What are the considerations for off-label use of bupropion (Wellbutrin) in a patient with a history of depression or smoking, potentially for conditions such as attention deficit hyperactivity disorder (ADHD) or weight loss?

Off-Label Use of Bupropion for ADHD and Weight Loss

Bupropion can be used off-label for ADHD in adults with low-quality evidence showing modest benefit, and is FDA-approved as naltrexone-bupropion combination for weight loss, though both uses require careful screening for absolute contraindications including seizure disorders, eating disorders, and uncontrolled hypertension. 1, 2, 3

Off-Label Use for ADHD

Evidence for Efficacy

• Low-quality evidence demonstrates that bupropion decreases ADHD symptom severity (standardized mean difference -0.50) and increases the proportion of patients achieving clinical improvement (50% increase versus placebo) in adults with ADHD. 3
• The evidence base consists of small studies (6 RCTs, 438 total participants) with 6-10 week treatment durations, limiting confidence in long-term outcomes. 3
• Bupropion may be particularly beneficial for patients with comorbid depression and ADHD, addressing both conditions simultaneously through its norepinephrine and dopamine reuptake inhibition. 4, 5

Dosing for ADHD

• Start with 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) if tolerated. 1
• Maximum dose should not exceed 450 mg per day to maintain seizure risk at 0.1%. 1, 2
• Allow 6-8 weeks at adequate dose before determining treatment response. 1

Critical Limitations

• The evidence for ADHD is characterized by poorly conducted trials, small sample sizes, and lack of long-term assessments, making it uncertain whether benefits persist beyond 10 weeks. 4, 3
• Bupropion is less effective than traditional stimulants for ADHD, making it a reasonable alternative only when stimulants are contraindicated or not tolerated. 4

FDA-Approved Use for Weight Loss (Naltrexone-Bupropion Combination)

Efficacy Evidence

• The naltrexone-bupropion ER combination is FDA-approved for obesity management, with clinical trials showing 5.8% mean weight loss at 1 year versus 2.2% with placebo, and 47.5% of patients achieving ≥5% weight loss. 6
• The combination works by bupropion activating pro-opiomelanocortin neurons while naltrexone blocks an inhibitory feedback loop that would otherwise limit bupropion's anorectic properties. 6

Dosing for Weight Management

• Titration schedule: Week 1: 8/90 mg once daily in morning; Week 2: 8/90 mg twice daily; Week 3: 16/180 mg morning + 8/90 mg evening; Week 4 onward: 16/180 mg twice daily (maintenance dose). 1
• The maintenance dose represents 32 mg naltrexone/360 mg bupropion daily. 1

Ideal Candidates

• Patients describing inadequate meal satiety are ideal candidates for this combination. 6
• Particularly appropriate for patients with diabetes and cardiometabolic disease who cannot receive stimulant-based weight loss medications, as the combination shows greater hemoglobin A1c reduction (0.9% vs 0.4% placebo) than expected for the degree of weight loss. 6

Absolute Contraindications (Apply to All Uses)

Seizure-Related Contraindications

• Any seizure disorder or conditions increasing seizure risk including severe head injury, arteriovenous malformation, CNS tumor, CNS infection, severe stroke, anorexia nervosa, bulimia, or abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. 2
• The seizure risk with bupropion at 300 mg/day is approximately 0.1% (1 in 1,000), but increases dose-dependently. 1, 2

Cardiovascular Contraindications

• Uncontrolled hypertension is an absolute contraindication, as bupropion can elevate blood pressure and heart rate. 1, 7
• Monitor blood pressure and heart rate periodically, especially during the first 12 weeks of treatment. 1

Drug Interaction Contraindications

• Current or recent (within 14 days) use of monoamine oxidase inhibitors (MAOIs). 1, 2
• For naltrexone-bupropion combination specifically: any current opioid use is absolutely contraindicated, as naltrexone will precipitate severe withdrawal. 1, 7

Special Population Contraindications

• All naltrexone-bupropion formulations are contraindicated in women who are or may become pregnant, and during breastfeeding. 8
• Bupropion monotherapy is also contraindicated during breastfeeding due to infant exposure through breast milk and case reports of seizures in breastfed infants. 8

Dose Adjustments for Organ Impairment

Hepatic Impairment

• Moderate to severe hepatic impairment: maximum dose 150 mg daily (one tablet). 1
• Mild hepatic impairment: reduce dose and/or frequency. 1

Renal Impairment

• Moderate to severe renal impairment (GFR <90 mL/min): reduce total daily dose by 50%. 1
• Avoid in end-stage renal disease. 1

Monitoring Requirements

Initial Monitoring (First 1-2 Weeks)

• Monitor for worsening depression, suicidal ideation, or behavioral changes, particularly in patients under 24 years of age, as the risk for suicide attempts is greatest during the first 1-2 months. 1, 2
• Assess for neuropsychiatric symptoms including agitation, anxiety, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, and akathisia. 2

Ongoing Monitoring

• Blood pressure and heart rate monitoring, especially during first 12 weeks. 1
• For naltrexone-bupropion: liver function tests every 3-6 months for long-term treatment. 7

Clinical Advantages Over Other Antidepressants

• Significantly lower rates of sexual dysfunction compared to SSRIs. 1
• Associated with minimal weight gain or even weight loss, unlike many other antidepressants. 1
• Lower rates of sedation than SSRIs. 1
• May be particularly beneficial for patients with depression characterized by low energy, apathy, or hypersomnia due to activating properties. 1

Common Pitfalls to Avoid

Timing of Doses

• Administer first dose in morning and second dose before 3 PM to minimize insomnia risk. 1
• The activating properties make late-day dosing problematic for sleep. 1

Formulation Switching

• Monitor patients closely when switching between brand and generic formulations or between SR and XL formulations, as historical bioequivalence issues may lead to loss of antidepressant effect. 1

Combination with Other Bupropion Products

• Do not combine with other bupropion-containing products (Zyban for smoking cessation, Wellbutrin SR/IR, Aplenzin) as this increases seizure risk. 2

Alcohol and Substance Use

• Minimize or avoid alcohol use, as excessive alcohol or abrupt discontinuation increases seizure risk. 2
• Bupropion treatment may lead to decreased alcohol tolerance. 2