Which antidepressant is most likely to cause hyponatremia?

Which Antidepressant is Most Likely to Cause Hyponatremia?

Selective serotonin reuptake inhibitors (SSRIs), particularly citalopram and sertraline, are most likely to cause hyponatremia among antidepressants, with the highest risk occurring within the first 2 weeks of treatment initiation.

Evidence for SSRI-Associated Hyponatremia

The strongest evidence demonstrates that SSRIs carry the highest risk:

• Citalopram shows the highest odds ratio for hospitalization due to hyponatremia among newly initiated antidepressants (adjusted OR 5.50,95% CI 4.71-6.44) 1
• Sertraline follows closely with an adjusted OR of 4.96 (95% CI 3.81-6.48) for newly initiated treatment 1
• SSRIs as a class demonstrate a 3-4 fold increased risk compared to non-users (OR 3.96,95% CI 1.33-11.83) 2 and a 3.3-fold increased risk compared to other antidepressant classes (OR 3.3,95% CI 1.3-8.6) 3

Other Serotonergic Antidepressants

Venlafaxine (SNRI) also carries substantial risk:

• Adjusted OR of 5.28 (95% CI 3.20-8.83) for newly initiated treatment 1
• Comparable risk profile to SSRIs 4

Mirtazapine demonstrates moderate risk:

• Adjusted OR of 2.54 (95% CI 2.04-3.16) for newly initiated treatment 1
• Frequently implicated in case reports involving older adults 4

Lower-Risk Alternatives

Bupropion appears to have the lowest risk for hyponatremia:

• Implicated less frequently in case reports and clinical studies 4
• May be the most appropriate choice for older adults at risk for antidepressant-induced hyponatremia 4
• The American Academy of Family Physicians suggests considering bupropion as an alternative in high-risk patients 5

Tricyclic antidepressants (TCAs) show lower risk:

• Adjusted OR of only 1.59 (95% CI 1.13-2.24) for newly initiated treatment 1
• Less frequently implicated than SSRIs 4

Trazodone is also implicated less often than SSRIs in the literature 4

Critical Timing and Risk Factors

The highest risk period is the first 2 weeks of treatment:

• Greatest risk occurs during initial 2 weeks of serotonergic antidepressant therapy 2
• This justifies sodium monitoring during the first weeks after treatment initiation 2
• The effect is not dose-dependent and typically resolves with treatment discontinuation 6

High-risk patient populations include:

• Elderly patients (≥65 years): At significantly greater risk with SSRIs and SNRIs 7, 8, 9
• Patients on diuretics: Elderly patients using diuretics concomitantly with SSRIs have the highest risk (OR 13.5,95% CI 1.8-101) 3
• Volume-depleted patients: Those otherwise volume depleted are at greater risk 7, 8, 9
• Female gender, low weight, and baseline sodium in lower limits increase risk 6

Clinical Recognition and Management

FDA labeling for SSRIs explicitly warns about hyponatremia:

• Sertraline: "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). Cases with serum sodium lower than 110 mmol/L have been reported" 7
• Escitalopram and citalopram contain identical warnings 8, 9

Clinical manifestations include:

• Headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness (which may lead to falls) 7, 8, 9
• More severe cases: hallucination, syncope, seizure, coma, respiratory arrest, and death 7, 8, 9

Management approach:

• Discontinue the antidepressant in patients with symptomatic hyponatremia 7, 8, 9
• Institute appropriate medical intervention 7, 8, 9
• Monitor sodium levels periodically, especially in high-risk patients 6

Important Caveat

Ongoing treatment (beyond initial weeks) shows minimal to no increased risk:

• Adjusted OR for ongoing citalopram treatment is actually protective at 0.57 (95% CI 0.52-0.63) 1
• This suggests the risk is primarily during treatment initiation, not maintenance therapy 1