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 in fetuses if taken during pregnancy, and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition. 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.
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.
Findings in words
Findings in numbers
Quality of evidence
Clinically significant response
When added to antipsychotic drugs valproate probably increases the chance of improvement. Data are based on moderate quality evidence.
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.
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.
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.
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.
It is worthy of mentioning that some adverse effects related to valproic acid may be dose-dependent such as pancytopenia.
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.
Valproate causes birth defects; 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. More rarely, with several other defects, including a "valproate syndrome".[sentence fragment] 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. While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.
Children of mothers taking valproate during pregnancy are at risk for lower IQs. Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%. A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%. The normal incidence for autism in the general population is estimated at 1 in 44 (2.3%). 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.
Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.
Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate. 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 worse outcomes for the fetus than exposure to valproate). Studies have shown that taking folic acid supplements can reduce the risk of congenital neural tube defects. The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union and the United States, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.
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.
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).
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.
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 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 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.
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.
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.
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.
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.
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).
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.
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.
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