Can Prozac (fluoxetine) cause restless leg syndrome (RLS)?

Can Prozac Cause Restless Leg Syndrome?

Yes, Prozac (fluoxetine) can cause or exacerbate restless leg syndrome (RLS), as serotonergic medications including SSRIs are recognized triggers for RLS symptoms.

Mechanism and Evidence

• The American Academy of Sleep Medicine explicitly identifies serotonergic medications as potential exacerbating factors for RLS and recommends addressing them as part of initial management 1

• Multiple SSRIs have been documented to induce or worsen RLS, including fluoxetine, sertraline, citalopram, paroxetine, and escitalopram 2, 3

• The mechanism likely involves serotonergic effects on dopaminergic pathways, as RLS pathophysiology is closely related to dopaminergic dysfunction 2

Clinical Presentation

When Prozac triggers RLS, patients typically experience:

• An urge to move the legs accompanied by uncomfortable sensations deep inside the limbs 2

• Symptoms that begin or worsen during periods of rest or inactivity 2

• Relief with movement, though temporary 2

• Worsening symptoms in the evening or at night 4

• Symptom onset usually occurs within days of starting or increasing the SSRI dose, and symptoms can range from mild to very severe 2

Management Algorithm

Step 1: Assess causality and severity

• Use the International Restless Legs Scale (IRLS) to quantify symptom severity 5
• Confirm temporal relationship between Prozac initiation/dose increase and RLS onset 2

Step 2: Check iron status immediately

• Obtain morning fasting serum ferritin and transferrin saturation (after avoiding iron supplements for 24 hours) 1
• Supplement with oral ferrous sulfate if ferritin ≤75 ng/mL or transferrin saturation <20% 1

Step 3: Discontinue or reduce Prozac

• The optimal treatment for SSRI-induced RLS is discontinuation of the offending agent 5, 2
• If discontinuation is not feasible due to psychiatric needs, reduce to the lowest effective dose 3
• Symptoms typically improve within 2 days of stopping and resolve completely within 1 week 2

Step 4: If Prozac cannot be discontinued and symptoms persist

• Switch to an alternative antidepressant with lower RLS risk (avoid other SSRIs and SNRIs) 2, 6, 3
• Consider vortioxetine, which may actually improve RLS symptoms in some patients with depression 6
• Initiate first-line RLS treatment with alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) starting at 300mg at bedtime, titrated to 1800-2400mg/day divided doses as needed 1, 7

Critical Pitfalls to Avoid

• Do not use dopamine agonists (pramipexole, ropinirole) as first-line treatment for drug-induced RLS, as they carry significant risk of augmentation—a paradoxical worsening of symptoms with long-term use 1, 7

• Do not rechallenge with Prozac or other SSRIs if severe RLS developed, as symptoms will recur rapidly 2

• Do not overlook iron deficiency, as correcting iron status may resolve symptoms even without stopping Prozac in mild cases 1

• Do not confuse RLS with akathisia, which is more common with antipsychotics and presents differently (inner restlessness without the characteristic sensory symptoms or circadian pattern) 8

Risk Factors

Patients at higher risk for developing SSRI-induced RLS include:

• Older age 3
• Family history of idiopathic RLS 5
• Gastrointestinal diseases 3
• Higher medication doses 3
• Concurrent use of multiple medications that affect dopaminergic or serotonergic systems 3