What dose of Depakote (divalproex sodium) should be started and titrated in an adult to achieve therapeutic serum levels?

Depakote (Divalproex Sodium) Dosing for Adults

Start divalproex sodium at 125 mg twice daily and titrate to achieve therapeutic serum levels of 50-125 mcg/mL, with the specific starting dose and titration rate depending on the indication being treated. 1, 2

Standard Dosing by Indication

For Acute Mania

• Initial dose: 750 mg daily in divided doses 2
• Increase rapidly to achieve therapeutic response with trough plasma concentrations between 50-125 mcg/mL 2
• Maximum concentrations typically achieved within 14 days 2
• Maximum recommended dosage: 60 mg/kg/day 2

For Epilepsy (Complex Partial Seizures)

• Initial dose: 10-15 mg/kg/day 2
• Increase by 5-10 mg/kg/week to achieve optimal clinical response 2
• Target therapeutic range: 50-100 mcg/mL 2
• Optimal response typically achieved at daily doses below 60 mg/kg/day 2
• If total daily dose exceeds 250 mg, give in divided doses 2

For Migraine Prophylaxis and Behavioral Symptoms

• Initial dose: 125 mg twice daily 1
• Titrate to therapeutic blood level of 40-90 mcg/mL 1
• Generally better tolerated than other mood stabilizers 1

Rapid Loading Protocol (Acute Mania Only)

For hospitalized patients with acute mania requiring rapid therapeutic levels:

• 30 mg/kg/day for 2 days, then 20 mg/kg/day thereafter 3, 4
• This achieves therapeutic levels (mean 93.5 mcg/mL) within 48-72 hours 3
• Well-tolerated even with concurrent psychotropic medications 3
• Extended-release formulation can be loaded at 30 mg/kg/day as a single daily dose 4

Formulation-Specific Considerations

Delayed-Release (Standard) Formulation

• Requires multiple daily doses for doses ≥2000 mg/day 5
• Once-daily dosing at high doses (≥2000 mg) produces excessive peak-trough fluctuation (4.4-6.2-fold) and risk of toxicity with Cmax >125 mg/L 5
• Do not use once-daily dosing for high total daily doses with this formulation 5

Extended-Release Formulation

• Appropriate for once-daily dosing across all dose ranges 5, 6
• Maintains therapeutic levels for 24 hours 5
• Superior tolerability with less tremor, weight gain, and gastrointestinal complaints compared to delayed-release 6
• Mean Cmin >73 mg/L at all doses tested 5

Monitoring Requirements

Essential laboratory monitoring:

• Liver enzyme levels at baseline and regularly during treatment 1
• Platelet count, PT, and PTT as indicated 1
• Serum valproate levels to guide dosing 2

Critical safety thresholds:

• Thrombocytopenia risk increases significantly at trough levels >110 mcg/mL in females and >135 mcg/mL in males 2
• Weigh benefit of higher doses against increased adverse reaction risk 2

Common Pitfalls to Avoid

• Never crush or chew delayed-release tablets - instruct patients to swallow whole 2
• Avoid once-daily dosing of delayed-release formulation at high doses - use extended-release instead or divide doses 5
• Do not exceed 60 mg/kg/day - no safety data supports higher doses 2
• Monitor for drug interactions - valproate affects levels of clonazepam, diazepam, ethosuximide, lamotrigine, phenobarbital, carbamazepine, and phenytoin 2

Special Populations

For elderly patients or those with hepatic impairment, consider lower starting doses and slower titration, though specific dosing adjustments are not provided in the FDA label 2