Can bupropion, mirtazapine, and trazodone cause hyponatremia?

Can Bupropion, Mirtazapine, and Trazodone Cause Hyponatremia?

Yes, all three antidepressants can cause hyponatremia, but the risk varies substantially: mirtazapine and trazodone carry moderate-to-high risk, while bupropion has the lowest risk among antidepressants and should be considered the preferred agent in patients at risk for hyponatremia.

Risk Stratification by Agent

Mirtazapine - Moderate-to-High Risk

• Mirtazapine-induced hyponatremia occurs in approximately 3.26% of patients, with SIADH being the most probable underlying mechanism 1.
• The FDA drug label specifically warns that elderly patients may be at greater risk of developing hyponatremia with mirtazapine 2.
• Hyponatremia typically develops within 6.5 days on average (range 7-10 days), with doses as low as 7.5 mg daily capable of causing this adverse effect 3.
• The mean sodium nadir in reported cases is 117.2 mEq/L, indicating clinically significant hyponatremia 3.
• Recovery occurs within a mean of 11 days after discontinuation 3.
• Clinical manifestations include confusion (57%), somnolence (42%), and altered speech (28%) 1.

Trazodone - Moderate Risk

• Trazodone was added to the 2019 AGS Beers Criteria list of drugs associated with hyponatremia or SIADH 4.
• While specific incidence data is limited, trazodone is implicated less frequently than SSRIs, SNRIs, and mirtazapine in case reports and clinical studies of older adults 5.
• The overall event rate for trazodone-associated hyponatremia is 0.89%, which is lower than SSRIs (5.59%) and mirtazapine (1.02%) 6.

Bupropion - Lowest Risk

• Bupropion may be the most appropriate antidepressant for older adults at risk for antidepressant-induced hyponatremia given its unique mechanism of action 5.
• Bupropion is implicated less often in hyponatremia case reports compared to SSRIs, SNRIs, mirtazapine, and trazodone 5.
• The FDA drug label for bupropion lists hyponatremia as a condition that can increase seizure risk, but does not list it as a direct adverse effect of the medication itself 7.
• One case report documents bupropion-induced hyponatremia in a 72-year-old female, but such reports are rare 8.

Clinical Implications and Monitoring

High-Risk Patient Identification

Monitor sodium levels closely in patients with these risk factors:

• Age ≥60 years - hyponatremia occurs predominantly in elderly patients 3, 5
• Female sex - 71.4% of mirtazapine-induced hyponatremia cases occur in women 1
• Diuretic use - increases hyponatremia risk 8
• Low BMI - associated with higher risk 8

Monitoring Protocol

• Check baseline sodium levels before initiating any antidepressant in high-risk patients 8.
• Recheck sodium within the first 2 weeks after starting treatment, as most cases develop within 7-10 days 3, 8.
• Monitor for unexplained mental status changes at any time during treatment, as these symptoms can be misinterpreted as worsening depression 8.

Management Algorithm

1. If hyponatremia develops: Discontinue the offending antidepressant immediately 3.
2. For patients requiring continued antidepressant therapy: Switch to bupropion as the preferred alternative 5.
3. Avoid switching to mirtazapine in patients who developed hyponatremia on other antidepressants, despite older recommendations suggesting otherwise 8, 6.
4. Recovery timeline: Expect sodium normalization within 7-11 days after discontinuation 3.

Important Caveats

The clinical symptoms of hyponatremia (confusion, somnolence, altered speech) can easily be mistaken for worsening depression or medication side effects, potentially leading to dose escalation rather than appropriate intervention 8. Maintain high clinical suspicion and check sodium levels whenever mental status changes occur during antidepressant treatment, regardless of time since initiation.