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valproate (divalproex)

Last reviewed 2025-09-23

Reviewed by PsychMed Editorial Team.

Compare valproate (divalproex) with other medsReview recent evidence
Related hubs: Bipolar hub · Support resources
Mood stabilizer

Brands: DEPAKOTE

Sources updated 2025 • 5 references

Quick summary

General Information

Valproate (divalproex sodium/valproic acid) is a broad-spectrum mood stabilizer effective for acute mania and maintenance in bipolar disorder, also widely used in neurology indications.

This profile concentrates on bipolar disorder management, emphasizing hepatotoxicity, teratogenicity, and metabolic monitoring.

The compare view and the valproate evidence feed can help weigh metabolic burden, serum monitoring, and teratogenic risks against alternative mood stabilizers when adjusting maintenance strategies alongside the bipolar disorder hub.

U.S. approvals

  • Acute mania (bipolar disorder) (1995)
  • Maintenance (off-label; widely used but no FDA approval) ()

Formulations & strengths

  • Divalproex sodium delayed-release tablets: 125 mg, 250 mg, 500 mg.
  • Divalproex sodium extended-release tablets: 250 mg, 500 mg.
  • Valproic acid capsules 250 mg, oral solution 250 mg/5 mL, sprinkle capsules 125 mg.

Generic availability

  • All formulations are available generically.

Favored for rapid control of mixed states and rapid cycling; clinicians vigilantly monitor liver function, weight, and teratogenic risks and counsel on contraception.

View labelExact

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Valproate enhances GABAergic neurotransmission, modulates voltage-gated sodium/calcium channels, and influences histone deacetylase activity, stabilizing mood and neuronal excitability.

Extensive hepatic metabolism and narrow safety margins necessitate serum level monitoring and laboratory surveillance.

  • Increases GABA synthesis and inhibits GABA degradation.
  • Blocks voltage-gated sodium channels and modulates T-type calcium channels.
  • Affects epigenetic regulation via HDAC inhibition.

Metabolism and Pharmacokinetics

  • High oral bioavailability (~90%); delayed-release peaks 3–4 hours, extended-release 6–8 hours.
  • Protein binding 80–95% (saturable); displacement occurs with hypoalbuminemia or higher concentrations.
  • Metabolized hepatically via glucuronidation, β-oxidation, and CYP-mediated oxidation to hepatotoxic metabolites.
  • Half-life 9–16 hours in adults (shorter with enzyme-inducing drugs).
  • Eliminated primarily in urine as metabolites; <5% excreted unchanged.

Dosing and Administration

  • Acute mania: initiate 750–1,000 mg/day (divided TID for DR or once daily ER) and titrate to serum 50–125 µg/mL; loading up to 20–30 mg/kg/day can achieve rapid control.
  • Maintenance: adjust to maintain serum 50–100 µg/mL (some target 80–120 µg/mL for relapse prevention).
  • Extended-release doses may need to be 8–20% higher than delayed-release to achieve equivalent exposure.
  • Pediatrics: weight-based 20–60 mg/kg/day divided BID/TID with regular levels.
  • Monitoring: baseline CMP, CBC with platelets, pregnancy test; recheck LFTs/CBC every 1–2 months for 6 months then every 6–12 months; valproate levels 3–5 days after dose adjustments and periodically thereafter.

Monitoring & Labs

  • Baseline: LFTs, CBC with platelets, pregnancy test if relevant, weight/BMI.
  • Level timing: 12-hour trough (extended-release may differ); target 50–125 µg/mL based on clinical context.
  • Ongoing: Periodic LFTs and CBC; monitor metabolic effects and sedation.
  • Precautions: Reinforce teratogenicity counseling; review pancreatitis and hepatotoxicity warnings.
  • Drug interactions: Adjust for enzyme induction (UGT), lamotrigine titration, and other interacting therapies.

Sources: FDA label; AGNP TDM consensus; guideline statements.

Adverse Effects

FDA boxed warnings

  • Hepatotoxicity (especially in young children or patients with mitochondrial disorders).
  • Pancreatitis, which may be fatal.
  • Fetal risk: major congenital malformations and decreased IQ following in utero exposure.

Common side effects (≥10%)

  • Gastrointestinal upset: Nausea, vomiting, diarrhea can be mitigated with food or ER formulation.
  • Tremor: Dose-related; treat with beta-blockers or dose adjustments.
  • Weight gain and increased appetite: Common with chronic therapy.
  • Sedation/fatigue: Often transient but monitor for daytime impairment.
  • Alopecia: Reversible; may respond to selenium/zinc supplementation.

Other notable effects

  • Thrombocytopenia and platelet dysfunction—monitor CBC, especially at levels >110 µg/mL.
  • Hyperammonemia with or without encephalopathy; consider checking ammonia if altered mental status occurs.
  • Polycystic ovary syndrome in reproductive-age females.
  • Teratogenicity (neural tube defects, craniofacial, cardiac anomalies) and neurodevelopmental effects—strong contraception counseling essential.

Interactions

  • Enzyme-inducing antiepileptics (carbamazepine, phenytoin, phenobarbital) lower valproate levels; adjust dosing.
  • Valproate increases lamotrigine levels significantly—reduce lamotrigine dose by 50–75%.
  • Aspirin and warfarin displace valproate from proteins—monitor bleeding parameters.
  • Topiramate increases hyperammonemia risk; monitor ammonia and mental status.
  • Carbapenem antibiotics markedly reduce valproate levels—avoid combination.

Other Useful Information

  • Provide thorough contraception counseling and document risk discussions for patients capable of pregnancy; consider folic acid supplementation.
  • Encourage lifestyle modifications (diet, exercise) to mitigate weight gain and metabolic effects; monitor BMI, lipids, glucose similar to SGAs.
  • Educate about signs of hepatic dysfunction, pancreatitis, and hyperammonemia requiring urgent evaluation.
  • Extended-release formulations improve adherence and GI tolerability; maintain consistent formulation for level interpretation.
  • Taper gradually when discontinuing to avoid relapse or seizure risk.

References

  1. DEPAKOTE (divalproex sodium) prescribing information — DailyMed (2025)
  2. CANMAT/ISBD guidance on valproate for bipolar disorder — Bipolar Disorders (2021)
  3. Valproate FOR THE Treatment OF Acute Bipolar Depression: Systematic Review AND Meta Analysis — Journal of Affective Disorders (2010)
  4. FDA safety communication: valproate contraindicated in pregnancy for migraine prophylaxis — U.S. Food and Drug Administration (2013)
valproate (divalproex) (DEPAKOTE) — PsychMed