Olanzapine vs. magnesium valproate vs. lamotrigine in anti-N-methyl-D-aspartic acid receptor encephalitis: a retrospective study.

BACKGROUND: This study aimed to compare the impact of olanzapine, magnesium valproate, and lamotrigine as adjunctive treatments for anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. And it is expected to add supporting points related to the rebalance of neurotransmitters in the brain through adjuvant therapy in the clinical management of anti-NMDAR encephalitis. METHODS: This retrospective study included patients diagnosed with anti-NMDAR encephalitis who received standardized immunotherapy at Hunan Brain Hospital between January 2018 and December 2020. RESULTS: Compared to the olanzapine group, both the magnesium valproate and lamotrigine groups showed lower scores on the positive and negative symptom scale (PANSS) total score after 3 weeks of treatment (all P < 0.05). The Montreal Cognitive Assessment Scale (MoCA) scores in the magnesium valproate and lamotrigine groups were significantly higher than in the olanzapine group after 3 weeks and 3 months of treatment (all P < 0.05). After 3 months of treatment, the proportions of patients with a modified Rankin scale score (mRS) of 0-1 in the magnesium valproate and lamotrigine groups were significantly higher than in the olanzapine group (all P < 0.05). The electroencephalogram (EEG) abnormality ranks at 3 months were significantly lower in the magnesium valproate and lamotrigine groups compared with the olanzapine group (all P < 0.05). Furthermore, the Glx/Cr ratio significantly decreased after 3 months of treatment (all P < 0.05) in the magnesium valproate and lamotrigine groups, while the Glx/Cr ratio in the olanzapine group showed no significant change (P > 0.05). CONCLUSION: Compared with olanzapine, the addition of magnesium valproate or lamotrigine to immunotherapy might be associated with a lower PANSS score, higher MoCA score, and lower mRS score. The improvement of neurological functions and cognitive function may be related to the decreased Glx/Cr ratio.

Lamotrigine Emerging as a Driver of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: An 8-Year Retrospective Study.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent severe manifestations of a potentially life-threatening spectrum defined by a desquamating rash of the skin and mucous membranes. This study was prompted by the observed increase in the off-label use of lamotrigine as a causal agent in SJS/TEN in our regional burn center. METHODS: A retrospective cohort of 48 patients presenting to the Connecticut Burn Center from 2015-2022 with suspicion for SJS/TEN were reviewed for age, sex, causative drug, presenting symptoms, hospital course, biopsy confirmation, length of stay, comorbidities, and 30-day mortality. Descriptive statistical analysis was conducted to identify trends in causative agent, clinical presentation, and mortality. RESULTS: Thirty patients in our cohort received a final diagnosis of SJS/TEN. While antibiotics remain the most frequent cause of SJS/TEN across the study period (33.3 %, n = 10), the incidence of cases attributable to lamotrigine increased from 1 case between 2015 and 2018 (6.7 %) to 6 cases between 2019 and 2022 (40 %). In 2020 alone, 50 % of all cases were attributable to lamotrigine (n = 4). Of the patients where lamotrigine was implicated, 71.4 % (n = 5) were prescribed lamotrigine for off-label use in the treatment of non-bipolar mood disorders. The average lamotrigine-associated SJS/TEN patient was younger (p < 0.001), had fewer comorbidities, and was more likely to be female than the general SJS/TEN population. CONCLUSION: Off-label use of lamotrigine is emerging as a major driver of SJS/TEN with notable changes in patient demographics. Further research is necessary to understand how changing trends in the patient population will impact clinical course and optimal management.

Effect of Genetic Polymorphisms of ABCB1, ABCG2, and SLC22A1 on the Steady-State Plasma Concentrations of Lamotrigine in Treatment-Resistant Depressed Patients Treated With Lamotrigine Augmentation Therapy.

OBJECTIVES: The authors have demonstrated that a plasma lamotrigine concentration of 12.7 µmol/L may be a threshold for a good therapeutic response to lamotrigine augmentation therapy in treatment-resistant depressed patients. Lamotrigine is a substrate of P-glycoprotein, breast cancer resistant protein and organic cation transporter 1, which are encoded by ABCB1 , ABCG2 , and SLC22A1 , respectively. There have been several polymorphisms that affect its function. The present study investigated the relationship between these polymorphisms and the steady-state plasma concentrations (Css) of lamotrigine in treatment-resistant depressed patients receiving lamotrigine as augmentation therapy. METHODS: One hundred twenty-nine treatment-resistant depressed patients were included in this study. Treatment resistance is defined as lack of therapeutic response to at least 3 psychotropics despite adequate doses and duration. Their diagnoses were as follows: major depressive disorder (n = 58), bipolar II disorder (n = 52), and bipolar I disorder (n = 19). Lamotrigine augmentation therapy for 8 weeks was conducted. The final lamotrigine doses were 75 mg/d for 39 patients with valproate and 100 mg/d for 90 without it. Blood was sampled at 8:00 am after the 8th week of treatment. Plasma lamotrigine levels were quantified by using LC/MS/MS. The polymorphisms of ABCB1 1236C>T, 2677G>T/A, 3435C>T, ABCG2 421C>A, and SLC22A1 1222G>A were detected by polymerase chain reaction analyses. RESULTS: No significant relationships were observed between these polymorphisms and the Css of lamotrigine in the patients with or without valproate. CONCLUSIONS: The present study suggests that these genetic polymorphisms do not play a role in controlling the Css of lamotrigine in treatment-resistant depressed patients treated with lamotrigine augmentation therapy.

Influence of UGT2B7, UGT1A4 and ABCG2 Polymorphisms on the Pharmacokinetics and Therapeutic Efficacy of Lamotrigine in Patients with Epilepsy.

BACKGROUND AND OBJECTIVES: A substantial inter-individual variability has been observed in the pharmacokinetics of lamotrigine. The aim of the study was to investigate the impact of genetic polymorphism of the metabolizing enzymes (UGT2B7, UGT1A4) and transporter (ABCG2) on the pharmacokinetics and therapeutic efficacy of lamotrigine in patients with epilepsy. METHODS: The genetic analysis of single-nucleotide polymorphisms was conducted using polymerase chain reaction sequence. High-performance liquid chromatography/tandem mass spectrometry was employed to measure the plasma concentrations of lamotrigine. The efficacy of lamotrigine was assessed by evaluating the reduction rate of epileptic seizure frequency. RESULTS: This study included a cohort of 331 patients who were treated with lamotrigine as monotherapy. A linear correlation was observed between the lamotrigine concentration and daily dose taken (r = 0.58, p < 2.2e-16). Statistically significant differences were found in both the median plasma concentration and dose-adjusted concentration (C/D ratio) when comparing the ineffective to the effective group (p < 0.05). Multivariate analysis showed that UGT1A4 rs2011425, ABCG2 rs2231142 polymorphisms and age had a significant relationship with the lamotrigine concentrations (p < 0.05). Age was a predictive factor for C/D ratio (p < 0.001). Lamotrigine concentration and weight were good predictive factors for effective seizure outcomes (odds ratio [OR] = 0.715, 95% CI 0.658-0.776, p < 0.001; OR = 0.926, 95% CI 0.901-0.951, p < 0.001, respectively). The cut-off values of lamotrigine trough concentrations for clinical outcomes in the age-related groups were determined as 2.49 µg/ml (area under the receiver-operating characteristic curve [AUC]: 0.828, 95% CI 0.690-0.966), 2.70 µg/ml (AUC: 0.805, 95% CI 0.745-0.866) and 3.25 µg/ml (AUC: 0.807, 95% CI 0.686-0.928) for the adult group, adolescent group, and toddler and school-age group, respectively. CONCLUSIONS: UGT1A4 rs2011425 and ABCG2 rs2231142 were correlated with lamotrigine concentrations. Lower lamotrigine trough concentration was found in the ineffective group and the troughs were associated with seizure outcomes.

Acute kidney injury in lamotrigine-induced DRESS syndrome.

We present a case of lamotrigine-triggered DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome with acute kidney injury stage 3. A 17-year-old girl with known epilepsy treated with lamotrigine presented with acute kidney injury as well as skin eruption, fever, and apathy. Extended diagnostics, considering infectious and autoimmune diseases, remained unremarkable. Lamotrigine blood levels were within the target range. Kidney biopsy showed acute interstitial nephritis with tubular necrosis. Methylprednisolone pulse therapy led to an improvement in kidney function; skin eruption and neurological symptoms resolved. During the hospital stay, the girl admitted to inconsistent and variable intake of lamotrigine, occasionally resulting in notable overdosing. This report demonstrates that acute kidney injury in lamotrigine-induced DRESS syndrome is an acute interstitial nephritis with tubular necrosis, an aspect that has not been deeply characterized so far. Additionally, we aim to elevate awareness towards non-adherence as cause of disease, especially among the adolescent population.

Lithium versus anticonvulsants and the risk of physical disorders - Results from a comprehensive long-term nation-wide population-based study emulating a target trial.

Bipolar disorder is associated with increased rates of many physical disorders, but the effects of medication are unclear. We systematically investigated the associations between sustained use of first line maintenance agents, lithium versus lamotrigine and valproate, and the risk of physical disorders using a nation-wide population-based target trial emulation covering the entire 5.9 million inhabitants in Denmark. We identified two cohorts. Cohort 1: patients with a diagnosis of bipolar disorder prior to first purchase (N = 12.607). Cohort 2: all 156.678 adult patients who had their first ever purchase (since 1995) of either lithium, lamotrigine or valproate between 1997 and 2021 regardless of diagnosis. Main analyses investigated the effect of sustained exposure defined as exposure for all consecutive 6-months periods during a 10-year follow-up. Outcomes included a diagnosis of incident stroke, arteriosclerosis, angina pectoris, myocardial infarction, diabetes mellitus, myxedema, osteoporosis, dementia, Parkinson's disease, chronic kidney disease and cancer (including subtypes). In both Cohorts 1 and 2, there were no systematic statistically significant differences in associations between sustained use of lithium versus lamotrigine and valproate, respectively, and any physical disorder, including subtypes of disorders, except myxedema, for which exposure to lithium increased the absolute risk of myxedema with 7-10 % compared with lamotrigine or valproate. In conclusion, these analyses emulating a target trial of "real world" observational register-based data show that lithium does not increase the risk of developing any kind of physical disorders, except myxedema, which may be a result of detection bias.

NF1 mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma.

BACKGROUND: With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation. METHODS: We leverage a collection of Nf1-mutant mice that spontaneously develop OPGs to alter both germline and retinal neuron-specific midkine expression. Nf1-mutant mice harboring several different NF1 patient-derived germline mutations were employed to evaluate neuronal excitability and midkine expression. Two distinct Nf1-OPG preclinical mouse models were used to assess lamotrigine effects on tumor progression and growth in vivo. RESULTS: We establish that neuronal midkine is both necessary and sufficient for Nf1-OPG growth, demonstrating an obligate relationship between germline Nf1 mutation, neuronal excitability, midkine production, and Nf1-OPG proliferation. We show anti-epileptic drug (lamotrigine) specificity in suppressing neuronal midkine production. Relevant to clinical translation, lamotrigine prevents Nf1-OPG progression and suppresses the growth of existing tumors for months following drug cessation. Importantly, lamotrigine abrogates tumor growth in two Nf1-OPG strains using pediatric epilepsy clinical dosing. CONCLUSIONS: Together, these findings establish midkine and neuronal hyperexcitability as targetable drivers of Nf1-OPG growth and support the use of lamotrigine as a potential chemoprevention or chemotherapy agent for children with NF1-OPG.

Lamotrigine-Induced Hemophagocytic Lymphohistiocytosis with DRESS.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory reaction syndrome caused by genetic or acquired immune dysregulation. The majority of adult HLH cases are caused by tumors, rheumatic immune disorders, and infections. However, drug-induced HLH is rarely reported. METHODS: We report a case of HLH in an adult caused by the administration of lamotrigine, to our knowledge, only nine other cases of lamotrigine-associated HLH have been reported in adult patients. RESULTS: After discontinuing lamotrigine and using steroid hormones for the HLH, the patient's condition has been brought under control. CONCLUSIONS: This case confirms that dexamethasone is also effective for drug-induced HLH. Usually, after discontinuing the relevant medications, there is no need for further maintenance treatment.

UHPLC-MS/MS for plasma lamotrigine analysis and comparison with a homogenous enzyme immunoassay.

Aims: To develop and validate a UHPLC-MS/MS method for lamotrigine (LTG) analysis in human plasma and evaluate its agreement with a homogenous enzyme immunoassay (HEIA). Materials & methods: The UHPLC-MS/MS method was developed and validated according to the USFDA/EMA guidelines. A Bland-Altman plot was used to evaluate the agreement between UHPLC-MS/MS and HEIA. Results: Samples were pretreated with one-step protein precipitation and separated in 2.6 min. The intra- and inter-day bias and imprecisions were -15.8 to 15.0% and less than 11.17%, respectively. The recovery and matrix factor were 98.30 to 111.97%. The mean overestimation of UHPLC-MS/MS compared with HEIA was 21.57%. Conclusion: A rapid, sensitive and robust UHPLC-MS/MS method for plasma LTG analysis was developed and validated and was a 21.57% overestimation compared with HEIA.

[Pharmacological Treatment of Trigeminal Neuralgia].

Although carbamazepine is the first-line treatment option for trigeminal neuralgia, it may not be sustained long-term. The benefits of carbamazepine are offset by adverse effects that lead to its withdrawal. The alternatives to carbamazepine include gabapentin, pregabalin, and microgabalin. Although used off-label in Japan, baclofen, lamotrigine, intravenous lidocaine, and botulinum toxin type A are also effective. Clinical experience has shown that alternative treatments are less effective than carbamazepine. Therefore, they can be used instead of or in addition to carbamazepine. The adverse effects of drugs include drowsiness, dizziness, rash, bone marrow suppression, and liver dysfunction. Carbamazepine and lamotrigine are particularly likely to cause severe drug eruptions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Low-dose titration is important to avoid the development of rashes and adverse effects.

Anticonvulsant Agents for Treatment of Restless Legs Syndrome: A Case Report With Lamotrigine and a Review of the Literature.

INTRODUCTION: Restless Legs Syndrome (RLS) is a neurological disorder primarily treated with pregabalin and gabapentin, followed by dopamine agonists later in the process due to the risk of augmenting RLS symptoms. In addition, clinical reports have disclosed varying degrees of success employing other agents in patients unresponsive to traditional agents. Here, we present a patient who had success in the reduction of RLS symptoms with lamotrigine, a broad-spectrum anticonvulsant. Previously, lamotrigine had been used in 2 trials with successful treatment of RLS. CASE REPORT: We present a 58-year-old right-handed lady with long-standing history of smoking, hypertension, dyslipidaemia, prediabetes, gastro-esophageal reflux disease, asthma, strabismus, uterine cancer, severe and debilitating course of RLS accompanied by unexplained deterioration. The patient initially demonstrated abnormal sensation in all her limbs, which worsened with radiotherapy treatment, and was eventually diagnosed with RLS based on the diagnostic criteria. Subsequent examinations were unremarkable and revealed no further explanation for the deterioration of the RLS symptoms. While the complexity of the patient's medical history had exposed her to a variety of medications, she reported that only lamotrigine, in addition to her original regimen of methadone and pramipexole, offered significant symptomatic relief. It must be noted that no adverse side effects, including impulse-control disorder, were reported by the patient. CONCLUSIONS: We present a case of a woman whose deteriorating symptoms of RLS were successfully alleviated by the administration of lamotrigine. This is only the third case in the literature to have successfully utilized lamotrigine as a treatment option for RLS.

Breast cancer resistance protein polymorphism ABCG2 c.421C>A (rs2231142) moderates the effect of valproate on lamotrigine trough concentrations in adults with epilepsy.

BACKGROUND: Valproate inhibits clearance of lamotrigine and greatly increases its concentrations. We assessed whether this effect was moderated by a polymorphism (ABCG2 c.421C>A) of the breast cancer resistance protein. METHODS: In two consecutive independent studies in adults with epilepsy on lamotrigine monotherapy or cotreated with valproate: (i) Exposure to valproate was considered treatment, (ii) dose-adjusted lamotrigine troughs at steady state were the outcome, and (iii) ABCG2 c.421C>A genotype (wild-type [wt] homozygosity or variant carriage) was the tested moderator. We used entropy balancing (primary analysis) and exact/optimal full matching (secondary analysis) to control for confounding, including polymorphisms (and linked polymorphisms) suggested to affect exposure to lamotrigine (UGT1A4*3 c.142T>G, rs2011425; UGT2B7-161C>T, rs7668258; ABCB1 1236C>T, rs1128503) to generate frequentist and Bayesian estimates of valproate effects (geometric means ratios [GMR]). RESULTS: The two studies yielded consistent results (replicated); hence, we analyzed combined data (total N = 471, 140 treated, 331 controls, 378 ABCG2 c.421C>A wt subjects, 93 variant carriers). Primary analysis: in variant carriers, valproate effect (GMR) on lamotrigine (treated, n = 21 vs. controls, n = 72) was around 60% higher than in wt subjects (treated, n = 119 vs. controls, n = 259)-ratio of GMRs 1.61 (95%CI 1.23-2.11) (frequentist) and 1.63 (95%CrI 1.26-2.10) (Bayes). Similar differences in valproate effects between variant carriers and wt subjects were found in the secondary analysis (valproate troughs up to 364 µmol/L vs. no valproate; or valproate ≥364 µmol/L vs. no valproate). Susceptibility of the estimates to unmeasured confounding was low. CONCLUSION: Data suggest that polymorphism rs2231142 moderates the effect of valproate on exposure to lamotrigine.

Curcumin protects against lamotrigine-induced chronic ovarian and uterine toxicity in rats by regulating PPAR-γ and ROS production.

Lamotrigine (LTG) is an antiepileptic drug with possible adverse effects on the female reproductive system. Curcumin was declared to improve ovarian performance. Therefore, this study aimed to clarify ovulatory dysfunction (OD) associated with LTG and the role of curcumin in ameliorating this dysfunction. Adult female Wister albino rats were assigned into four groups: negative control (received saline), positive control (received curcumin only), LTG, and LTG with curcumin groups. Drugs were administered for 90 days. The hormonal profile, including testosterone, estrogen, progesterone, luteinizing hormone, and follicle-stimulating hormone, in addition to the lipid profile and glycemic analysis, were tested. Oxidative stress biomarkers analysis in the ovaries and uterus and peroxisome proliferator-activated receptor-γ (PPAR-γ) gene expression were also included. Histopathological examination of ovarian and uterine tissues and immunohistochemical studies were also performed. Curcumin could improve the OD related to chronic LTG intake. That was proved by the normalization of the hormonal profile, glycemic control, lipidemic status, oxidative stress markers, and PPAR-γ gene expression. The histopathological and immunohistochemical examination of ovarian and uterine tissues revealed an improvement after curcumin administration. The results describe an obvious deterioration in ovarian performance with LTG through the effect on lipidemic status, PPAR-γ gene, and creating an oxidative stress condition in the ovaries of chronic users, with a prominent improvement with curcumin addition to the treatment protocol.

Characterization of drug-induced liver injury associated with drug reaction with eosinophilia and systemic symptoms in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53 years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes.

Lamotrigine and exogenous estrogen among females with epilepsy: A retrospective analysis of administrative claims data.

OBJECTIVE: Exogenous estrogen reduces lamotrigine serum concentrations. Little is known about whether providers adjust lamotrigine doses for addition of exogenous estrogen among people with epilepsy, despite expert recommendations. We determined the incidence of dose increases in lamotrigine following incident prescription of estrogen among females with epilepsy (FWE) in claims data. METHODS: We used Optum's de-identified Clinformatics® Data Mart Database to create a cohort of U.S. FWE prescribed lamotrigine at a stable dose, with a subsequent prescription for estrogen from 2011 to 2021. We calculated cumulative incidence functions of dose increases in lamotrigine following prescription of exogenous estrogen. We performed a Cox proportional hazards model for multiple candidate predictors of a lamotrigine dose increase. RESULTS: The cohort included 643 FWE, with median age of 31 (interquartile ratio [IQR] 20-42). The cumulative incidence of any lamotrigine increase was 28% (95% confidence interval [CI] 25%-32%). The median number of days after the first estrogen fill until the first lamotrigine adjustment was 118 (IQR 48-188). In unadjusted Cox models, older age, use of estrogen in hormone replacement therapy as opposed to contraception, and annual household income of $50,000-$99,999 (compared with <$50,000) were significant negative predictors of a dose adjustment in lamotrigine with hazard ratios (HRs) of 0.82 (95% CI 0.72-0.92), 0.63 (95% CI 0.42-0.95), and 0.62 (95% CI 0.40-0.95). In the adjusted Cox model, age and income remained significant predictors with HRs of 0.79 (95% CI 0.66-0.94) and 0.59 (95% CI 0.36-0.95). CONCLUSION: Dose increase of lamotrigine following addition of exogenous estrogen is rare among U.S. FWE, with potential disparities based on age and income level. More guidance may be needed for providers on this topic.

Investigation of cardiac arrhythmia events in patients treated with lamotrigine: FDA adverse event reporing system analysis.

OBJECTIVES: In October 2020 and March 2021, the U.S. Food and Drug Administration (FDA) classified lamotrigine as a class IB antiarrhythmic, announcing an increased risk of heart rhythm problems. We sought to investigate the nature of the arrhythmia signal with lamotrigine use compared to anticonvulsants with sodium-blocking and non-sodium-blocking mechanisms. METHODS: This retrospective pharmacovigilance case-non-case study used disproportionality analysis to detect signals of adverse reaction of interest reported with lamotrigine to the FDA Adverse Event Reporting System (FAERS) between 1998 and 2022. Our regression model adjusted for interacting concomitant medications. Sensitivity analyses included stratifying by indication and publication date. RESULTS: Overall, 2917 cases of heart rhythm problems with anticonvulsants were analyzed (1557 female [58.4%] and 1109 male [41.6%]). The mean age ± standard deviation (SD) was 43 ± 19, the groups did not differ significantly by age. Forty cases (7.91%) in the epileptic indication included more than one concomitant medication that influences cardiac conduction. The disproportionality signal for cardiac arrest did not differ for lamotrigine compared with other anticonvulsants, adjusted reporting odds ratio (adj.ROR, .88; 95% CI, .59-1.29) in the epileptic indication. A significantly lower reporting risk for bradyarrhythmia was identified with lamotrigine users in the epileptic population, (adj.ROR, .45; 95% confidence interval [CI], .29-.68). The psychiatric indication demonstrated a sixfold reporting risk for cardiac arrest compared to the epileptic indication. Concomitant medications that affect cardiac conduction, as well as reports on overdose and suicide attempts, were significant variables in psychiatric patients (ROR, 2.45; 95% CI, 2.21-2.71) and (ROR, 1.44; 95% CI, 1.34-1.55), respectively. SIGNIFICANCE: Our results do not support a significant difference in the reporting risk for cardiac arrest, syncope, tachyarrhythmia, and bradyarrhythmia with lamotrigine in the epileptic indication. Signals of cardiac arrest in lamotrigine could be explained by confounding factors in the psychiatric indication, such as greater concomitant use of medications with cardiac adverse events, and greater reports on overdose and suicide attempts. We recommend that patients with polypharmacy undergo clinical and electrocardiographic monitoring. We illustrate the importance of examining signals for separate indications.

Improvement of synaptic plasticity and cognitive function in RASopathies-a monocentre, randomized, double-blind, parallel-group, placebo-controlled, cross-over clinical trial (SynCoRAS).

BACKGROUND: Cognitive impairment is a common medical issue in rat sarcoma (RAS) pathway disorders, so-called RASopathies, like Neurofibromatosis type 1 (NF1) or Noonan syndrome (NS). It is presumed to be caused by impaired synaptic plasticity. In animal studies, pathway-specific pharmacological interventions with lovastatin (LOV) and lamotrigine (LTG) have been shown to improve synaptic plasticity as well as cognitive function. The aim of this clinical trial is to translate the findings of animal studies to humans and to probe the effect of lovastatin (NS) and lamotrigine (NS and NF1) on synaptic plasticity and cognitive function/alertness in RASopathies. METHODS: Within this phase IIa, monocentre, randomized, double-blind, parallel-group, placebo-controlled, cross-over clinical trial (syn. SynCoRAS), three approaches (approaches I-III) will be carried out. In patients with NS, the effect of LTG (approach I) and of LOV (approach II) is investigated on synaptic plasticity and alertness. LTG is tested in patients with NF1 (approach III). Trial participants receive a single dose of 300 mg LTG or placebo (I and III) and 200 mg LOV or placebo (II) daily for 4 days with a cross-over after at least 7 days. Synaptic plasticity is investigated using a repetitive high-frequency transcranial magnetic stimulation (TMS) protocol called quadri-pulse theta burst stimulation (qTBS). Attention is examined by using the test of attentional performance (TAP). Twenty-eight patients are randomized in groups NS and NF1 with n = 24 intended to reach the primary endpoint (change in synaptic plasticity). Secondary endpoints are attention (TAP) and differences in short interval cortical inhibition (SICI) between placebo and trial medication (LTG and LOV). DISCUSSION: The study is targeting impairments in synaptic plasticity and cognitive impairment, one of the main health problems of patients with RASopathies. Recent first results with LOV in patients with NF1 have shown an improvement in synaptic plasticity and cognition. Within this clinical trial, it is investigated if these findings can be transferred to patients with NS. LTG is most likely a more effective and promising substance improving synaptic plasticity and, consecutively, cognitive function. It is expected that both substances are improving synaptic plasticity as well as alertness. Changes in alertness may be a precondition for improvement of cognition. TRIAL REGISTRATION: The clinical trial is registered in ClinicalTrials.gov (NCT03504501; https://www. CLINICALTRIALS: gov ; date of registration: 04/11/2018) and in EudraCT (number 2016-005022-10).

Understanding Lamotrigine's Role in the CNS and Possible Future Evolution.

The anti-epileptic drug lamotrigine (LTG) has been widely used to treat various neurological disorders, including epilepsy and bipolar disorder. However, its precise mechanism of action in the central nervous system (CNS) still needs to be determined. Recent studies have highlighted the involvement of LTG in modulating the activity of voltage-gated ion channels, particularly those related to the inhibition of neuronal excitability. Additionally, LTG has been found to have neuroprotective effects, potentially through the inhibition of glutamate release and the enhancement of GABAergic neurotransmission. LTG's unique mechanism of action compared to other anti-epileptic drugs has led to the investigation of its use in treating other CNS disorders, such as neuropathic pain, PTSD, and major depressive disorder. Furthermore, the drug has been combined with other anti-epileptic drugs and mood stabilizers, which may enhance its therapeutic effects. In conclusion, LTG's potential to modulate multiple neurotransmitters and ion channels in the CNS makes it a promising drug for treating various neurological disorders. As our understanding of its mechanism of action in the CNS continues to evolve, the potential for the drug to be used in new indications will also be explored.

Implications of BCRP modulation on PTZ-induced seizures in mice: Role of ko143 and metformin as adjuvants to lamotrigine.

Blood-brain barrier (BBB) efflux transporters' overexpression hinders antiepileptic drug brain entry. Breast cancer resistance protein (BCRP) is a major BBB efflux transporter. In the present work, BCRP's role as a mechanism that might contribute to drug-resistant epilepsy (DRE) in a mouse model of acute seizures was studied with further assessment of the effect of its inhibition by ko143 and metformin (MET) on lamotrigine (LTG) bioavailability and efficacy. 42 male mice divided into 6 groups: G1: Normal control, G2: LTG-injected healthy mice: LTG 20 mg/kg i.p., G3: Acute seizures (A.S) mice: Pentylenetetrazole (PTZ) 50 mg/kg i.p., G4: LTG-treated A.S mice: LTG 20 mg/kg + PTZ 50 mg/kg i.p., G5: Ko143 + LTG treated A.S mice: Ko143 15 mg/kg i.p. before LTG + PTZ, G6: MET + LTG treated A.S mice: MET 200 mg/kg i.p. before LTG + PTZ. Seizures severity, serum, brain LTG, and brain BCRP were assessed. PTZ group experienced the highest seizure frequency and brain BCRP expression. Ko143 and MET groups showed a significant decrease in brain BCRP with subsequent improvement in brain LTG level and better seizure control. BCRP has a significant role in epilepsy resistance and its inhibition with ko143 or MET adds value to DRE management.