What are the appropriate adult dosing, contraindications, side effects, and alternative therapies for bupropion when used for major depressive disorder and smoking cessation?

Bupropion for Major Depressive Disorder and Smoking Cessation

Adult Dosing

Major Depressive Disorder

For depression, start bupropion SR at 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total daily dose), which is the standard therapeutic target. 1

• The bupropion XL formulation can be dosed as 150 mg once daily initially, then increased to 300 mg once daily in the morning 1
• Maximum dose for SR formulation is 400 mg/day; maximum for XL is 450 mg/day, though 300 mg is usually sufficient 1
• Allow 6–8 weeks at therapeutic dose before determining treatment response 1
• Energy levels may improve within the first few weeks, but full antidepressant effect requires the complete 6–8 week trial 1

Smoking Cessation

Begin bupropion 1–2 weeks before the target quit date at 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total), and continue for 7–12 weeks after quitting. 1, 2

• The maximum dose for smoking cessation is 300 mg/day—do not exceed this to maintain seizure risk at 0.1% 1, 2
• This pre-quit lead time is essential to establish therapeutic drug levels before cessation attempts 1
• Bupropion increases 12-month abstinence rates by approximately 9–10 percentage points compared to placebo (≈19% vs 11%) 2
• Combining bupropion with nicotine replacement therapy yields 35.5% abstinence at 12 months versus 30.3% with bupropion alone, though this difference is not statistically significant 1

Special Population Dosing

For older adults (≥65 years), start at 37.5 mg every morning and increase by 37.5 mg every 3 days as tolerated, with a maximum of 150 mg twice daily (300 mg total). 1

• Moderate to severe hepatic impairment: Maximum 150 mg daily (one tablet) 1, 2
• Moderate to severe renal impairment (GFR <90 mL/min): Reduce total daily dose by 50% 1, 2
• End-stage renal disease: Avoid bupropion entirely—hemodialysis does not effectively clear the active metabolite hydroxybupropion 1

Timing Considerations

Administer the first dose in the morning and the second dose before 3 PM to minimize insomnia risk. 1

• Bupropion has activating properties that improve energy and reduce apathy, making morning administration ideal 1
• Late-day dosing significantly increases insomnia risk 1

Absolute Contraindications

Bupropion is absolutely contraindicated in patients with any seizure disorder, current or recent MAOI use (within 14 days), eating disorders (bulimia/anorexia), or abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs. 1, 2

Complete List of Absolute Contraindications

• Seizure-predisposing conditions: Prior seizure disorder, stroke, brain tumor, head trauma, brain metastases 1, 2
• MAOI therapy: Current use or within 14 days of discontinuation 1, 2
• Eating disorders: Bulimia nervosa or anorexia nervosa (increased seizure risk) 1
• Abrupt substance withdrawal: Alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 1
• Uncontrolled hypertension: Bupropion can elevate blood pressure and heart rate 1, 2
• Concurrent tamoxifen therapy: Due to CYP2D6 inhibition 1
• Closed-angle glaucoma: Risk of intraocular pressure elevation 2
• Naltrexone-bupropion combination with opioid therapy: Naltrexone precipitates severe opioid withdrawal 1

Side Effects and Safety Profile

Common Side Effects (Generally Tolerable)

The most common side effects are insomnia (≈24% vs 15% placebo), dry mouth (≈13% vs 5% placebo), headache, and nausea. 2, 3, 4

• Insomnia can be mitigated by scheduling the second dose before 3 PM 1, 2
• Nervousness and agitation occur due to bupropion's activating properties 3, 5
• Sexual dysfunction is significantly lower with bupropion compared to SSRIs—a major advantage 1
• Weight gain is minimal or patients may experience modest weight loss, unlike many other antidepressants 1

Serious Adverse Effects (Rare)

Seizure risk is approximately 0.1% (1 in 1,000) at the standard 300 mg/day dose for smoking cessation. 1, 2, 4

• Risk increases markedly above 450 mg/day or with rapid dose escalation 2
• Seizure risk is similar to other antidepressants at therapeutic doses 2, 4
• Severe hypersensitivity reactions (urticaria, angioedema) occur in approximately 1 per 1,000 to 1 per 10,000 patients 1
• Allergic reactions occur at a rate of approximately 3% 4

Neuropsychiatric Safety

The large EAGLES trial (n=8,144) found no statistically significant increase in neuropsychiatric adverse events with bupropion compared to nicotine patch or placebo, even among participants with pre-existing psychiatric disorders. 1, 2

• FDA black-box warning: Increased risk of suicidal thoughts and behaviors in patients younger than 24 years, with greatest risk during the first 1–2 months 1
• Monitor for suicidal ideation, agitation, irritability, or unusual behavioral changes during weeks 1–2 1
• Bupropion can cause agitation or behavioral activation, particularly in already-agitated patients 1

Cardiovascular Effects

Bupropion can cause modest elevations in blood pressure and heart rate, requiring baseline assessment and periodic monitoring, especially during the first 12 weeks. 1, 2

• Uncontrolled hypertension is a contraindication 1, 2
• Bupropion combined with nicotine replacement therapy can be administered safely to individuals with established coronary heart disease 1

Monitoring Requirements

Monitor blood pressure, heart rate, and neuropsychiatric symptoms (suicidal ideation, agitation) within 1–2 weeks of initiation and periodically throughout treatment. 1, 2

• The risk for suicide attempts is greatest during the first 1–2 months of treatment 1
• Patients younger than 24 years require especially close monitoring 1, 2
• Screen for seizure risk factors before initiating therapy 1, 2
• If no adequate response by 6–8 weeks at therapeutic doses, modify the treatment approach 1

Alternative and Augmentation Therapies

For Major Depressive Disorder

If bupropion monotherapy fails after 6–8 weeks, augment with an SSRI (such as sertraline or escitalopram) rather than switching to another antidepressant. 1

• Augmenting SSRIs with bupropion decreases depression severity more effectively than buspirone augmentation 1
• Bupropion augmentation of citalopram produced 30.3% remission rates with significantly lower discontinuation rates (12.5%) compared to buspirone (20.6%, P<0.001) 1
• The combination addresses depression through complementary mechanisms: SSRIs via serotonin, bupropion via norepinephrine/dopamine 1
• Bupropion may counteract SSRI-induced sexual dysfunction, a significant clinical advantage 1

Alternative First-Line Antidepressants

SSRIs (sertraline 50–200 mg daily, escitalopram 10–20 mg daily) and SNRIs (venlafaxine XR 75–225 mg daily) provide comparable overall efficacy to bupropion (42–49% remission rates). 1

• Fluoxetine is the only FDA-approved antidepressant for pediatric depression (ages 8 and older) and should be first-line in adolescents 1
• Bupropion is not FDA-approved for patients younger than 18 years 1
• Venlafaxine may produce better response rates in depression with prominent anxiety but has higher discontinuation rates than SSRIs 1

For Smoking Cessation

Varenicline achieves higher 12-month quit rates (≈28%) than bupropion (≈19%) and is considered superior, though bupropion remains an appropriate first-line option. 2

• Nicotine replacement therapy (NRT) has equivalent efficacy to bupropion (relative risk 0.99) 2
• Combining bupropion with NRT shows the highest abstinence rates 1, 2
• All pharmacotherapy should be combined with behavioral counseling for optimal outcomes—comprehensive programs with individualized counseling plus pharmacotherapy can increase 6-month cessation rates from 6.8% to 21.3% 2

Clinical Advantages and Specific Indications

Bupropion is particularly beneficial for patients with depression characterized by low energy, apathy, or hypersomnia due to its activating properties. 1

• Dual benefit for patients with comorbid depression and nicotine dependence, addressing both conditions simultaneously 1, 2
• Lower rates of sexual dysfunction compared to SSRIs 1
• Minimal weight gain or modest weight loss 1
• Lower rates of sedation than SSRIs 1
• May reduce cessation-related weight gain (1.5–1.7 kg vs 2.1 kg with placebo at 7 weeks) 1

Critical Clinical Pitfalls to Avoid

Do not exceed 450 mg/day total dose to prevent marked increase in seizure risk. 1

Do not start bupropion on the quit date for smoking cessation—the 1–2 week lead time is essential for therapeutic drug levels. 1, 2

Do not skip intensive monitoring 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 due to hypertensive crisis risk. 1, 6

Do not use in patients with eating disorders, as seizure risk is markedly elevated. 1, 2

Do not prescribe naltrexone-bupropion combination to patients on opioid therapy—naltrexone will precipitate severe withdrawal. 1

Do not use bupropion monotherapy (without mood stabilizers) in patients with bipolar disorder—risk of mood destabilization and rapid cycling. 1