Which selective serotonin reuptake inhibitor (SSRI) is least likely to cause hyponatremia?

Which SSRI is Least Likely to Cause Hyponatremia

Based on the most recent evidence, fluvoxamine appears to be the SSRI least likely to cause hyponatremia. 1

Understanding SSRI-Associated Hyponatremia

Hyponatremia is a well-documented adverse effect of SSRIs, occurring in approximately 0.5% to 12% of older adults, typically within the first month of treatment 2. The mechanism is primarily related to the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Risk Factors for SSRI-Induced Hyponatremia:

• Older age (particularly adults over 60)
• Female gender
• Low body weight
• Concomitant use of diuretics
• Baseline low sodium levels
• First month of therapy

Comparative Risk Among SSRIs

The 2022 triangulation study combining retrospective cohort, disproportionality, and pharmacodynamic analyses provides the most comprehensive recent evidence on this topic 1:

• Fluvoxamine: Showed no significant decrease in serum sodium levels (+0.74 ± 0.75 mmol/L) and had no significant increase in hyponatremia reports (reporting odds ratio 1.48)
• Other SSRIs: Generally showed significant decreases in serum sodium levels (mean change -1.00 ± 0.23 mmol/L)

The 2025 study from the All of Us Research Program found that among commonly prescribed SSRIs 3:

• Paroxetine: Had the lowest risk of hyponatremia (HR = 0.78 compared to sertraline)
• Escitalopram: Had the highest risk among SSRIs (HR = 1.16 compared to sertraline)
• Bupropion (not an SSRI but included for comparison): Had a lower risk than most SSRIs (HR = 0.83)

Mechanism of Differential Risk

The difference in hyponatremia risk appears to correlate with binding affinity for the serotonin transporter (SERT) 1:

• Lower binding affinity for SERT = Lower risk of hyponatremia
• Fluvoxamine has a relatively lower binding affinity for SERT compared to other SSRIs

Clinical Recommendations

When prescribing SSRIs to patients at high risk for hyponatremia:

1. First choice: Consider fluvoxamine as it appears to have the lowest risk of causing hyponatremia 1
2. Alternative choice: Consider paroxetine as it showed lower hyponatremia risk in the recent large cohort study 3
3. Avoid if possible: Escitalopram and duloxetine, which were associated with higher hyponatremia risk 3

Monitoring Recommendations

For all patients starting SSRI therapy, especially those at high risk:

• Check baseline serum sodium levels
• Monitor sodium levels within the first month of treatment (when hyponatremia is most likely to develop) 2
• Be vigilant for early symptoms of hyponatremia: weakness, confusion, headache, nausea, and in severe cases, seizures 4, 5

Special Populations

Elderly Patients

Older adults are particularly susceptible to SSRI-induced hyponatremia. The risk is higher in this population (0.5-12%) 2, and monitoring should be more frequent.

Patients on Diuretics

Concomitant use of diuretics significantly increases the risk of hyponatremia. Consider more frequent monitoring in these patients and potentially selecting fluvoxamine or paroxetine.

Important Caveats

While fluvoxamine may have the lowest risk of hyponatremia, other factors must be considered when selecting an SSRI, including:

• Drug interactions (fluvoxamine has significant CYP450 interactions)
• Other side effect profiles
• Patient-specific factors
• Treatment indication

Remember that all SSRIs carry some risk of hyponatremia, and monitoring is essential regardless of which agent is selected.