What are the recommended dosing regimens, contraindications, side effects, and alternative therapies for bupropion (for major depressive disorder and smoking cessation)?

Bupropion for Major Depressive Disorder and Smoking Cessation

Recommended Dosing Regimens

For major depressive disorder, 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 dose. 1, 2 The maximum dose is 400 mg/day for SR formulation or 450 mg/day for XL formulation. 2

For smoking cessation, begin bupropion SR 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total), starting 1–2 weeks before the target quit date to establish therapeutic drug levels before cessation attempts. 3, 1, 2 Continue treatment for 7–12 weeks after the quit date, with formal efficacy assessment after this period. 3, 1, 2

Critical Timing Considerations

• Administer the first dose in the morning and the second dose before 3 PM to minimize insomnia risk, as bupropion has activating properties. 2
• The 1–2 week lead time before the quit date is essential—do not start smoking cessation treatment without allowing drug levels to build up. 2
• Nicotine withdrawal symptoms typically peak within 1–2 weeks of quitting and then subside. 2

Special Population Dosing

• For older adults (≥65 years), start with 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). 2 This lower starting dose—approximately 50% of standard adult doses—reduces adverse reaction risk. 2
• For moderate to severe hepatic impairment, reduce the total daily dose to a maximum of 150 mg daily (one tablet). 1, 2
• For moderate to severe renal impairment (GFR <90 mL/min), reduce the total daily dose by 50% because bupropion and its metabolites are cleared renally and accumulate significantly. 1, 2
• Avoid bupropion entirely in end-stage renal disease, as hemodialysis does not effectively clear the primary active metabolite hydroxybupropion. 2

Absolute Contraindications

Bupropion is absolutely contraindicated in patients with seizure disorders or any condition that predisposes to seizures (e.g., prior head trauma, brain tumor, stroke, brain metastases), as the drug lowers the seizure threshold. 3, 1, 2, 4

Additional absolute contraindications include:

• Current or recent MAOI use (within 14 days of discontinuation), due to risk of hypertensive crisis. 2, 4
• Eating disorders (bulimia nervosa or anorexia nervosa), due to markedly increased seizure risk. 2
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, which increases seizure risk. 2, 4
• Uncontrolled hypertension, as bupropion can elevate blood pressure and heart rate. 1, 2
• Concurrent tamoxifen therapy, due to CYP2D6 inhibition by bupropion. 2
• Closed-angle glaucoma, due to risk of intraocular pressure elevation. 2

Common and Serious Side Effects

Most Common Side Effects (≥5% incidence)

• Insomnia (11–16%), dry mouth (6–11%), dizziness (7–11%), agitation (3–9%), anxiety (5–6%), tremor (6%), sweating (5–6%), nausea, headache, and tinnitus (6%). 4, 5 These side effects are typically more common with bupropion than with nicotine replacement therapy alone. 3

Serious Adverse Effects

• Seizure risk is approximately 0.1% (1 in 1,000) at the standard 300 mg/day dose for smoking cessation. 3, 2, 5 Risk increases markedly above 450 mg/day. 2
• Severe hypersensitivity reactions (urticaria, angioedema, anaphylaxis) occur in approximately 1 per 1,000 to 1 per 10,000 patients. 2, 4 Instruct patients to discontinue immediately if they develop skin rash, pruritus, hives, chest pain, edema, or shortness of breath. 4
• Neuropsychiatric effects: Although the high-quality EAGLES trial (n=8,144) showed no statistically significant increase in neuropsychiatric adverse events compared with placebo, 3, 2 rare serious events including allergic reactions, neuropsychiatric symptoms, and chest pain have been reported. 3

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, 2, 4

Monitoring Requirements

Begin monitoring patient status, therapeutic response, and adverse effects within 1–2 weeks of initiation, particularly for suicidal ideation, agitation, irritability, or unusual behavioral changes. 1, 2 This early monitoring is critical because the risk for suicide attempts is greatest during the first 1–2 months of treatment. 2

Monitor blood pressure and heart rate periodically, especially during the first 12 weeks, as bupropion can cause elevations in both parameters. 1, 2

Assess for adequate therapeutic response at 6–8 weeks before considering treatment modification. 1, 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. 1, 2

Efficacy Data

Major Depressive Disorder

• Bupropion demonstrates efficacy equivalent to SSRIs, with remission rates of approximately 42–49%. 2 At 300 mg daily, bupropion has demonstrated efficacy for treating major depression. 1
• The American College of Physicians recommends bupropion as one of the second-generation antidepressants that can be selected based on adverse effect profiles, cost, and patient preferences. 1

Smoking Cessation

• A 2014 Cochrane review of 44 trials showed a relative risk of 1.62 (95% CI, 1.49–1.76) for successful smoking cessation with bupropion versus placebo. 3, 1
• In the EAGLES trial (n=8,144), bupropion achieved superior abstinence rates compared with placebo (OR, 2.07; 95% CI, 1.75–2.45). 3, 1 Efficacy was similar to nicotine patch but less than varenicline. 3
• Bupropion increases 12-month abstinence by approximately 9–10 percentage points compared with placebo (≈19% quit rate vs 11% with placebo). 2

Dual Benefit

Bupropion may be particularly beneficial as a smoking cessation agent for persons with depression, addressing both conditions simultaneously. 3, 1, 2 A trend toward improved efficacy was noted in patients with a history of depression. 3

Alternative and Combination Therapies

For Major Depressive Disorder

If bupropion monotherapy fails after 6–8 weeks, augment with an SSRI or SNRI rather than switching to another antidepressant. 2 Adding an SSRI to existing bupropion therapy demonstrates superior efficacy compared to other augmentation strategies, with significantly lower discontinuation rates due to adverse events (12.5% vs. 20.6% for buspirone, P < 0.001). 2

Alternative first-line monotherapy options include:

• SSRIs (sertraline, escitalopram, citalopram), which have similar overall efficacy to bupropion but higher rates of sexual dysfunction. 1, 2
• Venlafaxine XR, which may produce statistically better response rates in depression with prominent anxiety, though with higher discontinuation rates. 2
• Mirtazapine, which has a significantly faster onset of action but may cause weight gain. 6

For Smoking Cessation

Recommended subsequent therapy options include combination NRT with bupropion or bupropion alone (category 2B). 3 A double-blind RCT showed the highest abstinence rates at 12 months with bupropion plus NRT (35.5%) compared to bupropion alone (30.3%), though the difference was not statistically significant. 3, 2

Begin nicotine patches on the actual quit date (not when starting bupropion), while bupropion should be started 1–2 weeks before the quit date. 2

Unique Advantages of Bupropion

Bupropion has significantly lower rates of sexual dysfunction compared with SSRIs, making it advantageous for patients concerned about this side effect. 1, 2, 7 In fact, 16% of patients spontaneously reported improvement in SSRI-associated sexual dysfunction when bupropion was added. 7

Bupropion is associated with minimal weight gain or even weight loss, unlike many other antidepressants. 1, 2 Mean weight gain was approximately 0.5 lb (0.2 kg) for those completing 9 weeks of treatment. 7

Bupropion has minimal anticholinergic effects, making it preferred over tricyclic antidepressants, especially in older adults. 2

Bupropion may be particularly beneficial for patients with depression characterized by low energy, apathy, or hypersomnia due to its activating properties. 2

Common Clinical Pitfalls

• Do not skip the intensive monitoring window during weeks 1–2, as this period carries the highest risk for emergent suicidal ideation. 2
• Do not exceed a total bupropion dose of 450 mg/day, because seizure risk rises markedly above this threshold. 2
• Do not start smoking cessation treatment without the 1–2 week lead time for drug levels to build up. 2
• Do not discontinue treatment prematurely before 6–8 weeks unless significant adverse effects occur. 2
• Avoid prescribing bupropion to patients taking opioid medications if considering the naltrexone-bupropion combination, as naltrexone will precipitate severe withdrawal. 2