What is the appropriate dosing regimen, contraindications, and common adverse effects of bupropion (Wellbutrin) for treating major depressive disorder in adults?

Bupropion (Wellbutrin) for Major Depressive Disorder

Bupropion is an effective first-line antidepressant for major depressive disorder with distinct advantages over SSRIs, including significantly lower rates of sexual dysfunction and minimal weight gain, making it particularly suitable for patients concerned about these side effects. 1

Dosing Regimen

Standard Dosing for Depression

For bupropion SR (sustained-release), start with 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total daily dose) if tolerated. 2

• The maximum dose for bupropion SR is 400 mg per day 2
• For bupropion XL (extended-release), start with 150 mg once daily in the morning, with a maintenance dose of 150-300 mg once daily 2
• The maximum dose for bupropion XL is 450 mg per day 2

Timing of Administration

Administer the first dose of bupropion SR in the morning and the second dose before 3 PM to minimize insomnia risk. 2

• Bupropion has activating properties that can improve energy levels, making morning administration ideal 2
• Late-day dosing significantly increases the risk of insomnia 2

Special Population Dosing

For older adults (≥65 years), start with 37.5 mg every morning and gradually increase by 37.5 mg every 3 days as tolerated, with a maximum dose of 150 mg twice daily (300 mg total). 2

For moderate to severe hepatic impairment, the maximum dose is 150 mg daily (one tablet), and for mild hepatic impairment, reduce the dose and/or frequency. 2

For moderate to severe renal impairment (eGFR <90 mL/min), reduce the total daily dose by 50%. 2

Avoid bupropion entirely in end-stage renal disease, as hemodialysis does not effectively clear the active metabolite hydroxybupropion. 2

Absolute Contraindications

Bupropion is absolutely contraindicated in patients with:

• Seizure disorders or any condition predisposing to seizures (prior head trauma, brain tumor, stroke, brain metastases) because bupropion lowers the seizure threshold 2
• Current or recent MAOI use (within 14 days of discontinuation) 2
• Eating disorders (bulimia or anorexia nervosa) due to increased seizure risk 2
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs due to markedly increased seizure risk 2
• Uncontrolled hypertension, as bupropion can elevate blood pressure and heart rate 2

Common Adverse Effects

Most Frequent Side Effects

The most common adverse effects of bupropion include:

• Insomnia (most common, related to its activating properties) 2, 3
• Dry mouth 2, 4
• Headache 1
• Nausea 1
• Agitation or nervousness 3, 4
• Constipation 1
• Tremor 4

Serious Adverse Effects

Seizure risk is approximately 0.1% (1 in 1,000) at the standard 300 mg/day dose, but increases markedly above 450 mg/day. 2

Sexual dysfunction occurs significantly less frequently with bupropion compared to SSRIs like fluoxetine and sertraline. 1

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 treatment. 2

Monitoring Requirements

Initial Monitoring (Weeks 1-2)

Assess patients for suicidal ideation, agitation, irritability, or unusual behavioral changes during the first 1-2 weeks after starting bupropion, as the risk of suicide attempts is highest in the initial 1-2 months. 2

Monitor blood pressure and heart rate at baseline and periodically during treatment, especially in the first 12 weeks, as bupropion can cause elevations in both parameters. 2

Efficacy Assessment

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 occurs by 6-8 weeks at therapeutic doses, modify the treatment approach by increasing the dose, switching agents, or adding augmentation therapy 2

Clinical Advantages

Bupropion offers several distinct advantages over SSRIs:

• Significantly lower rates of sexual dysfunction compared to fluoxetine, sertraline, and paroxetine 1
• Minimal weight gain or even modest weight loss, unlike many other antidepressants 2, 5
• Lower rates of sedation compared to SSRIs 2
• Dual benefit for patients with comorbid depression and nicotine dependence, as it is FDA-approved for both major depressive disorder and smoking cessation 2, 3

Drug Interactions

Bupropion inhibits CYP2D6, raising concern for clinically relevant drug interactions with medications metabolized by this enzyme. 3

Do not combine bupropion with MAOIs or initiate within 14 days of MAOI discontinuation due to risk of hypertensive crisis. 2, 3

Exercise extreme caution when combining bupropion with other drugs that lower seizure threshold. 2

Treatment Duration

After achieving remission in a first-episode depressive disorder, continue bupropion for a minimum of 4-9 months to consolidate remission. 2

For recurrent depression (≥2 episodes), maintenance therapy should extend to ≥1 year or longer, as relapse risk rises to 70% after two episodes and 90% after three episodes. 2

Critical Clinical Pitfalls to Avoid

Do not exceed 450 mg/day total daily dose, as seizure risk increases markedly above this threshold. 2

Do not skip the intensive monitoring window during weeks 1-2, as this period carries the highest risk for emergent suicidal ideation, particularly in patients under 24 years. 2

Do not discontinue treatment prematurely before 6-8 weeks unless significant adverse effects occur, as full therapeutic effect requires this duration. 2

Do not prescribe bupropion to patients taking tamoxifen, as bupropion inhibits CYP2D6 and may reduce tamoxifen efficacy. 2

When switching between brand and generic formulations or between SR and XL formulations, monitor patients closely for loss of antidepressant effect, as historical bioequivalence issues have been reported. 2