Which antidepressant is least likely to cause hyponatremia?

Antidepressant Least Likely to Cause Hyponatremia

Mirtazapine is the antidepressant least likely to cause hyponatremia and should be the first-line choice for patients at risk of this complication. 1, 2, 3, 4

Evidence-Based Ranking by Risk

Lowest Risk (Preferred Options)

• Mirtazapine has the lowest hyponatremia event rate at 1.02% and is significantly less likely to cause hyponatremia compared to SSRIs (OR = 0.607,95% CI 0.385-0.957) 4

• Mirtazapine showed no decrease in serum sodium levels within 30 days of initiation (+0.55 ± 0.47 mmol/L, P = 0.24) in older adults 3

• The lower binding affinity of mirtazapine for serotonin transporter (SERT) is responsible for its reduced hyponatremia risk 3

• Bupropion is the second-best choice with a hazard ratio of 0.83 (95% CI 0.73-0.94) compared to sertraline, representing a 17% lower risk 5

• Bupropion can cause syndrome of inappropriate antidiuretic hormone secretion (SIADH), but this is rare with only isolated case reports 6, 7

Moderate Risk

• Paroxetine has a hazard ratio of 0.78 (95% CI 0.65-0.93) compared to sertraline 5
• Fluvoxamine showed no decrease in serum sodium levels (+0.74 ± 0.75 mmol/L, P = 0.33) and no significant increase in hyponatremia reports (reporting OR 1.48,95% CI 0.94-2.32) 3
• Milnacipran (SNRI) showed no decrease in serum sodium levels (+0.08 ± 0.87 mmol/L, P = 0.93) and no significant increase in hyponatremia reports (reporting OR 0.85,95% CI 0.45-1.62) 3
• Tricyclic antidepressants (TCAs) have lower odds ratios (1.1-4.9) compared to SSRIs and an event rate of 2.66% 2, 4

Highest Risk (Avoid in At-Risk Patients)

• SNRIs as a class have the highest event rate at 7.44% and are significantly more likely to cause hyponatremia than SSRIs (OR = 1.292,95% CI 1.120-1.491) 4
• Duloxetine has the highest hazard ratio at 1.37 (95% CI 1.19-1.58) compared to sertraline 5
• Venlafaxine has incidence rates ranging from 0.08% to 70% depending on the population studied 2
• Escitalopram has a hazard ratio of 1.16 (95% CI 1.01-1.33) compared to sertraline 5
• SSRIs as a class have odds ratios of 1.5-21.6 and an event rate of 5.59% 2, 4

Clinical Algorithm for Selection

Step 1: Identify High-Risk Patients

• Age >60 years (OR = 6.3 for hyponatremia) 2
• Concomitant thiazide diuretic use (OR = 11.2-13.5) 2
• Baseline sodium <135 mmol/L 1
• History of SIADH or hyponatremia 8

Step 2: Choose Antidepressant Based on Risk Profile

• For high-risk patients: Use mirtazapine first-line 1, 4
• For moderate-risk patients: Consider bupropion (especially if low energy/anhedonia present) or paroxetine 1, 5
• Avoid in high-risk patients: SNRIs (especially duloxetine and venlafaxine), escitalopram 5, 4

Step 3: Monitoring Protocol

• Check baseline sodium before initiating any antidepressant 1
• Recheck sodium at 1-2 weeks and 4 weeks after initiation (highest risk period is within first 30 days) 5, 3
• Sodium <135 mmol/L is clinically significant; <130 mmol/L requires immediate intervention 1

Step 4: Management of Hyponatremia

• If hyponatremia develops on SSRI/SNRI: Switch immediately to mirtazapine or bupropion 1
• Discontinue implicated medication, implement fluid restriction, and ensure adequate oral salt intake 8
• Consider vasopressin antagonists only for persistent severe hyponatremia with cognitive symptoms despite water restriction 8

Additional Clinical Considerations

Mirtazapine offers additional benefits beyond low hyponatremia risk, including appetite stimulation and sleep improvement, making it particularly valuable in older adults with depression 1

Bupropion advantages include activating properties beneficial for low energy and anhedonia, plus significantly lower rates of sexual adverse effects compared to SSRIs/SNRIs 9, 10

Overall incidence: Hyponatremia occurs in 0.87% of patients within 30 days and 10.5% within 3 years of antidepressant initiation, emphasizing the importance of appropriate selection and monitoring 5

Common pitfall: The Beers Criteria identifies antidepressants as a cause of SIADH in older adults, but clinicians often fail to consider antidepressant class differences when prescribing for high-risk patients 8