What is Depakote used for. How does Depakote work as a mood stabilizer. What are the potential side effects of Depakote. Is Depakote safe for pregnant women. How should Depakote be dosed and administered. What are the long-term effects of taking Depakote. Can Depakote be safely discontinued.

Understanding Depakote: Uses and Mechanism of Action

Depakote, also known by its generic name divalproex sodium, is a versatile medication primarily used as an anticonvulsant. Its applications extend beyond seizure control, making it a valuable tool in managing various neurological and psychiatric conditions.

The U.S. Food and Drug Administration (FDA) approved Depakote in 1996, marking a significant milestone in the treatment of bipolar disorder, seizures, and migraine prevention. But how does this medication work?

Depakote functions by calming the hyperactivity of the brain, particularly during manic episodes associated with bipolar disorder. This mechanism of action makes it especially effective in cases where patients experience rapid cycling of mood episodes.

Key Uses of Depakote:

• Treatment of manic symptoms in bipolar disorder
• Control of seizures in epilepsy
• Prevention of migraine headaches

As an anticonvulsant, Depakote stands out from other antipsychotics used in bipolar disorder treatment. Its unique properties make it a preferred choice for certain patients, particularly those who have not responded well to other medications.

Dosage and Administration of Depakote

Proper dosing of Depakote is crucial for its effectiveness and safety. The FDA recommends a starting dosage of 750 mg daily for treating mania. However, dosage can vary based on individual patient needs and response to the medication.

What is the maximum recommended dosage for Depakote? The maximum recommended dosage is 60 mg/kg per day. It’s important to note that this is a general guideline, and your healthcare provider may adjust the dose based on your specific condition and response to the medication.

Dosing Considerations:

1. Start with the recommended initial dose
2. Gradually increase the dose as needed under medical supervision
3. Monitor for side effects and therapeutic response
4. Adjust dosage based on individual patient needs

Missing a dose of Depakote can happen, but it’s important to handle it correctly. If you miss a dose, take it as soon as you remember. However, if it’s almost time for your next scheduled dose, skip the missed dose and continue with your regular dosing schedule. Never double up on doses to make up for a missed one.

Side Effects and Safety Considerations of Depakote

Like all medications, Depakote can cause side effects. Understanding these potential effects is crucial for patients and caregivers to ensure safe and effective use of the medication.

Common Side Effects:

• Headaches
• Sleepiness
• Nausea and vomiting
• Tremors
• Fatigue
• Dizziness
• Blurred vision
• Stomach pain
• Diarrhea
• Weight gain
• Hair loss or thinning
• Coordination problems
• Flu-like symptoms

While these side effects are generally mild, some patients may experience more severe reactions. It’s important to report any concerning symptoms to your healthcare provider immediately.

Can Depakote cause psychological side effects? Yes, in rare cases, Depakote can cause suicidal thoughts. Patients and caregivers should be vigilant for any changes in behavior or mood, especially during the initial stages of treatment or when adjusting dosages.

Serious Side Effects to Watch For:

• Red or purple spots on skin
• Swelling or pain in joints
• Unusual bruising
• Significant changes in mental status
• Sudden drop in body temperature
• Fever
• Severe rash or hives
• Mouth sores
• Peeling of skin
• Facial swelling
• Difficulty swallowing or breathing

If you experience any of these serious side effects, seek medical attention immediately. You can also report side effects to the FDA at 1-800-FDA-1088 or through their online reporting system.

Long-Term Effects and Risks of Depakote Use

While Depakote can be an effective treatment for various conditions, it’s important to be aware of potential long-term effects and risks associated with its use.

One of the most significant concerns with long-term Depakote use is the potential for liver damage. This risk is particularly high during the first 6 months of treatment. What are the signs of liver damage to watch for? Patients should be alert for symptoms such as:

• Nausea or vomiting
• Loss of appetite
• Abdominal pain
• Dark-colored urine
• Facial swelling
• Yellowing of the skin or whites of the eyes (jaundice)

Another potential long-term risk is pancreatitis. Cases of pancreatitis have been reported in both children and adults taking Depakote. Symptoms of pancreatitis can include severe abdominal pain, nausea, and vomiting.

Regular monitoring and follow-up with your healthcare provider are essential to manage these risks effectively. Your doctor may recommend periodic blood tests to check liver function and monitor for other potential issues.

Depakote and Pregnancy: Risks and Considerations

The use of Depakote during pregnancy is a significant concern due to the potential risks to the developing fetus. Is it safe for pregnant women to take Depakote? The answer is generally no, as Depakote can cause birth defects and fetal harm when taken during pregnancy.

Women who are pregnant, planning to become pregnant, or nursing should discuss their treatment options with their healthcare provider. In most cases, alternative medications may be recommended for treating seizures or bipolar disorder in patients who are or may become pregnant.

Key Points About Depakote and Pregnancy:

• Depakote can cause serious birth defects
• The drug can be transferred via breast milk and potentially harm a nursing infant
• Depakote should only be used during pregnancy if other medications have failed to provide adequate relief
• Women of childbearing age should use effective contraception while taking Depakote

Healthcare providers must carefully weigh the potential benefits of Depakote treatment against the risks when considering its use in pregnant women or those who may become pregnant.

Interactions and Contraindications of Depakote

Depakote can interact with numerous other medications, making it crucial for patients to inform their healthcare providers about all drugs, supplements, and herbal products they are taking.

What are some common medications that interact with Depakote? Some notable interactions include:

• Hepatic enzyme-inducing drugs
• Aspirin
• Carbapenem antibiotics
• Diazepam
• Ethosuximide
• Lamotrigine
• Phenytoin
• Amitriptyline
• Nortriptyline
• Warfarin
• Zidovudine
• Topiramate

These interactions can affect the efficacy of Depakote or increase the risk of side effects. Your healthcare provider can help manage these interactions and adjust your treatment plan as needed.

Are there medical conditions that make someone ineligible for Depakote therapy? Certain medical conditions may contraindicate the use of Depakote. These include:

• Liver disease
• Mitochondrial disease
• Urea cycle disorders

Patients with these conditions are typically advised not to take Depakote due to the increased risk of severe side effects. Always provide your healthcare provider with a complete medical history before starting Depakote treatment.

Discontinuing Depakote: Withdrawal and Considerations

Discontinuing Depakote requires careful management to avoid potential withdrawal symptoms and ensure patient safety. Abruptly stopping the medication can lead to various adverse effects and potentially worsen the underlying condition being treated.

What symptoms can occur if Depakote is discontinued? Withdrawal symptoms may include:

• Irritability
• Anxiety
• Return of manic or depressive symptoms
• Dizziness
• Tremors

To minimize these risks, discontinuation of Depakote should always be done under medical supervision. Your healthcare provider will typically recommend a gradual tapering of the dose over time, allowing your body to adjust and reducing the likelihood of withdrawal symptoms.

Steps for Safe Discontinuation:

1. Consult with your healthcare provider about the decision to discontinue
2. Develop a tapering plan tailored to your individual needs
3. Monitor for any signs of withdrawal or worsening of your condition
4. Follow up regularly with your healthcare provider during the discontinuation process
5. Have a plan in place for managing any breakthrough symptoms

Remember, the decision to discontinue Depakote should be made in consultation with your healthcare provider, taking into account your overall health, the condition being treated, and any potential risks or benefits of stopping the medication.

Special Considerations for Children Taking Depakote

While Depakote can be an effective treatment for certain conditions in children, there are important considerations and precautions to keep in mind. The use of Depakote in pediatric patients requires careful monitoring and assessment of risks versus benefits.

Can children take Depakote safely? Children can take Depakote, but there are age-related restrictions and increased risks to consider. Children younger than 2 years old are at higher risk for liver damage when taking the medication. Additionally, the use of Depakote ER (extended-release) is not recommended in children younger than 10 years old.

Key Points for Pediatric Use of Depakote:

• Increased risk of liver damage in children under 2 years old
• Not recommended for children under 10 years old in its extended-release form
• Requires close monitoring for side effects and therapeutic response
• Dosage should be carefully calculated based on the child’s weight and condition
• Regular liver function tests may be necessary

Parents and caregivers should have a thorough discussion with their child’s healthcare provider about the potential risks and benefits of Depakote treatment. This conversation should include a review of alternative treatment options and a clear understanding of monitoring requirements and potential side effects to watch for.

How should parents monitor their child while on Depakote? Parents should be vigilant for any signs of liver problems, unusual bleeding or bruising, changes in behavior or mood, and other side effects. Regular follow-up appointments and communication with the child’s healthcare provider are essential for safe and effective treatment.

Managing Depakote Side Effects and Improving Quality of Life

While Depakote can be an effective treatment for various conditions, managing its side effects is crucial for maintaining a good quality of life. Understanding how to mitigate these effects can help patients continue their treatment while minimizing discomfort and potential risks.

Strategies for Managing Common Side Effects:

• Nausea and stomach upset: Take Depakote with food or consider a slow-release formulation
• Weight gain: Maintain a balanced diet and regular exercise routine
• Hair loss: Consult with a dermatologist about hair care strategies and potential supplements
• Fatigue: Adjust dosing schedule in consultation with your healthcare provider
• Tremors: Discuss dosage adjustment or addition of beta-blockers with your doctor

Can lifestyle changes help in managing Depakote side effects? Yes, certain lifestyle modifications can significantly improve your experience with Depakote. These may include:

1. Maintaining a consistent sleep schedule
2. Avoiding alcohol and recreational drugs
3. Staying hydrated
4. Practicing stress-reduction techniques like meditation or yoga
5. Attending regular check-ups and being open with your healthcare provider about any concerns

It’s important to remember that while side effects can be challenging, they often improve over time as your body adjusts to the medication. However, if side effects persist or significantly impact your quality of life, don’t hesitate to discuss alternatives or adjustments with your healthcare provider.

Depakote in Comparison to Other Mood Stabilizers and Anticonvulsants

Understanding how Depakote compares to other medications in its class can help patients and healthcare providers make informed decisions about treatment options. While Depakote is effective for many, it’s not the only choice available for managing bipolar disorder, seizures, or migraines.

How does Depakote differ from other mood stabilizers? Unlike some other mood stabilizers, Depakote is an anticonvulsant that works by altering neurotransmitter levels in the brain. This mechanism can be particularly effective for patients with rapid cycling bipolar disorder.

Comparison with Other Common Mood Stabilizers:

• Lithium: Often considered the gold standard for bipolar disorder treatment, but requires close monitoring of blood levels
• Carbamazepine: Another anticonvulsant used for mood stabilization, with a different side effect profile
• Lamotrigine: Particularly effective for bipolar depression, with a lower risk of weight gain
• Antipsychotics: Such as quetiapine or olanzapine, which can be used as mood stabilizers but work through different mechanisms

When choosing between Depakote and other options, healthcare providers consider factors such as the specific symptoms being treated, potential side effects, patient medical history, and individual response to treatment.

Is Depakote more effective than other anticonvulsants for seizure control? The effectiveness of anticonvulsants can vary greatly between individuals. While Depakote is highly effective for many types of seizures, other anticonvulsants like levetiracetam or topiramate may be preferred in certain cases due to their side effect profiles or specific mechanisms of action.

Ultimately, the choice of medication should be a collaborative decision between the patient and healthcare provider, taking into account all relevant factors and carefully weighing the potential benefits against the risks.

Facts, Side Effects, Cost, Dosing

What is Depakote? Depakote is a medication known as an anticonvulsant that is used to treat the manic symptoms of bipolar disorder. It is also used to treat seizures and prevent migraine headaches.

When did the U.S. Food and Drug Administration (FDA) approve the medication? Depakote was approved by the FDA in 1996.

Is there a generic version of Depakote? Yes, the generic version is known as divalproex sodium and is sold in the U.S.

Are there any major differences between Depakote and other antipsychotics used to treat bipolar disorder? Depakote belongs to the class of medications known as anticonvulsants. Anticonvulsants are used to treat seizures and sometimes are taken to treat the manic episodes associated with bipolar disorder. Depakote is sometimes prescribed when patients experience rapid cycling of mood episodes and works by calming the hyperactivity of the brain during mania.

Can children take Depakote? Children younger than 2 are at higher risk for liver damage when taking the medication. Talk to your child’s doctor about the risks of using the medication. It is important to note that the use of Depakote ER is not recommended in children younger than 10.

Are there potential interaction issues for people taking Depakote and any other drugs? There are hundreds of drugs which are known to interact with Depakote in major, moderate, or mild ways, so let your doctor know what other medications you are taking before you begin taking the medication. Some of these include hepatic enzyme-inducing drugs, aspirin, carbapenem antibiotics, diazepam, ethosuximide, lamotrigine, phenytoin, amitriptyline, nortriptyline, warfarin, zidovudine, and topiramate.

Are there any other medical conditions that would make someone ineligible for Depakote therapy? Talk to your doctor about other medical conditions before you take Depakote. Persons with liver disease, mitochondrial disease, and urea cycle disorders are typically advised not to take Depakote.

What is the typical dose that would be prescribed to someone taking Depakote? The FDA recommends that dosage for treating mania begin at 750 mg daily. The maximum recommended dosage is 60mg/kg per day.

What do I do if I miss a dose? Take the dose of Depakote when you remember, but skip the missed dose if it is almost time for your next dose. You should never take extra doses of the medication to make up for missed doses.

What side effects can Depakote cause? The side effects of Depakote can include:

• headaches

• sleepiness

• nausea

• tremors

• fatigue

• vomiting

• dizziness

• blurred vision

• stomach pain

• diarrhea

• weight gain

• hair loss or thinning

• coordination problems

• flu-like symptoms

It also is recommended that you wait to drive or operate machinery until you know how the medication affects you. It is also recommended that people avoid alcohol and illegal drugs while on the medication, as they can worsen adverse effects. Report major side effects to your doctor immediately, which can include red or purple spots on skin, swelling or pain in joints, bruising, drowsiness, vomiting, change in mental status, drop in body temperature, fever, rash, hives, mouth sores, peelings of skin, swelling of face, and trouble swallowing or breathing. You can also report side effects to the FDA at 1-800-FDA-1088 or online.

What are the potential psychological side effects of taking Depakote? Depakote causes suicidal thoughts in a small percentage of people who take the medication. Seek medical help if you experience these thoughts or other changes in your behavior or mood.

What are the potential long-term effects of taking Depakote? Depakote can cause liver damage, and the risk is more likely to occur during the first 6 months of taking the medication. Signs might include nausea or vomiting, loss of appetite, abdominal pain, dark-colored urine, facial swelling, and yellowing of the skin or white of eyes. Cases of pancreatitis among children and adults taking the medication have also been reported.

Is it safe for a woman who is pregnant, about to become pregnant, or nursing to take Depakote? Depakote can cause birth defects and fetal harm when taken during pregnancy. The drug can be transferred via breast milk and potentially harm a baby. Depakote should not be used for treatment of seizures or bipolar disorder in patients who plan to become pregnant unless other medications have failed to provide adequate relief. Therefore, talk to your doctor if you are pregnant, planning to become pregnant, or are nursing before you take Depakote.

Can symptoms occur if Depakote is discontinued? It’s important not to discontinue use of the drug before talking with your doctor. Withdrawal symptoms of Depakote can include irritability, anxiety, the return of manic or depressive symptoms, dizziness, and tremors.

What should I do if I overdose on Depakote? An overdose of Depakote could be fatal, so seek immediate help or call the Poison Help Line at 1-800-222-1222 if you overdose. Overdose symptoms can include irregular heartbeat, sleepiness, and loss of consciousness resulting in a coma.

Is Depakote habit-forming? Depakote has no habit-forming potential, but it is not recommended that you discontinue use of the drug before talking with your doctor, as withdrawal symptoms can occur.

How much does Depakote cost? According to goodrx.com, 60 tablets of 500 mg brand-name divalproex sodium cost approximately $400. As for generic divalproex, 60 tablets of 500mg costs about $28.

Are there any disadvantages to Depakote? The biggest disadvantages of Depakote are potential side effects which include possible liver damage or pancreatitis. Pregnant women are also typically advised not to take the medication due to the risk of birth defects.

DISCLAIMER: The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. This article mentions drugs that were FDA-approved and available at the time of publication and may not include all possible drug interactions or all FDA warnings or alerts. The author of this page explicitly does not endorse this drug or any specific treatment method. If you have health questions or concerns about interactions, please check with your physician or go to the FDA site for a comprehensive list of warnings.

• NIH – Depakote
• FDA – Depakote

Notes: This article was originally published January 2, 2017 and most recently updated September 26, 2022.

Valproic Acid – StatPearls – NCBI Bookshelf

Continuing Education Activity

Valproic acid is an anticonvulsive and mood stabilizer medication. It is extensively used in the adult population to treat convulsions, migraines, and bipolar disorders. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team) in the treatment of patients with epilepsy and related conditions.

Objectives:

• Identify the mechanism of action of valproic acid.

• Describe the adverse effects of valproic acid.

• Review the appropriate monitoring for patients receiving valproic acid.

• Summarize inter-professional team strategies for improving care coordination and communication to advance valproic acid therapy and improve outcomes.

Access free multiple choice questions on this topic.

Indications

Valproic acid is a branched, and short-chain fatty acid is a derivative of naturally occurring valeric acid. Valproic acid’s primary use is as an anti-seizure medication, as well as in migraine, bipolar, mood, and anxiety disorders. Recent work has also demonstrated its efficacy as adjuvant therapy in HIV, cancer, and neurodegenerative diseases as its histone deacetylase (HDAC) inhibition property. Valproic acid is a widely used therapy for pediatric epilepsy for its multiple targets and acceptable safety profile. The highly variable dose requirements and interactions with a wide range of drugs warrant regular patient follow-up and therapeutic drug monitoring. However, the clinical and adverse drug effects correlate poorly with the serum concentrations of the drug. 

Divalproex sodium is the stable, coordinated compound of sodium valproate and valproic acid. Due to its characteristic broad spectrum anticonvulsive activity, divalproex sodium is used to treat a wide range of seizure disorders such as myoclonic epilepsy syndromes, absence epilepsy, generalized convulsions, partial seizures, and status epilepticus.[1][2] Divalproex sodium is also efficient in managing acute depressive episodes of bipolar mood disorder and severe manic or mixed episodes.[3] Its use has significantly increased over the past decades as a mood stabilizer as well as replacing lithium. However, a retrospective cohort study of patients with bipolar found that patients treated with lithium had a lower risk of suicide attempt and suicide death than when treated with divalproex sodium. [4] Nevertheless, the 2002 APA Guidelines recommendation for treatment of severe manic or mixed episodes is the initiation of lithium or divalproex sodium plus an atypical antipsychotic as first-line therapy.

Patients who experience less severe events can have treatment with divalproex, lithium, or an atypical antipsychotic as monotherapy. Lamotrigine is a modern antiepileptic agent that has received approval for the prevention of depressive episodes in bipolar disorder. The pharmacological guidelines for treating bipolar disorder remain complex and recommend augmentation with lamotrigine for patients who respond partially to combined therapy with lithium and divalproex.[5][6] Caution is necessary as valproic acid increases the elimination half-life of lamotrigine.[7] Furthermore, valproic acid has become widely recognized for the prophylaxis of migraine headaches since approved by the FDA for this indication in 1996.[8] In the pediatric population, valproic acid has shown promising efficacy in treating bipolar mood disorder and conduct disorder and targeting symptoms of irritability, aggression, and impulsivity. [7] Research on the use of valproic acid in cancer therapy is still in its infancy and provides insight into new areas of its application.[9] 

Mechanism of Action

Valproic acid exhibits its pharmacologic effects in a couple of ways, such as by acting on GABA (γ aminobutyric acid) levels in the CNS, blocking voltage-gated ion channels, and inhibiting histone deacetylase. Impaired GABAergic inhibitory activity is established pathophysiology of seizure initiation and propagation, given that controlling this pathway a potential target for antiepileptic drugs. GABA is synthesized from α-ketoglutarate through the tricarboxylic acid(TCA) cycle and metabolized into succinate semialdehyde and then to succinate by GABA transaminase and succinate semialdehyde dehydrogenase, respectively. Previous studies have shown that valproic acid inhibits GABA transaminase and succinate semialdehyde dehydrogenase, increasing the GABA concentration by reducing its degradation (Figure-1).

Valproic acid may also exert antiepileptic effects by reducing the high-frequency firing of neurons by voltage-gated sodium, potassium, and calcium channel blockade.  Valproic acid modulates the biochemical phenomenon of aura and affects nociception by modulating GABA and/or glutamate-mediated neurotransmission. In neuropathic pain, it has been demonstrated that valproic acid blocks neurogenic inflammation by GABA-A receptor-mediated inhibition. Recently, valproic acid showed to be an inhibitor of histone deacetylase (HDAC), particularly HDAC1, as well as other HDAC. Histone deacetylase inhibition potentially upregulates the expression of genes that regulates apoptosis and antitumor action.[10]

Additionally, valproic acid affects signaling systems like the Wnt/Beta-Catenin and ERK pathways, which similarly interfere with inositol and arachidonate metabolism. Valproate use plays a role in the expression of multiple genes involved in cell survival, transcription regulation, ion homeostasis, signal transduction, and cytoskeletal modifications. Both immediate biochemical effect and genomic influences as a long-term effect can explain the underlying effect of valproic acid in treating all three indications listed above. [11][12][10][13]

Administration

Valproic acid is administered orally in tablet form and sprinkles or capsules. The tablet is available in a delayed-release form 125 mg, 250 mg, and 500 mg or an extended-release form of 250 mg and 500 mg. Capsules are available in 125 mg strength.

For the Treatment of Epilepsy

• Valproic acid can be used as monotherapy or as adjunctive therapy in complex partial seizures. The dosage is usually started at 10 to 15 mg/kg/day, not to exceed 60 mg/kg/day. If daily doses exceed 250 mg, it is given in divided doses.

For the Treatment of Mania

• The initial dose for treatment of mania is 250 mg 3 times a day.

• For the ER form, the initial dose is 25 mg/kg once a day, with a rapid increase of up to 60 mg/kg/day in an attempt to achieve the desired clinical effect.

For Migraine Prophylaxis

• Valproic acid’s initial dose indicated in migraine prophylaxis is 250 mg twice a day for one week.

• The ER form can be started at 500 mg once daily for one week. The dose can be increased up to 1000 mg/day if needed.

Therapeutic Range

• Epilepsy: 50 to 100 mcg/ml total valproate

• Mania: 50 to 125 mcg/ml total valproate

• It takes about 14 days for valproic acid to reach maximum concentration.

Dose Modifications

• Renal impairment: no adjustment needed

• Hepatic impairment: administer with caution and in lower doses. Valproic acid is contraindicated in cases of severe hepatic impairment.

Adverse Effects

Serious Reactions

Valproic acid has multiple serious adverse reactions such as hepatotoxicity, hallucinations, suicidality, psychosis, toxic epidermal necrolysis, Steven Johnson Syndrome, anaphylaxis, hyponatremia, SIADH, pancreatitis, thrombocytopenia, pancytopenia, hyperammonemia, myelosuppression, hypothermia, aplastic anemia, bleeding, erythema multiforme, polycystic ovarian syndrome, cerebral pseudo atrophy, encephalopathy, and coma. Abrupt discontinuation of the drug can cause withdrawal seizures.

Common Reactions

More common reactions that have been reported in patients using valproic acid are headache, abdominal pain, somnolence, dizziness, thrombocytopenia, asthenia, nausea & vomiting, diarrhea, dizziness, tremor, weight changes, alopecia, constipation, emotional lability, insomnia, petechiae & ecchymosis, depression, rash, nervousness, appetite changes, ALT and AST elevation, tinnitus, blurred vision, nystagmus, photosensitivity, myalgia, and dyspnea.

Contraindications

Valproic acid is contraindicated in patients with hepatic disorders, significant hepatic impairment, hypersensitivity to components of the drug and class of drug, urea cycle disorders, mitochondrial disorders, or suspected disorders in patients <2-year-old, and pregnancy (for migraine headache prophylaxis use of valproic acid).

Also, valproic acid use requires caution in patients under two years old, pediatric, elderly, renal impairment, organic brain disorders, head injury, mental retardation with seizure disorders, congenital metabolic disorders, hereditary mitochondrial disorders, multiple anticonvulsant treatments, myelosuppression, decreased GI transit time, hepatic disease, an active or a history of depression, and bleeding risk.

Black Box Warnings

• Serious or fatal hepatic failure has been reported during the first six months of treatment. Patients <2-year-old are in greater danger of hepatic toxicity. There is an increased risk of fatality in anticonvulsant polytherapy. In older patients, hepatotoxicity may present with symptoms of weakness, lethargy, anorexia, facial edema, vomiting, and loss of seizure control; monitoring symptoms and LFTs at baseline and then frequently is recommended, particularly during the first 6months of treatment.

• The use of valproic acid in patients with mitochondrial disease (POLG-related Mitochondrial disorders) has been demonstrated to increase the risk of hepatotoxicity and death. Valproic acid should only be used in patients over two years old with suspected Mitochondrial disorders who have failed to respond to other anticonvulsant treatments, with frequent monitoring of LFT and POLG mutation screening.

• It can cause life-threatening pancreatitis. Cases of hemorrhagic-pancreatitis with rapid progression to death have been reported in all ages regardless of treatment duration. If patients have symptoms of pancreatitis such as nausea, vomiting, abdominal pain, or anorexia, advise them to discontinue the medication and start alternative treatment based on clinical indication.[14][15] 

• It can cause severe congenital malformations such as neural tube defects and lower IQ scores after in-utero exposure. Additionally, in-utero exposure to valproic acid correlates with an increased risk of autism spectrum disorders in children.[16][17] The use of valproic acid in pregnant women for migraine headaches is contraindicated unless there is no other alternative anticonvulsant therapy. According to APA guidelines, additional screening is recommended for women with bipolar disorder who choose to continue taking valproic acid during pregnancy.[18]

Monitoring

• LFTs should be monitored at baseline and then frequently, especially during the first six months of treatment or in the presence of hereditary mitochondrial disease.

• CBC with differential, coagulation test, and ammonia should be monitored at baseline, periodically, before planned surgery, and during pregnancy.

• Screen for symptoms of depression, behavior changes, and suicidality.

• Serum Drug level (therapeutic level for epilepsy: 50 to 100 mcg/ml; and for mania 50 to 125 mcg/ml) and toxic levels: >175 mcg/ml (before morning dose). As valproate is protein-bound, it is important to test the free levels in the presence of hypoalbuminemia. The concentration of the total may be inaccurate.

Enhancing Healthcare Team Outcomes

Valproic acid is a widely used medication having efficacy in treating multiple neuropsychiatric disorders. A wide range of indications involves multiple medical specialties administering therapy with valproic acid appropriately. Thus, an interprofessional healthcare team, including clinicians (MDs, DOs, NPs, PAs), nurses, and pharmacists, with knowledge of its contraindications, dose adjustments, and potential adverse effects, is necessary for health care workers to ensure patient safety and the best outcome. By exercising collaborative efforts and open communication, dosing and management of valproic acid can optimize patient therapy for its various indications. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

Figure

Figure-1: Mechanism of action of valproic acid. Figure demonstrates the metabolic pathway of GABA synthesis and metabolism by alfa-ketogluterate dehydrogenase, GABA transaminase and Succinate dehydrogenase. Valproic acid inhibits the two downstream catabolic (more…)

References

1.

Willmore LJ. Divalproex and epilepsy. Psychopharmacol Bull. 2003;37 Suppl 2:43-53. [PubMed: 15021860]

2.

Olsen KB, Taubøll E, Gjerstad L. Valproate is an effective, well-tolerated drug for treatment of status epilepticus/serial attacks in adults. Acta Neurol Scand Suppl. 2007;187:51-4. [PubMed: 17419829]

3.

Bond DJ, Lam RW, Yatham LN. Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis. J Affect Disord. 2010 Aug;124(3):228-34. [PubMed: 20044142]

4.

Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 2003 Sep 17;290(11):1467-73. [PubMed: 13129986]

5.

Calabrese JR, Vieta E, Shelton MD. Latest maintenance data on lamotrigine in bipolar disorder. Eur Neuropsychopharmacol. 2003 Aug;13 Suppl 2:S57-66. [PubMed: 12957721]

6.

López-Muñoz F, Shen WW, D’Ocon P, Romero A, Álamo C. A History of the Pharmacological Treatment of Bipolar Disorder. Int J Mol Sci. 2018 Jul 23;19(7) [PMC free article: PMC6073684] [PubMed: 30041458]

7.

Rana M, Khanzode L, Karnik N, Saxena K, Chang K, Steiner H. Divalproex sodium in the treatment of pediatric psychiatric disorders. Expert Rev Neurother. 2005 Mar;5(2):165-76. [PubMed: 15853487]

8.

Freitag FG. Divalproex sodium extended-release for the prophylaxis of migraine headache. Expert Opin Pharmacother. 2003 Sep;4(9):1573-8. [PubMed: 12943487]

9.

Činčárová L, Zdráhal Z, Fajkus J. New perspectives of valproic acid in clinical practice. Expert Opin Investig Drugs. 2013 Dec;22(12):1535-47. [PubMed: 24160174]

10.

Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, Altman RB, Klein TE. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2013 Apr;23(4):236-41. [PMC free article: PMC3696515] [PubMed: 23407051]

11.

Owens MJ, Nemeroff CB. Pharmacology of valproate. Psychopharmacol Bull. 2003;37 Suppl 2:17-24. [PubMed: 14624230]

12.

Löscher W. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs. 2002;16(10):669-94. [PubMed: 12269861]

13.

Rosenberg G. The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci. 2007 Aug;64(16):2090-103. [PubMed: 17514356]

14.

Cofini M, Quadrozzi F, Favoriti P, Favoriti M, Cofini G. Valproic acid-induced acute pancreatitis in pediatric age: case series and review of literature. G Chir. 2015 Jul-Aug;36(4):158-60. [PMC free article: PMC4732585] [PubMed: 26712070]

15.

Jones MR, Hall OM, Kaye AM, Kaye AD. Drug-induced acute pancreatitis: a review. Ochsner J. 2015 Spring;15(1):45-51. [PMC free article: PMC4365846] [PubMed: 25829880]

16.

Chomiak T, Turner N, Hu B. What We Have Learned about Autism Spectrum Disorder from Valproic Acid. Patholog Res Int. 2013;2013:712758. [PMC free article: PMC3871912] [PubMed: 24381784]

17.

Nicolini C, Fahnestock M. The valproic acid-induced rodent model of autism. Exp Neurol. 2018 Jan;299(Pt A):217-227. [PubMed: 28472621]

18.

Gotlib D, Ramaswamy R, Kurlander JE, DeRiggi A, Riba M. Valproic Acid in Women and Girls of Childbearing Age. Curr Psychiatry Rep. 2017 Sep;19(9):58. [PubMed: 28726062]

Disclosure: Masum Rahman declares no relevant financial relationships with ineligible companies.

Disclosure: Hoang Nguyen declares no relevant financial relationships with ineligible companies.

📖 Pharmacology, Valproates, Chapter 4. Normotimics (mood stabilizers). Guide to psychopharmacotherapy. Arana D. Page 37. Read online

Valproic acid has been shown to be comparable to lithium in the treatment of bipolar disorder in a large number of well-designed studies. Initially, valproic acid was used as an anticonvulsant for the treatment of small (petit mal) myoclonic and grand mal seizures. Valproic acid is less effective in the treatment of partial seizures, regardless of the presence of complex symptoms. At 19In 1995, valproic acid was approved by the FDA for use as an anti-manic drug. It turned out that in the treatment of rapid cycling and dysphoric mania, valproic acid is more effective than lithium. Moreover, unlike lithium, the anti-manic effect of valproic acid does not decrease with a long course of the disease with a large number of manic episodes. Currently, many doctors use valproic acid preparations as the main treatment for mania, especially in the presence of comorbid disorders.

Pharmacology.

Several preparations of valproic acid (Table 4.6) are available in capsule or syrup form. Divalproex sodium is an enteric-coated preparation containing equal parts of valproic acid and sodium valproate. Both valproic acid and valproex circulate in the blood in an ionized form. Valproic acid is rapidly absorbed when taken orally. The maximum concentration of the drug in the blood is reached 1-2 hours after ingestion on an empty stomach and 4-5 hours after ingestion with food. Divalproex sodium is absorbed more slowly, reaching the maximum serum level in 3-8 hours.

Table 4.6. Valproic acid and carbamazepine preparations

* Not registered in Russia

Psychology bookap 90 008

** The drug was introduced by the editor as the most famous generic in Russia

80-95% of valproic acid binds to plasma proteins. The drug is rapidly metabolized in the liver. Active metabolites are unknown. Interactions with other drugs that bind to plasma proteins or are metabolized in the liver are possible. The half-life of valproic acid is 8 hours, therefore, for the treatment of epilepsy, it is recommended to take the drug 3 times a day. The need to divide the dose into three doses in bipolar disorder has not been established.

The relationship between plasma concentration and the antimanic effect of valproic acid is weak. Usually the concentration is maintained in the range from 50 to 150 µg/ml. Plasma concentrations are measured by immunoassay or gas chromatography.

The exact mechanism of action of valproic acid in bipolar disorder is unknown, but there is evidence that it increases synaptic levels of gamma-aminobutyric acid (GABA), the brain’s main inhibitory neurotransmitter. It has been experimentally shown that valproic acid blocks the convulsive effects of GABA-A receptor antagonists picrotoxin and bicuculin. It is possible that valproic acid and lithium share some common mechanisms (eg, CGS-3α/wnt mechanism). This possibility is being actively explored at the present time.

Indications.

Bipolar disorder

As mentioned above, many physicians consider valproic acid to be the drug of first choice in the treatment of bipolar disorder. If valproic acid monotherapy does not give good results, combination with lithium, carbamazepine or other drugs is possible. Valproic acid is much better tolerated than lithium and, unlike carbamazepine, rarely causes tolerance. Valproate is often used for long-term prophylaxis, despite the paucity of well-designed studies. According to open studies, valproate is more effective in preventing the development of manic than depressive phases. Open studies and clinical observations do not support the antidepressant effect of valproic acid. However, with the combined use of valproic acid and antidepressants, the risk of developing manic episodes in bipolar patients may be reduced.

Schizoaffective psychosis

Based on open studies and clinical observations, valproate may replace lithium as a mood stabilizer in the treatment of manic-delusional attacks in schizoaffective psychosis. Valproic acid is ineffective in patients with schizophrenia or schizoaffective patients with depressive episodes.

Other psychiatric indications

Valproic acid may serve as an alternative to benzodiazepines (see Chapter 5) in the treatment of alcohol withdrawal, which often accompanies hospitalization mania.

Application.

Standard procedures prior to valproic acid therapy have not been developed. It is recommended to take a general history and conduct a general examination, paying particular attention to what other drugs the patient is taking and whether he has had liver disease or bleeding disorders. Ideally, laboratory tests that evaluate liver function and a complete blood count with platelet count should be performed. In liver diseases, valproic acid is not recommended.

Psychology bookap

To reduce side effects, valproic acid therapy should be initiated gradually. The first trial dose of 250 mg is best taken with food. If there are no gastrointestinal symptoms and sedation, then within a few days you can increase the dosage, bringing it up to 250 mg three times a day. If necessary, the dose can be increased to 1800 mg / day. The optimal blood level of the drug in the treatment of epilepsy and bipolar disorder has not been clearly established, but is likely to be in the range of 50 to 150 mcg/ml. Until stabilization of the condition, the concentration of the drug in the blood plasma can be determined weekly. Many doctors recommend liver function tests and complete blood counts at the same time. The antimanic effect usually appears within 1-2 weeks after the required concentration is established.

There is an alternative approach in which valproic acid is taken orally at a rate of 20-30 mg/kg body weight. At the same time, the weakening of manic symptoms occurs faster, within a few days, thereby reducing the need for the use of antipsychotics in the early stages of treatment. The prophylactic effect of valproic acid with its long-term use is comparable to that of lithium.

At steady state, plasma drug concentrations, liver function tests, and complete blood counts are performed every six months. However, if side effects appear, additional tests should be performed. For example, if nausea, loss of appetite, or rapid fatigue appear after stabilization of the condition, it is necessary to determine the concentration of the drug in the blood plasma and conduct a laboratory diagnosis of liver function.

Use during pregnancy.

The use of valproic acid during pregnancy has not been adequately studied. However, the use of valproate is associated with severe congenital malformations, such as spina bifida (spina bifida). In 5% of cases when using valproic acid in the first trimester of pregnancy, neural tube defects of the fetus occur. Therefore, valproate is not the drug of choice over lithium. However, there is speculation that folic acid supplementation may reduce the risk associated with the action of valproate. Bleeding disorders also pose a risk to the mother and fetus in the later stages of pregnancy and during childbirth. It is preferable to use safer means such as ECT and powerful antipsychotics (see Lithium use during pregnancy above). Valproic acid is excreted in breast milk, where its concentration is 1-10% of the plasma concentration. The effect of valproates on the development of the child is unknown.

Adverse and toxic effects.

Mild side effects usually occur at the beginning of therapy and usually resolve on their own. These include gastrointestinal disturbances (nausea, vomiting, anorexia, heartburn, diarrhoea), sedation, tremor, and ataxia (Table 4.7). To reduce gastrointestinal symptoms, you can take valproic acid with meals or use drugs such as divalproex, which is coated with an enteric coating. Blockers H ₂ receptors for histamine, such as ranitidine, can also attenuate gastrointestinal disturbances, but there is a risk of drug interactions. At the beginning of therapy, approximately half of the patients have a sedative effect. With continued use of valproic acid, this effect is reduced. Sedation can become a serious problem if valproic acid is used with other anticonvulsants, especially phenobarbital, which is not used to treat bipolar disorder. Long-term use of valproic acid preparations can lead to some impairment of cognitive functions. In this respect, they are somewhat worse than carbamazepine, but better than phenytoin or barbiturates. Other side effects of valproic acid are alopecia and weight gain.

Table 4.7. Side effects and toxic effects of valproic acid

Common side effects

Gastrointestinal: nausea, vomiting, anorexia, heartburn, diarrhea

Psychology bookap

Hematologic: thrombocytopenia, impaired platelet aggregation

Hepatic: slight increase in transaminases

Neurological: sedation, tremor, ataxia

Others: alopecia, weight gain

Less common side effects

Hematological: bleeding

Psychology bookap

Metabolic: hyperammonemia

Neurological: incoordination, fluttering tremor, stupor, coma, behavioral automatism

Severe idiosyncratic side effects

Hepatitis / liver failure

Psychology bookap

Pancreatitis

Eruptions including exudative erythema

Hepatotoxicity

In 15-30% of patients, valproic acid causes a reversible asymptomatic increase in aspartate transaminase and alanine transaminase activity, which serves as a signal for monitoring, but not for stopping therapy. The most pronounced violations of laboratory parameters are observed during the first 3 months of treatment. Isolated hyperammonemia, which may be accompanied by confusion or lethargy, is rare. Liver tests usually improve with dose reduction. Cases of lethal toxic liver damage have been described with the use of valproic acid. For the period from 1978 to 1984, there were 37 cases of toxic liver damage with a fatal outcome. All but one patient had a medical condition other than epilepsy for which valproic acid was prescribed. These indications included mental and general retardation, congenital disorders and other neurological diseases. For the period from 1985 to 1986, the proportion of lethal toxic liver damage was 2.5 per 100,000 patients. In patients taking valproic acid as the only anticonvulsant drug, the proportion of fatal liver toxicity was 0.85 per 100,000 patients. Over the next 10 years, there was not a single case of toxic liver damage with a fatal outcome in patients using valproic acid as the only anticonvulsant drug. Studies have been conducted on the use of combination therapy with lithium and valproic acid in the treatment of mental illness (not epilepsy). The risk of liver toxicity has been shown to be low, and certainly lower than the risk to life due to bipolar disorder. A slight increase in liver transaminases is a common reaction during valproic acid therapy and should not be considered as a symptom of worsening liver function. If significant liver dysfunction or symptoms of hepatitis (general malaise, loss of appetite, jaundice, abdominal pain or swelling) are detected, it is necessary to immediately stop taking the drug and conduct a thorough examination of the patient.

Neurotoxicity

A serious problem with valproic acid therapy is sedation, and the most common and long-lasting neurological side effect is hand tremor. As a rule, this side effect decreases with a decrease in the dose. Cases have been described in which tremor was eliminated by β-blockers, such as propranolol (as well as with lithium therapy; see Chapter 6). However, β-blockers themselves can cause CNS side effects, including depression. When using high doses of valproic acid, ataxia may develop. Rare side effects Fluttering tremor, stupor, coma and behavioral automatism.

Hematological toxicity

Valproic acid may cause thrombocytopenia or impaired platelet aggregation, but only rarely leads to increased bleeding. This effect is usually observed when taking high doses of the drug. Patients taking valproic acid, before any surgical intervention, it is necessary to determine the number of platelets and the time of blood clotting.

Other idiosyncratic side effects

Hemorrhagic pancreatitis may occur during the first 6 months of therapy. This side effect is extremely rare, but can be fatal. Another rare idiosyncratic side effect is agranulocytosis. Cases of rashes, including exudative erythema, have also been described. There is concern that women taking valproic acid are more likely to develop polycystic ovaries. It is not yet clear whether the use of valproic acid is the cause of this disease or only accompanies other factors such as obesity or epilepsy. Further study of this phenomenon is required.

Toxic effects due to overdose

An excessive increase in the concentration of valproate in the blood plasma may occur as a result of drug interactions or an intentional overdose of the drug. In case of overdose, characteristic neurological symptoms appear. Hemodialysis is used to treat poisoning with valproic acid. Cases of fatal poisoning are rare.

Drug interactions.

Valproic acid may be involved in pharmacodynamic interactions with other psychotropic drugs, including carbamazepine, lithium, and antipsychotics. These interactions are manifested by a joint toxic effect on the central nervous system. With the combined use of psychotropic drugs, it is always necessary to monitor the possible deterioration of the mental state.

Psychology bookap

Valproic acid also enters into pharmacokinetic interactions with many drugs. It inhibits the oxidation of drugs in the liver, thereby increasing the concentration of cyclic antidepressants, as well as SSRIs, phenytoin, phenobarbital and other drugs. Valproic acid can also increase the concentration of other drug compounds associated with plasma proteins, and, conversely, other drugs, such as aspirin, can displace valproic acid from protein complexes and accelerate its toxic effect. Therefore, if it is necessary to prescribe other drugs that bind to plasma proteins, such as warfarin, the patient should be closely monitored at the beginning of combination therapy.

The concentration of valproic acid in the blood may decrease with the use of carbamazepine and other drugs that induce microsomal liver enzymes. Inhibitors of microsomal liver enzymes, such as SSRIs, can cause an increase in the concentration of valproic acid.

It should be noted that valproic acid is partially excreted in the urine as a ketometabolite, which sometimes leads to misinterpretation of the urine ketone test.

Depakote

Depakote, which is generically known as Valporic acid, is a drug used to treat migraine and schizophrenia. It is an anticonvulsant or mood stabilizer. It is manufactured by Abbott Laboratories for the United States markets and sold under alternative names like Depakene and Epival.
Valporic acid was discovered over 100 years ago, but it was in 1983 that it became FDA approved to treat schizophrenia. It has also been used to treat epilepsy, bipolar disorder and epilepsy.
Unfortunately, like many other drugs used to treat schizophrenia, Depakote has some very serious side effects. Perhaps most worrying is the possibility of birth defects when pregnant women are prescribed this drug. For some reason, some physicians believe that it is an acceptable risk to prescribe Depakote to women who are in the middle of pregnancy without warning these women of the possibly catastrophic birth defects that this drug might cause.
Depakote birth defects include (some of these are proven while others are speculated):
Skeletal Deformities
Spina Bifida
Neural Tube Deformity
Valporate Syndrome
Trigonocephaly
Decreased IQ
Epicanthic Folds
Autism
Most health professionals suggest that women taking this drug should switch to another drug as soon as they know they are pregnant. It is estimated that Depakote will affect approximately 5% of pregnant women and cause mental birth defects.
However, Depakote also has many other debuffs associated with it that affect the taker rather than the offspring.
Depakote side effects include but are not limited to the following:
Kidney Impairment
Thrombocytopenia
Polonged Coagulation
Blood Discasia
Impaired Liver Fuction
Nausea
Weight Gain
Hair Loss 9 0017 Shivers
Acne
Hematological Toxicity
Myelodysplasia
Parkinson’s Signs
Sedation
Peripheral Edema
Overdose
In addition, there are many contraindications for this remedy.