What is bupropion?

What is Bupropion?

Bupropion is a norepinephrine and dopamine reuptake inhibitor that also blocks nicotinic acetylcholine receptors, FDA-approved for major depressive disorder, seasonal affective disorder, and smoking cessation. 1, 2

Mechanism of Action

Bupropion works through three distinct pathways that differentiate it from other antidepressants:

• Inhibits reuptake of norepinephrine and dopamine in the central nervous system, though it is a relatively weak inhibitor compared to other agents 2, 3
• Blocks nicotinic acetylcholine receptors, which contributes significantly to its smoking cessation efficacy 4, 1, 5
• Does NOT inhibit serotonin reuptake or monoamine oxidase, making it mechanistically distinct from SSRIs, SNRIs, and MAOIs 2, 3

The exact mechanism by which these actions produce antidepressant effects remains unknown, but the noradrenergic and dopaminergic activity is presumed to be responsible 2.

FDA-Approved Indications

Bupropion has three regulatory approvals:

• Major depressive disorder (all formulations) 1, 2
• Seasonal affective disorder (extended-release formulations) 1
• Smoking cessation (sustained-release formulation marketed as Zyban) 4, 1

Available Formulations

Three oral formulations exist, all bioequivalent in terms of total systemic exposure to bupropion 3:

• Immediate-release (IR): Administered three times daily, rarely used in modern practice 3
• Sustained-release (SR): Administered twice daily (e.g., 150 mg twice daily for 300 mg total) 4, 1, 3
• Extended-release (XL): Administered once daily (e.g., 300 mg once daily) 1, 3

The SR formulation uses a wax-matrix vehicle for slow release, with peak plasma concentrations occurring around 3 hours post-dose 6. The XL formulation reaches peak concentrations at approximately 5 hours 2.

Clinical Efficacy

Depression Treatment

• Remission rates of 42-49% in major depressive disorder, equivalent to SSRIs and tricyclic antidepressants 1, 3
• Particularly beneficial for patients with low energy, apathy, or hypersomnia due to its activating dopaminergic properties 1, 6
• May be especially effective in patients with comorbid depression and smoking, addressing both conditions simultaneously 4, 1

Smoking Cessation

• Increases 12-month abstinence rates by 9-10 percentage points compared to placebo (approximately 19% quit rate versus 11% with placebo) 4, 6
• Relative risk of 1.62 (95% CI, 1.49-1.76) for successful cessation based on a 2014 Cochrane review of 44 trials 4, 1
• In the EAGLES trial (n=8,144), bupropion achieved superior abstinence versus placebo (OR 2.07; 95% CI, 1.75-2.45), with efficacy similar to nicotine patch but less than varenicline 4, 1

Dosing Protocols

For Major Depressive Disorder

• SR formulation: Start 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) 1, 6
• XL formulation: Start 150 mg once daily, increase to 300 mg once daily as needed 1, 6
• Maximum dose: 400 mg/day for SR; 450 mg/day for XL 1, 6

For Smoking Cessation

• Begin 1-2 weeks before the target quit date to establish therapeutic drug levels 4, 1, 6
• Titration: 150 mg once daily for days 1-3, then 150 mg twice daily (300 mg total) if tolerated 1, 6
• Maximum dose for smoking cessation is 300 mg/day to maintain seizure risk at 0.1% 1, 6
• Treatment duration: 7-12 weeks after the quit date, with formal efficacy assessment after this period 4, 1, 6

Timing Considerations

• First dose should be taken in the morning to leverage activating properties 1, 6
• Second dose (SR formulation) must be given before 3 PM to minimize insomnia risk 1, 6

Unique Advantages Over Other Antidepressants

Bupropion offers several distinct benefits:

• Significantly lower rates of sexual dysfunction (approximately 8%) compared to SSRIs like fluoxetine or sertraline, making it the antidepressant with the least sexual side effects 1, 3
• Associated with minimal weight gain or even weight loss, unlike most other antidepressants 4, 1, 3
• Lower rates of sedation compared to SSRIs 1, 3
• Minimal anticholinergic effects, making it better tolerated in elderly patients compared to tricyclic antidepressants 6, 7

Critical Safety Considerations

Seizure Risk

The most important safety concern with bupropion is dose-dependent seizure risk:

• At recommended doses (≤300 mg/day for smoking cessation, ≤450 mg/day for depression), seizure risk is approximately 0.1% (1 in 1,000) 4, 1, 6, 7
• Risk increases markedly above maximum doses 1, 6

Absolute Contraindications

Bupropion must NOT be used in patients with:

• Seizure disorders or any condition predisposing to seizures (prior head trauma, brain tumor, stroke, brain metastases) 4, 1, 6
• Current or recent MAOI use (within 14 days of discontinuation) 1, 6
• Eating disorders (bulimia nervosa, anorexia nervosa) due to increased seizure risk 1, 6
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs due to markedly elevated seizure risk 1, 6, 8
• Uncontrolled hypertension (particularly for naltrexone-bupropion combinations) 4, 1, 6

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 greatest risk during the first 1-2 months of therapy 1, 6

Common Side Effects

The most frequently reported adverse effects include:

• Dry mouth (most common) 4, 7
• Disturbed sleep/insomnia 4, 1
• Headaches 4, 1
• Nausea 4
• Agitation or behavioral activation due to dopaminergic properties 1, 6

Special Population Considerations

Renal Impairment

• Moderate to severe renal impairment (GFR <90 mL/min): Reduce total daily dose by 50% because bupropion and its metabolites are cleared renally 1, 6
• End-stage renal disease: Avoid bupropion entirely as hemodialysis does not effectively clear active metabolites 6

Hepatic Impairment

• Moderate to severe hepatic impairment: Maximum dose 150 mg daily 1, 6
• Mild hepatic impairment: Consider dose reduction and/or decreased frequency 6

Elderly Patients

• Start at approximately 50% of standard adult doses (e.g., 37.5 mg once daily, increasing by 37.5 mg every 3 days as tolerated) 1, 6
• Bupropion is considered a preferred antidepressant for older adults due to minimal anticholinergic effects 6

Drug Interactions

Critical Interactions

• Tamoxifen: Bupropion inhibits CYP2D6 and should not be combined with tamoxifen, as it may interfere with tamoxifen metabolism 1, 6
• Naltrexone-bupropion combination products are absolutely contraindicated with any opioid therapy (including buprenorphine/naloxone) because naltrexone will precipitate severe opioid withdrawal 6

Cardiovascular Monitoring

• Bupropion can elevate blood pressure and heart rate, requiring baseline assessment and periodic monitoring, especially during the first 12 weeks 4, 1, 6

Combination Therapy and Augmentation

Augmenting SSRIs

• When SSRI monotherapy fails after 6-8 weeks, adding bupropion is superior to other augmentation strategies 6
• In the STAR*D trial, augmenting citalopram with bupropion achieved 30.3% remission rates with significantly lower discontinuation rates (12.5%) compared to buspirone augmentation (20.6%, P<0.001) 6

Combination with Nicotine Replacement Therapy

• Bupropion plus NRT shows the highest abstinence rates for smoking cessation (35.5% at 12 months versus 30.3% with bupropion alone), though the difference is not statistically significant 4, 6

Timeline for Clinical Effect

Depression

• Full antidepressant effects typically emerge 6-8 weeks after achieving therapeutic dosing 1, 6
• Early improvement in energy levels may occur within the first few weeks, faster than with SSRIs 6
• If no adequate response by 6-8 weeks at therapeutic doses, modify treatment approach (increase dose, switch agents, or add augmentation) 1, 6

Smoking Cessation

• Nicotine withdrawal symptoms typically peak within 1-2 weeks of quitting and then subside 6
• Formal efficacy assessment should occur after 7-12 weeks of treatment 4, 1, 6

Metabolites and Pharmacokinetics

• Bupropion is extensively metabolized to three active metabolites: hydroxybupropion, threohydrobupropion, and erythrohydrobupropion 2, 3
• The (2S,3S)-hydroxybupropion isomer is more potent than bupropion itself at inhibiting norepinephrine and dopamine reuptake and antagonizing α4β2 nicotinic receptors 5, 9
• Mean elimination half-life is 21 hours (±9 hours), with steady-state plasma concentrations reached within 8 days 2