Bupropion Does Not Cause RLS and May Actually Improve It; Fluoxetine (Prozac) May Worsen RLS
Based on the most recent 2025 AASM guidelines, bupropion is suggested against for treating RLS (not because it causes it), while the evidence suggests bupropion may actually improve RLS symptoms rather than cause them. 1 Fluoxetine (Prozac), on the other hand, has evidence suggesting it can induce or exacerbate RLS symptoms, though the clinical significance remains debated.
Bupropion and RLS: The Evidence
Guideline Perspective
The 2025 AASM clinical practice guideline recommends against using bupropion for the treatment of RLS (conditional recommendation, moderate certainty of evidence). 1 This recommendation is about therapeutic efficacy, not about bupropion causing RLS.
Clinical Evidence Shows Potential Benefit
Contrary to causing RLS, the research evidence consistently suggests bupropion may improve RLS symptoms:
A randomized controlled trial (2011) demonstrated that bupropion 150 mg sustained-release significantly improved RLS symptoms compared to placebo at 3 weeks (10.8-point reduction vs 6.0-point reduction on IRLSSG scale, p=0.016). 2 While the difference was not statistically significant at 6 weeks, the study concluded bupropion does not exacerbate RLS and may be a reasonable antidepressant choice for patients with RLS.
Multiple case reports document rapid and complete amelioration of RLS symptoms within days of starting bupropion. 3, 4
A 2018 systematic review concluded that "bupropion may reduce restless legs syndrome symptoms, at least in the short term." 5
Mechanism
Bupropion's dopamine and norepinephrine reuptake inhibition may explain its potential benefit in RLS, as it modulates dopaminergic systems without the augmentation risks associated with dopamine agonists. 4
Fluoxetine (Prozac) and RLS: The Evidence
Higher Risk Profile
Fluoxetine has more concerning evidence regarding RLS:
A 2010 literature review using a qualitative scoring system identified fluoxetine as having "the strongest evidence available for drug-induced RLS" based on case reports and trials of medication cessation. 6
The same 2010 review also identified fluoxetine as having strong evidence for inducing periodic limb movements in sleep (PLMS), with scores ≥10. 6
The 2018 systematic review noted that "sertraline, fluoxetine, and amitriptyline appear to increase periodic limb movements that do not disrupt sleep and are thus unlikely to be clinically significant." 5 This suggests the clinical impact may be limited.
FDA Label Considerations
The FDA label for fluoxetine does not specifically list RLS as an adverse effect, though it does note various neurological side effects. 7 The bupropion FDA label mentions that adverse reactions when combined with dopaminergic drugs (levodopa/amantadine) have included "restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness," but this is in the context of drug interactions, not RLS causation. 8
Clinical Implications
For Patients Requiring Antidepressants with Comorbid RLS:
- Bupropion is a reasonable first-line choice as it does not worsen and may improve RLS symptoms
- Avoid fluoxetine and other SSRIs (sertraline, paroxetine, citalopram) if possible, as they have evidence for inducing or worsening RLS/PLMS
- Consider mirtazapine cautiously as it may be associated with higher rates of RLS 5
- Sedating antidepressants (trazodone, nefazodone, doxepin) do not appear to aggravate periodic limb movements 5
Important Caveats:
- The evidence for antidepressant-induced RLS is limited by poor study design, inadequate use of standardized questionnaires, and heterogeneous populations 5
- Most studies show that onset or exacerbation of RLS following antidepressant initiation is uncommon overall 5
- Individual patient responses vary considerably
- The 2025 AASM guidelines prioritize iron supplementation (IV ferric carboxymaltose) and α2δ ligands (gabapentin, pregabalin) as first-line RLS treatments, with dopamine agonists now discouraged due to augmentation risks 1
In summary: Bupropion does not cause RLS and may help it; fluoxetine has evidence for potentially worsening RLS but the clinical significance is debated and occurrence is uncommon.