Lamotrigine-antiparkinsonian activity by blockade of glutamate release?

Summary Recent experiments provide evidence that the NMDA-antagonist MK-801 has a locomotor-stimulating effect in monoamine-depleted rodents. These findings are based upon a hypothetical pathway-circuit including the basal ganglia as a model reflecting hypo- and hyperkinetic movement disorders. We have treated 5 patients suffering from Parkinson's disease with the antiepileptic drug lamotrigine which does not appear to be an NMDA-antagonist but acts functionally as a glutamate antagonist by inhibition of presynaptic glutamate release.     

氟桂利嗪和拉莫三嗪对胎鼠缺血缺氧性脑损害的保护作用

目的研究氟桂利嗪(FNZ)、拉莫三嗪(LTG)及两药联合经孕鼠给药,对胎鼠宫内缺血缺氧性脑损害的保护作用。方法将孕20 d Wistar大鼠40只,随机均分为FNZ组、LTG组、FNZ LTG组和对照组。前3组大鼠于脑缺血缺氧术前3 d开始灌胃给药,每天1次,分别为FNZ 0.5 mg/(kg.d),LTG 10 mg/(kg.d),FNZ 0.5 mg/(kg.d) LTG 10 mg/(kg.d)。第3天给药后3 h,每组取8只孕鼠制作宫内缺血缺氧模型,剩余2只孕鼠直接行剖宫产取胎鼠,每胎5只。于缺血缺氧后6、12、24、48 h分别取胎鼠血清0.5 ml,采用ELISA法测定血清神经元特异性烯醇化酶(NSE)和酸性钙结合蛋白(S-100)水平。结果胎鼠缺血缺氧后,血清NSE和S-100水平明显升高。FNZ组、LTG组及FNZ LTG组胎鼠缺血缺氧后各个时间点血清NSE和S-100较对照组明显降低,差异均有极显著性意义(均P<0.01)。联合用药组效果更明显,组间比较差异亦有极显著性意义(P<0.01)。结论产前预防性灌胃FNZ、LTG对胎鼠宫内缺血缺氧性脑损伤具有保护作用,联合用药效果更明显。     

Conversion from immediate-release to extended-release lamotrigine improves seizure control

BackgroundImmediate release lamotrigine (LTG-IR) dosing can be limited by peak toxicity. It is thought that peak levels are responsible for some adverse effects such as dizziness, blurred vision, double vision and unsteadiness. At the same time, trough levels may be associated with reduced seizure threshold. The use of extended release lamotrigine (LTG-XR) to replace LTG-IR will be associated with less fluctuation in drug levels-lower peak levels may reduce adverse effects and higher trough levels may improve seizure control. This hypothesis was tested by analyzing seizure control and adverse effects before and after conversion from LTG-IR to LTG-XR in patients who underwent such conversion in 2009–2011.MethodsWe searched our patient database to identify patients converted from LTG-IR to LTG-XR for persistent seizures or adverse effects from August 2009 until December 31, 2011. We included only patients who took LTG-IR and LTG-XR for at least 6 months each. We excluded patients with nonepileptic seizures, progressive cause of epilepsy, or not keeping a seizure record. We collected the following parameters: age at conversion, LTG-IR dose and dosing schedule, duration on that dose, LTG-XR dose and dosing schedule, LTG serum level before and after conversion, duration of LTG-XR treatment, seizure frequency before and after conversion, and change in adverse experience profile. We also recorded baseline AEDs and any AED change during the course of the analysis.ResultsFifty five patients (26 female) satisfied the inclusion/exclusion criteria. Their mean age was 45 years (range 23 to 86). Ten were on LTG-IR monotherapy, 24 took LTG-IR plus one other AED, most commonly levetiracetam, and the remaining 21 took LTG-IR plus at least 2 other AEDs. The mean LTG-IR dose was 544 mg/day (range 150–1100 mg/day). The mean LTG-IR serum level was 11.6 (available in 53 patients-range 4.6–21 mcg/ml). Twenty six patients were converted to the same dose and one patient took a mixture of LTG-XR and LTG-IR at the same total daily dose, while 21 had their dose slightly increased and 7 had their dose slightly decreased due to adverse effects. The mean serum level after conversion was 11.8 (available in 49 patients-range 2.6–21.2 mcg/ml). As a result of the conversion, 26 patients (47%) experienced >50% reduction in seizure frequency. There was a 46% median reduction in seizure frequency overall. Seven patients reported improvement in adverse effects.ConclusionA conversion from LTG-IR to LTG-XR can help improve seizure control in some individuals with drug-resistant epilepsy, in addition to improving tolerability. While it is indicated in individuals experiencing peak adverse effects, it should also be considered in patients who have received incomplete seizure control from LTG-IR.     

Review of lamotrigine and its clinical applications in epilepsy

Lamotrigine is an anti-epileptic agent with broad efficacy. Lamotrigine works at voltage-sensitive sodium channels, thereby stabilising the neuronal membrane and inhibiting the release of excitatory neurotransmitters such as glutamate and aspartate. Early preclinical animal studies indicate its broad-spectrum efficacy, which was later confirmed in clinical trials. Multiple randomised, placebo-controlled and comparative trials demonstrate its efficacy against partial and secondarily generalised seizures. Open-label trials show its efficacy against generalised seizures, especially absence seizures of childhood absence epilepsy and generalised seizures of juvenile myoclonic epilepsy. Lamotrigine has a wide clinical dose range and possesses favourable pharmacokinetic properties. It has a good tolerability and safety profile, which enhance compliance. Its small risk of serious skin rash should be weighed against its potential benefits when choosing lamotrigine on an individual basis. Lamotrigine is an excellent therapeutic option in epilepsy.     

不同剂量拉莫三嗪治疗老年癫痫的比较研究

目的 探讨不同剂量拉莫三嗪治疗老年癫痫患者的临床疗效。方法 选择2014年7月—2018年2月洛阳市第三人民医院神经内科诊治的老年癫痫患者88例作为研究对象,根据拉莫三嗪使用剂量分为对照组（40例）和观察组（48例）。对照组患者给予大剂量拉莫三嗪片治疗,拉莫三嗪起始剂量25 mg/d,2周后为50 mg/d,第5周以后为目标剂量100 mg/d,维持100 mg/d治疗观察至第8周。观察组患者给予小剂量拉莫三嗪片治疗,起始剂量25 mg/d,2周后为50 mg/d,第5周以后为目标剂量50 mg/d,维持50 mg/d治疗观察至第8周。观察两组患者的临床疗效,同时比较两组患者蒙特利尔认知评估量表（MoCA）评分、P300潜伏期、波幅和不良反应情况。结果 治疗后,对照组和观察组总有效率分别为97.5%、97.9%,两组对比差异无统计学意义。治疗后,两组患者的MoCA评分均显著高于治疗前,同组治疗前后比较差异具有统计学意义（P<0.05）;且观察组治疗后的MoCA评分显著高于对照组,两组比较差异具有统计学意义（P<0.05）。治疗后,观察组的P300潜伏期显著降低,波幅明显升高,同组治疗前后比较差异具有统计学意义（P<0.05）;且观察组治疗后P300潜伏期及波幅显著优于对照组,两组比较差异具有统计学意义（P<0.05）。观察组治疗期间的不良反应发生率为6.3%,显著低于对照组的32.5%,两组比较差异具有统计学意义（P<0.05）。结论 相对于大剂量,小剂量拉莫三嗪治疗老年癫痫患者能达到很好的疗效,能减少不良反应的发生,改善患者的神经电生理功能与认知功能。     

Evidence‐based treatment strategies for treatment‐resistant bipolar depression: a systematic review

Sienaert P, Lambrichts L, Dols A, De Fruyt J.
Evidence‐based treatment strategies for treatment‐resistant bipolar depression: a systematic review.
Bipolar Disord 2012: 00: 000–000. © 2012 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd. Objectives: Treatment resistance in bipolar depression is a common clinical problem that constitutes a major challenge for the treating clinician as there is a paucity of treatment options. The objective of this paper was to review the evidence for treatment options in treatment‐resistant bipolar depression, as found in randomized controlled trials and with special attention to the definition and assessment of treatment resistance. Methods: A Medline search (from database inception to May 2012) was performed using the search terms treatment resistance or treatment refractory, and bipolar depression or bipolar disorder, supplemented with 43 separate searches using the various pharmacologic agents or technical interventions as search terms. Results: Only seven studies met our inclusion criteria. These studies examined the effects of ketamine (n = 1), (ar)modafinil (n = 2), pramipexole (n = 1), lamotrigine (n = 1), inositol (n = 1), risperidone (n = 1), and electroconvulsive therapy (ECT) (n = 2). Conclusions: The available level I evidence for treatment strategies in resistant bipolar depression is extremely scarce, and although the response rates reported are reassuring, most of the strategies remain experimental. There is an urgent need for further study in homogeneous patient samples using a clear concept of treatment resistance.     

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

ABSTRACT

Background: 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.