Why do Selective Serotonin Reuptake Inhibitors (SSRIs) cause hyponatremia?

From the Guidelines

SSRIs cause hyponatremia primarily through the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which is a rare but potentially life-threatening side effect. These medications, including fluoxetine, sertraline, paroxetine, citalopram, and escitalopram, increase serotonin levels in the brain, which stimulates the release of antidiuretic hormone (ADH) from the posterior pituitary gland 1. Excessive ADH causes the kidneys to retain water while continuing to excrete sodium, leading to dilutional hyponatremia where the sodium concentration in the blood becomes abnormally low.

Key Points to Consider

• The effect typically develops within the first few weeks of treatment and is more common in elderly patients, women, and those taking other medications that affect water balance 1.
• Patients with SSRI-induced hyponatremia may experience symptoms like headache, confusion, nausea, muscle cramps, and in severe cases, seizures or coma.
• The risk increases with higher doses and can occur with any SSRI, though some studies suggest sertraline and escitalopram may have slightly lower risks 1.
• Regular monitoring of sodium levels is important, especially in high-risk patients during the initial weeks of treatment or after dose adjustments.

Clinical Implications

• Clinicians should be aware of the potential for SSRI-induced hyponatremia and monitor patients closely, especially those at high risk.
• Patients should be educated on the signs and symptoms of hyponatremia and instructed to seek medical attention if they experience any concerning symptoms.
• In cases where hyponatremia is suspected, serum sodium levels should be checked promptly, and treatment should be adjusted accordingly to minimize the risk of complications.

From the FDA Drug Label

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including sertraline. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia — Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Prozac. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)

SSRIs, including sertraline, cause hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This condition can lead to a range of symptoms, from mild to severe, including headache, difficulty concentrating, and weakness.

• Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs.
• Patients taking diuretics or who are otherwise volume depleted may also be at greater risk. 2 3

From the Research

Mechanism of SSRI-Induced Hyponatremia

• The mechanism by which SSRIs cause hyponatremia is thought to be secondary to the development of Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) 4.
• SIADH leads to an excessive release of antidiuretic hormone, resulting in water retention and subsequent hyponatremia.

Risk Factors for SSRI-Induced Hyponatremia

• Older age is a significant risk factor for the development of hyponatremia with SSRIs 5, 4, 6.
• Female gender is also a risk factor for SSRI-induced hyponatremia 5, 4.
• Concomitant use of diuretics, such as thiazide diuretics, increases the risk of hyponatremia with SSRIs 7, 4, 6.
• Low body weight and lower baseline serum sodium concentration are additional risk factors for SSRI-induced hyponatremia 4.

Incidence and Prevalence of SSRI-Induced Hyponatremia

• The incidence of hyponatremia with SSRIs varies from 0.5% to 32% 4.
• The prevalence of hyponatremia was 10.4% in patients taking thiazides alone and 9.0% in those taking SSRIs alone, while patients on both medications had a hyponatremia prevalence of approximately 13.0% 7.
• The adjusted odds ratio of hyponatremia with concomitant use of thiazide diuretics and SSRIs was 1.24 (95% CI: 1.22-1.26) for SSRI users and 1.27 (95% CI: 1.24-1.29) for thiazide users 7.

Treatment and Management of SSRI-Induced Hyponatremia

• Treatment of isovolemia hypotonic hyponatremia associated with SSRI use includes water restriction and mild diuresis with a loop diuretic 4.
• More severe cases may be treated with higher doses of loop diuretics and hypertonic saline 4.
• Discontinuation of the SSRI or substitution with a non-serotonergic antidepressant, such as bupropion, may be necessary in some cases 8.