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The drug Depakote (divalproex sodium) is used to treat seizure disorders, mitigate the manic phase of bipolar disorder, and prevent migraine headaches. However, it and related valproate medications have serious side effects, including birth defects in children whose mothers take the drugs while pregnant.

depakote 250 mg tablet
Depakote Facts
  1. Dosage 10 - 15 mg/kg/day for epilepsy, 750 mg/day for mania, 500 mg/day for migraine
  2. Used to Treat Epilepsy, the manic phase of bipolar disorder, and migraine headaches
  3. Related Drugs Depakene, valproate medications
  4. Manufacturer AbbVie
  5. Black Box Warnings Hepatotoxicity, fetal risk, pancreatitis
  6. FDA Approval 1983 for epilepsy, 1995 for bipolar disorder, 1996 for migraine

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Depakote is a multi-use drug manufactured by AbbVie (formerly by Abbott Laboratories prior to 2013) that comes in varying forms, including Depakote tablets, Depakote ER extended-release tablets, and Depakote Sprinkle Capsules (delayed-release capsules). It was first approved by the U.S. Food and Drug Administration in 1983 for the treatment of epilepsy (seizure disorder

Depakote’s uses were later expanded to include the manic (euphoric – feelings of intense excitement and happiness) episodes associated with bipolar disorder as well as migraine prevention.

A closely related medication, Depakene (valproic acid), comes in capsule and liquid form, while another variety of valproic acid, Stavzor, is no longer manufactured. Additionally, in 2008, the FDA approved the first generic version of Depakote. Collectively, these drugs are known as valproate products.

Valproate is a chemical substance that has been linked to several serious side effects and contraindications, including birth defects to fetuses when taken during early pregnancy.

The adverse reactions and potential risks associated with this active ingredient in these primary anti-seizure medicines has led to the inclusion of several FDA-mandated warnings on the labeling for Depakote and related products, including various black box warnings, the FDA’s most serious kind.

What Is Depakote?

Depakote contains the active ingredient divalproex sodium, which is a combination of sodium valproate and valproic acid. It comes in a white powder form that is manufactured into a tablet to be taken by mouth for the treatment of various conditions that affect the brain.

Depakote is shown to be effective in managing and stabilizing moods by way of the drug’s chemical ingredient valproate. The medication works by increasing the amount of gamma-aminobutyric acid (GABA) in the brain. This naturally produced chemical neurotransmitter, or brain messenger, helps to calm and relax nerves.

Not only is this biological process important in stabilizing moods by reducing erratic behaviors resulting from faster than normal electrical impulses in the brain that overstimulate the nerves, but increasing GABA can also prevent abnormal brain signals that lead to seizures.

Depakote Uses

Depakote is approved by the FDA to treat epilepsy, bipolar disorder and migraine headaches. The anti-seizure and mental illness drug was initially approved by the federal agency in 1983 for epilepsy treatment. Its uses expanded over a decade later to include the treatment of manic episodes in bipolar disorder in 1995, and as a migraine prevention treatment in 1996.

The FDA issued information in 2015 that valproate products, including Depakote, are also often and routinely used off-label (for unapproved uses) in the treatment of other conditions, particularly for certain other psychiatric conditions.

Depakote is used to treat epilepsy, a brain disorder that causes recurring, unprovoked seizures. Depakote blocks voltage-gated sodium channels in the brain and helps prevent brain signals that lead to seizures. Depakote may be prescribed either alone or in combination with other medications to treat epilepsy for adults and children 10 and older who suffer from complex partial seizures and simple and complex absence seizures.
Bipolar Disorder
Depakote treats bipolar disorder manic episodes, which are marked by feelings of euphoria, elevated energy levels, and heightened creativity. During the manic phase of bipolar disorder people may have racing thoughts, talk rapidly, be highly distractible, and act recklessly. Depakote acts as a mood stabilizer. Depakote and other valproate medications work by increasing the amount of the neurotransmitter gamma-aminobutyric acid (GABA) in the brain, which contributes to motor control, vision, and other cortical functions. GABA also regulates anxiety.
Migraine Headaches
Depakote is also used to lessen the recurrence of migraine headaches. Although researchers have not pinpointed what causes migraines, many believe they are caused by a mix of genetic and environmental factors. Depakote is an effective prophylactic when taken before the onset of migraines. Depakote has been approved for use in adults and children 10 and older for seizure treatment and age 16 and older for migraine prevention. It is not approved to treat bipolar conditions in children.

Depakote Indications and Precautions

For seizures, the recommended initial dose depends on the weight of the patient. For mania, the recommended initial dosage is 750 mg in divided doses. For migraine prevention, the typical initial dose of Depakote is 250 mg twice per day, but doses of up to 1500 mg per day are common.

Depakote manufacturer AbbVie warns that you should not take Depakote or Depakene if you:
  • Have liver problems
  • Have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome)
  • Are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene
  • Have a genetic problem called urea cycle disorder
  • Are pregnant
Depakote 250mg tablet
Depakote 250mg tablet
Depakote 500mg tablet
Depakote 500mg tablet

Side Effects

A common side effect of Depakote and Depakene is nausea, especially during the first month of treatment. This can be overcome by starting on a low dosage and slowly increasing the amount. Taking the medication on a full stomach can also help.

Rare side effects of Depakote and Depakene include:
  • Liver problems
  • Low platelets
  • Pancreatitis (inflammation of the pancreas). Symptoms of pancreatitis include severe stomach pain, nausea, vomiting, and not feeling hungry.
  • Increased ammonia levels. Symptoms may include confusion, disorientation, or difficulty thinking.
Serious side effects of Depakote and Depakene include:
  • Liver and pancreas damage
  • Birth defects
  • Suicidal thoughts

Also, women who take Depakote are more likely to develop polycystic ovarian syndrome (PCOS), which can cause ovarian cysts and affect the ability to get pregnant. Depakote’s serious side effects, especially birth defects, have led to numerous lawsuits against the drug’s maker.

Depakote and Birth Defects

Studies have shown that Depakote can cause harm to human fetuses and should only be taken during pregnancy if no other medications can be used to treat a condition. Depakote can cause birth defects, including neural tube defects such as spina bifida, cleft palate and lowered intelligence. These defects occur in fewer than two out of every 100 babies born to mothers who use Depakote or Depakene during pregnancy. These defects can begin in the first month of pregnancy, even before a woman knows she is pregnant. Depakote may be responsible for other birth defects that affect the structures of the fetus’s heart, head, arms, legs and penis and can lower IQ. In addition, Depakote is excreted in breast milk; its effect on infants is unknown.

Depakote Birth Defects

Neural Tube Defects, Including Spina Bifida

Depakote can cause neural tube defects, in which the brain, spine or spinal cord is damaged. In 2009 the FDA added a warning to Depakote concerning the danger of neural tube birth defects. The FDA found that taking Depakote during pregnancy increases the risk of developing birth defects such as neural tube defects from 1 in 1,500 babies to 1 in 20. A study published in the New England Journal of Medicine indicated that children whose mothers took Depakote during the first trimester of pregnancy are more than 12 times more likely to be born with spina bifida, a neural tube defect that results from the spinal column not completely closing during fetal development, leaving the spinal cord exposed.

Other Physical Defects

Researchers comparing other studies of valproic acid against the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic study database found six malformations linked to women’s Depakote use during the first trimester of pregnancy, including spina bifida and:

  • Atrial septal defect (ASD), a hole in the wall between the two upper chambers (atria) of the heart
  • Cleft palate, a condition where the tissue that makes up the roof off the mouth fails to join completely
  • Hypospadias, a condition where the opening of the urethra in boys is on the underside of the penis rather than the end
  • Craniosynostosis, a condition where the bones of the skull close too early
  • Polydactyly, an extra finger or toe

Cognitive Effects

The FDA warns that children born to mothers taking Depakote during pregnancy received lower scores on cognitive tests, such as IQ tests, than children born to mothers who take other anti-seizure medications. The tests were given at multiple ages and measured intelligence, abstract reasoning and problem-solving. An article published in the Journal of the American Medical Association linked prenatal valproate exposure to autism spectrum disorders and childhood autism.

Depakote and Suicide

2008 FDA analysis of 199 trials of people taking antiepileptic drugs, including Depakote, found that those taking the drugs have twice the risk of suicidal thinking than patients taking a placebo. The analysis revealed an increase in suicidal thinking and behavior in one in every 530 people treated. Suicidal thoughts and behavior were observed within seven days of treatment.

Psychiatrists warn that families and caregivers of anyone with bipolar disorder should be alert for warning signs:
  • Thoughts about suicide or dying
  • Attempts to commit suicide
  • New or worsening depression
  • New or worsening anxiety
  • Feeling agitated or restless
  • Panic attacks
  • Trouble sleeping (insomnia)
  • New or worsening irritability
  • Acting aggressive, being angry or violent
  • Acting on dangerous impulses
  • An extreme increase in activity and talking (mania)
  • Other unusual changes in behavior or mood

Depakote comes in a tablet form intended to be taken by mouth, swallowed whole and not crushed or chewed. Its extended-release pill is meant to be taken less often, or once a day, so that the drug is released slowly over time keeping medication levels consistent in the body. Other versions of the anti-seizure drug should be taken daily as prescribed.

Depakote delayed-release tablets are supplied in three different strengths including 125 milligrams (pink), 250 milligrams (peach) and 500 milligrams (lavender), while Depakote ER (extended-release) is only available in 250- (white) and 500-milligram (gray) tablets.

The recommended dosages for patients prescribed Depakote and Depakote ER for the treatment of mania associated with bipolar disorder, epilepsy and migraines include:

Condition Depakote Dosages Depakote ER Dosages
Mania Recommended initial dose is 750 mg a day taken in divided doses; the maximum recommended long-term dosage is 60 mg a day. Recommended initial dose is 25 mg taken once daily; the maximum recommended dosage is 60 mg a day.
Epilepsy Children aged 10 years and older and adults should begin initial therapy at 10 to 15 mg and increase by 5 to 10 mg a week to achieve optimal clinical response Children aged 10 years and older and adults should begin initial therapy at 10 to 15 mg and increase by 5 to 10 mg a week to achieve optimal clinical response. Normally, optimal clinical response is achieved at daily doses below 60 mg. Safety recommendations do not exist for the use of valproate in the treatment of seizures at doses above 60 mg a day.
Migraine The recommended starting dose is 250 mg taken twice a day. Some patients may benefit from doses up to 1,000 mg a day, but clinical trials found no evidence of greater effectiveness with higher doses. The recommended starting dose is 500 mg taken once daily for one week. After that time, the dose increases to 1,000 mg taken once daily. Doses other than 1,000 mg taken once a day have not been evaluated in patients with migraine, but dosing should be individualized with an effective dose range between 500 and 1,000 mg. Depakote should be used as an alternative for patients requiring smaller doses than that available with Depakote ER.

When converting from Depakote to Depakote ER, adult patients and pediatric patients ages 10 and older with epilepsy should be administered Depakote ER once a day at a dose 8 to 20 percent higher than the total daily dose of Depakote.

For all other patients with conditions other than epilepsy, where the total daily dose of Depakote cannot be directly converted to Depakote ER, discretion is left to the health care provider whether to increase the patient’s total daily dose to the next higher dosage of Depakote before converting to Depakote ER.

Overdose of Depakote and Depakote ER

Overdose associated with the use of Depakote, Depakote ER and other valproate products, may result in somnolence (a strong desire for sleep or sleeping for unusually long periods), heart blockages and deep coma. While deaths due to overdose have been reported, patients have recovered from valproate dosing levels as high as 2,120 mcg/mL.

In cases of Depakote overdose, hemodialysis (a process of purifying the blood) or hemodialysis used along with hemoperfusion (a technique for removing poisons from the blood) can result in significant drug removal since the amount of drug that does not bind to protein in the body is high.

The benefit of stomach pumping or inducing vomiting will vary based on the time since ingestion of the drug. Particular attention should be paid to the maintenance of adequate urine output in dealing with overdoses of Depakote.

Naloxone, a medication used to reverse the effects of narcotic drugs used during surgery or to treat pain, has been reported to also reverse the depressant effects of valproate overdosage on the central nervous system (CNS) (made up of the brain, spinal cord and optic nerves). However, naloxone should be used with caution in patients with epilepsy as it can also reverse the anti-seizure effects of valproate.

Please seek the advice of a medical professional before making health care decisions.

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9 Cited Research Articles

  1. DailyMed, NIH. (2017, May 9). Label: Depakote ER – divalproex sodium tablet, extended release. Retrieved from:
  2. Epilepsy Therapy Project. (2012). What are the most common side effects of Depakote?: Basic.
  3. U.S. Food and Drug Administration. (2011, October 7). Depakote (divalproex sodium): Full Prescribing Information. Retrieved from:
  4. U.S. Food and Drug Administration. (2015, July 10). Valproate Information. Retrieved from:
  5. Frost, P. (2012, May 8). Abbott Laboratories settles Depakote case for $1.6 billion. Chicago Tribune.
  6. Monson, K. (2008, September 4). Depakote. eMedTV. Retrieved from
  7. Monson, K. (2017, January 2). How Does Depakote Work? Retrieved from:
  8. Schneider, B. (2014, October 31). What Is Depakote (Divalproex Sodium)? Retrieved from:
  9. U.S. National Library of Medicine. (2012). Drug Record: Valporate. Retrieved from
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