Depakote: A Proven Mood Stabilizer for Bipolar Disorder
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Synonyms
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Depakote (divalproex sodium) is an established anticonvulsant medication approved by the FDA for the treatment of epilepsy, migraine prophylaxis, and the manic episodes associated with bipolar disorder. Its primary mechanism involves enhancing gamma-aminobutyric acid (GABA) activity in the brain, which contributes to its mood-stabilizing and antiepileptic properties. This delayed-release formulation is designed to minimize gastrointestinal irritation while providing consistent therapeutic serum levels, making it a cornerstone in neuropsychiatric and neurological treatment protocols.
Features
- Active ingredient: Divalproex sodium (a stable coordination compound of valproic acid)
- Available formulations: Delayed-release tablets, extended-release tablets, sprinkle capsules, and intravenous solution
- Standard strengths: 125 mg, 250 mg, 500 mg delayed-release tablets; 500 mg extended-release tablets
- Pharmacokinetics: Bioavailability approximately 90%; protein binding 80-90%; metabolized hepatically via glucuronidation and beta-oxidation
- Half-life: Range of 9-16 hours in adults, influenced by concomitant medications and liver function
- Special coating: Enteric-coated to prevent gastric degradation and reduce upper GI adverse effects
Benefits
- Effectively reduces the severity and frequency of manic episodes in bipolar I disorder
- Provides prophylactic migraine relief, decreasing attack frequency by ≥50% in numerous patients
- Demonstrates broad-spectrum efficacy in multiple seizure types, including complex partial seizures
- Offers flexible dosing formulations to accommodate individual patient needs and adherence patterns
- Established long-term safety profile with decades of clinical use and post-marketing surveillance
- May be used as monotherapy or in combination with other psychotropic agents when clinically indicated
Common use
Depakote is predominantly prescribed for the management of acute manic or mixed episodes associated with bipolar disorder, frequently serving as a first-line mood stabilizer. In neurological practice, it is utilized for the treatment of complex partial seizures that occur either in isolation or in association with other seizure types. The medication is also FDA-approved for migraine prophylaxis in adults, significantly reducing the frequency of these debilitating headaches. Off-label uses include the treatment of neuropathic pain syndromes, agitation in dementia (with caution), and as an adjunct in certain anxiety disorders, though robust evidence for these applications varies.
Dosage and direction
Initial dosing for bipolar mania typically begins at 750 mg daily in divided doses, with increases of 5-10 mg/kg/day every 1-3 days until therapeutic response is achieved. The target therapeutic range for valproic acid concentrations is generally 50-125 μg/mL, though clinical response should guide ultimate dosing. For migraine prophylaxis, the starting dose is 250 mg twice daily, which may be increased to a maximum of 1000 mg/day based on tolerability and efficacy. Epilepsy dosing is weight-based, initiating at 10-15 mg/kg/day, increasing by 5-10 mg/kg/week until seizure control is attained. All doses should be taken with food to minimize gastrointestinal discomfort, and tablets must be swallowed whole without crushing or chewing to preserve the enteric coating.
Precautions
Hepatotoxicity represents the most serious risk, particularly during the first six months of therapy; baseline LFTs should be obtained and monitored periodically. Pancreatitis, though rare, can occur at any time and requires immediate evaluation if abdominal pain, nausea, or vomiting develop. Thrombocytopenia and impaired platelet aggregation may occur, necessitating periodic CBC monitoring. Hyperammonemia with or without encephalopathy has been reported, even with normal liver function tests. Teratogenicity risk is significant (neural tube defects occur in 1-2% of exposures), requiring stringent contraception in women of childbearing potential. Weight gain, hair loss, and tremor are common dose-related effects that may require management. Patients should be cautioned about the potential for sedation and advised against operating hazardous machinery until they know how the medication affects them.
Contraindications
Depakote is contraindicated in patients with known hypersensitivity to valproate, divalproex sodium, or any component of the formulation. It must not be used in individuals with significant hepatic impairment or active liver disease. The medication is contraindicated in patients with known urea cycle disorders due to the risk of hyperammonemic encephalopathy. Concomitant use with other hepatotoxic agents should generally be avoided. It is contraindicated in pregnancy for migraine prophylaxis but may be used for epilepsy or bipolar disorder if other alternatives are unsuitable and with full informed consent regarding teratogenic risks.
Possible side effects
Common adverse reactions (≥10% incidence) include nausea (31%), somnolence (30%), dizziness (25%), vomiting (23%), asthenia (20%), abdominal pain (19%), diarrhea (13%), dyspepsia (13%), and tremor (25%). Less frequent but clinically significant effects include thrombocytopenia (8%), alopecia (6%), increased appetite (6%), weight gain (4%), and blurred vision (3%). Serious but rare adverse events include hepatic failure, pancreatitis, hemorrhagic pancreatitis, suicidal ideation, DRESS syndrome, and polycystic ovary syndrome in women. Cognitive effects such as memory impairment, confusion, and decreased concentration may occur, particularly at higher doses or in elderly patients.
Drug interaction
Depakote exhibits numerous clinically significant interactions due to its inhibition of hepatic enzymes including CYP2C9, UGT, and epoxide hydrolase. It increases plasma levels of phenobarbital, lamotrigine, and carbamazepine-10,11-epoxide while decreasing levels of carbamazepine. Concomitant use with clonazepam may induce absence status. Aspirin, felbamate, and erythromycin may increase valproate levels. Carbapenem antibiotics (imipenem, meropenem) significantly reduce valproate concentrations. CYP2C9 inducers such as rifampin may decrease valproate levels. Warfarin metabolism is inhibited, requiring close INR monitoring. The medication may enhance the CNS depressant effects of alcohol, barbiturates, and benzodiazepines.
Missed dose
If a dose is missed, it should be taken as soon as possible unless it is接近 the time for the next scheduled dose. In that case, the missed dose should be skipped and the regular dosing schedule resumed. Patients should never double the dose to make up for a missed one. Consistency in dosing is particularly important for seizure control, so patients with epilepsy should maintain strict adherence. For bipolar disorder and migraine prophylaxis, occasional missed doses are less likely to cause immediate clinical deterioration, but may increase the risk of symptom recurrence over time.
Overdose
Valproate overdose presents a medical emergency characterized by somnolence, heart block, deep coma, and metabolic acidosis. Serum levels exceeding 150 μg/mL constitute significant overdose, with levels >850 μg/mL often fatal. Management includes gastric lavage if presented within 1-2 hours of ingestion, though efficacy may be limited due to delayed absorption. Activated charcoal may be beneficial, especially with extended-release formulations. Hemodialysis effectively removes valproate and corrects metabolic abnormalities. Naloxone has reversed CNS depression in some cases. Supportive care with particular attention to respiratory status, electrolyte balance, and ammonia levels is essential. Cerebral edema may occur and require management with mannitol or hypertonic saline.
Storage
Depakote tablets should be stored at controlled room temperature (20-25°C or 68-77°F) in their original container with the lid tightly closed. The medication must be protected from moisture and light. The sprinkle capsules are particularly hygroscopic and require careful handling. Unused medication should be disposed of properly through medication take-back programs rather than flushing. The intravenous formulation should be stored at room temperature and used within 24 hours of mixing. Travel through extreme temperature conditions should be avoided, as both heat and freezing may compromise the enteric coating’s integrity.
Disclaimer
This information is provided for educational purposes only and does not constitute medical advice. Treatment decisions must be made by qualified healthcare professionals based on individual patient circumstances. The prescribing physician should be consulted for specific dosage recommendations and monitoring requirements. Depakote carries significant risks including hepatotoxicity, teratogenicity, and pancreatitis that require careful consideration before initiation. Patients should report any adverse effects to their healthcare provider promptly. Medication should never be shared with others, even if they exhibit similar symptoms.
Reviews
Clinical studies demonstrate Depakote’s efficacy in bipolar mania with response rates of 48% versus 25% for placebo in controlled trials. In migraine prophylaxis, 44% of patients achieved ≥50% reduction in migraine frequency compared to 21% with placebo. Epilepsy studies show 59% of patients experiencing ≥50% reduction in complex partial seizures. Patient-reported outcomes indicate satisfaction with mood stabilization but frequent concerns regarding weight gain (mean of 3-5 kg in first year) and cognitive dulling. Long-term adherence is challenged by metabolic side effects, though many patients value the mood-stabilizing benefits. Real-world evidence supports its effectiveness particularly in mixed episodes and rapid-cycling bipolar disorder.