Wellbutrin XL vs SR: Key Differences
Both Wellbutrin XL and SR formulations are bioequivalent in terms of systemic bupropion exposure and demonstrate comparable efficacy for major depressive disorder, but XL offers the advantage of once-daily dosing (improving adherence) while SR requires twice-daily administration. 1, 2, 3
Dosing Schedules
Wellbutrin SR (Sustained-Release)
- Standard dosing: 150 mg twice daily (total 300 mg/day) 4, 5
- Titration: Start with 150 mg once daily for 3 days, then increase to 150 mg twice daily if tolerated 5
- Timing: First dose in the morning, second dose before 3 PM to minimize insomnia risk 5
- Maximum dose: 400 mg per day 5
Wellbutrin XL (Extended-Release)
- Standard dosing: 300 mg once daily in the morning 5, 1
- Titration: Start with 150 mg once daily for 4-7 days, then increase to 300 mg once daily 1
- Timing: Single morning dose 1
- Maximum dose: 450 mg per day 5
Efficacy Comparison
Both formulations demonstrate equivalent antidepressant efficacy when given at the same total daily dose. 2, 3
- SR formulation has been extensively studied and proven as effective as SSRIs and tricyclic antidepressants, with advantages of less somnolence and sexual dysfunction compared to SSRIs 2, 3
- XL formulation established efficacy in 2 of 6 well-designed placebo-controlled studies for primary outcomes, with additional efficacy demonstrated in secondary outcomes across 5 studies 2, 3
- When switching between formulations, the FDA recommends giving the same total daily dose when possible 1
Safety and Tolerability Profile
The safety profiles are essentially identical between formulations, with both carrying a seizure risk of approximately 0.1% when dosed appropriately (≤300 mg/day for SR, ≤450 mg/day for XL). 4, 6, 7
Common Adverse Effects (Both Formulations)
- Insomnia (most common, often transient) 6, 2, 3
- Dry mouth 6, 2, 3
- Headache 6, 8
- Nausea 6, 8
- Constipation 8
- Dizziness 8
Critical Safety Considerations
- Seizure risk: Contraindicated in patients with seizure disorders, brain metastases, or stroke history 4
- Neuropsychiatric effects: Monitor for hostility, depression, or suicidal behavior, though recent EAGLES trial showed no significant increase versus placebo 4
- Contraindications: MAO inhibitors (14-day washout required), tamoxifen use, closed-angle glaucoma 4, 1
Clinical Decision-Making Algorithm
Choose XL formulation when:
- Adherence is a concern (once-daily dosing improves compliance) 2, 3
- Patient prefers simplified medication regimen 2, 3
- Maximum dose requirements may exceed 300 mg/day (XL allows up to 450 mg) 5
Choose SR formulation when:
- More flexible dose titration is needed for side effect management 5
- Patient experiences intolerable side effects with XL and benefits from split dosing 5
- Lower maximum daily dose is appropriate (particularly in hepatic/renal impairment) 5
Special Population Dosing
Hepatic Impairment
- Moderate to severe (Child-Pugh 7-15): Maximum 150 mg every other day for XL 1
- Mild (Child-Pugh 5-6): Consider dose/frequency reduction 1
Renal Impairment
- GFR <90 mL/min: Reduce total daily dose by half and monitor closely 5
Older Adults
- Start with 37.5 mg every morning, increase by 37.5 mg every 3 days as tolerated 5
- Maximum 150 mg twice daily (300 mg total) 5
Important Clinical Pearls
- Bioequivalence concerns: Historical issues with generic SR formulations not being bioequivalent to brand-name Wellbutrin SR warrant close monitoring when switching between brand and generic or between formulations 5
- Smoking cessation: SR formulation at 150 mg twice daily (300 mg total) is the established regimen, initiated 1-2 weeks before quit date 4
- Comorbid depression: Bupropion may be particularly beneficial for patients with depression and concurrent smoking cessation needs 4
- Sexual dysfunction advantage: Both formulations have among the lowest incidence of sexual dysfunction compared to SSRIs 2, 3, 8