What is the recommended formulation and dosing of Bupropion (Wellbutrin) for a patient with depression, considering the differences between extended-release (XL) and immediate-release (IR) formulations?

Bupropion XL vs IR for Depression

Formulation Recommendation

For treating major depressive disorder, bupropion XL (extended-release) is the preferred formulation over IR (immediate-release), dosed at 150 mg once daily in the morning for 4 days, then increased to 300 mg once daily. 1

The immediate-release formulation requires three-times-daily dosing and is no longer commonly used in clinical practice, while XL offers once-daily administration with equivalent efficacy and improved adherence. 2, 3

Dosing Protocol for Bupropion XL

Initial Dosing

• Start with 150 mg once daily in the morning 1
• After 4 days, increase to the target dose of 300 mg once daily 1
• Administer in the morning, with or without food 1
• Swallow tablets whole—do not crush, divide, or chew 1

Maximum Dosing

• The maximum dose for XL formulation is 450 mg per day 4
• For SR formulation, maximum is 400 mg per day 4
• Gradual dose titration minimizes seizure risk (approximately 0.1% at therapeutic doses) 4, 1

Pharmacokinetic Advantages of XL Formulation

All three bupropion formulations (IR, SR, XL) are bioequivalent in terms of systemic exposure to bupropion and its active metabolites. 2, 3 However, the absorption profiles differ significantly:

• XL formulation: T(max) approximately 5 hours 2
• SR formulation: T(max) approximately 3 hours 2
• IR formulation: T(max) approximately 1.5 hours 2

The prolonged absorption of XL provides steady drug levels throughout the day with once-daily dosing, eliminating the need for multiple daily doses. 2

Clinical Efficacy Evidence

XL Formulation Performance

• Bupropion XL demonstrated efficacy in 2 of 6 well-designed placebo-controlled studies for primary outcomes 5, 3
• Secondary outcomes showed efficacy in 5 of these studies 5, 3
• XL was equivalent to escitalopram in two placebo-controlled trials 5, 3
• XL showed similar efficacy to venlafaxine XR in two trials, though venlafaxine was superior in one additional trial 5, 3

IR Formulation Evidence

• The original IR formulation established bupropion's efficacy in two 4-week inpatient trials and one 6-week outpatient trial 1
• IR was as efficacious as TCAs and fluoxetine, with advantages of less somnolence and weight gain 5, 3

Monitoring and Response Assessment

Early Monitoring (Critical for Safety)

• Begin monitoring within 1-2 weeks of initiation for suicidal ideation, agitation, or behavioral changes 6, 4
• This is particularly critical in patients under 24 years old 4
• The risk for suicide attempts is greatest during the first 1-2 months of treatment 4

Efficacy Assessment Timeline

• Allow 6-8 weeks at adequate dose before determining treatment response 6, 4
• Energy levels may improve more rapidly, sometimes within the first few weeks 4
• If no adequate response by 6-8 weeks, modify treatment 6, 4

Special Population Dosing Adjustments

Hepatic Impairment

• Moderate to severe impairment (Child-Pugh 7-15): Maximum 150 mg every other day 1
• Mild impairment (Child-Pugh 5-6): Consider dose reduction and/or frequency adjustment 1

Renal Impairment

• GFR <90 mL/min: Reduce total daily dose by 50% 4
• Consider reducing dose and/or frequency 1

Older Adults

• Start with 37.5 mg every morning 4
• Increase by 37.5 mg every 3 days as tolerated 4
• Maximum dose: 150 mg twice daily (300 mg total daily) 4
• Administer second dose before 3 PM to minimize insomnia 4

Critical Safety Considerations

Absolute Contraindications

• Seizure disorders or any condition lowering seizure threshold 4, 1
• Current or recent MAOI use (within 14 days) 1
• Eating disorders (bulimia, anorexia nervosa) 4
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 4
• Uncontrolled hypertension 4

Monitoring Parameters

• Blood pressure and heart rate, especially first 12 weeks 4
• Neuropsychiatric symptoms and suicidal ideation 4
• Body weight (3.7% of patients experienced ≥7% weight loss) 7

Switching Between Formulations

When switching from IR or SR to XL, give the same total daily dose when possible. 1 However, monitor patients closely when switching between brand and generic formulations or between SR and XL due to historical bioequivalence issues that may lead to loss of antidepressant effect. 4

Discontinuation Protocol

When discontinuing bupropion XL 300 mg once daily, taper to 150 mg once daily before complete discontinuation. 1 This gradual taper minimizes potential withdrawal effects and maintains seizure risk management. 8

Clinical Advantages of Bupropion

Side Effect Profile

• Lower rates of sexual dysfunction compared to SSRIs 6, 4
• Minimal weight gain or even weight loss 4
• Lower rates of sedation than SSRIs 4
• Less somnolence than TCAs 5, 3

Specific Patient Populations Who Benefit

• Patients with depression characterized by low energy, apathy, or hypersomnia due to activating properties 4, 7
• Patients concerned about sexual dysfunction or weight gain 4
• Patients with comorbid depression and smoking cessation goals 4

Common Pitfalls to Avoid

• Do not administer late in the day—give in the morning to minimize insomnia risk 1
• Do not exceed maximum doses (450 mg/day for XL) to maintain seizure risk at 0.1% 4
• Do not discontinue prematurely before 6-8 weeks unless significant adverse effects occur 4
• Do not assume all generic formulations are equivalent—monitor closely with any formulation change 4
• Do not crush, divide, or chew XL tablets—this destroys the extended-release mechanism 1