What are the dosing guidelines, contraindications, adverse effects, and alternative therapies for Wellbutrin (bupropion) used for depression and smoking cessation?

Wellbutrin (Bupropion): Comprehensive Clinical Guide

Dosing Guidelines

Major Depressive Disorder

Start bupropion SR at 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) if tolerated. 1 The maximum dose is 400 mg/day for SR formulation and 450 mg/day for XL formulation. 1

• Bupropion XL is dosed at 150 mg once daily initially, with maintenance at 150–300 mg once daily 1
• Older adults should start at 37.5 mg every morning, increasing by 37.5 mg every 3 days as tolerated, with a maximum of 150 mg twice daily 1
• Second dose timing is critical: administer before 3 PM to minimize insomnia risk 1

Smoking Cessation

Begin bupropion SR 150 mg once daily for days 1–3, then increase to 150 mg twice daily (300 mg total) starting 1–2 weeks before the target quit date. 2, 1 The maximum dose for smoking cessation is 300 mg/day to maintain seizure risk at 0.1%. 2, 1

• Continue treatment for 7–12 weeks after the quit date 2, 1
• Assess efficacy formally after this 7–12 week period 2, 1
• Combining bupropion with nicotine replacement therapy yields 12-month abstinence rates of 35.5% versus 30.3% with bupropion alone 1

Absolute Contraindications

Bupropion is absolutely contraindicated in patients with seizure disorders, brain metastases, or any condition predisposing to seizures (stroke, head trauma, brain tumor). 2, 1 The seizure risk at 300 mg/day is approximately 0.1% (1 in 1,000), but increases markedly above 450 mg/day. 2, 1

Additional absolute contraindications include:

• Current or recent MAOI use (within 14 days of discontinuation) due to hypertensive crisis risk 2, 1
• Eating disorders (bulimia, anorexia nervosa) due to increased seizure risk 1
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 1
• Concurrent tamoxifen therapy (bupropion inhibits CYP2D6, reducing tamoxifen efficacy) 2
• Uncontrolled hypertension (bupropion elevates blood pressure and heart rate) 1
• Chronic opioid therapy when using naltrexone-bupropion combination products 1

Dose Adjustments for Special Populations

Hepatic Impairment

• Moderate to severe impairment: maximum 150 mg daily (one tablet) 1
• Mild impairment: reduce dose and/or frequency 1

Renal Impairment

• Moderate to severe (GFR <90 mL/min): reduce total daily dose by 50% 1
• End-stage renal disease: avoid bupropion entirely—metabolites accumulate and dialysis does not effectively clear them 1

Critical Safety Monitoring

Black Box Warning

All antidepressants, including bupropion, carry an FDA black box warning for increased risk of suicidal thoughts and behaviors in patients younger than 24 years, with the greatest risk during the first 1–2 months of therapy. 1

• Monitor intensively during weeks 1–2 for suicidal ideation, agitation, irritability, or unusual behavioral changes 1
• Begin monitoring patient status within 1–2 weeks of initiation 1
• The risk for suicide attempts is greatest during the first 1–2 months of treatment 1

Cardiovascular Monitoring

• Measure baseline blood pressure and heart rate before initiating treatment 1
• Monitor periodically during the first 12 weeks, as bupropion can elevate both parameters 1
• Uncontrolled hypertension precludes bupropion use 1

Neuropsychiatric Safety

High-quality evidence from the EAGLES trial (n=8,144) demonstrates that neuropsychiatric adverse events with bupropion are not significantly increased compared to nicotine patch or placebo, even in patients with pre-existing psychiatric disorders. 2 However, providers should still monitor for development or worsening of depression and suicidal ideation. 2

Timeline for Clinical Effect

Allow 6–8 weeks at an adequate therapeutic dose before determining treatment response. 1 If no adequate response occurs by 6–8 weeks, modify the treatment approach. 1

• Energy levels may improve earlier, sometimes within the first few weeks 1
• Response rates to antidepressant therapy may be as low as 50%, with 38% of patients not achieving treatment response during 6–12 weeks 1
• Do not discontinue treatment prematurely before 6–8 weeks unless significant adverse effects occur 1

Adverse Effects Profile

Common Side Effects

• Nervousness and insomnia are the most common 3
• Dry mouth, headaches, and nausea 1
• Disturbed sleep 1

Favorable Side Effect Profile

Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs (decreased risk versus trend toward increased risk with escitalopram and paroxetine). 1 This makes it advantageous for patients concerned about sexual side effects. 1

• Minimal weight gain or even weight loss, unlike many other antidepressants 1
• Lower rates of sedation than SSRIs 1
• Nausea appears slightly less common than with SSRIs 3

Alternative and Augmentation Strategies

When Bupropion Fails

If bupropion monotherapy fails after 6–8 weeks, augment with an SSRI or SNRI rather than switching to another antidepressant. 1 This strategy demonstrates superior efficacy compared to other augmentation approaches. 1

• Adding an SSRI to existing bupropion therapy shows similar remission rates (30.3%) as buspirone augmentation, but with significantly lower discontinuation rates due to adverse events (12.5% vs. 20.6%, P < 0.001) 1
• Bupropion augmentation of SSRIs reduces depression severity more effectively than buspirone augmentation 1

Switching Strategies

If bupropion is ineffective or contraindicated after 6–8 weeks at therapeutic doses:

• Switch to an SSRI (sertraline 50–200 mg daily or escitalopram 10–20 mg daily) as first-line alternative 1
• SSRIs provide overall antidepressant efficacy comparable to bupropion (remission rates 42–49%) 1
• The STAR*D trial showed no significant differences in response when switching from citalopram to bupropion SR, sertraline, or venlafaxine XR (response rates 21–28%) 1

Special Clinical Situations

Comorbid Depression and Smoking

Bupropion is particularly beneficial for patients with depression who also want to quit smoking, addressing both conditions simultaneously. 2, 1 This dual indication makes it a preferred option when both interventions are needed. 1

Comorbid Anxiety

Baseline anxiety does not diminish the comparative efficacy of bupropion versus other second-generation antidepressants. 1 The STAR*D trial meta-analysis found no interaction between anxiety status and treatment response. 1

• Anxiety rates with bupropion (0.6%–5.4%) are not significantly different from placebo (0.2%–4.3%) 1

Pregnancy and Breastfeeding

• Limited data suggest no major congenital malformations with bupropion use, though small increases in specific cardiovascular defects have been reported 1
• Bupropion is present in breast milk at low levels; two case reports of seizures in breastfed infants warrant caution 1
• All weight management formulations containing bupropion are contraindicated in women who are or may become pregnant 1

Formulation Differences

Bioequivalence

All three formulations (IR, SR, XL) are bioequivalent in terms of systemic exposure to bupropion. 4, 5 However:

• SR formulation uses a wax-matrix vehicle providing slow release, with peak plasma concentrations at approximately 3 hours 1
• XL formulation is administered once daily in the morning 1
• Monitor closely when switching between brand and generic formulations or between SR and XL, as historical bioequivalence issues may lead to loss of antidepressant effect 1

Maintenance Therapy Duration

After a satisfactory response in a first-episode depressive episode, continue bupropion for a minimum of 4–9 months to consolidate remission. 1

• For recurrent depression (≥2 episodes): extend maintenance therapy to ≥1 year or longer 1
• Relapse risk rises to 70% after two episodes and 90% after three episodes 1

Common Clinical Pitfalls

• Do not exceed 450 mg/day total dose to maintain seizure risk at 0.1% 1
• Do not skip the intensive monitoring window during weeks 1–2, as this period carries the highest risk for emergent suicidal ideation 1
• Do not combine with MAOIs or initiate within 14 days of MAOI discontinuation 2, 1
• Do not start smoking cessation treatment without the 1–2 week lead time for drug levels to build up 1
• Do not use in patients with undiagnosed bipolar disorder, as antidepressants may trigger manic or hypomanic episodes 1