Should an adult patient being treated for major depressive disorder or smoking cessation be started on bupropion immediate‑release or extended‑release formulation?

Starting Bupropion: Extended-Release (XL) Is the Preferred Initial Formulation

For both major depressive disorder and smoking cessation, initiate treatment with bupropion extended-release (XL) rather than immediate-release or sustained-release formulations. The once-daily XL formulation offers equivalent efficacy with superior adherence, simpler dosing, and a more favorable pharmacokinetic profile compared to older formulations. 1

Rationale for Preferring Extended-Release

Pharmacokinetic Advantages

• Bupropion XL delivers steady plasma concentrations throughout the day with once-daily morning dosing, eliminating the need for multiple daily doses and reducing the risk of missed doses that can compromise efficacy. 2

• The XL formulation reaches peak plasma concentration at approximately 5 hours, compared to 1.5 hours for immediate-release and 3 hours for sustained-release, providing more gradual onset and sustained therapeutic levels. 2

• All three formulations—immediate-release, sustained-release, and extended-release—are bioequivalent in total systemic exposure, meaning XL provides the same antidepressant effect as older formulations while offering practical advantages. 2, 3

Clinical Dosing Protocol

For Major Depressive Disorder:

• Start bupropion XL 150 mg once daily in the morning. 1
• After 4 days, increase to the target dose of 300 mg once daily in the morning if tolerated. 1
• The maximum dose is 450 mg once daily; do not exceed this to maintain seizure risk at approximately 0.1%. 4

For Smoking Cessation:

• Start bupropion XL 150 mg once daily in the morning. 4
• Begin treatment 1–2 weeks before the target quit date to establish therapeutic drug levels before cessation attempts. 4
• After 3 days, increase to 150 mg twice daily (or 300 mg XL once daily) if tolerated. 4
• The maximum dose for smoking cessation is 300 mg per day—do not exceed this threshold. 4
• Continue treatment for 7–12 weeks after the quit date, with formal efficacy assessment after this period. 4

Why Not Sustained-Release or Immediate-Release?

Sustained-Release Limitations

• Bupropion SR requires twice-daily dosing, with the second dose needing to be taken before 3 PM to minimize insomnia risk—a timing constraint that complicates adherence. 4

• The SR formulation uses a wax-matrix vehicle that provides slower release than immediate-release but still requires BID dosing, making it less convenient than XL without offering additional clinical benefit. 2

Immediate-Release Is Obsolete for Initiation

• Immediate-release bupropion requires three times daily dosing, which significantly impairs adherence and is no longer recommended for initiating treatment. 5, 3

• The rapid peak at 1.5 hours with immediate-release may contribute to more pronounced side effects compared to the gradual absorption profile of XL. 2

Critical Safety Screening Before Initiation

Absolute Contraindications

• Seizure disorders or any condition predisposing to seizures (prior head trauma, brain tumor, stroke, brain metastases). 4, 1
• Current or recent MAOI use (within 14 days of discontinuation). 4, 1
• Eating disorders (bulimia nervosa, anorexia nervosa) due to increased seizure risk. 4
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs—this dramatically increases seizure risk. 4
• Uncontrolled hypertension—bupropion can elevate blood pressure and heart rate. 4

Special Population Dose Adjustments

• Moderate to severe hepatic impairment: Maximum dose 150 mg daily (or 150 mg every other day in severe impairment). 4
• Moderate to severe renal impairment (eGFR <90 mL/min): Reduce total daily dose by 50%. 4
• End-stage renal disease: Avoid bupropion entirely—metabolites accumulate and dialysis does not effectively clear them. 4
• Older adults (≥65 years): Start at approximately 50% of standard adult doses (e.g., 37.5 mg daily, increasing by 37.5 mg every 3 days as tolerated) to reduce adverse reactions. 4

Monitoring Requirements

Early Phase (Weeks 1–2)

• Assess for suicidal ideation, agitation, irritability, or unusual behavioral changes, especially in patients younger than 24 years—the risk of suicide attempts is highest during the first 1–2 months. 4, 1

• Monitor blood pressure and heart rate at baseline and periodically, especially during the first 12 weeks, as bupropion can cause elevations in both parameters. 4

Response Assessment Timeline

• Allow 6–8 weeks at therapeutic doses before determining treatment response. 4
• If no adequate response occurs by 6–8 weeks, modify the treatment approach by increasing the dose (up to 450 mg XL daily for MDD), switching agents, or adding augmentation therapy. 4
• Do not discontinue prematurely before 6–8 weeks unless significant adverse effects occur—approximately 38% of patients fail an initial antidepressant trial, but switching after an adequate trial yields remission in about 25%. 4

Common Pitfalls to Avoid

• Do not switch between brand and generic formulations or between SR and XL without close monitoring—historical bioequivalence issues have led to loss of antidepressant effect in some patients. 4, 6

• Do not exceed 450 mg/day for MDD or 300 mg/day for smoking cessation—seizure risk increases markedly above these thresholds. 4, 1

• Do not combine with tamoxifen—bupropion inhibits CYP2D6 and can reduce tamoxifen's conversion to its active metabolite. 4

• Do not use naltrexone-bupropion combination products in patients taking any opioid medications—naltrexone will precipitate severe opioid withdrawal. 4

Clinical Advantages of Bupropion XL

• Significantly lower rates of sexual dysfunction compared to SSRIs (decreased risk versus trend toward increased risk with escitalopram and paroxetine). 4

• Minimal weight gain or even weight loss, unlike many other antidepressants. 4

• Lower rates of sedation than SSRIs, making it particularly beneficial for patients with depression characterized by low energy, apathy, or hypersomnia. 4

• Dual benefit for patients with both depression and nicotine dependence, addressing both conditions simultaneously. 4, 5