Can Depakote (valproate) cause hyponatremia?

Depakote and Hyponatremia

Yes, Depakote (valproate) can cause hyponatremia through a syndrome of inappropriate antidiuretic hormone secretion (SIADH)-like mechanism, though this is a relatively uncommon adverse effect.

Mechanism and Evidence

Valproate induces hyponatremia by impairing the kidney's ability to excrete free water in a dose-dependent manner 1. Water loading tests have demonstrated that higher doses of valproate progressively reduce water excretion capacity, confirming an SIADH-like syndrome 1. The mechanism involves inappropriate urinary concentration despite low serum osmolality, characteristic of SIADH 2.

Risk Magnitude

The risk of hyponatremia with valproate is moderate compared to other antiepileptic drugs:

• Newly initiated valproate carries an adjusted odds ratio of 4.96 (95% CI 2.44-10.66) for hospitalization due to hyponatremia compared to controls 3
• This risk is substantially lower than carbamazepine (OR 9.63), oxcarbazepine, or levetiracetam (OR 9.76), but higher than lamotrigine (OR 1.67) or gabapentin (OR 1.61) 3
• In older adults, valproate use (grouped with phenytoin and topiramate) showed a 30-day hospitalization risk of 0.17% versus 0.06% in nonusers (RR 2.62,95% CI 1.57-4.36) 4

Clinical Presentation

Valproate-induced hyponatremia can manifest as:

• Chronic hyponatremia during maintenance therapy, often asymptomatic with sodium levels around 127-128 mEq/L 1, 2
• Acute-on-chronic hyponatremia with overdose, potentially causing profound drops (documented as low as 99 mEq/L) 2
• Neuropsychiatric symptoms including confusion, somnolence, and agitation 2, 5

Monitoring Recommendations

Monitor serum sodium levels during high-dose valproate therapy 1. This is particularly important:

• During treatment initiation (highest risk period within 90 days) 3
• When using doses ≥2,000 mg/day 1
• In older adults (≥65 years) who have 8-fold higher hospitalization risk with carbamazepine and 2.6-fold higher risk with valproate compared to nonuse 4
• In patients with additional risk factors for hyponatremia (hypothyroidism, diuretic use, other SIADH-inducing medications) 2

Management Approach

When valproate-induced hyponatremia is suspected:

1. Exclude other causes: Rule out hypothyroidism, adrenal insufficiency, volume depletion, and other medications causing SIADH 1, 2
2. Confirm SIADH: Check serum osmolality (low), urine osmolality (inappropriately high >100 mOsm/kg), and urine sodium 2
3. Withhold valproate: Sodium levels typically normalize within 36-72 hours after discontinuation 2
4. Consider alternative antiepileptics: Lamotrigine and gabapentin have the lowest hyponatremia risk during both initiation and ongoing treatment 3

Common Pitfall

Do not overlook mild chronic hyponatremia (130-135 mmol/L) in patients on valproate, as this may represent subclinical SIADH that can acutely worsen with dose increases or overdose 2. Even mild hyponatremia increases fall risk and mortality 6.