Lamotrigine Levels Research Articles

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.

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. 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. No significant relationships were observed between these polymorphisms and the Css of lamotrigine in the patients with or without valproate. 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.

Development of an HPLC method using relative molar sensitivity for the measurement of blood concentrations of nine pharmaceutical compounds

We developed a reliable high-performance liquid chromatographic analysis method using a relative molar sensitivity (RMS) technique that does not require an authentic, identical reference analyte material to quantify blood serum carbamazepine, phenytoin, voriconazole, lamotrigine, meropenem, mycophenolic acid, linezolid, vancomycin, and caffeine levels for routine blood concentration measurements. Carbamazepine and caffeine were also used as non-analyte reference materials to calculate the RMS of each analyte. The RMS was calculated from the ratio of the slope of the calibration equation (analyte/non-analyte reference material), then used to quantify analytes in control serum samples spiked with carbamazepine, phenytoin, voriconazole, meropenem, mycophenolic acid, linezolid or vancomycin. In addition, the concentrations of these six drugs in control serum samples determined by the proposed RMS method agreed well with that obtained using a conventional method. The proposed RMS method is a promising tool for the clinical determination of nine drugs, given the accuracy, precision, and efficiency of quantifying these analytes.

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.

Suspected Role of Long-term Anticonvulsant Use in the Development of Squamous Cell Carcinoma

Squamous cell carcinomas (SCC) are typically a tumor of advancing age (mean age at diagnosis: 70), with more than 80% of cases occurring among people aged 60 and older[1]. In addition, these cancers commonly appear on sun-exposed areas of the body such as face, ears, neck, non-hair bearing scalp, and dorsal aspect of extremities and hands[2]. Due to the rare presentation of the aforementioned case, involving a younger female patient with SCC on the hair-bearing scalp, secondary risk factors should be examined. Many commonly used anticonvulsants, including lamotrigine and valproic acid, have known photosensitizing properties[3]. In susceptible patients, the long-term interaction between photosensitizing medications and UV radiation elevates risk of damage from the sun and has the potential to increase the likelihood of developing skin cancer over time[4]. There have been minimal studies that examine a possible association between anticonvulsants and various skin cancers, though the topic remains controversial and without consensus. Among the known adverse effects lamotrigine are several cutaneous photosensitivity issues, including exaggerated sunburn, skin irritation, hypersensitivity and rash[5]. Valproic acid is often co-administered with lamotrigine for better management of epilepsy due to the synergistic effects. When given in combination, valproic acid has been found to significantly increase plasma levels and half-life oflamotrigine[6]. These increased lamotrigine levels and exposure could in turn increase the risk of photosensitivity reactions and additional sequelae, including skin cancers. We report a 45-year-old woman who developed SCC on the scalp with a 10-year history of anticonvulsant use including lamotrigine and valproic acid.

Evaluation of the clinical and quantitative performance of a practical HPLC-UV platform for in-hospital routine therapeutic drug monitoring of multiple drugs

BackgroundIn-hospital therapeutic drug monitoring (TDM) requires a suitable quantification method for target drugs from the viewpoint of precision, throughput, and testing costs. We previously developed a practical HPLC-UV platform for quantification of serum levels of various drugs. In this report, the platform was effectively applied to the quantification of patient serum levels of five different drugs by clinical professionals in our hospital during their daily work.MethodsThe residual sera of patients receiving carbamazepine (CBZ), phenytoin (PHT), lamotrigine (LTG), vancomycin (VCM), or voriconazole (VRCZ) were used in the present clinical study. The quantification method for each drug consisted of rapid solid-phase extraction (SPE) of each drug in the patient serum, followed by optimized HPLC-UV analysis of the drug in the SPE eluate. Furthermore, patient serum levels of PHT, CBZ, and VCM were also measured by ligand-binding assay using a cobas® analyzer in our hospital, and those of LTG and VRCZ were measured by HPLC-MS/MS at an outsourced provider. Passing–Bablok regression analysis and Bland–Altman analysis were employed to analyze the agreement of drug levels in patient sera, which was separately quantified using two different methods—our HPLC-UV platform and the cobas analyzer, or HPLC-UV and HPLC-MS/MS.ResultsAll analytical conditions of the present method using our HPLC-UV platform were well optimized for each target drug quantification in the patient’s serum, and the quantification method for each drug was fully validated for accuracy, precision and reproducibility. Furthermore, Passing–Bablok regression analysis and Bland–Altman analysis revealed that patient serum levels of PHT, CBZ, and VCM quantified by our HPLC-UV platform were closely correlated with those quantified by the cobas® analyzer, and the levels of LTG and VRCZ quantified by our HPLC-UV platform were also correlated with those quantified by HPLC-MS/MS.ConclusionsOur HPLC-UV platform can be performed without requiring special analytical techniques. This platform is expected to be used for the measurement of blood levels of multiple drugs for in-hospital routine TDM.

Changes in Psychotropic Drug Blood Levels After SARS-CoV-2 Vaccination: A Two-Center Cohort Study.

Limited evidence from case reports suggests that coronavirus disease 2019 (COVID-19) vaccination may interact with the treatment outcomes of psychiatric medications. Apart from clozapine, reports on the effect of COVID-19 vaccination on other psychotropic agents are scarce. This study aimed to investigate the impact of COVID-19 vaccination on the plasma levels of different psychotropic drugs using therapeutic drug monitoring. Plasma levels of psychotropic agents, including agomelatine, amisulpride, amitriptyline, escitalopram, fluoxetine, lamotrigine, mirtazapine, olanzapine, quetiapine, sertraline, trazodone, and venlafaxine, from inpatients with a broad spectrum of psychiatric diseases receiving COVID-19 vaccinations were collected at 2 medical centers between 08/2021 and 02/2022 under steady-state conditions before and after vaccination. Postvaccination changes were estimated as a percentage of baseline. Data from 16 patients who received COVID-19 vaccination were included. The largest changes in plasma levels were reported for quetiapine (+101.2%) and trazodone (-38.5%) in 1 and 3 patients, respectively, 1 day postvaccination compared with baseline levels. One week postvaccination, the plasma levels of fluoxetine (active moiety) and escitalopram increased by 31% and 24.9%, respectively. This study provides the first evidence of major changes in the plasma levels of escitalopram, fluoxetine, trazodone, and quetiapine after COVID-19 vaccination. When planning COVID-19 vaccination for patients treated with these medications, clinicians should monitor rapid changes in bioavailability and consider short-term dose adjustments to ensure safety.

Factors associated with lamotrigine concentration/dose ratio in individuals with bipolar disorders

Monitoring of lamotrigine levels is recommended in epilepsy. However, in bipolar disorders (BD), no study has described the therapeutic range in daily practice and factors being associated to it.We used retrospective data of individuals with BD, treated with lamotrigine, and included in the FondaMental Advanced Centers of Expertise for Bipolar Disorders cohort. We extracted clinical and biological data and explored associations between these variables and lamotrigine concentration/dose (C/D) ratio.The database included 675 individuals who received lamotrigine at inclusion, whose main characteristics were female sex (68.3%) and BD type 2 (52.1%). Data about lamotrigine C/D ratio were available for 205 individuals. Lamotrigine C/D ratio was significantly associated with: Body Mass Index (BMI) (r=-0.159), estimated GFR (glomerular filtration rate) (r=-0.228), total bilirubin (r = 0.241) and at a trend level, antidepressant co-prescription (U = 3169). The model obtained was: lamotrigine C/D ratio = 1.736 - 0.013*BMI + 0.095*total bilirubin (UI/L) - 0.007*eGFR (ml/min) + 0.210*AST/ALT – 0.004*GGT (UI/L) + 0.014*age (year) + 0.303*currently smoking (yes or no) – 0.588*antidepressant co-prescription (yes or no) – 0.357*gender (F = 1.899, p = 0.057, adjusted R2 = 0.11)Information about plasma lamotrigine C/D ratio were available for only 205 out of the 675 individuals in the database and has been obtained from different laboratories. The representativeness of the included sample may be questionable.This is the first study providing information on a large sample of individuals with BD regarding factors associated with lamotrigine C/D ratio. This study allows to propose a model of lamotrigine C/D ratio that would deserve further replication.

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.

Joint use of population pharmacokinetics and machine learning for optimizing antiepileptic treatment in pediatric population

Purpose: Unpredictable drug efficacy and safety of combined antiepileptic therapy is a major challenge during pharmacotherapy decisions in everyday clinical practice. The aim of this study was to describe the pharmacokinetics of valproic acid (VA), lamotrigine (LTG), and levetiracetam (LEV) in a pediatric population using nonlinear mixed-effect modeling, while machine learning (ML) algorithms were applied to identify any relationships among the plasma levels of the three medications and patients’ characteristics, as well as to develop a predictive model for epileptic seizures. Methods: The study included 71 pediatric patients of both genders, aged 2–18 years, on combined antiepileptic therapy. Population pharmacokinetic (PopPK) models were developed separately for VA, LTG, and LEV. Based on the estimated pharmacokinetic parameters and the patients’ characteristics, three ML approaches were applied (principal component analysis, factor analysis of mixed data, and random forest). PopPK models and ML models were developed, allowing for greater insight into the treatment of children on antiepileptic treatment. Results: Results from the PopPK model showed that the kinetics of LEV, LTG, and VA were best described by a one compartment model with first-order absorption and elimination kinetics. Reliance on random forest model is a compelling vision that shows high prediction ability for all cases. The main factor that can affect antiepileptic activity is antiepileptic drug levels, followed by body weight, while gender is irrelevant. According to our study, children’s age is positively associated with LTG levels, negatively with LEV and without the influence of VA. Conclusion: The application of PopPK and ML models may be useful to improve epilepsy management in vulnerable pediatric population during the period of growth and development.

Risk factors of elevated blood ammonia level in epilepsy patients treated with lamotrigine.

The aim of this study was to explore the effect of lamotrigine (LTG) on blood ammonia level in patients with epilepsy and identify risk factors affecting blood ammonia level.This study included 91 epilepsy patients who were treated with LTG at Department of Neurology, Zhongshan Hospital, Xiamen University from January 2011 to April 2016, and were followed up for 3 years. Blood samples were taken during the interictal state and analyzed for blood LTG and ammonia levels. Total of 46.1% of the samples exceeded the median blood ammonia level, and 2.1% of patients had hyperammonemia. Blood ammonia level was positively correlated with LTG blood concentration. LTG combined with valproic acid therapy, seizure within 1 year, and elevated neutrophils affected blood ammonia level. Blood ammonia level was significantly correlated with plasma concentration of LTG. LTG combined with valproic acid therapy, seizure within 1 year, and elevated neutrophils may be risk factors for elevated blood ammonia level in epilepsy patients treated with LTG.

Comparison of HPLC-DAD and UPLC-MS/MS in Monitoring Serum Concentration of Lamotrigine

Background: Lamotrigine (LTG) is a broad-spectrum and first-line anti-epileptic drug. To monitor the serum levels of LTG in epileptic seizures patients, high-performance liquid chromatography with diode-array detection (HPLC-DAD) and ultra-performance liquid chromatography-- tandem mass spectrometry (UPLC-MS/MS) methods were established and compared. Methods: Imatinib was used as the internal standard (IS) for both methods. LTG and IS were detected at 246 nm by HPLC-DAD. In UPLC-MS/MS, LTG and IS positive ion were detected by multiple reaction monitoring (MRM), with m/z of 256/210.9 and 494/394.02, respectively. A total of 37 blood samples from epileptic patients were determined and studied by these two methods. Results: There was an acceptable linearity for the two methods. The concentration range of LTG was 0.59 ~ 22.20 mg/L by HPLC, and 0.28 ~ 23.97 mg/L by UPLC-MS/MS. The Pearson regression coefficient of Deming regression was 0.9653 (95% CI: 0.9332 to 0.9821). Bland–Altman method demonstrated that the concentration of LTG determined by UPLC-MS/MS was 8.3% higher than that determined by HPLC (limits of agreement, -32.0% to +48.6%). Conclusion: There was a significant correlation between the two methods. Both HPLC and UPLC- MS/MS can be used for routine clinical monitoring of LTG.

Lamotrigine Extraction and Quantification by UPLC-DAD in Plasma from Patients with Bipolar Disorder.

A sensitive and efficient analytical process for detecting lamotrigine in acidic solution based in ultra-high-performance liquid chromatography-diode array detector (UPLC-DAD) was developed; the stationary phase used was a C8, 150 × 4.6 mm, 2.6 µm. The mobile phase consisted of acetonitrile/acidified water (0.01% H3PO4 and 0.005% triethylamine, pH 2.4) (25 : 75 v/v). Limits of detection and quantification were 0.02 µg/mL and 0.05 µg/mL, respectively. The working interval for the evaluation of the method ranged from 0.05 to 12 µg/mL, and the linear fit of the experimental data has a value of r2≥0.98. Before quantifying lamotrigine in plasma of patients with bipolar disorder, lamotrigine was released from plasma proteins with a 0.2 M sodium hydroxide solution, and then proteins were removed by precipitation with acetonitrile. Afterward, the lamotrigine base was dissolved in ethyl acetate. This extract was reconstituted in potassium phosphate solution (pH 2.4) to obtain more than 98% of lamotrigine protonated in N2, which was detected and quantified as indicated above. The absolute percentage of lamotrigine recovery is ≥80% for all tested concentration levels. The accuracy and precision of the method have %CV values <4% for the lamotrigine levels of 3, 6, and 9 µg/mL. The correlation coefficient for the used concentration range is 0.99. The analytical method is precise and sensitive to measure lamotrigine levels expected in plasma of BD patients and these levels were in the therapeutic dose range.

Association of Optimal Lamotrigine Serum Levels and Therapeutic Efficacy in Mood Disorders: A Systematic Review.

The aim of the study was to appraise the current evidence on the optimal serum level for lamotrigine (LAM) in the treatment of mood disorders (major depressive disorder, bipolar disorder). Major databases were searched for randomized controlled trials, open-label trials, and observational studies reporting serum LAM levels in adult patients treated with LAM for mood disorders. A total of 814 abstracts were screened and 24 articles were selected for full-text review. Seven studies (226 bipolar disorder and 17 major depressive disorder patients) including 1 randomized controlled trial (n = 43), 3 prospective (n = 53), and 3 retrospective (n = 147) studies met the study criteria with a study duration range from 6 to 96 weeks. Lamotrigine daily dosage varied from 25 to 425 mg/d among the studies. Studies reported inconsistent findings between LAM concentration and efficacy. Three studies did not identify a relationship between LAM levels and a significant improvement in mood symptoms. Two studies (n = 99) reported higher response rates with LAM serum levels of greater than 3.25 μg/mL and 1 study (n = 25) reported a wide therapeutic window of 5 to 11 μg/mL. Overall, LAM was well tolerated with no major significant adverse effects. Most studies showed a minimum LAM threshold level of 3 μg/mL in patients with mood disorders; however, the data are inconsistent regarding the therapeutic range for LAM. Based on the pooled data, there is inconsistent evidence to make conclusive recommendations on therapeutic LAM serum levels for mood improvement. Further studies including larger sample sizes are required to address this relevant clinical question.

Evaluation of the interference of lamotrigine on the analysis of synthetic cannabinoids in urine by the immunoassay method

We aimed to evaluate the interference of lamotrigine (LMG) on the synthetic cannabinoids metabolite-K2/1 (SCm/K1) urine test by Homogeneous Enzyme Immunoassay (Immune-SCm/K1). This study consists of two parts: case-control and interference effect research. In the case-control study, two groups using LMG and a non-use of LMG were formed, all of them non-SC users. In the interference effect research, four groups were formed by adding either a LMG stock solution or a LMG user’s urine to a SCm/K1 negative urine, and Immune-SCm/K1 test calibrators and quality control (QC) materials. Immune-SCm/K1, SCm/K1 by LC/MS-MS and LMG tests were performed on all samples in the study. The case-control study was performed on a total of 55 participants (mean age 39.76 ± 9.84 years). Both groups were statistically insignificant in terms of age and gender. Urine LMG levels were 5.71 ± 10.61 mg/L in the LMG group and <0.30 mg/L in the control group. Immune-SCm/K1 results were 35.84 ± 7.62 ng/mL in the LMG group, <3.00 ng/mL in the control group and the LC/MS-SCm/K1 urine test of both groups were found to be ‘NEGATIVE’. Results were interpreted as a cross-reaction in the interference study and a statistically significant relationship was found between LMG levels and Immune-SCm/K1 levels in the SCm/K1 negative samples (groups 1 and 2) (R 2 = 0.9341 and R 2 = 0.9941, respectively; p < .001). LMG interference was observed in SCm/K1 positive samples ranging from −6.17 to 714.77%. LMG in the specimen interferes with the Immune-SCm/K1 screening test and causes false positivities.

Redefining the age-specific therapeutic ranges of lamotrigine for patients with epilepsy: A step towards optimizing treatment and increasing cost-effectiveness

ObjectiveThe pharmacokinetics of lamotrigine exhibits age-related characteristics. Nevertheless, current evidence regarding the therapeutic range of lamotrigine has been derived almost exclusively from studies in adult patients, and the applicability of this therapeutic range to the pediatric population remains unclear. The purpose of this study was to establish the appropriate age-specific therapeutic ranges of lamotrigine corresponding to adequate clinical responses for patients with epilepsy. MethodsThis prospective cohort study of therapeutic drug monitoring included 582 Chinese epilepsy patients receiving lamotrigine monotherapy. Patients were divided into three age-related subgroups: (1) toddler and school-age group (2–12 years old, n = 168), (2) adolescent group (12–18 years old, n = 171), and (3) adult group (>18 years old, n = 243). Patients with a reduction in seizure frequency of 50 % or greater than baseline were defined as responders, and the remaining patients were non-responders. The relationship between lamotrigine serum concentrations and clinical response was assessed using multivariate logistic regression analysis. A receiver operating characteristic curve was generated to determine the representative cut-off values of lamotrigine trough levels, to distinguish responders from non-responders. The upper margin of the therapeutic range of lamotrigine was determined by developing concentration-effect curves for the three age-related subgroups. ResultsThe median trough levels of lamotrigine were significantly higher in responders than in non-responders from all three age-related groups (P < 0.0001). Results of logistic regression analysis revealed that higher serum concentrations of lamotrigine predicted a higher probability that seizure frequency would be reduced by more than 50 % compared to baseline (adjusted odds ratio: 1.228, 95 % CI: 1.137–1.327; P < 0.0001), and younger children were less likely to be responders (adjusted odds ratio: 1.027, 95 % CI: 1.012–1.043; P = 0.001). Based on a trade-off between sensitivity and specificity, the optimal cut-off values for lamotrigine trough concentrations corresponding to clinical response were 3.29 mg/L, 2.06 mg/L, and 1.61 mg/L in the toddler and school-age group, adolescent group, and adult group, respectively. By reducing interpatient variability, the results of the concentration-effect curves suggested no additional clinical benefit from a continued increase of doses for lamotrigine concentrations exceeding 9.08 mg/L, 8.43 mg/L, and 10.38 mg/L in the toddler and school-age group, adolescent group, and adult group, respectively. In conclusion, the therapeutic ranges of lamotrigine trough concentrations corresponding to adequate clinical response were 3.29–9.08 mg/L in the toddler and school-age group, 2.06–8.43 mg/L in the adolescent group, and 1.61–10.38 mg/L in the adult group. ConclusionsThe study determined age-specific therapeutic ranges corresponding to optimal clinical efficacy for lamotrigine. Our findings lay the foundation for catalyzing novel opportunities to optimize treatment and reduce therapeutic costs. Based on the age-specific therapeutic ranges identified in this study, individualized and cost-effective algorithms for lamotrigine treatment of epilepsy patients may be developed and validated in larger cohort studies of therapeutic drug monitoring.

Correlation of elevated lamotrigine and levetiracetam serum/plasma levels with toxicity: A long-term retrospective review at an academic medical center.

Lamotrigine and levetiracetam are widely used second-generation anti-epileptic drugs. Existing literature indicates that overdose of either drug is typically benign, but neurologic and cardiac toxicity can occur in some cases. In this retrospective study, we analyzed a large dataset of serum/plasma drug levels for lamotrigine and levetiracetam. The data covered 1,930 unique patients (5,046 levels) for lamotrigine and 2,451 patients (4,359 levels) for levetiracetam. We performed detailed chart review on all patients with one or more lamotrigine levels greater than 14.0 mg/L (293 unique patients) and all patients with one or more levetiracetam levels of 80 mg/L or higher (106 unique patients). No deaths directly attributable to lamotrigine or levetiracetam toxicity were reported. For cases with lamotrigine levels greater than 14.0 mg/L, the majority of patients were asymptomatic (55.3 %, n = 162). The most common presenting symptoms were ataxia (14.3 %, n = 42), seizures (14.0 %, n = 41), dizziness (11.9 %, n = 35), and altered mental status (11.6 %, n = 34). There were 12 overdoses (11 intentional) involving lamotrigine, all of which presented with either altered mental status (n = 8) or seizures (n = 4). The highest estimated dose reportedly ingested was 20 g. Cardiac toxicity was observed in two cases involving intentional overdose of lamotrigine. For patients with levetiracetam serum/plasma levels of 80 mg/L or higher, 48 patients (45.3 %) were asymptomatic. Symptomatic patients most commonly presented with seizures (31.1 %, n = 33) and altered mental status (15.1 %, n = 16), and none showed cardiac symptoms. There were only two cases involving intentional levetiracetam overdose, one of which presented with altered mental status after ingestion of 45 g and the other asymptomatic after ingestion of 6 g. Overall, our data is consistent with previous investigations that lamotrigine and levetiracetam toxicity most typically presents with neurologic symptoms and rarely cardiac arrhythmias. Approximately half of the patients with elevated lamotrigine or levetiracetam drug levels are asymptomatic.

A LC-MS3 strategy to determine lamotrigine by Q-Q-trap tandem mass spectrometry coupled with triple stage fragmentation to enhance sensitivity and selectivity.

A high-performance liquid chromatography tandem mass spectrometry cubed (HPLC/MS3) method was developed and validated to quantify lamotrigine in human plasma with carbamazepine as an internal standard. The HPLC/MS/MS system is composed of a Shimadzu UFLC XR high-performance liquid chromatograph coupled with a hybrid linear ion trap triple quadrupole mass spectrometer. Following simple protein precipitation with methanol, the separation of lamotrigine and carbamazepine was performed on an Agilent Poroshell 120 SB-C18 column (4.6 × 50 mm, 2.7 μm) using gradient elution with 0.1% formic acid in water (solvent I) and 0.1% formic acid in methanol (solvent II) at a flow rate of 0.8 mL min-1. The total run time for each sample was 5 min. The method was validated for accuracy, precision, linearity, lower limit of quantification (LLOQ), selectivity, and other parameters. The LC/MS3 method was linear in the concentration range of 0.50-50.0 μg mL-1 (R2 ≥ 0.995). The LLOQ was 0.5 μg mL-1, requiring only 30 μL of human plasma. Intra- and inter-day accuracies were <6.17% and precisions were <11.4% at all concentrations. The absolute recoveries (%) and matrix effect (%) for lamotrigine in human plasma were between 83.8 and 90.7. The developed and validated LC-MS3 assay was successfully applied to monitor the lamotrigine levels in human plasma after the administration of lamotrigine.

Contraceptive vaginal ring reduces lamotrigine levels

ObjectiveThe objective of the study was to describe the effect of the vaginal ring and transdermal patch on lamotrigine serum levels in women with epilepsy. BackgroundPrevious studies demonstrate that oral hormonal contraceptives containing synthetic estrogen increase lamotrigine clearance through induction of glucuronidation. This leads to variable lamotrigine serum concentrations throughout monthly cycles in women who are on combined oral contraceptives (COCs). The effects of estrogen-containing nonoral hormonal contraceptive methods, including the vaginal ring and transdermal patch, on lamotrigine pharmacokinetics are not well described. MethodsRetrospective chart review was performed to identify serum lamotrigine levels drawn from women with epilepsy while on the active phase of vaginal ring or transdermal patch and while off contraception. Wilcoxon signed-rank tests for paired data were used to compare the difference in dose-corrected lamotrigine concentration in plasma between values while on hormonal contraception to those while off contraception in patients using a vaginal ring. ResultsSix patients were using the vaginal ring, and one patient was using the transdermal patch. Lamotrigine dose-corrected concentrations were decreased during the active phase of the vaginal ring compared with concentrations during the period off contraception (p = .04). There was one patient without a decrease in concentration, but the other five patients on the vaginal ring had a decrease in dose-corrected lamotrigine concentration ranging from 36 to 70% while on the vaginal ring. Similarly, one patient using the transdermal patch had a decrease of 37% in dose-corrected lamotrigine concentration while on the patch. ConclusionsThe findings support that the vaginal ring contraceptive method decreases lamotrigine concentrations during the active phase of treatment. This has important implications for contraceptive counseling and maintaining therapeutic levels in women of childbearing age with epilepsy.

Lamotrigine Toxicosis Treated with Intravenous Lipid Emulsion Therapy in a Dog

A female spayed dachshund/mixed-breed dog was evaluated following ingestion of lamotrigine tablets with subsequent rapid onset of vomiting, diarrhea, and generalized tremoring. On initial examination, the dog was moderately obtunded and nonambulatory with intermittent myoclonus and hyperesthesia. Electrocardiogram revealed sinus tachycardia with prolongation of the QT interval. Intravenous lipid emulsion (ILE) infusion was initiated, with reduction in tremoring and improved patient mentation being noted after ∼20 min of therapy. An elevated cardiac troponin I value measured at 1.02 ng/mL the day after presentation. Serum toxicological assay revealed marked reduction in serum lamotrigine levels following ILE and continued reduction during hospitalization. The dog's clinical signs resolved, corrected QT interval returned to normal, and the patient was discharged 38 hr after presentation. Individual cases of lamotrigine toxicosis have not been fully reported in veterinary literature. This case report documents the rapid onset of clinical signs including neurologic dysfunction, cardiac arrhythmias, and transient corrected QT prolongation. Serial serum concentrations of lamotrigine showed a rapid reduction with ILE therapy and corresponded with clinical recovery, suggesting efficacy of ILE treatment in this case.

SAT-480 Myxedema Madness: A Rare Case of Severe Hypothyroidism Presenting as Psychosis

IntroductionMyxedema coma is a rare, life-threatening medical emergency resulting from uncontrolled hypothyroidism. Myxedema coma refers to the neurological sequelae of severe hypothyroidism, which classically manifests as depressed mental status. Rarely, myxedema coma can present with a hyperactive mental state and psychosis. We present an unusual case of a drug overdose secondary to myxedema coma-induced psychosis.Clinical CaseA 48 year old woman with a history of seizure disorder and hypothyroidism presented to the hospital after lamotrigine overdose. The patient’s spouse witnessed her ingest forty-five tablets of lamotrigine after an argument. The patient had no previous psychiatric diagnoses or suicide attempts. On examination, the patient was hemodynamically stable but was agitated, disoriented, and uncooperative. She had a normal neurologic exam and no peripheral edema. Her lamotrigine level was 25.4 ug/ml (2.5-15.0 ug/ml). The patient’s mental status did not improve with lamotrigine cessation. Psychiatry determined that the patient’s psychosis was not consistent with lamotrigine overdose. Given these recommendations, alternative causes of psychosis were considered. The patient’s husband stated she had not taken levothyroxine for over one year. Thyroid function tests revealed a thyroid stimulating hormone (TSH) of 299 mcIU/ml (0.35-5.50 mcIU/ml) with a free thyroxine (T4) level of 0.27 ng/dl (0.89-1.76 ng/gl). The patient was started on levothyroxine intravenously. After five doses of intravenous levothyroxine, her mental status improved to baseline and she was transitioned to oral levothyroxine. She denied that the lamotrigine ingestion was a suicide attempt. Based on the patient’s presentation and clinical course, we concluded that her overdose was due to severe hypothyroidism leading to myxedema madness.ConclusionSevere hypothyroidism with myxedema coma often presents with depressed mental status, which can manifest as progressive confusion, lethargy, and eventually coma. However, in the case of our patient, severe hypothyroidism presented as psychosis, a rare manifestation. Remarkably, the patient had no other obvious physical manifestations of severe hypothyroidism. Psychosis, though rare, has been seen in cases typically after thyroidectomy or in patients with previously undiagnosed Hashimoto’s thyroiditis. In this patient’s case, it is likely that her myxedema madness was precipitated by long-term nonadherence with her thyroid replacement therapy, as the patient had no prior psychiatric history. Additionally, her rapid reversal of symptoms after the administration of levothyroxine supports the diagnosis of hypothyroid-induced myxedema madness.