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 &amp Toxicology (Impact Factor: 2.93). 06/2009; 5(5):539-51. DOI: 10.1517/17425250902911455
Source: PubMed

ABSTRACT 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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    • "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.
    BioMed Research International 04/2014; 2014:217269. DOI:10.1155/2014/217269 · 2.71 Impact Factor
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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. "
    Recent Advances in Autism Spectrum Disorders - Volume I, Edited by Michael Fitzgerald, 03/2013: chapter Valproic Acid in Autism Spectrum Disorder: From an Environmental Risk Factor to a Reliable Animal Model: pages 143-163; INTECH.
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    • "Valproic acid (VPA) has been routinely used to treat bipolar disorder and epilepsy for decades (Koch-Weser and Browne, 1980). It is well known that VPA exerts multiple pharmacological effects, including its ability to enhance g-aminobutyric acid (GABA) neurotransmission, while reducing glutamate and dopamine neurotransmission in the brain (Haddad et al, 2009). Recent studies have shown that VPA shows neuroprotective effects in cellular and animal models of neurodegenerative diseases, including stroke (Chuang et al, 2009). "
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    ABSTRACT: Mesenchymal stem cells (MSCs) show high potential for the therapy of several human diseases; however, the effectiveness of MSC transplantation has been hampered by the relatively poor migratory capacity of these cells toward disease target sites. This study investigated whether treatment of MSCs with two mood stabilizers-valproic acid (VPA) and lithium-would enhance cell migration and, if so, to explore the mechanisms underlying their effects. Short-term (3 h) exposure of MSCs to a relatively high concentration (2.5 mM) of VPA markedly increased the transcript and protein levels of CXC chemokine receptor 4 (CXCR4). VPA-induced CXCR4 expression required inhibition of histone deacetylases (HDACs), including the HDAC1 isoform, and involved histone hyperacetylation at the promoter region of the CXCR4 gene. Notably, VPA treatment enhanced stromal cell-derived factor-1α (SDF-1α)-mediated MSC migration, which was completely blocked by AMD3100, a CXCR4 antagonist. Treatment of MSCs with lithium (2.5 mM for 1 day) selectively elevated the transcript and protein levels of matrix metalloproteinase-9 (MMP-9) and its enzymatic activity; these effects were mimicked by inhibition or gene silencing of glycogen synthase kinase-3β (GSK-3β). Lithium treatment also potentiated SDF-1α-dependent MSC migration across the extracellular matrix, which was suppressed by two MMP-9 inhibitors, doxycycline and GM6001. Combining VPA and lithium treatment further increased MSC migration. Overall, VPA and lithium stimulated MSC migration through distinct targets and mediators: HDAC-CXCR4 and GSK-3β-MMP-9, respectively.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2010; 35(11):2225-37. DOI:10.1038/npp.2010.97 · 7.83 Impact Factor
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