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PubMed2005

Lithium- and valproate-induced alterations in circadian locomotor behavior in Drosophila.

Lithium and valproate are commonly used mood stabilizers, but their action pathways are not clearly understood. They also suffer from multiple toxic effects that limit their utility. Elucidating their action mechanisms could lead to newer agents and better understanding of the etiopathogenesis of bipolar disorder. We have expanded the study of signaling mechanisms of lithium and valproate by using Drosophila circadian locomotor activity as a robust behavioral assay that is amenable to genetic manipulations. We demonstrate that lithium affects the circadian system of Drosophila similarly to what has been reported in the mammalian studies. We show that lithium and valproate share effects on the circadian locomotor activity of Drosophila: they lengthen the period of circadian rhythms and increase arrhythmicity. Valproate exerts these effects in a weaker fashion than does lithium. We also tested the circadian alterations in multiple mutant lines of Drosophila bearing defects in the GSK-3beta gene and other clock genes in response to lithium administration. We show that lithium partially rescues the shortening of circadian period when the GSK-3beta gene is overexpressed only in specific circadian pacemaker neurons, thus implicating GSK-3beta as a component in lithium's effect on the circadian oscillator. Moreover, lithium also lengthens the period in GSK-3beta heterozygous mutants and doubletime long mutants. These results establish a basis for using Drosophila genetics to investigate more fully lithium and valproate action mechanisms.

Animals↗

PubMedDate not supplied

Wolff Award 1996. The actions of valproate and neurosteroids in a model of trigeminal pain.

Gamma-aminobutyric acid (GABA) receptors are ubiquitous inhibitory receptors in the central and peripheral nervous systems. Valproic acid (2-propylpentanoic acid), which enhances GABA synthesis and blocks degradation, is useful in migraine treatment and may act through activation of GABA receptors to modulate trigeminal nociceptive neurons innervating the meninges. To investigate this possibility, we tested the effect of valproate and allopregnanolone, a metabolite of progesterone, which binds and modulates the GABA receptor in an animal model of cephalic pain. One hundred ten Hartley guinea pigs were pretreated with either valproate or allopregnanolone 30 minutes prior to activation of trigeminal afferent fibers via intracisternal injection of the irritant, capsaicin. The effects of valproic acid and allopregnanolone were examined on c-fos expression within the trigeminal nucleus caudalis (lamina I, II), the termination site for small unmyelinated C fibers projecting from the meninges. C-fos positive cells were counted at three representative levels (rostral, middle, and caudal) by an observer naive to the treatment group. We found that valproate (> or = 10 mg/kg, IP) reduced labeled cells by 52% (P < 0.05) and allopregnanolone (> or = 100 mg/kg, IP) reduced labeled cells by 42% (P < 0.01). Bicuculline (GABAA antagonist), but not phaclofen (GABAB antagonist), blocked the valproate effect, thereby documenting the importance of GABAA receptors. We conclude that the attenuation of c-fos-LI by valproate and allopregnanolone is mediated via GABAA receptors. These studies complement prior experiments showing that valproic acid and allopregnanolone block neurogenic inflammation within the meninges via GABAA receptor-mediated mechanisms. The findings suggest a potential strategy for discovering new antimigraine drugs with high affinity for the GABAA receptor and its modulatory sites.

Animals↗

PubMed2002

Sodium valproate prophylaxis in childhood migraine.

UNLABELLED: Migraine is a cause of recurrent headache in childhood. The efficacy of sodium valproate is well known in the prophylactic treatment of adult migraine, but there are few studies involving the drug's effect in pediatric migraine. OBJECTIVE: To determine the efficacy of sodium valproate in the prophylactic treatment of childhood migraine. METHODS: Fifteen children with migraine according to International Headache Society criteria were included in the study. Headache severity was measured and assessed by Algology unit by a using visual analog scale and a numerical rating scale. All of the subjects were asked to keep a headache diary for 8 weeks. Three subjects who had no headache attacks during the baseline period and two cases who were lost to follow up were excluded. Thus, sodium valproate was initiated in 10 subjects (six boys, four girls), 500 mg/night, and the daily dose was increased up to 1000 mg according to blood levels. Their ages ranged from 9 to 17 (mean age 13.6 +/- 3.2 years). Therapy continued for at least 12 weeks. RESULTS: Headache severity as measured via the mean visual analog score was 6.8 +/- 1.8 at baseline and was 0.7 +/- 1.2 at the end of the treatment period (P = 0.000). Mean headache attacks per month were 6 +/- 4.2 at baseline and were 0.8 +/- 1.9 at the end of the treatment period (P = 0.002). The duration of headache was significantly decreased from a mean of 5.5 +/- 3.9 hours to 1.1 +/- 2.5 hours with treatment (P = 0.001). The observed side effects were dizziness, drowsiness, and increase in appetite; none required drug withdrawal. In two cases, headache attacks recurred after the cessation of valproate, and therapy was restarted. Headache control lasted for six months following cessation of the drug in the remainder of the subjects. CONCLUSION: Sodium valproate appears to be effective and safe in selected patients with childhood migraine.

Adolescent↗

PubMed2004

Effect of sodium valproate on esophageal motility in healthy subjects and patients with gastroesophageal reflux.

BACKGROUND: There is experimental evidence to show that upper gastrointestinal tract motility is influenced by a GABAergic mechanism. Sodium valproate acts as a GABA agonist, and has been proven to affect the human internal anal sphincter. The aim of this study was to evaluate any possible effect of sodium valproate on esophageal motility in healthy subjects and patients with gastroesophageal reflux disease (GERD). METHODS: Ten healthy volunteers (4 M, 6 F; age range: 20-61 years) and 12 patients (4 M, 8 F; age range: 25-70 years) with GERD were included in the study. Standard esophageal manometry and ambulatory 24-h esophageal pH monitoring were performed before and 5 days after oral administration of sodium valproate (400 mg four times per day). Main measurements included a) lower esophageal sphincter (LES) resting pressure and amplitude and duration of peristalsis at 5, 10 and 15 cm proximal to LES, and b) percentage of time with esophageal pH <4 and number of reflux episodes. RESULTS: Sodium valproate (i) significantly increased LES resting pressure in both groups (P<0.05), without affecting either the LES postdeglutition relaxation or any of the parameters of the esophageal peristaltic activity, (ii) significantly reduced the number of reflux episodes at the postprandial period in both healthy subjects (P=0.02) and reflux patients without hiatal hernia (P=0.04) and (iii) the time percentage with esophageal pH <4 at the postprandial period in reflux patients (P=0.01). CONCLUSIONS: Sodium valproate increases normal and reduced tonic activity of the human LES and reduces the number of reflux episodes in health and GERD. This action could be attributed to a central GABAergic mechanism.

Adult↗

PubMed1998

Lithium plus valproate as maintenance polypharmacy for patients with bipolar I disorder: a review.

Standard pharmacotherapy for the maintenance treatment of patients with bipolar I disorder consists of lithium, valproate, or carbamazepine. However, many patients fail to respond to monotherapy with any of these agents, and as a result, psychiatrists often resort to polypharmacy. Findings from some open-label trials and retrospective chart reviews suggest this approach may be useful, but in the few controlled trials that have been conducted, the results have been negative. One drug combination that warrants further study as maintenance therapy is lithium plus valproate. Each is approved by the U.S. Food and Drug Administration for treatment of acute mania, and lithium has demonstrated efficacy for maintenance treatment as well. Some preliminary evidence suggests that the combination can be effective for patients who do not respond to monotherapy, and it seems to be no more dangerous than monotherapy. Concomitant administration of lithium plus valproate does not significantly alter lithium pharmacokinetics, and statistically significant changes that arise in valproate pharmacokinetics are not clinically significant. Although it is not known whether the drugs interact to augment response, many of their effects in the central nervous system do differ, and there is no indication of pharmacodynamic interactions that oppose each other. Finally, some evidence suggests that lithium and valproate may differ with regard to clinical variables that predict response to treatment.

Antidepressive Agents↗

PubMed1997

The effect of repeated-dose activated charcoal on the pharmacokinetics of sodium valproate in healthy volunteers.

AIMS: We investigated the effects of repeated-dose charcoal administered several hours after sodium valproate on the pharmacokinetics of a single dose of the drug in healthy volunteers. METHODS: The pharmacokinetics of sodium valproate were studied in seven healthy volunteers after administration of a syrup (300 mg) on two occasions, one of which was followed by administration of repeated doses of oral charcoal starting 4 h after the drug up to 32 h (total dose 80 g). RESULTS: Valproate was rapidly absorbed with maximum concentrations 1 h after administration. The area under the plasma concentration-time curve to 48 h (AUC (0.48 h)) was 408 +/- 114.5 (s.d.) mg l-1 h in the control phase and 398 +/- 108.6 mg l-1 h after charcoal and the t1/2 elimination was 20 +/- 6.8 h in the control phase, and 22 +/- 9.2 h after charcoal (NS). CONCLUSIONS: Repeated-dose activated charcoal does not appear to enhance the rate of elimination of sodium valproate after therapeutic doses of the drug and any beneficial effect of charcoal in overdose may be to prevent absorption of valproate still present in the gut.

Adult↗

PubMed2006

Carnitine does not improve weight loss outcomes in valproate-treated bipolar patients consuming an energy-restricted, low-fat diet.

OBJECTIVES: Carnitine deficiency impairs fatty acid beta-oxidation and may partly explain weight gain in valproate-treated patients. The aim of this study was to determine whether l-carnitine supplementation improves weight loss outcomes in bipolar patients taking sodium valproate. METHODS: Sixty bipolar patients with clinically significant weight gain thought to be related to sodium valproate, who had been taking sodium valproate for >or=6 months, were randomized to l-carnitine (15 mg/kg/day) or placebo for 26 weeks, in conjunction with a moderately energy-restricted, low-fat diet. The primary outcome measure was weight change. RESULTS: l-carnitine had no effect on mean weight loss compared with placebo (-1.9 kg versus - 0.9 kg) (F = 0.778, df = 1,58, p = 0.381). The number of people in each group able to lose any weight was identical ( = 0, p = 1.0); more patients in the carnitine group (nine versus five) achieved a clinically significant weight loss (>or=5%) but this was not statistically significant (p = 1.0, Fisher's exact test). CONCLUSIONS: At the dose prescribed in this study carnitine supplementation did not improve weight loss outcomes in valproate-treated bipolar patients consuming an energy-restricted, low-fat diet.

Adult↗

PubMedDate not supplied

Bioavailability of valproate after gastric and direct intestinal administration in rats.

1. The chemical characteristics of sodium valproate suggest that it might be absorbed from stomach as well as from intestine. 2. Absorption from these sites was assessed in rats by measuring plasma drug levels after administering [14C]-valproate or unlabelled valproate separately into (a) intact animals (by gavage), (b) ligated intestine, or (c) ligated stomach. 3. After gastric administration, mean plasma valproate at 1 h, and the mean area under the 0-3 h plasma radioactivity-time curves were 53% and 64% respectively, of the corresponding values after intestinal administration. 4. It is concluded that sodium valproate is absorbed from rat stomach, although at a slower rate than from the whole intestine.

Absorption↗

PubMed1982

Brain maturation following administration of phenobarbital, phenytoin, and sodium valproate to developing rats or to their dams: effects on synthesis of brain myelin and other subcellular membrane proteins.

The anticonvulsant drugs phenobarbital, phenytoin, sodium valproate, and phenytoin-sodium valproate in combination were administered daily to (a) pregnant rats starting on the 5th day after conception, and continued through 17 days postpartum, or (b) to developing rats between 3 and 17 days of age. Each drug was prepared in water and administered at either a therapeutic dose (TD), three times therapeutic dose (3TD), or 9TD. Drug administration had no discernible effect on litter size or sex ratio in the offspring; however, phenobarbital administration to dams caused small but significant reductions in birth weights. Body weights of developing rats treated with anticonvulsant drugs either via dams of directly by intraperitoneal injection lagged behind controls. At 20-24 days of age the brain weights of the offspring of phenobarbital (9TD)-exposed dams lagged control weights by 5% whereas brain weights in the offspring of the other treated groups were indistinguishable from controls. In contrast, administration of phenobarbital directly to developing rats caused no significant brain weight deficits whereas significant deficits were observed with phenytoin (9TD), sodium valproate (9TD), and phenytoin-sodium valproate (9TD) in combination. AT 20-24 days of age the relative incorporation of radioactive leucine into purified myelin and crude nuclear proteins of drug-treated rats or the offspring of drug-treated dams was reduced by 10-20% in all cases. Dose-related differences were not observed however, and the effects of phenytoin and sodium valproate in combination approximated those of phenytoin administered alone.

Animals↗

PubMed1990

How chronically administered valproate increases chlordiazepoxide transfer through the blood-brain barrier.

Sodium valproate (VPA) is a drug widely used in the treatment of epileptics often in association with benzodiazepines. Recent animal studies have shown that the addition of valproate increases diazepam levels in the cortex and the cerebellum (Hariton et al, 1985). The aim of our study was to determine the effect of VPA on the transfer of benzodiazepines through the blood-brain barrier. They were investigated using the intracarotid injection technique in rats as described by Oldendorf (1971). Our results show that the 14C-chlordiazepoxide brain extraction is significantly higher in rats on prolonged valproate treatment than in controls. With regard to plasma protein binding effects on chlordiazepoxide transport, our data indicate that a fraction of the protein-bound chlordiazepoxide could transfer from the intracapillary space to the brain tissue space because of enhanced drug dissociation from albumin in the brain microcirculation (Kd in vitro = 74.1 microM; Kd in vivo = 793.7 microM). Two distinct mechanisms can be deduced from this study: 1) chlordiazepoxide is displaced from HSA by valproate, 2) in addition, this fatty acid could increase drug permeation through the blood brain barrier (PS/F (chlordiazepoxide) = 0.60 in controls, PS/F (chlordiazepoxide) = 0.97 in treated rats). On the contrary, the washout of the benzodiazepine from the rat brain does not seem to be modified by the addition of valproate.

Animals↗

PubMed1985

Concentration of valproate during pregnancy, in the newborn and in breast milk.

The serum-valproate level of four patients with epilepsy was followed during pregnancy. A decrease in serum level occurred late in pregnancy and was followed by a pronounced increase in the first week after delivery. The maternal serum concentration of valproate was compared to that of the umbilical cord. The level in cord blood was 145-219% higher than that in maternal blood. The concentration of valproate in breast milk was found to be 5-10% of the maternal serum concentration. The serum concentration was measured in one breastfed child. The level was 7.6% of the maternal serum concentration. All children were healthy without any signs of intoxication or malformation. Based on our experience, pregnant patients treated with valproate must be carefully controlled especially during the last month of pregnancy and in the first two weeks after delivery. The amount of valproate excreted into the breast milk was negligible and should not prevent breast feeding.

Adult↗

PubMed1988

Valproate: a new drug in migraine prophylaxis.

22 patients with severe migraine resistant to previous prophylactic treatments participated in a prospective open trial of valproate in migraine prophylaxis; 17 had common and 5 classic migraine. The attack frequency was from 4 to 16(30)/month (1 patient suffered from attacks every day). The dose of valproate was 600 mg twice a day from start of treatment, successively adjusted to a serum level about 700 mumol/l. Follow-up was from 3 to 12 months; 11 patients were free from migraine attacks, 6 had a significant reduction of the frequency; in one patient there was no effect; 4 dropped out because of lack of cooperation; 3 who had been free from migraine for 3 months, participated in a withdrawal experiment during which they all experienced relapse. After reinstitution of valproate the attacks disappeared again. How valproate acts in migraine prophylaxis is not known, but this prospective open trial demonstrates that valproate has an appreciable prophylactic effect in patients suffering from severe migraine, and calls for controlled clinical trials.

Adult↗

PubMed1985

The effects of phenytoin and sodium valproate on the periodontal health of adult epileptic patients.

The periodontal health of 30 adult epileptic patients treated with either sodium valproate or phenytoin was compared with a control group (n = 15) of otherwise healthy patients. The 3 groups were matched for age and sex. Patients on phenytoin therapy showed significantly higher plaque scores (P less than 0.05), gingival index (P less than 0.05) and pocketing (P less than 0.05) than patients in the control group. The % of gingival hyperplasia was significantly higher (P less than 0.05) in the phenytoin-treated patients than those on sodium valproate or in the control group. However, patients on phenytoin therapy had significantly less bone loss than those on sodium valproate (P less than 0.05) or in the control group (P less than 0.01). No significant differences were observed between the sodium valproate group and the control group on any of the parameters assessed. The results from this study would suggest that sodium valproate has no unwanted effects on periodontal health and may be considered a safe alternative, regarding the periodontal aspects, to phenytoin for the treatment of adult onset epilepsy.

Adolescent↗

PubMed1988

Effect of sodium valproate on midazolam distribution.

The displacement of midazolam, a new water-soluble, short acting benzodiazepine, from its plasma binding sites by sodium valproate, has been studied in man. An increase of its free fraction (ranging from 2.71 to 5.35%) in plasma from epileptic patients receiving sodium valproate was observed. A similar situation was created in rabbits by pretreatment with sodium valproate (600 mg kg-1 day-1) and posterior hypnosis with midazolam. Due to the interaction, sodium valproate-pretreated rabbits showed an increase in midazolam brain levels (130.91 micrograms g-1 in cortex vs 84.55 micrograms g-1 in control animals). Therefore, it seems likely that displacement of midazolam by sodium valproate in epileptic patients could lead to an increase of the midazolam response.

Adult↗

PubMed1980

Continuous sodium valproate or phenobarbitone in the prevention of 'simple' febrile convulsions. Comparison by a double-blind trial.

Of the 265 children aged between 6 and 18 months admitted to hospital in a 26-month period each with his first febrile convulsion, there were 64 who satisfied our criteria for a simple febrile convulsion. Of these, 43 (random) were entered into a double-blind trial of continuous sodium valproate versus phenobarbitone, and 21 were untreated. The dosage was phenobarbitone 3-6 mg/kg per day; sodium valproate 30-60 mg/kg per day. 39 completed treatment (21 phenobarbitone, 18 sodium valproate), 2 in each group being withdrawn because of unacceptable side effects. Close supervision and random serum drug estimations showed compliance to be good. After a mean treatment period of 12 months (mean age 25 months) there had been one recurrence in the sodium valproate group compared with 7 in the untreated group (P less than 0.05), and 4 recurrences in the phenobarbitone group. The difference between treatment and no treatment was significant (P less than 0.05). These results suggest that in simple febrile convulsions occurring between 6 and 18 months of age sodium valproate is as effective as phenobarbitone in preventing recurrence and that either treatment is better than none.

Clinical Trials as Topic↗

PubMed2026

Risk of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis: a living meta-analysis-version 1.

OBJECTIVE: To evaluate the association of paternal use of valproate during spermatogenesis compared with paternal use of lamotrigine or levetiracetam on offspring risk of neurodevelopmental disorders (NDDs). METHODS: Eligibility criteria: observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate vs lamotrigine or levetiracetam during spermatogenesis. INFORMATION SOURCES: the databases PubMed, Embase, Cochrane Library and Web of Science were systematically searched from January 1995 to October 2025.Synthesis of results and risk of bias: a random-effects model was used to estimate pooled HRs and 95% CI, with heterogeneity assessed using I2 statistic for any NDD.We present a meta-analysis of observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate versus lamotrigine or levetiracetam during spermatogenesis. Given the major regulatory implications of paternal valproate safety, the recent emergence of new population-based data, and the expectation of further large studies, we designed this work as a living systematic review and meta-analysis that will be updated as new eligible evidence becomes available. RESULTS: We identified three eligible studies based on data from (1) Norway and Sweden, (2) Norway and Taiwan and (3) Denmark. As two studies included Norwegian data, their results are referred to as 'Norway 1' and 'Norway 2' for clarity. In the meta-analysis of data from Denmark, Sweden and Norway 1, the pooled HR of offspring NDDs was 1.05 (95% CI 0.87 to 1.27; I2=0.0%), and in meta-analysis of data from Denmark, Sweden and Norway 2, it was 1.03 (95% CI 0.85 to 1.24; I2=0.0%).In the meta-analysis including Taiwan, Denmark, Sweden and Norway 1, the pooled HR was 1.06 (95% CI 0.88 to 1.27; I2=0.0%), and when including data from Taiwan, Denmark, Sweden and Norway 2, the pooled HR was 1.04 (95% CI 0.87 to 1.25; I2=0.0%). CONCLUSIONS: In this living meta-analysis, we found no evidence that paternal exposure to valproate compared with lamotrigine/levetiracetam during spermatogenesis was associated with increased risk of NDDs in offspring.

Humans↗

PubMed1998

Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognised ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency is an X linked disorder and the most common inherited cause of hyperammonaemia. Fluctuating concentrations of ammonia, glutamine, and other excitotoxic amino acids result in a chronic or episodically recurring encephalopathy. A heterozygous female patient first presented with protein intolerance, attacks of vomiting, and signs of mental retardation in early childhood. At the age of 16 complex partial seizures occurred which were treated with sodium valproate. Seven days after initiation of valproate therapy, she developed severe hyperammonaemic encephalopathy with deep somnolence. The maximum concentration of ammonia was 480 micromol/l. After withdrawal of valproate, three cycles of plasma dialysis, and initiation of a specific therapy for the inborn metabolic disease, ammonia concentrations fell to normal values. The patient remitted, returning to her premorbid state. Valproate can cause high concentrations of ammonia in serum in patients with normal urea cycle enzymes and may worsen a pre-existing hyperammonaemia caused by an enzymatic defect of the urea cycle. Sufficient diagnostic tests for the detection of metabolic disorders must be performed before prescribing valproate for patients with a history of encephalopathy.

Adolescent↗

PubMed2003

Acute antimanic efficacy and safety of intravenous valproate loading therapy: an open-label study.

This open-label study investigated whether acute antimanic effects and safety of intravenous valproate loading therapy is superior to oral valproate loading. Eighteen patients with DSM-IV diagnosis of either bipolar affective disorder or schizomania who met the study criteria were recruited (9 in the intravenous and 9 in the oral valproate group). Psychopathology was assessed with the scale for manic and mixed states on days 0 and 4. A checklist was used for the assessment of side effects. The results showed about 36% reduction in total mean manic scores with intravenous valproate loading; however, statistically, the degree of reduction in manic scores was comparable between the groups. A nonsignificant increase in the rate of adverse events was noted in the intravenous group. Despite its limitations, this study suggests that acute antimanic effects of both intravenous and oral valproate loading are comparable.

Administration, Oral↗