Can Lacosamide, Lamotrigine, or Depakote (Valproate) cause hyponatremia?

Hyponatremia Risk with Antiepileptic Medications

Yes, all three medications—lacosamide, lamotrigine, and Depakote (valproate)—can cause hyponatremia, but they differ significantly in their risk profiles, with valproate and lacosamide posing higher risks than lamotrigine.

Risk Stratification by Medication

Valproate (Depakote) - Highest Risk

• Valproate has a moderate to strong association with hyponatremia, with an adjusted odds ratio of 4.96 (2.44-10.66) for hospitalization due to hyponatremia with newly initiated treatment 1
• Valproate can cause an SIADH-like syndrome with dose-dependent reduction in water excretion capacity 2
• Severe cases have been documented, including profound hyponatremia with serum sodium as low as 99 mEq/L following valproate overdose, though chronic use at therapeutic doses typically causes milder hyponatremia (around 127-128 mEq/L) 3
• The mechanism involves inappropriate antidiuretic hormone secretion, leading to impaired free water clearance 2

Lacosamide - Moderate to High Risk

• Lacosamide carries a lower incidence of arousal-related adverse events compared to carbamazepine, but hyponatremia remains a recognized complication 4
• While specific odds ratios for lacosamide-induced hyponatremia are not provided in the evidence, the drug is acknowledged as capable of causing this electrolyte disturbance 5, 6
• The risk appears comparable to other sodium channel blockers, though potentially less than carbamazepine or oxcarbazepine 4

Lamotrigine - Lowest Risk

• Lamotrigine has the lowest risk among these three medications, with an adjusted odds ratio of only 1.67 (0.70-4.08) for newly initiated treatment—a non-significant association 1
• During ongoing treatment, lamotrigine maintains a favorable safety profile regarding hyponatremia 1
• Lamotrigine may be advantageous in patients at risk of developing hyponatremia and can be considered as an alternative when switching from higher-risk antiepileptics 1

Clinical Monitoring Recommendations

Initial Assessment

• Obtain baseline serum sodium, serum osmolality, urine osmolality, and urine sodium before initiating any of these medications 7
• Check thyroid function (TSH) and assess for adrenal insufficiency to rule out other causes of hyponatremia 7, 2
• Evaluate volume status (check for orthostatic hypotension, dry mucous membranes, jugular venous distention, peripheral edema) 7

Monitoring Schedule

• Check serum sodium 1-2 weeks after initiation and after any dose increase, particularly with valproate or lacosamide 4, 7
• For valproate specifically, monitor serum sodium levels during treatment with high dosages (>1,500-2,000 mg/day) 2
• Continue monitoring every 3-6 months during maintenance therapy, especially in elderly patients or those with other risk factors 7

High-Risk Populations Requiring Closer Surveillance

• Elderly patients (increased susceptibility to SIADH) 5, 6
• Patients on concomitant medications that can cause hyponatremia (diuretics, SSRIs, other antiepileptics) 5, 6
• Patients with baseline renal impairment or heart failure 4, 7
• Those with a history of hyponatremia from other medications 5

Management of Drug-Induced Hyponatremia

Mild Hyponatremia (130-135 mmol/L)

• Continue the antiepileptic with close monitoring of serum electrolytes 7
• Avoid excessive fluid intake and counsel patients about thirst management 4
• Consider dose reduction if clinically feasible 7

Moderate Hyponatremia (120-130 mmol/L)

• Implement fluid restriction to 1-1.5 L/day 7
• Consider switching to lamotrigine or gabapentin, which have lower hyponatremia risk 1
• If continuing the current medication, increase monitoring frequency to weekly 7

Severe Hyponatremia (<120 mmol/L)

• Discontinue the offending antiepileptic immediately 7, 3
• For symptomatic patients (confusion, seizures), administer 3% hypertonic saline with target correction of 6 mmol/L over 6 hours 7
• Do not exceed correction rate of 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 7
• Switch to an alternative antiepileptic with lower hyponatremia risk once sodium is corrected 1

Critical Pitfalls to Avoid

• Do not ignore mild hyponatremia (130-135 mmol/L), as even mild reductions increase fall risk and mortality 7
• Avoid "re-challenge" with the same medication after documented drug-induced hyponatremia—inform the patient and document this clearly 5
• Do not attribute hyponatremia solely to other causes without considering the antiepileptic as a potential contributor 6
• Recognize that hyponatremia risk is highest during the first 90 days of treatment initiation but can occur with chronic use 1, 3