Lamotrigine In Patients 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.

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

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

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.

Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications.

Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan‐Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of NaV1.5 block and to support the observed clinical safety of lamotrigine. We used HEK‐293 cells stably expressing the hNaV1.5 channel and voltage clamp electrophysiology to quantify the potency (half‐maximal inhibitory concentration) against peak and late channel current, on‐/off‐rate binding kinetics, voltage‐dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late NaV1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak NaV1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder.

Efficacy and tolerability of Seizar (lamotrigine) in the treatment of epilepsy (experience of Svt. Luka’s Institute of Child Neurology and Epilepsy)

Background.We have accumulated extensive experience in the use of lamotrigine in patients with epilepsy; its mechanism of action, effectiveness, safety, and tolerability are well known. The results of numerous studies indicate its high efficacy and potentially better tolerabilitycompared to other drugs in the treatment of a wide range of epilepsy forms and epileptic syndromes (focal and generalized seizures). Thesecharacteristics of lamotrigine determined its priority administration as initial or alternative monotherapy in women with epilepsy.Objective:to review efficacy and tolerability of Seizar in patients with various forms of epilepsy based on long-term experience of using thisdrug in our center.Materials and methods.We analyzed therapeutic effects of Seizar in 22 patients aged between 3 and 34 years (mean age 15.3 years) treatedin Svt. Luka’s Institute of Child Neurology and Epilepsy. The sample included 8 adults and 14 children (under 18 years of age), including6 children aged from 3 to 12 years. Ten patients were male and twelve patients were female.Study participants were diagnosed with the following forms of epilepsy: idiopathic (genetic) generalized epilepsy (n = 9), idiopathic (genetic)focal epilepsy (n = 2), focal epilepsy of unknown etiology (n = 1), structural and probably structural focal epilepsy (n = 4), genetic and probably genetic epileptic encephalopathies (n = 6).Seizar was used as monotherapy in 9 patients and as an additional drug in 13 patients. Children aged 3 to 12 years received Seizar only as an additional drug in polytherapy (n = 6); patients aged between 12 and 18 years received it either as monotherapy (n = 4) or in addition to othertreatments (n = 4). Five adults received Seizar alone, whereas 3 adults received it as a part of polytherapy. In total, 9 participants receivedmonotherapy with Seizar and 13 participants received Seizar with other treatments. In two patients, combination therapy was successfullychanged to monotherapy with Seizar (they are currently receiving it as monotherapy). Seizar dose varied between 75 and 400 mg per daygiven in 1–2 portions. Importantly, prolonged action of Seizar and convenient dose of 200 mg per tablet allows its administration once a day.Currently, 4 patients (one 15-year-old girl and 3 adults) are receiving Seizar once a day (3 of them at bedtime and one of them in the morning).The follow-up period was between 4 months and 5 years.Results.Therapeutic remission with Seizar was achieved in 7 out of 22 patients (31.8 %); 10 patients (45.5 %) demonstrated at least 50 %reduction in seizure frequency; 5 patients (22,7 %) had no effect. None of the participants had seizure aggravation. Seizar was ceased in 2 patients(9 %) due to its inefficacy.Therefore, therapeutic effect (clinical remission or more than 50 % reduction in seizure frequency) was achieved in 17 out of 22 patients(77 %), which is a very good result considering the fact that all participants had severe forms of epilepsy.Seizar was most effective in patients with idiopathic epilepsy (≥50 % reduction in seizure frequency/clinical remission was observed in 9 out11 patients (81 %), including 5 patients receiving Seizar as monotherapy) and structural focal epilepsy or focal epilepsy of unknown etiology(≥50 % reduction in seizure frequency/clinical remission was observed in 4 out of 5 patients (80 %)). Positive effect was achieved in 4 outof 6 participants (66 %) with epileptic encephalopathies; this group included patients with extremely severe forms of epilepsy and resistanceto many antiepileptic drugs (AED).Seizar was well tolerated by patients: 72.8 % of them had no side effect and only 5 patients (22.7 %) had transient disorders of the centralnervous system and gastrointestinal tract (nausea, loss of appetite) that did not require discontinuation of the drug. Only one patient (4.5 %)required its cessation. In 4 female patients of reproductive age, Seizar was used to optimize therapy as a part of preparation for pregnancy.High efficacy and good tolerability of Seizar are confirmed by patients’ adherence to treatment: 19 of 22 patients included into the study (86 %)still continue to receive Seizar (the duration of follow-up period varies between 4 months and 5 years). Only 3 participants required drugdiscontinuation due to skin rash (n = 1; 4.5 %) and low efficacy (n = 2; 9 %).Conclusions.Over the past decades, clinicians have accumulated evidence of good safety and tolerability of lamotrigine, including such aspectsas its positive effect on cognitive functions, behavior, mood (including that in children), and particularly good safety profile in women of reproductive age.Lamotrigine and levetiracetam are currently considered the safest AED for women of reproductive age in terms of their impact on the neuroendocrine system of women, fertility, and potential teratogenic effect. The number of pregnancies among women receiving lamotrigine is significantly higher than that among women receiving other AED. Thus, the safety of lamotrigine during pregnancy (as well as other aspects of itssafety and tolerability) are studied much better compared to other AED. It is very important that lamotrigine is considered a safe drug.

Lamotrigine in the Prevention of Migraine With Aura: A Narrative Review.

Lamotrigine is not recommended in the prevention of migraine in general but some reports suggest that it might be effective for treating specifically migraine with aura (MA). This review aims to summarize the related data from the literature and to better understand this discrepancy. All reports from the literature related to the use of lamotrigine in migraine with or without aura published prior to February 2019 found using PUBMED and the 2 keywords "migraine" AND "lamotrigine" were reviewed. Original studies, published in full, systematic reviews, and all case reports were synthetized. We also examined the risk profile, pharmacokinetics, and mode of action of lamotrigine in view of the presumed mechanism of MA. Lamotrigine was tested in different populations of migraineurs, but previous studies had small sample sizes (n<35) and might not have been powered enough for detecting a potential benefit of lamotrigine in MA. Accumulating data suggest that the drug can reduce both the frequency and severity of aura symptoms in multiple conditions and is well tolerated. Lamotrigine appears promising for treating attacks of MA and related clinical manifestations because of its high potential of efficacy, low-risk profile, and cost. Additional studies are needed for testing lamotrigine in patients with MA.

The lack of influence of IVS5-91 G>A polymorphism of the SCN1A gene on efficacy of lamotrigine in patients with focal epilepsy

ABSTRACTBackground: IVS5-91G>A (rs3812718) polymorphism of the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene has been associated with inadequate responsiveness to common antiepileptic drugs which act as sodium channel blockers. This study was performed to investigate the effect of IVS5-91G>A (rs3812718) polymorphism on lamotrigine (LTG) efficacy in a cohort of patients with non-lesional focal epilepsy taking LTG as monotherapy.Methods: A total of 100 of patients with non-lesional focal epilepsy on LTG monotherapy was included in this prospective interventional study. After reaching a stable dose of LTG patients were followed-up for 12 consecutive months. LTG responsiveness was defined as a 75% or more reduction in seizure frequency on a stable dose of LTG. Genotyping was performed at the end of the study using standard procedures and data were correlated with clinical data.Results: There were no significant differences in the prevalence of responsiveness to LTG between carriers of different genotypes. Average maintenance LTG doses in the responder group differed by genotype in the order AA>GA>GG, but these differences did not reach statistical significance.Conclusion: Our data suggest lack of association between SCN1A IVS5-91G>A (rs3812718) polymorphism and response to LTG.

Relationship Between UGT1A4 and UGT2B7 Polymorphisms and the Steady-State Plasma Concentrations of Lamotrigine in Patients With Treatment-Resistant Depressive Disorder Receiving Lamotrigine as Augmentation Therapy.

In a previous study, the authors had shown that in treatment-resistant depressive disorder, an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentrations. Lamotrigine is mainly metabolized by UGT1A4 and UGT2B7, and polymorphisms of said UGTs that affect enzyme activities have been reported. This study investigated the effect of these polymorphisms on the steady-state plasma concentrations (Css) of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy. The subjects were 103 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 = 46), bipolar II disorder (n = 44), and bipolar I disorder (n = 13). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 67 subjects who were not taking valproate and 75 mg/d for 36 subjects taking valproate, respectively. Blood sampling was performed at the 8th week. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. The genotypes of UGT1A4 142T>G, UGT2B7 -161C>T, and UGT2B7 372A>G were identified by polymerase chain reaction analyses. There were no significant relationships between these polymorphisms and the Css of lamotrigine in the subjects regardless of valproate comedication. This study suggests that these genetic polymorphisms do not affect the Css of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy.

Pregabalin and lamotrigine in central poststroke pain: A pilot study.

Comparative study of Class I drugs in central poststroke pain (CPSP) is lacking. To evaluate the safety and efficacy of pregabalin and lamotrigine in patients with CPSP. Tertiary care teaching referral hospital. We included consecutive patients with CPSP having ≥50 mm score on Visual Analog Scale (VAS) and randomized them to receive either oral pregabalin or oral lamotrigine. Their clinical findings, serum chemistry, and cranial magnetic resonance imaging findings were noted. The severity of CPSP was assessed by VAS while the allodynia was assessed on a 0-10 scale. The hospital anxiety and depression (HAD) score was also recorded. The primary outcome was> 50% reduction in the VAS score while the secondary outcome was> 50% reduction in the severity of allodynia and improvement in HAD score at 3 months. Adverse reactions were noted in both the groups. There were 30 patients with CPSP with a median age of 54.5 years (Male:Female = 36:4). While both pregabalin (P < 0.0001) and lamotrigine (P < 0.0001) resulted in significant improvement in the VAS score (63.3% vs. 53.3%), allodynia (66.7% vs. 75%), and HAD score (80% vs. 81.8%) compared to the baseline, the was no significant intergroup difference. Lamotrigine had to be withdrawn in three patients due to skin rash. Both pregabalin and lamotrigine are equally effective in CPSP, but significant side effects leading to drug withdrawal occured with lamotrigine administration.

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.

A Randomized Double-Blind Placebo-Controlled Study to Compare Preemptive Analgesic Efficacy of Novel Antiepileptic Agent Lamotrigine in Patients Undergoing Major Surgeries.

Background:If postoperative acute pain remains unrelieved, it may result in significant morbidity and mortality. Preemptive analgesic initiated before surgery offers premature analgesia even before exposure to an initial noxious stimulus bestowing effective postoperative analgesia. In developed countries, it is regularly practiced as a part of well-defined protocol. In our country however, only a few centers practice it and that too irregularly and with undefined protocol. Few studies support preemptive analgesic efficacy of novel antiepileptic agent gabapentin. Though lamotrigine is a proven analgesic in animal models of chronic pain and clinical studies of gabapentin-resistant neuropathic pain, a literature search revealed scarce data on its preemptive analgesic efficacy.Aims:The present study is designed to study the preemptive analgesic efficacy of lamotrigine in comparison with diclofenac sodium in postoperative pain control.Materials and Methods:This randomized clinical trial included 90 patients of both sexes, between 18 years and 70 years undergoing major surgeries. Patients were randomly allocated into placebo, control, and test groups and received the respective treatment 30 min before the induction of anesthesia. Aldrete score and pain score were recorded using visual analog scale (VAS), facial rating scale (FRS), and behavioral rating scale (BRS) at awakening and at 1 h, 2 h, 4 h, 6 h, and 24 h. Postoperative rescue analgesic consumption for 24 h was recorded.Results:Significantly higher pain scores were observed in the placebo 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). The test group patients were more comfortable throughout the study and postoperative analgesic requirement was significantly less (P < 0.05).Conclusions:The study recommends the use of single oral dose lamotrigine as preemptive analgesic for effective postoperative pain control.

Efficacy and safety of lamotrigine in patients with trigeminal neuralgia: a comparison with carbamazepine

Background: Antiepileptic drugs are increasingly used in the treatment of pain syndromes. This study evaluates efficacy and safety of lamotrigine in comparison with carbamazepine (CBZ) in trigeminal neuralgia (TN) patients. Methods: A total of 50 previously and newly diagnosed patients of TN were administered with lamotrigine (LTG) in comparison to CBZ. The final titration in dose for LTG was 400 mg/day and 1200 mg/day for CBZ. Clinical assessment (pain relief) was done before and after 15, 30, and 60 days of drug administration by visual analog scale and verbal rating scale. Side effects were recorded during study in both groups. Results: Of 25 patients in Group I who received CBZ, 16 patients (64%) experienced complete pain relief, while in Group II (LTG), 21 patients experienced complete pain relief. LTG was generally well tolerated except one patient was withdrawn due to skin rashes. CBZ was associated with mild hematological and central nervous system side effects. Conclusion: LTG is as effective and safe treatment for the management of TN as compared to CBZ.

EPA-0569 – Lamotrigine in patients with recurrent depression, which is resistant to antidepressive pharmacotherapy.

Objective To estimate the efficacy of lamotrigine as add-on therapy in patients with recurrent depression resistant to antidepressive pharmacotherapy. Object The study included 55 patients of both sexes aged 18-65 years with recurrent depressive disorder. At the time of inclusion in the study, patients received antidepressive pharmacotherapy for 2 months with a reduction in depressive symptoms less than 25%. Results According to the results of clinical observations, patients with atypical variants of depressive symptoms have been isolated - Anxious or agitated depression with dominance or significant share of anxiety affect, ideational and motor excitation, high suicide risk; - Apathetic depression - lack of desire and motivation to work, intolerance to intellectual and physical activities; - Adynamic or anergic depression dominated by slackness, weakness in the presence of the desire for activity; - Dysphoric depression with an angry, irritable background mood, a tendency to auto-and getero-agressive actions. In patients with atypical depression and (anxious and dysphoric), lamotrigine adjunctive therapy, a significantly more positive dynamic state was observed than in patients with classical clinical picture of depression. On the Hamilton depression scale decreased to 13 points or less (no anxiety-depressive symptoms) with 25 points or more (clinical symptoms of anxiety depression) at the beginning of the research; Conclusion The efficacy of lamotrigine to overcome treatment resistance in recurrent depression. The most expedient is to use it for additional therapy in combination with antidepressants in recurrent depression with atypical clinical picture of depression - anxious and dysphoric.

Observational study to evaluate the clinical benefit of lamotrigine add-on therapy in bipolar patients in a naturalistic treatment setting

The objective of the current study was to assess, in a naturalistic treatment setting, the clinical benefits of lamotrigine add-on therapy for patients with bipolar disorder. This was an open-label, prospective, naturalistic, 12-week, observational study that included 98 bipolar patients treated with lamotrigine add-on therapy, in addition to mood stabilizers or atypical antipsychotics for 1-4 weeks. The clinical benefits of lamotrigine augmentation were evaluated using the Clinical Global Impression-Clinical Benefit (CGI-CB) Scale, and the Clinical Global Impression of Bipolar Disorder-Severity scale was used to evaluate the severity of the patients' conditions. According to paired t-test analyses, the mean CGI-CB score significantly decreased from 7.2 ± 2.7 at baseline to 3.8 ± 2.5 at Week 12. Likewise, the mean score for Clinical Global Impression of Bipolar Disorder-Severity scale significantly decreased from 4.7 ± 0.9 at baseline to 3.1 ± 1.2 at Week 12. Analysis of covariance showed that the extent to which CGI-CB scores changed from baseline to Week 12 did not significantly differ between patients with bipolar I and II disorder. However, the change in CGI-CB scores between Weeks 4 and 12 was significantly smaller in bipolar II patients than bipolar I patients. A total of 21 (21.4%) patients dropped out during the course of the study, and 30 patients (30.6%) reported 82 adverse events. The results of this study demonstrated that the use of lamotrigine in patients with bipolar disorder, especially those whom conventional mood stabilizers or antipsychotics are insufficiently effective or intolerable, can be beneficial regardless of the type of bipolar disorder.

PP143—Impact of UGT1A4 genotype in the clinical response to lamotrigine in patients with epilepsy

PP143—Impact of UGT1A4 genotype in the clinical response to lamotrigine in patients with epilepsy

Pregabalin monotherapy for epilepsy

Many people with epilepsy suffer from poorly controlled seizures, despite current antiepileptic treatments. Due to high rates of treatment resistance, there is interest in new pharmacological treatment options such as pregabalin. However, it remains unclear whether existing evidence of pregabalin is rigorous enough to support its monotherapy. To determine the efficacy and tolerability of pregabalin in people with epilepsy. We searched the Cochrane Epilepsy Group's Specialized Register (August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7 ), MEDLINE (1946 to August week 1, 2012), EMBASE (1974 to August 2012) and the Chinese Biomedical Literature Database (CBM) (1978 to August 2012). No language restrictions were imposed. Randomised controlled trials (RCTs) comparing pregabalin with placebo or another antiepileptic drug monotherapy for epilepsy. Two review authors (QZ and LY) independently extracted trial data and assessed trial quality. We assessed the following outcomes: (1) time to withdrawal after randomisation; (2) time to achieve six-, 12- or 24-month remission; (3) the proportion of participants who remained seizure-free for six or more continuous months; (4) time to first seizure after randomisation; (5) validated quality of life measures; (6) health economic outcomes; (7) adverse effects. We expressed time-to-event outcomes as hazard ratios (HRs) with 95% confidence interval (CI), where an HR > 1 indicates an event is more likely to occur earlier on pregabalin than the comparator. Two short-term studies involving 753 participants met the inclusion criteria. Only one study investigated the effects of pregabalin compared with lamotrigine in patients with newly diagnosed partial seizures, and the other study investigated the effects of pregabalin compared with gabapentin in hospitalised patients with refractory partial epilepsy. There were no studies on generalised-onset tonic-clonic seizures (with or without other generalised seizure types).We found that pregabalin was inferior in comparison to lamotrigine when measuring time to withdrawal due to inadequate seizure control after dose stabilisation from randomisation: hazard ratio (HR) 4.52; 95% confidence interval (CI) 1.93 to 10.60; time to achieve six-month remission after dose stabilisation from randomisation: HR 0.56; 95% CI 0.41 to 0.76; the proportion of participants who remained seizure-free for six or more continuous months: RR 0.76, 95% CI 0.67 to 0.87 (Europe: 0.83, 95% CI 0.69 to 0.99; Asia: RR 0.70, 95% CI 0.57 to 0.86; the Americas: RR 0.62, 95% CI 0.33 to 1.19); and time to first seizure after dose stabilisation from randomisation: HR 1.74; 95% CI 1.26 to 2.39. There was no significant difference in safety-related outcomes between pregabalin and lamotrigine, but more participants in the pregabalin group developed somnolence, weight increase and convulsion. Pregabalin was better than gabapentin when measuring time to withdrawal due to all reasons after randomisation: HR 0.25; 95% CI 0.11 to 0.57; and time to withdrawal due to inadequate seizure control after randomisation: HR 0.41; 95% CI 0.18 to 0.92. No significant difference was found in safety-related outcomes between pregabalin and gabapentin. But we found some limitations in the study design which may have had an influence on the results. Pregabalin seems to have similar tolerability but inferior efficacy in comparison to lamotrigine for newly diagnosed partial seizures. However, considering the limitations in the study design (such as the short-term follow-up and the low initial target dose selection), the results should be interpreted with caution. The available data were too limited to draw any conclusions between pregabalin and gabapentin. The result indicated that the treatment effects were influenced by the study regions. The clinical disadvantage of pregabalin was more prominent in Asia when compared with lamotrigine. We should determine whether pregabalin has ethnic differences in the treatment of epilepsy in the future. This review does not inform any treatment policy for patients with generalized onset tonic-clonic seizures. Further long-term trials are needed to investigate the genuine effectiveness of pregabalin as monotherapy.

Functional Brain Imaging for Pain: A Clinical Drug Trial

Objectives. The aim of the present study was to evaluate central nervous system circuitry using functional magnetic resonance imaging (fMRI) activated/affected by the anticonvulsant lamotrigine in patients with facial neuropathic pain.

Lack of Interaction between Sertraline and Lamotrigine in Psychiatric Patients: A Retrospective Study

This study evaluates the pharmacokinetic interaction between sertraline and lamotrigine in psychiatric patients. We identifi ed patients with at least 1 measurement of trough lamotrigine plasma concentration (at steady-state) during lamotrigine therapy and compared dose and plasma concentrations between patients who received lamotrigine with sertraline and patients who received lamotrigine without sertraline. The dose corrected concentration of lamotrigine in patients receiving lamotrigine in combination with sertraline was 60.4 μmol/L × 1,000/mg/day (SD: 31.1) (N = 7) compared to 51.1 μmol/L × 1 000/mg/day (SD: 27.6) (N = 44) in patients using lamotrigine without sertraline (p = 0.42). The slightly slower metabolism of lamotrigine in patients receiving lamotrigine with sertraline compared with those receiving lamotrigine alone is not believed to be of clinical signifi cance. However, due to the limited power, we may have overlooked a diff erence that could be clinically relevant.

Influence of Concomitant Antiepileptic Drugs on Plasma Lamotrigine Concentration in Adult Japanese Epilepsy Patients

Lamotrigine (LTG) is an antiepileptic drug (AED) that was approved in Japan in 2008. We evaluated the influence of AEDs that induce hepatic enzymes (including phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ)), valproic acid (VPA), and various combinations of these drugs, on plasma LTG concentration in adult Japanese epilepsy patients. A total of 621 patients (mean age 34.4±11.8 years) were evaluated retrospectively. We calculated the concentration to dose ratio (CD ratio) for LTG with different AED regimens, and employed multiple regression analysis to determine factors influencing the LTG concentration. There was a linear correlation between the dose and concentration of LTG in patients treated with LTG (group I), LTG+VPA (group II), LTG+inducers (group III), or LTG+VPA+inducers (group IV). The mean CD ratio of patients on LTG monotherapy was 1.43±0.4 (μg/mL)/(mg/kg). When LTG was combined with VPA, the CD ratio increased about 2.2-fold, but there was no significant correlation between the CD ratio and VPA concentration. The mean CD ratios calculated in patients receiving LTG+PHT, LTG+PB, and LTG+CBZ were 0.56, 0.84, and 0.91, respectively. Addition of PHT significantly reduced the CD ratio in a concentration-dependent manner, in comparison with PB and CBZ (p<0.005 and p<0.001, respectively). Stepwise multiple regression analysis showed that the coefficient of determination of groups I, II, III, and IV were 0.94, 0.94, 0.90, and 0.91, respectively. In the clinical setting, these findings can help to estimate LTG concentrations and predict the inducing or inhibiting effects of concomitant AEDs.

Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial

Efficacious and safe monotherapy options are needed for adult patients with newly diagnosed epilepsy. As an adjunctive treatment for partial seizures, pregabalin compares favourably with lamotrigine and is an effective, approved treatment. We studied the efficacy and safety of pregabalin as monotherapy, using a design that complied with European regulatory requirements and International League Against Epilepsy guidelines. This phase 3, double-blind, randomised, non-inferiority study compared the efficacy and tolerability of pregabalin and lamotrigine monotherapy in patients with newly diagnosed partial seizures at 105 centres, mostly in Europe and Asia. Randomisation to treatment groups (1:1 ratio) was by a computer-generated pseudorandom code (random permuted blocks), with patients sequentially assigned numbers by telephone. Investigators, site staff, and patients were masked to the assigned treatment. After randomisation, patients were titrated to either 75 mg oral pregabalin or 50 mg oral lamotrigine twice daily during a 4-week dose-escalation phase, followed by a 52-week efficacy assessment phase during which the daily dose could be increased as needed to a maximum of 600 mg and 500 mg, respectively. The primary efficacy endpoint was the proportion of patients who remained seizure-free for 6 or more continuous months during the efficacy assessment phase; analysis included all patients who were randomly assigned to treatment groups and received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT00280059. 660 patients were randomly assigned to treatment groups (330 pregabalin, 330 lamotrigine), of whom 622 entered the efficacy assessment phase (314 pregabalin, 308 lamotrigine). Fewer patients in the pregabalin group than in the lamotrigine group became seizure-free for 6 or more continuous months (162 [52%] vs 209 [68%]; difference in proportion, -0·16, 95% CI -0·24 to -0·09). The overall incidence of adverse events was similar between the groups and consistent with that in previous studies; dizziness (55 [17%] vs 45 [14%] patients), somnolence (29 [9%] vs 14 [4%]), fatigue (27 [8%] vs 19 [6%]), and weight increase (21 [6%] vs 7 [2%]) were numerically more common in the pregabalin group than in the lamotrigine group. Pregabalin has similar tolerability but seems to have inferior efficacy to lamotrigine for the treatment of newly diagnosed partial seizures in adults. Inferior efficacy of pregabalin might have been attributable to limitations in the study design, as treatment doses might have not been optimised adequately or early enough. Pfizer Inc.