Impact of UGT1A4 and UGT2B7 polymorphisms on lamotrigine plasma concentration in patients with bipolar disorder.

PURPOSE: The purpose of this study was to evaluate the effect of UGT1A4 and UGT2B7 polymorphisms on the plasma concentration of lamotrigine in Chinese patients with bipolar disorder. METHODS: A total of 104 patients were included in this study. Steady-state plasma lamotrigine concentrations were determined in each patient after at least 21 days of continuous treatment with a set dose of the drug. Lamotrigine plasma concentrations were ascertained using ultra-performance liquid chromatography. Simultaneously, plasma samples were used for patient genotyping. RESULTS: The age, sex, BMI, daily lamotrigine dose, plasma lamotrigine concentration, and lamotrigine concentration/dose ratio of patients exhibited significant differences, and these were associated with differences in the genotype [ UGT1A4 -142T>G and UGT2B7 -161C>T ( P  < 0.05)]. Patients with the GG and GT genotypes in UGT1A4 -142T>G had significantly higher lamotrigine concentration/dose values (1.6 ±â€…1.1 and 1.7 ±â€…0.5 µg/ml per mg/kg) than those with the TT genotype (1.4 ±â€…1.1 µg/ml per mg/kg). Likewise, patients with the UGT2B7 -161C>T TT genotype had significantly higher lamotrigine concentration/dose values (1.6 ±â€…1.1 µg/ml per mg/kg) than those with the CC genotype (1.3 ±â€…1.3 µg/ml per mg/kg). Multiple linear regression analysis showed that sex, lamotrigine dose, UGT1A4 -142T>G, and UGT2B7 -161C>T were the most important factors influencing lamotrigine pharmacokinetics ( P  < 0.001). CONCLUSION: The study results suggest that the UGT1A4 -142T>G and UGT2B7 -161C>T polymorphisms affect lamotrigine plasma concentrations in patients with bipolar disorder.

Dose-dependent effect of lamotrigine on quetiapine serum concentration in patients using instant release tablets.

PURPOSE: Lamotrigine was previously reported to reduce serum concentration of quetiapine. The aim of this study was to investigate whether lamotrigine dose or quetiapine formulation was of importance for the drug interaction. METHODS: Patients combining lamotrigine with quetiapine (cases) were included retrospectively from a routine therapeutic drug monitoring (TDM) service, as were a control group of patients using quetiapine without any interacting drugs. The case and control groups were divided into groups using immediate release (IR) and extended release (XR) quetiapine. The case group was further split into high-dose (> 200 mg/day) and low-dose (≤ 200 mg/day) lamotrigine users. Quetiapine concentration-to-dose (C/D) ratio and metabolite-to-parent ratio (MPR) were compared between the control group and dose-separated case groups using ANOVA test and t-tests. RESULTS: In total, 406 patients were included. The mean C/D ratio of IR quetiapine was 46% lower in the high-dose lamotrigine group compared with the control group (P < 0.001), while no interaction effect was present in the low dose lamotrigine group (P = 0.7). Regardless of lamotrigine dose, there was no difference in quetiapine C/D ratio for patients using the XR formulation (P = 0.4). The quetiapine MPR was unaffected regardless of formulation and lamotrigine dose (P ≥ 0.06). CONCLUSION: The effect of lamotrigine in reducing quetiapine concentration is only significant for patients using quetiapine IR tablets who are treated with lamotrigine doses > 200 mg/day. Because of high variability in the interaction effect, TDM of quetiapine should be recommended during co-prescription of high-dose lamotrigine.

Correlation of drug dose estimated from national prescription registers with mean blood level of antiseizure medication in pregnancy.

PURPOSE: The purpose was to examine the correlation of antiseizure medication drug dose estimated from prescription fill records from prescription registers with blood levels during pregnancy. METHODS: We conducted a Nation-wide study of mothers who gave birth in Denmark between 1 January 2014 and 31 December 2018 using data from Danish Prescription and Laboratory Registers. We identified mothers with blood level measurements of antiseizure medication. The main exposure was estimated antiseizure medication dosage estimated from pregnancy-filled prescriptions in the Danish Prescription Register. The main outcome was the correlation of estimated dose with mean blood level of antiseizure medication in pregnancy. For privacy reasons, the number of blood level measurement and prescription fills were rounded to nearest 10, but proportions reported as exact values. RESULTS: Among 298 560 pregnancies, we identified pregnancies with recorded prescription fill from the prescription register for valproate (N = 90), lamotrigine (N = 1360), levetiracetam (N = 340), topiramate (N = 100), and carbamazepine (N = 60). In these pregnancies, blood level measurements were available in 50 (53%) pregnancies for valproate, 850 (62%) pregnancies for lamotrigine, 320 (93%) pregnancies for levetiracetam, 50 (68%) pregnancies for carbamazepine, and 40 (35%) pregnancies for topiramate. Pearsons's correlation coefficients for the correlation of estimated antiseizure medication dose with mean blood levels were 0.67 (p < 0.0001) for valproate, 0.63 (p < 0.0001) for lamotrigine, 0.63 (p < 0.0001) for levetiracetam, 0.76 (<0.0001) for carbamazepine and 0.89 (<0.0001) for topiramate. CONCLUSIONS: Dose of antiseizure medication estimated from prescription fills was a good proxy for blood levels and thus for biological exposure in pregnancy, suggesting that administrative prescription fill records may be a valuable resource for estimating exposure to antiseizure medication in pregnancy.

A Single-Blind Randomized Comparison of Lithium and Lamotrigine as Maintenance Treatments for Managing Bipolar II Disorder.

PURPOSE/BACKGROUND: No study to date has compared lithium and lamotrigine as maintenance mood stabilizers for bipolar II disorder. The aim of this study was to evaluate and compare these two medications in terms of their maintenance efficacy and side effect profile, thus evaluating their comparative cost/benefit profile. METHODS/PROCEDURES: Forty-four subjects with a newly diagnosed bipolar II disorder were randomly assigned to receive either lithium or lamotrigine treatment in a 20-week single-blinded study. Subjects received either slow-release lithium progressively up-titrated to achieve a serum level of 0.8 mEq/L, or lamotrigine increased progressively to a maintenance dose of 200 mg/d. Our primary outcome measure examined daily data on hypomanic and depressive symptoms. Secondary measures evaluated hypomanic and depressive symptom severity, global functioning, and global improvement in hypomanic and depressive symptoms. FINDINGS/RESULTS: We terminated the trial principally because of severe ongoing side effects experienced by many of those receiving lithium, and with additional concerns about initial severe side effects (including psychosis) experienced by several assigned to lamotrigine. Analyses of study completer data for 28 participants suggested comparable efficacy of both medications; however, lamotrigine had a distinctly lower rate of severe side effects across the study. We calculated that if study trends on outcome measures were valid, then an extremely large sample would be required to demonstrate superiority of either drug, thus making it unlikely that any such adequately powered study will be mounted in the future. IMPLICATIONS/CONCLUSIONS: The small sample size limits any definitive conclusions, but our data suggest that lithium and lamotrigine are likely to have equal efficacy as mood stabilizers for those with a bipolar II condition but that, as maintenance treatments, lithium has more distinctive side effects.

Estrogen profile- and pharmacogenetics-based lamotrigine dosing regimen optimization: Recommendations for pregnant women with epilepsy.

During pregnancy, various physiological changes occur that can alter the pharmacokinetics of antiepileptic drugs, such as lamotrigine (LTG). Anticipating the change in LTG dose required to achieve a pre-pregnancy target concentration is challenging. This study aimed to develop a refined population pharmacokinetic (PopPK) model of LTG in pregnant women with epilepsy (WWE) to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen. On that basis, a coarsened model containing only clinical variables was also developed to examine its predictive performance compared to the refined model. In total, 322 concentration-time points from 51 pregnant WWE treated with LTG were employed to establish a refined PopPK model that included endogenous estrogen profiles, variants of candidate genes encoding LTG-metabolizing enzymes and -transporter proteins, and other clinical variables and a coarsened model that included only clinical variables, respectively. Data from an additional 11 patients were used for external validation of these two models. A nonlinear mixed-effect modeling approach was used for PopPK analysis of LTG. The standard goodness-of-fit method, bootstrap, normalized prediction distribution errors and external evaluation were adopted to estimate the stability and predictive performance of the candidate models. Akaike information criterion (AIC) was used to compare the goodness of fit between these two models. A lower AIC indicates a better fit of the data and the preferred model. Recommended dosing regimens for pregnant WWE were selected using Monte Carlo simulation based on the established optimal model. In the refined PopPK model, the population mean of apparent LTG clearance (CL/F) in pregnant WWE was estimated to be 2.82 L/h, with an inter-individual variability of 23.6%. PopPK analysis indicated that changes in estrogen profile during pregnancy were the predominant reason for the significant variations in LTG-CL/F. Up to the 3rd trimester, the concentration accumulation effect of E2 increased LTG-CL/F by 5.109 L/h from baseline levels. Contrary to effect of E2, E3 as the main circulating estrogen in pregnancy with a peak value of 34.41 ng/mL is 1000-fold higher than that in non-pregnancy reduced LTG-CL/F by 1.413 L/h. In addition, the UGT2B7 rs4356975 C > T and ABCB1 rs1128503 A > G variants may contribute to a better understanding of the inter-individual variability in LTG-CL/F. LTG-CL/F was 1.66-fold higher in UGT2B7 rs4356975 CT or TT genotype carriers than in CC genotype carriers. In contrast, ABCB1 rs1128503 GG genotype carriers had only 71.9% of the LTG-CL/F of AA or AG genotype carriers. In the coarsened PopPK model, the gestational age was a promising predictor of changes in LTG-CL/F. When comparing these two models, the refined PopPK model was favored over the coarsened PopPK model (AIC = -30.899 vs. -20.017). Monte Carlo simulation based on optimal PopPK model revealed that the LTG dosage administered to carriers of the UGT2B7 rs4356975 CT or TT genotype required a 33-50% increase to reach the pre-pregnancy target concentration, and carriers of the ABCB1 rs1128503 GG genotype required a 33-66% lower dose of LTG than carriers of the ABCB1 rs1128503 AA or AG genotype. Changes in estrogen profile during pregnancy was a better predictor of variations in LTG-CL/F than gestational age. The developed model based on estrogen profile and pharmacogenetics can serve as a foundation for further optimization of dosing regimens of LTG in pregnant WWE.

Anti-seizure medications for Lennox-Gastaut syndrome.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is an age-specific epilepsy syndrome characterised by multiple seizure types, including drop seizures. LGS has a characteristic electroencephalogram, an onset before age eight years and an association with drug resistance. This is an updated version of the Cochrane Review published in 2013. OBJECTIVES: To assess the efficacy and tolerability of anti-seizure medications (ASMs) for LGS. SEARCH METHODS: We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 28 February 2020) on 2 March 2020. CRS Web includes randomised controlled trials (RCTs) or quasi-RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL); the Specialised Registers of Cochrane Review Groups, including Cochrane Epilepsy; PubMed; Embase; ClinicalTrials.gov; and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies. SELECTION CRITERIA: We considered RCTs, including cross-over trials, of ASMs for LGS in children and adults. We included studies of ASMs used as either monotherapy or as an add-on (adjunctive) therapy. We excluded studies comparing different doses of the same ASM. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures, including independent, dual assessment for risk of bias and application of the GRADE approach to rate the evidence certainty for outcomes. MAIN RESULTS: We found no trials of ASM monotherapy. The review included 11 trials (1277 participants; approximately 11 weeks to 112 weeks follow-up after randomisation) using add-on ASMs for LGS in children, adolescents and adults. Two studies compared add-on cannabidiol (two doses) with add-on placebo in children and adolescents only. Neither study reported overall seizure cessation or reduction. We found high-certainty evidence that 72 more people per 1000 (confidence interval (CI) 4 more to 351 more) had adverse events (AE) leading to study discontinuation with add-on cannabidiol, compared to add-on placebo (two studies; 396 participants; risk ratio (RR) 4.90, 95% CI 1.21 to 19.87). One study compared add-on cinromide with add-on placebo in children and adolescents only. We found very low-certainty evidence that 35 more people per 1000 (CI 123 fewer to 434 more) had 50% or greater average reduction of overall seizures with add-on cinromide compared to add-on placebo (one study; 56 participants; RR 1.15, 95% CI 0.47 to 2.86). This study did not report participants with AE leading to study discontinuation. One study compared add-on clobazam (three doses) with add-on placebo. This study did not report overall seizure cessation or reduction. We found high-certainty evidence that 106 more people per 1000 (CI 0 more to 538 more) had AE leading to study discontinuation with add-on clobazam compared to add-on placebo (one study; 238 participants; RR 4.12, 95% CI 1.01 to 16.87). One study compared add-on felbamate with add-on placebo. No cases of seizure cessation occurred in either regimen during the treatment phase (one study; 73 participants; low-certainty evidence). There was low-certainty evidence that 53 more people per 1000 (CI 19 fewer to 716 more) with add-on felbamate were seizure-free during an EEG recording at the end of the treatment phase, compared to add-on placebo (RR 2.92, 95% CI 0.32 to 26.77). The study did not report overall seizure reduction. We found low-certainty evidence that one fewer person per 1000 (CI 26 fewer to 388 more) with add-on felbamate had AE leading to study discontinuation compared to add-on placebo (one study, 73 participants; RR 0.97, 95% CI 0.06 to 14.97). Two studies compared add-on lamotrigine with add-on placebo. Neither study reported overall seizure cessation. We found high-certainty evidence that 176 more people per 1000 (CI 30 more to 434 more) had ≥ 50% average seizure reduction with add-on lamotrigine compared to add-on placebo (one study; 167 participants; RR 2.12, 95% CI 1.19 to 3.76). We found low-certainty evidence that 40 fewer people per 1000 (CI 68 fewer to 64 more) had AE leading to study-discontinuation with add-on lamotrigine compared to add-on placebo (one study; 169 participants; RR 0.49, 95% CI 0.13 to 1.82). Two studies compared add-on rufinamide with add-on placebo. Neither study reported seizure cessation. We found high-certainty evidence that 202 more people per 1000 (CI 34 to 567 more) had ≥ 50% average seizure reduction (one study; 138 participants; RR 2.84, 95% CI 1.31 to 6.18). We found low-certainty evidence that 105 more people per 1000 (CI 17 fewer to 967 more) had AE leading to study discontinuation with add-on rufinamide compared to add-on placebo (one study; 59 participants; RR 4.14, 95% CI 0.49 to 34.86). One study compared add-on rufinamide with another add-on ASM. This study did not report overall seizure cessation or reduction. We found low-certainty evidence that three fewer people per 1000 (CI 75 fewer to 715 more) had AE leading to study discontinuation with add-on rufinamide compared to another add-on ASM (one study; 37 participants; RR 0.96, 95% CI 0.10 to 9.57). One study compared add-on topiramate with add-on placebo. This study did not report overall seizure cessation. We found low-certainty evidence for ≥ 75% average seizure reduction with add-on topiramate (one study; 98 participants; Peto odds ratio (Peto OR) 8.22, 99% CI 0.60 to 112.62) and little or no difference to AE leading to study discontinuation compared to add-on placebo; no participants experienced AE leading to study discontinuation (one study; 98 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: RCTs of monotherapy and head-to-head comparison of add-on ASMs are currently lacking. However, we found high-certainty evidence for overall seizure reduction with add-on lamotrigine and rufinamide, with low-certainty evidence for AE leading to study discontinuation compared with add-on placebo or another add-on ASM. The evidence for other add-on ASMs for overall seizure cessation or reduction was low to very low with high- to low-certainty evidence for AE leading to study discontinuation. Future research should consider outcome reporting of overall seizure reduction (applying automated seizure detection devices), impact on development, cognition and behaviour; future research should also investigate age-specific efficacy of ASMs and target underlying aetiologies.

Treatment of epilepsy for people with Alzheimer's disease.

BACKGROUND: Any type of seizure can be observed in Alzheimer's disease. Antiepileptic drugs seem to prevent the recurrence of epileptic seizures in most people with Alzheimer's disease. There are pharmacological and non-pharmacological treatments for epilepsy in people with Alzheimer's disease, however there are no current systematic reviews to evaluate the efficacy and tolerability of these treatments. This review aims to investigate these different modalities. This is an updated version of the Cochrane Review previously published in 2018. OBJECTIVES: To assess the efficacy and tolerability of pharmacological or non-pharmacological interventions for the treatment of epilepsy in people with Alzheimer's disease (including sporadic Alzheimer's disease and dominantly inherited Alzheimer's disease). SEARCH METHODS: For the latest update, on 3 August 2020 we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 31 July 2020). CRS Web includes randomized or quasi-randomized controlled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups, including Cochrane Epilepsy. In an effort to identify further published, unpublished and ongoing trials, we searched ongoing trials registers, reference lists and relevant conference proceedings; we also contacted trial authors and pharmaceutical companies. SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials investigating treatment for epilepsy in people with Alzheimer's disease, with the primary outcomes of proportion of participants with seizure freedom and proportion of participants experiencing adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to there being limited available data. MAIN RESULTS: We included one randomized controlled trial (RCT) on pharmacological interventions; the trial included 95 participants. No studies were found for non-pharmacological interventions. Concerning the proportion of participants with seizure freedom, no significant differences were found for the comparisons of levetiracetam versus lamotrigine (RR) 1.20, 95% CI 0.53 to 2.71; 67 participants; very low-certainty evidence), levetiracetam versus phenobarbital (RR 1.01, 95% CI 0.47 to 2.19; 66 participants; very low-certainty evidence), or lamotrigine versus phenobarbital (RR 0.84, 95% CI 0.35 to 2.02; 57 participants; very low-certainty evidence). It seemed that levetiracetam could improve cognition and lamotrigine could relieve depression, while phenobarbital and lamotrigine could worsen cognition, and levetiracetam and phenobarbital could worsen mood. The risk of bias relating to allocation, blinding and selective reporting was unclear. We judged the certainty of the evidence for all outcomes to be very low. AUTHORS' CONCLUSIONS: This review does not provide sufficient evidence to support levetiracetam, phenobarbital or lamotrigine for the treatment of epilepsy in people with Alzheimer's disease. Regarding efficacy and tolerability, no significant differences were found between levetiracetam, phenobarbital and lamotrigine. Large RCTs with a double-blind, parallel-group design are required to determine the efficacy and tolerability of treatment for epilepsy in people with Alzheimer's disease.

Lamotrigine loaded nano-liposomes enhance brain selectivity in vivo.

For many patients with refractory epilepsy, antiepileptic drugs (AEDs) cannot reach effective therapeutic concentration in brain due to drugtolerance. In order to increase the selectivity of lamotrigine in brain, lamotrigine loaded nano-liposomes (LTG-NL) were designed, prepared, and the physio-chemical characterizations were observed. The distribution of LTG-NL in mice was studied by detecting the concentration of LTG extracted from animal organs, then targeting efficiency (TE) and targeting index (TI) were calculated to evaluate the brain targeting effect of LTG-NL. The mechanism of LTG-NL entry into cell was determined by A549 cell internalization experiments. The results showed that LTG-NL were small and uniform spherical particles with high entrapment efficiency and release. In vivo distribution study showed brain selectivity of LTG-NL, and TE and TI values further demonstrated the targeting capacity of LTG-NL. The cell internalization of LTG-NL was mainly by the pathway of clathrin-mediated endocytosis and macropinocytosis. These findings suggested this lipid formulation would be a drug delivery system for insoluble drugs to promote drug release and enhance brain selectivity.

Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy.

Genetic and nongenetic factors may contribute to lamotrigine (LTG) plasma concentration variability among patients. We simultaneously investigated the association of UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1 variants, as well as antiepileptic drug co-treatment, on LTG plasma concentration in 97 Mexican Mestizo (MM) patients with epilepsy. UGT1A4*1b was associated with lower LTG dose-corrected concentrations. Patients with the UGT2B7-161T allele were treated with 21.22% higher LTG daily dose than those with CC genotype. Two novel UGT1A4 variants (c.526A>T; p.Thr185= and c.496T>C; p.Ser166Leu) were identified in one patient. Patients treated with LTG + valproic acid (VPA) showed higher LTG plasma concentration than patients did on LTG monotherapy or LTG + inducer. Despite the numerous drug-metabolizing enzymes and transporter genetic variants analyzed, our results revealed that co-treatment with VPA was the most significant factor influencing LTG plasma concentration, followed by UGT1A4*1b, and that patients carrying UGT2B7 c.-161T required higher LTG daily doses. These data provide valuable information for the clinical use of LTG in MM patients with epilepsy.

Pharmacodynamic interactions of antiepileptic drugs: From bench to clinical practice.

BACKGROUND: Approximately 50% of patients do not achieve seizure control with antiepileptic drug (AED) monotherapy, and polytherapy, with more than one AED, is often required. To date, no evidence-based criteria on how to combine AEDs exist. OBJECTIVE: This narrative review aimed to provide critical findings of the available literature about the role of pharmacodynamic AEDs' interactions in patients whose epilepsies were treated with polytherapy. METHODS: Electronic databases, Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica dataBASE (EMBASE), were systematically searched to identify relevant studies on pharmacodynamic AEDs' interactions in patients with epilepsy. RESULTS AND CONCLUSION: Most data on AED combinations are coming from animal models and preclinical studies. Combining AEDs with different mechanisms of actions seems to have greater effectiveness and lower risk of adverse event development. Conversely, the combination of AEDs may cause pharmacodynamic synergistic effects that may result in not only increased efficacy but also more adverse effects. Despite some AED associations that have been proven to be effective in specific epilepsy/seizure type (e.g., phenobarbital+/phenytoin for tonic seizures and ethosiximide + valproate for absences; lamotrigine + valproate for various epilepsy/seizure types), no clear and definitive evidence exists about AED combinations in humans. Examples of pharmacodynamic interactions that possibly explain the synergistic effects on efficacy or adverse effects include the combination between vigabatrin or pregabalin and sodium channel blockers (supra-additive antiseizure effect) and lacosamide combined with other sodium channel blockers (infra-additive antiseizure effect and neurotoxicity synergistic). The pharmacodynamic lamotrigine-valproate interaction is also supported by synergistic adverse events. Therefore, well-designed double-blind prospective studies recruiting a sufficient number of patients possibly with a crossover design and carefully ascertain the role of pharmacokinetic interactions and variations of AEDs' levels in the blood are needed.

Lamotrigine add-on therapy for drug-resistant focal epilepsy.

BACKGROUND: This is an updated version of the Cochrane Review previously published in 2016. Epilepsy is a common neurological disorder, affecting 0.5% to 1% of the population. For nearly 30% of these people, their epilepsy is resistant to currently available drugs. Pharmacological treatment remains the first choice to control epilepsy. Lamotrigine is one of the newer antiepileptic drugs. Lamotrigine, in combination with other antiepileptic drugs (add-on), can reduce seizures, but with some adverse effects. OBJECTIVES: To determine the effects of lamotrigine on (1) seizures, (2) adverse-effect profile, and (3) cognition and quality of life, compared to placebo, when used as an add-on treatment for people with drug-resistant focal epilepsy. SEARCH METHODS: For the latest update of the review, we searched the following databases on 9 March 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to March 06, 2020). CRS Web includes randomized or quasi-randomized, controlled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. No language restrictions were imposed. SELECTION CRITERIA: Randomised placebo-controlled trials of people with drug-resistant focal epilepsy of any age, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded, placebo-controlled. For cross-over studies, the first treatment period was treated as a parallel trial. Eligible participants were adults or children with drug-resistant focal 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 (RRs) with 95% confidence intervals (95% Cls) were estimated for the primary outcomes of seizure frequency and treatment withdrawal. For adverse effects, we calculated pooled RRs and 99% Cls. MAIN RESULTS: We did not identify any new studies for this update, therefore, the results and conclusions are unchanged. In previous updates of this review, the authors found five parallel add-on studies, eight cross-over studies in adults or children with drug-resistant focal epilepsy, and one parallel add-on study with a responder-enriched design in infants. In total, these 14 studies included 1806 eligible participants (38 infants, 199 children, 1569 adults). Baseline phases ranged from four to 12 weeks; treatment phases from eight to 36 weeks. Overall, 11 studies (1243 participants) were rated as having low risk of bias, and three (697 participants) had unclear risk of bias due to lack of reported information around study design. Effective blinding of studies was reported in four studies (563 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 trials, 1322 participants (adults and children); moderate-certainty evidence) 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 0.91 to 1.37; 14 trials; 1806 participants; moderate-certainty evidence). The adverse events significantly associated with lamotrigine were: ataxia, dizziness, diplopia (double vision), and nausea. The RR of these adverse effects were as follows: ataxia 3.34 (99% Cl 2.01 to 5.55; 12 trials; 1525 participants; high-certainty evidence); dizziness 2.00 (99% Cl 1.52 to 2.64;13 trials; 1768 participants; moderate-certainty evidence); diplopia 3.79 (99% Cl 2.15 to 6.68; 3 trials, 944 participants; high-certainty evidence); nausea 1.81 (99% Cl 1.22 to 2.68; 12 studies,1486 participants; moderate-certainty evidence). 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 certainty, due to incomplete data for some outcomes. AUTHORS' CONCLUSIONS: Lamotrigine as an add-on treatment for drug-resistant focal 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 lamotrigine with other add-on drugs.

Safety evidence on the administration of Fucus vesiculosus L. (bladderwrack) extract and lamotrigine: data from pharmacokinetic studies in the rat.

Fucus vesiculosus is often incorporated in weight loss dietary supplements to improve weight loss in overweight adults. Obesity is a common condition in epilepsy patients and is indeed increasing in refractory epilepsy and in patients under polytherapy. Since lamotrigine (LTG) is a first-line antiepileptic drug, used in monotherapy or adjunctive therapy, the main objective of this work was to investigate the potential pharmacokinetic-based interactions between F. vesiculosus and LTG in rats. In a first pharmacokinetic study, a single oral dose of F. vesiculosus extract (575 mg/kg, p.o.) was co-administered with a single-dose of LTG (10 mg/kg, p.o.). In a second study, rats were orally pretreated with F. vesiculosus extract (575 mg/kg/day, p.o.) for 14 days and received LTG (10 mg/kg, p.o.) on the 15th day. In the control groups, rats received water instead of the extract. After LTG administration, blood samples were taken until 96 h post-dose, and LTG concentrations measured in plasma were submitted to a non-compartmental pharmacokinetic analysis. The co-administration of F. vesiculosus extract and LTG caused no significant changes in the drug kinetics. However, the repeated pretreatment with F. vesiculosus extract significantly reduced the peak concentrations of LTG and caused a slightly decrease in the extent of systemic drug exposure. Overall, based on these results, no significant clinical impact is expected from the administration of F. vesiculosus dietary supplements and LTG.

Investigation of the Absorption of Nanosized lamotrigine Containing Nasal Powder via the Nasal Cavity.

Nasal drug delivery has become a popular research field in the last years. This is not surprising since the nose possesses unique anatomical and physical properties. Via the nasal mucosa local, systemic, and directly central nerve systemic (CNS) effect is achievable. Powders have favorable physicochemical properties over liquid formulations. Lamotrigine (LAM) is an antiepileptic agent with a relatively mild side effect spectrum, but only available in tablet form on market. Reducing the particle size to the nano range can affect the bioavailability of pharmaceutical products. The aim of this article was to continue the work started, compare the in vitro properties of a nanonized lamotrigine containing nasal powder (nanoLAMpowder) and its physical mixture (PM) that were prepared by dry milling. Moreover, to study their trans-epithelial absorption to reach the blood and target the brain by axonal transport. Due to the dry milling technique, the particle size of LAM, their surface and also their structure changed that led to higher in vitro dissolution and permeability rate. The results of the in vivo tests showed that the axonal transport of the drug was assumable by both intranasal formulations because the drug was present in the brain within a really short time, but the LAM from the nanoLAMpowder liberated even faster.

Lamotrigine Therapy and Biomarkers of Cerebral Energy Metabolism in Older Age Bipolar Depression.

OBJECTIVE: This study compared brain energy metabolism, as measured by cerebral concentrations of glutamate (Glu), glutamine (Gln), and N-acetyl aspartate (NAA), in older age bipolar depression (OABD) to that of psychiatrically healthy comparison subjects using proton (1H) magnetic resonance spectroscopy imaging at 4-Tesla. Metabolite levels were assessed in OABD subjects before and after 8 weeks of lamotrigine therapy with the goal of determining relationships between cerebral energy metabolism, depression symptom severity, and changes in depression symptom response. METHODS: Individuals (n = 21, mean age: 62.0 ± 5.9 years) with bipolar disorder, current episode depressed, and a healthy comparison group (n = 14, mean age: 67.5 ± 8.8 years) were selected. Participants with bipolar disorder, current episode depressed, were treated in open label fashion with lamotrigine monotherapy for 8 weeks. All subjects were scanned with 1H magnetic resonance spectroscopy at 4T at baseline and again after 8 weeks to assess levels of cerebral metabolites in the anterior cingulate cortex and parieto-occipital cortex. Metabolite levels were examined as ratios relative to creatine (Cr). Response to 8 weeks of lamotrigine treatment in the bipolar disorder, current episode depressed group, was assessed as a continuous measure on the Montgomery-Asberg Depression Rating Scale. RESULTS: NAA/Cr ratio in OABD was significantly lower by 14% (95% confidence interval: [1%, 26%]) than in comparison subjects at baseline. However, there were no associations between NAA/Cr, Glu/Cr, or Gln/Cr and either depression severity or lamotrigine treatment. CONCLUSION: Group differences in NAA suggest evidence for a deficit in cerebral energy metabolism in OABD.

Adjustment of the area under the concentration curve by terminal rate constant for bioequivalence assessment in a parallel-group study of lamotrigine.

AIM: A new strength of lamotrigine extended-release formulation unexpectedly failed to show bioequivalence with the existing strengths at the same dose in a parallel-group study. We report the post-hoc analyses conducted to identify the cause and propose an approach for future evaluations in similar situations. METHODS: A seemingly bimodal distribution of the half-life among the study participants prompted the use of terminal-phase-rate-constant-adjusted area under the concentration curve as the endpoint for bioequivalence assessment. Population pharmacokinetic modelling was also performed to assess the bimodal distribution of apparent clearance and the potential treatment effects on bioavailability. RESULTS: The cause for failing to achieve bioequivalence appeared to be a biased representation of a bimodal clearance distribution between the groups. The pharmacokinetic modelling with a mixture routine identified two subpopulations: 88% had a mean clearance of 1.99 l h-1 ; 12% had a mean clearance of 0.64 l h-1 . The low-clearance population was unequally represented by 13% and 4% of subjects in the reference and test groups, respectively, and treatment appeared to have no significant effect on oral bioavailability. The bioequivalence comparison using the adjusted area concluded with a 90% confidence interval of 0.91-1.06, suggesting that treatment had no significant effect on bioavailability and the formulations would meet regulatory criteria for bioequivalence. CONCLUSIONS: The adjustment of the area under the concentration curve adjusted by terminal-phase rate constant should be considered for situational application in bioequivalence assessment when there are multiple clearance subpopulations in a parallel-group study.

Remedial dosing recommendations for delayed or missed doses of lamotrigine in pediatric patients with epilepsy using Monte Carlo simulations.

OBJECTIVE: This study investigated the effect of delayed or missed doses on the pharmacokinetics (PK) of lamotrigine (LTG) in children with epilepsy and established remedial dosing recommendations for nonadherent patients. METHODS: The Monte Carlo simulation based on a published LTG population PK model was used to assess the effect of different scenarios of nonadherence and the subsequently administered remedial regimens. The following three remedial approaches were investigated for each delayed dose: A) A partial dose was administered immediately, and the regular dose was administered at the next scheduled time. B) The delayed dose was administered immediately, followed by a partial dose at the next scheduled time. C) The delayed and partial doses were coadministered immediately, the next scheduled dose was skipped, and the regular dosing was resumed at the subsequent scheduled time. The most appropriate remedial regimen was that with the shortest deviation time from the individual therapeutic window. RESULTS: The effect of nonadherence on PK was dependent on the delay duration and daily dose, and the recommended remedial dose was related to the delay duration and concomitant antiepileptic drugs. Remedial dosing strategies A and B were almost equivalent, whereas C showed a larger PK deviation time. If one dose was missed, double doses were not recommended for the next scheduled time. CONCLUSIONS: Simulations provide quantitative insight into the remedial regimens for nonadherent patients, and clinicians should select the optimal regimen based on the status of patients.

Fetal antiepileptic drug exposure and learning and memory functioning at 6 years of age: The NEAD prospective observational study.

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study was a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate). In this report, we examine fetal AED exposure effects on learning and memory functions in 221 six-year-old children (including four sets of twins) whose mothers took one of these AEDs during pregnancy. Their performance was compared with that of a national sample of normally developing six year olds from the standardization sample of the Children's Memory Scale (CMS). The major results of this study indicate that the mean performance levels of children exposed to valproate were significantly below that of the children in the normal comparison group across all seven of the CMS Indexes. With one exception, this finding held up at the subtest level as well. These findings taken together with nonsignificant verbal and nonverbal forgetting scores appear to indicate that, as a group, children exposed to valproate experienced significant difficulty in their ability to process, encode, and learn both auditory/verbal as well as visual/nonverbal material. In addition, they exhibited significant difficulty holding and manipulating information in immediate auditory working memory. However, once the information was learned and stored, the valproate-exposed children appeared to be able to retrieve the information they did learn at normal levels. Finally, the processing, working memory, and learning deficits demonstrated by the valproate-exposed children are dose-related. In contrast to valproate, the findings pertaining to the children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy are less clear. Therefore, further research will be required to delineate the potential risks to learning and memory functions in children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy during pregnancy. Additional research employing larger prospective studies will be required to confirm the long-term cognitive and behavioral risks to children of mothers who are prescribed these four AEDs during pregnancy as well as to delineate any potential risks of newer AEDs and to understand the underlying mechanisms of adverse AED effects on the immature brain.

Lamotrigine-induced obsessive-compulsive disorder in patients with bipolar disorder.

IntroductionLamotrigine is a commonly used drug in the treatment of bipolar disorder. Although there are reports of its effectiveness in the management of bipolar disorder and comorbid obsessive-compulsive disorder (OCD), lamotrigine has also been associated with obsessionality in patients with bipolar disorder. METHODS: Charts of 8 patients with bipolar disorder who had de novo onset of obsessions and compulsions after the use of lamotrigine were reviewed. The Naranjo scale was used to assess the likelihood of patients developing OCD due to lamotrigine use. RESULTS: Two to 8 months after the initiation of lamotrigine, patients with no such prior history developed obsessions and compulsions meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for medication-induced OCD. In all except 1 patient, the symptoms resolved within a month of lamotrigine discontinuation. CONCLUSIONS: Some patients with bipolar disorder may develop OCD after initiation of lamotrigine. Due to the inherent limitations of a case series, the findings should be interpreted with caution.

Docosahexaenoic acid prevents resistance to antiepileptic drugs in two animal models of drug-resistant epilepsy.

Objectives: One-third of epileptic patients are resistant to antiepileptic drugs. Few clinical studies with small sample size indicate that polyunsaturated fatty acids could control drug-resistant epilepsy. We examined the efficacy of acute and chronic administration of docosahexaenoic acid (DHA) in two animal models of drug-resistant epilepsies, i.e. 6-Hz psychomotor seizures in mice and lamotrigine (LTG)-resistant kindled rats. Methods: Mice received a single injection of DHA (300 µM, i.c.v.) along with phenytoin (PHT) or LTG (i.p.). Six-Hz electroshock (0.2 milliseconds rectangular pulse width, 3 seconds duration, 44 mA current) was given 15 minutes after DHA, and seizure behaviors were recorded. In LTG-resistant kindled rats, a single dose of DHA (300 µM, i.c.v.) was administered with LTG, and seizure parameters were measured. In chronic treatment, mice received DHA (0.1 g/day, orally) for 30 days. Then, a single dose of LTG or PHT was administered to mice and 6-Hz-induced seizures were recorded. In rats, DHA (1 µM, i.c.v.) was administered during kindling development and effect of LTG in DHA-pretreated LTG-resistant kindled rats was verified. Results: LTG and PHT did not inhibit 6-Hz seizures in mice after single injection of DHA. However, LTG and PHT inhibited 6-Hz seizures in mice that received DHA for 1 month. Acute or chronic administration of DHA to LTG-resistant kindled rats led to the suppression of kindled seizure parameters by LTG. Discussion: DHA removes the 'inherent resistance' of 6-Hz seizures to PHT and LTG, and prevents the development of pharmacodynamic tolerance to LTG in LTG-resistant kindled rats. DHA might have potential to be used as add-on therapy in patients with refractory epilepsy.