Bupropion (Wellbutrin)
NDRI • Last reviewed 2025-09-23
General information
Bupropion is an aminoketone antidepressant approved for major depressive disorder, seasonal affective disorder prevention, and smoking cessation (as bupropion SR under the brand Zyban). Although not an antipsychotic, it is listed as an adjunctive medication in PsychMed due to frequent use with mood stabilizers and antipsychotics to manage depressive symptoms or mitigate antipsychotic-induced weight gain and sexual dysfunction.
Immediate-release (IR), sustained-release (SR), and extended-release (XL) tablets are available in strengths ranging from 75 mg to 450 mg. IR dosing typically starts at 100 mg twice daily with a maximum of 450 mg/day divided. SR dosing begins at 150 mg once daily, increasing to 150 mg twice daily. XL formulations start at 150 mg once daily, increasing to 300 mg once daily and up to 450 mg daily for MDD if needed.
Bupropion inhibits norepinephrine and dopamine reuptake with minimal direct serotonergic effects. It antagonizes nicotinic acetylcholine receptors, underpinning smoking cessation efficacy. Because it lacks significant serotonergic activity, it carries a low risk of sexual dysfunction and weight gain relative to SSRIs.
The medication is extensively metabolized by CYP2B6 to active metabolites (hydroxybupropion, threohydrobupropion, erythrohydrobupropion) which have longer half-lives (20-37 hours) than the parent (21 hours). Peak levels occur within 2 hours (IR), 3 hours (SR), and 5 hours (XL).
Dosing & administration
MDD (IR): 100 mg twice daily for 3 days, then 100 mg three times daily; maximum single dose 150 mg, maximum daily 450 mg.
MDD (XL): start 150 mg once daily, increase to 300 mg once daily on day 4; may increase to 450 mg after several weeks if inadequate response.
Smoking cessation (SR): 150 mg once daily for 3 days, then 150 mg twice daily for 7-12 weeks; start 1-2 weeks before quit date.
Dose adjustments: reduce frequency in hepatic impairment or with concomitant CYP2B6 inhibitors; avoid single doses >150 mg to reduce seizure risk.
Key dosing considerations
- Seizure risk factors
- Limit total daily dose to 300 mg; avoid in active seizure disorder.
- Hepatic impairment
- Moderate to severe: do not exceed 150 mg/day (SR/XL).
- Renal impairment
- Use lower or less frequent dosing (e.g., 150 mg every other day) and monitor metabolite accumulation.
- Pediatrics
- Not FDA-approved for pediatric depression; monitor closely if used off-label.
Mechanism of action
Bupropion inhibits norepinephrine and dopamine transporters (NET, DAT) increasing synaptic concentrations in mesolimbic and prefrontal circuits, improving mood and energy. It also acts as a noncompetitive antagonist at nicotinic acetylcholine receptors (alpha4beta2, alpha3beta4), reducing craving and withdrawal in smokers.
Unlike SSRIs, bupropion has minimal impact on serotonin receptors, which explains the favorable sexual side effect profile and relative absence of serotonin syndrome but limits usefulness for anxiety disorders.
- DAT inhibition Ki ~560 nM; NET inhibition Ki ~1,400 nM (metabolites more potent).
- Nicotinic receptor antagonism diminishes nicotine reinforcement.
- Not a monoamine oxidase inhibitor; combination with MAOIs contraindicated due to hypertension risk.
Metabolism & pharmacokinetics
Bupropion absorption is extensive with peak concentrations dependent on formulation (IR 2 h, SR 3 h, XL 5 h). Bioavailability is reduced by first-pass metabolism but not precisely quantified.
CYP2B6 is the primary metabolic pathway; hydroxybupropion exposure is 10-fold greater than parent drug and contributes substantially to clinical effect. Genetic polymorphisms (CYP2B6 poor metabolizers) result in higher bupropion and lower metabolite concentrations.
Drug interactions
MAOIs are contraindicated due to hypertensive reactions; allow 14-day washout.
Strong CYP2B6 inhibitors (ticlopidine, clopidogrel) increase bupropion levels and reduce metabolites; adjust dose or monitor for adverse effects.
Bupropion inhibits CYP2D6, increasing concentrations of drugs such as venlafaxine, duloxetine, antipsychotics, and beta-blockers.
| Mechanism | Agents / factors | Management |
|---|---|---|
| CYP2B6 inhibition | Ticlopidine, clopidogrel | Consider reducing bupropion dose and monitor for adverse effects. |
| CYP2D6 inhibition | Metoprolol, venlafaxine, risperidone | Monitor for toxicity; dose reductions of substrates may be needed. |
| Lower seizure threshold | Antipsychotics, tramadol, systemic steroids | Avoid exceeding 300 mg/day; evaluate risks before coadministration. |
Monitoring & safety checks
Blood pressure
Baseline and periodically • Hypertension can occur, particularly with nicotine replacement.
Weight and appetite
Baseline and follow-up • Weight loss is common; monitor underweight patients.
Neuropsychiatric symptoms
Each visit • Assess for activation, agitation, suicidal ideation.
Counsel patients regarding seizure risk: avoid high single doses, excessive alcohol, or abrupt withdrawal from sedatives.
Extended-release tablets should not be crushed or chewed; the XL shell may appear in stool.
Discontinuation guidance
Taper over at least 1 week to minimize irritability or anxiety, although discontinuation syndrome is less common than with SSRIs.
If used for smoking cessation, continue therapy for 7-12 weeks; longer courses (up to 6 months) reduce relapse in some patients.
Special populations
Pregnancy: observational data suggest low teratogenic risk, but consider risk-benefit; neonatal monitoring for jitteriness is advised if exposure occurs late in pregnancy.
Hepatic impairment: in moderate to severe impairment (Child-Pugh 7-15), reduce dose or frequency to 150 mg every other day.
Renal impairment: metabolites accumulate; use lower frequency (e.g., 150 mg every other day) when eGFR <45 mL/min.
Common adverse effects
Most common: insomnia, dry mouth, nausea, tremor, anxiety, increased sweating.
Rare but serious: seizures (dose-related), angle-closure glaucoma, severe hypertension.
Less sexual dysfunction and weight gain compared with SSRIs.
References
- WELLBUTRIN XL (bupropion hydrochloride) prescribing information — DailyMed (2024)
- CANMAT task force recommendations for the management of seasonal affective disorder — Canadian Medical Association Journal (2019) DOI: 10.1503/cmaj.181573
- Bupropion for smoking cessation: a review of the evidence — Drugs (2016) DOI: 10.1007/s40265-016-0631-2
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.