A review of valproate in psychiatric practice

Greater Manchester West Mental Health, NHS Foundation Trust, Cromwell House, Cromwell Road, Eccles, Salford, Manchester M300GT, UK.
Expert Opinion on Drug Metabolism & Toxicology (Impact Factor: 2.83). 06/2009; 5(5):539-51. DOI: 10.1517/17425250902911455
Source: PubMed


Valproate (2-propylpentanoate) is available as valproic acid, sodium valproate and semisodium valproate. It has actions on dopamine, GABA and glutamate neurotransmission and intracellular signaling. Its main psychiatric use is to treat bipolar disorder. It has been used in other psychiatric disorders, including schizophrenia and borderline personality disorder, but data are insufficient to recommend this. In acute mania, valproate monotherapy has similar efficacy to antipsychotic drugs and lithium whereas the combination of valproate and an antipsychotic is more effective than either drug alone. In maintenance treatment of bipolar disorder, valproate monotherapy has comparable efficacy to olanzapine although placebo-controlled evidence is limited. Maintenance treatment with valproate and quetiapine or olanzapine is more efficacious than valproate alone when an acute episode responds to the combination. Common adverse effects of valproate include weight gain, gastrointestinal symptoms, sedation, tremor and mild elevation of hepatic enzymes. Serious hepatic toxicity is rare in adults. Many adverse effects are dose related and resolve with dose reduction. Valproate is teratogenic and specifically associated with neural tube defect. Preliminary evidence has linked in utero exposure to decreased verbal intelligence in the offspring. These effects, plus a probable increased risk of polycystic ovary syndrome, limit valproate's use in women of childbearing potential.

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    • "Valproic acid (VPA) is one of the most frequently prescribed antiepileptic drugs (Löscher, 2002) and is also increasingly used for other indications, such as bipolar psychiatric disorder (Bowden and Singh, 2005), schizophrenia, borderline personality disorder (Haddad et al., 2009), and migraine prophylaxis (Mathew et al., 1995). Antiepileptic therapy often takes years and may even last the entire lifetime of a patient. "
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    ABSTRACT: Weight gain is the most frequent adverse effect of valproic acid (VPA) treatment, resulting in poor compliance and many endocrine disturbances. Similarities in the weight change of monozygotic twins receiving VPA strongly suggestes that genetic factors are involved in this effect. However, few studies have been conducted to identify the relevant genetic polymorphisms. Additionally, the causal relationship between the VPA concentration and weight gain has been controversial. Thus, we investigated the effects of SNPs in several appetite stimulation and energy homeostasis genes and the steady state plasma concentrations (Css) of VPA on the occurrence of weight gain in patients. A total of 212 epilepsy patients receiving VPA were enrolled. Nineteen SNPs in 11 genes were detected using Sequenom MassArray iPlex platform, and VPA Css was determined by HPLC. After six months of treatment, 20.28% of patients were found to gain a significant amount of weight (weight gained ≥ 7%). Three SNPs in leptin receptor (LEPR), ankyrin repeat kinase domain containing 1 (ANKK1) and α catalytic subunit of AMPK (PRKAA2) showed significant associations with VPA-induced weight gain (p<0.001, p=0.017 and p=0.020, respectively). After Bonferroni correction for multiple tests, the genotypic association of LEPR rs1137101, the allelic association of LEPR rs1137101 and ANKK1 rs1800497 with weight gain remained significant. However, the VPA Css in patents who gained weight were not significantly different from those who did not gain weight (p=0.121). LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    Full-text · Article · Mar 2015 · The International Journal of Neuropsychopharmacology
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    • "VPA also blocks the voltage-gated sodium channels and T-type calcium channels [8]. These mechanisms make VPA a broad spectrum anticonvulsant drug and it is also prescribed for the treatment of bipolar disorder, schizoaffective disorder, social phobias, neuropathic pain, and for the prophylaxis and treatment of migraine headaches [9] [10]. It is highly protein bound to albumin (87–95%) and extensively metabolized in liver. "
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    ABSTRACT: Valproic acid, a branched short-chain fatty acid, has numerous action mechanisms which turn it into a broad spectrum anticonvulsant drug and make its use possible in some other pathologies such as bipolar disorder. It is extensively metabolized in liver, representing β -oxidation in the mitochondria one of its main metabolic route (40%). Carnitine is responsible for its entry into the mitochondria as any other fatty acid. Long-term high-dose VPA therapy or acute VPA overdose induces carnitine depletion, resulting in high levels of ammonia in blood. As a high correlation between salivary valproic acid levels and plasma ultrafiltrate levels was found in humans, saliva becomes a promising monitoring fluid in order to study valproic acid pharmacokinetics and its toxic effect. Extended-release (twice daily) formulations of valproic acid or carnitine supplementation are the proposed two therapeutic strategies in order to reverse hyperammonemia.
    Full-text · Article · Apr 2014 · BioMed Research International
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    • "Valproic acid (VPA) has traditionally been prescribed for epilepsy, but is increasingly used for psychiatric condition, such as bipolar disease by its modulation on GABA neurotransmission [7]. Furthermore, it has been also shown to be associated with an increased prevalence of autism. "

    Full-text · Chapter · Mar 2013
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