing heavy alcohol consumption, and superior in reducing some clinical outcomes. Neither rs2832407 nor rs1799971 had effects on topiramate and naltrexone treatments, respectively.

Nonspecific oral medications versus anti-calcitonin gene-related peptide monoclonal antibodies for migraine: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To compare calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) versus nonspecific oral migraine preventives (NOEPs). BACKGROUND: Insurers mandate step therapy with NOEPs before approving CGRP mAbs. METHODS: Databases were searched for class I or II randomized controlled trials (RCTs) comparing CGRP mAbs or NOEPs versus placebo for migraine prevention in adults. The primary outcome measure was monthly migraine days (MMD) or moderate to severe headache days. RESULTS: Twelve RCTs for CGRP mAbs, 5 RCTs for topiramate, and 3 RCTs for divalproex were included in the meta-analysis. There was high certainty that CGRP mAbs are more effective than placebo, with weighted mean difference (WMD; 95% confidence interval) of -1.64 (-1.99 to -1.28) MMD, which is compatible with small effect size (Cohen's d -0.25 [-0.34 to -0.16]). Certainty of evidence that topiramate or divalproex is more effective than placebo was very low and low, respectively (WMD -1.45 [-1.52 to -1.38] and -1.65 [-2.30 to -1.00], respectively; Cohen's d -1.25 [-2.47 to -0.03] and -0.48 [-0.67 to -0.29], respectively). Trial sequential analysis showed that information size was adequate and that CGRP mAbs had clear benefit versus placebo. Network meta-analysis showed no statistically significant difference between CGRP mAbs and topiramate (WMD -0.19 [-0.56 to 0.17]) or divalproex (0.01 [-0.73 to 0.75]). No significant difference was seen between topiramate or divalproex (0.21 [-0.45 to 0.86]). CONCLUSIONS: There is high certainty that CGRP mAbs are more effective than placebo, but the effect size is small. When feasible, CGRP mAbs may be prescribed as first-line preventives; topiramate or divalproex could be as effective but are less well tolerated. The findings of this study support the recently published 2024 position of the American Headache Society on the use of CGRP mAbs as the first-line treatment.

Topiramate-induced ocular complications: case series.

Several ocular adverse effects have been attributed to Topiramate, a sulfonamide derivative. It can cause problems in the eye such as choroidal effusion syndrome, acute angle closure glaucoma, myopic shift, visual field defects, and Myokymia. If not identified early, it can be vision-threatening. It is commonly used for migraine prophylaxis, partial onset, and generalized tonic-clonic seizures. It has also been prescribed for bipolar disorder and alcoholism. The risk of adverse reactions with this drug is 3%. The prognosis is favorable if it is discontinued early and prompt therapy is initiated. OBJECTIVE: This article reported a case series of topiramate-induced ocular complications. MATERIALS AND METHODS: The patients presented with high intraocular pressure and blurred vision following a topiramate prescription for headache. CONCLUSION: Timely recognition and intervention can prevent potential visual loss in such cases.

Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs. METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678. FINDINGS: 14 605 citations were identified by our search, of which 132 eligible trials enrolled 48 209 participants. All drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·98, 95% CI -9·27 to -6·69) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·79, 95% CI -6·34 to -5·25). Naltrexone-bupropion (OR 2·69, 95% CI 2·10 to 3·44), phentermine-topiramate (2·40, 1·68 to 3·44), GLP-1 receptor agonists (2·22, 1·74 to 2·84), and orlistat (1·71, 1·42 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·40, 95% CI -12·51 to -10·29). INTERPRETATION: In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective. FUNDING: 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

Comparative analysis of adverse drug reactions associated with new antiseizure medications from the Korea Adverse Event Reporting System database.

OBJECTIVE: This study aimed to compare and characterize the safety profiles of new antiseizure medications (ASMs) using a nationwide pharmacovigilance database from a long-term perspective in Korea. METHODS: We reviewed adverse event reports from the Korea Adverse Event Reporting System database between January 2013 and December 2022 for descriptive analysis of six new ASMs (lacosamide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, and zonisamide). We investigated the frequency and characteristics of adverse drug reactions (ADRs) based on the MedDRA terminology, system organ classes, and modified WHO classification. RESULTS: We identified 5,733 reported cases of ADRs. The commonly reported ADRs associated with total ASMs were rash/urticaria (1,822, 31.8 %), dizziness (409, 7.1 %), somnolence/drowsiness (311, 5.4 %), and hepatotoxic effects (273, 4.8 %). Type B (idiosyncratic) effects (2,932; 51.1 %) were more commonly reported than Type A (related to known drug mechanisms) effects (2,613; 45.6 %). Skin and subcutaneous tissue disorders and type B effects were most commonly reported for lamotrigine and oxcarbazepine, whereas nervous system disorders and type A effects were most commonly reported for lacosamide, topiramate, and zonisamide. The pediatric group (<18 years) exhibited skin and subcutaneous tissue disorders and type B effects relatively more frequently than the adult and older adult groups. CONCLUSION: Hypersensitivity skin reactions and type B effects remained significant ADRs in the new ASMs; however, type A effects were more commonly reported in some ASMs. The pediatric group showed a higher rate of type B effects. Overall, new ASMs should also be used with caution.

Effectiveness analysis of three-drug combination therapies for refractory focal epilepsy.

Selecting appropriate antiseizure medications (ASMs) for combination therapy in patients with drug-resistant epilepsy (DRE) is a complex task that requires an empirical approach, especially in patients receiving polytherapy. We aimed to analyze the effectiveness of various three-drug combinations in a group of patients with DRE under real-world conditions. This single-center, longitudinal observational study investigated patients with drug-resistant focal epilepsy who received three-drug regimens in the outpatient clinic of Tongji Hospital from September 2019 to December 2022. The effectiveness of each triple regimen was evaluated by the seizure-free rate and within-patient ratio of the seizure frequency (a seizure frequency ratio [SFR]<1 indicated superior efficacy). The independent t-test or Mann-Whitney U test was used for effectiveness analysis, and P values were adjusted by the Benjamini-Hochberg method for multiple comparisons. A total of 511 triple trials comprising 76 different regimens were conducted among 323 enrolled patients. Among these triple regimens, lamotrigine (LTG)/valproic acid (VPA)/topiramate (TPM) was the most frequently prescribed (29.4%, n â€‹= â€‹95). At the last clinical visit, 14.9% (n â€‹= â€‹48) of patients achieved seizure freedom after receiving triple therapy. LTG/VPA/TPM and LTG/VPA/levetiracetam (LEV) exhibited the highest seizure-free rates at 17.9% and 12.8%, respectively. These two regimens also had significantly lower median SFRs of 0.48 (interquartile range [IQR], 0.17-0.85; adjusted P â€‹< â€‹0.001) and 0.63 (IQR, 0.21-1.04; adjusted P â€‹< â€‹0.01), respectively. LTG/VPA/perampanel (PER) was another promising regimen that showed marginal effectiveness (median SFR â€‹= â€‹0.67; adjusted P â€‹= â€‹0.053). LTG/VPA/phenobarbital had the highest incidence of regimen-specific side effects (40.0%, 4/10), while the incidence of side effects from LTG/VPA/LEV was minimal (5.1%, 2/39). In conclusion, LTG/VPA/TPM and LTG/VPA/LEV exhibited superior efficacy and good tolerability in treating patients with DRE. Our results provide preliminary insights into the selection of ASMs for three-drug combination therapies in this clinically challenging population.

Comparison of the Efficacy of Anti-Obesity Medications in Real-World Practice.

Purpose: Anti-obesity medications (AOMs), along with lifestyle interventions, are effective means of inducing and maintaining weight loss in patients with obesity. Although the efficacy of AOMs has been reported, there have been no direct comparisons of these drugs. Therefore, in the present study, we aimed to compare the efficacy of all the AOMs available in Korea in a real-world setting. Patients and Methods: The body weight and composition of 205 adults treated with phentermine, phentermine/topiramate, liraglutide, naltrexone/bupropion, lorcaserin, or orlistat for at least 6 months were analyzed at 2 month intervals. The prevalence of the achievement of a ≥5% weight loss and the changes in body composition were compared between participants using each AOM at each visit. Results: A total of 132 (64.4%) participants achieved ≥5% weight loss within 6 months (prevalence of ≥5% weight loss after 6 months: phentermine, 87.2%; phentermine/topiramate, 67.7%; liraglutide, 58.1%; naltrexone/bupropion, 35.3%; lorcaserin, 75%; orlistat, 50%). At each visit, after adjustment for age, sex, and baseline body weight, phentermine use was associated with a significantly higher prevalence of ≥5% weight loss than the use of the other AOMs, except for liraglutide. There were significant differences in the body weight, body mass index and body fat mass among the AOM groups by visit (P for interaction <0.05), but not in their waist circumference, skeletal muscle mass, percentage body fat, or visceral fat area. Conclusion: All the AOMs were effective at inducing and maintaining weight loss, in the absence of significant changes in muscle mass, over a 6 month period, and the short-term use of phentermine and the long-term use of phentermine/topiramate or liraglutide would be practical choices for the treatment of obesity. However, further, large-scale studies are necessary to confirm these findings.

Neurodevelopmental and Functional Outcomes Following In Utero Exposure to Antiseizure Medication: A Systematic Review.

BACKGROUND AND OBJECTIVES: To undertake a systematic review of the available literature to examine the relationship between prenatal antiseizure medication (ASM) exposure and adverse postnatal neurodevelopmental outcomes, focusing on social, emotional, behavioral, and adaptive domains of human function, and the frequency of neurodevelopmental and psychiatric disorders in ASM-exposed offspring. METHODS: Electronic searches of MEDLINE, PsychINFO, and EMBASE were conducted and limited to studies published between 1990 and 2023 in English. Studies were eligible if they prospectively or retrospectively reported neurodevelopmental outcomes of ASM-exposed offspring. The Newcastle-Ottawa scale was used to conduct methodologic quality assessments of included studies, and a narrative synthesis integrated the review findings. RESULTS: Forty-three studies were included. Valproate has been consistently associated with a 2- to 4-fold increased risk of autism spectrum disorder (ASD), 2- to 5-fold increased risk of intellectual disability (ID), and poor adaptive functioning. Growing evidence indicates that topiramate is associated with a 2-fold increased risk of ASD and 3- to 4-fold increased risk of ID. The risks of adverse neurodevelopmental outcomes for valproate and topiramate seem to be dose dependent. Phenobarbital has been suggested to be associated with deleterious neurodevelopmental effects, but data are limited. Levetiracetam has recently been linked with an increased risk of attention deficit hyperactivity disorder and anxiety disorders in a single study. Carbamazepine has been associated with variable neurodevelopmental outcomes. Lamotrigine seems to be "safe" in terms of postnatal neurodevelopment. Data for oxcarbazepine, phenytoin, and clonazepam are limited but seem to have little-to-no risk of adverse outcomes. Evidence for the remaining ASMs, including gabapentin, pregabalin, lacosamide, zonisamide, clobazam, perampanel, ethosuximide, or brivaracetam, is lacking. Several methodologic limitations impeded data synthesis, including heterogeneity in outcome measures and small samples of monotherapy exposures. DISCUSSION: The findings of this review support the conclusion that valproate and topiramate use during pregnancy is associated with a significantly increased risk of neurodevelopmental effects on the fetus. Apart from lamotrigine, which seems to be free of adverse neurodevelopmental effects, data for the other ASMs are mixed or inadequate to draw definite conclusions. Further research into the neurodevelopmental effects of prenatal exposure to ASMs, including most newer agents, is much needed.

Caffeine Decreases Topiramate Levels in Zebrafish Larvae in a Pentylenetetrazol-Induced Seizure Model.

Epilepsy ranks as the second-most prevalent neurological disease, and is characterized by seizures resulting in neurobiological and behavioral impairment. Naturally occurring in coffee beans or tea leaves, the alkaloid caffeine (CAF) is the most prevalent global stimulant. Caffeine has been observed to influence epileptic seizures and the efficacy of antiepileptic medications, with a notable impact on topiramate (TPM). This study aimed to explore the influence of CAF on TPM's anticonvulsant effects in zebrafish larvae within a PTZ-induced seizure model, concurrently determining TPM concentrations through a sophisticated analytical approach based on ultrahigh-performance liquid chromatography and subsequent mass spectrometric detection. Zebrafish larvae four days post-fertilization were incubated for 18 h with varying doses of TPM or combinations of CAF + TPM, and locomotor activity was then assessed. Seizures were induced by introducing a PTZ solution to achieve a final concentration of 20 mM. Utilizing liquid chromatography-mass spectrometry (LC-MS/MS), TPM levels in the larvae were quantified. CAF co-administration (especially in higher doses) with TPM caused a decrease in the average locomotor activity in the larvae compared to TPM alone. Moreover, CAF decreased TPM levels in the larvae at all investigated doses. In conclusion, these findings offer a novel perspective on the interplay between CAF and TPM, shedding light on previously unexplored facets. The potential impact of CAF consumption in assisting with epileptic seizure control, unless proven otherwise, suggests a noteworthy consideration for future research and clinical practices.

Is erenumab an efficient alternative for the prevention of episodic and chronic migraine in Spain? Results of a cost-effectiveness analysis.

BACKGROUND: The reimbursement of erenumab in Spain and other European countries is currently restricted because of the cost of this novel therapy to patients with migraine who have experienced previous failures to traditional preventive treatments. However, this reimbursement policy should be preferably based on cost-effectiveness studies, among other criteria. This study performed a cost-effectiveness analysis of erenumab versus topiramate for the prophylactic treatment of episodic migraine (EM) and versus placebo for chronic migraine (CM). METHODS: A Markov model with a 10-year time horizon, from the perspective of the Spanish National Healthcare System, was constructed based on data from responder and non-responder patients. A responder was defined as having a minimum 50% reduction in the number of monthly migraine days (MMD). A hypothetical cohort of patients with EM with one or more prior preventive treatment failures and patients with CM with more than two treatment failures was considered. The effectiveness score was measured as an incremental cost per quality-adjusted life year (QALY) gained and cost per migraine day (MD) avoided. Data from clinical outcomes and patient characteristics were obtained from erenumab clinical trials (NCT02066415, STRIVE, ARISE, LIBERTY and HER-MES). Deterministic and probabilistic sensitivity analyses were performed to validate the robustness of the model. RESULTS: After a 10-year follow-up, the estimated QALYs were 5.88 and 6.11 for patients with EM treated with topiramate and erenumab, respectively. Erenumab showed an incremental cost per patient of €4,420 vs topiramate. For CM patients, erenumab resulted in 0.756 QALYs gained vs placebo; and an incremental cost of €1,814. Patients treated with erenumab achieved reductions in MD for both EM and CM (172 and 568 MDs, respectively). The incremental cost per QALY gained with erenumab was below the Spanish threshold of €30,000/QALY for both health and societal perspectives (EM €19,122/QALY and CM €2,398/QALY). CONCLUSIONS: Erenumab is cost-effective versus topiramate as a preventive treatment for EM and versus placebo for patients with CM from the perspective of the Spanish National Health System.

Vascular dysfunction programmed in male rats by topiramate during peripubertal period.

AIM: The present study evaluated whether topiramate (TPM) treatment during the peripubertal period affects vascular parameters of male rats and whether oxidative stress plays a role in these changes. MAIN METHODS: Rats were treated with TPM (41 mg/kg/day, gavage) or vehicle (CTR group) from the postnatal day (PND) 28 to 50. At PND 51 and 120 the rats were evaluated for: thoracic aorta reactivity to phenylephrine, in the presence (Endo+) or absence of endothelium (Endo-), to acetylcholine and to sodium nitroprusside (SNP), aortic thickness and endothelial nitric oxide synthase (eNOS) expression. In serum were analyzed: the antioxidant capacity by ferric reducing antioxidant power assay; endogenous antioxidant reduced glutathione, and superoxide anion. Results were expressed as mean ± s.e.m., differences when p < 0.05. STATISTICS: Two-way ANOVA (and Tukey's) or Student t-test. KEY FINDINGS: At PND 51, the contraction induced by phenylephrine in Endo+ ring was higher in TPM when compared to CTR. At PND 120, the aortic sensitivity to acetylcholine in TPM rats was reduced in comparison with CTR. The aortic eNOs expression and the aortic thickness were similar between the groups. At PND 51 and 120, TPM group presented a decrease in antioxidants when compared to CTR groups and at PND 120, in TPM group the superoxide anion was increased. SIGNIFICANCE: Taken together, the treatment of rats with TPM during peripubertal period promoted permanent impairment of endothelial function probably mediated by oxidative stress.

Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure.

BACKGROUND: Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use. METHODS: We identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control. RESULTS: The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine. CONCLUSIONS: The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. (Funded by the National Institute of Mental Health.).

Efficacy of topiramate in reducing second-generation antipsychotic-associated weight gain among children: A systematic review and meta-analysis.

AIMS: To conduct a systematic review and meta-analysis with the aim of synthesizing existing data on the efficacy and safety of topiramate as an adjunctive treatment for reducing second-generation antipsychotic (SGA)-associated weight gain in children aged 4-18 years. METHODS: We conducted a comprehensive search of PubMed, Embase, PsychNet and Web of Science from time of their inception up to 12 February 2024, including randomized controlled trials that compared SGA treatment with and without topiramate co-administration in children. The primary outcomes were changes in body weight and body mass index (BMI). Heterogeneity was assessed using I2 statistics. RESULTS: This systematic review included five randomized trials, totalling 139 participants (43.9% female; mean [SD] age 11.9 [3.5] years). Four of these trials were included in the meta-analysis, comprising 116 subjects. We found that topiramate was significantly effective both in reducing SGA-associated weight gain, with a mean difference of -2.80 kg (95% confidence interval [CI] -5.28 to -0.31; p = 0.037, I2 = 86.7%) and a standardized mean difference (SMD) of -1.33 (95% CI -2.14 to -0.51; p = 0.014, I2 = 31.7%), and in reducing BMI change compared to placebo (SMD -1.90, 95% CI -3.09 to -0.70; p = 0.02, I2 = 0%). Sedation risk was lower with topiramate than with placebo (odds ratio 0.19, 95% CI 0.11-0.32; p < 0.01, I2 = 0%). No significant differences were found in dropouts, any other side effects, and metabolic parameters, such as triglycerides, total cholesterol, low-density lipoprotein, high-density lipoprotein, and glucose. None of the included studies reported assessments on cognitive side effects. CONCLUSION: This meta-analysis suggests that topiramate is an effective and safe option for mitigating SGA-associated weight gain in children.

Utilization of Anti-obesity Medications After Bariatric Surgery: Analysis of a Large National Database.

PURPOSE: A significant proportion of patients experience insufficient weight loss or weight regain after bariatric surgery. There is a paucity of literature describing anti-obesity medication (AOM) use following bariatric surgery. We sought to identify prevalence and trends of AOM use following bariatric surgery. MATERIALS AND METHODS: We utilized the IBM Explorys® database to identify all adults with prior bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy). Those prescribed AOMs (semaglutide, liraglutide, topiramate, phentermine/topiramate, naltrexone/bupropion, orlistat) within 5 years of surgery were further identified. Data was analyzed to characterize AOM utilization among different age, demographic, and comorbid populations. RESULTS: A total of 59,160 adults with prior bariatric surgery were included. Among AOMs studies, prevalence of use was highest for topiramate (8%), followed by liraglutide (2.9%), phentermine/topiramate (1.03%), naltrexone/bupropion (0.95%) semaglutide (0.52%), and orlistat (0.17%). Age distribution varied, with the highest utilization among those age 35-39 years for topiramate, 40-44 years for phentermine/topiramate and naltrexone/bupropion, 45-49 years for semaglutide, and 65-69 years for liraglutide and orlistat. African American race was associated with higher utilization across all AOMs. Among comorbidities, hypertension, hyperlipidemia, and diabetes mellitus were most associated with AOM use. CONCLUSION: Despite a relatively high incidence of weight regain, AOMs are underutilized following bariatric surgery. It is imperative that barriers to their use be addressed and that AOMs be considered earlier and more frequently in patients with insufficient weight loss or weight regain after bariatric surgery.

Comparing the efficacy of anti-seizure medications using matched cohorts on a large insurance claims database.

Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients continue to experience seizures. We used retrospective insurance claims data on 280,587 patients with uncontrolled epilepsy (UE), defined as status epilepticus, need for a rescue medicine, or admission or emergency visit for an epilepsy code. We conducted a computational risk ratio analysis between pairs of ASMs using a causal inference method, in order to match 1034 clinical factors and simulate randomization. Data was extracted from the MarketScan insurance claims Research Database records from 2011 to 2015. The cohort consisted of individuals over 18 years old with a diagnosis of epilepsy who took one of eight ASMs and had more than a year of history prior to the filling of the drug prescription. Seven ASM exposures were analyzed: topiramate, phenytoin, levetiracetam, gabapentin, lamotrigine, valproate, and carbamazepine or oxcarbazepine (treated as the same exposure). We calculated the risk ratio of UE between pairs of ASM after controlling for bias with inverse propensity weighting applied to 1034 factors, such as demographics, confounding illnesses, non-epileptic conditions treated by ASMs, etc. All ASMs exhibited a significant reduction in the prevalence of UE, but three drugs showed pair-wise differences compared to other ASMs. Topiramate consistently was associated with a lower risk of UE, with a mean risk ratio range of 0.68-0.93 (average 0.82, CI: 0.56-1.08). Phenytoin and levetiracetam were consistently associated with a higher risk of UE with mean risk ratio ranges of 1.11 to 1.47 (average 1.13, CI 0.98-1.65) and 1.15 to 1.43 (average 1.2, CI 0.72-1.69), respectively. Large-scale retrospective insurance claims data - combined with causal inference analysis - provides an opportunity to compare the effect of treatments in real-world data in populations 1,000-fold larger than those in typical randomized trials. Our causal analysis identified the clinically unexpected finding of topiramate as being associated with a lower risk of UE; and phenytoin and levetiracetam as associated with a higher risk of UE (compared to other studied drugs, not to baseline). However, we note that our data set for this study only used insurance claims events, which does not comprise actual seizure frequencies, nor a clear picture of side effects. Our results do not advocate for any change in practice but demonstrate that conclusions from large databases may differ from and supplement those of randomized trials and clinical practice and therefore may guide further investigation.

Prenatal Exposure to Antiseizure Medications and Risk of Epilepsy in Children of Mothers With Epilepsy.

Importance: Use of valproate and certain other antiseizure medications (ASMs) in pregnancy is associated with abnormal fetal brain development with potential long-term implications for the child. Objective: To examine whether use of valproate and other ASMs in pregnancy among mothers with epilepsy is associated with epilepsy risk in their children. Design, Setting, and Participants: This prospective, population-based register cohort study included singletons born to mothers with epilepsy in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Data analysis was performed from October 2022 to December 2023. Exposure: Redeemed prescription for an ASM from 30 days before pregnancy until birth. Main Outcomes and Measures: The main outcome was epilepsy in children, assessed using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses from hospital care. Adjusted hazard ratios (AHRs) and 95% CIs were estimated using Cox proportional hazards regression. Secondary analyses included dose-response analyses, analyses using children of mothers who discontinued ASM prior to pregnancy as the reference, and sibling analyses. Results: This cohort study included 38 663 children of mothers with epilepsy (19 854 [51.4%] boys). Children were followed up from birth; the mean length of follow-up was 7.2 years (range 0-22 years). Compared with 22 207 children of mothers not using an ASM in pregnancy, increased risks of epilepsy in children of mothers who used valproate in pregnancy (monotherapy: AHR, 2.18; 95% CI, 1.70-2.79; polytherapy: AHR, 2.10; 95% CI, 1.49-2.96) were observed. However, there was no dose-dependent association, and there was a similar risk of epilepsy in siblings who were exposed and unexposed to valproate (AHR, 0.95; 95% CI, 0.50-1.82). Prenatal exposure to topiramate monotherapy was associated with increased risk of epilepsy (AHR, 2.32; 95% CI, 1.30-4.16), and the risk was greater for higher doses, but the risk attenuated in comparisons with children of mothers who discontinued topiramate before pregnancy (AHR, 1.19; 95% CI, 0.26-5.44). Prenatal exposure to clonazepam monotherapy was also associated with increased epilepsy risk (AHR, 1.90; 95% CI, 1.16-3.12), but limited follow-up and low numbers precluded further analyses. No associations were observed for prenatal exposure to lamotrigine (AHR, 1.18; 95% CI, 0.95-1.47), levetiracetam (AHR, 1.28; 95% CI, 0.77-2.14), carbamazepine (AHR, 1.13; 95% CI, 0.85-1.50), or oxcarbazepine (AHR, 0.68; 95% CI, 0.44-1.05). Conclusions and Relevance: In this cohort study of children born to mothers with epilepsy, the associations found between prenatal exposure to certain ASMs and the child's risk of epilepsy did not persist in sensitivity analyses, suggesting that maternal ASM use in pregnancy may not increase epilepsy risk in children beyond that associated with the maternal epilepsy itself. These findings are reassuring for women in need of treatment with ASM in pregnancy.

Hepatotoxicity of newer antiseizure medications in children: an overview and disproportionality analysis of VigiBase.

BACKGROUND: We aimed to characterize newer antiseizure medications (ASMs)-induced hepatotoxicity in children and identify signals of disproportionate reporting of hepatotoxicity-related adverse drug events (ADEs). RESEARCH DESIGN AND METHODS: Case reports reported to VigiBase were accessed using Empirica™ Signal software. To summarize characteristics of the retrieved cases, descriptive statistics were used. A disproportionality analysis was conducted using the Multi-item Gamma Poisson Shrinker algorithm, which calculates Empirical Bayesian Geometric Mean value and its lower and upper 95% confidence limits (EB05 and EB95, respectively). EB05 > 2, N > 0 was considered a signal. RESULTS: Based on 870 analyzed cases, a higher proportion of cases was reported in girls than in boys and in patients aged 2-11 years than in other age groups. Most cases were serious. In 25 cases, hepatotoxicity resulted in death. A high proportion of patients (n = 275, 31.61%) experienced hypersensitivity reactions, mostly due to lamotrigine. The disproportionality analysis yielded 17 signals concerning felbamate, lamotrigine, levetiracetam, oxcarbazepine, stiripentol, and topiramate. Four signals were for severe liver injury and concerned felbamate, lamotrigine, levetiracetam, and topiramate. Gender-biased reporting frequency was detected for four ASM-ADE combinations. CONCLUSION: Our results should serve to raise clinicians' awareness about the potential association between several newer ASMs and drug-induced liver injury in children.

The teratogenesis risk associated with antiseizure medication duotherapy in women with epilepsy.

PURPOSE: To investigate rates of occurrence of pregnancies associated with a foetal malformation (FM pregnancy rates) following simultaneous intrauterine exposure to two antiseizure medications in 524 pregnancies in women with epilepsy from the Australian Pregnancy Register who were treated simultaneously with various combinations and dosages of two antiseizure medications (duotherapy). RESULTS: FM pregnancy rates tended to be higher in those exposed simultaneously to two antiseizure medications, each of which was a statistically significant teratogen (valproate, topiramate, or carbamazepine), than when there was exposure to only one such teratogen. When there was exposure to only one such teratogen together with clonazepam or levetiracetam, for neither of which there was statistically significant evidence of heightened teratogenicity, the FM pregnancy rates also tended to be higher, but less so. When lamotrigine was the other component of the duotherapy with an established teratogen, FM pregnancy rates tended to be lower than that for the teratogen used as monotherapy. CONCLUSION: Leaving aside issues in relation to seizure control, our data suggest that it would be best to avoid using established teratogenic antiseizure medications (carbamazepine, valproate and topiramate) in combination with each other due to the increased FM risks. When combining an established teratogenic medication with a less teratogenic one, i.e. lamotrigine, levetiracetam or clonazepam, lamotrigine appears to be the safer option.