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 a 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 the baby 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 0.14 and 0.52 USD per day.[9] In the United States, it costs roughly $0.90 USD per day.[1] It is marketed under the brand names Depakote and Epilim, among others.[1][10]
Contents
1Terminology
2Medical uses
2.1Epilepsy
2.2Mental illness
2.2.1Bipolar disorder
2.2.2Schizophrenia
2.2.3Dopamine dysregulation syndrome
2.3Migraines
2.4Other
3Adverse effects
3.1Other possible side effects
3.2Pregnancy
3.3Elderly
3.4Contraindications
3.5Interactions
3.6Overdose and toxicity
4Pharmacology
4.1Pharmacodynamics
4.1.1Endocrine actions
4.2Pharmacokinetics
4.2.1Metabolism
5Chemistry
6History
7Society and culture
7.1Cost
7.2Approval status
7.3Off-label uses
7.4Formulations
7.4.1Brand names of valproic acid
7.4.2Brand names of sodium valproate
7.4.2.1Portugal
7.4.2.2United States
7.4.2.3Australia
7.4.2.4New Zealand
7.4.2.5UK
7.4.2.5.1UK only
7.4.2.6Germany, Switzerland, Norway, Finland, Sweden
7.4.2.7South Africa
7.4.2.8Malaysia
7.4.2.9Romania
7.4.2.10Canada
7.4.2.11Japan
7.4.2.12Europe
7.4.2.13Taiwan
7.4.2.14Iran
7.4.2.15Israel
7.4.2.16India, Russia and CIS countries
7.4.3Brand names of valproate semisodium
8References
9Further reading
10External links
Terminology
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.[11]
Medical uses
It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.[12]
Epilepsy
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.[12][13] It has also been successfully given intravenously to treat status epilepticus.[14][15]
Mental illness
Bipolar disorder
Valproate products are also used to treat manic or mixed episodes of bipolar disorder.[16]
Schizophrenia
A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:[17]
Summary
There is limited evidence that the augmentation of antipsychotics with valproate may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Evidence was entirely based on open randomized controlled trials. Valproate was associated with a number of adverse events among which sedation and dizziness appeared significantly more frequently than in the control groups.[17]
Outcome
Findings in words
Findings in numbers
Quality of evidence
Global outcome
Clinically significant response
When added to antipsychotic drugs valproate probably increases the chance of improvement. Data are based on moderate quality evidence.
RR 1.31 (1.16 to 1.47)
Moderate
Leaving the study early for any reason
Valproate in combination with antipsychotics may slightly reduces the chance of leaving the study early, but the difference between the two treatments is not clear. Data supporting this finding are based on moderate quality evidence.
RR 0.76 (0.47 to 1.24)
Moderate
Use of additional medication for sedation
The combination of valproate and antipsychotic drugs may increase the chance of being given additional sedating medication, but, at present it is not possible to be confident about the difference between the two treatments and data supporting this finding are very limited.
RR 3.65 (0.11 to 122.31)
Very low
Mental state
Average score (PANSS total, high = poor)
On average, people receiving the valproate combination scored lower (better) than people treated with antipsychotics in combination with placebo or antipsychotic drugs alone. There was a clear difference between the groups, but, the meaning of this in day-to-day care is unclear.
MD 5.85 lower (7.8 lower to 3.91 lower)
Moderate
Adverse events
Abnormal liver function (blood test changes)*
Adding valproate to antipsychotic drug treatment does not clearly cause liver problems. Data supporting this finding are based on moderate quality evidence.
RR 1.26 (0.72 to 2.22)
Moderate
Nausea
Adding valproate to antipsychotic drugs probably causes little or no increase to the chance of feeling sick, but the difference between the two treatments is not clear. Data supporting this finding are based on moderate quality evidence.
RR 1.22 (0.80 to 1.86)
Moderate
Missing outcomes and notes
Quality of life outcomes were not reported in the included studies. *Increase in alanine transaminase/gamma-glutamyl transpeptidase
Dopamine dysregulation syndrome
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.[18][19][20]
Migraines
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.[21]
Other
The medication has been tested in the treatment of AIDS and cancer, owing to its histone deacetylase-inhibiting effects.[22]
Adverse effects
See also: List of adverse effects of valproic acid and List of adverse effects of valproate semisodium
Most common adverse effects include:[21]
Nausea (22%)
Drowsiness (19%)
Dizziness (12%)
Vomiting (12%)
Weakness (10%)
Serious adverse effects include:[21]
Bleeding
Low blood platelets
Encephalopathy
Suicidal behavior and thoughts
Low body temperature
Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.[21]
Other possible side effects
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[23][24][25][26] Valproic acid can also cause mydriasis, a dilation of the pupils.[27] 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.[28] Weight gain is also possible.[29]
Pregnancy
Valproate causes birth defects;[30] 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.[31][32] More rarely, with several other defects, including a "valproate syndrome".[33] 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.[34] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[35]
Children of mothers taking valproate during pregnancy are at risk for lower IQs.[36][37][38] Maternal valproate use during pregnancy has been associated with a significantly higher probability of autism in the offspring.[39] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[40] The normal incidence for autism in the general population is estimated at less than one percent.[41] 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.[42][43][44]
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.[45][46]
Women who intend to become pregnant should switch to a different medication if possible, or decrease their dose of valproate.[47] 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.[21]
Elderly
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.[21]
Contraindications
Contraindications include:[48]
Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.
Known hypersensitivity to valproate or any of the ingredients used in the preparation
Urea cycle disorders
Hepatic porphyria
Hepatotoxicity[48]
Mitochondrial disease[48]
Pancreatitis[48]
Porphyria[49]
Interactions
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.[48] It may also potentiate the CNS depressant effects of alcohol.[48] 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.[48] It may also interact with:[21][48][50]
Aspirin: may increase valproate concentrations. May also interfere with valproate's metabolism.
Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
Carbapenem antibiotics: reduces valproate levels, potentially leading to seizures.
Cimetidine: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
Erythromycin: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
Ethosuximide: may increase ethosuximide concentrations and lead to toxicity.
Felbamate: may increase plasma concentrations of valproate.
Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
Oral contraceptives: may reduce plasma concentrations of valproate.
Primidone: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure.
Rifampin: increases the clearance of valproate, leading to decreased valproate concentrations
Warfarin: may increase warfarin concentration and prolong bleeding time.
Zidovudine: may increase zidovudine serum concentration and lead to toxicity.
Overdose and toxicity
Therapeutic range of valproic acid
Form
Lower limit
Upper limit
Unit
Total (including protein bound)
50[51]
125[51]
µg/mL or mg/l
350[52]
700[52]
μmol/L
Free
6[51]
22[51]
µg/mL or mg/l
35[52]
70[52]
μmol/L
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.[53]
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).[54]
In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[55][56] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.[21] Supplemental L-carnitine is indicated in patients having an acute overdose[57][58] and also prophylactically[57] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[59] than L-carnitine.
Pharmacology
Pharmacodynamics
Although the mechanism of action of valproate is not fully understood,[48] traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).[48] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[48] 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.[48]
Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism.[60] Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[61]
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.[62][63]
Endocrine actions
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.[64] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[65] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[64][65]
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.[66][67] High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.[67]
Pharmacokinetics
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Metabolism
The vast majority of valproate metabolism occurs in the liver.[68] In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as a glucuronide conjugate.[68] The other major pathway in the metabolism of valproate is mitochondrial beta-oxidation, which typically accounts for over 40% of an administered dose.[68] Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.[68] Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.[68]
Valproate is known to be metabolized by the Cytochrome P450 enzymes: CYP2A6, CYP2B6, CYP2C9, and CYP3A5.[68] It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes: UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15.[68] 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.[68]
Chemistry
Valproic acid is a branched short-chain fatty acid and a derivative of valeric acid.[5]
History
Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.[69] 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.[70] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[71] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[72]
Society and culture
Cost
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.[73][citation needed] In the United States, it costs about $0.90 USD per day.[1]
Approval status
Indications
FDA-labelled indication?[2]
TGA-labelled indication?[12]
MHRA-labelled indication?[74]
Literature support
Epilepsy
Yes
Yes
Yes
Limited (depends on the seizure type; it can help with certain kinds of seizures: drug-resistant epilepsy, partial and absence seizures, can be used against glioblastoma and other tumors both to improve survival and treat seizures, and against tonic-clonic seizures and status epilepticus).[75][76][77][78]
Bipolar mania
Yes
Yes
Yes
Limited.[79]
Bipolar depression
No
No
No
Moderate.[80]
Bipolar maintenance
No
No
No
Limited.[81]
Migraine prophylaxis
Yes
Yes (accepted)
No
Limited.
Acute migraine management
No
No
No
Only negative results.[82]
Schizophrenia
No
No
No
Weak evidence.[83]
Agitation in dementia
No
No
No
Weak evidence. Not recommended for agitation in people with dementia.[84] Increased rate of adverse effects, including a risk of serious adverse effects.[84]
Fragile X syndrome
Yes (orphan)
No
No
Limited.[85]
Familial adenomatous polyposis
Yes (orphan)
No
No
Limited.
Chronic pain & fibromyalgia
No
No
No
Limited.[86]
Alcohol hallucinosis
No
No
No
One randomised double-blind placebo-controlled trial.[87]
Intractable hiccups
No
No
No
Limited, five case reports support its efficacy, however.[88]
Non-epileptic myoclonus
No
No
No
Limited, three case reports support its efficacy, however.[89]
Cluster headaches
No
No
No
Limited, two case reports support its efficacy.[90]
West syndrome
No
No
No
A prospective clinical trial supported its efficacy in treating infantile spasms.[91]
HIV infection eradication
No
No
No
Double-blind placebo-controlled trials have been negative.[92][93][94]
Myelodysplastic syndrome
No
No
No
Several clinical trials have confirmed its efficacy as a monotherapy,[95] as an adjunct to tretinoin[95] and as an adjunct to hydralazine.[96]
Acute myeloid leukaemia
No
No
No
Two clinical trials have confirmed its efficacy in this indication as both a monotherapy and as an adjunct to tretinoin.[97][98][99]
Cervical cancer
No
No
No
One clinical trial supports its use here.[100]
Malignant melanoma
No
No
No
One phase II study has seemed to discount its efficacy.[101]
Breast cancer
No
No
No
A phase II study has supported its efficacy.[102]
Impulse control disorder
No
No
No
Limited.[103][104]
Off-label uses
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.[105][106]
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.[107]
Brand names of valproic acid
Branded products include:
Absenor (Orion Corporation Finland)
Convulex (G.L. Pharma GmbH Austria)
Depakene (Abbott Laboratories in US and Canada)
Depakine (Sanofi Aventis France)
Depakine (Sanofi Synthelabo Romania)
Depalept (Sanofi Aventis Israel)
Deprakine (Sanofi Aventis Finland)
Encorate (Sun Pharmaceuticals India)
Epival (Abbott Laboratories US and Canada)
Epilim (Sanofi Synthelabo Australia and South Africa)
Stavzor (Noven Pharmaceuticals Inc.)
Valcote (Abbott Laboratories Argentina)
Valpakine (Sanofi Aventis Brazil)
Orfiril (Desitin Arzneimittel GmbH Norway)
Brand names of sodium valproate
Portugal
Tablets – Diplexil-R by Bial.
United States
Intravenous injection – Depacon by Abbott Laboratories.
Syrup – Depakene by Abbott Laboratories. (Note Depakene capsules are valproic acid).
Depakote tablets are a mixture of sodium valproate and valproic acid.
Tablets – Eliaxim by Bial.
Australia
Epilim Crushable Tablets Sanofi
Epilim Sugar Free Liquid Sanofi
Epilim Syrup Sanofi
Epilim Tablets Sanofi
Sodium Valproate Sandoz Tablets Sanofi
Valpro Tablets Alphapharm
Valproate Winthrop Tablets Sanofi
Valprease tablets Sigma
New Zealand
Epilim by Sanofi-Aventis
All the above formulations are Pharmac-subsidised.[108]
UK
Depakote Tablets (as in USA)
Tablets – Orlept by Wockhardt and Epilim by Sanofi
Oral solution – Orlept Sugar Free by Wockhardt and Epilim by Sanofi
Syrup – Epilim by Sanofi-Aventis
Intravenous injection – Epilim Intravenous by Sanofi
Extended release tablets – Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio.
Enteric-coated tablets – Epilim EC200 by Sanofi is a 200-mg sodium valproate enteric-coated tablet.
UK only
Capsules – Episenta prolonged release by Beacon
Sachets – Episenta prolonged release by Beacon
Intravenous solution for injection – Episenta solution for injection by Beacon
Germany, Switzerland, Norway, Finland, Sweden
Tablets – Orfiril by Desitin Pharmaceuticals
Intravenous injection – Orfiril IV by Desitin Pharmaceuticals
South Africa
Syrup – Convulex by Byk Madaus
Tablets – Epilim by Sanofi-synthelabo
Malaysia
Tablets – Epilim by Sanofi-Aventis
Romania
Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH
Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets
Canada
Intravenous injection – Epival or Epiject by Abbott Laboratories.
Syrup – Depakene by Abbott Laboratories its generic formulations include Apo-Valproic and ratio-Valproic.
Japan
Tablets – Depakene by Kyowa Hakko Kirin
Extended release tablets – Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa
Syrup – Depakene by Kyowa Hakko Kogyo
Europe
In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.
Tablets –Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo
Israel
Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by Sanofi-Aventis.
India, Russia and CIS countries
Valparin Chrono by Sanofi India limited
Valprol CR by Intas Pharmaceutical (India)
Encorate Chrono by Sun Pharmaceutical (India)
Serven Chrono by Leeven APL Biotech (India)
Brand names of valproate semisodium
Brazil – Depakote by Abbott Laboratories and Torval CR by Torrent do Brasil
Canada – Epival by Abbott Laboratories
Mexico – Epival and Epival ER (extended release) by Abbott Laboratories
United Kingdom – Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics
United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics
India – Valance and Valance OD by Abbott Healthcare Pvt Ltd, Divalid ER by Linux laboratories Pvt Ltd, Valex ER by Sigmund Promedica, Dicorate by Sun Pharma
Germany – Ergenyl Chrono by Sanofi-Aventis and generics
Chile – Valcote and Valcote ER by Abbott Laboratories
France and other European countries — Depakote
Peru – Divalprax by AC Farma Laboratories
China – Diprate OD
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Further reading
Chateauvieux S, Morceau F, Dicato M, Diederich M (2010). "Molecular and therapeutic potential and toxicity of valproic acid" (PDF). J. Biomed. Biotechnol. 2010: 1–18. doi:10.1155/2010/479364. PMC 2926634. PMID 20798865.
Monti B, Polazzi E, Contestabile A (2009). "Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection" (PDF). Curr Mol Pharmacol. 2 (1): 95–109. doi:10.2174/1874467210902010095. PMID 20021450.
External links
PsychEducation: Valproate/divalproex (divalproex)
The Comparative Toxicogenomics Database:Valproic Acid
Chemical Land21: Valproic Acid
RXList.com: Depakene (Valproic Acid) (U.S.)
South African Electronic Package Inserts: Convulex
5. 成人の双極性障害：急性躁病と軽躁への薬物療法の選択 bipolar disorder in adults choosing pharmacotherapy for acute mania and hypomania
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