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Genes Oct 2022The association between autism spectrum disorders (ASD) and epilepsy has been extensively documented, and the estimated prevalence varies depending upon the selected...
The association between autism spectrum disorders (ASD) and epilepsy has been extensively documented, and the estimated prevalence varies depending upon the selected population and the clinical characteristics. Currently, there are a lack of studies assessing the patient care pathways in ASD, particularly for comorbidity with epilepsy, despite its personal, familial, and economic impacts. Genetic abnormalities are likely implicated in the association of ASD and epilepsy, although they are currently detectable in only a small percentage of patients, and some known genetic and medical conditions are associated with ASD and epilepsy. There is no specificity of seizure type to be expected in children and adolescents with ASD compared with other neurodevelopmental disorders or epileptic syndromes. Treatment options include antiepileptic drugs (AED) and developmentally-based early interventions for ASD. Carbamazepine and lamotrigine are the most used AED, but further studies are needed to more precisely define the most suitable medications for this specific group of children with ASD.
Topics: Child; Adolescent; Humans; Anticonvulsants; Autistic Disorder; Lamotrigine; Epilepsy; Carbamazepine
PubMed: 36292706
DOI: 10.3390/genes13101821 -
The Journal of Pharmacology and... May 2022More than thirty antiseizure medications (ASMs) are available for treating epilepsy. ASMs differ in their potency and efficacy in controlling seizures by acting on... (Review)
Review
More than thirty antiseizure medications (ASMs) are available for treating epilepsy. ASMs differ in their potency and efficacy in controlling seizures by acting on diverse targets in the brain, often with variable pharmacokinetics. Moreover, nearly 30% of people with epilepsy have drug-resistant or intractable seizures. Generic substitution of ASMs is a complex issue. It is thought that frequent generic substitution in people with epilepsy may cause problems because the U.S. Food and Drug Administration (FDA) rules allow too much variability across products. The standard bioequivalence range (80% to 125%) appears too broad for many ASMs, especially those exhibiting little separation between therapeutic and toxic levels. Hence, sub-therapeutic concentration may lead to therapeutic failure with seizure recurrence, which could be life threatening. A supra-therapeutic level could result in adverse effects or compliance issues. There are reported issues with generic substitutions of phenytoin, topiramate, levetiracetam, carbamazepine, and lamotrigine. There is discussion in the epilepsy community about additional guidelines, including designation of generic ASMs as Narrow Therapeutic Index (NTI) drugs and how patient education plays a role in generic substitution. Overall, based on the published evidence on specific generic ASMs, FDA bioequivalence standards are not the cause of problems with generic ASM substitution. Rather, it is imperative that physicians and pharmacists provide adequate patient education on what to expect when switching to generic ASMs, including changes in medication shape and color. Another suggestion would be to consider that all ASMs be considered for inclusion in NTI class to prevent the clinical outcome issues associated with generic ASM switching. SIGNIFICANCE STATEMENT: There are critical aspects to consider when switching from a brand name antiseizure medication (ASM) when a generic becomes available or switching between generics. Generic ASMs are interchanged with little consideration of differences in therapeutic equivalence and other clinical factors. This article describes key issues on generic substitution of ASMs and highlights critical pharmacotherapeutic issues associated with generic ASMs.
Topics: Anticonvulsants; Drug Substitution; Drugs, Generic; Epilepsy; Humans; Lamotrigine; Pharmaceutical Preparations; Seizures
PubMed: 35241634
DOI: 10.1124/jpet.121.000994 -
BMJ Open Jun 2015To identify adverse drug reactions associated with lamotrigine in children and compare the safety profile with other antiepileptic drugs. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To identify adverse drug reactions associated with lamotrigine in children and compare the safety profile with other antiepileptic drugs.
SETTING
Databases EMBASE (1974-April 2015), MEDLINE (1946-April 2015), PubMed and the Cochrane library for randomised controlled trials were searched for studies on safety of lamotrigine.
PARTICIPANTS
All studies involving paediatric patients aged ≤ 18 years who have received at least a single dose of lamotrigine with safety as an outcome measure were included.
PRIMARY AND SECONDARY OUTCOME MEASURES
The primary outcome measure was safety of lamotrigine. Drug interaction of lamotrigine was the secondary outcome.
RESULTS
A total of 78 articles involving 3783 paediatric patients were identified. There were 2222 adverse events (AEs) reported. Rash was the most commonly reported AE, occurring in 7.3% of the patients. Stevens-Johnson syndrome was rarely reported, with a risk of 0.09 per 100 patients. Discontinuation due to an adverse drug reaction (ADR) was recorded in 72 children (1.9% of all treated patients). Fifty-eight per cent of treatment discontinuation was attributed to different forms of rash and 21% due to increased seizures. Children on lamotrigine monotherapy had lower incidences of AEs. Headache (p=0.02), somnolence (<0.001), nausea (p=0.01), vomiting (p<0.001), dizziness (p<0.001) and abdominal pain (p=0.01) were significantly lower among children on monotherapy.
CONCLUSIONS
Rash was the most common ADR of lamotrigine and the most common reason for treatment discontinuation. Children receiving polytherapy have a higher risk of AEs than monotherapy users.
TRIAL REGISTRATION NUMBER
CRD42013006910.
Topics: Abdominal Pain; Anticonvulsants; Child; Dizziness; Drug Therapy, Combination; Exanthema; Headache; Humans; Lamotrigine; Nausea; Triazines; Vomiting
PubMed: 26070796
DOI: 10.1136/bmjopen-2015-007711 -
Clinical and Translational Science Aug 2022Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive...
Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan-Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of Na 1.5 block and to support the observed clinical safety of lamotrigine. We used HEK-293 cells stably expressing the hNa 1.5 channel and voltage clamp electrophysiology to quantify the potency (half-maximal inhibitory concentration) against peak and late channel current, on-/off-rate binding kinetics, voltage-dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late Na 1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak Na 1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder.
Topics: Anticonvulsants; Flecainide; HEK293 Cells; Humans; Lamotrigine; Mexiletine; Sodium Channel Blockers; Sodium Channels
PubMed: 35579204
DOI: 10.1111/cts.13311 -
Eating and Weight Disorders : EWD Jun 2022Adults with bulimia nervosa (BN) and co-occurring emotional dysregulation and multiple impulsive behaviors are less responsive to existing interventions. Initial data...
Changes in cognitive and behavioral control after lamotrigine and intensive dialectical behavioral therapy for severe, multi-impulsive bulimia nervosa: an fMRI case study.
PURPOSE
Adults with bulimia nervosa (BN) and co-occurring emotional dysregulation and multiple impulsive behaviors are less responsive to existing interventions. Initial data suggest that the combination of Dialectical Behavior Therapy (DBT) and a mood stabilizer, lamotrigine, significantly reduces symptoms of affective and behavioral dysregulation in these patients. Identifying candidate neurobiological mechanisms of change for this novel treatment combination may help guide future randomized controlled trials and inform new and targeted treatment development. Here, we examined neurocognitive and symptom changes in a female patient with BN and severe affective and behavioral dysregulation who received DBT and lamotrigine.
METHODS
Go/no-go task performance data and resting-state functional MRI scans were acquired before the initiation of lamotrigine (after 6 weeks in an intensive DBT program), and again after reaching and maintaining a stable dose of lamotrigine. The patient completed a battery of symptom measures biweekly for 18 weeks over the course of treatment.
RESULTS
After lamotrigine initiation, the patient made fewer errors on a response inhibition task and showed increased and new connectivity within frontoparietal and frontolimbic networks involved in behavioral and affective control. Accompanying this symptom improvement, the patient reported marked reductions in bulimic symptoms, behavioral dysregulation, and reactivity to negative affect, along with increases in DBT skills use.
CONCLUSION
Improved response inhibition and cognitive control network connectivity should be further investigated as neurocognitive mechanisms of change with combined DBT and lamotrigine for eating disorders. Longitudinal, controlled trials integrating neuroimaging and symptom measures are needed to fully evaluate the effects of this treatment.
LEVEL OF EVIDENCE
IV: Evidence obtained from multiple time series with or without the intervention, such as case studies.
Topics: Adult; Behavior Control; Behavior Therapy; Bulimia Nervosa; Cognition; Female; Humans; Impulsive Behavior; Lamotrigine; Magnetic Resonance Imaging
PubMed: 34661882
DOI: 10.1007/s40519-021-01308-z -
Proceedings of the National Academy of... Oct 2023Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the...
Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Na1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Na1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Na channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Na channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs.
Topics: Humans; Anticonvulsants; Lamotrigine; Cannabidiol; Sodium; Voltage-Gated Sodium Channels
PubMed: 37782796
DOI: 10.1073/pnas.2309773120 -
BMJ Case Reports Jan 2021
Topics: Anticonvulsants; Cataract; Humans; Lamotrigine; Valproic Acid
PubMed: 33504541
DOI: 10.1136/bcr-2020-240997 -
The Cochrane Database of Systematic... Dec 2013This is an update of the original Cochrane review entitled Lamotrigine for acute and chronic pain published in Issue 2, 2007, and updated in Issue 2, 2011. Some... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an update of the original Cochrane review entitled Lamotrigine for acute and chronic pain published in Issue 2, 2007, and updated in Issue 2, 2011. Some antiepileptic medicines have a place in the treatment of neuropathic pain (pain due to nerve damage). This updated review adds no new additional studies looking at evidence for lamotrigine as an effective treatment for chronic neuropathic pain or fibromyalgia. The update uses higher standards of evidence than previously.
OBJECTIVES
To assess the analgesic efficacy of lamotrigine in the treatment of chronic neuropathic pain and fibromyalgia, and to evaluate adverse effects reported in the studies.
SEARCH METHODS
We identified randomised controlled trials (RCTs) of lamotrigine for chronic neuropathic pain and fibromyalgia (including cancer pain) from MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). We ran searches for the original review in 2006, in 2011 for the first update, and subsequent searches in August 2013 for this update. We sought additional studies from the reference lists of the retrieved papers. The original review and first update included acute pain, but no acute pain studies were identified.
SELECTION CRITERIA
RCTs investigating the use of lamotrigine (any dose, by any route, and for any study duration) for the treatment of chronic neuropathic pain or fibromyalgia. Assessment of pain intensity or pain relief, or both, using validated scales. Participants were adults aged 18 and over. We included only full journal publication articles.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We performed analysis using three tiers of evidence. The first tier used data where studies reported the outcome of at least 50% pain reduction from baseline, lasted at least eight weeks, had a parallel group design, included 200 or more participants in the comparison, and reported an intention-to-treat analysis. First-tier studies did not use last observation carried forward (LOCF) or other imputational methods for dropouts. The second tier used data that failed to meet this standard and second-tier results were therefore subject to potential bias.
MAIN RESULTS
Twelve included studies in 11 publications (1511 participants), all with chronic neuropathic pain: central post-stroke pain (1), chemotherapy-induced neuropathic pain (1), diabetic neuropathy (4), HIV-related neuropathy (2), mixed neuropathic pain (2), spinal cord injury-related pain (1), and trigeminal neuralgia (1). We did not identify any additional studies. Participants were aged between 26 and 77 years. Study duration was two weeks in one study and at least six weeks in the remainder; eight were of eight-week duration or longer.No study provided first-tier evidence for an efficacy outcome. There was no convincing evidence that lamotrigine is effective in treating neuropathic pain and fibromyalgia at doses of 200 mg to 400 mg daily. Almost 10% of participants taking lamotrigine reported a skin rash.
AUTHORS' CONCLUSIONS
Large, high-quality, long-duration studies reporting clinically useful levels of pain relief for individual participants provided no convincing evidence that lamotrigine is effective in treating neuropathic pain and fibromyalgia at doses of about 200 to 400 mg daily. Given the availability of more effective treatments including antiepileptics and antidepressant medicines, lamotrigine does not have a significant place in therapy based on the available evidence. The adverse effect profile of lamotrigine is also of concern.
Topics: Acute Disease; Adult; Analgesics; Anticonvulsants; Chronic Disease; Fibromyalgia; Humans; Lamotrigine; Neuralgia; Randomized Controlled Trials as Topic; Triazines
PubMed: 24297457
DOI: 10.1002/14651858.CD006044.pub4 -
Canadian Family Physician Medecin de... Jun 2007One of my female patients has epilepsy and is currently receiving lamotrigine monotherapy. She has recently found that she is 6 weeks pregnant and is concerned about...
QUESTION
One of my female patients has epilepsy and is currently receiving lamotrigine monotherapy. She has recently found that she is 6 weeks pregnant and is concerned about possible side effects of lamotrigine on her fetus. How should I advise her and should I switch to another antiepileptic drug?
ANSWER
Lamotrigine (LTG) has not been associated with an increased risk for major malformations in monotherapy in most available studies. Risk of major malformations has been suggested when LTG was taken in doses higher than 200 mg/d and when clefts not caused by any known syndrome have been associated with LTG treatment. Therefore, safety for the fetus cannot yet be proven or rejected, although the drug does not appear to be a major human teratogen.
Topics: Abnormalities, Drug-Induced; Anticonvulsants; Cleft Palate; Drug Evaluation; Epilepsy; Female; Humans; Lamotrigine; Pregnancy; Pregnancy Complications; Risk; Triazines
PubMed: 17872777
DOI: No ID Found -
The Cochrane Database of Systematic... Jun 2016This is an updated version of the Cochrane review published in The Cochrane Library 2010, Issue 1.Epilepsy is a common neurological disorder, affecting almost 0.5% to 1%... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the Cochrane review published in The Cochrane Library 2010, Issue 1.Epilepsy is a common neurological disorder, affecting almost 0.5% to 1% of the population. For nearly 30% of these people, their epilepsy is refractory to currently available drugs. Pharmacological treatment remains the first choice to control epilepsy. Lamotrigine is one of the newer antiepileptic drugs and is the topic of this review. Lamotrigine in combination with other antiepileptic drugs (add-on) can reduce seizures, but with some adverse effects. The aim of this systematic review was to overview the current evidence for the efficacy and tolerability of lamotrigine when used as an adjunctive treatment for people with refractory partial epilepsy.
OBJECTIVES
To determine the effects of lamotrigine on (1) seizures, (2) adverse effect profile, and (3) cognition and quality of life, compared to placebo controls, when used as an add-on treatment for people with refractory partial epilepsy.
SEARCH METHODS
For the previous version of the review, the authors searched the Cochrane Epilepsy Group Specialized Register (January 2010), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 1), MEDLINE (1950 to January 2010), and reference lists of articles.For this update, we searched the Cochrane Epilepsy Group Specialized Register (28 May 2015), CENTRAL (The Cochrane Library 2015, Issue 4), MEDLINE (Ovid, 1946 to May 2015), and reference lists of articles. We also contacted the manufacturers of lamotrigine (GlaxoSmithKline). No language restrictions were imposed.
SELECTION CRITERIA
Randomised placebo-controlled trials of people with drug-resistant partial epilepsy of any age, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded. For cross-over studies, the first treatment period was treated as a parallel trial. Eligible participants were adults or children with drug-resistant partial epilepsy.
DATA COLLECTION AND ANALYSIS
For this update, two review authors independently assessed the trials for inclusion, and extracted data. Outcomes included 50% or greater reduction in seizure frequency, treatment withdrawal (any reason), adverse effects, effects on cognition and quality of life. Primary analyses were by intention-to-treat. Sensitivity best and worse case analyses were undertaken to account for missing outcome data. Pooled Risk Ratios (RR) with 95% confidence intervals (95% Cl) were estimated for the primary outcomes of seizure frequency and treatment withdrawal. For adverse effects, pooled RRs and 99% Cls were calculated.
MAIN RESULTS
We did not identify any new studies for this update, therefore, the results are unchanged.For the previous version of the review, the authors found five parallel add-on studies and eight cross-over studies in adults or children with refractory focal epilepsy, and one parallel add-on study with a responder-enriched design in infants. In total, these 14 studies included 1958 participants (38 infants, 199 children, and 1721 adults). Baseline phases ranged from 4 to 12 weeks; treatment phases from 8 to 36 weeks. Overall, eleven studies (n = 1243 participants) were rated as having a low risk of bias, and three (n = 715 participants) had un unclear risk of bias due to lack of reported information around study design. Effective blinding of studies was reported in three studies (n = 504 participants). The overall risk ratio (RR) for 50% or greater reduction in seizure frequency was 1.80 (95% CI 1.45 to 2.23; 12 RCTs) for twelve studies (n = 1322 participants, adults and children) indicating that lamotrigine was significantly more effective than placebo in reducing seizure frequency. The overall RR for treatment withdrawal (for any reason) was 1.11 (95% CI 0.90 to 1.36; 14 RCTs) for fourteen studies (n = 1958 participants). The adverse events significantly associated with lamotrigine were: ataxia, dizziness, diplopia, and nausea. The RR of these adverse effects were as follows: ataxia 3.34 (99% Cl 2.01 to 5.55; 12 RCTs; n = 1524); dizziness 2.00 (99% Cl 1.51 to 2.64;13 RCTs; n = 1767); diplopia 3.79 (99% Cl 2.15 to 6.68; 3 RCTs; n = 943); nausea 1.81 (99% Cl 1.22 to 2.68; 12 RCTs; n = 1486). The limited data available precluded any conclusions about effects on cognition and quality of life. No important heterogeneity between studies was found for any of the outcomes. Overall, we assessed the evidence as high to moderate quality, due to incomplete data for some outcomes.
AUTHORS' CONCLUSIONS
Lamotrigine as an add-on treatment for partial seizures appears to be effective in reducing seizure frequency, and seems to be fairly well tolerated. However, the trials were of relatively short duration and provided no evidence for the long-term. Further trials are needed to assess the long-term effects of lamotrigine, and to compare it with other add-on drugs.Since we did not find any new studies, our conclusions remain unchanged.
Topics: Adult; Anticonvulsants; Child; Cognition; Cross-Over Studies; Drug Resistance; Drug Therapy, Combination; Epilepsies, Partial; Humans; Lamotrigine; Quality of Life; Randomized Controlled Trials as Topic; Triazines
PubMed: 27329345
DOI: 10.1002/14651858.CD001909.pub2