Bupropion: Comprehensive Prescribing Guidelines

Primary Indications

Bupropion is FDA-approved for major depressive disorder, seasonal affective disorder, and smoking cessation, making it a versatile first-line agent particularly suited for patients with low energy, apathy, or concerns about sexual dysfunction. 1, 2

Bupropion demonstrates equivalent efficacy to SSRIs and SNRIs for acute major depression, with response rates of approximately 42-49% 1
The drug is particularly advantageous for patients with depression characterized by low energy, apathy, or hypersomnia due to its activating dopaminergic and noradrenergic properties 1, 3
For smoking cessation, bupropion increases 12-month abstinence rates by approximately 9-10 percentage points above placebo (19% vs 11%) 1
Bupropion offers dual benefit when both depression and smoking cessation are needed, addressing both conditions simultaneously 1, 3

Absolute Contraindications

Before prescribing bupropion, you must screen for seizure disorders, eating disorders, uncontrolled hypertension, current MAOI use, and abrupt substance withdrawal—these are non-negotiable contraindications.

Seizure-Related Contraindications

Any seizure disorder or history of epilepsy (bupropion significantly lowers seizure threshold with dose-dependent risk) 1, 3, 2
Head trauma, brain metastases, CNS tumors, or stroke 1, 3
Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 1, 2

Psychiatric Contraindications

Current or prior bulimia or anorexia nervosa (higher seizure incidence observed in these populations) 1, 3, 2
Current or recent MAOI use (within 14 days of discontinuation) 1, 3, 2
Concurrent tamoxifen therapy (due to CYP2D6 inhibition) 1

Cardiovascular Contraindications

Uncontrolled hypertension (bupropion can elevate blood pressure and heart rate) 1, 3, 2

Other Contraindications

Closed-angle glaucoma 1, 2
Pregnancy and breastfeeding (for naltrexone-bupropion combination products) 4
Concurrent opioid therapy (for naltrexone-bupropion combination only) 1, 4

Dosing Guidelines by Indication

Major Depressive Disorder

Standard Adult Dosing:

Bupropion SR: Start 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) 1, 3
Bupropion XL: Start 150 mg once daily, increase to 150-300 mg once daily 1
Maximum doses: SR = 400 mg/day; XL = 450 mg/day 1, 2

Older Adults (≥65 years):

Start with 37.5 mg every morning 1, 3
Increase by 37.5 mg every 3 days as tolerated 1, 3
Maximum dose: 150 mg twice daily (300 mg total daily) 1

Timing Considerations:

Administer first dose in the morning to leverage activating properties 1
Give second dose (for SR formulation) before 3 PM to minimize insomnia risk 1, 3

Smoking Cessation

Standard Protocol:

Start 150 mg once daily for 3 days, then 150 mg twice daily (300 mg total) 1, 5
Maximum dose: 300 mg/day (do not exceed to maintain seizure risk at 0.1%) 1, 5
Begin 1-2 weeks before target quit date to establish therapeutic drug levels 1
Continue for 7-12 weeks after quit date 1, 5
Assess efficacy formally after 7-12 weeks 1

Combination Therapy:

Bupropion plus nicotine replacement therapy (NRT) shows highest abstinence rates (35.5% vs 30.3% with bupropion alone) 1
Start NRT on the actual quit date, not when starting bupropion 1

Dose Adjustments for Special Populations

Hepatic Impairment

Mild impairment: Reduce dose and/or frequency 1
Moderate to severe impairment: Maximum 150 mg daily (one tablet) 1, 2
Severe hepatic cirrhosis: Maximum 150 mg every other day 1

Renal Impairment

Moderate to severe (GFR <90 mL/min): Reduce total daily dose by 50% 1, 2
End-stage renal disease: Avoid bupropion 1

Pediatric Patients

Bupropion is NOT FDA-approved for patients <18 years 1
Fluoxetine remains the only FDA-approved antidepressant for pediatric depression (ages ≥8 years) 1
If used off-label after fluoxetine failure, requires structured weekly monitoring for the first month 1

Critical Safety Monitoring

Black Box Warning: Suicidal Ideation

All antidepressants, including bupropion, carry an FDA black-box warning for increased risk of suicidal thoughts and behaviors in patients <24 years, with greatest risk during the first 1-2 months. 1, 2

Monitoring Protocol:

Assess patient status within 1-2 weeks of initiation 1, 3
Monitor closely for agitation, irritability, unusual behavior changes, or suicidal thoughts 1, 3
Risk for suicide attempts is greatest during the first 1-2 months 1

Seizure Risk

Incidence at 300 mg/day: approximately 0.1% (1 in 1,000 patients) 1, 5
Risk increases with doses >450 mg/day, rapid dose escalation, or predisposing conditions 1, 5
Never exceed maximum daily doses: SR = 400 mg; XL = 450 mg; smoking cessation = 300 mg 1, 2, 5

Cardiovascular Monitoring

Measure baseline blood pressure and heart rate before initiation 1, 3
Monitor periodically during treatment, especially first 12 weeks 1, 3
Bupropion can elevate both blood pressure and heart rate 1, 3

Neuropsychiatric Monitoring

Watch for activation of mania/hypomania, psychosis, or other neuropsychiatric reactions 2
High-quality evidence (EAGLES trial, n=8,144) shows no significant increase in neuropsychiatric adverse events compared to placebo, even in patients with pre-existing psychiatric disorders 1

Common Adverse Effects

Most frequent side effects (generally transient and resolve without intervention):

Insomnia (most common; administer second dose before 3 PM to minimize) 1, 5
Dry mouth 1, 5, 6
Headache 5, 6
Nausea 5, 6
Anxiety (also a nicotine withdrawal symptom) 5

Clinically Important Advantages:

Significantly lower rates of sexual dysfunction compared to SSRIs 1, 3, 6
Minimal weight gain or even weight loss (unlike many other antidepressants) 1, 6
Lower rates of sedation than SSRIs 1, 6
Minimal anticholinergic effects 7

Rare but Serious (approximately 0.1% each):

Seizures 1, 5
Severe hypersensitivity reactions (urticaria, angioedema) 1, 2

Time to Clinical Effect

Allow 6-8 weeks at adequate dose before determining treatment response. 1, 3

Begin monitoring within 1-2 weeks for adverse effects and early response 1, 3
Bupropion may produce more rapid improvement in energy levels compared to other antidepressants, sometimes within the first few weeks 1
If no adequate response by 6-8 weeks at therapeutic doses, modify treatment approach (increase dose, switch, or augment) 1, 3
Response rates to antidepressant therapy may be as low as 50%, with 38% not achieving response and 54% not achieving remission during 6-12 weeks 1

Augmentation Strategies

When bupropion monotherapy fails after 6-8 weeks, augment with an SSRI or SNRI rather than switching. 1

Adding an SSRI/SNRI to bupropion demonstrates superior efficacy compared to other augmentation strategies 1
Bupropion augmentation of SSRIs reduces depression severity more effectively than buspirone augmentation 1
Bupropion augmentation shows significantly lower discontinuation rates due to adverse events (12.5%) compared to buspirone (20.6%, P<0.001) 1
Maximum dose must not exceed 450 mg/day to maintain seizure risk at 0.1% 1

Critical Drug Interactions

MAOIs

Do not use within 14 days of discontinuing an MAOI 1, 3, 2
Allow at least 14 days after stopping bupropion before starting an MAOI 2
Includes phenelzine, isocarboxazid, moclobemide, isoniazid, and linezolid 1

Drugs That Lower Seizure Threshold

Use extreme caution when combining with other drugs that lower seizure threshold 1
Adhere strictly to maximum dosing guidelines when combining 1

CYP2D6 Interactions

Bupropion inhibits CYP2D6, raising concern for clinically-relevant drug interactions 8
Avoid concurrent tamoxifen therapy 1

Opioids

Naltrexone-bupropion combination is absolutely contraindicated with any opioid therapy (will precipitate severe withdrawal) 1, 4
Bupropion monotherapy does not have this contraindication 1

Alcohol

Avoid alcohol use during bupropion therapy 2
Abrupt alcohol discontinuation is a contraindication for starting bupropion 1, 2

Formulation Considerations

All three formulations (IR, SR, XL) are bioequivalent in terms of systemic exposure to bupropion. 6

SR formulation: 150 mg twice daily (total 300 mg/day) 1
XL formulation: 300 mg once daily in the morning 1
Monitor closely when switching between brand and generic formulations or between SR and XL due to historical bioequivalence issues 1
Some generic versions of bupropion SR were previously found not bioequivalent to brand-name Wellbutrin SR 1

Special Clinical Scenarios

Pregnancy and Breastfeeding

Naltrexone-bupropion ER is explicitly contraindicated during pregnancy and breastfeeding 4
Limited data suggest no major congenital malformations with bupropion monotherapy, 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, 4

Bipolar Disorder/Cyclothymia

Naltrexone-bupropion should be avoided in patients with bipolar disorder, including cyclothymia 4
Bupropion may be less likely to provoke mania than antidepressants with prominent serotonergic effects 8

Cardiovascular Disease

Bupropion combined with NRT can be administered safely to individuals with established coronary heart disease 1

Clinical Advantages Summary

Bupropion is the preferred first-line antidepressant for patients who:

Have depression with low energy, apathy, or hypersomnia 1, 3
Are concerned about sexual dysfunction 1, 3, 6
Are concerned about weight gain 1, 6
Need both depression treatment and smoking cessation 1, 3
Experience excessive sedation with SSRIs 1, 6

Critical Pitfalls to Avoid

Never exceed maximum daily doses (SR=400mg, XL=450mg, smoking cessation=300mg) to prevent seizure risk >0.1% 1, 2, 5
Never prescribe to patients with seizure disorders, eating disorders, or uncontrolled hypertension 1, 3, 2
Never start within 14 days of MAOI discontinuation 1, 3, 2
Never skip intensive monitoring in weeks 1-2, especially in patients <24 years (highest risk for suicidal ideation) 1, 3
Never administer second dose after 3 PM (increases insomnia risk) 1, 3
Never discontinue abruptly—taper gradually to minimize withdrawal symptoms 1
Never combine naltrexone-bupropion with opioids (will precipitate severe withdrawal) 1, 4

What are the recommended dosing guidelines, contraindications, common adverse effects, and monitoring recommendations for bupropion (including extended‑release and immediate‑release formulations) in adult patients?

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