What is the best antidepressant to prevent Restless Legs Syndrome (RLS)?

Best Antidepressant for Preventing Restless Legs Syndrome (RLS)

Bupropion is the best antidepressant choice for patients with RLS as it does not exacerbate symptoms and may actually improve RLS, unlike most other antidepressants which typically worsen symptoms. 1

Understanding RLS and Antidepressant Effects

Most antidepressants are known to exacerbate RLS symptoms, making treatment challenging when both conditions coexist. The following antidepressants are particularly problematic for RLS patients:

• Selective serotonin reuptake inhibitors (SSRIs)
• Venlafaxine
• Some tetracyclic antidepressants
• Mirtazapine
• Mianserin
• Tricyclic antidepressants 2, 3

Evidence Supporting Bupropion for RLS

Bupropion stands out as a unique option because:

1. A randomized controlled trial showed bupropion (150 mg sustained-release daily) significantly improved RLS symptoms at 3 weeks compared to placebo (10.8 point vs 6.0 point reduction on the IRLSSG severity scale, p=0.016) 1

2. Multiple case reports demonstrate rapid and complete amelioration of RLS symptoms with bupropion, often within days of initiation 4, 5

3. Bupropion's mechanism as a dopamine and noradrenaline reuptake inhibitor likely explains its beneficial effects, as it enhances dopaminergic activity without the augmentation risks associated with direct dopamine agonists 5

Treatment Algorithm for RLS with Comorbid Depression

1. First-line approach:

   • Assess and treat iron deficiency (if ferritin <50 ng/mL) 6
   • Consider bupropion as first-choice antidepressant 1, 4, 5
   • Start with bupropion 150 mg daily 1

2. If additional RLS treatment needed:

   • Add alpha-2-delta ligands (pregabalin or gabapentin) as first-line RLS treatment 6
   • Consider non-pharmacological approaches (regular exercise, smoking cessation, alcohol avoidance, caffeine reduction) 6

3. For severe or refractory cases:

   • Consider short-term dopamine agonists (ropinirole, pramipexole, or rotigotine) with careful monitoring for augmentation 6
   • Low-dose opioids may be considered for severe cases that have failed other therapies 6

Important Monitoring Considerations

• Watch for augmentation with dopamine agonists (paradoxical worsening of symptoms)
• Monitor iron status regularly (serum ferritin)
• Assess for common secondary causes of RLS including renal disease, diabetes, and pregnancy 6
• Regular follow-up to evaluate symptom control and medication effectiveness

Clinical Pearls and Pitfalls

• Key pitfall: Using typical antidepressants (SSRIs, SNRIs, TCAs) in RLS patients can significantly worsen symptoms and sleep quality
• Important consideration: If a patient on another antidepressant develops insomnia, always evaluate for possible RLS as a medication side effect 2
• Practical advantage: Bupropion has a favorable side effect profile compared to dopamine agonists, which are standard RLS treatments but carry risks of augmentation 1
• Dosing note: Even low doses of bupropion may provide rapid relief of RLS symptoms 5
• Alternative option: If bupropion is contraindicated, agomelatine is another antidepressant that may be suitable for patients with RLS and comorbid insomnia 3