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Depakote Side Effects

Used for treating epilepsy, migraines and mania associated with bipolar disorder, Depakote and Depakote ER have been linked to serious, potentially deadly, side effects and complications. The threats from these anti-seizure drugs can include liver damage, life-threatening pancreatitis, birth defects, suicidal thoughts and actions, and various blood and metabolic disorders.


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Depakote and Depakote ER have been linked to several serious side effects that can cause permanent disability and death. Some of the complications resulting from use of the anti-seizure drugs can even affect babies born to mothers who take Depakote or Depakote ER while pregnant.

Most of the side effects are associated with an ingredient, valproate, found in the active compound present in the manufacture of Depakote drugs called divalproex sodium. Valproate is a mood stabilizer initially approved to treat epilepsy (seizures) by the U.S. Food and Drug Administration (FDA), and later expanded to treat migraines and bipolar disorder as well.

Elderly man with a migraine
Valproate, an ingredient in Depakote, can be used to treat migraines

Although included in the World Health Organization’s (WHO) Model List of Essential Medicines, valproate is associated with liver problems that require regular monitoring of liver function, life-threatening pancreatitis (damage to the pancreas), birth defects, increased risk of suicide, and other serious and potentially deadly side effects.

Depakote and Liver Damage (Hepatotoxicity)

Depakote can cause liver failure in patients prescribed the multi-use medication. Depakote drug labeling contains a boxed warning regarding liver failure, or hepatotoxicity, which is an inflammation of the liver.Hepatotoxicity is a serious and sometimes fatal condition.

Drug-induced liver damage is a potential complication of nearly every prescription medication, according to the New England Journal of Medicine (NEJM), because the liver is a vital organ in the metabolism of many drugs and other substances entering the body.

While most drugs are typically metabolized by the liver without complication or injury, serious and life-threatening occurrences of hepatotoxicity are possible and especially dangerous for very young children.

The liver is the largest organ in the body with the primary responsibility of removing toxins and chemicals, such as medications, from the blood stream and changing them into products that can then be removed from the body as waste. If toxins build up in the body faster than the liver can process them, then liver damage can occur.

When liver damage occurs, it can lead to the under-functioning or irregular functioning of the essential organ, which can affect other important biological functions aside from the filtering of toxic substances.

Liver Diagram
Diagram of the liver
The liver also plays a significant role in the following processes:
  • Removal of old or damaged red blood cells from the blood (working alongside the spleen)
  • Production of critical clotting factors (aiding in the formation of clots to stop bleeding)
  • Production of bile to assist in the absorption and digestion of fats in the intestine
  • Processing and storing vitamins, minerals, proteins, fats and glucose (sugar)

Side Effects of Hepatotoxicity

Some patients may not experience any immediate symptoms of liver damage. Symptoms, when they do occur, can also be non-specific, including a general feeling of illness, discomfort or unease (malaise) and a lack of energy and enthusiasm (lethargy). The cause of these symptoms may be initially difficult to pinpoint or can go ignored.

Some other non-specific signs that may precede hepatotoxicity and draw more attention to the serious, potentially deadly, problem include facial swelling, anorexia (loss of appetite, starvation and weight loss) and vomiting.

A primary indicator of liver damage is often jaundice, which results in the yellowing of the skin, whites of the eyes and mucous membranes (moist areas around eyes and mouth), due to higher than normal levels of bilirubin present in the body. Bilirubin is a brownish-yellow substance found in bile that gives stool (waste) its coloring.

This compound is produced during the body’s regular break down of old red blood cells, which is then excreted from the liver in the bile. When the liver cells are damaged, bilirubin may not be able to be excreted properly, causing an abnormal build-up of the product in the blood and body fluids. High levels of bilirubin can be detected with a blood test.

Other symptoms that can be experienced by patients affected by liver damage from hepatotoxicity include:
  • Severe fatigue
  • Fever
  • Abdominal pain and nausea
  • Diarrhea
  • Bleeding that does not stop after a few minutes
  • Unusual swelling in the feet and legs, or weight gain greater than 3 to 5 pounds in one week
  • Dark-colored urine and pale bowel movements

Diagnosis and Treatment of Liver Damage

Various tests can be used to diagnose liver damage. These tests can include blood tests to measure the body’s bilirubin levels as well as liver enzymes (proteins that trigger important chemical reactions in the body).

Doctor performing a liver biopsy
A liver biopsy can be performed to detect liver damage.

Other tests that can be done to detect liver damage include liver biopsies, which examines a small sample of liver tissue under a microscope, CT scans, often with radioactive dye, and endoscopic retrograde cholangiopancreatography (ERCP), which is a procedure to examine the bile duct (the tube that carries bile from the liver to the gall bladder) and comes with its own complications.

There is no treatment, cure or reversal for liver damage. The primary course of treatment is to discontinue any medications processed through the liver and avoid alcohol. Patients may be prescribed medications that help to reduce the symptoms of liver damage, such as a diuretic to reduce fluid accumulation and swelling (edema).

Depakote and Pancreas Damage (Pancreatitis)

Life-threatening pancreatitis has been reported in children and adults taking Depakote. Some cases have even been described as hemorrhagic with a rapid progression from initial symptoms to death, according to the boxed warning on the drug’s label. This deadly condition can occur shortly after initial use of Depakote or after several years of use.

Use of Depakote resulting in injury to the pancreas can cause death in both adults and children.

Pancreatitis is inflammation of the pancreas. The pancreas is a long, flattened gland situated deep in the belly (abdomen) behind the stomach and close to the first part of the small intestine. It is important in the process of digestion and maintenance of blood-sugar levels.

The pancreas is essentially two glands combined as one. The endocrine portion of the pancreas releases the hormones insulin and glucagon into the bloodstream to help control blood sugar, or glucose, levels in the body. The bulk of the pancreas, composed of exocrine cells, secretes digestive juices into the small intestine by way of the pancreatic duct (a tube connecting the pancreas, gallbladder and duodenum of the small intestine).

Pancreatitis occurs when these digestive enzymes start digesting the pancreas itself, according to the National Institutes of Health (NIH). The condition can be acute (occurring suddenly and of short duration, but severe and intense) or chronic (long-term and constantly recurring). Both forms of damage to the pancreas are serious and can lead to other complications and/or death.

Chronic pancreatitis does not heal or improve. The condition can therefore get worse over time and lead to permanent damage of the vital gland.

Chronic pancreatitis is most commonly seen in individuals with one of the following conditions:
  • Heavy alcohol use
  • Cystic fibrosis (CF) and other genetic disorders
  • High levels of calcium or fats in the blood
  • Use of some medications (such as Depakote)
  • Autoimmune conditions (when the immune system attacks the body)

Symptoms of Pancreatitis

Chronic pancreatitis occurs more often in men than in women, and most commonly develops in those between the ages of 30 to 40. Repeated episodes of acute pancreatitis can lead to a chronic condition.

When scarring of the pancreas occurs, the gland is no longer able to make the right amounts of enzymes, and the body may be unable to digest fats and other elements in food.

Damage to certain parts of the pancreas that aid in making insulin can lead to diabetes, with patients experiencing symptoms associated with the blood sugar disease including blurry vision, excess thirst, fatigue, frequent urination, hunger and weight loss.

Symptoms specific to pancreatitis include:
  • Abdominal pain
  • Fatty or oily stools
  • Diarrhea, nausea and vomiting
  • Pale or clay-colored bowel movements
  • Chronic weight loss, even with no change in eating habits

Diagnosis and Treatment of Pancreatitis

Pancreatitis is a serious disease that can lead to permanent injury and death. Avoiding alcohol and being aware of the risks associated with certain medications is important to reduce one’s likelihood of developing chronic pancreatitis and can also assist in treatment (maintenance) of the condition.

Possible complications that can occur as a result of damage to the pancreas include ascites (build-up of fluid in the space between the lining of the abdomen and abdominal organs), blockage of the small intestine or bile ducts, fluid build-up in the pancreas causing infection, diabetes, and poor absorption of fats, nutrients and vitamins.

Tests performed to diagnose pancreatitis can include a fecal fat test (measuring the amount of fat in the stool) and blood tests to measure an increase of certain digestive enzymes.

Imaging tests can also be done to show swelling, scarring or others changes to the pancreas.

medical ultrasound of internal organs
An ultrasound of the abdomen can help diagnose pancreatitis
Pancreas imaging tests include:
  • CT scan of the abdomen
  • Ultrasound of the abdomen
  • Endoscopic ultrasound (inserting a probe into a hollow organ)
  • Endoscopic retrograde cholangiopancreatography (ERCP)
  • Magnetic resonance cholangiopancreatography (MRCP) – a noninvasive procedure that uses of magnetic resonance imaging to see the biliary and pancreatic ducts

People with severe pain or weight loss, mostly associated with acute pancreatitis and the worsening or progression of chronic pancreatitis, may require hospitalization.

During the hospital stay, patients may be treated with pain medications, fluids through a vein via an IV, the slow reintroduction of an oral diet to limit the activity of the pancreas and promote healing, or, in some instances, the insertion of a tube through the nose or mouth to empty the contents of the stomach.

Diet and fluid intake is important for patients with chronic pancreatitis to keep a healthy weight and get the proper nutrients. Pancreatic enzymes may also be taken with every meal to help patients digest food and gain weight. Insulin treatments may be required in some patients to control blood sugar levels in the blood.

If a blockage is found, surgery may be necessary to remove the obstruction. In severe cases, removal of part, or all, of the pancreas may be recommended.

Depakote and Fetal Risk (Neural Tube Defects)

Depakote is not recommended for use in pregnant women or women who are planning to, or may become, pregnant due to its potential to cause birth defects, such as neural-tube defects, or other risks of fetal harm, including lowered intelligence. The FDA, in 2009, urged health care providers and women who are or may be pregnant to consider other therapies prior to taking Depakote, especially for non-life-threatening conditions, such as migraines.

Depakote is not recommended for use by pregnant women.

Using Depakote during the first 12 weeks of pregnancy increases the risk of major malformations, including neural-tube defects, to about 1 in 20 affected babies, according to the FDA. This is much greater than the average 1 in 1,500 babies typically found to be born in the U.S. with the same defects.

Accordingly, the FDA determined that “the rates for neural tube defects in babies exposed to valproate [an ingredient present in Depakote in the form of divalproex sodium] during the first trimester are 30 to 80 times higher than the rate for neural tube defects in the general U.S. population.” In pregnant women with epilepsy, taking Depakote was linked to a four-fold higher rate of major malformations than other epilepsy medications.

Neural-tube defects are birth defects that affect the brain, spine or spinal cord, according to the National Institutes of Health (NIH). They occur within the first month of pregnancy, often before a woman even knows she’s pregnant. A baby’s neural tube, which start out as a tiny, flat ribbon and then turns into a tube at the end of the first month of pregnancy, normally develops into the brain and spinal cord.

Taking Depakote while pregnant can cause serious injuries to 1 in 20 fetuses.

Neural-tube defects occur when the tube doesn’t close completely. The two most common neural-tube defects are spina bifida and anencephaly, according to the NIH. Spina bifida is the result of the fetal spinal column (tiny bones of the vertebrae) not closing completely, causing part of the spinal cord to stick out through the spine. The condition usually results in nerve damage that can cause at least partial paralysis in the legs as well problems controlling the bladder and bowel.

Anencephaly is one of the most severe neural-tube defects. It happens when the upper part of the neural tube that forms the brain does not close completely. In this deadly condition, most of the baby’s brain, skull and scalp do not develop. Infants born with anencephaly do not live long after they are born, typically just for a few hours. Girls are more likely than boys to suffer from this birth defect, which can occur alongside other defects of the head and face as well as other parts of the body.

Prevention of Neural Tube Defects

The exact causes of neural-tube defects are unknown. However, there are several factors that put an expectant mother at a greater risk of having an infant with such conditions, such as taking certain anti-seizure medicines. Avoiding these medications, if possible, can help to reduce the risk of neural tube defects from occurring.

Studies in the general population show that folic acid, a type of B vitamin, taken about one month prior to becoming pregnant and during early pregnancy before the neural tube closes, can reduce the risk of neural-tube defects, according to an FDA safety communication.

The March of Dimes recommends that women of childbearing age take a multivitamin with at least 400 micrograms of folic acid if trying to become pregnant. That dosage is recommended to increase once pregnant to 600 micrograms of folic acid every day as a part of a prenatal vitamin. It is not advised to take more than 1,000 micrograms of the vitamin B supplement without first speaking with a health care provider.

Folic acid also comes from several different foods. In its naturally occurring form found in foods, folic acid is called folate. Packaging labels containing the words “fortified” and “enriched” are typically found on foods with added folic acid.

The following foods are good sources of folic acid and folate:
  • Bread
  • Breakfast cereal
  • Pasta
  • Cornmeal
  • White rice
  • Flour
  • Products made from corn masa flour
  • Some fruits and vegetables, including beans, leafy green vegetables and orange juice

Diagnosis and Treatment of Neural-Tube Defects

Neural-tube defects are usually diagnosed before the infant is born in lab and imaging tests. A blood test, called a quad screen, measures four substances in the expectant mother’s blood to detect if the pregnancy is at an increased risk of having neural-tube defects.

Additionally, an ultrasound in pregnancy is a diagnostic-imaging technique that is used to see internal body structures, such as inside the woman’s uterus (womb). It provides health care providers with an inside look at the developing fetus and surrounding structures (such as the placenta) to detect any abnormalities or malformations.

Doctor performing Amniocentesis
a procedure called amniocentesis can be done to diagnose specific birth defects in the fetus.

If a problem is suspected, a prenatal test called an amniocentesis can be done to diagnose specific birth defects in the fetus. The procedure involves using a long needle to extract amniotic fluid from inside the uterus to test for certain health conditions. The screening procedure is not without risks, however. There’s a small chance that a woman can experience a miscarriage following an amniocentesis.

There is no cure for neural-tube defects. The nerve damage and loss of function associated with the various conditions, and present at birth, are usually permanent. If diagnosed early in the pregnancy, however, treatment options may be available, including surgery soon after or even before birth. Research shows that surgery to repair spina bifida before birth (while the fetus is still in the mother’s uterus) is more effective than surgery performed after birth, according to the March of Dimes.

Several different treatment options are available to some infants born with neural-tube defects to prevent further damage and help with complications. However, in some cases, such as with anencephaly, there is no way to prevent imminent loss of life.

Depakote and Suicidal Thoughts

Depakote has been linked to other serious and potentially life-threatening side effects and complications, such as suicidal thoughts and actions. Taking certain anti-seizure medications, including Depakote ER, can increase a patient’s risk of suicidal thoughts and behaviors, according to drug labeling. Patients taking the medication for epilepsy were determined in clinical trials to be at the greatest risk.

Depakote warnings
Patients taking Depakote should be closely watched for signs of the beginning stages or worsening of depression, suicidal thoughts and/or actions, and/or any unusual changes in mood or behavior

Signs and symptoms of suicidal thoughts and behaviors as a side effect of taking Depakote can be observed as early as one week after starting treatment, labels say. Once these signs become apparent, they can continue for the duration of treatment. However, clinical trials have not studied this effect beyond 24 weeks of treatment, so patients’ risk of suicidal thoughts and actions with treatment lasting longer than 24 weeks is unknown.

Depakote and Blood & Metabolic Disorders

In addition to the risk of thoughts and actions related to suicide, Depakote is associated with bleeding and other hematopoietic (pertaining to hematopoiesis, or the formation of blood cells) disorders.

Bleeding and other hematopoietic disorders associated with Depakote include:
  • Abnormal/low platelet counts (thrombocytopenia)
  • Decreases in other blood cells
  • Poorly formed or dysfunctional blood cells (myelodysplasia)
  • Hemorrhage, bruising or a disorder of blood clotting

Hyperammonemia, a metabolic disorder characterized by too much ammonia in the blood, is another complication that can occur in patients taking Depakote. Ammonia forms in the body when protein is broken down by bacteria in the intestines. It is then converted into urea by the liver and eliminated from the body through urination.

Patients with a urea cycle disorder, a genetic disorder caused by a deficiency of one of the enzymes in the urea cycle responsible for removing ammonia from the blood stream, are at an even higher risk of developing a sometimes fatal condition called hyperammonemia encephalopathy.

Signs and symptoms of this condition may include unexplained lack of energy, vomiting or changes in one’s mental status.

Other serious side effects experienced by patients taking Depakote can include:
An unintentional drop in core body temperature.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (Multiorgan Hypersensitivity)
Typically presents with fever, rash, and/or swollen lymph nodes in association with other organ system involvement, and may be deadly.
Somnolence in the Elderly
A state of a strong desire for sleep or sleeping for unusually long periods of time; especially present in elderly patients with dementia taking Depakote.
Medication Residue in the Stool
Rare reports have indicated patients finding traces of the medication in their stool (feces); sometimes present with diarrhea.

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

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9 Cited Research Articles

  1. U.S. Food and Drug Administration. (2011 July 5). FDA drug safety podcast for healthcare professionals: children born to mothers who took valproate products while pregnant may have impaired cognitive development. Retrieved from
  2. Epilepsy Foundations of Connecticut. (2010, June 11). Anticonvulsant Valproic Acid Increases Risk of Congenital Disorders. Retrieved from
  3. Ornoy, A. (2009 July). Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reproductive Toxicology, 28:1. Retrieved from
  4. Smith, M. (2010, June 10). Antiseizure Drug Increases Birth Defect Risk. ABC News. Retrieved from
  5. Joffe, H.; Cohen, L.; Suppes, T.; McLaughlin, W.; Lavori, P.; Hwang, C.; Hall, J.; & Sachs, GS. (2006, January 31). Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with bipolar disorder. Biological Psychiatry, 59:11. Retrieved from
  6. Myers, C. (2008, December 17). FDA Requires Warnings about Risk of Suicidal Thoughts and Behavior for Antiepileptic Medications. Retrieved from
  7. PubMed Health. (n.d.). Valproic Acid. Retrieved from
  8. Underwood, T. & Frye, C. (1993 June). Drug-induced pancreatitis. Clinical Pharmacology 12:6. Retrieved from
  9. U.S. Food and Drug Administration. (2009 January). Depakene (valproic acid) Solution. Retrieved from,018082s032lbl.pdf
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