Wellbutrin XL | Pharmacology Mentor

Generic Name

Bupropion hydrochloride extended‑release (Wellbutrin XL)

Mechanism

Bupropion exerts its antidepressant effect by:
• Inhibiting dopamine (DAT) and norepinephrine (NET) transporters – increasing synaptic levels of these monoamines in key brain regions (prefrontal cortex, limbic system).
• Weak non‑competitive inhibition of monoamine oxidase B (MAO‑B) at therapeutic doses, which may modestly augment dopamine tone.
• The drug has minimal serotonergic activity, which accounts for its lower risk of sexual dysfunction and weight gain compared with SSRIs/SNRIs.

Pharmacokinetics

Absorption – Oral E‑release tablets: peak plasma concentration (Tmax) at ~4 h; absolute bioavailability ~30 %.
Metabolism – Extensive hepatic metabolism via CYP2B6 to hydroxybupropion (the active metabolite) and other minor pathways (CYP2C19, CYP2D6).
Elimination – Renally excreted (~70 % as metabolites); half‑life ~22 h for the parent drug, ~26 h for hydroxybupropion.
Drug‑drug interactions – CYP2B6 inhibitors (e.g., rifampin) increase plasma concentrations; C‑inhibitors (nitrendipine) also raise levels.
Population variability – Genotype‑dependent: CYP2B6 poor metabolizers can experience higher plasma levels and increased seizure risk.

Indications

Major depressive disorder (MDD) – adult and pediatric (≥18 yrs).
Seasonal affective disorder (SAD) – adjunct or monotherapy.
Smoking cessation – off‑label; bupropion SR/XL reduces withdrawal symptoms.
Off‑label: bipolar depression (at low doses, cautious use), attention‑deficit/hyperactivity disorder (ADHD) in select cases.

Contraindications

Seizure disorders – generalized tonic‑clonic, myoclonic, or absence seizures; recent seizures.
Rapid‑weight loss or eating disorders – anorexia nervosa, bulimia (↑ seizure risk).
Concurrent MAO‑I therapy – or within 14 days of discontinuation (↑BP, serotonin syndrome).
Pimozide, haloperidol, or other QT‑prolonging agents – risk of torsades de pointes.
Hypertensive crisis – uncontrolled hypertension.
Pregnancy category C – avoid if fetal testing is pending.

_Warning_: Monitor for hypertension, insomnia, agitation, and sudden changes in mood (mania, suicidal ideation).

Dosing

1. Initial dose – 150 mg once daily (usually taken at bedtime).
2. Titration – Increase by 150 mg increments after 3–5 days once tolerated.
3. Target dose – 300 mg daily (150 mg BID is an alternative).
4. Max dose – 400 mg/day (or 200 mg BID, extended‑release).
5. Re‑titration – Avoid abrupt discontinuation; taper by 150 mg every 3–5 days.

Take precautions: Avoid crushing or chewing the XL tablet; it could result in dose dumping and seizures.

Adverse Effects

Common (≥5 %)
• Dry mouth
• Insomnia
• Tremor, tension, agitation
• Weight loss or decreased appetite
• Hypertension (mild to moderate)
• Headache, nausea, constipation

Serious (<1 %)
• Seizures – incidence 0.8 % at 300 mg/day; increased in high‑risk patients.
• QTc prolongation – monitor with ECG if combined with other QT‑extending drugs.
• Acute psychosis or mania—rare but documented.
• Severe allergic dermatitis (rare).

Monitoring

Parameter	Frequency	Rationale
Blood pressure & pulse	Baseline, then every 2–4 weeks until stable	Hypertensive effect
Weight	Every 4–6 weeks	Weight loss is therapeutic and may warrant dose adjustment
Seizure history	At each visit	Identify new seizures, increase monitoring
Electrolytes/renal function	Baseline, then every 1–2 months	Metabolite excretion, fluid balance
ECG (if QT‑prolonging concomitants)	Baseline, then as indicated	Detect QTc prolongation risk
Mood/behavior scale (e.g., PHQ‑9)	Every 4–6 weeks	Evaluate antidepressant response and emergent mania

Clinical Pearls

Extended‑release design provides smoother plasma concentration, reducing the peak‑induced insomnia seen with SR formulations.
CYP2B6 polymorphism: Poor metabolizers get higher plasma levels → consider genetic testing or lower starting dose (~100 mg).
Smoking cessation synergy: Adding bupropion to nicotine replacement can enhance quit rates; initiate at least 5 days before quitting.
Pregnancy: If pregnancy is confirmed unexpectedly, discontinue bupropion swiftly and switch to a first‑line SSRI with a more favorable safety profile.
Dose‑splitting: While the XL tablet should not be split, the 300‑mg dose can be achieved by two 150‑mg tablets if the XL formulation is unavailable.
Adverse effect mitigation: Taking the dose at bedtime reduces insomnia; chewing gum or sipping water can help with dry mouth.
Seizure threshold: In patients with a history of seizures, start at 75 mg to evaluate tolerance before titration.

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• Key Takeaway: *Wellbutrin XL* offers a unique antidepressant profile with dopaminergic/noradrenergic action, minimal serotonergic side effects, and an extended‑release formulation that improves tolerability. A thorough patient history, dose titration, and vigilant monitoring are critical for optimal therapeutic outcomes.