Valproate (VPA), and its valproic acid, sodium valproate, and valproate semisodium forms, are medications primarily used to treat epilepsy and bipolar disorder and to prevent migraine headaches.[1] They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.[1] They can be given intravenously or by mouth.[1] Long and short acting formulations of tablets exist.[1] Common side effects include nausea, vomiting, sleepiness, and dry mouth.[1] Serious side effects can include liver problems and regular monitoring of liver function tests is therefore recommended.[1] Other serious risks include pancreatitis and an increased suicide risk.[1] The drug is known to cause serious abnormalities in babies if taken during pregnancy.[1][3] Because of this it is not typically recommended in women of childbearing age who have migraines.[1] It is unclear exactly how valproate works.[1][4] Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases.[5][6] Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.[5] Valproate was first made in 1881 and came into medical use in 1962.[7] Valproate is included in the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[8] It is available as a generic medication.[1] The wholesale cost in the developing world is between US$0.14 and US$0.52 per day.[9] In the United States, it costs roughly US$0.90 per day.[1] It is marketed under the brand names Depakote and Epilim, among others.[1][10] In 2016 it was the 129th most prescribed medication in the United States with more than 5 million prescriptions.[11] Valproic acid (VPA) is an organic weak acid. The conjugate base is valproate. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as valproate semisodium.[12] It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.[13] Valproate has a broad spectrum of anticonvulsant activity, although it is primarily used as a first-line treatment for tonic-clonic seizures, absence seizures and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms.[13][14] It has also been successfully given intravenously to treat status epilepticus.[15][16] Valproate products are also used to treat manic or mixed episodes of bipolar disorder.[17] A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:[18] Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the dopamine dysregulation syndrome that arise from the treatment of Parkinson's disease with levodopa.[19][20][21] Valproate is also used to prevent migraine headaches. Because this medication can be potentially harmful to the fetus, valproate should be considered for those able to become pregnant only after the risks have been discussed.[22] The medication has been tested in the treatment of AIDS and cancer, owing to its histone deacetylase-inhibiting effects.[23] Most common adverse effects include:[22] Serious adverse effects include:[22] Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.[22] There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[24][25][26][27] Valproic acid can also cause mydriasis, a dilation of the pupils.[28] There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder.[29] Weight gain is also possible.[30] Valproate causes birth defects;[31] exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug.[32][33] More rarely, with several other defects, including a "valproate syndrome".[34] Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.[35] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[36] Children of mothers taking valproate during pregnancy are at risk for lower IQs.[37][38][39] Maternal valproate use during pregnancy has been associated with a significantly higher probability of autism in the offspring.[40] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[41] The normal incidence for autism in the general population is estimated at less than one percent.[42] A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.[43][44][45] Sodium valproate has been associated with the rare condition paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.[46][47] Women who intend to become pregnant should switch to a different medication if possible, or decrease their dose of valproate.[48] Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have even worse consequences). Studies have shown that taking folic acid can reduce the risk of congenital neural tube defects.[22] The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the EU, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.[49] Valproate in elderly people with dementia caused increased sleepiness. More people stopped the medication for this reason. Additional side effects of weight loss and decreased food intake was also associated in one half of people who become sleepy.[22] Contraindications include:[50] Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves.[50] It may also potentiate the CNS depressant effects of alcohol.[50] It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including carbamazepine, lamotrigine, phenytoin and phenobarbitone) and itself.[50] It may also interact with:[22][50][52] Excessive amounts of valproic acid can result in sleepiness, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/l during controlled therapy, but may reach 150–1500 mg/l following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.[55] In contrast to other antiepileptic drugs, at present there is little favorable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproate's weak acid property (pKa of 4.9).[56] In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[57][58] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.[22] Supplemental L-carnitine is indicated in patients having an acute overdose[59][60] and also prophylactically[59] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[61] than L-carnitine. Although the mechanism of action of valproate is not fully understood,[50] traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).[50] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[50] In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.[50] Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism.[62] Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[63] It also has histone deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.[64][65] Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels.[66] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[67] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[66][67] Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men.[68][69] High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.[69] The vast majority of valproate metabolism occurs in the liver.[70] In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as a glucuronide conjugate.[70] The other major pathway in the metabolism of valproate is mitochondrial beta-oxidation, which typically accounts for over 40% of an administered dose.[70] Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.[70] Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.[70] Valproate is known to be metabolized by the Cytochrome P450 enzymes: CYP2A6, CYP2B6, CYP2C9, and CYP3A5.[70] It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes: UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.[70] Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include: 2-ene-valproic acid, 3Z-ene-valproic acid, 3E-ene-valproic acid, 4-ene-valproic acid, valproic acid β-O-glucuronide, 3-oxovalproic acid, 3-hydroxyvalproic acid, 4-hydroxyvalproic acid, 5-hydroxyvalproic acid, and valproyl-CoA, among others.[70] Valproic acid is a branched short-chain fatty acid and a derivative of valeric acid.[5] Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.[71] Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats.[72] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[73] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[74] It is available as a generic medication.[1] The wholesale cost in the developing world is between $0.14 and $0.52 USD per day.[9] In the European Union, end-user costs are less than 0.60 EUR for an average daily dose in Germany.[75][citation needed] In the United States, it costs about $0.90 USD per day.[1] In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.[107][108] Valproate exists in two main molecular variants: sodium valproate and valproic acid without sodium (often implied by simply valproate). A mixture between these two is termed semisodium valproate. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.[109] Branded products include: All the above formulations are Pharmac-subsidised.[110] In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above. Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by Sanofi-Aventis.