Dose Of Lamotrigine Research Articles

Bioequivalence Between Generic and Branded Lamotrigine in People With Epilepsy

Switching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs. To evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products. The Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (≥18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to-treat analyses. Participants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected. The primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%). Of the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57%) were men and 21 (43%) were women, 42 (86%) self-identified as white, and 46 (16) years was the mean (SD) age. The 3 drug products were considered bioequivalent because the 90% CIs were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC0-96, 96.9% and 101.9%). Replicate testing demonstrated no significant differences in within-subject variability across the 3 products (likelihood ratios, χ22 for log-transformed variables: AUC0-96, 2.58; Cmax, 0.64; and AUC0-∞, 4.05; P ≥ .13) and that the 3 products were also bioequivalent according to scaled ABE and individual bioequivalence criteria with no subject × formulation interaction (Cmax, 0.00; AUC0-96, 0.54; and AUC0-∞, 0.36; P ≥ .76). This study provides evidence that the disparate lamotrigine products studied are bioequivalent when tested in people with epilepsy taking concomitant antiepileptic drugs. clinicaltrials.gov Identifier: NCT01733394.

Are doses of Lamotrigine or Levetiracetam Adjusted During Pregnancy?

Subtherapeutic levels of lamotrigine and levetiracetam are more likely to occur during pregnancy owing to the effect of pregnancy on their pharmacokinetics. This can lead to suboptimal control of epilepsy, and guidelines recommend proactive dose adjustment in the second and third trimesters alongside therapeutic drug monitoring (TDM). This retrospective cohort study using administrative databases aimed to investigate whether prescribers adjust the dose of lamotrigine or levetiracetam during and after pregnancy and whether TDM is used to manage dose adjustment. In 460 individual pregnancies, 232 women (61.4%) had their lamotrigine dose increased in the second and third trimesters and 44 women (53.7%) had their levetiracetam dose increased. Only 57 women (12.4%) had any TDM. The dose was not always decreased postpartum, and 157 women (56.9% of those who had escalated doses during pregnancy) had dose reduced following birth. Between 2012 and 2015, 29 women had an epilepsy-coded hospital discharge during pregnancy and were more likely to have had their dose of lamotrigine or levetiracetam increased. Overall, doses of lamotrigine and levetiracetam were not increased during pregnancy in 40% of the study population, dose changes were not often guided by TDM, and doses were not always reduced postpartum.

POSSIBLE TERATOGENIC EFFECTS OF ANTIEPILEPTICS IN ALBINO RATS: COMPARATIVE STUDY BETWEEN OLD AND NEW GENERATIONS: PART II

All antiepileptic drugs (AEDs) are either known or suspected of being teratogenic. The possible teratogenic mechanism is likely to be multiple even for the same drug. Treatment of females with epilepsy in the childbearing period raises questions due to interactions between epilepsy, antiepileptic drugs (AEDs) and different forms of reproductive life. The use of AEDs in these females is a balance between seizure control and adverse effects of these drugs, which are both potentially harmful to the developing fetus, neurological development, growth and subsequent pediatric progress, which presents unique challenges to both the clinicians and their patients. Recently, number of commercially available AEDs has steadily increased. This work is a randomized single blind control trial that aims to study the possible teratogenic effects of AEDs by comparing carbamazepine (old generation) with lamotrigine (new generation) in order to detect the drug that can be used safely by epileptic pregnant females. Pregnant female albino rats (120 in number) were used. They were randomly classified into six groups (2 control and 4 treated groups) each contained 20 pregnant rats. Animals were killed on the 20th day of gestation, dissected and fetuses were exposed and randomly classified into two subgroups: The first (1/3 of fetuses) were eviscerated and preserved in 95% ethyl alcohol for skeletal staining, using Alizarin red stain. Examination included: bones of axial skeleton (skull, vertebral column, sternum and ribs) and appendicular skeleton (clavicle, scapula, forelimbs and hind limbs). The second (2/3) were fixed in Bouin’ s solution for visceral examination. Examination of the axial skeleton: craniofacial bones showed highly significant reduction in complete ossification centers (OCs) of all treated groups in comparison with the control with no significant difference between lamotrigine and carbamazepine in therapeutic doses. Other parts of axial skeleton were not affected in therapeutic treated groups. Appendicular skeleton, except metacarpal OCs, showed no difference from control in therapeutic doses. There was a highly significant reduction in complete metacarpal OCs of both doses of carbamazepine and ¼ LD50 of lamotrigine, in comparison with the control, but there was a highly significant increase in both doses of lamotrigine in comparison with corresponding doses of carbamazepine. Similarly, there was a highly significant reduction in complete metatarsal OCs in both ¼ LD50 doses in comparison with the control. No significant difference was recorded in complete metatarsal OCs of therapeutic dose of lamotrigine and a highly significant increase in ¼ LD50 dose in comparison with corresponding doses of carbamazepine.Visceral findings: no abnormalities were detected among fetuses in therapeutic doses of treated groups. Fetuses of ¼ LD50 treated groups showed internal abnormalities in heads cross sections, while other levels showed no difference from control. Conclusion: lamotrigine in therapeutic dose can be used safely by epileptic pregnant females.

Effect of lamotrigine on seizure development in a rat pentylenetetrazole kindling model

IntroductionEpileptogenesis is a process of seizure development. Lamotrigine is a novel antiepileptic drug which is also used for antiepileptogenic research. Kindling models are recommended as potentially useful tools for antiepileptogenic treatment discovery. However, previous studies demonstrated that the antiepileptogenic effect of lamotrigine is controversial in the electrical kindling model. Chemical kindling such as with pentylenetetrazole is another kindling model. The aims of this study were to examine whether lamotrigine could prevent the development of seizure in pentylenetetrazole kindling rats.MethodsFemale rats were kindled by subconvulsive doses of pentylenetetrazole (35 mg/kg) once every other day for 15 times. Thereafter, the kindled rats received different doses of lamotrigine (5, 10 and 20 mg/kg) before pentylenetetrazole to observe the anticonvulsant effect. For the antiepileptogenic experiment, rats were kindled as the same way while pretreated (1 h) with different doses of lamotrigine (5, 10 and 20 mg/kg) before each injection of pentylenetetrazole. After a washout period for 1 week, the rats were administrated with pentylenetetrazole again for 3 times. The seizures were recorded each time. Later it was in vivo electrophysiological experiments followed with histologic analysis.ResultsFor the anticonvulsant experiment lamotrigine dose‐dependently suppressed pentylenetetrazole‐induced seizures. Here, 20 mg/kg of lamotrigine pretreatment significantly blocked the seizure development in rats for their seizure stages remained longer in 1–3 during the kindling phase. Mean seizure stages or generalized seizure durations in the 10 and 20 mg/kg lamotrigine pretreated groups were significantly lower or shorter when received 3 times of pentylenetetrazole after the washout period. Electrophysiological study also demonstrated 20 mg/kg of lamotrigine pretreatment obviously eliminated increased population spike amplitude in hippocampus. However, different doses of lamotrigine pretreatment could not alleviate severity of hippocampal neuronal damage.ConclusionsThe results suggest that adequate doses of lamotrigine can prevent seizure development in the pentylenetetrazole kindling rat model.

Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy.

Seizures in patients with medically refractory epilepsy remain a substantial clinical challenge, not least because of the dearth of evidence-based guidelines as to which antiepileptic drug (AED) regimens are the most effective, and what doses of these drugs to employ. We sought to determine whether there were regions in the dosage range of commonly used AEDs that were associated with superior efficacy in patients with refractory epilepsy. We retrospectively analyzed treatment records from 164 institutionalized, developmentally disabled patients with refractory epilepsy, averaging 17years of followup per patient. We determined the change in seizure frequency in within-patient comparisons during treatment with the most commonly used combinations of 12 AEDs, and then analyzed the response to treatment by quartile of the dose range for monotherapy with carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), or phenytoin (PHT), and the combination LTG/VPA. We found that of the 26 most frequently used AED regimens, only LTG/VPA yielded superior efficacy, similar to an earlier study. For the monotherapies, patients who were treated in the lowest quartile of the dose range had significantly better long-term reduction in seizure frequency compared to those treated in the 2nd and 3rd quartiles of the dose range. Patients with paired exposures to CBZ in both the lowest quartile and a higher quartile of dose range experienced an increase in seizure frequency at higher doses, while patients treated with LTG/VPA showed improved response with escalation of LTG dosage. We conclude that in this population of patients with refractory epilepsy, LTG/VPA was the most effective AED combination. The best response to AEDs used in monotherapy was observed at low dosage. This suggests that routine exposure to maximally tolerated AED doses may not be necessary to identify those patients with drug-resistant seizures who will have a beneficial response to therapy. Rather, responders to a given AED regimen may be identified with exposure to low AED doses, with careful evaluation of the response to subsequent titration to identify non-responders or those with exacerbation of seizure frequency at higher doses.

The effect of lamotrigine on learning in mice using the passive avoidance model.

Lamotrigine (LTG) is an antiepileptic drug that inhibits the release of glutamate by blocking sodium channels. The present study was conducted to evaluate the effect of LTG in different stages of memory using a passive avoidance learning task in mice. Male albino mice in the weight range 20-25g were used. They were divided into four groups (control group and three groups receiving various doses of LTG). LTG was given in three doses of 10, 25, and 50mg/kg as intraperitoneal (IP) injections. The doses of LTG were used in three injection groups: before acquisition, after consolidation, and before retrieval at 24h. The retention latency times in each group were recorded using a step-through passive avoidance task 24h and one week after consolidation. Retention latency in the group receiving a high dose of LTG (25mg/kg) after one week was significantly increased in comparison to the group receiving a low dose of LTG (10mg/kg) (267±49.96 vs. 198.87±57.22, P=0.015). With injection of LTG after consolidation, the retention latency times were increased in all doses after a one-week retrieval compared to the control (P=0.023). Kaplan-Mayer surveillance analysis also showed significant differences in the latencies of the LTG-receiving group after 24h and one week's retrieval (P=0.041). Administration of LTG before retrieval at 24h showed a significant difference in retention latency time, which was increased for two doses of LTG (10 and 50mg/kg) after one week (203.5±63.67 vs. 270.25±19.78, P=0.024). LTG at higher doses may facilitate the learning process in mice and appears to improve memory function at different stages.

Effects of lamotrigine on attention-deficit hyperactivity disorder in pediatric epilepsy patients.

PurposeThe purpose of this study was to investigate the effects of lamotrigine for the treatment of attention-deficit hyperactivity disorder (ADHD) symptoms in children with epilepsy.MethodsPediatric patients newly diagnosed with epilepsy (n=90 [61 boys and 29 girls]; mean age, 9.1±3.4 years) were enrolled. All patients were evaluated with the Korean ADHD rating scale (K-ARS)-IV before treatment with lamotrigine and after doses had been administered. The mean interval of ADHD testing was approximately 12.3 months. The initial dosage of lamotrigine was 1 mg/kg/day (maximum 25 mg/day for the first 2 weeks), and increased by 1 mg/kg every 2 weeks until titrated up to 7 mg/kg/day (or maximum 200 mg/day).ResultsThe mean ADHD test score of the 90 subjects was 17.0±1.8 at baseline. It was slightly reduced to 15.6±1.7 after lamotrigine monotherapy (P >0.01). Prior to treatment, a total of 31 patients (34.4%) met the diagnostic criteria for ADHD according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, Of these 31 patients, 27 (87.1%) had significantly improved ADHD scores with lamotrigine monotherapy (28.0±1.6 reduced to 18.1±2.6, P<0.001). Among these 27 patients, 25 (92.6%) showed normalized electroencephalogram (EEG) and 26 (96.3%) achieved total freedom from seizures within 12 months of the initiation of lamotrigine monotherapy.ConclusionThe results from our study show that lamotrigine had a positive effect in pediatric epilepsy patients by reducing ADHD symptoms, preventing seizures, and normalizing EEG. However, further research is required to determine whether lamotrigine is efficacious against ADHD symptoms independent of its effects on epileptic seizures.

Dose Related Psychiatric Adverse Effect of Lamotrigine in Management of Bipolar Disorder

Lamotrigine is increasingly being used as an effective maintenance treatment in bipolar disorders to control mood swings. This medication is generally well tolerated with most of its adverse reactions being well documented. However there are some reports of certain psychiatric symptoms associated with the use of Lamotrigine for treatment of mental disorders, but there is a paucity of data to support such findings. Here we discuss the case of a Caucasian female who presented to us with a history of bipolar disorder which was well controlled with Lithium. However the patient was advised to taper the use of Li due to long term Li induced damage to kidneys. She was started on Lamotrigine as an add-on, on a cross taper model. Initially she tolerated Lamotrigine well with mild-moderate physical side effects of nausea, warm flashes and constipation. After the dose was titrated to 100 mg/day of Lamotrigine, the patient demonstrated some psychiatric side effects such as vivid dreams and nightmares, which was resolved on reducing the dose of Lamotrigine to 50 mg/daily. However over the long term, she had a relapse of bipolar symptoms as Lamotrigine seemed not to be tolerated at high enough dose to prevent such a relapse. This case is consistent with some previous reports of occurrence of dose related psychiatric adverse side effect of Lamotrigine.

Ketogenic diet therapy for epilepsy during pregnancy: A case series

PurposeEvaluation of ketogenic diet (KD) therapies for seizure control during pregnancy when safety and appropriate management become considerations. Until now, no information has been available on seizure reduction and human pregnancy related outcomes in women treated with KD therapies. MethodWe describe two cases of pregnant women with epilepsy treated with KD therapy either as monotherapy (Case 1) or as adjunctive therapy (Case 2). ResultsCase 1: A 27 year old woman, gravida1, started the classic KD with medium chain triglyceride (MCT) emulsion and 75g carbohydrate-restriction, later reduced to 47g. Glucose levels were 4–6mmol/L and blood ketone levels ranged from 0.2 to 1.4mmol/L. Seizure frequency decreased and seizure-free days increased. Mild side effects included intolerance to MCT, reduced serum carnitine and vitamin levels, and mild hyperlipidemia. Fetal and neonatal growth was normal as was growth and development at 12 months.Case 2: A 36 year-old nulliparous woman was treated with a 20 gram carbohydrate-restricted Modified Atkins Diet (MAD) and lamotrigine, resulting in reduction of seizure frequency to once per month prior to pregnancy. Once pregnant, carbohydrates were increased to 30g. When seizures increased, lamotrigine dose was doubled. Urine ketones trended down during second trimester. A male was born with bilateral ear deformities of unknown significance. The child had a normal neurodevelopment at eight months. ConclusionNon-pharmacological epilepsy therapies like KD and MAD may be effective during human pregnancy. However, safety still has to be established. Further monitoring to identify potential long term side effects is warranted.

Brugada Pattern Caused by a Flecainide Overdose

BackgroundBrugada pattern can be found on the electrocardiogram (ECG) of patients with altered mental status, usually with fever or drug intoxication. Diagnosis remains challenging, because the ECG changes are dynamic and variable. In addition, triggers are not always clearly identified. In patients with atrial fibrillation (AF), the use of class IC antidysrhythmic drugs can unmask a Brugada pattern on the ECG, especially if combined with other medications acting on sodium channels. Case ReportA 62-year-old man with a medical history of AF was admitted to our emergency department for altered mental status. The ECG at the time of admission showed a Brugada pattern, triggered by a flecainide overdose (about 1 g), in association with an unknown dose of lamotrigine and quetiapine. After discontinuation of all medications, the Brugada pattern disappeared and his ECG showed no abnormalities. Why Should an Emergency Physician be Aware of This?In patients with AF, the use of class IC antidysrhythmic drugs, if overdosed, can trigger a Brugada ECG pattern, and therefore it can increase the risk for malignant dysrhythmias. It is important to provide, to all patients with a Brugada ECG pattern, a list of drugs to avoid, and to underline the synergistic interplay between drugs, taking into consideration all patients' comorbidities.

Lamotrigine and levetiracetam exert a similar modulation of TMS-evoked EEG potentials.

SummaryObjectiveAntiepileptic drug (AED) treatment failures may occur because there is insufficient drug in the brain or because of a lack of relevant therapeutic response. Until now it has not been possible to measure these factors. It has been recently shown that the combination of transcranial magnetic stimulation and electroencephalography (TMS‐EEG) can measure the effects of drugs in healthy volunteers. TMS‐evoked EEG potentials (TEPs) comprise a series of positive and negative deflections that can be specifically modulated by drugs with a well‐known mode of action targeting inhibitory neurotransmission. Therefore, we hypothesized that TMS‐EEG can detect effects of two widely used AEDs, lamotrigine and levetiracetam, in healthy volunteers.MethodsFifteen healthy subjects participated in a pseudo‐randomized, placebo‐controlled, double‐blind, crossover design, using a single oral dose of lamotrigine (300 mg) and levetiracetam (3,000 mg). TEPs were recorded before and 120 min after drug intake, and the effects of drugs on the amplitudes of TEP components were statistically evaluated.ResultsA nonparametric cluster‐based permutation analysis of TEP amplitudes showed that AEDs both increased the amplitude of the negative potential at 45 msec after stimulation (N45) and suppressed the positive peak at 180 msec (P180). This is the first demonstration of AED‐induced modulation of TMS‐EEG measures.SignificanceDespite the different mechanism of action that lamotrigine and levetiracetam exert at the molecular level, both AEDs impact the TMS‐EEG response in a similar way. These TMS‐EEG fingerprints observed in healthy subjects are candidate predictive markers of treatment response in patients on monotherapy with lamotrigine and levetiracetam.

Safety of Long-term Use of Lamotrigine for the Treatment of Psychiatric Disorders.

Lamotrigine (LTG) is a drug commonly used to treat epilepsy and can also be used to manage mood disorders, such as bipolar disorder. One of the most dangerous adverse effects of LTG is skin rash, which can make early cessation necessary. Here, we examine the adverse effects associated with long-term use of LTG for the treatment of mood disorders. Data were obtained from the medical records of 101 psychiatric patients who were prescribed long-term treatment with LTG. Patients were retrospectively divided into those who discontinued treatment within 6 months and those who continued for longer, and the groups were compared for adverse effects. We also compared the incidence of adverse effects in high and low doses. Fifty-four patients continued LTG treatment for 6 months or longer; 47 discontinued within 6 months. A history of allergy was more prevalent among the patients who discontinued treatment early than in those who continued. Of the patients who continued treatment for 6 months or longer, only 2 later discontinued treatment because of adverse effects. Lamotrigine monotherapy showed no difference in the incidence of adverse effects for different doses of LTG (>200 mg = 4.8% vs >100 mg, ≤200 mg = 7.7%; P = 1, vs >50 mg, ≤100 mg = 0%; P = 1 vs ≤50 mg = 0%; P = 1). Clinicians must be mindful of the adverse effects occurring early during the titration phase. However, long-term use of LTG was very well tolerated, even at high maintenance doses.

Variation in dose and plasma level of lamotrigine in patients discharged from a mental health trust.

The objectives of this study were to investigate the dose of lamotrigine when prescribed with an enzyme inhibitor or enzyme inducer in patients discharged from a mental health trust and to determine the corresponding lamotrigine plasma concentrations and the factors that may affect these. All patients discharged on lamotrigine between October 2007 and September 2012 were identified using the pharmacy dispensing database. We recorded demographic details, lamotrigine dose and plasma levels and coprescribed medication. During the designated period, 187 patients were discharged on lamotrigine of whom 117 had their plasma levels recorded. The mean lamotrigine daily dose was 226.1 mg (range 12.5-800 mg) and the mean plasma level 5.9 mg/l (range 0.8-18.1 mg/l). Gender, ethnicity, diagnosis and smoking status had no significant effect on dose or plasma levels. Patients taking an enzyme-inducing drug (n = 6) had significantly lower plasma levels [mean (SD) 3.40 (1.54) mg/l] than those not taking enzyme inducers [n = 111; 6.03 (3.13) mg/l; p = 0.043]. Patients taking an enzyme-inhibiting drug (n = 23) had significantly higher levels [7.47 (3.99) mg/l] than those not taking an inhibitor [n = 94; 5.52 (2.75) mg/l; p = 0.035]. No significant difference was found between the doses of lamotrigine in patients taking an enzyme inhibitor and those not taking one (p = 0.376). No significant difference was found between the doses of lamotrigine in patients taking an enzyme-inducing drug and those not taking any (p = 0.574). Current dosing recommendations indicate that lamotrigine doses should be halved in individuals taking enzyme inhibitors and doubled in those on enzyme inducers. In our survey these recommendations were rarely followed with the consequence that patients received too high or too low a dose of lamotrigine, respectively.

Comparative Pre-Emptive Analgesic Efficacy Study of Novel Antiepileptic Agents Lamotrigine and Topiramate in Patients Undergoing Major Surgeries at a Tertiary Care Hospital: A Randomized Double Blind Clinical Trial

Background: Central nervous sensitization, following surgical injury, leads to postoperative pain hypersensitivity due to lowered pain threshold in peripheral nociceptors and increased excitability of spinal neurons. Pre-emptive analgesia is intended to decrease pain perception and overall analgesic need by use of drug regimen, seizing CNS sensitization before exposure to painful stimuli. Few studies support pre-emptive analgesic efficacy of novel antiepileptic agent Gabapentin. Though Topiramate and Lamotrigine have been proven analgesic in animal models of chronic pain and clinical studies of Gabapentin-resistant neuropathic pain, literature search revealed scarce data on its pre-emptive analgesic efficacy. Purpose: This study is designed to study and compare the pre-emptive analgesic efficacy of Lamotrigine, Topiramate, and Diclofenac sodium in postoperative pain control. Methods: This randomized clinical trial included 90 patients of either sex, between 18 and 70 years undergoing major surgeries. Patients were randomly allocated to control and test groups and received respective treatment 30 min before induction of anesthesia. Aldrete's and pain scores were recorded using the Visual Analog Scale, Facial and Behavioral Rating Scale at awakening and at 1, 2, 4, 6, and 24 h. Postoperative rescue analgesic consumption for 24 h was recorded. Results: Significantly higher pain scores were observed in the Topiramate group postoperatively for 2 h on all pain scales (p < 0.05), whereas in the control group it was significantly higher at 1 h (p < 0.05). Lamotrigine-treated patients were more comfortable throughout the study with significantly less (p < 0.05) postoperative analgesic requirement. Conclusions: Study results strongly suggest the pre-emptive analgesic efficacy of a single oral dose of Lamotrigine over Diclofenac and Topiramate in postoperative pain control.

初期投与量のLamotrigineでStevens–Johnson症候群を発症し，リチウム中毒によると思われる失調性構音障害を呈した双極性障害の1例(A case of woman with bipolar disorder presented with Stevens–Johnson syndrome induced by an initial dosage of Lamotrigine and ataxic dysarthria possible to be caused by lithium toxicity)

Lamotrigine（LTG）は，てんかんや双極性障害に対し小児から成人まで幅広く投与されている薬剤である。今回我々は，初期投与量のLTG 25mg/dayで皮膚粘膜眼症候群（Stevens–Johnson症候群：SJS）を発症し集中治療の末救命しえたが，リチウム中毒によると思われる失調性構音障害を残した症例を経験した。本例の初期症状は急性咽頭炎様の所見を呈し，口腔粘膜症状や皮疹に乏しく感染症との鑑別を要し，SJSの診断に難渋した。症例報告をするとともに文献的考察を行い，近年報告されているLTGによる重症薬疹の注意喚起をし，リチウム服用者の留意点についてリチウム中毒による神経学的後遺症の観点から述べる。 Recently, patients with epilepsy or bipolar disorder increasingly are prescribed lamotrigine (LTG). A 31–year–old woman presented with Stevens–Johnson syndrome (SJS) because of an initial dosage of LTG 25mg/day and was treated by intensive care. Furthermore, she also suffered from ataxic dysarthria possible to be caused by lithium toxicity. She initially presented with only fever and throat pain, and so it was difficult to differentiate SJS from other infectious diseases. We report and describe this case using a literature study. We call attention to serious adverse drug eruption induced by Lamotrigine and to neurological sequelae due to lithium toxicity. 患 者：31歳女性 主 訴：発熱，咽頭痛 現病歴：双極性障害の既往があり，当院の精神神経科に通院中であった。入院10日前（投薬0日目）に当院の精神神経科にて服用中の炭酸リチウム800mg/day（血中濃度0.93mEq/L）に加えてLamotrigine（LTG）25mg/dayが開始された。入院2日前から38°Cの発熱と頭痛が出現し，入院日（第1病日，投薬10日目）に40°Cの発熱と悪寒があり当院に救急受診され，同日緊急入院となった。 内服薬：炭酸リチウム（200mg）4錠 分2夕後眠前，ラモトリギン（25mg）1錠 分1朝後，酸化マグネシウム（330mg）6錠 分3後，ビフィズス菌製剤 3錠 分3後，エスゾピクロン（2mg）1錠 分1眠前，フルニトラゼパム（1mg）1錠 眠前 アレルギー：和そば，パイナップルで皮疹の出現あり 既往歴：双極性障害 家族歴：特記事項なし 宗教歴：本人・母親がエホバの証人，＊父親・同胞2人（兄，弟）は無宗教 来院時身体所見：意識清明，体温40.0°C，脈拍97/min，血圧155/84mmHg，SpO2 97%（room air），呼吸数24/min，両側の眼球結膜は充血し，顔面は紅潮し両眼瞼浮腫を認めた。咽頭は発赤し，右頸部に圧痛を認めたが，リンパ節は触知できなかった。項部硬直はなく，呼吸音は清，腹部は特記すべき所見なく，発疹は顔面の紅潮以外は認めなかった。神経学的な異常所見も認めなかった。 細菌培養（咽頭，尿，血液2セット）：すべて細菌陰性 胸部X–ray：特記すべき所見なし 血算・生化学分析結果（第1病日）：WBC 6,000/mm3（Neut 90.6%），Hb 12.8g/dL，Ht 38.8%，Plt 8.5万/mm3，T–Bil 0.4mg/dL，AST 71IU/L，ALT 29IU/L，LDH 489IU/L，ALP 185IU/L，γ–GTP 28IU/L，Alb 3.2g/dL，BS 107mg/dL，Amy 124IU/L，BUN 14.6mg/dL，Crea 0.7mg/dL，CK 129IU/L，Na 133mEq/L，K 4.1mEq/L，Cl 104mEq/L，CRP 5.2mg/dL，PT 13.3sec，APTT 35.6sec，Fib 297mg/dL，FDP 72.0µg/mL その他の検査結果： ・薬物血中濃度（第3病日）炭酸リチウム1.43mmol/L（0.6–1.2），ラモトリギン0.91µg/mL ・プロカルシトニン（第4病日）2.05（0.00–0.05ng/mL） ・ウイルス検査 アデノウイルス迅速検査陰性，CMV–IgM（EIA）陰性，CMV–IgG（EIA）陽性，EB VCA–IgM（FA）<10倍，EB VCA–IgG（FA）320倍，EB EBNA 320倍，ムンプスIgM（EIA）陰性，ムンプスIgG（EIA）陽性 ・HHV–6検査 1回目（第8病日）HHV–6 IgM 10倍未満，HHV–6 IgG 40倍，HHV–6 PCR 陰性 2回目（第22病日）HHV–6 IgM 10倍未満，HHV–6 IgG 80倍 ・DLST（ラミクタール）：薬剤誘発性リンパ球刺激試験（drug–induced lymphocyte stimulation test） 1回目（第8病日）陰性（最大SI 1.5<1.8） 2回目（第22病日）陽性（最大SI 10.5≧1.8） 入院後経過（Fig. 1）：急性咽頭炎を考え入院時から抗生剤（CTRX 2g/day）を点滴投与し，内服薬は続行としていた。しかし発熱の改善はなく顔面の浮腫が増悪（Fig. 2），第3病日に収縮期血圧70mmHgのショック状態となり集中治療室に転棟となった。入院時に採取した細菌培養はすべて陰性であった。LTGを含め内服薬はすべて中止したところ，第4病日には精神状態が不安定（LTG服薬への焦燥感）になり精神科医と相談しLTG（25mg）1錠のみ再開した。これが結果的にチャレンジテストとなり，服用後に播種状紅斑が全身に出現し（Fig. 3），38°Cまで軽快しつつあった発熱も40°Cへ再上昇しLTGによる薬疹と診断した。鑑別疾患としたCMV，EBV，ムンプスウイルスはいずれも既感染パターンであった。第5病日よりprednisolone（PSL）30mg/dayを開始したが，口唇及び口腔内のびらん・出血が出現し始め（Fig. 4），SJSの診断基準 1（Fig. 5）のうち主要所見3項目を満たしSJSと診断し，第6病日よりステロイドパルス（methylprednisolone 1g/day × 3日間）を開始した。しかし同日より意識状態が悪化してJCS III–100まで低下し，第7病日より全身痙攣を来した。頭部CTでは異常はなく，腰椎穿刺はDICのため実施できず原因は特定できなかった。重症薬疹の鑑別疾患である薬剤性過敏症症候群（drug– induced hypersensitivity syndrome: DIHS）はHHV–6の再活性化を認めず否定的であった。PSLは第9病日より60mg/dayから5日ごとに漸減し，徐々に意識状態及び全身状態は改善した。第18病日に一般病棟に転棟となったが，失調性の構音障害を残した。第50病日にPSL 7.5mgで退院となり，第90病日にPSLは中止となった。第26病日及び退院3か月後の頭部MRIでは異常はなく，1年経過した現在も外来通院中であるが，構音障害の改善は認めていない。なお第22病日のLTGのDLSTは陽性であった。 Summary of the clinical course. She presented with throat pain and fever on hospitalization (day1), but gradually she was getting into shock. She was treated in the ICU (intensive care unit) between day3 and day18. On day4 she presented with maculopapular eruption of her trunk and extremities soon after re–exposure to LTG 25mg. On day7 she presented with erosions and bleeding of her lips and oral cavity. So we diagnosed SJS due to LTG and treated by steroid pulse (mPSL 1g/day × 3days). After that we started PSL 60mg/day and gradually decreased every 5days. She suffered from generalized seizure during day7–9 and pleural effusions during day5–16, but she was treated by anticonvulsants and NPPV. Then she was gradually getting better and discharged ICU on day18. Y axis means body temperature (BT). CTRX: ceftriaxone, LTG: lamotrigine, PSL: prednisolone, mPSL: methylprednisolone, NPPV: non–invasive positive pressure ventilation Facial edema (day3). She presented with facial edema, especially bilateral eyelids’ edema on day3. Maculopapular eruption of her knee (day4). She presented with maculopapular eruption of her trunk and extremities after re–exposure to LTG 25mg on day4. Erosions and bleeding of her lips (day7). She presented with general edema. Furthermore we found erosions and bleeding of her lips and oral mucosa. But on this photograph we slightly can see erosions and bleeding of her lips. According to this symptoms, we clinically diagnosed SJS due to LTG on day7. Diagnostic criteria for Stevens–Johnson syndrome. 1 本例では最終的に強い口腔粘膜のびらん・出血を呈し診断基準（Fig. 5）よりSJSと診断したが，皮膚病変は病像の最終段階においても全身性の播種状紅斑が見られたのみで，初期は口腔粘膜症状や皮疹に乏しく，感染症との鑑別を要し診断に難渋した。重症薬疹の死亡例では，皮疹よりも発熱が先行するケースがSJS・TENで各々75%・47%と高く 2，皮疹が出ない場合の重症薬疹の診断の難しさを裏付けている。本例では結果的にチャレンジテストとなり臨床診断したが，重症薬疹の補助診断である皮膚の迅速病理診断は本例のように皮疹に乏しい症例では実施できない。またDLSTもLTGでは福田らの「薬疹情報」によるとSJS 7/8（87.5%），中毒性表皮壊死症（toxic epidermal necrolysis: TEN）6/6（100%），DIHS 15/16（93.8%），その他の薬疹タイプでも19/21（90.5%）と陽性率は高い 3ものの，結果に時間を要することが欠点であり早期の診断は難しく，病歴及び臨床症状が診断に最も重要である。LTGによる重症薬疹については，本例加療中の2015年2月4日に厚生労働省より安全性速報（ブルーレター）が通達され，16名の死亡報告 4がなされた。さらに2016年1月20日に3学会合同ステートメント（日本うつ病学会，日本神経精神薬理学会，日本臨床精神神経薬理学会）が発表され，注意喚起がなされている 5。LTGによる重症薬疹の頻度は小児で0.3～0.8%，成人で0.08～0.3%とされる 6が，LTGは投与方法が少し複雑で，用法用量の非遵守例で死亡に至る重症化が顕著とされる。しかし，重症薬疹発症例のうち57.8%は用法用量が守られており，必ずしも回避できるわけではなく 5，本例でも用法遵守はされていたが初期投与量（25mg/day）の服薬8日目で発症している。一般的にSJS・TENの死亡率は各々3%・19%とされ 2，たとえ救命できても後遺症として失明に至る視力障害，眼瞼癒着，ドライアイなどの眼後遺症を残すことが多く 7，その社会的な問題は大きい。LTGは催奇形性において若年女性に使用しやすい抗てんかん薬であり，双極性障害においても，うつ病エピソードの再発予防に効果のある数少ない薬剤であり，使用頻度は今後も増えることが予想され，LTGによる重症薬疹に遭遇する頻度は稀とはいえ減る可能性は低い。本例のように重症薬疹の発症形態が非典型的な場合，皮膚科または眼科を受診せず，一般当直医が対応するケースがありうる。まずは発熱・口腔咽頭の発赤腫脹が初期症状になる重症薬疹症例があることを銘記し，基本的なことだが，薬剤の服用歴について問診し，早期の診断治療を心がけるべきである。 本例ではステロイドパルスが奏効したが，後遺症として構音障害を残した。以前よりリチウム中毒による遅発性の小脳失調症状は報告 8があり，症状出現後数か月後から1年後に画像上小脳萎縮を呈する報告 9もある。1987年にAdityanjee 10は，「the Syndrome of Irreversible Lithium–Effectuated Neurotoxicity」の頭文字をとってSILENTと提唱しており，神経学的異常所見が以前になくリチウム服薬中止後2か月以上経過をしても改善しない神経学的後遺症を残すものとされている 11, 12。症状は小脳失調症状が最も多く，他にも錐体外路症状，認知機能障害，脳幹機能障害があり，非典型的なものに視神経炎，垂直性眼振，myopathy（ミオパチー）などがある 8, 12。本例でも失調性構音障害の特徴とされる断綴性言語を確認したが，他の神経学的所見は異常なく，画像上も変化を確認できなかった。しかし，他の薬剤等では失調性構音障害の原因は説明できず，リチウム中毒による後遺症を考えた。詳細な病態は分かっていないが，SILENTは病理学的に多発する脱髄所見が見られ，中枢神経を中心に末梢神経でも確認されており，小脳に多く，Purkinje細胞の減少，小脳の萎縮，小脳皮質のgliosis等が見られるとされる 12, 13, 14。このようなリチウム中毒による神経学的後遺症は急性の大量服用だけでなく，長期服用者で血中濃度が正常範囲内でも1.25%で起こるとされ 15，危険因子は肺炎などの感染症の併発，脱水，急性腎不全などのリチウムの血中濃度が上昇する病態，他の薬剤（抗精神病薬，三環系抗うつ薬，抗てんかん薬，一部のNSAIDs，ACE阻害薬など）との併用とされている 16, 17。機序として発熱により血液脳関門（blood–brain barrier）の透過性が亢進し，リチウムの取り込みが増加することが考えられていることに加え 8, 18，急性期の大量服用と異なりリチウムを以前から服用している場合は常用による細胞内への蓄積があり，急性中毒と異なりすでにリチウムに暴露されており，中毒症状として重症になる傾向が報告 19されている。本例では第3病日のリチウム血中濃度は1.43mmol/Lと軽度の上昇であったが，SJS発症に伴い細胞内のリチウム濃度が上昇した可能性がある。リチウム中毒の治療の根幹は既知のごとく血液透析であるが，血中濃度と細胞内のリチウム濃度が必ずしも相関しないことは以前から報告 17, 18があり，透析後リチウム血中濃度の再上昇予防のためCHDF（continuous hemodiafiltration：持続的血液濾過透析）併用もされている。血液透析の適応は，①4mmol/L以上，服薬量として40mg/kg以上の服薬，②2.5mmol/L以上で重篤な症状（痙攣や意識障害など）がある，または腎機能障害や心不全等の合併がある場合，③2.5mmol/L以下でも末期腎不全や入院後にリチウム濃度が上昇する場合，また治療30時間後でも1mmol/L以下にならないときとされる 17。本例の場合は③の適応が考えうるが，本例ではSJSへの対応をしている最中で状態も悪く，リチウム中毒について失念しておりフォローできなかった。本例のようにリチウム服用者が感染症や脱水，急性腎不全など血中濃度が上昇するような病態を併発した際には，原疾患が重篤であればリチウム中毒の対応に注意が向かない可能性がある。また急性中毒だけでなくSILENTも念頭において治療にあたる必要があり，とくに血液透析については従来の急性中毒の適応のみでは不十分であり 20，リチウム長期服用者では閾値を下げて考えたほうがよい。 LTGによるSJSの症例を経験した。重症薬疹であっても，急性上気道炎様の症状で一般医が診療する可能性もあるため注意が必要である。また本例では，リチウム中毒によるであろう失調性構音障害を残した。リチウムの長期服用者では，その血中濃度と中毒症状の発現が相関しないことがある。リチウム長期服用者の中毒に対する血液透析の適応については，十分なコンセンサスが得られていないものの，神経学的な後遺症の観点からは血液透析を考慮する必要がある。 本報告の一部は第43回日本救急医学会総会（2015年10月22日）で発表した。 利益相反はない。

An investigation of the influence of patient-related factors and comedications on lamotrigine clearance in patients with epilepsy.

Lamotrigine (LTG) is one of the most widely used antiepileptic drugs. Confusion still exists in the literature as to the relative influence of age, body weight, and concomitant drug therapy on LTG pharmacokinetics. So, the objective of this study is to evaluate the influence of patient-related factors and comedication on LTG apparent oral clearance (CL/F). A therapeutic drug-monitoring database was used to identify steady-state plasma LTG concentrations in 210 patients. LTG CL/F values were calculated for each patient according to the equationCL/F (L/h per kg)=LTG daily dose (mg/kg)/Css (steady state concentration) (mg/L)×24h. A linear-regression model was used to assess the influence of gender, dose, age, and body weight in LTG CL/F. The influence of comedication on LTG CL/F was investigated by applying the Bonferroni post-test. The lowest LTG CL/F was found in patients comedicated with valproate (VPA) (mean, 0.0183L/h per kg), followed by patients receiving VPA+ enzyme inducers (0.0271L/h per kg), patients on LTG monotherapy (0.0298L/h per kg) and patients comedicated with enzyme inducers (0.056L/h per kg) LTG CL/F correlated significantly with LTG dose (P<0.01), but showed no significant relationship with gender, weight, and age. LTG CL/F is influenced by the type of antiepileptic comedication. The correlation with dose may be a spurious finding related to the fact that physicians, in adjusting dosage according to clinical response, are more likely to use larger doses in patients with high clearance values.

Pharmacological evidence for the involvement of the NMDA receptor and nitric oxide pathway in the antidepressant-like effect of lamotrigine in the mouse forced swimming test

Lamotrigine is an anticonvulsant agent that shows clinical antidepressant properties. The aim of the present study was to investigate the involvement of N-methyl-d-aspartate (NMDA) receptors and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) synthesis in possible antidepressant-like effect of lamotrigine in forced swimming test (FST) in mice. Intraperitoneal administration of lamotrigine (10mg/kg) decreased the immobility time in the FST (P<0.01) without any effect on locomotor activity in the open-field test (OFT), while higher dose of lamotrigine (30mg/kg) reduced the immobility time in the FST (P<0.001) as well as the number of crossings in the OFT. Pretreatment of animals with NMDA (75mg/kg), l-arginine (750mg/kg, a substrate for nitric oxide synthase [NOS]) or sildenafil (5mg/kg, a phosphodiesterase [PDE] 5 inhibitor) reversed the antidepressant-like effect of lamotrigine (10mg/kg) in the FST. Injection of l-nitroarginine methyl ester (l-NAME, 10mg/kg, a non-specific NOS inhibitor), 7-nitroindazole (30mg/kg, a neuronal NOS inhibitor), methylene blue (20mg/kg, an inhibitor of both NOS and soluble guanylate cyclase [sGC]), or MK-801 (0.05mg/kg), ketamine (1mg/kg), and magnesium sulfate (10mg/kg) as NMDA receptor antagonists in combination with a sub-effective dose of lamotrigine (5mg/kg) diminished the immobility time of animals in the FST compared with either drug alone. None of the drugs produced significant effects on the locomotor activity in the OFT. Based on our findings, it is suggested that the antidepressant-like effect of lamotrigine might mediated through inhibition of either NMDA receptors or NO-cGMP synthesis.

Prediction of an Optimal Dose of Lamotrigine for Augmentation Therapy in Treatment-Resistant Depressive Disorder From Plasma Lamotrigine Concentration at Week 2

The authors have previously shown that an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder. The present study investigated whether or not an optimal dose of lamotrigine could be predicted from plasma lamotrigine concentration at week 2. The subjects were 37 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 15), bipolar I disorder (n = 6), and bipolar II disorder (n = 16). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 16 subjects who were not taking valproate and 75 mg/d for 21 subjects taking valproate, respectively. Blood sampling was performed at weeks 2 and 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. There were significant linear relationships between the plasma lamotrigine concentrations at week 2 (x) and those at week 8 (y) for subjects who were not taking valproate (P < 0.01) and those taking valproate (P < 0.01). Regression equations were y = 2.032x + 2.549 for the former and y = 3.599x + 5.752 for the latter, respectively. Based on the equations, a nomogram to estimate an optimal dose of lamotrigine could be calculated. The present study suggests that an optimal dose of lamotrigine for augmentation therapy in treatment-resistant depressive disorder can be predicted from a plasma lamotrigine concentration at week 2.

Lamotrigine Induced Whole Body Tics: A Case Report and Literature Review

Lamotrigine is an anticonvulsant medication that also has utility in the treatment of bipolar disorder. It has been associated with many side effects, including rashes that can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis. It has also been associated with the development of motor tics, most commonly in the head, neck, and shoulders. We will now present the case of a 45-year-old woman who developed tics that involved the entire left side of her body after her dose of lamotrigine was increased from 200 mg daily (2.0 mg/kg/day) to 225 mg daily (2.3 mg/kg/day). We will review the prior cases of lamotrigine induced tics, and compare them to the circumstances surrounding our patient. We will also discuss the neurobiology of tics and make suggestions to improve the tics, based on the reported cases.

A Predictive Model of Plasma Lamotrigine Levels.

Introduction: Lamotrigine is one of several mood stabilizers and its effects for the treatment and prevention of depressive episodes, particularly in bipolar disorder, are generally accepted. Although the findings about a therapeutic window of lamotrigine are yet to be determined, it seems important to obtain information on individual pharmacokinetic peculiarities. This study was conducted to formulate the predictive model of plasma lamotrigine levels. Methods: Using the data of 47 patients whose lamotrigine levels, liver function, and renal function were measured, predictive models of lamotrigine levels were formulated by stepwise multiple regression analyses. The predictive power of the models was compared using another dataset of 25 patients. Results: Two models were created using stepwise multiple regression. The first model was: plasma lamotrigine level (μg/mL)=2.308+0.019×lamotrigine dose (mg/day). The second model was: plasma lamotrigine level (μg/mL)=0.08+0.024×lamotrigine dose (mg/day)+4.088×valproate combination (no=0, yes=1). The predictive power of the second model was better than that of the first model. Discussion: The present study proposes a prompt and relatively accurate equation to predict lamotrigine levels.