Lamotrigine Therapy Research Articles

Not All Patients with a Headache need a CT Scan, but they should be Listened to, and also with a Stethoscope: A Report of a Large Arteriovenous Malformation with a Loud Cranial Bruit.

Arteriovenous malformations (AVMs) are abnormal direct connections between arterial and venous systems, without an interposed capillary bed. This permits high-flow arteriovenous shunting, which precipitates structural changes in the afferent and efferent vessels, namely arterial smooth muscle hyperplasia and thinning of venous walls. Patients with intracranial AVMs typically present with a haemorrhage, headache or seizure. Treatment is either via medical management aimed at control of seizures, headache and blood pressure, or interventional via surgical, radiation or radiologically guided embolisation. We report the case of a woman in her early 40s presenting with a tonic-clonic seizure against a background of a 31-year history of migraine and an 18-month history of tremors in her right arm. The clinical examination was remarkable for an extremely loud cranial bruit and a right homonymous hemianopia. Imaging diagnosed an 8 cm Martin-Spetzler grade V intracranial arteriovenous malformation in her left parietal lobe, which was deemed unsuitable for operative or radiotherapy-based intervention. The patient was managed through observation and relatively good control of her breakthrough seizures was achieved through the addition of brivaracetam to her lamotrigine and carbamazepine-based therapy, six years after her initial presentation. Arteriovenous malformations may go undetected for decades.The presence of a cranial bruit is an important sign and tool in diagnosing an intracranial arteriovenous malformation. The presence of a homonymous hemianopia, of which a patient may be unaware, helps to localise an intracranial lesion.The risks of operative or radiological intervention must be balanced with the risks of haemorrhage or refractory seizure when adopting a strategy for the treatment of an intracranial arteriovenous malformation. Good control of epileptic symptoms in those deemed not suitable for operative or radiological intervention can be achieved by careful titration of anti-seizure medications.

Influence of Long-Term Anti-Seizure Medications on Redox Parameters in Human Blood.

Epilepsy is a chronic brain disease affecting millions of people worldwide, but little is known about the impact of anti-seizure medications on redox homeostasis. This study aimed to compare the effects of the long-term use of oral anti-seizure medications in monotherapy (lamotrigine, carbamazepine, and valproate) on antioxidant enzymes: superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, haemoglobin, and methaemoglobin content in erythrocytes, and concentrations of total proteins and thiols, nitrites, lipid peroxides and total glutathione in the plasma of epilepsy patients and drug-naïve patients. The results showed that lamotrigine therapy led to lower superoxide dismutase activity (p < 0.005) and lower concentrations of total thiols (p < 0.01) and lipid peroxides (p < 0.01) compared to controls. On the other hand, therapy with carbamazepine increased nitrite levels (p < 0.01) but reduced superoxide dismutase activity (p < 0.005). In the valproate group, only a decrease in catalase activity was observed (p < 0.005). Canonical discriminant analysis showed that the composition of antioxidant enzymes in erythrocytes was different for both the lamotrigine and carbamazepine groups, while the controls were separated from all others. Monotherapy with anti-seizure medications discretely alters redox homeostasis, followed by distinct relationships between antioxidant components.

UGT1A4*3 polymorphism influences serum concentration and therapeutic effect of lamotrigine for epilepsy treatment: A meta-analysis.

Lamotrigine as a broad-spectrum antiepileptic drug, is widely applied and its clinical efficacy is highly recognized. However, significant differences are observed in blood drug concentration of lamotrigine among individuals, which may have an impact on its efficacy. UGT1A4 is the main metabolic enzyme. However, it was inconsistent for the influence of UGT1A4 genetic polymorphism on concentration and efficacy of lamotrigine therapy. This study aimed to evaluate the influences of UGT1A4*3 genetic polymorphisms on lamotrigine concentration and therapeutic effect through meta-analysis. The literature search was conducted in Medline, Embase, PubMed, Web of Science, Wan Fang Database, China National Knowledge Infrastructure, China Science and Technology Journal Database until January 2024. The primary outcome included the mean serum concentration, concentration-to-dose-ratio by body weight (CDR), or efficacy related to different UGT1A4*3 genotype for lamotrigine therapy. Data were collected to access the Mean Difference or odds ratio with 95% confidence interval. Meta-analysis was performed by RevMan 5.2. A total of eleven studies were enrolled. The meta-analysis for mean serum concentration of lamotrigine showed no significant difference between patients carrying TT genotypes and TG and GG genotypes group (MD: 0.12, 95% [-0.35, 0.58], P = 0.62). There was significant difference in CDR (MD: 0.49, 95% [0.03, 0.94], P = 0.04) and therapeutic efficacy (OR: 7.18, 95% [4.01, 12.83], P<0.00001) of lamotrigine, however no significant difference was found in subgroup analysis of CDR of children (MD: 0.03, 95% [-0.35, 0.42], P = 0.87) between patients carrying TT genotypes and TG and GG genotypes group. Polymorphism of UGT1A4*3 influenced the CDR and therapeutic efficacy of lamotrigine for antiepileptic therapy. Genotype analysis provided reference for personalized medication in the future. However, more high-quality evidences are necessary for precise and definitive conclusion.

Efficacy of Ketamine with and without Lamotrigine in Treatment-Resistant Depression: A Preliminary Report.

Intravenous (IV) ketamine and FDA-approved intranasal (IN) esketamine are increasingly used for treatment-resistant depression (TRD). Preliminary studies have suggested a synergistic effect of ketamine and lamotrigine, although the data are inconclusive. Herein, we report the response to serial ketamine/esketamine treatment among patients with TRD with or without lamotrigine therapy. In this historical cohort study, we included adult patients with TRD who received serial IV racemic ketamine (0.5 mg/kg over 40-100 min) or IN esketamine (56/84 mg) treatments. A change in depressive symptoms was assessed using the 16-item Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) scale. There were no significant differences in response or remission rates among the patients on or not on lamotrigine during the ketamine/esketamine treatments. For a percent change in the QIDS-SR from baseline, no interaction was found between the lamotrigine groups and treatment number (p = 0.70), nor the overall effect of the group (p = 0.38). There was a trend towards lower dissociation (based on the CADSS score) among current lamotrigine users, especially in patients who received IV ketamine. A major limitation is the limited number of patients taking lamotrigine (n = 13). This preliminary study provides insufficient evidence that continuing lamotrigine therapy attenuates the antidepressant effect of repeated ketamine/esketamine; however, there seems to be a signal toward attenuating dissociation with lamotrigine in patients receiving serial ketamine treatments. Further observational studies or randomized controlled trials are needed to replicate these findings.

Lamotrigine as an alternative treatment for paroxysmal kinesigenic dyskinesia

Brief episodes of involuntary movement triggered by purposeful actions are characteristic of paroxysmal kinesigenic dyskinesia (PKD) and can interfere with daily life.1 Carbamazepine and oxcarbazepine are effective at reducing episodes but have teratogenic risks that limit their therapeutic potential.2 There is limited information describing alternate sodium channel blockers as first-line therapies for PKD, and specifically there is no recommendation for the use of alternative agents for females of childbearing potential. We conducted an institutional retrospective chart review of patients with PKD seen between 2013 and 2022. Our research ethics board approved the identification of participants by diagnostic code in the electronic medical records and waived the requirement for written informed consent. Patient 1: Onset estimated age 8 years, her episodes involve an aura (“tickling sensation”) in the foot followed by unilateral posturing of the arm or leg (left or right) +/− facial dystonia. Provoked by running or walking. Duration: 30 s. Frequency: “many”/day. Treated at age 15 with lamotrigine 25 mg daily, increased to twice daily, tolerated for 4.5 years at time last seen. Has an affected sibling and pathogenic mutation in PRRT2. Patient 2: Onset age 10 years, she describes a feeling of weakness in the right side of the body, with head turn to the right, right arm posturing towards chest, and muscles feel tense or “paralyzed.” Episodes are stereotyped and consistently provoked by walking up stairs. Duration: 5 s. Frequency: “multiple”/day. Treated at age 16 with lamotrigine 50 mg daily, tolerated for 1.5 years at time last seen. Did not pursue genetic testing. Both patients reported complete resolution of their events on lamotrigine with recurrence only with missed doses. We propose lamotrigine as a preferred agent in females of childbearing potential. Pharmacological management of PKD is indicated for frequent, intolerable episodes that interfere with daily life. There are no clinical trials for PKD, so physicians must rely on Class IV evidence to guide management. The literature supports the use of carbamazepine and oxcarbazepine as equivalent first-line agents in the management of PKD.1, 3-5 Lamotrigine has been suggested as a second-line agent for PKD with few reports of use as a first-line agent.6-8 The largest cohort reported 100% attack-free rate after four weeks of lamotrigine in 18 pre-pubescent children.6 Of particular importance is the evidence that carbamazepine and oxcarbazepine can cause rare but significant fetal malformations when used in females of childbearing age, whereas lamotrigine has the lowest risk of fetal malformation.2 A recent meta-analysis found a statistically significant increase in major congenital malformations with carbamazepine monotherapy (odds ratio [OR] 1.37) and oxcarbazepine (OR 1.32 *not statistically significant) compared to lamotrigine (OR 0.96).2 The need for an alternative agent in this population is not adequately addressed in the literature. Our experience suggests that lamotrigine is an effective agent in adolescent post-pubertal patients and may be a safe and effective option for females of childbearing potential. Further studies with larger cohorts will be required to investigate lamotrigine's efficacy and tolerability as a first-line agent for PKD and to better understand the effect of pregnancy on PKD and on lamotrigine therapy. Heather Leduc-Pessah: Conceptualization (supporting); methodology (lead); data curation (lead); writing—original draft (lead); writing—review and editing (equal). Asif Doja: Conceptualization (lead); methodology (supporting); writing—review and editing (equal); supervision (lead). The authors thank the CHEO EPIC data warehouse team for their assistance with the record review. No specific funding supported this work. The authors declare no conflicts of interest.

Cardiac morbidity and mortality associated with the use oflamotrigine.

The US Food and Drug Administration recently issued a warning against the use of the antiseizure medication lamotrigine in people at risk of cardiac rhythm and conduction abnormalities. This study assessed the risk of cardiac morbidity and mortality in new users of lamotrigine. In a Danish population-based cohort study, we followed cohort members aged ≥15 years for the first 2 years after they initiated lamotrigine therapy. The main outcomes were cardiac conduction disorders in people without pre-existing cardiac morbidity and all-cause mortality in people with pre-existing cardiac morbidity. Cox proportional hazards models provided hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for comparison of the risk in current versus past users of lamotrigine. There were 91 949 (36 618 males [39.8%]) new users of lamotrigine (median age=45.7 years, interquartile range=32.0-60.2 years). Among users without pre-existing cardiac disease (n=86 769), 194 (.23%) developed a cardiac conduction disorder. Comparison of the risk in current and past lamotrigine treatment periods yielded an adjusted HR of new onset cardiac conduction disorder of 1.03 (95% CI = .76-1.40). Among users with pre-existing cardiac disease (n=5180), 1150 (22.2%) died. Comparison of the risk in current and past lamotrigine treatment periods yielded an adjusted HR for all cause-mortality of 1.05 (95% CI = .93-1.19). In this large population-based study, lamotrigine use was associated neither with a risk of cardiac conduction disorders in people without pre-existing cardiac morbidity nor with all-cause mortality in people with pre-existing cardiac morbidity.

LAMOTRIGINE FOR THE TREATMENT OF EPILEPSY WITH CONCOMITANT COGNITIVE, EMOTIONAL-VOLITIONAL AND BEHAVIORAL DISORDERS IN GIRLS

The aim of the study is to evaluate lamotrigine efficacy on concomitant cognitive, emotional-volitional and behavioral disorders in girls with epilepsy.&#x0D; Materials and Methods. The study enrolled 17 girls aged 4–11 (mean age 7.4) with epilepsy, cognitive and/or emotional-volitional and behavioral deficits. The authors examined initial cognitive, emotional-volitional and behavioral impairments.&#x0D; To objectify the impairments, the results are expressed as percentage. The coefficient was calculated by summarizing the percentages of a particular function for each girl and then dividing the sum by the total number of subjects. After psychological and pedagogical testing, all girls underwent titrated lamotrigine monotherapy. Three-hour video-EEG monitoring (wakefulness and sleep) was carried out after 3, 6, 12, 18 and 24 months, and control Psychological and pedagogical testing – after 6, 12, 18 and 24 months.&#x0D; Results. Before lamotrigine therapy 7 girls (41.5 %) demonstrated focal seizures, 10 girls (58.5 %) had focal seizures with secondary bilateral synchronization. After 3 months, the number of seizures decreased in 4 girls (25.5 %), and a year later – in 14 girls (82.3 %). The group-wide indicators of perception and psychomotor pathologies were 41 %, aptitude for learning and memory – 43 %, speech – 54 %, reasoning – 41 %, social intelligence – 73 %. The indicators of emotional-volitional disorders by the hyperexcitable type were 36 %, by the inhibited type – 82 %. The indicator of ADHD was 32 %, demonstrative behavior – 91 %, negativism – 73 %, aggression – 79 %.&#x0D; There was a decrease in the number of seizures and the severity of concomitant complications of epilepsy in patients with lamotrigine therapy. The overall level of negativism and aggression improved, ADHD symptoms decreased in most girls, emotional-volitional control improved significantly. Significant positive changes were noted in speech, reasoning, aptitude for learning and memory. Socialization skills also improved.&#x0D; Conclusion. Lamotrigine is an effective antiepileptic drug. It has an antiepileptic effect, and is able to correct cognitive, emotional-volitional and behavioral disorders in patients with epilepsy.

Exanthema after lamotrigine use: A clinical case

Introduction: Lamotrigine is a phenyltriazine compound that inhibits sodium and potassium channels in presynaptic neurons. Maculopapular exanthema is a common side effect of Lamotrigine therapy, occurring most frequently during the first eight weeks of treatment in approximately 3–10% of patients. Case Report: A 74-year-old female had started Lamotrigine 50 mg due to emotional lability and depression. About 8–9 weeks after the introduction of the drug she presented a rash with exanthema, maculopapular in appearance. The attending physician suggested discontinuation of the medication and reevaluation. Complete regression of the clinical picture occurred. No severe skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis were observed. Conclusion: Lamotrigine is effective for a variety of types of conditions involving neuronal excitability, however, such drug exposes the individual to side reactions ranging from mild skin rashes to even those leading to hospitalization. Measures such as adherence to the manufacturer’s dosing guidelines, titration, and intrinsic characteristics of the individual can minimize this effect.

A case report of inhibition and severe desnutrition: negative symptoms in resistant schizophrenia

IntroductionThe appearance of inhibitory symptoms encompassed in what are known as negative symptoms is part of the usual symptoms of schizophrenia. Sometimes this inhibition reaches a significant severity, so it is essential to know its approach.ObjectivesCase report and literature review regarding the treatment of resistant schizophrenia with a predominance of negative symptomsMethodsWe present the clinical case of a 28-year-old man diagnosed with schizophrenia at 23 years old, whose onset was characterized by delusional ideas of harm (poisoning) and delusions with a mystic-religious theme that lead him to reduce his intake until requiring a first admission for severe desnutrition. Subsequently, after two more admissions, the patient presents selective reduction in food intake, decrease in daily activity and apathy without positive symptoms.ResultsThroughout the treatment, several lines of antipsychotic treatments have been tried at the maximum tolerated dose (haloperidol, oral paliperidone and depot, aripiprazole and clozapine up to a dose of 600 mg). Clozapine resistance required testing various augmentation strategies (Venlafaxine, Lamotrigine and Electroconvulsive therapy) with low results. Finally, to complement the treatment, the patient was transferred to a mid-stay unit where psychosocial treatment with a multidisciplinary approach was started. This has allowed more continuous follow-up and thus a partial improvement of the clinic.ConclusionsNumerous studies describe numerous augmentation strategies for clozapine-resistant schizophrenia with negative symptoms. However, the results are still inconclusive, needing more research. Meanwhile, we want to highlight the importance of complementing the treatment with psychosocial approaches.DisclosureNo significant relationships.

Impact of Selected Initial Titration Schedules on Safety and Long-Term Effectiveness of Lamotrigine for the Treatment of Mood Disorders.

PurposeLamotrigine (LTG) is used for treatment of mood disorders, but it is associated with the risk of rash occurrence in the initial administration phase. Although slow titration reduces this risk, its effectiveness in the treatment of mood disorders has not been verified. The effects of titration method on the safety and effectiveness of LTG for the treatment of mood disorders were examined in this study.MethodsThis retrospective cohort study included 312 patients with mood disorders who underwent initiation of LTG therapy. Data regarding baseline demographics, titration schedules, concomitant medications, and time to and cause of discontinuation of LTG were collected. A multivariate analysis was used to evaluate the effects of the titration schedules. The 12-month effectiveness was also evaluated.ResultsThe 12-month discontinuation rate of LTG was 16.7%. The most frequent cause of discontinuation was development of a rash (47.7%, n = 312). Fast titration (adjusted odds ratio, 8.15) significantly increased the risk of rash development, and slow titration (adjusted odds ratio, 0.29) significantly decreased this risk. The time to all-cause discontinuation was not significantly different between the slow and standard titration groups (n = 303). After 12 months of treatment, the condition of 46.7% patients were rated much or very much improved using CGI-C.ConclusionsAlthough slow titration of LTG reduces the occurrence of a rash, it is not more effective than standard titration in the long term. Optimizing the initial LTG titration schedule for patients with mood disorders is challenging.

Lamotrigine therapy in patients after bariatric surgery: Potentially hampered solubility and dissolution

Bariatric surgery is an effective treatment of obesity and related comorbidities. With surgery, the stomach undergoes major anatomical/physiological changes that may affect the oral exposure of drugs, especially marginally soluble weak bases, such as lamotrigine. The aim of this work was to study the solubility/dissolution of lamotrigine in conditions simulating the stomach before vs. after bariatric surgery. Lamotrigine solubility was studied in-vitro, as well as ex-vivo in gastric content aspirated from patients before vs. after bariatric surgery. We then compared the dissolution kinetics of various marketed lamotrigine products in pre- vs. post-operative stomach conditions, different in volume, pH, agitation strength and speed. Decreased lamotrigine solubility with increasing pH (from 1.37 ± 0.09 (pH = 1) to 0.22 ± 0.03 mg/mL (pH = 7)) was obtained. Twelve-fold higher lamotrigine solubility was revealed in gastric content aspirated before vs. after surgery (8.5 ± 0.7 and 0.7 ± 0.01 mg/mL, respectively). Dissolution studies showed that only the lowest dose (25 mg) fully dissolved in the post-surgery stomach conditions, while at higher doses, lamotrigine tablet dissolution was impaired. Neither fast-dissolving tablet, nor tablet crushing, helped resolving this problem. Based on these results, and given that dissolution of the drug dose governs the subsequent absorption, close monitoring of this essential drug is advised after bariatric surgery.

Changes in cognitive and behavioral control after lamotrigine and intensive dialectical behavioral therapy for severe, multi-impulsive bulimia nervosa: an fMRI case study

PurposeAdults 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.MethodsGo/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.ResultsAfter 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.ConclusionImproved 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 EvidenceIV: Evidence obtained from multiple time series with or without the intervention, such as case studies.

Lamotrigine induced Blepharospasm in a bipolar depression type-ii: A case report

The association of extrapyramidal side effects (EPS) with the use of conventional antipsychotics is well established, however, EPS can occur during treatment with anticonvulsant medications as well. There are several case reports of the development of involuntary movement disorders including chorea and tic disorder after lamotrigine (LTG) treatment. However, LTG-induced involuntary eyelid movement disorder is extremely rare. Most of this side effect was reported in patients with partial and generalized seizures, and only very few cases were in nonepileptic patients. In contrast, we present the case of 42 years old bipolar patient who developed blepharospasm during LTG therapy and again during re-challenge with the same agent. The focus of discussion will be on common side effects of this medication and previous reports of lamotrigine associated blepharospasm. We will also discuss a possible underlying mechanism.

Stevens-Johnson Syndrome while on lamotrigine and NSAID:A case report

Stevens-Johnson syndrome is a severe immune-mediated cutaneous reaction occurring due to exposure to certain drugs. Lamotrigine is an FDA approved drug used in the treatment of bipolar depression. When it is given concomitantly with sodium valproate, the risk of developing Stevens-Johnson syndrome increases. Here we present the report of a patient with bipolar depression who developed serious skin rashes while on lamotrigine and NSAID prescribed by a local doctor, who recovered after timely management. This case highlights the importance of following proper dosing, drug escalation regimen and managing drug interactions during lamotrigine therapy.

The Effects of Lamotrigine on Fetus Resorption and Histologic Changes in Cranium of Fetus of Albino Mice

Background: Lamotrigine is a member of antiepileptic drugs, it belongs to the sodium channel blocking agent’s class and it is pregnancy category C drug. While its teratogenic effects are not hidden by the doctors but it is the preferred drug being prescribed in pregnancy. The current study aims to investigate the effects of fetus resorption and histologic changes in cranium of fetus of albino mice and to compare their weight changes due to lamotrigine therapy.&#x0D; Methodology: It was an experimental animal study conducted in collaboration of anatomy and surgery department at animal house of University of Lahore in 2019. The duration of study was 25 days, twenty-four albino mice (12 males and 12 females) were placed in conventional cages in pairs for mating purpose. Female mice Group A, controls in which normal saline was administered intraperitoneally on 10th day of gestation and Group B, in which lamotrigine was given intraperitoneally on the 10th day at the dose of 10 mg/kg. Maternal health was monitored daily during the intervention. Body weight, food and water consumption, and changes in general health, behavior, activity and any sign of toxicity were checked daily. After 18th day the pregnant mice were sacrificed under euthanasia and fetuses were removed and histologic assessment was carried out.&#x0D; Results: Weight of mice treated with lamotrigine decreased significantly (p-value=0.03) and fetus resorptions were also more (p-value=0.013) in Group B. Histologic assessment reveled that there were cleft of lip and palate in group B.&#x0D; Conclusion: Lamotrigine increased the fetal resorption and decrease the weight and seemed to be responsible for inducing cleft of lip and palate at 10mg/kg dose in albino mice.

Lamotrigine and gabapentin ameliorate neurotoxicity induced by lipopolysaccharide in mice

Background: Alzheimer’s disease (AD), the most common cause for dementia, is an irreversible progressive neurodegenerative disorder. Aim: To investigate the potential protective role of Lamotrigine (LTG) and Gabapentin (GBP) either alone and in combination in Lipopolysaccride-induced Alzheimer's disease (AD) in mice. Materials and Methods: Mice were divided into 5 groups: Normal control group, Lipopolysaccride (LPS) group (animals were injected by single I.P. dose of LPS in a dose of 0.8 mg/kg), LTG group (animals were injected by single I.P. dose of LPS 0.8 mg/kg and received oral LTG 30 mg/kg/day), GBP group (animals were injected by single I.P. dose of LPS 0.8 mg/kg and received oral GBP 200 mg/kg/day) and LTG+GBP group (animals were injected by single I.P. dose of LPS 0.8 mg/kg and received both oral LTG 30 mg/kg/day and GBP 200 mg/kg/day), therapy started 2-h after LPS injection for 7 successive days. Novel object recognition and Y-maze tests were conducted. Brain homogenate used for the estimation of superoxide dismutase (SOD), acetylcholine esterase (AchE) activity, glutamate, reduced glutathione (GSH) and malonyialdehyde (MDA) contents. Results: LPS significantly induced neurobehavioral disturbances compared to normal control with significantly higher MDA, AchE and glutamate contents, with a reduction in SOD and GSH levels. Treatment with either LTG or GBP significantly ameliorated the effects of LPS injection on neurobehavioral tests, oxidative milieu with a significant reduction in AchE activity and glutamate content in favor of LTG. Combined therapy significantly improved both neurobehavioral testing and the estimated biochemical markers. Conclusion: GBP and/or LTG therapy improved neurobehavioral testing in LPS- induced AD in mice by restoring oxidant/antioxidant milieu with a concomitant reduction in AchE activity and glutamate content. Furthermore; the combination of both drugs resulted in significant improvement than either one of them alone that merits further clinical investigation.

Dosing Recommendations Based on Population Pharmacokinetics of Lamotrigine in Mexican Adult Patients With Epilepsy

Dose individualization is essential in epilepsy treatment, especially in antiepileptic drugs that present high interindividual variability such as lamotrigine. We aimed an observational study to develop a population pharmacokinetic model for quantitative evaluation of the factors that influence lamotrigine pharmacokinetics in Mexican adults with epilepsy. Patients on stable treatment with lamotrigine therapy were included, plasma concentrations were analyzed by a high-performance liquid chromatography method and UGT2B7–161C > T polymorphism was determined. The data were analyzed by NONMEM® 7.3, model validation was performed using bootstrap approach and visual predictive check. Finally, stochastic simulations were carried out to propose dosage regimens. A total of 73 lamotrigine plasma concentrations from 2 h after last dose and up to 0.5 h prior to next administration were fitted to a one-compartment open model. The final population pharmacokinetic model for lamotrigine indicates that concomitant treatment with valproic acid and carbamazepine should be considered to individualize epilepsy treatment with this drug. Based on this model, we proposed dosage regimens to achieve trough lamotrigine concentrations within reference interval (2.5–15 mg/L). These results provide clinical useful data to give more rational anticonvulsant therapy in our population.

Comparison of plasma, saliva, and hair lamotrigine concentrations

BackgroundIn some clinical situations (pregnancy, aging, drug resistance, toxicity), measurements of lamotrigine plasma levels may be reliable. Limited studies indicate that saliva and hair could be alternative sources for monitoring lamotrigine therapy. The drug content in hair can also be used to assess the history of drug therapy and to ascertain long-term patient compliance. The aims of this study were to 1) determine the correlations among plasma, saliva, and hair lamotrigine concentrations, 2) evaluate saliva as an alternative matrix for monitoring drug levels and 3) evaluate hair as a source of information on adherence to antiepileptic treatment and on the correlation of hair concentrations with clinical outcomes in patients with epilepsy. MethodsPlasma, saliva, and hair lamotrigine concentrations were measured by liquid chromatography–tandem mass spectrometry in positive ionization mode. The study group (n = 85) was recruited among the epileptic patients at the Institute of Psychiatry and Neurology, Warsaw, Poland. ResultsPlasma concentrations were not influenced by sex, age, or the concomitant use of other antiepileptic drugs. Lamotrigine saliva and plasma concentrations were strongly correlated (r = 0.82, p < 0.001). Lamotrigine hair concentrations were correlated with the plasma concentrations (r = 0.53, p < 0.001) and daily dose in mg/kg (r = 0.23, p = 0.024). The analysis revealed no significant correlation between lamotrigine hair levels and the number of seizures in the previous 3 months (r = -0.1, p > 0.05). ConclusionsThe lamotrigine saliva concentration is strongly correlated with its plasma level, and saliva can be used as an alternative matrix to plasma for monitoring. Lamotrigine can also be successfully measured in hair, and the drug levels in hair tend to be correlated with the levels in plasma. However, lamotrigine levels in hair may not correspond to clinical outcomes (i.e., seizure episodes).

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

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. 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. 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. Group differences in NAA suggest evidence for a deficit in cerebral energy metabolism in OABD.

Lamotrigine drug interactions in combination therapy and the influence of therapeutic drug monitoring on clinical outcomes in paediatric patients.

The aim was to study the impact of therapeutic drug monitoring (TDM) on paediatric patients on lamotrigine therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. During the period of 2001-2015, 1308 pre-dose samples were taken from 430 patients <15years of age as part of routine TDM. Drug interactions were evaluated using calculation of lamotrigine clearance. Valproic acid decreased lamotrigine clearance by 54% in bitherapy, and by 21% in triple therapy with carbamazepine. Carbamazepine increased lamotrigine clearance by 191% in bitherapy. Levetiracetam and topiramate had no effect. The upper limit of lamotrigine therapeutic range (TR) was exceeded in 2% of cases in monotherapy, and in 6%-7% of cases in bi- or triple therapy. About 61% of plasma levels were found within the TR during 2001-2005, compared to 75% and 74% during 2006-2010 and 2011-2015, respectively. Adverse drug reactions (ADRs) were reported in 22 cases. Higher number of supratherapeutic levels in combination therapy led to a 3-fold increase in incidence of ADRs. Seizures occurred more often daily and monthly during 2001-2005 and in patients with three or four antiepileptic drugs in combination. Carbamazepine only partially compensated for the inhibitory effect of valproic acid. Lamotrigine clearance in monotherapy in children is similar to adults, but in polytherapy was found higher susceptibility to induction. A significantly higher number of supratherapeutic lamotrigine levels were found in combinations with valproate. Despite poor correlation with TR, both seizure frequency and ADRs declined after the implementation of TDM.