Can Zoloft (Sertraline) Cause Restless Leg Syndrome?
Yes, Zoloft (sertraline) can cause or exacerbate restless leg syndrome, and the American Academy of Sleep Medicine specifically recommends addressing serotonergic medications as potential exacerbating factors in all patients with clinically significant RLS. 1
Mechanism and Evidence
Selective serotonin reuptake inhibitors (SSRIs), including sertraline, have been consistently reported to induce or worsen RLS symptoms through their effects on central dopaminergic pathways. 2, 3 The pathophysiology relates to serotonergic modulation of dopamine function, which is central to RLS development. 3
- Multiple SSRIs including fluoxetine, paroxetine, citalopram, escitalopram, and sertraline specifically have documented case reports of causing RLS symptoms. 2, 3
- One case series noted that sertraline was associated with RLS aggravation when used as a replacement therapy, though it was previously suggested to have lower risk due to some dopamine reuptake blocking properties. 4
- The onset of SSRI-induced RLS typically occurs within days to weeks of starting therapy or dose increases. 3
Clinical Recognition
When evaluating for sertraline-induced RLS, confirm the following diagnostic criteria: 5
- An urge to move the legs accompanied by uncomfortable sensations
- Symptoms beginning or worsening during rest or inactivity
- Symptoms relieved by movement
- Symptoms worsening in the evening or at night
A critical pitfall is distinguishing RLS from akathisia, which can also be caused by SSRIs and presents with similar restlessness but lacks the circadian pattern and specific limb sensations. 6
Management Algorithm
Step 1: Assess iron status first - Check morning fasting ferritin and transferrin saturation before making medication changes. 1 If ferritin ≤75 ng/mL or transferrin saturation <20%, initiate iron supplementation as this may resolve symptoms even without stopping sertraline. 1
Step 2: Evaluate necessity of sertraline - If depression/anxiety treatment is essential and RLS symptoms are mild, consider continuing sertraline while addressing iron deficiency and adding RLS-specific treatment. 1
Step 3: Consider medication switch if symptoms are moderate to severe - Discontinue sertraline and switch to an antidepressant with lower RLS risk:
- Bupropion is the preferred alternative as it may actually improve RLS symptoms through dopaminergic effects. 4
- Vortioxetine has emerging evidence suggesting it may not worsen and potentially improve RLS symptoms in 5 of 7 patients in one case series. 2
Step 4: Initiate RLS-specific treatment if symptoms persist - The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line therapy rather than dopamine agonists. 1 Start gabapentin 300mg at bedtime, titrating to 1800-2400mg/day divided into multiple doses as needed. 1
Important Caveats
- Do not use dopamine agonists (pramipexole, ropinirole) as first-line treatment due to high risk of augmentation—a paradoxical worsening of symptoms with long-term use. 1
- Symptoms typically improve within 2-7 days of stopping the offending SSRI, with complete resolution within 1-2 weeks. 3
- If sertraline must be continued, never use clonazepam as monotherapy for RLS due to insufficient efficacy evidence and side effect concerns. 1