Can Mirtazapine Cause SIADH?
Yes, mirtazapine can cause SIADH and hyponatremia, though the risk is moderate and lower than SSRIs or venlafaxine. The FDA drug label explicitly warns that "hyponatremia may occur as a result of treatment with serotonergic antidepressants, including mirtazapine tablets" and states that "in many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)" 1.
Incidence and Risk Profile
The incidence of mirtazapine-induced hyponatremia is 3.26% (95% CI 3.06-3.45%), with SIADH being the most probable underlying mechanism 2.
Mirtazapine carries a moderate risk compared to other antidepressants, with SSRIs and venlafaxine showing consistently higher odds ratios (1.5-21.6 for SSRIs) versus mirtazapine's moderate risk profile 3.
This moderate risk profile supports mirtazapine as an alternative treatment option for patients with risk factors for hyponatremia, though it does not eliminate the risk entirely 3.
High-Risk Patient Populations
Your patient's history warrants particular caution:
Elderly patients are at significantly increased risk (odds ratio = 6.3), as are patients taking diuretics (odds ratio = 11.2-13.5) 3.
The FDA specifically warns that elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia 1.
Previous SIADH from pregabalin indicates this patient has demonstrated susceptibility to drug-induced SIADH, which should heighten vigilance 4.
Patients with cancer or neurological conditions may have additional risk factors for SIADH from their underlying disease 5, 6.
Clinical Presentation and Timeline
Hyponatremia typically manifests within 34 days (average) of starting mirtazapine, though it can occur at any time during treatment 2.
The most common clinical manifestations include confusion (57%), somnolence (42%), and altered speech (28%) 2.
Mean serum sodium levels in reported cases were 117 mEq/L (ranging from 113-130 mEq/L), with cases documented as low as 116 mmol/L 2, 7.
The FDA warns that signs and symptoms include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls 1.
Monitoring and Management Strategy
For this patient with prior pregabalin-induced SIADH:
Check baseline serum sodium before initiating mirtazapine 5.
Monitor serum sodium within 2 weeks of starting therapy and again at 4-6 weeks, as hyponatremia can develop at any time but typically occurs within the first month 2, 3.
If symptomatic hyponatremia develops, discontinue mirtazapine immediately and institute appropriate medical intervention 1.
For mild asymptomatic hyponatremia (sodium 120-134 mEq/L), implement fluid restriction to 1 L/day and consider discontinuing the medication 5.
For severe symptomatic hyponatremia (sodium <120 mEq/L with neurological symptoms), transfer to ICU, administer 3% hypertonic saline targeting correction of 6 mmol/L over 6 hours, with maximum correction not exceeding 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 5.
Critical Clinical Pitfall
Female patients appear at higher risk, with 71.4% of reported cases occurring in women 2. Combined with your patient's history of pregabalin-induced SIADH, this represents a particularly high-risk scenario that warrants either selecting an alternative antidepressant with lower SIADH risk (such as bupropion, which has insufficient evidence linking it to SIADH) or implementing aggressive monitoring if mirtazapine is chosen 5, 3.