Divalproex (Depakote) is an anti-seizure drug that has been used for almost fifty years. It is also used to manage bipolar disorder, epilepsy, and migraines. But it can cause a number of side effects ranging from nausea to liver damage. Read on to discover more about the uses and side effects of Divalproex.
What is Divalproex (Depakote)?
Divalproex sodium (brand name Depakote) is a drug that is FDA-approved to treat various types of seizures, manic episodes associated with bipolar disorder, and to help prevent migraines [1].
This medication is also sometimes used off-label to treat several other conditions including schizophrenia symptoms and depression [2].
Divalproex vs Other Forms
There are several medications that are very similar to Divalproex, which may cause some confusion. These different forms (and their brand names) include [1]:
- Valproic acid (Depakene) – the active form of the drug
- Valproate sodium (Depacon) – the salt form of valproic acid
- Divalproex sodium (Depakote) – contains both valproic acid and valproate sodium
All of these medications are eventually converted into valproic acid in the body, which is the form that has a biological effect. The dosage of each different medication represents the activity of valproic acid [3].
Research suggests that these three different forms (valproic acid/valproate/Divalproex) have similar effectiveness. However, these drugs are not considered bioequivalent by the FDA, meaning they cannot be used interchangeably [3, 4, 5].
Other differences include how often they are dosed (Divalproex is available in an extended-release form) and price (Divalproex is usually much more expensive) [4, 5].
Mechanism of Action
The mechanism of action of Divalproex is not completely understood. Research suggests that valproic acid (the active form of the drug) may have several different mechanisms, including [6]:
- 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.
There is also emerging research that valproic acid may inhibit an enzyme called histone deacetylases (HDAC). Researchers are currently exploring valproic acid’s potential anti-cancer effects due to its ability to inhibit HDACs [7, 8, 9].
Uses of Divalproex (Depakote)
FDA-Approved Uses
1) Epilepsy
Divalproex has long been used to treat epilepsy and is considered the first-line treatment for several types of seizures, including partial seizures, absence seizures, and tonic-clonic seizures [10, 11].
In a review of 7 clinical trials including 1,809 patients, researchers concluded that Divalproex is as effective as many other antiepileptic drugs (like lamotrigine and topiramate) for treating generalized tonic-clonic seizures. Additionally, Divalproex and ethosuximide appear to be the best options for absence seizures [12].
In another review of 12 clinical trials, those taking Divalproex reported the most seizure-free responses compared to those on other common antiepileptic medications. This drug also had the lowest incidences of serious side effects [13].
Divalproex is also commonly used for children with epilepsy. A systematic review of 8 clinical trials found that Divalproex may be more effective than lamotrigine for the treatment of absence seizures in children. However, the researchers also found that side effects were more frequent in children taking Divalproex [14].
2) Migraine Prevention
According to a number of clinical trials, Divalproex may help prevent migraines and is one of the first-line medications used for migraine prevention in certain patients [15].
The American Academy of Neurology and the American Headache Society reviewed 29 clinical trials and concluded that Divalproex is effective at reducing the frequency and severity of migraines [15].
Divalproex can also be used to prevent migraines in children. Multiple reviews suggest that this medication may decrease the frequency and severity of migraines in children as well [16, 17].
3) Manic Episodes in Bipolar Disorder
Those with bipolar disorder often experience periods of depression along with episodes of mania, where they feel abnormally energized and elated. Divalproex is approved for the treatment of bipolar disorder, especially for managing manic episodes [18].
According to a systematic review of 25 clinical trials including 3,252 patients, Divalproex may be effective for the treatment of acute mania. However, the drug did not appear to be effective for treatment in children and adolescents [19].
Another systematic review of 6 clinical trials suggests that Divalproex may be effective for the long-term treatment of bipolar disorder, but the evidence is limited [20].
On the other hand, there is some evidence that Divalproex may also be effective for depression associated with bipolar disorder. Three meta-analyses have concluded that this drug is effective at reducing depressive symptoms in bipolar disorder [21, 22, 23].
Off-Label Uses
Divalproex is used for several off-label conditions, which we’ll discuss in the following sections. If you are prescribed this medication, always take the medication as directed by your doctor.
4) Anxiety
Divalproex is sometimes used to treat anxiety symptoms.
For example, an open clinical trial with 10 patients with panic disorder found that Divalproex may reduce panic symptoms and anxiety while also improving unstable mood [24].
In a randomized placebo-controlled trial of 17 patients with social anxiety disorder, Divalproex reduced anxiety symptoms in approximately half of the patients [25].
Other research suggests that Divalproex may be the drug of choice in patients with both anxiety and bipolar disorder [26].
5) Depression
As previously discussed, Divalproex may be effective for depression associated with bipolar disorder. However, there is also evidence that this drug may help with general depression that’s not associated with other conditions.
A small open-label study of 33 patients with major depressive disorder found that Divalproex reduces depression symptoms in up to 86% of patients after 8 weeks of treatment [27].
In a 7-month study of 14 patients with depression that did not respond to conventional antidepressants, Divalproex decreased symptoms and helped prevent relapse when added to their normal therapy [28].
6) Schizophrenia Symptoms
According to a meta-analysis of 11 clinical trials including 889 patients, Divalproex may reduce the symptoms of schizophrenia when added to conventional treatment with antipsychotics. However, this effect was only seen in short-term trials [29].
7) Schizoaffective Disorder
Schizoaffective disorder is closely related to schizophrenia but includes depression and mania symptoms in addition to the common symptoms of schizophrenia [30].
In a retrospective study of 20 schizoaffective patients, Divalproex improved symptoms in 75% of the patients [31].
According to a different study of 15 patients with schizoaffective disorders, Divalproex may reduce the length and intensity of symptoms over 2 to 4 years of treatment [32].
Clinical Research On Divalproex (Depakote)
Clinical research is exploring the use of Divalproex for several other conditions, which are described below. However, this research is preliminary and investigational only. The safety and effectiveness of Divalproex for these conditions is unclear until more studies are performed.
Cancer Research
Divalproex has not been shown to treat or prevent cancer. The potential anti-cancer effect of Divalproex has only studied in preliminary phase I and II trials. More clinical trials are needed to evaluate the safety and effectiveness of this medication for this use.
Tumor cells can sometimes develop resistance to anti-cancer drugs, reducing their effects over time. There is some evidence from phase I and II clinical trials that Divalproex may help re-sensitize some tumors to anti-cancer drugs they were previously resistant to [33].
Research suggests Divalproex may have this effect in several types of cancer, including [33, 34]:
- Advanced solid tumors [35]
- Breast cancer [36]
- Melanoma [37]
- Advanced cervical cancer [38]
- Mesothelioma [39]
According to some researchers, the anti-cancer effect of Divalproex may be due to its ability to alter the activity of genes by inhibiting the enzyme histone deacetylase [33].
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.
A pilot study in 22 HIV patients found that Divalproex may improve cognition in those with HIV-related cognitive impairments [40].
However, research also shows that Divalproex does not prevent HIV infection or reduce the virus’ ability to spread within the body [41].
Hair Loss
A randomized placebo-controlled trial of 40 patients with male pattern baldness (androgenic alopecia) suggests that a topical form of Divalproex may promote hair growth when applied to the scalp [42].
However, hair loss is also a reported side effect of Divalproex [43].
Divalproex (Depakote) Safety
Side Effects
Side effects can be common when taking Divalproex. If any side effects persist or worsen, let your doctor know. This is also not a complete list of possible side effects. Tell your doctor if you experience any serious side effects or notice any effects not listed here.
Some common side effects include [43]:
- Nausea
- Vomiting
- Hair loss (alopecia)
- Abdominal pain
- Blurred vision
- Insomnia
- Dizziness
- Shakiness (motor tremors)
Some reported long-term side effects include [44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55]:
- 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 appear to be specific to children who take Divalproex, such as [56, 57, 58]:
- Increased need for sleep
- Hypothyroidism
- Fanconi syndrome (a disorder that impairs the ability of the kidneys to absorb essential nutrients)
Warnings
Pregnancy Risks
Divalproex has been shown to cause birth defects and should be avoided during pregnancy whenever possible. Divalproex should only be used during pregnancy if a doctor determines that the benefits outweigh the risks [43].
According to research, some potential birth defects include heart, urinary, genital, neural, and bone abnormalities, with higher doses causing more defects [59, 60, 61, 62, 63, 64].
Liver Risks
Divalproex may cause damage to the liver. For those taking Divalproex, the FDA recommends regular tests to monitor liver function [43].
Suicide Risk
Divalproex is associated with a higher risk of suicidal thinking and behavior. Those taking this medication should be monitored and any changes in behavior should be reported to a doctor [43].
Pancreatitis
There have been reported deaths in those with pancreatitis (inflammation of the pancreas) who took Divalproex. Patients with pancreatitis should avoid using this medication [43].
Contraindications
Liver Disease
Divalproex may cause damage to the liver, especially in the first 6 months of treatment. Fatal cases of liver toxicity have been reported. Those with liver disease should avoid taking this medication [43]
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. Divalproex may interfere with the urea cycle, which can make urea cycle disorders even more dangerous [65, 66].
Hypersensitivities
People who are sensitive or allergic to Divalproex should refrain from taking this medication [43].
Drug Interactions
The following drugs have been reported to interact with Divalproex. However, this is not a complete list, let your doctor know of all the medications you are currently taking to avoid any unexpected interactions.
Alcohol
Divalproex 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 [67].
Combining these two drugs may also cause [67]:
- Drowsiness
- Restlessness
- Dizziness
- Loss of appetite
- Joint pain
- Muscle pain
- Depression
Aspirin
There have been multiple cases of patients experiencing toxicity symptoms when taking Divalproex and aspirin together. If both medications are taken together, blood levels of Divalproex may need to be monitored [43].
Antibiotics
Divalproex can interact with antibiotics, especially ones from the “carbapenem” family, such as meropenem. Taking these drugs together can lead to rapid decreases in Divalproex levels [43].
Because Divalproex normally reduces the activity of neurons in the brain, a sudden drop in Divalproex levels can cause the brain to suddenly become overactive, which may lead to seizures (even in people who have not previously had seizures before) [68, 69, 70].
Antiepileptics
Divalproex has been shown to interact with at least 3 other common anti-seizure drugs: lamotrigine, levetiracetam, and phenytoin.
An open-label study of 18 male subjects found that taking Divalproex with lamotrigine may decrease the clearance of lamotrigine. This may lead to increased levels of active lamotrigine in the body, which could increase the risk of toxicity or overdose [71].
A study of 52 epileptic patients found that Divalproex and levetiracetam together led to an increase in the total amount of Divalproex in the body, increasing the likelihood of toxicity and overdose [72].
A case study in a 12-year-old child with epilepsy found that Divalproex can release phenytoin from the proteins that bind to it in order to inactivate it during transport through the body. This may lead to dangerous levels of activated phenytoin in the body, leading to phenytoin toxicity [73].
Antidepressants
Divalproex may have interactions with at least 4 other relatively common antidepressants: doxepin, venlafaxine, lamotrigine, and amitriptyline.
A retrospective study of 57 depression patients found that taking Divalproex may lead to abnormally elevated levels of doxepin and venlafaxine, thereby leading to potentially dangerous toxic effects [74].
Similarly, a randomized crossover study with 18 male patients found that Divalproex may decrease the rate at which the body breaks down lamotrigine, which could lead to dangerously elevated active levels of this drug [71].
Finally, a retrospective study of 66 depression patients found that taking Divalproex with amitriptyline may also lead to abnormally high levels of active amitriptyline in the bloodstream [75].
Antipsychotics
Two case studies report an adverse interaction between Divalproex 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 [76, 77].
In another case report, a patient taking Divalproex developed inflammation of the brain after risperidone was added to their treatment [78].
Dosage
Always take pregabalin as directed by a doctor and do not discontinue the medication abruptly.
Divalproex 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 Divalproex 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 [79]:
- 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.
