Valproate Causes Hyponatremia, Not Hypernatremia
No, valproate does not cause hypernatremia—it causes the opposite electrolyte disturbance: hyponatremia through a syndrome of inappropriate antidiuretic hormone secretion (SIADH).
The Actual Electrolyte Disturbance
Valproate is well-documented to cause hyponatremia (low sodium), not hypernatremia (high sodium). This occurs through an SIADH-like mechanism where the drug impairs the kidney's ability to excrete free water in a dose-dependent manner 1.
Mechanism and Clinical Evidence
Water loading tests performed at different valproate dosages confirmed that the ability to excrete water is reduced in a dose-dependent manner, leading to dilutional hyponatremia 1.
The syndrome presents with classic SIADH features: hyponatremia, low plasma osmolality, inappropriately elevated urine osmolality, and normal to elevated urine sodium 2.
Documented cases show serum sodium levels dropping as low as 99 mEq/L with valproate overdose, though chronic use typically causes more modest reductions (e.g., 127-128 mEq/L) 2, 3.
Clinical Patterns to Recognize
Asymptomatic presentation is common: Patients may have significantly reduced sodium levels (128 mEq/L) discovered only on routine laboratory monitoring without clinical symptoms 1, 3.
Dose-dependent effect: Higher valproate doses carry greater risk for developing hyponatremia 1.
Reversibility upon discontinuation: Serum sodium normalizes within 8 days to 72 hours after stopping valproate, and hyponatremia recurs upon rechallenge, confirming causality 2, 3.
Acute-on-chronic pattern: Patients on chronic valproate therapy may have baseline mild hyponatremia that worsens dramatically with overdose or dose increases 2.
Monitoring Implications
While current guidelines emphasize monitoring liver function tests, complete blood counts, and reproductive hormone effects 4, the evidence suggests that serum sodium monitoring should be considered, particularly:
- In patients on high-dose valproate therapy 1
- During routine monitoring visits (every 3-6 months as already recommended for other parameters) 4
- In patients with unexplained neurological symptoms or altered mental status 2
Common Pitfall to Avoid
Do not confuse the "sodium" in "sodium valproate" with the electrolyte effect—the sodium content of the medication does not prevent or cause hypernatremia. The drug mechanism actually causes the opposite problem by inducing SIADH 1, 3, 5.