Can Divalproex (valproate) cause hyponatremia?

Divalproex Sodium Can Cause Hyponatremia

Yes, divalproex sodium (valproate) can cause hyponatremia, as demonstrated in multiple case reports documenting this adverse effect. 1, 2, 3

Mechanism and Evidence

• Divalproex sodium has been associated with hyponatremia through a syndrome of inappropriate antidiuretic hormone secretion (SIADH)-like mechanism 2
• Case reports have documented hyponatremia occurring as an adverse effect of divalproex sodium, with some cases showing severe hyponatremia with sodium levels as low as 99 mEq/L 3
• In one documented case, water loading tests performed at different dosages confirmed that the ability to excrete water was reduced in a dose-dependent manner with valproate 2
• Acute hyponatremia with accompanying hyperammonemia has been reported following initiation of divalproex sodium for psychiatric disorders 1

Clinical Presentation and Risk Factors

• Hyponatremia due to divalproex may present with:
  • Somnolence 3
  • Altered mental status 1
  • Delirium in severe cases 4
• Risk factors that may increase likelihood of hyponatremia with divalproex:
  • Higher doses of medication 2
  • Older age (similar to other medication-induced hyponatremia patterns) 5
  • Combination therapy with other antiepileptic drugs 5

Monitoring Recommendations

• Monitor serum sodium levels:
  • At baseline before initiating therapy 1
  • After initiation of therapy or dose increases 1
  • Periodically during maintenance therapy, especially with high dosages 2
• Consider monitoring blood ammonia levels if patients develop unexplained changes in mental status while on divalproex, as hyperammonemia can occur concurrently with hyponatremia 1, 4

Management of Divalproex-Induced Hyponatremia

• If mild to moderate hyponatremia develops:
  • Consider dose reduction of divalproex sodium 2
  • Implement fluid restriction if appropriate 3
• For severe hyponatremia or symptomatic cases:
  • Withhold divalproex sodium 3
  • Monitor serum sodium levels closely during correction 3
  • Consider alternative mood stabilizers or antiepileptic medications if appropriate 1

Clinical Pitfalls and Caveats

• Hyponatremia may develop gradually and can be chronic in patients on long-term valproate therapy 3
• Acute overdose of valproate can precipitate acute hyponatremia on top of chronic hyponatremia 3
• The combination of hyponatremia and hyperammonemia can lead to diagnostic confusion, as symptoms may be attributed to other causes 4
• Normal liver function tests do not rule out divalproex-induced hyponatremia 4
• Clinicians should maintain a high index of suspicion for this adverse effect, as it may be missed if not specifically monitored 1