Mirtazapine and Leg Swelling
Yes, mirtazapine can cause peripheral edema (leg swelling) as documented in the FDA drug label and case reports, though it is considered an uncommon side effect.
Evidence for Mirtazapine-Induced Leg Swelling
The FDA drug label for mirtazapine specifically lists peripheral edema as an adverse reaction occurring in approximately 2% of patients taking mirtazapine compared to 1% of those on placebo 1. This makes it an uncommon but recognized side effect of the medication.
Recent case reports further support this association:
- A 2025 case report documented peripheral edema in a patient with advanced oral cavity cancer just three days after starting mirtazapine 15 mg daily, with complete resolution after discontinuation 2
- Another case report described papilledema (optic disc swelling) associated with mirtazapine use, noting that while mirtazapine may rarely cause peripheral edema, this was the first reported case of papilledema 3
Mechanism of Action and Side Effect Profile
Mirtazapine is a tetracyclic antidepressant that works by:
- Blocking alpha-2 adrenergic autoreceptors and heteroreceptors
- Inhibiting 5-HT2 and 5-HT3 receptors
- Enhancing both noradrenergic and serotonergic neurotransmission 4, 5
The most common side effects of mirtazapine include:
- Somnolence (54% vs 18% placebo)
- Increased appetite (17% vs 2% placebo)
- Weight gain (12% vs 2% placebo)
- Dry mouth (25% vs 15% placebo)
- Constipation (13% vs 7% placebo) 1
Clinical Implications and Management
When peripheral edema occurs with mirtazapine:
- Assess causality: Determine if the edema began after starting mirtazapine and rule out other causes
- Consider discontinuation: If edema is troublesome or concerning, discontinuation of mirtazapine may be necessary as it resolved the edema in the reported case 2
- Alternative options: If mirtazapine was prescribed for depression, consider switching to another antidepressant with a different side effect profile 6
When to Be Concerned
Seek immediate medical attention if leg swelling is:
- Sudden or severe
- Accompanied by shortness of breath
- Associated with chest pain
- Unilateral (one-sided) with warmth, redness, or pain (could indicate DVT)
Conclusion
While mirtazapine is an effective antidepressant with unique benefits for patients with insomnia or poor appetite 6, 7, peripheral edema is a recognized adverse effect that clinicians should monitor for, particularly when initiating therapy. The benefit-risk profile should be carefully considered, especially in patients with pre-existing edema or cardiovascular conditions.