Depakote (Valproic Acid) is an anti-seizure drug that has been used for almost fifty years. It is also used to manage bipolar disorder, schizophrenia, and migraines. But it can cause a number of side effects ranging from nausea to liver damage. Read on to discover more on the uses and side effects of Depakote.

Note: 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 scientific literature. Please discuss your medications with your doctor.

What is Depakote?

Depakote is the brand name for valproic acid. The discovery of the effects of valproic acid was a completely serendipitous one [R].

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 a 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 [R].

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 [R].

In generic formulations, valproic acid is also referred to as divalproex, valproate, sodium valproate, and valproate semisodium [R, R, R. R].

Aside from Depakote, common brand names include [R, R, R, R]:

  • Depakene
  • Epilim
  • Epival

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 drug that is also effective for reducing migraine headaches as well as a treatment for a variety of psychological disorders.

It achieves its effects through multiple different mechanisms [R, R, R]:

  • 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) [R].
  • These enzymes can also increase the spreading of cancer, and valproic acid may help combat cancer by blocking their effects [R].

Uses of Depakote (Valproic Acid)

1) Valproic Acid 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 (DB-RCT) 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 [R].

Two retrospective studies of 544 patients with a deadly brain cancer (glioblastoma multiforme) found that valproic acid reduced seizures and extended survival (with chemotherapy) [R, R].

It is also used as part of the established therapy for chronic seizures (status epilepticus) in children [R].

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 [R].

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 [R].

In a DB-RCT 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 [R].

2) Valproic Acid Can Prevent Migraines

Valproic Acid Can Prevent Migraines

In a six-month open-label study of 97 patients with chronic (recurring) migraines, valproic acid reduced migraine frequency [R].

This benefit was confirmed in larger clinical trials and valproic acid officially approved by the FDA for preventing migraines [R].

3) Valproic Acid Reduces Anxiety

Valproic Acid Reduces Anxiety

Valproic acid has been used as an anti-anxiety drug since the late 20th century [R, R].

In an open trial with 10 panic disorder patients, valproic acid reduced panic symptoms and anxiety while improving low and unstable mood [R].

A study (SB-RCT) of 17 patients with social anxiety disorder found that valproic acid significantly reduced symptoms in approximately half of the patients [R].

4) Valproic Acid May Help Treat Depression

Valproic Acid 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 [R].

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 [R].

5) Valproic Acid Can Help Treat Bipolar Disorder

Valproic Acid Can Help Treat Bipolar Disorder

Valproic acid has been used to treat bipolar disorder for over 30 years.

Three meta-analyses have concluded that valproic acid is highly effective at reducing depressive symptoms in people with acute bipolar disorder [R, R, R].

An additional meta-analysis found that taking valproic acid regularly was beneficial for keeping bipolar symptoms in remission [R].

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) [R].

6) Valproic Acid Reduces Schizophrenia Symptoms

Valproic Acid 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) [R].

This finding is supported by several small open-label trials [R, R, R].

7) Valproic Acid Improves Schizoaffective Disorder

Schizoaffective disorder is closely related to schizophrenia but includes depression and mania symptoms in addition to the common symptoms of schizophrenia [R].

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) [R].

In a retrospective study of 20 schizoaffective patients, 75% of patients improved on valproic acid alone, without experiencing significant side effects [R].

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 [R].

8) Valproic Acid May Fight Cancer

Valproic Acid May 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 [R]:

  • 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 [R].

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) [R].

9) Valproic Acid 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 [R].

However, a study (placebo-controlled pilot) in 22 AIDS patients found that valproic acid improved mental performance in those who had HIV-related cognitive impairments [R].

10) Valproic Acid May Reduce Hair Loss

Valproic Acid 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 [R].

11) Valproic Acid May Protect the Brain

Valproic Acid 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 [R].
  • Parkinson’s disease (PD): in a study on brain cells, valproic acid may help prevent neurons from dying, crucial for PD [R].
  • 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 [R, R].
  • 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 [R, R].
  • 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  [R].

Valproic Acid Overdose

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 [R].

Valproic Acid Side Effects

Valproic acid can potentially cause a number of short- and long-term side effects.

The most common short-term side effects of valproic acid include [R, R, R, R]:

  • Nausea
  • Vomiting
  • Hair loss (alopecia)
  • Dizziness
  • Shakiness (motor tremors)

The potential long-term side effects include [R, R, R, R, R, R, R, R, R, R, R, R]:

  • Easy bruising
  • Liver damage
  • Weight gain/obesity
  • Hair loss
  • Diabetes
  • Polycystic ovarian syndrome
  • Metabolic syndrome
  • Pancreatitis
  • Parkinson-like syndrome
  • Dementia

There are also a few side effects that seem to be specific to children who take valproic acid, such as [R, R, R]:

  • Excessive need for sleep (increased sleep duration)
  • Hypothyroidism
  • Fanconi syndrome (a disorder that impairs the ability of the kidneys to absorb essential nutrients)

Withdrawal Symptoms

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) [R].

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 [R].

A case report showed two children who stopped valproic acid experienced hallucinations, and that these went away when they started taking the drug again [R].

Forms of Valproic Acid/Depakote

Valproic acid is available in oral, rectal, and intravenous (injected) forms.

Depakote is available as regular tablets (Depakote), extended-release tablets (Depakote ER), and delayed-release capsules (Depakote Sprinkle Capsules).

Other oral forms of valproic acid include immediate-release capsules and syrups [R].

Dosage

Dosages for valproic acid can vary significantly depending on the particular condition it is being used to treat.

For treating seizures/epilepsy, doses usually starts at around 600 mg/day (divided into two daily doses), and increase by about 200 mg every 3 days until the patient shows improvement. For most patients, this final dose usually ranges between 1,000-2,000 mg/day [R].

However, other factors can also influence the dosage, such as the age of the patient, the particular type of seizures/epilepsy being treated, and whether the seizures are caused by some other health condition, such as brain cancer [R, R, R].

For treating bipolar disorder, doses usually begin at around 250 mg/day, and gradually increased until the patient shows a good response [R].

Patients experiencing anxiety disorders (such as panic disorder) are generally started at around 500 mg/day, and again gradually increased up to a maximum of 2,250 mg/day [R].

Those experiencing major depression are generally given stable doses of between 375-1,000 mg/day [R].

For migraine prevention, most studies have started with doses of 500mg/day (divided into two doses), going up to 1,000 mg/day as needed [R].

Depakote (Valproic Acid) Overdose

Symptoms of a valproic acid overdose vary widely, and can include [R, R]:

  • Slowing or stopping of breathing (respiratory depression)
  • Low blood pressure
  • Rapid heart rate (tachycardia)
  • Fever
  • Drowsiness / fatigue
  • Nausea and vomiting
  • Diarrhea
  • Small (constricted) pupils
  • Agitation
  • Tremors
  • Muscle tension
  • Brain swelling (cerebral edema)
  • Coma

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) [R].

Depakote Interactions

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”).

Examples of other drugs that can trigger negative reactions when combined with valproic acid include [R, R, R]:

  • 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 [R]:

It is also possible to have a hypersensitivity to valproic acid itself, which can cause symptoms such as [R, R, R, R, R, R, R, R]:

  • Reduced immunity
  • Reduced blood clotting
  • Inflammation of blood vessels
  • Skin inflammation (dermatitis)
  • Throat inflammation
  • Swollen lymph nodes
  • Red eyes
  • Psoriasis-like rashes
  • Fever
  • 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

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 [R].

Combining these two drugs may also cause [R]:

  • Drowsiness
  • Restlessness
  • Dizziness
  • Loss of appetite
  • Joint pain
  • Muscle pain
  • Depression

Valproic Acid and Aspirin

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 [R].

The recommendation against taking both drugs has also been backed up by several recent reviews [R, R].

Valproic Acid and Antibiotics

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) [R, R, R].

Valproic Acid and Pregnancy

Valproic acid is known to cause birth defects and should be avoided during pregnancy whenever possible. The FDA holds this drug at grade D, indicating there is significant evidence for the potential of harming the developing child [R].

Some studies suggest that using valproic acid is associated with a 10-20x 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) [R, R].

Other potential birth defects include heart, urinary, genital, and bone abnormalities, with higher doses causing more defects [R, R, R, R].

Valproic Acid and Antiepileptics

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 [R].

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 [R].

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 [R].

This release of phenytoin by valproic acid results in an unpredictable blood level of both drugs [R].

Valproic Acid and Antidepressants

Valproic acid has known interactions with at least 4 other relatively common antidepressants: doxepin, venlafaxine, lamotrigine, and amitriptyline.

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 [R].

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 [R].

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 [R].

Valproic Acid and Antipsychotics

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 [R, R].

In another case report, a patient taking valproic acid developed inflammation of the brain after risperidone was added to their treatment [R].

Valproic Acid and Lithium

Two small studies (a DB-RCT 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 [R, R].

Valproic Acid and Liver Disease

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 [R].

Valproic Acid and 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 [R, R].

Valproic Acid and Mitochondrial Disorders

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 [R].

Because it interferes with liver metabolism, patients with mitochondrial disorders should avoid valproic acid, as this can worsen seizures and cause acute liver failure [R, R].

Genetics/Genetic Predispositions

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 [R, R].

Another polymorphism (Val158Met of the COMT gene) predicted whether people responded to any of the medications for bipolar disorder, including valproic acid [R].

If you got your genes sequenced, SelfDecode can help you determine if your health issues may be a result of your genes, and then pinpoint what you can do about it. If you’re sick and tired of guessing about your health, SelfDecode can help you find specific answers that conventional doctors/diagnostics may never uncover.

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.

User Experiences

Seizures: Patients generally say the medication is effective at reducing or preventing seizures, although many also say that they have experienced side effects such as poor attention, tremors, muscle and/or joint pain, depression, and weight gain. For some, these side effects outweighed the benefits, which made them decide to stop taking the drug.

Bipolar Disorder: Most patients reported effective and consistent stabilization of their moods while their physician was closely monitoring their dose. However, some people report side effects such as constipation, sudden diarrhea, rashes on arms and/or legs, worsening of mania, nausea, hallucinations, aggression, heartburn, weight gain, brain fog, palpitations, and fatigue.

Schizoaffective Disorder: Most state they had better control of valproic acid, but there were some mentions of it causing seizures.

Migraine Control: User feedback is generally positive for migraine prevention with no major side effects reported.

Health Tools I Wish I Had When I Was Sick

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