What are the recommended starting doses, titration schedules, and monitoring parameters for Depakote XR (divalproex sodium extended‑release) in adults with epilepsy, bipolar disorder, migraine prophylaxis, children (≥10 kg), and elderly patients?

Depakote Extended-Release Dosing

Starting Doses by Indication

For bipolar disorder and migraine prophylaxis in adults, initiate Depakote XR at 25 mg/kg/day given once daily, which typically translates to 500–750 mg once daily for most patients. 1

Epilepsy (Adults)

• Start at 500 mg once daily in the evening 2, 3
• For patients requiring higher doses (>2000 mg/day), Depakote XR is strongly preferred over standard divalproex because once-daily dosing of standard divalproex at high doses produces dangerously high peak concentrations (>125 mg/L) that risk toxicity 4

Bipolar Disorder (Adults)

• Initial dose: 125 mg twice daily (250 mg/day) for gradual titration, or 500–750 mg once daily for more rapid control 1, 5
• Target therapeutic range: 40–90 mcg/mL 1, 5

Migraine Prophylaxis (Adults)

• Start at 500 mg once daily 1
• Titrate to therapeutic levels of 40–90 mcg/mL 1

Pediatric Patients (≥10 kg)

• Initiate at 10–15 mg/kg/day 6
• Use more conservative dosing with careful monitoring of side effects 1

Elderly Patients

• Begin at 125 mg twice daily (lower end of dosing range) due to reduced intrinsic clearance and increased free drug fraction 5
• Slower titration is essential 1

Titration Schedules

Increase the dose by 250–500 mg daily at weekly intervals, guided by serum valproate levels and clinical response. 1

Standard Titration Protocol

• Week 1: Continue starting dose 1
• Week 2: Increase by 250–500 mg if subtherapeutic 1
• Subsequent weeks: Continue weekly increments of 250–500 mg until therapeutic levels (40–90 mcg/mL) are achieved 1
• Aim for mid-range levels of 65–85 mcg/mL to balance efficacy and tolerability 1

Rapid Titration (Acute Mania, Inpatient Setting)

• Loading dose: 20–30 mg/kg IV for status epilepticus or severe acute mania 5
• This approach is reserved for inpatient settings and should not be used in outpatient adolescents due to higher adverse effect rates 1

Conversion from Standard Divalproex to Depakote XR

• Increase the total daily dose by 8–20% when converting from standard divalproex to Depakote XR to maintain equivalent plasma exposure 2, 3, 7
• The bioavailability of Depakote XR is approximately 89% that of standard divalproex 3
• Example: A patient on 1000 mg/day standard divalproex should receive 1080–1200 mg/day of Depakote XR 3

Maximum Dosing

The maximum total daily dose is typically 3000 mg/day for adults, though doses should be titrated to achieve therapeutic blood levels of 40–90 mcg/mL rather than to a fixed maximum. 1

• For most adults with bipolar disorder, doses range from 750–3000 mg/day 1
• Doses exceeding 3000 mg/day require clear documentation that symptoms could not be controlled at lower doses and that no side effects (weight loss, blood pressure changes, agitation) are present 1
• Children weighing <25 kg should not receive single doses >15 mg 6

Monitoring Parameters

Baseline (Pre-Initiation)

• Liver function tests (AST, ALT, bilirubin) 1, 5
• Complete blood count with platelets 1, 5
• Prothrombin time (PT) and partial thromboplastin time (PTT) 1, 5
• Pregnancy test in females of reproductive age 1

During Titration

• Check serum valproate levels 3–5 days after each dose adjustment to guide further titration 1
• Assess for sedation, gastrointestinal upset (nausea/vomiting), tremor, and weight gain at each visit 1

Maintenance Monitoring

• Serum valproate levels every 3–6 months once stable therapeutic levels are achieved 1
• Liver function tests and CBC with platelets every 3–6 months to detect delayed hepatotoxicity or hematologic toxicity 1, 5
• Monitor for polycystic ovary disease in females 1

Optimal Sampling Technique

• Obtain trough (pre-dose) levels for accurate interpretation 1
• For once-daily Depakote XR, draw blood immediately before the morning dose 1
• Ensure steady-state has been reached (approximately 5 half-lives, or 2–3 days for valproate) before interpreting levels 1

Special Considerations

Formulation Advantages of Depakote XR

• Lower peak-to-trough fluctuation compared to standard divalproex (4.4–6.2-fold less fluctuation) 2, 4
• Consistent trough concentrations that reliably represent the lowest concentration during the dosing interval, facilitating therapeutic drug monitoring 2
• Once-daily dosing improves adherence and convenience 2, 8

High-Dose Considerations

• At doses ≥2000 mg/day, standard divalproex dosed once daily produces mean peak concentrations ≥125 mg/L, risking clinical toxicity 4
• Depakote XR is the only appropriate formulation for once-daily administration at high total daily doses (>2000 mg/day) 4

Drug Interactions

• The combination of risperidone and divalproex sodium is safe and well-tolerated for severe agitation in adolescents, with no dose adjustments required 1

Hepatic Impairment

• Use with extreme caution; clearance is reduced by 50% in cirrhosis and 16% in acute hepatitis 5
• Monitor liver enzymes closely 5

Expected Timeline for Response

• Therapeutic serum levels are typically reached within 5–14 days after attaining the target dose 1
• Full clinical benefits may take 2–3 months to become apparent; allow an adequate trial period before judging efficacy 1

Common Pitfalls to Avoid

• Do not use standard divalproex once daily at high doses (≥2000 mg/day) due to excessive peak concentrations 4
• Do not sample valproate levels before steady-state (at least 2–3 days after dose change) to avoid misleading results 1
• Do not forget to increase the dose by 8–20% when converting from standard divalproex to Depakote XR 2, 3, 7
• Do not use rapid loading regimens in outpatient adolescents due to higher adverse effect rates 1