Which antidepressant is least likely to cause hyponatremia?

Antidepressant Selection to Minimize Hyponatremia Risk

Mirtazapine is the first-choice antidepressant for patients at risk of hyponatremia, followed by bupropion as a second option. 1

Primary Recommendations Based on Hyponatremia Risk

First-Line Choice: Mirtazapine

• The American Heart Association recommends mirtazapine as the preferred antidepressant for patients with hyponatremia risk factors, offering the additional benefits of appetite stimulation and sleep improvement 1
• Mirtazapine demonstrates moderate risk for hyponatremia compared to SSRIs and SNRIs, making it a safer alternative for high-risk patients 2
• Evidence from multiple studies consistently shows lower incidence rates of hyponatremia with mirtazapine compared to SSRIs and venlafaxine 2

Second-Line Choice: Bupropion

• Bupropion is recommended as the second choice, particularly for patients with low energy and anhedonia 1
• Given its unique mechanism of action as a norepinephrine-dopamine reuptake inhibitor (NRI), bupropion may be the most appropriate antidepressant for older adults at risk for antidepressant-induced hyponatremia 3
• Recent large-scale data from the All of Us Research Program shows bupropion has the lowest risk of hyponatremia among commonly prescribed antidepressants (HR = 0.83 [0.73-0.94] compared to sertraline) 4
• Bupropion was implicated less often in case reports and clinical studies of hyponatremia in older adults compared to SSRIs, SNRIs, and mirtazapine 3

Antidepressants to Avoid in High-Risk Patients

Highest Risk: SSRIs and SNRIs

• SSRIs carry odds ratios of 1.5-21.6 for hyponatremia, consistently higher than tricyclic antidepressants (OR 1.1-4.9) 2
• Among SSRIs, duloxetine (HR = 1.37 [1.19-1.58]) and escitalopram (HR = 1.16 [1.01-1.33]) are associated with the highest overall risk of hyponatremia compared to sertraline 4
• SSRIs are associated with a 3.3-fold increased risk of hyponatremia (95% CI 1.3,8.6) compared with other classes of antidepressant drugs 5
• Venlafaxine shows particularly high incidence rates ranging from 0.08% to 70% in various studies 2

Moderate Risk Options

• Paroxetine shows lower risk among SSRIs (HR = 0.78 [0.65-0.93] compared to sertraline) 4
• Tricyclic antidepressants demonstrate lower incidence figures compared to SSRIs, though still carry some risk 2
• Trazodone was implicated less often in hyponatremia case reports, though it remains a recognized risk factor 3

High-Risk Patient Populations Requiring Careful Selection

Age-Related Risk

• Older age is associated with a 6.3-fold increased odds ratio for antidepressant-induced hyponatremia 2
• Antidepressant-induced hyponatremia in older adults is fairly common, with SSRIs, SNRIs, and mirtazapine implicated in the majority of cases 3

Medication Interactions

• Concomitant use of thiazide diuretics carries odds ratios of 11.2-13.5 for hyponatremia 2
• Elderly patients using diuretics concomitantly with SSRIs face the highest risk (OR 13.5; 95% CI 1.8,101) 5

Pre-existing Conditions

• Patients with a history of SIADH or hyponatremia are at increased risk 1
• The American Geriatrics Society identifies antidepressants as a cause of SIADH in older adults, emphasizing the need to consider antidepressant class differences when prescribing for high-risk patients 1

Management When Hyponatremia Develops

Immediate Action Required

• If hyponatremia develops on SSRI/SNRI, switch immediately to mirtazapine or bupropion 1
• Discontinue the implicated medication, implement fluid restriction, and ensure adequate oral salt intake 1
• A case report demonstrates full recovery when sertraline was replaced with bupropion in an elderly patient with persistent hyponatremia 1

Monitoring Thresholds

• Sodium <135 mmol/L is considered clinically significant 1
• Sodium <130 mmol/L requires intervention 1
• For persistent severe hyponatremia with cognitive symptoms despite water restriction, consider vasopressin antagonists 1

Common Pitfalls to Avoid

• Do not assume all antidepressants carry equal hyponatremia risk—SSRIs and SNRIs have substantially higher risk than bupropion and mirtazapine 4, 2
• Avoid prescribing SSRIs to elderly patients already on diuretics without close sodium monitoring, as this combination creates the highest risk profile 5
• Do not overlook mild hyponatremia (130-135 mmol/L) as clinically insignificant, as even mild reductions are associated with increased fall risk and mortality 1
• Recognize that hyponatremia incidence varies widely in studies (0.06%-40% for SSRIs) due to different cutoff values and populations, but the relative risk hierarchy remains consistent 2