What is Bupropion
Bupropion is an aminoketone antidepressant that works primarily through norepinephrine and dopamine reuptake inhibition, approved for major depressive disorder, seasonal affective disorder, and smoking cessation. 1
Mechanism of Action
Bupropion's exact mechanism remains incompletely understood, but it is presumed to work through noradrenergic and/or dopaminergic pathways 1. The drug is a relatively weak inhibitor of neuronal uptake of norepinephrine and dopamine, and notably does not inhibit monoamine oxidase or serotonin reuptake 1. This distinguishes it from most other antidepressants and accounts for its unique side effect profile 2.
The drug is extensively metabolized to three active metabolites: hydroxybupropion (formed via CYP2B6-mediated hydroxylation), threohydrobupropion, and erythrohydrobupropion 1. Hydroxybupropion reaches plasma concentrations approximately 7 times higher than the parent drug and has an AUC 13 times that of bupropion at steady state 1.
Approved Indications
Major Depressive Disorder
- Starting dose: 150 mg once daily 1
- Target dose: 300 mg once daily 1
- After 4 days, may increase to 300 mg once daily 1
- Maximum dose: 450 mg per day 1
Seasonal Affective Disorder
- Initiate treatment in autumn prior to onset of seasonal symptoms 1
- Starting dose: 150 mg once daily 1
- Target dose: 300 mg once daily 1
- After one week, may increase to 300 mg once daily 1
- Continue through winter season 1
Smoking Cessation
- Initiate dosing 1-2 weeks prior to quit date 3
- Days 1-3: 150 mg orally once daily 3
- Day 4 through 12 weeks: 150 mg orally twice daily if tolerated 3
- Maximum: 300 mg per day 3
- Duration: 7-12 weeks, may extend to 6 months-1 year for continued cessation 3
Dosing Regimens by Formulation
Bupropion is available in three formulations, all bioequivalent for systemic exposure 2:
- Immediate-release (IR): Three times daily dosing 2
- Sustained-release (SR): Twice daily dosing 2
- Extended-release (XL): Once daily dosing 2
The extended-release formulation reaches peak plasma concentrations at approximately 5 hours, with steady-state achieved within 8 days 1. The elimination half-life is 21 (±9) hours 1.
Contraindications
Absolute Contraindications
- Seizure disorder (current or history) 1, 3
- Current or prior bulimia or anorexia nervosa 1, 3
- Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs 1, 3
- MAO inhibitor use within 14 days 1
- Known hypersensitivity to bupropion or tablet ingredients 1
Special Population Contraindications
- Brain metastases or stroke due to seizure risk 3
- Concurrent tamoxifen use (drug interaction) 3
- Closed-angle glaucoma 3
Dose Adjustments Required
- Moderate to severe hepatic impairment: 150 mg every other day 1
- Mild hepatic impairment: Consider reducing dose and/or frequency 1
- Renal impairment: Consider reducing dose and/or frequency 1
Common Adverse Effects
Most Frequent (≥5% incidence, ≥2× placebo)
The following adverse effects occur commonly 1:
- Dry mouth
- Nausea
- Insomnia
- Dizziness
- Pharyngitis
- Abdominal pain
- Agitation
- Anxiety
- Tremor
- Palpitation
- Sweating
- Tinnitus
- Myalgia
- Anorexia
- Urinary frequency
- Rash
Dose-Related Effects
Dry mouth and insomnia are dose-related and rarely cause discontinuation 3. In clinical practice settings, medication discontinuation due to adverse effects occurred in 25.9% of patients on 150 mg/day and 31.1% on 300 mg/day 3.
Seizure Risk
Bupropion carries a dose-dependent seizure risk of approximately 1/1000 when maintained at ≤450 mg/day 3. Risk factors include:
- Any prior seizure history 3
- Structural brain lesions from stroke, tumor, operation, or trauma 3
- Alcohol abuse 3
- Concomitant medications that lower seizure threshold 3
The NCCN guidelines specifically note that bupropion reduces seizure threshold and should be avoided in patients with brain metastases 3.
Neuropsychiatric Effects
Although uncommon, providers must monitor for development or worsening of serious neuropsychiatric issues including depression, suicidal ideation/behavior, hostility, agitation, and anxiety 3. The FDA issued a black box warning regarding increased risk of suicidal thinking and behavior in children, adolescents, and young adults 1.
However, the large EAGLES trial (n=8,144) found that neuropsychiatric adverse event rates with bupropion were not significantly increased relative to nicotine patches or placebo in patients with or without psychiatric disorders 3.
Cardiovascular Effects
Bupropion can increase blood pressure 1. The USPSTF review found no significant difference in serious cardiovascular adverse events or major cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke) with bupropion compared to placebo 3. Blood pressure should be monitored before and periodically during treatment 1.
Advantages Over Other Antidepressants
Bupropion demonstrates minimal sexual dysfunction, lower rates of weight gain, and less somnolence compared to SSRIs and other antidepressants 2, 4, 5. It causes fewer anticholinergic, orthostatic, and cardiac conduction side effects than tricyclic antidepressants 2.
Clinical Efficacy
Bupropion demonstrates efficacy comparable to SSRIs and other second-generation antidepressants for major depressive disorder 2, 4. For smoking cessation, the EAGLES trial showed superior abstinence rates compared to placebo (OR 2.07; 95% CI 1.75-2.45), with efficacy similar to nicotine patch but less than varenicline 3.