Disclaimer: By writing this post, we are not recommending this drug. Some of our readers who were already taking the drug requested that we commission a post on it, and we are simply providing information that is available in the clinical and scientific literature. Please discuss your medications with your doctor.
What is Depakote (Valproic Acid)?
Depakote is the brand name for valproic acid. The discovery of the effects of valproic acid was a completely serendipitous one .
Valproic acid is a fatty acid, originally created by American chemists in 1881 and used as an industrial and pharmaceutical solvent. It was used as a solvent in the lab until 1963, when a French scientist was testing the activity of the herbal medication (khellin), using valproic acid as a solvent. To his surprise, he found that valproic acid alone – the seemingly inactive solvent or “vehicle” – had anti-seizure effects .
Once it was discovered that valproic acid reduces seizures, scientists started testing it for other effects. From that point on it emerged not only as a treatment for seizures, but also for depression, mania, and migraines. It remains in use as a medication to this day .
But many others exist, depending on the manufacturer and the country. To avoid the confusion, we will refer to Depakote and various brand names as valproic acid in this article (unless if a claim is specific to Depakote).
Mechanism of Action
Valproic acid is a potent anti-seizure/anti-convulsant drug that is also effective for reducing migraine headaches as well as a treatment for a variety of psychological disorders.
- Increasing levels of GABA, an inhibitory neurotransmitter that reduces overstimulation in the brain.
- Reducing excessive communication between neurons (by blocking voltage-gated sodium and calcium ion channels in the brain), which is a common trigger for seizures.
- Protecting the brain and the growth of new brain cells by blocking enzymes in the body that alter the activity of genes (histone deacetylases) .
- These enzymes can also increase the spreading of cancer, and valproic acid may help combat cancer by blocking their effects .
Valproic Acid vs. Divalproex
Depakote is available in several different generic formulations, which can lead to some confusion. The most common forms seen in the U.S. are valproic acid and divalproex .
Valproic acid is the active form of the drug .
Divalproex contains both valproic acid and sodium valproate (the salt form of valproic acid). Once in the body, all of divalproex is converted to valproic acid .
Despite this difference, the two forms generally have the same effectiveness.
For example, one study of 28 mental health patients found no difference in clinical response or side effects between the two .
A different study of 4624 bipolar patients also found no significant difference between valproic acid and divalproex .
Uses of Depakote (Valproic Acid)
1) Reduces Seizures
The earliest and most prominent medical use of valproic acid was to treat seizures, and it is still used for this purpose today.
A study (double-blind randomized controlled trial) in 453 epileptic children found that valproic acid was similar in effectiveness to ethosuximide (the current standard anti-epileptic medication) for improving absence seizures. Children with absence seizures can blank out and lose consciousness for brief periods of time .
It is also used as part of the established therapy for chronic seizures (status epilepticus) in children .
A cohort study of 3,622 patients found that valproic acid provided superior control of epileptic seizures caused by strokes, leading to fewer hospitalizations and emergency department visits .
A pilot study of 54 patients with juvenile epilepsy showed that low doses of valproic acid alone were highly effective in reducing the overall number and frequency (incidence) of seizures .
In a double-blind randomized controlled trial of 72 patients with strokes due to a blood vessel rupture in the brain (hemorrhagic stroke), valproic acid both reduced the occurrence of seizures in the early period following stroke and improved mental functioning in these patients .
2) Can Prevent Migraines
This benefit was confirmed in larger clinical trials and valproic acid officially approved by the FDA for preventing migraines .
3) Reduces Anxiety
A study (single-blind randomized controlled trial) of 17 patients with social anxiety disorder found that valproic acid significantly reduced symptoms in approximately half of the patients .
4) May Help Treat Depression
A small study (open-label) of 33 patients with major depressive disorder showed that valproic acid alone could reduce depression symptoms in up to 86% of patients who completed the study after 8 weeks .
In a 7-month study of 14 patients with the treatment-resistant major depressive disorder, valproic acid decreased symptoms and helped prevent relapse when added to therapy .
5) Can Help Treat Bipolar Disorder
Valproic acid has been used to treat bipolar disorder for over 30 years.
An additional meta-analysis found that taking valproic acid regularly was beneficial for keeping bipolar symptoms in remission .
Another meta-analysis reported that valproic acid can reduce symptoms of mania in bipolar patients, although it is not necessarily the best drug for treating these (an antipsychotic drug called haloperidol was the most effective for reducing mania in these patients) .
6) Reduces Schizophrenia Symptoms
According to a meta-analysis, valproic acid reduces the symptoms of schizophrenia when added to common treatment (antipsychotics such as haloperidol). The effect was strongest when given short-term (four weeks) .
7) Improves Schizoaffective Disorder
Schizoaffective disorder is closely related to schizophrenia but includes depression and mania symptoms in addition to the common symptoms of schizophrenia .
In a chart review of 63 mixed patients (with the schizoaffective or bipolar disorder), 75% responded to treatment with valproic acid after failing therapy with more common medications (such as carbamazepine and lithium) .
In a retrospective study of 20 schizoaffective patients, 75% of patients improved on valproic acid alone, without experiencing significant side effects .
Finally, in a study of 15 patients with schizoaffective disorders, valproic acid reduced the length and intensity of symptoms over 2 to 4 years of treatment, along with fewer and shorter hospital stays .
8) May Help Fight Cancer
A common problem in cancer treatment is that tumor cells can sometimes develop resistance to anti-cancer drugs, reducing their effects over time. However, valproic acid may re-sensitize some tumors to anti-cancer drugs they were previously resistant to.
This effect has been found in several types of cancer, including :
- Advanced cervical cancer
- Metastatic breast cancer
- Non-small cell lung cancer
- Mesothelioma (the type of cancer most commonly caused by exposure to asbestos)
Valproic acid is considered an “epigenetic agent”, since it can alter the activity of genes, including those that contribute to cancer spreading. It blocks one of the key enzymes involved in epigenetic changes: histone deacetylases. The other form of epigenetic changes is methylation .
In a retrospective study of US military veterans with bipolar disorder, PTSD, migraines, or seizures, those who had taken valproic acid in the past had significantly lower rates of developing smoking-related head and neck cancers. Valproic acid did not have an effect on other types of cancer (such as lung, colon, and prostate cancers) .
9) May Improve HIV-Related Dementia
Although the HIV virus is primarily known for its effects on the immune system, HIV infections can also cause cognitive impairments as the disease progresses into AIDS.
Valproic acid does not prevent an HIV infection or reduce the virus’ ability to spread within the body .
10) May Reduce Hair Loss
Although hair loss can often be a side effect of taking valproic acid for a long time, a study of 40 patients with male pattern baldness (androgenic alopecia) found that valproic acid promoted hair growth when sprayed onto the scalp .
11) May Protect the Brain
Although these effects have not yet been studied in humans, a number of animal and cell studies have found that valproic acid may help protect the nervous system from damage, including:
- Lou Gehrig’s disease (amyotrophic lateral sclerosis, or ALS): valproic acid prolonged the lifespan of mice with ALS .
- Parkinson’s disease (PD): in a study on brain cells, valproic acid may help prevent neurons from dying, crucial for PD .
- Alzheimer’s disease (AD): valproic acid may help reverse the course of an AD by causing brain stem cells to develop into new neurons, according to several animal and cell studies [50, 51].
- Multiple sclerosis (MS): valproic acid may protect against the loss of neurons in the retina of the eye that leads to a loss of vision (optic neuritis), a common symptom of MS, according to several studies in cells and mice [52, 53].
- Stroke: valproic acid protected against the loss of cognitive function due to loss of brain cells following a stroke, according to a study in rats .
Depakote (Valproic Acid) Side Effects
Valproic acid can potentially cause a number of short- and long-term side effects.
- Hair loss (alopecia)
- Shakiness (motor tremors)
- Easy bruising
- Liver damage
- Weight gain/obesity
- Hair loss
- Polycystic ovarian syndrome
- Metabolic syndrome
- Parkinson-like syndrome
- Excessive need for sleep (increased sleep duration)
- Fanconi syndrome (a disorder that impairs the ability of the kidneys to absorb essential nutrients)
Because valproic acid is used to treat seizures, migraines, bipolar disorder and depression, the most common concern for patients who stop taking it are that the symptoms of these disorders will come back (remission) .
Apart from this, valproic acid does not often cause withdrawal when people stop taking it. However, withdrawal can happen if treatment is stopped all at once without gradually reducing (“tapering off”) the dose over time .
A case report showed two children who stopped valproic acid experienced hallucinations, and that these went away when they started taking the drug again .
When valproic acid is ingested, it binds to proteins in the bloodstream, making it difficult for the body to clear it out. This makes it easy for valproic acid to build up in the blood, which can lead to accidental overdoses. It is important to keep an eye on the level of valproic acid in the bloodstream, especially for people who take it on a regular or long-term basis .
- Slowing or stopping of breathing (respiratory depression)
- Low blood pressure
- Rapid heart rate (tachycardia)
- Drowsiness / fatigue
- Nausea and vomiting
- Small (constricted) pupils
- Muscle tension
- Brain swelling (cerebral edema)
Naloxone, a medication used to treat opioid overdoses, can sometimes be used to counteract cases of valproic acid overdose, especially when there is breathing-related symptoms present (such as respiratory depression) .
Valproic acid is known to cause birth defects and should be avoided during pregnancy whenever possible .
Some studies suggest that using valproic acid is associated with a 10-20 times greater risk of neural malformations in developing children, such as spina bifida and myelocele (protrusions of the spinal cord due to incomplete formation of the spine) [81, 82].
Valproic acid is broken down in the liver, so those with liver disease should be extra careful about their valproic acid levels. A damaged liver is less effective at breaking down drugs, which means that people with liver disease have an increased risk of overdosing on valproic acid, even at doses that would be safe for other people .
Urea Cycle Disorders
Urea cycle disorders are rare genetic diseases that cause the body to break down proteins incorrectly. This leads to a buildup of ammonia in the blood, which can cause the brain to swell, which can result in symptoms ranging from nausea and hallucinations to coma. Valproic acid has been known to interfere with the urea cycle, which can make urea cycle disorders even more dangerous [87, 88].
Mitochondria are the energy-producing machines of every cell in your body. Genetic defects can prevent them from functioning normally, interfering with a wide variety of cellular functions. This causes a range of problems including deafness, blindness, and seizures .
Allergies and Drug Hypersensitivities
People with allergies or hypersensitivities to certain drugs should be cautious when taking Depakote (valproic acid), as many case reports have shown that it can trigger other allergies and drug sensitivities (“cross-reactions”).
- Tricyclic antidepressants
- Lamotrigine (a mood stabilizer)
- Olanzapine (an antipsychotic drug)
Valproic acid can also trigger negative reactions if you have certain health conditions, such as :
- Brucellosis infection
- c-ANCA positivity (a marker of some autoimmune diseases)
- Reduced immunity
- Reduced blood clotting
- Inflammation of blood vessels
- Skin inflammation (dermatitis)
- Throat inflammation
- Swollen lymph nodes
- Red eyes
- Psoriasis-like rashes
- Brain inflammation (reversible encephalopathy)
- Severe liver failure
- Multiorgan dysfunction syndrome (a whole-body inflammatory reaction that damages internal organs)
- Steven-Johnson syndrome (a serious skin and mucous membrane disorder that causes widespread pain, rashes, and fever, and which requires hospitalization)
Valproic acid and alcohol are both broken down by the liver. Taking them together may overload the liver, causing liver damage and resulting in the drug building up to dangerous levels in the body .
Combining these two drugs may also cause :
- Loss of appetite
- Joint pain
- Muscle pain
It has been known for decades that valproic acid can be dangerous when combined with aspirin, which commonly results in dangerously elevated levels of valproic acid in the blood. Early case reports show patients who had an increase in active valproic acid levels, and one developed symptoms of valproic acid toxicity – all of which resolved after the aspirin was stopped .
Valproic acid can interact with antibiotics, especially ones from the “carbapenem” family, such as meropenem. Taking these drugs together can lead to rapid decreases in valproic acid levels. Because valproic acid normally reduces the activity of neurons in the brain, a sudden drop in valproic acid levels can cause the brain to suddenly become overactive, which can lead to seizures (even in people who have not previously had seizures before) [106, 107, 108].
Valproic acid has known interactions with at least 3 other common anti-seizure drugs: lamotrigine, levetiracetam, and phenytoin.
Valproic acid and lamotrigine are both broken down by similar pathways in the liver. A study (open-label, randomized crossover) of 18 male subjects found that taking these medications together decreased the clearance of lamotrigine (increased the half-life of the drug). This led to increased levels of active lamotrigine in the body, which could increase the risk of toxicity or overdose .
A study of 52 epileptic patients found that taking valproic acid and levetiracetam together led to an increase in the total amount of active (unbound) valproic acid in the body, increasing the likelihood of valproic acid toxicity and overdose .
A case study in a 12-year-old child with epilepsy found that valproic acid can release phenytoin from the proteins that bind to it in order to inactivate it during transport through the body. This can lead to dangerous levels of activated phenytoin in the body, leading to phenytoin toxicity .
This release of phenytoin by valproic acid results in an unpredictable blood level of both drugs .
A retrospective study of 57 depression patients found that taking valproic acid may lead to abnormally elevated levels of doxepin and venlafaxine, thereby leading to potentially dangerous toxic effects .
Similarly, a study with 18 male patients (randomized crossover) found that valproic acid can decrease the rate at which the body breaks down lamotrigine, which could lead to dangerously elevated active levels of this drug .
Finally, a retrospective study of 66 depression patients found that taking valproic acid with amitriptyline could also lead to abnormally high levels of active amitriptyline in the bloodstream .
Two case studies report an adverse interaction between valproic acid and quetiapine, leading to high levels of ammonia in the blood as well as symptoms of delirium, which went away after these patients stopped taking quetiapine [115, 116].
In another case report, a patient taking valproic acid developed inflammation of the brain after risperidone was added to their treatment .
Two small studies (a double-blind randomized controlled trial and a randomized, placebo-controlled crossover) in mania patients and healthy controls showed that combining valproic acid with lithium (a drug commonly used to treat the manic phases of bipolar disorder) was generally safe, and is not likely to lead to any major adverse side effects [118, 119].
Depakote (Valproic Acid) Dosage
Depakote is available in a variety of forms, including tablets, extended-release tablets, and delayed-release capsules.
Normal-release tablets come in 125 mg, 250 mg, and 500 mg strengths.
Dosing for Depakote is individualized and requires titration – starting low and slowly increasing the dose until an optimal response or blood level is achieved. Doses can also be limited by side effects.
Initial doses, according to the FDA, are :
- Mania: Start at 750 mg daily (in divided doses), increasing as fast as possible
- Complex Partial Seizures: Start at 10 to 15 mg/kg daily, increasing at 1 week intervals
- Absence Seizures: Start at 15 mg/kg daily, increasing at 1 week intervals
- Migraine: Start at 250 mg twice a day, can be increased to a max of 1000 mg daily.
However, dosing can vary depending on the dosage form, drug interactions, and age.
Limitations and Caveats
Valproic acid is a relatively old drug with a lot of human studies and remains a popular treatment choice for many different health conditions. However, research into some of the newer uses – such as its neuroprotective properties – are mostly based on cell studies and animal models, and may not necessarily translate to human uses without further research.
Additionally, valproic acid was used as an add-on treatment for many mental health disorders, but not tested as a standalone treatment.
Genetics can play a significant role in how different people respond to valproic acid.
The 116C/G polymorphism (a term for a common type of genetic mutation) of the XBP1 gene plays a role in the development of bipolar disorder. People with the “G” variant respond better to valproic acid, while those with the C variant respond better to lithium [121, 122].
Despite being created over 100 years ago, it’s still not entirely clear how valproic acid works. As mentioned earlier, there are likely multiple mechanisms at play .
Its anti-seizure effect is usually attributed to increasing GABA levels and blocking specific brain pathways (the so-called voltage-gated sodium channels) .
Valproic acid also inhibits an enzyme called histone deacetylase (HDAC). This effect might help protect the brain and possibly fight cancer .
In the following list, we detail some natural compounds that share these same mechanisms.
You should always consult your doctor before changing or stopping any of your medications.
It’s also important to let your doctor know of all the supplements you are currently taking, in case of potential interactions.
1) Ketogenic Diet
The ketogenic diet (or keto diet) has gained mainstream popularity as a way to lose weight and boost energy.
But the diet actually dates back to the 1920s, where it was first developed as a treatment for epileptic seizures in children. However, the diet fell out of favor when anti-seizure medications became available .
The basic idea behind the diet is the consumption of high-fat, low-carb, and adequate-protein foods. This forces the body to switch over from using glucose as energy to using fat .
It’s not totally clear why this diet helps with seizures. The mechanism might involve inflammatory pathways, GABA signaling, and neuronal transporters. Ketone bodies themselves may have anti-seizure properties [124, 125].
What we do know is that the keto diet is fairly effective for seizure control.
A review of 4 clinical trials including 289 children found that the keto diet provides short- to medium-term benefits in seizure control .
Research also shows that the keto diet is more effective than other diet variants, like the Atkins diet and the medium-chain triglycerides (MCT) diet .
Check out our keto diet article for more information on the health benefits and if the diet is right for you.
One of the more intriguing benefits of medical marijuana is its anticonvulsant effects. Many people claim that cannabis is the only treatment that provides adequate seizure control.
There is increasing scientific evidence that cannabinoids, especially CBD, can reduce seizures .
Research in humans has only begun in the last few years, but the initial results are encouraging .
For example, one clinical trial examined CBD’s effect in Dravet syndrome. This childhood epilepsy disorder is usually resistant to medications and often leads to premature death. In the study, CBD reduced the average number of seizures per month from 12 to 6 .
CBD may also be effective for another rare childhood disorder associated with severe seizures (Lennox-Gastaut syndrome). A review of 2 clinical trials with 396 patients found that CBD reduces seizure frequency by at least half in 40% of users .
The good bacteria (probiotics) in your gut can ferment the dietary fibers that you eat, producing a compound called butyrate. A type of fatty acid, butyrate is used as an energy source for colon cells .
Butyrate’s beneficial effects in the gut may have important implications for brain health as well. Your gut and brain actually talk to each other through chemical signals in a process called the gut-brain axis .
Research shows that butyrate is also an HDAC inhibitor much like valproic acid. This means butyrate increases the expression of anti-inflammatory pathways, while reducing pro-inflammatory ones .
One rat study demonstrates that this anti-inflammatory effect may protect against brain damage caused by stroke .
Butyrate may also potentially help with bipolar disorder symptoms. A study found that butyrate reduces manic and risk-taking behavior in rats .
These results are promising, but no clinical trials have been performed just yet. It remains to be seen if butyrate offers the same brain benefits in humans .
How can you increase butyrate?
Resistant starch and fiber-rich foods can provide bacteria with more material to produce butyrate .
Clinical trials of valerian have identified a number of potential health benefits, including:
- Improved sleep [157, 158, 159]
- Improved concentration in children [160, 161]
- Reduced menstrual cramp pain 
- Reduced hot flashes 
Kavain is one of the major active compounds inside kava. Cell studies show that kavain enhances the activity of GABAA receptors .
A rat study found that kava enhances the anticonvulsant effect of diazepam, a medication commonly used for anxiety and seizures. This allowed for lower doses of diazepam to be effective, possibly leading to fewer side effects .
6) Magnolia Bark
Magnolia bark (Magnolia officinalis) is commonly used in traditional Chinese medicine.
It contains two main active compounds: honokiol and magnolol. Studies show these two components act as GABAA modulators .
Want More Targeted Ways to Improve Mood?
If you’re interested in natural and more targeted ways of improving your mood, we at SelfHacked recommend checking out this mood wellness report. It gives genetic-based diet, lifestyle and supplement tips that can help improve your mood. The recommendations are personalized based on your genes.
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