Mirtazapine is the Least Likely Antidepressant to Cause Hyponatremia

Mirtazapine is the least likely antidepressant to cause hyponatremia based on its pharmacodynamic profile and clinical evidence. 1

Risk of Hyponatremia Among Antidepressant Classes

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) have the highest risk of causing hyponatremia, with odds ratios ranging from 1.5 to 21.6 for SSRIs and similar elevated risk for SNRIs 2, 3
Tricyclic antidepressants (TCAs) have a lower risk compared to SSRIs, with odds ratios between 1.1 and 4.9 2
Mirtazapine (a noradrenergic and specific serotonergic antidepressant) shows no significant decrease in serum sodium levels and has the lowest risk among commonly used antidepressants 1

In a comprehensive triangulation study combining retrospective cohort, disproportionality, and pharmacodynamic analyses, mirtazapine did not cause a significant decrease in serum sodium levels (+0.55 ± 0.47 mmol/L, P = 0.24) 1
The same study showed SSRIs and SNRIs caused significant decreases in serum sodium levels (mean change -1.00 ± 0.23 mmol/L and -1.01 ± 0.31 mmol/L, respectively) 1
Mirtazapine had a reporting odds ratio of 1.08 (95% CI 0.74-1.58) for hyponatremia, which was not statistically significant, unlike the significantly elevated risk with SSRIs (4.41) and SNRIs (5.66) 1

The lower risk of hyponatremia with mirtazapine is attributed to its lower binding affinity for the serotonin transporter (SERT) 1
Pharmacodynamic analysis revealed a significant correlation between decreased serum sodium levels and binding affinity for SERT (r = -0.84, P = 0.02) 1
Mirtazapine's unique mechanism of action as a noradrenergic and specific serotonergic antidepressant differs from SSRIs and SNRIs, explaining its lower propensity to cause hyponatremia 2, 1

Within the SSRI class, fluvoxamine showed no significant decrease in serum sodium levels (+0.74 ± 0.75 mmol/L, P = 0.33) 1
Among SNRIs, milnacipran demonstrated no significant effect on serum sodium (+0.08 ± 0.87 mmol/L, P = 0.93) 1
However, mirtazapine has the most consistent evidence supporting its safety profile regarding hyponatremia risk 2, 1

Older age (odds ratio = 6.3) significantly increases the risk of hyponatremia with any antidepressant 2, 3
Concomitant use of thiazide diuretics substantially increases risk (odds ratios = 11.2-13.5) 2, 4
Female gender, low body weight, and baseline sodium levels in the lower normal range are additional risk factors 5
Most cases of antidepressant-induced hyponatremia occur within the first month of treatment 5

Check serum sodium levels before initiating antidepressant therapy, especially in high-risk patients 4
Monitor sodium levels within 2-4 weeks after starting treatment or changing medication 4
For high-risk patients (elderly, those on diuretics, or with history of hyponatremia), more frequent monitoring may be necessary 3, 4

When treating patients with risk factors for hyponatremia, mirtazapine should be considered as the first-line antidepressant 2, 1
If an SSRI or SNRI is clinically indicated, consider fluvoxamine among SSRIs or milnacipran among SNRIs as they have shown lower risk profiles 1
For patients who have previously experienced antidepressant-induced hyponatremia, switching to mirtazapine is a reasonable strategy 2

Failing to recognize that hyponatremia symptoms can mimic depression or psychosis, leading to misdiagnosis 6
Ignoring mild hyponatremia (Na 130-135 mmol/L) as clinically insignificant 4
Not considering antidepressant-induced hyponatremia in patients presenting with confusion, lethargy, or seizures 4
Overlooking the need to monitor electrolytes when initiating antidepressant therapy, especially in high-risk patients 5, 6