What is the recommended adult dose and titration schedule for Wellbutrin (bupropion) 300 mg for major depressive disorder, and what are its contraindications and common side effects?

Wellbutrin (Bupropion) 300 mg: Dosing, Titration, Contraindications, and Side Effects

Recommended Adult Dosing and Titration for Major Depressive Disorder

For major depressive disorder, start bupropion XL at 150 mg once daily in the morning, then increase to the target dose of 300 mg once daily after 4 days if tolerated. 1

Standard Titration Schedule

• Initial dose: 150 mg once daily in the morning 2, 1
• Titration timing: After 4 days, increase to 300 mg once daily 1
• Target therapeutic dose: 300 mg once daily 2, 1
• Maximum dose: 450 mg per day for XL formulation (do not exceed to minimize seizure risk) 2, 1

Alternative Formulation (Sustained-Release)

• Bupropion SR: Start 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) 2
• Timing of second dose: Must be given before 3 PM to minimize insomnia risk 2
• Maximum SR dose: 400 mg per day 2

Special Population Adjustments

Older adults require lower starting doses: Begin with 37.5 mg every morning, then gradually increase by 37.5 mg every 3 days as tolerated, with a maximum of 150 mg twice daily (300 mg total daily) 2

Hepatic impairment:

• Moderate to severe: 150 mg every other day (maximum) 2, 1
• Mild: Consider reducing dose and/or frequency 1

Renal impairment: Reduce total daily dose by 50% for moderate to severe impairment (GFR <90 mL/min) 2, 1

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Absolute Contraindications

Bupropion is absolutely contraindicated in the following conditions: 1

1. Seizure disorder (current or history) 2, 1
2. Current or prior diagnosis of bulimia or anorexia nervosa 2, 1
3. Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 2, 1
4. MAOI use: Do not use within 14 days of stopping an MAOI or starting bupropion 2, 1
5. Known hypersensitivity to bupropion 1
6. Concurrent tamoxifen therapy (due to CYP2D6 inhibition) 2

Additional High-Risk Conditions Requiring Avoidance

• Uncontrolled hypertension (bupropion can elevate blood pressure) 2
• Any condition predisposing to seizures: head trauma, brain tumor, stroke, brain metastases 2
• Untreated anatomically narrow angles (risk of angle-closure glaucoma) 1
• Concurrent opioid therapy (if using naltrexone-bupropion combination) 2

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Seizure Risk and Safety

The seizure rate at therapeutic doses (≤300 mg/day) is approximately 0.1% (1 in 1,000 patients). 2, 3

Minimizing Seizure Risk

• Never exceed 450 mg/day (seizure risk increases markedly above this threshold) 2, 1
• Gradual dose titration is mandatory to reduce seizure risk 1
• Avoid in patients with any seizure predisposition 2, 1
• Screen for eating disorders (bulimia/anorexia increase seizure risk) 2, 1

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Common Side Effects

The most common adverse reactions (incidence ≥5%; ≥2× placebo rate) include: 1

• Dry mouth
• Nausea
• Insomnia
• Dizziness
• Pharyngitis
• Abdominal pain
• Agitation
• Anxiety
• Tremor
• Palpitation
• Sweating
• Tinnitus
• Myalgia
• Anorexia
• Urinary frequency
• Rash

Comparative Advantages

Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs (a major clinical advantage for many patients) 2, 4, 5

Bupropion is associated with minimal weight gain or even weight loss, unlike many other antidepressants 2, 5

Lower rates of sedation compared to SSRIs 2

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Critical Monitoring Requirements

Black Box Warning: Suicidal Thoughts and Behaviors

All patients younger than 24 years have increased risk of suicidal thinking and behavior, with the greatest risk during the first 1–2 months of treatment. 2, 1

• Monitor intensively during weeks 1–2 for suicidal ideation, agitation, irritability, or unusual behavioral changes 2
• Continue close monitoring throughout the first 2 months 2

Cardiovascular Monitoring

Monitor blood pressure and heart rate before initiating treatment and periodically during therapy, especially in the first 12 weeks. 2, 1

• Bupropion can elevate both blood pressure and heart rate 2, 1
• Uncontrolled hypertension is a contraindication 2

Response Assessment Timeline

Allow 6–8 weeks at an adequate therapeutic dose before determining treatment response. 2

• Early improvement in energy levels may occur within the first few weeks 2
• If no adequate response by 6–8 weeks, modify treatment approach (dose adjustment, augmentation, or switch) 2

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Clinical Advantages and Special Considerations

Bupropion may be particularly beneficial for patients with:

• Depression characterized by low energy, apathy, or hypersomnia (due to activating properties) 2
• Comorbid depression and smoking cessation needs (addresses both conditions) 2
• Concerns about sexual dysfunction or weight gain 2, 5

Bupropion has a favorable side effect profile with lower rates of anticholinergic effects, orthostatic hypotension, and cardiac conduction problems compared to tricyclic antidepressants. 6, 7

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Critical Pitfalls to Avoid

1. Do not exceed 450 mg/day (markedly increases seizure risk) 2, 1
2. Do not skip the intensive monitoring window in weeks 1–2 (highest risk for suicidal ideation) 2
3. Do not use in patients with seizure predisposition 2, 1
4. Do not combine with MAOIs or use within 14 days of MAOI discontinuation 2, 1
5. Do not give the second SR dose after 3 PM (increases insomnia risk) 2
6. Do not assume generic formulations are equivalent (historical bioequivalence issues require close monitoring when switching) 2