Valproate in the treatment of epilepsy in girls and women of childbearing potential

This document provides guidance on the use of valproate in girls and women of childbearing age from a joint Task Force of the Commission on European Affairs of the International League Against Epilepsy (CEA‐ILAE) and the European Academy of Neurology (EAN), following strengthened warnings from the Coordination Group for Mutual Recognition and Decentralised Procedures‐Human (CMDh) of the European Medicines Agency (EMA), which highlight the risk of malformations and developmental problems in infants who are exposed to valproate in the womb. To produce these recommendations, the Task Force has considered teratogenic risks associated with use of valproate and treatment alternatives, the importance of seizure control and of patient and fetal risks with seizures, and the effectiveness of valproate and treatment alternatives in the treatment of different epilepsies. The Task Force's recommendations include the following: (1) Where possible, valproate should be avoided in women of childbearing potential. (2) The choice of treatment for girls and women of childbearing potential should be based on a shared decision between clinician and patient, and where appropriate, the patient's representatives. Discussions should include a careful risk–benefit assessment of reasonable treatment options for the patient's seizure or epilepsy type. (3) For seizure (or epilepsy) types where valproate is the most effective treatment, the risks and benefits of valproate and other treatment alternatives should be discussed. (4) Valproate should not be prescribed as a first‐line treatment for focal epilepsy. (5) Valproate may be offered as a first‐line treatment for epilepsy syndromes where it is the most effective treatment, including idiopathic (genetic) generalized syndromes associated with tonic–clonic seizures. (6) Valproate may be offered as a first‐line treatment in situations where pregnancy is highly unlikely (e.g., significant intellectual or physical disability). (7) Women and girls taking valproate require regular follow‐up for ongoing consideration of the most appropriate treatment regimen.     

Characterization of plasma acylcarnitines in patients under valproate monotherapy using ESI-MS/MS

Objectives: The effect of administration of the antiepileptic drug valproate (VPA), on the composition of the plasma acylcarnitine profile (including free carnitine) was investigated.

Design and methods: Plasma samples were obtained from 18 individuals (13♂:5♀; 15–65y) on long-term treatment with VPA (resulting in plasma levels of 14.6–135.0 mg/L; therapeutic conc.: 40–100 mg/L). Acylcarnitines (AC) in plasma were quantified by electrospray tandem mass spectrometry (ESI-MS/MS).

Results: VPA was found to increase the levels (mean ± SD, μM) of 3-hydroxy-isovalerylcarnitine (0.10 ± 0.04; controls: 0.02–0.06), C14:2 acylcarnitine (0.11 ± 0.05; controls: 0.02–0.08), propylglutarylcarnitine (0.06 ± 0.05; controls: 0.00–0.04), and C18-0H-acylcarnitine (0.09 ± 0.05; controls: 0.00−0.04). The free carnitine (C) (42.2 ± 9.0; controls: 22.3–54.9) and the total carnitine (52.3 ± 10.1; controls: 26.5–73.6) were not significantly altered by VPA. Other AC (C2-C18, monounsaturated and hydroxylated) were all within the control range and especially no increase of C8 (valproyl) carnitine was observed. A positive correlation was found between the ratios [AC] / [C] (p < 0.05) or [long-chain AC (C10-C18)] / [C] (p < 0.09) with the plasma VPA concentration.

Conclusions: The unequivocal increase in 3-hydroxy-isovalerylcarnitine is consistent with the increase of 3-hydroxy-isovaleric acid observed in urine of VPA treated patients. This finding suggests an interaction mechanism of VPA with specific enzymes, namely involved in leucine metabolism. Adult patients under VPA monotherapy do not suffer from carnitine deficiency; the effect of the accumulating acylcarnitines is ill-defined.     

Evaluation of acetylcholinesterase in an animal model of mania induced by d-amphetamine

The present study aims to investigate the effects of mood stabilizers, lithium (Li) and valproate (VPA), on acetylcholinesterase (AChE) activity in the brains of rats subjected to an animal model of mania induced by d-amphetamine (d-AMPH). In the reversal treatment, Wistar rats were first given d-AMPH or saline (Sal) for 14 days. Between days 8 and 14, the rats were treated with Li, VPA, or Sal. In the prevention treatment, rats were pretreated with Li, VPA, or Sal. AChE activity was measured in the brain structures (prefrontal cortex, hippocampus, and striatum). Li, alone in reversion and prevention treatments, increased AChE activity in the brains of rats. VPA, alone in prevention treatment, increased AChE activity in all brain regions evaluated; in the reversion, only in the prefrontal. However, d-AMPH decreased activity of AChE in the striatum of rats in both the reversion and prevention treatments. VPA was able to revert and prevent this AChE activity alteration in the rat striatum. Our findings further support the notion that the mechanisms of mood stabilizers also involve changes in AChE activity, thus reinforcing the need for more studies to better characterize the role of acetylcholine in bipolar disorder.     

Efficacy and tolerability of lamotrigine in Juvenile Myoclonic Epilepsy in adults: A prospective,unblinded randomized controlled trial

PurposeControlled randomized studies recommending the clinical use of lamotrigine in adult populations with the diagnosis of Juvenile Myoclonic Epilepsy are still lacking. To compare the efficacy and tolerability of lamotrigine versus valproate in adult patients with JME.MethodsThis was a prospective, randomized, controlled, pragmatic, long-term and open-label treatment trial. Patients were randomized to use valproate or lamotrigine. The primary end points of the study were: (1) time from randomization to treatment failure (withdrawal); (2) time from randomization to seizures remission. Secondary ending points were: (1) frequency of clinically important adverse events and (2) change in the QOLIE-31 after randomization. The definition of seizure remission was based on disappearance of all seizure types and EEG discharges.ResultsWe found that the time to withdraw treatment after randomization was not significantly different in lamotrigine and valproate groups. Long-term seizures freedom was equal in the both groups of the trial; only 8 (19.1%) patients randomized to lamotrigine and 6 (19.4%) randomized to valproate were not seizure free after 4 months of treatment. Between 17.03% (lamotrigine) and 35.3% (valproate) of patients reported adverse reactions at some point in the intention-to treat study (p = 0.07). All subscales of the QOLIE-31 questionnaire, except that related to side effects of medication, improved more than 5 points with respect to baseline period in both groupsConclusionLamotrigine is effective in adult patients with Juvenile Myoclonic Epilepsy and better tolerated than valproate, although the incidence of idiosyncratic reactions could be a cause of concern.     

Lurasidone adjunctive with lithium or valproate for bipolar depression: A placebo-controlled trial utilizing prospective and retrospective enrolment cohorts

In this study, designed to evaluate the efficacy of lurasidone as adjunctive therapy with lithium or valproate, patients with bipolar I depression were randomized to 6 weeks of double-blind treatment with lurasidone (N = 180) or placebo (N = 176), added to background treatment with lithium or valproate. All patients were treated with lithium or valproate for a minimum of 4 weeks prior to screening. This was confirmed either by prospective treatment after study enrolment (run-in cohort), or retrospectively, with blood levels of lithium and valproate at screening (non-run-in cohort). Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP-S), respectively. Treatment with lurasidone was associated with non-significant improvement at week 6 vs. placebo for the MADRS total score (−11.8 vs −10.4; P = 0.176), and the CGI-BP-S score (−1.36 vs −1.13; P = 0.095). Significant separation from placebo was observed from weeks 2–5 for the MADRS and weeks 3–5 for the CGI-BP-S. Improvement in the placebo-subtracted MADRS total score was notably larger at week 6 for the non-run-in cohort compared to the run-in cohort (LS mean difference in endpoint change scores, −4.6; P = 0.009). Adverse events most frequently reported for lurasidone were akathisia, somnolence, and extrapyramidal side effects. In conclusion, lurasidone adjunctive with lithium or valproate demonstrated significant improvement in depressive symptoms based on the MADRS from weeks 2–5 but not at the primary week 6 endpoint.     

Treatment of experimental status epilepticus with synergistic drug combinations

During status epilepticus (SE), synaptic γ‐aminobutyric acid A receptors (GABA_ARs) become internalized and inactive, whereas spare N‐methyl‐d ‐aspartate receptors (NMDARs) assemble, move to the membrane, and become synaptically active. When treatment of SE is delayed, the number of synaptic GABA_ARs is drastically reduced, and a GABA_A agonist cannot fully restore inhibition. We used a combination of low‐dose diazepam (to stimulate the remaining GABA_ARs), ketamine (to mitigate the effect of the NMDAR increase), and valproate (to enhance inhibition at a nonbenzodiazepine site) to treat seizures in a model of severe cholinergic SE. High doses of diazepam failed to stop electrographic SE, showing that benzodiazepine pharmacoresistance had developed. The diazepam‐ketamine‐valproate combination was far more effective in stopping SE than triple‐dose monotherapy using the same individual drugs. Isobolograms showed that this drug combination's therapeutic actions were synergistic, with positive cooperativity between drugs, whereas drug toxicity was simply additive, without positive or negative cooperativity. As a result, the therapeutic index was improved by this drug combination compared to monotherapy. These results suggest that synergistic drug combinations that target receptor changes can control benzodiazepine‐refractory SE.     

Brief Communication: NO EFFECT OF LONG-TERM VALPROATE THERAPY ON THYROID AND PARATHYROID FUNCTIONS IN CHILDREN

In this study, we studied serum calcium, phosphorus, alkaline phosphatase, thyroid hormones (total thyroxine, free thyroxine, thyroid-stimulating hormone), parathyroid hormone, and osteocalcine levels in children with epilepsy who had been receiving long-term valproate (VPA) therapy in order to determine whether there was any effect of VPA therapy on these hormones. The study included 31 patients with epilepsy receiving VPA and 22 healthy age-matched controls. The age ranged from 15 months to 16 years and 18 months to 17 years in the study and control group, respectively. The duration of VPA use was between 12 months and 5 years (1.93 &#45 1.90 years). When comparing the results, we did not find any significant difference in any of the parameters, including serum calcium, phosphorus, alkaline phosphatase, osteocalcine, and thyroid and parathyroid hormone levels, between the study and control group. We suggest that VPA can safely be used with regard to thyroid and parathyroid dysfunction in childhood epilepsy.     

丙戊酸钠联合喹硫平治疗双相情感障碍躁狂发作的疗效

目的探讨喹硫平联合丙戊酸钠治疗双相情感障碍躁狂发作的疗效及对认知功能的影响。方法选取2013-2014年我院收治的双相情感障碍躁狂发作患者80例,随机平均分为观察组与对照组,分别行丙戊酸钠联合喹硫平与利培酮治疗,均早晚2次服用,持续6周。于治疗前和治疗6周后采用杨氏躁狂量表(YRMS)评定临床疗效,采用威斯康星卡片分类测验(WCST)、持续操作测验(CPT)和霍普金斯词语学习测验修订版(HVLT-R)评定认知功能。结果观察组临床治愈率、显效率、总有效率与对照组相比均无显著性差异(P0.05)。治疗后2组完成分类数、错误应答数、持续应答数均明显改善,持续注意水平明显改善,观察组错误应答数与持续应答数改善更为明显(P0.05)。结论喹硫平联合丙戊酸钠能够有效治疗双相情感障碍躁狂发作,改善患者的部分认知功能。     

注射用丙戊酸钠联合碳酸锂治疗急性躁狂发作的临床疗效

目的通过观察和分析,讨论注射用丙戊酸钠联合碳酸锂治疗急性躁狂发作的临床疗效。方法选取我院自2010年4月-2012年12月期间所得躁狂症并且不断有急性躁狂发作的患者132例,作为本次临床试验的观察对象。先对这132例患者采用碳酸锂进行治疗,若是在4周后病情未控制住,再采用丙戊酸钠联合碳酸锂进行治疗。将全部患者列为对照组,采用联合治疗的患者列为观察组。观察两组患者的好转情况和并发症情况。结果在1周时两组患者的评分无明显差异(P0.05),在2、3、4周后差异有统计学意义(P0.05)。观察组患者的并发症比对照组少33.33%,χ2=5.9183,P0.05,差异具有统计学意义。结论注射用丙戊酸钠联合碳酸锂治疗急性躁狂发作具有显著疗效,并且副作用较少,值得临床广泛应用。