Bupropion: Comprehensive Clinical Guide
FDA-Approved Indications
Bupropion is FDA-approved for major depressive disorder, seasonal affective disorder, and smoking cessation. 1
Dosing Regimens
Major Depressive Disorder
For bupropion SR, start with 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total daily). 1
- Bupropion XL is typically administered as 300 mg once daily in the morning 1
- Maximum doses: 400 mg/day for SR formulation; 450 mg/day for XL formulation 1
- Older adults should start with 37.5 mg every morning, increasing by 37.5 mg every 3 days as tolerated, with a maximum of 150 mg twice daily (300 mg total) 1
Timing is critical: Administer the first dose in the morning and the second dose (for SR) before 3 PM to minimize insomnia risk. 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). 1, 2
- Maximum dose for smoking cessation is 300 mg/day—do not exceed this to maintain seizure risk at 0.1% 1, 2
- Continue treatment for 7–12 weeks after the quit date, with formal efficacy assessment after this period 1, 2
- 12-month abstinence rates: Approximately 19% with bupropion versus 11% with placebo 2
Combination therapy: Adding nicotine replacement therapy (NRT) to bupropion yields 35.5% abstinence at 12 months versus 30.3% with bupropion alone, though this difference is not statistically significant 1
Dose Adjustments for Special Populations
Hepatic Impairment
For moderate to severe hepatic impairment, the maximum dose is 150 mg every other day; for mild impairment, reduce dose and/or frequency. 1
Renal Impairment
For moderate to severe renal impairment (GFR <90 mL/min), reduce the total daily dose by 50%. 1
Avoid bupropion entirely in end-stage renal disease—hemodialysis does not effectively clear the active metabolite hydroxybupropion. 1
Absolute Contraindications
Bupropion is absolutely contraindicated in the following conditions: 1, 2, 3
- Any seizure disorder or condition predisposing to seizures (prior seizure, brain metastases, stroke, head trauma, brain tumor)
- Current or recent MAOI use (within 14 days of discontinuation)
- Eating disorders (bulimia nervosa, anorexia nervosa)—due to markedly increased seizure risk
- Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs—precipitates withdrawal seizures
- Concurrent tamoxifen therapy (CYP2D6 inhibition)
- Closed-angle glaucoma
- Uncontrolled hypertension (particularly for naltrexone-bupropion combinations) 1
- Chronic opioid therapy (for naltrexone-bupropion combinations only—bupropion monotherapy does not have this contraindication) 1
Common Adverse Effects
Most Frequent (from FDA label and clinical trials) 3
At 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus, tremor
At 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia (24% vs 15% placebo), myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, urinary frequency
Serious but Rare
Seizure risk is approximately 0.1% (1 in 1,000) at 300 mg/day, increasing markedly above 450 mg/day. 1, 2
Allergic reactions (urticaria, angioedema) occur in approximately 1 per 1,000 to 1 per 10,000 patients 1
Neuropsychiatric Safety
The large EAGLES trial (n=8,144) found no statistically significant increase in neuropsychiatric adverse events with bupropion compared with nicotine patch or placebo, even among participants with pre-existing psychiatric disorders. 1
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, 3
Monitor intensively during weeks 1–2 for suicidal ideation, agitation, irritability, or unusual behavioral changes. 1
Drug Interactions
Critical Interactions
Bupropion is a CYP2D6 inhibitor—exercise caution when co-prescribing with drugs cleared by this enzyme (e.g., tamoxifen, certain antipsychotics, beta-blockers). 4, 5
Do not combine with MAOIs or initiate within 14 days of MAOI discontinuation—risk of hypertensive crisis. 1
Avoid combining with other drugs that lower seizure threshold (e.g., antipsychotics, theophylline, systemic corticosteroids, tramadol). 1
Safe Combinations
Immediate transition from bupropion to escitalopram is safe—no washout period is needed because neither drug is an MAOI. 1
Bupropion can be safely combined with SSRIs (e.g., fluoxetine, sertraline, escitalopram) for augmentation strategies, with lower discontinuation rates (12.5%) compared to buspirone augmentation (20.6%, P<0.001). 1
Bupropion combined with NRT can be administered safely to individuals with established coronary heart disease. 1
Monitoring Parameters
Baseline Assessment
- Blood pressure and heart rate—bupropion can cause modest elevations 1
- Seizure-risk factors—meticulous screening is essential 1, 2
- Psychiatric history and suicide risk—especially in patients under 24 years 2
- Pregnancy status—all weight-management formulations containing bupropion are contraindicated in women who are or may become pregnant 1
Ongoing Monitoring
Monitor blood pressure and heart rate periodically, especially during the first 12 weeks. 1
Assess for neuropsychiatric symptoms (hostility, agitation, depressive mood, suicidal ideation) within 1–2 weeks of initiation and regularly thereafter. 1, 2
Evaluate treatment response at 6–8 weeks—if no adequate response occurs, modify the treatment approach (dose adjustment, switch, or augmentation). 1
Clinical Advantages Over SSRIs
Bupropion has significantly lower rates of sexual dysfunction compared to SSRIs (decreased risk with bupropion versus trend toward increased risk with escitalopram and paroxetine). 1
Bupropion is associated with minimal weight gain or even weight loss, unlike many other antidepressants. 1
Bupropion has lower rates of sedation than SSRIs. 1
Remission rates are equivalent: 42–49% with bupropion, similar to SSRIs and SNRIs. 1
Augmentation Strategies
When bupropion monotherapy fails after 6–8 weeks, augment with an SSRI or SNRI rather than switching to another antidepressant. 1
Augmenting SSRIs with bupropion decreases depression severity more effectively than augmentation with buspirone in patients who failed initial SSRI monotherapy. 1
For patients who smoke, augment bupropion with NRT to address both depression and smoking cessation. 1
Alternative Therapies
For Major Depressive Disorder
If bupropion is ineffective or contraindicated after 6–8 weeks at therapeutic doses, switch to an SSRI (e.g., sertraline 50–200 mg daily or escitalopram 10–20 mg daily) as a first-line alternative. 1
Venlafaxine XR 75–225 mg daily may produce statistically better response rates in depression with prominent anxiety, but is associated with higher discontinuation rates than SSRIs. 1
For Smoking Cessation
Varenicline achieves higher 12-month quit rates (≈28%) than bupropion (≈19%) and is considered superior; however, bupropion remains an appropriate first-line option for patients who cannot use varenicline. 2
NRT has equivalent efficacy to bupropion (relative risk 0.99). 2
Special Clinical Scenarios
Dual Indication: Depression + Smoking Cessation
Bupropion uniquely offers simultaneous treatment of depression and smoking cessation, making it a preferred option for patients requiring both interventions. 1, 2
The 300 mg dose provides superior antidepressant response and smoking-cessation efficacy compared with 150 mg. 1
Comorbid Anxiety
Baseline anxiety does not diminish the comparative efficacy of bupropion versus other second-generation antidepressants. 1
Anxiety rates with bupropion are 0.6%–5.4% versus 0.2%–4.3% with placebo—no statistically significant difference. 1
Pregnancy and Breastfeeding
Limited data suggest no major congenital malformations with bupropion use during pregnancy, though small increases in specific cardiovascular defects have been reported. 1
Bupropion is present in breast milk at low levels; two case reports of seizures in breastfed infants warrant caution. 1
Adolescents
Bupropion is not FDA-approved for major depressive disorder in patients younger than 18 years; fluoxetine remains the only antidepressant with FDA approval for pediatric depression (ages 8 years and older). 1
Off-label bupropion may be considered only after failure or intolerance of fluoxetine, after confirming the absence of absolute contraindications, after discussing the black-box warning with the patient and family, and only with a structured weekly monitoring plan for the first month. 1
Critical Clinical Pitfalls
Do not skip the 1–2 week lead time before the quit date for smoking cessation—therapeutic drug levels must be established. 1, 2
Do not exceed 450 mg/day total dose—seizure risk rises markedly above this threshold. 1
Do not discontinue abruptly—consider gradual dose reduction to minimize withdrawal symptoms. 1
Do not start bupropion without screening for bipolar disorder—antidepressants may trigger manic or hypomanic episodes in undiagnosed bipolar disorder. 1
Do not combine naltrexone-bupropion products with any opioid therapy—naltrexone will precipitate severe opioid withdrawal. 1