Mechanism of Action and Effects of Wellbutrin (Bupropion)
Bupropion works primarily as a norepinephrine and dopamine reuptake inhibitor while also blocking nicotinic acetylcholinergic receptors, making it uniquely effective for depression and smoking cessation without the sexual dysfunction and weight gain common to other antidepressants. 1
Mechanism of Action
Primary Neurochemical Effects
- Bupropion inhibits the reuptake of norepinephrine and dopamine at presynaptic sites, though it is a relatively weak inhibitor compared to other antidepressants 2, 3
- The drug does NOT inhibit serotonin reuptake or monoamine oxidase, distinguishing it from SSRIs and MAOIs 2, 4
- Bupropion acts as an inhibitor of nicotinic acetylcholinergic receptors, which contributes to its smoking cessation efficacy 1
Metabolic Activation
- Bupropion undergoes hepatic metabolism via CYP2B6 to form hydroxybupropion, an active metabolite that reaches plasma concentrations approximately 7 times higher than the parent drug at steady state 2, 3
- Two additional active metabolites (threohydrobupropion and erythrohydrobupropion) are formed via reduction of the carbonyl group 2
- The elimination half-life is approximately 21 hours for bupropion and 20 hours for hydroxybupropion, allowing for once or twice daily dosing 2
Neuronal Effects
- Sustained bupropion treatment decreases norepinephrine neuron firing by 61-80% through enhanced activation of inhibitory alpha-2 adrenoceptors, suggesting the drug enhances norepinephrine release rather than simply blocking reuptake 5
- Bupropion increases serotonin neuron firing by 100% through a norepinephrine-dependent mechanism, despite having no direct serotonergic activity 5
- Dopamine neuron firing in the ventral tegmental area remains unaffected at therapeutic doses 5
Clinical Effects and Indications
FDA-Approved Uses
- Major depressive disorder: Bupropion demonstrates efficacy comparable to SSRIs and tricyclic antidepressants 1
- Smoking cessation: A 2014 Cochrane review of 44 trials showed a relative risk of 1.62 (95% CI, 1.49-1.76) for successful cessation 1
- Seasonal affective disorder 3
Comparative Efficacy
- For depression, bupropion is non-inferior to escitalopram and other SSRIs in achieving remission 6
- For smoking cessation, the EAGLES trial (n=8,144) showed bupropion achieved superior abstinence rates versus placebo (OR 2.07; 95% CI, 1.75-2.45), with efficacy similar to nicotine patch but less than varenicline 1
- Bupropion may be particularly beneficial for patients with comorbid depression who want to quit smoking, addressing both conditions simultaneously 1, 7
Onset of Action
- Antidepressant effects typically begin within 1-3 weeks of initiating treatment 8
- Mirtazapine has faster onset than bupropion, but bupropion's unique profile may make it preferable for specific patients 1
Adverse Effects Profile
Common Side Effects
- Disturbed sleep, dry mouth (13% of patients), headaches, and nausea are the most frequently reported 1, 8
- Bupropion is activating rather than sedating and can antagonize sedative effects of alcohol and benzodiazepines 8
- The drug is weight-neutral or promotes weight loss, unlike most antidepressants that cause weight gain 1, 9
Sexual Dysfunction
- Bupropion has significantly lower rates of sexual dysfunction (approximately 8%) compared to SSRIs like fluoxetine or sertraline 1
- This makes it the antidepressant with the least sexual side effects 1
Serious Adverse Events
Seizure Risk
- Bupropion lowers the seizure threshold with a 0.1% seizure risk at recommended doses 1
- Avoid bupropion in patients with seizure disorders, brain metastases, eating disorders (bulimia/anorexia), or any elevated seizure risk 1, 7, 10
- The maximum dose should not exceed 450 mg/day to minimize seizure risk 10
Neuropsychiatric Effects
- While neuropsychiatric effects were initially a concern, recent systematic reviews show serious neuropsychiatric adverse events are rare with bupropion 1
- The EAGLES trial found no significant increase in neuropsychiatric events with bupropion versus nicotine patch or placebo 1
Cardiovascular Safety
- Meta-analyses show no elevated risk of serious cardiovascular effects with bupropion for smoking cessation 1
- Bupropion does not cause orthostatic hypotension, impaired cardiac conduction, or reduced myocardial contractility, unlike tricyclic antidepressants 8
Dosing Considerations
Standard Dosing
- For depression (SR formulation): Start 150 mg once daily for 3 days, then increase to 150 mg twice daily (300 mg total) 10
- For smoking cessation: 150 mg twice daily (300 mg total), beginning 1-2 weeks before quit date, for 7-12 weeks 7, 10
- Maximum dose: 450 mg/day for XL formulation, 400 mg/day for SR formulation 10
Special Populations
- For moderate to severe hepatic impairment: Do not exceed 150 mg daily 10
- For moderate to severe renal impairment (GFR <90 mL/min): Reduce total daily dose by half 10
- For older adults: Start with 37.5 mg every morning, increase by 37.5 mg every 3 days as tolerated, maximum 300 mg/day 10
Clinical Pearls and Contraindications
Absolute Contraindications
- Seizure disorders or conditions that increase seizure risk 1, 7
- Current or recent (within 14 days) MAOI use 10
- Eating disorders (bulimia nervosa, anorexia nervosa) due to increased seizure risk 10
- Abrupt discontinuation of alcohol or sedatives (increases seizure risk) 2
Drug Interactions
- Bupropion inhibits CYP2D6, raising concern for interactions with drugs metabolized by this pathway 3
- Avoid combining with tamoxifen, as bupropion may interfere with its metabolism 10
Optimal Patient Selection
- Choose bupropion for patients who cannot tolerate SSRI sexual side effects or weight gain 1, 6
- Ideal for smokers with depression who want to address both conditions 1, 7
- May be less likely to provoke mania than serotonergic antidepressants in bipolar depression 3
- Useful as augmentation therapy when SSRIs provide partial response, with evidence showing bupropion decreases depression severity more than buspirone when augmenting citalopram 7