# Valproate

Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.
Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth. Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended. Other serious risks include pancreatitis and an increased suicide risk. Valproate is known to cause serious abnormalities or birth defects in the unborn child if taken during pregnancy, and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition and the person is also prescribed a contraceptive. Reproductive warnings have also been issued for men using the drug. The United States Food and Drug Administration has indicated a black box warning given the frequency and severity of the side effects and teratogenicity. Additionally, there is also a black box warning due to risk of hepatotoxicity and pancreatitis. As of 2022 the drug was still prescribed in the UK to potentially pregnant women, but use declined by 51% from 2018–19 to 2020–21. Vaproate has been in use in Japan for the prophylaxis of migraine since 2011. It is approved as an antimaniac and anti seizure in Japan as well. In UK, vaproate is approved for bipolar mania and epilepsy, and both valproate and divalproex are approved, although divalproex sodium is known as valproate semisodium.
Valproate's precise mechanism of action is unclear. Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, inhibiting histone deacetylases, and increasing LEF1. Valproic acid is a branched short-chain fatty acid (SCFA), a derivative of valeric acid.
Valproate was originally synthesized in 1881 and came into medical use in 1962. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2022, it was the 174th most commonly prescribed medication in the United States, with more than 2 million prescriptions.

## Medical uses

Valproate or valproic acid is used primarily to treat epilepsy and bipolar disorder and to prevent migraine headaches.

### 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. It has also been successfully given intravenously to treat status epilepticus.
In the US, valproic acid is also prescribed as an anti-epileptic drug indicated for the treatment of manic episodes associated with bipolar disorder; monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in people with multiple seizure types that include absence seizures.

### Mental illness

Valproate products are used to treat manic or mixed episodes of bipolar disorder.
A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:
There is limited evidence that adding valproate to antipsychotics may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Valproate was associated with a number of adverse events among which sedation and dizziness appeared more frequently than in the control groups. :
| 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 reduce 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 | | |

### Other neurological indications

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.
Valproate is not commonly used to prevent or treat migraine headaches, but it may be prescribed if other medications are not effective.

### Other

The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects. It has cardioprotective, kidney protective, antiinflammatory, and antimicrobial effects.

## Contraindications

Contraindications include:
* Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.
* Pregnancy 11% risk of birth defects and 30-40% risk of neuro-developmental disabilities which can be permanent
* Known hypersensitivity to valproate or any of the ingredients used in the preparation
* Urea cycle disorders
* Hepatic porphyria
* Hepatotoxicity
* Mitochondrial disease
* Pancreatitis
* Porphyria

## Adverse effects

Most common adverse effects include:
* Nausea (22%)
* Drowsiness (19%)
* Dizziness (12%)
* Vomiting (12%)
* Weakness (10%)
Serious adverse effects include:
* 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.
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height. Valproic acid can also cause mydriasis, a dilation of the pupils. 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. Weight gain is also possible.

### Elderly

Valproate may cause increased somnolence in the elderly. In a trial of valproate in elderly patients with dementia, a significantly higher portion of valproate patients had somnolence compared to placebo. In approximately one-half of such patients, there was associated reduced nutritional intake and weight loss.

## Overdose and toxicity

Therapeutic range of valproic acid :
| Form | Lower limit | Upper limit | Unit |
| Total (including protein bound) | 50 | 125 | μg/mL or mg/L |
| Total (including protein bound) | 350 | 700 | μmol/L |
| Free | 6 | 22 | μg/mL or mg/L |
| Free | 35 | 70 | μmol/L |
Excessive amounts of valproic acid can result in somnolence, 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. 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).
In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body. Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored. Supplemental L-carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly than L-carnitine.

## 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. It may also potentiate the CNS depressant effects of alcohol. 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. It may also interact with:
* 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: reduce 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: valproate 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.
* Rifampicin: increases the clearance of valproate, leading to decreased valproate concentrations.
* Warfarin: valproate may increase free warfarin concentration and prolong bleeding time.
* Zidovudine: valproate may increase zidovudine serum concentration and lead to toxicity.

## Pharmacology
### Pharmacodynamics

Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of the inhibitory synaptic neurotransmitter gamma-aminobutyric acid (GABA). The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate. In animals, sodium valproate raises cerebral and cerebellar levels of 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. Prevention of neurotransmitter-induced hyperexcitability of nerve cells via Kv7.2 channel and AKAP5 may also contribute to its mechanism. Valproate has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.
Valproate is a histone deacetylase inhibitor. By inhibition of histone deacetylase, it promotes more transcriptionally active chromatin structures, that is it exerts an epigenetic effect. This has been proven in mice: Valproic acid induced histone hyperacetylation had brain function effects on the next generation of mice through changes in sperm DNA methylation. Intermediate molecules include VEGF, BDNF, and GDNF.

#### 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. In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations. These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.
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. High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.

### Pharmacokinetics

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut. When in the bloodstream, 80–90% of the substance are bound to plasma proteins, mainly albumin. Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patient's age, additional use of other drugs such as aspirin, as well as liver and kidney impairment. Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.
The vast majority of valproate metabolism occurs in the liver. Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6, CYP2B6, CYP2C9, and CYP3A5. It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15. Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):
* via glucuronidation (30–50%): valproic acid β-O-glucuronide
* via beta oxidation (>40%): 2E-ene-valproic acid, 2Z-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid
* via omega oxidation: 5-hydroxyvalproic acid, 2-propyl-glutaric acid
* some others: 3E-ene-valproic acid, 3Z-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acid
All in all, over 20 metabolites are known.
In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate. The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose. Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine. Only a small amount is excreted via the faeces. Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.

## Chemistry

Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.

## History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian. 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. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine prophylaxis and bipolar disorder.

## Society and culture

Valproate is available as a generic medication.

### Approval status

| Indications | FDA-labelled indication? | TGA-labelled indication? | MHRA-labelled indication? | 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). |
| Bipolar mania | Yes | Yes | Yes | Limited. |
| Bipolar depression | No | No | No | Moderate. |
| Bipolar maintenance | No | No | No | Limited. |
| Migraine prophylaxis | Yes | Yes (accepted) | No | Limited. |
| Acute migraine management | No | No | No | Only negative results. |
| Schizophrenia | No | No | No | Weak evidence. |
| Agitation in dementia | No | No | No | Weak evidence. Not recommended for agitation in people with dementia. Increased rate of adverse effects, including a risk of serious adverse effects. |
| Fragile X syndrome | Yes (orphan) | No | No | Limited. |
| Familial adenomatous polyposis | Yes (orphan) | No | No | Limited. |
| Chronic pain & fibromyalgia | No | No | No | Limited. |
| Alcohol hallucinosis | No | No | No | One randomised double-blind placebo-controlled trial. |
| Intractable hiccups | No | No | No | Limited, five case reports support its efficacy, however. |
| Non-epileptic myoclonus | No | No | No | Limited, three case reports support its efficacy, however. |
| Cluster headaches | No | No | No | Limited, two case reports support its efficacy. |
| West syndrome | No | No | No | A prospective clinical trial supported its efficacy in treating infantile spasms. |
| HIV infection eradication | No | No | No | Double-blind placebo-controlled trials have been negative. |
| Myelodysplastic syndrome | No | No | No | Several clinical trials have confirmed its efficacy as a monotherapy, as an adjunct to tretinoin and as an adjunct to hydralazine. |
| 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. |
| Cervical cancer | No | No | No | One clinical trial supports its use here. |
| Malignant melanoma | No | No | No | One phase II study has seemed to discount its efficacy. |
| Breast cancer | No | No | No | A phase II study has supported its efficacy. |
| Impulse control disorder | No | No | No | Limited. |

### Off-label uses

In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.
Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.

### Formulations

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 mass of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself. In USA, Europe and many countrie the three variantes of vaproate are sold: vaproic acid, sodium valproate and valproate semisodium also known as divalproex sodium, the latter is believed to have fewer gastrointestinal side-effects. Divalproex sodium tablets are a formulation comprising valproate sodium and valproic acid in a 1:1 molar relationship

### Terminology

Valproate is a negative ion. The conjugate acid of valproate is valproic acid (VPA). Valproic acid is fully ionized into valproate at the physiologic pH of the human body, and valproate is the active form of the drug. Sodium valproate is the sodium salt of valproic acid. Divalproex sodium is a coordination complex composed of equal parts of valproic acid and sodium valproate.

#### 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)
* Depakin (Sanofi S.R.L. Italy)
* Depakine (Sanofi Aventis France)
* Depakine (Sanofi Synthelabo Romania)
* Depalept (Sanofi Aventis Israel)
* Deprakine (Sanofi Aventis Finland)
* Encorate (Sun Pharmaceuticals India)
* 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.

##### 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 (200 ENTERIC COATED) by Sanofi-Aventis
* Controlled release tablets – Epilim Chrono (500 CONTROLLED RELEASE) 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.

##### Taiwan

* Tablets (white round tablet) – Depakine (Chinese: 帝拔癲; pinyin: di-ba-dian) by Sanofi Winthrop Industrie (France)

##### Iran

* Tablets – Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo
* Slow release tablets – Depakine Chrono by Sanofi Winthrop Industrie (France)

##### 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
* Valprol CR by Intas Pharmaceutical (India)
* Encorate Chrono by Sun Pharmaceutical (India)
* Serven Chrono by Leeven APL Biotech (India)

##### Uruguay

* Tablets – DI DPA by Megalabs

#### 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

## Research

A 2023 systematic review of the literature identified only one study in which valproate was evaluated in the treatment of seizures in infants aged 1 to 36 months. In a randomized control trial, valproate alone was found to show poorer outcomes for infants than valproate plus levetiracetam in terms of reduction of seizures, freedom from seizures, daily living ability, quality of life, and cognitive abilities.