In a patient whose restless‑legs syndrome symptoms resolve completely with mirtazapine, could the improvement be due to a RLS mimic such as nocturnal leg cramps, peripheral neuropathy, akathisia, or anxiety‑related restlessness rather than true RLS?

Complete Symptom Resolution with Mirtazapine Strongly Suggests an RLS Mimic Rather Than True RLS

Your patient's complete symptom resolution with mirtazapine is highly atypical for true RLS and should prompt reconsideration of the diagnosis—most likely she has anxiety-related restlessness, akathisia (if previously exposed to dopamine-blocking agents), or nocturnal leg cramps rather than genuine restless legs syndrome.

Why This Points Away from True RLS

The 2025 AASM guidelines make no mention of mirtazapine as a treatment for RLS 1. In fact, the evidence points in the opposite direction: mirtazapine is documented to cause or worsen RLS, not treat it 2, 3, 4. A systematic review found 69 cases of RLS associated with mirtazapine use, with symptom onset averaging 7.54 days after starting the medication 2.

The FDA label for mirtazapine lists no indication for RLS and describes its mechanism as antagonism of α2-adrenergic, histamine H1, and serotonin receptors 5. These properties explain its sedative and anxiolytic effects—which could relieve symptoms that mimic RLS but would not address true RLS pathophysiology.

Most Likely Alternative Diagnoses

Anxiety-Related Restlessness

• Mirtazapine's strong H1 antagonism and anxiolytic properties would completely resolve anxiety-driven leg restlessness 5
• Unlike true RLS, anxiety-related restlessness lacks the characteristic circadian pattern (worse in evening) and doesn't respond to dopaminergic therapy 6
• The prominent sedative effect at bedtime would mask any nighttime symptoms

Akathisia (if relevant medication history)

• Critical distinction: Akathisia involves a generalized urge to move the whole body without the uncomfortable leg sensations characteristic of RLS 7, 8
• If your patient was previously on antipsychotics or other dopamine-blocking agents, mirtazapine's sedation could suppress akathisia symptoms
• However, akathisia typically requires dopamine agonists or benzodiazepines for true resolution, not mirtazapine 6, 9

Nocturnal Leg Cramps

• These lack the urge to move and circadian pattern of RLS 1
• Mirtazapine's muscle-relaxing properties through H1 antagonism could completely eliminate cramping
• Cramps are typically brief, painful, and involve visible muscle contraction—not the dysesthesias of RLS

Diagnostic Approach to Confirm

Verify the 2012 IRLSSG essential criteria 1, 10:

1. Urge to move with uncomfortable sensations: True RLS requires both components. Pure restlessness without dysesthesias suggests akathisia or anxiety
2. Worsens with rest/inactivity: If symptoms occur during activity or don't improve with movement, it's not RLS
3. Relief with movement: Must be present (though may not be noticeable in severe cases)
4. Circadian pattern: Symptoms must be worse in evening/night. Absence of this pattern excludes RLS
5. Not better explained by another condition: This is where your patient likely falls

Key questions to ask:

• Does she have uncomfortable sensations (crawling, tingling, burning) in her legs, or just restlessness?
• Are symptoms specifically worse in the evening/night, or present throughout the day?
• Did symptoms improve with movement before starting mirtazapine?
• Any history of antipsychotic or SSRI use (which could cause akathisia)?
• Does she have depression or anxiety that improved with mirtazapine?

The Dopaminergic Test

If you suspect true RLS, trial a dopaminergic agent (though the 2025 guidelines now recommend against standard use due to augmentation risk 1):

• True RLS responds dramatically to dopamine agonists or levodopa 6
• If symptoms were truly RLS, they should have worsened or remained unchanged on mirtazapine, not resolved
• Consider a trial of gabapentin (strong AASM recommendation for RLS) 1—if she doesn't respond, it further confirms this isn't RLS

Clinical Bottom Line

The complete resolution of symptoms with mirtazapine is pharmacologically inconsistent with true RLS. The most parsimonious explanation is that she has anxiety-related restlessness or another mimic that responds to mirtazapine's sedative and anxiolytic properties. The 2025 AASM guidelines emphasize that "neuropathy, akathisia, spasticity, positional discomfort, joint discomfort, and nocturnal leg cramps are among the conditions that can present with symptoms resembling RLS" and that "a careful clinical history is imperative as there is no objective test to aid in making an RLS diagnosis" 1.

If she truly had RLS, the evidence-based treatments would be gabapentin, pregabalin, or IV iron (if iron deficient)—not mirtazapine 1.