Which Selective Serotonin Reuptake Inhibitor (SSRI) is associated with the lowest risk of causing hyponatremia?

SSRI-Associated Hyponatremia: Comparative Risk Assessment

Based on the most recent evidence, bupropion and paroxetine are associated with the lowest risk of hyponatremia among antidepressants, with bupropion having a hazard ratio of 0.83 compared to sertraline. 1

Comparative Risk of Hyponatremia Among Antidepressants

The 2025 study from the All of Us Research Program provides the most comprehensive and recent data on differential risks of hyponatremia among common antidepressants:

Lowest Risk

• Bupropion (HR = 0.83 [0.73-0.94] compared to sertraline)
• Paroxetine (HR = 0.78 [0.65-0.93] compared to sertraline)

Moderate Risk

• Sertraline (reference standard)
• Fluoxetine
• Citalopram
• Venlafaxine

Highest Risk

• Escitalopram (HR = 1.16 [1.01-1.33] compared to sertraline)
• Duloxetine (HR = 1.37 [1.19-1.58] compared to sertraline)

Risk Factors for SSRI-Induced Hyponatremia

Several important risk factors increase vulnerability to SSRI-induced hyponatremia:

• Advanced age (particularly elderly patients) 2, 3
• Female gender 3
• Low body mass index 4, 3
• Concomitant use of diuretics 4, 3
• Lower baseline serum sodium concentration 3
• History of previous hyponatremia 4
• Severe physical illness 4

Clinical Implications and Monitoring

Hyponatremia associated with SSRIs typically:

• Develops within the first few weeks of treatment 4, 3
• Resolves within approximately 2 weeks after discontinuation 3
• Occurs in 0.5% to 32% of patients (varying by study) 3
• Has a first 30-day incidence of 0.87% and 3-year incidence of 10.5% 1

The mechanism is thought to be secondary to syndrome of inappropriate secretion of antidiuretic hormone (SIADH) 5, 6, 3.

Clinical Presentation

Symptoms of SSRI-induced hyponatremia are predominantly neuropsychiatric:

• Restlessness
• Lethargy
• Cognitive impairment
• In severe cases: confusion, seizures, coma 4

Any worsening in psychiatric symptoms in at-risk patients should prompt checking of serum electrolytes.

Practical Recommendations

1. For patients at high risk for hyponatremia (elderly, female, low BMI, using diuretics):

   • Consider bupropion or paroxetine as first-line agents
   • Avoid escitalopram and duloxetine if possible

2. Monitoring recommendations:

   • Check baseline sodium levels before starting therapy
   • Monitor sodium levels within 2 weeks of starting treatment in high-risk patients
   • Continue monitoring periodically during the first month of treatment

3. If hyponatremia occurs:

   • For mild cases: water restriction and mild diuresis with loop diuretics
   • For severe cases: higher doses of loop diuretics and hypertonic saline 3
   • Consider discontinuation of the SSRI and switching to bupropion

Important Caveats

• Individual patient response may vary
• The benefits of treating depression must be weighed against the risk of hyponatremia
• Rechallenge with the same or another SSRI after an episode of hyponatremia may lead to recurrence 3
• Bupropion, while having the lowest risk of hyponatremia, may not be suitable for all patients due to its different side effect profile and contraindications (e.g., seizure disorders)

In conclusion, when hyponatremia is a significant concern, bupropion represents the safest choice among antidepressants, followed by paroxetine. For patients who specifically require an SSRI and have risk factors for hyponatremia, paroxetine would be the preferred option.