What antidepressants are not typically associated with hyponatremia?

Antidepressants with Lower Risk of Hyponatremia

Bupropion is the antidepressant with the lowest risk of hyponatremia and should be considered first-line therapy when hyponatremia is a concern. 1

Risk Stratification of Antidepressants for Hyponatremia

Lower Risk Options

• Bupropion: Has a unique mechanism of action as a norepinephrine and dopamine reuptake inhibitor with no significant effect on serotonin, which likely explains its minimal association with hyponatremia 1
• Mirtazapine: Has a significantly lower risk of hyponatremia compared to SSRIs (OR = 0.607), though cases have been reported, particularly in elderly patients 2, 3

Moderate to High Risk Options

• SSRIs: Associated with hyponatremia with an event rate of approximately 5.59% 2
• SNRIs: Carry the highest risk among antidepressants with an event rate of 7.44%, significantly higher than SSRIs (OR = 1.292) 2
• TCAs: Associated with hyponatremia with an event rate of approximately 2.66% 2

Clinical Considerations

Risk Factors for Antidepressant-Induced Hyponatremia

• Age: Patients over 60 years have significantly higher risk 4, 5
• Gender: Female patients appear more susceptible 6
• Timing: Hyponatremia can develop within days to weeks of starting therapy 6
• Medication interactions: Concurrent use of diuretics or other medications affecting sodium balance increases risk 4

Monitoring Recommendations

• Baseline serum sodium measurement before initiating antidepressant therapy, especially in high-risk patients 4
• Follow-up sodium levels within the first 2 weeks of treatment and periodically thereafter 4
• Monitor for clinical signs of hyponatremia: confusion, somnolence, altered speech, headache, and seizures 6

Evidence Quality and Clinical Application

The evidence regarding antidepressants and hyponatremia comes primarily from observational studies and case reports. The most recent meta-analysis (2024) provides the strongest evidence for differential risk among antidepressant classes 2.

A large population-based cohort study found that second-generation antidepressant use was associated with approximately 5-fold increased risk of hospitalization with hyponatremia compared to non-use, though absolute risk increase was low at 1.31% 5.

Special Populations

Elderly Patients

• Elderly patients are at particularly high risk for antidepressant-induced hyponatremia 4
• In patients over 60, bupropion should be strongly considered as first-line therapy when hyponatremia is a concern 1, 2
• If bupropion is contraindicated or poorly tolerated, mirtazapine may be a reasonable alternative, though monitoring is still required 2

Patients with History of Hyponatremia

• For patients with previous episodes of hyponatremia on an antidepressant, switching to bupropion is recommended 1, 2
• Case reports document recurrent hyponatremia when switching between different serotonergic antidepressants (e.g., from citalopram to mirtazapine) 7

Common Pitfalls and Caveats

• Hyponatremia may develop even after months of stable antidepressant therapy 7
• Symptoms of hyponatremia may be mistaken for worsening depression or cognitive decline 6
• No antidepressant is completely risk-free for hyponatremia, so monitoring remains important even with lower-risk options 2
• The FDA drug label for bupropion does not list hyponatremia as a significant adverse effect, unlike many other antidepressants 1