Do buspirone (Buspar), escitalopram (Lexapro), and bupropion (Wellbutrin) cause restless legs syndrome?

Do Buspar, Lexapro, and Wellbutrin Cause Restless Legs Syndrome?

Lexapro (escitalopram) can cause or exacerbate restless legs syndrome, while Wellbutrin (bupropion) does not appear to cause RLS and may actually improve symptoms; Buspar (buspirone) has been reported to cause RLS in postmarketing surveillance but the evidence is limited.

Lexapro (Escitalopram) and RLS

Escitalopram is associated with inducing or worsening RLS. A case report documented a 34-year-old woman who developed very severe RLS symptoms within 2 days of starting escitalopram 10 mg, with symptoms resolving within 2 days of discontinuation 1. When rechallenged at a lower dose, her severe RLS symptoms reappeared, achieving a Naranjo adverse drug reaction probability scale score of 9 (indicating a definite adverse drug reaction) 1.

The evidence consistently shows that selective serotonin reuptake inhibitors (SSRIs), including escitalopram, are associated with RLS:

• A systematic review of pharmacovigilance data found escitalopram among the antidepressants most frequently associated with movement disorders, including RLS 2
• A prospective study in neurological offices found that 5-10% of patients on SSRIs (including escitalopram) developed new or worsened RLS, typically within the initial days of treatment 3
• A systematic review concluded that SSRIs may induce or worsen RLS and increase periodic limb movements 4

Wellbutrin (Bupropion) and RLS

Bupropion does not cause RLS and may actually be beneficial. The 2025 American Academy of Sleep Medicine (AASM) guidelines specifically state that bupropion should not be used for the treatment of RLS (conditional recommendation, moderate certainty of evidence) 5, but this recommendation addresses its ineffectiveness as a treatment, not its causation of RLS.

The evidence supporting bupropion's safety in RLS patients:

• A randomized controlled trial of 60 participants found that bupropion 150 mg sustained-release improved RLS symptoms compared to placebo at 3 weeks (10.8 vs 6.0 point reduction in severity scores, p=0.016) 6
• The study concluded that "bupropion does not exacerbate the symptoms of RLS and may be a reasonable choice if an antidepressant is needed in individuals with RLS" 6
• A systematic review noted that bupropion may reduce RLS symptoms, at least in the short term 4

However, one pharmacovigilance study found bupropion associated with periodic limb movements in sleep (PLMS) based on disproportionality reporting 7, and another large database study found a potential association with movement disorders generally 2. These findings likely reflect confounding factors rather than true causation.

Buspar (Buspirone) and RLS

The FDA drug label for buspirone includes restless leg syndrome in its postmarketing experience section, noting "rare occurrences" of "restless leg syndrome, and restlessness" 8. The label explicitly states: "Because of the uncontrolled nature of these spontaneous reports, a causal relationship to buspirone hydrochloride treatment has not been determined" 8.

The evidence for buspirone causing RLS is weak:

• The drug label also mentions that "a syndrome of restlessness, appearing shortly after initiation of treatment, has been reported in some small fraction of buspirone-treated patients" which "may be attributable to dopaminergic effects (i.e., represent akathisia)" 8
• No controlled studies or case reports in the provided evidence specifically link buspirone to RLS
• The mechanism is unclear, as buspirone binds to central dopamine receptors, which theoretically could affect RLS pathophysiology 8

Clinical Implications

When prescribing antidepressants to patients with or at risk for RLS:

• Avoid SSRIs like escitalopram if possible, as they have the strongest evidence for inducing or exacerbating RLS
• Consider bupropion as a safer alternative, as it does not worsen RLS and may provide some benefit
• Use buspirone with caution, monitoring for new-onset restlessness or RLS symptoms, though the risk appears low

Common pitfall: Confusing akathisia (inner restlessness, inability to sit still) with RLS. True RLS involves uncomfortable sensations deep in the limbs with an urge to move that worsens at rest and improves with movement, typically occurring in the evening/night. Akathisia is more generalized restlessness without the circadian pattern or limb-specific sensations.

If RLS develops after starting any of these medications, symptoms typically appear within the first few days of treatment 3 and should resolve within days of discontinuation 1.