What are the approved and off‑label uses, dosing regimens, contraindications, and alternative therapies for bupropion (including Zyban)?

Bupropion: Approved and Off-Label Uses, Dosing, Contraindications, and Alternatives

FDA-Approved Indications

Bupropion is FDA-approved for major depressive disorder (MDD), seasonal affective disorder (SAD), and smoking cessation. 1, 2, 3

• Major Depressive Disorder: Bupropion demonstrates efficacy equivalent to SSRIs and SNRIs, with response rates of 42-49% and remission rates comparable to other second-generation antidepressants 4, 5, 3
• Seasonal Affective Disorder: Approved specifically for this indication with demonstrated clinical benefit 2, 3
• Smoking Cessation: Marketed as Zyban, bupropion increases 12-month abstinence rates by approximately 9-10 percentage points versus placebo, with quit rates of 19% compared to 11% with placebo 1, 6

Off-Label Uses

• Attention Deficit Hyperactivity Disorder (ADHD): Used off-label with anecdotal support, though not FDA-approved 7
• Augmentation therapy for treatment-resistant depression: Low-quality evidence shows augmenting SSRIs with bupropion decreases depression severity more effectively than buspirone augmentation, with lower discontinuation rates (12.5% vs 20.6%, P < 0.001) 4
• Weight management: Available as naltrexone-bupropion ER combination (Contrave) for obesity 4
• Methamphetamine dependence: Demonstrates efficacy particularly in patients with low-to-moderate baseline use 4

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Dosing Regimens by Indication

Major Depressive Disorder

Bupropion SR (Sustained Release):

• Initial: 150 mg once daily for 3 days 4
• Maintenance: 150 mg twice daily (300 mg total daily) 4, 3
• Maximum: 400 mg per day for SR formulation 4, 2

Bupropion XL (Extended Release):

• Initial: 150 mg once daily 4
• Maintenance: 150-300 mg once daily 4
• Maximum: 450 mg per day for XL formulation 4, 2

Critical timing: Administer first dose in the morning; second SR dose must be given before 3 PM to minimize insomnia risk 4

Time to effect: Monitor for response within 1-2 weeks for adverse effects and suicidal ideation; allow 6-8 weeks at adequate dose before determining treatment response 4, 3

Smoking Cessation

Standard protocol:

• Days 1-3: 150 mg once daily 1, 6
• Day 4 through 7-12 weeks: 150 mg twice daily (300 mg total) if tolerated 1, 6
• Maximum: 300 mg per day for smoking cessation (do not exceed to maintain seizure risk at 0.1%) 1, 6

Critical timing: Begin dosing 1-2 weeks before the target quit date to establish therapeutic drug levels 1, 6

Duration: Continue for 7-12 weeks after quit date; assess efficacy formally after this period 1, 6

Combination therapy: Adding nicotine replacement therapy (NRT) to bupropion yields 12-month abstinence rates of 35.5% versus 30.3% with bupropion alone (difference not statistically significant) 4, 6

Special Population Dosing

Older adults (≥65 years):

• Start with 37.5 mg every morning 4
• Increase by 37.5 mg every 3 days as tolerated 4
• Maximum: 150 mg twice daily (300 mg total daily) 4

Hepatic impairment:

• Moderate to severe: Maximum 150 mg daily (one tablet); for mild impairment, reduce dose and/or frequency 4, 6

Renal impairment:

• Moderate to severe (GFR <90 mL/min): Reduce total daily dose by 50% 4, 6
• End-stage renal disease: Avoid bupropion 4

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Absolute Contraindications

Bupropion is absolutely contraindicated in the following conditions:

1. Seizure disorders or any condition predisposing to seizures (stroke, brain metastases, head trauma, brain tumor) 1, 6
2. Current or recent MAOI use (within 14 days of discontinuing MAOIs due to increased risk of hypertensive reactions) 1, 4, 6
3. Eating disorders (bulimia or anorexia nervosa) due to increased seizure risk 4
4. Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs (increased seizure risk) 4, 6
5. Concurrent tamoxifen therapy 1, 4
6. Closed-angle glaucoma 1
7. Uncontrolled hypertension (bupropion can elevate blood pressure and heart rate) 4, 6
8. Chronic opioid therapy (for naltrexone-bupropion combination only; naltrexone precipitates severe opioid withdrawal) 4

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Critical Safety Monitoring

Seizure Risk

• Incidence: Approximately 0.1% (1 in 1,000) at 300 mg/day for smoking cessation 1, 6
• Risk increases with: Doses exceeding 450 mg/day, rapid dose escalation, predisposing conditions 1, 6
• Prevention: Never exceed maximum doses; gradual titration is mandatory 1, 6

Neuropsychiatric Monitoring

• Black box warning: Increased risk of suicidal thoughts and behavior in patients younger than 24 years 4
• Monitor for: Hostility, agitation, depressed mood, suicidal ideation, behavioral changes 1, 6
• High-quality evidence: The EAGLES trial (n=8,144) found no significant increase in neuropsychiatric adverse events with bupropion versus nicotine patch or placebo, even in patients with pre-existing psychiatric disorders 1, 6

Cardiovascular Monitoring

• Blood pressure and heart rate: Monitor periodically, especially during first 12 weeks, as bupropion can cause elevations 4, 6
• Safety in cardiovascular disease: Bupropion can be used safely in patients with established cardiovascular disease, including peripheral artery disease 6

Allergic Reactions

• Risk: 1 in 1,000 to 1 in 10,000 1, 6
• Presentation: Severe urticaria and angioedema may occur, even with delayed onset (4 weeks after initiation) 7

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Common Adverse Effects

Most frequent side effects:

• Insomnia (≈24% vs 15% with placebo) – mitigate by scheduling second dose before 3 PM 6
• Dry mouth (≈13% vs 5% with placebo) 6
• Headache and nausea 6, 2
• Nervousness and agitation 2, 8
• Constipation and tremor 2

Favorable side effect profile:

• Minimal sexual dysfunction (significantly lower than SSRIs) 4, 5, 3
• Minimal weight gain or weight loss (unlike many SSRIs) 4, 5, 3
• Lower rates of sedation than SSRIs 4, 5

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Alternative Therapies

For Major Depressive Disorder

First-line alternatives with equivalent efficacy:

• SSRIs (sertraline, escitalopram, fluoxetine): Similar response and remission rates to bupropion 4, 3
• SNRIs (venlafaxine XR): Comparable efficacy in most trials, though one trial showed venlafaxine XR superior 3
• Other second-generation antidepressants (mirtazapine, vortioxetine, vilazodone): Similar efficacy with different side effect profiles 2

When to choose bupropion over alternatives:

• Patients with low energy, apathy, or hypersomnia (bupropion has activating properties) 4
• Patients concerned about sexual dysfunction (bupropion has lowest rates) 4, 5, 3
• Patients concerned about weight gain (bupropion associated with weight loss) 4, 5
• Patients with comorbid smoking cessation needs (dual benefit) 1, 6

For Smoking Cessation

Comparative effectiveness:

• Varenicline: Superior to bupropion with 12-month quit rates of 28% versus 19% 6
• Nicotine replacement therapy (NRT): Equivalent efficacy to bupropion (relative risk 0.99) 6
• Nortriptyline: Similar efficacy to bupropion but considered second-line due to side effects 6

Combination strategies:

• Bupropion + NRT: Highest abstinence rates (35.5% at 12 months) though not statistically superior to bupropion alone 4, 6
• Behavioral counseling + pharmacotherapy: Increases 6-month cessation rates from 6.8% to 21.3% versus verbal advice alone 6

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Clinical Advantages and Unique Considerations

Bupropion offers distinct advantages:

• Only antidepressant with no appreciable serotonin activity (dopamine-norepinephrine reuptake inhibitor) 2
• Dual indication for depression and smoking cessation (particularly beneficial for patients with both conditions) 1, 6
• May counteract SSRI-induced sexual dysfunction when used as augmentation 4
• Lower risk of mania provocation compared to serotonergic antidepressants 8

Formulation considerations:

• All three formulations (IR, SR, XL) are bioequivalent in systemic exposure to bupropion 3
• Monitor closely when switching between brand and generic formulations due to historical bioequivalence issues 4
• XL formulation offers once-daily dosing advantage 3

Augmentation strategy:

• When SSRI monotherapy fails, augmenting with bupropion is equally effective as switching to another antidepressant but avoids discontinuation symptoms 4
• Bupropion augmentation of citalopram achieved 30.3% remission rates with significantly lower discontinuation due to adverse events versus buspirone (12.5% vs 20.6%, P < 0.001) 4