Valproate (Divalproex, Depakote)
Mood stabilizer • Last reviewed 2025-09-23
General information
Valproate (divalproex sodium, valproic acid) is an anticonvulsant and mood stabilizer approved for acute mania, mixed episodes associated with bipolar disorder, migraine prophylaxis, and seizure disorders. It is heavily utilized for bipolar maintenance, rapid cycling, and aggression in serious mental illness.
Formulations include delayed-release divalproex tablets (125, 250, 500 mg), sprinkle capsules (125 mg), and extended-release (ER) tablets (250, 500 mg). Acute mania dosing typically starts at 750 mg/day in divided doses (delayed-release) or 25 mg/kg once daily (ER), titrated to clinical response and serum levels.
Valproate increases gamma-aminobutyric acid (GABA) concentrations, blocks voltage-dependent sodium channels, and modulates glutamate-mediated excitation. It also impacts epigenetic regulation via histone deacetylase inhibition, potentially contributing to mood stabilization.
The drug is hepatically metabolized via glucuronidation and beta-oxidation in mitochondria; minor CYP metabolism occurs. Elimination half-life is 9-16 hours in adults but longer in the elderly. Therapeutic serum levels for bipolar disorder range from 50-125 mcg/mL (total valproate).
Dosing & administration
Acute mania (delayed-release): start 250 mg three times daily; increase by 250-500 mg every 1-3 days to target serum 50-125 mcg/mL.
Acute mania (ER): start 25 mg/kg once daily; adjust every 3-5 days based on clinical response and trough levels.
Maintenance: adjust to lowest effective serum concentration (often 50-100 mcg/mL).
Switching formulations: ER requires 8-20% higher total daily dose compared with delayed-release.
Monitoring and dose adjustments
- Baseline labs
- CBC with platelets, LFTs, pregnancy test, weight.
- Serum valproate
- Check 3-5 days after initiation/dose change; trough before morning dose.
- Hepatic impairment
- Contraindicated in significant hepatic disease.
- Renal impairment
- Monitor free levels; protein binding reduced leading to higher free fraction.
Mechanism of action
Valproate enhances GABA synthesis and inhibits degradation, increasing inhibitory neurotransmission.
It blocks voltage-gated sodium channels and T-type calcium channels, dampening excitatory neuronal firing. Histone deacetylase inhibition may exert neuroprotective effects.
- No direct receptor binding; modulates neurotransmitter systems and ion channels.
- Inhibits GABA transaminase and succinic semialdehyde dehydrogenase.
- Increases brain-derived neurotrophic factor expression.
Metabolism & pharmacokinetics
High oral bioavailability (>90%); peak levels 1-4 hours (DR) and 4-17 hours (ER).
Highly protein-bound (~90%); free fraction increases with higher concentrations or hypoalbuminemia. Metabolized via glucuronidation and mitochondrial beta-oxidation; clearance reduced in hepatic impairment.
- Tmax
- DR 1-4 h; ER 4-17 h
- Half-life
- 9-16 h (longer in elderly)
- Therapeutic serum range
- 50-125 mcg/mL
Drug interactions
Enzyme inhibitors (e.g., fluoxetine) can increase valproate levels; enzyme inducers (carbamazepine, phenytoin) decrease levels.
Valproate inhibits UGT enzymes, increasing lamotrigine levels (risk of rash); requires lamotrigine dose reduction.
Coadministration with topiramate increases risk of hyperammonemia and encephalopathy.
| Mechanism | Agents / factors | Management |
|---|---|---|
| UGT inhibition | Lamotrigine | Lamotrigine dose should be halved when combined; monitor for rash. |
| Enzyme induction | Carbamazepine, phenytoin | Increase valproate dose as needed; monitor levels. |
| Hyperammonemia | Topiramate | Monitor ammonia if lethargy occurs; consider dose reductions. |
Monitoring & safety checks
Serum valproate level
3-5 days after dose change; every 3 months maintenance • Maintain therapeutic range and detect toxicity.
Liver function tests
Baseline, monthly for first 6 months, then periodically • Risk of hepatic failure, especially early treatment.
CBC with platelets
Baseline and periodically • Detect thrombocytopenia.
Ammonia
If unexplained lethargy, vomiting, or cognitive changes • Hyperammonemic encephalopathy possible.
Counsel regarding teratogenic risk (neural tube defects); use effective contraception.
Monitor weight and metabolic parameters; valproate can cause weight gain and PCOS in women.
Discontinuation guidance
Taper over several weeks to avoid relapse of mania or seizures; reduce by 250-500 mg every 5-7 days.
Ensure alternative mood stabilizer coverage when discontinuing due to adverse effects.
Special populations
Pregnancy: contraindicated for migraine prophylaxis and generally avoided in pregnancy due to major teratogenic risk; if continued, use lowest effective dose and folic acid supplementation.
Women of childbearing potential: counsel on contraception and risks; monitor for polycystic ovary syndrome.
Elderly: start at lower doses due to decreased clearance and increased free fraction.
Adverse effects
Common: gastrointestinal upset, tremor, weight gain, hair thinning.
Serious: hepatotoxicity, pancreatitis, hyperammonemic encephalopathy, thrombocytopenia.
Neurologic: dose-related sedation, ataxia; rare encephalopathy even with normal ammonia.
References
- DEPAKOTE (divalproex sodium) prescribing information — DailyMed (2024)
- CANMAT/ISBD guidance on valproate for bipolar disorder — Bipolar Disorders (2021) DOI: 10.1111/bdi.13135
- Valproate for bipolar disorder: evidence update — Current Opinion in Psychiatry (2010) DOI: 10.1097/YCO.0b013e328339a0d2
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.