Depakote - Drug Monograph

Introduction

Depakote (divalproex sodium) is an anticonvulsant medication that is also used as a mood stabilizer and for migraine prophylaxis. It is a prodrug of valproic acid that was first approved by the FDA in 1983. Depakote represents an important therapeutic option across multiple neurological and psychiatric conditions due to its broad mechanism of action and established efficacy profile.

Mechanism of Action

Depakote exerts its therapeutic effects through multiple mechanisms:

• Increases GABA levels in the brain by inhibiting GABA transaminase and succinic semialdehyde dehydrogenase
• Enhances GABAergic neurotransmission through postsynaptic receptor effects
• Modulates voltage-gated sodium channels
• May affect T-type calcium channels
• Exhibits weak inhibition of histone deacetylases

The exact mechanism for each indication varies, with anticonvulsant effects primarily mediated through enhanced GABA transmission and channel modulation, while mood-stabilizing effects may involve more complex neurochemical pathways.

Indications

• Monotherapy and adjunctive therapy for complex partial seizures, simple and complex absence seizures
• Mania associated with bipolar disorder
• Migraine prophylaxis

• Other seizure types (generalized tonic-clonic, myoclonic)
• Neuropathic pain
• Agitation in dementia
• Impulse control disorders

Dosage and Administration

• Initial: 10-15 mg/kg/day, increasing by 5-10 mg/kg/week
• Maintenance: 30-60 mg/kg/day in divided doses
• Maximum: 60 mg/kg/day

• Initial: 750 mg/day in divided doses
• Target: 20-30 mg/kg/day
• Maximum: 60 mg/kg/day

• Initial: 250 mg twice daily
• Target: 500-1000 mg/day
• Maximum: 1000 mg/day

• Elderly: Start with lower doses due to reduced clearance
• Hepatic impairment: Reduce dose and monitor closely
• Renal impairment: No specific guidelines; use caution
• Pediatrics: 15-45 mg/kg/day (epilepsy only)

Pharmacokinetics

Contraindications

• Known hypersensitivity to valproate products
• Hepatic disease or significant hepatic dysfunction
• Known urea cycle disorders
• Pregnancy for migraine prophylaxis (Category X)
• Patients with mitochondrial disorders caused by POLG mutations

Warnings and Precautions

• Hepatotoxicity: Fatal hepatic failure reported, especially in children under 2 years
• Teratogenicity: Neural tube defects and other major malformations
• Pancreatitis: Life-threatening cases reported

• Thrombocytopenia and impaired platelet function
• Hyperammonemia with or without encephalopathy
• Somnolence in elderly patients
• Suicidal ideation and behavior
• Multiorgan hypersensitivity reactions

Drug Interactions

• Lamotrigine: ↑ risk of serious rash
• Carbapenem antibiotics: ↓ valproate levels by 60-100%
• Phenobarbital, phenytoin, carbamazepine: ↓ valproate levels
• Warfarin: Altered anticoagulant effect
• Aspirin: ↑ free valproate levels
• Benzodiazepines: ↑ CNS depression
• Zidovudine: ↑ zidovudine levels

• Felbamate, fluoxetine, isoniazid

• Phenobarbital, phenytoin, lamotrigine

Adverse Effects

• Nausea, vomiting, diarrhea
• Drowsiness, dizziness
• Tremor
• Weight gain
• Alopecia

• Hepatotoxicity
• Pancreatitis
• Thrombocytopenia
• Hyperammonemic encephalopathy
• Stevens-Johnson syndrome
• Agranulocytosis

• Polycystic ovarian syndrome
• Metabolic syndrome
• Bone density reduction
• Cognitive impairment

Monitoring Parameters

• CBC with platelets
• Liver function tests
• Ammonia level
• Pregnancy test in women of childbearing potential
• Comprehensive metabolic panel

• LFTs every 2 weeks for first 3 months, then periodically
• CBC with platelets periodically
• Ammonia level if symptoms suggest encephalopathy
• Valproate levels: therapeutic range 50-125 μg/mL
• Weight and metabolic parameters regularly
• Neurological and mental status assessment

Patient Education

• Take with food to minimize GI upset
• Do not crush or chew delayed-release tablets
• Report immediately: nausea/vomiting, abdominal pain, jaundice, unusual bleeding/bruising
• Use effective contraception; discuss pregnancy plans with provider
• Avoid alcohol consumption
• Be aware of potential drowsiness; avoid driving until effects known
• Do not abruptly discontinue medication
• Regular monitoring is essential for safety
• Report mood changes or suicidal thoughts

References

1. FDA Prescribing Information: Depakote (divalproex sodium) 2. American Epilepsy Society Guidelines (2016) 3. Goodwin GM; Consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for treating bipolar disorder. J Psychopharmacol. 2016;30(6):495-553 4. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults. Neurology. 2012;78(17):1337-1345 5. Johannessen CU, Johannessen SI. Valproate: past, present, and future. CNS Drug Rev. 2003;9(2):199-216 6. Nanau RM, Neuman MG. Adverse drug reactions induced by valproic acid. Clin Biochem. 2013;46(15):1323-1338 7. Clinical Pharmacokinetics of Valproate: A Review. Clin Pharmacokinet. 2017;56(8):869-881