Can Depakote (valproate) cause hyponatremia?

Depakote (Valproate) and Hyponatremia

Yes, Depakote (valproate) can cause hyponatremia through a syndrome of inappropriate antidiuretic hormone secretion (SIADH)-like mechanism, with multiple case reports documenting this adverse effect.

Mechanism and Evidence

Valproate has been documented to cause hyponatremia through what appears to be a SIADH-like mechanism:

• Case reports have demonstrated that valproate can reduce the ability to excrete water in a dose-dependent manner 1
• Severe cases of hyponatremia with sodium levels as low as 99 mEq/L have been reported with valproate toxicity 2
• The first documented case of valproate-induced SIADH was reported in 1994, with hyponatremia resolving after discontinuation and recurring upon rechallenge 3

Risk Factors for Valproate-Induced Hyponatremia

Several factors increase the risk of developing hyponatremia while on valproate:

• Higher doses of valproate (>600 mg/day) 4
• Older age 4
• Low body weight 4
• Polypharmacy, particularly concomitant use of:
  • Other antiepileptic drugs (especially carbamazepine) 4
  • Phenobarbital 4
  • Benzodiazepines 4
  • Antipsychotics 4

Comparative Risk Among Antiepileptic Drugs

A large population-based case-control study found that valproate has a moderate association with hospitalization due to hyponatremia compared to other antiepileptic drugs 5:

• Newly initiated valproate: adjusted OR 4.96 (95% CI 2.44-10.66)
• This risk is lower than carbamazepine (OR 9.63) and levetiracetam (OR 9.76)
• But higher than lamotrigine (OR 1.67) and gabapentin (OR 1.61)

Monitoring and Management

For patients on Depakote (valproate) therapy:

1. Baseline and periodic monitoring of serum sodium levels is recommended, especially:

   • During initiation of therapy
   • After dose increases
   • In elderly patients
   • In patients with low body weight
   • In patients on multiple medications

2. Clinical monitoring for signs and symptoms of hyponatremia:

   • Early: headache, nausea, vomiting, lethargy
   • Advanced: confusion, somnolence, seizures, coma

3. Management of hyponatremia:

   • If mild and asymptomatic: consider dose reduction
   • If severe (sodium <130 mmol/L) or symptomatic: consider discontinuation of valproate and switching to an alternative antiepileptic with lower risk (lamotrigine or gabapentin) 5
   • Fluid restriction may be necessary in symptomatic cases
   • Correction of sodium should not exceed 8 mmol/L per day to avoid central pontine myelinolysis 6

Clinical Pearls and Pitfalls

• Hyponatremia may develop gradually and can be chronic in patients on long-term valproate therapy
• The risk appears to be dose-dependent, with higher doses carrying greater risk 4
• Patients may be asymptomatic despite significant hyponatremia
• Concomitant use of valproate with carbamazepine may potentiate the risk of hyponatremia 4
• Lamotrigine and gabapentin appear to have the lowest risk of hyponatremia among antiepileptic drugs and may be preferred alternatives in patients at high risk 5

Clinicians should maintain a high index of suspicion for hyponatremia in patients on valproate therapy, particularly those with risk factors, and monitor sodium levels accordingly.