Does bupropion at therapeutic doses cause QTc prolongation or other ECG abnormalities, particularly in patients with baseline risk factors such as congenital long QT syndrome, electrolyte disturbances, concomitant QT‑prolonging drugs, severe cardiac disease, or renal/hepatic impairment?

Bupropion and QTc Abnormalities

Bupropion causes QTc prolongation primarily in overdose situations, not at therapeutic doses, and this effect may be artifactually exaggerated by the tachycardia-induced overcorrection inherent in the Bazett formula. 1, 2, 3, 4

QTc Effects at Therapeutic Doses

At therapeutic doses (≤450 mg daily), bupropion does not cause clinically significant QTc prolongation. 3, 5

• A cross-sectional study of 487 subjects found no difference in QTc between patients taking citalopram, sertraline, bupropion, or tricyclic antidepressants at therapeutic doses. 5
• No dose-dependent relationship was detected between bupropion and QTc prolongation within the therapeutic range. 5
• The risk of adverse cardiovascular effects from bupropion at therapeutic doses appears minimal. 3, 5

QTc Effects in Overdose

In overdose situations (typically >3 grams), bupropion causes QTc prolongation through I(Kr) potassium channel blockade, with a reported IC50 of 34 μM. 2, 3

• A prospective study of 59 bupropion overdose cases found that 76% (95% CI 50-93%) had QTc >440 msec, with mean QTc of 461 ± 34 msec. 4
• However, the uncorrected QT interval did not differ from controls, suggesting that the prolonged QTc may represent overcorrection due to bupropion-induced tachycardia (present in 76% of overdose cases) rather than true cardiac toxicity. 4
• A case report documented a 14-year-old who ingested 15 grams of extended-release bupropion, developing status epilepticus, prolonged QT, and deterioration to pulseless ventricular tachycardia requiring 5 cardioversions and 1 defibrillation. 1

Unique Cardiac Electrophysiological Profile

Bupropion causes QRS widening through a novel mechanism: inhibition of gap junction intercellular communication, not sodium channel blockade. 2

• Unlike class I antiarrhythmics, bupropion does not block cardiac sodium channels (I(Na)) but instead reduces cardiac intercellular coupling. 2
• Bupropion mimics the effects of gap junction inhibitors (glycyrrhetinic acid and heptanol), causing reductions in MAP amplitude and phase 0 dV/dt. 2
• This mechanism explains the QRS widening observed in overdose without the typical sodium channel blockade seen with other antidepressants. 2

Risk Factors Requiring Heightened Monitoring

Patients with baseline risk factors for QTc prolongation should be monitored more carefully, though therapeutic-dose bupropion remains low-risk even in these populations. 6

High-Risk Baseline Conditions:

• Congenital long QT syndrome – Bupropion should be avoided entirely in these patients, as any QTc-prolonging medication is potentially harmful. 6
• Baseline QTc >500 ms – Represents absolute contraindication to initiating bupropion. 6
• Electrolyte disturbances – Hypokalemia (<4.5 mEq/L), hypomagnesemia (<1.7 mg/dL), or hypocalcemia (<4.65 mg/dL) exponentially increase arrhythmia risk. 6
• Concurrent QT-prolonging medications – Combining multiple QTc-prolonging agents creates exponentially increased (not simply additive) risk. 7, 6
• Female gender and age >65 years – These patients have approximately two-fold higher incidence of drug-induced torsades de pointes. 7, 6
• Structural heart disease or heart failure – Requires extreme caution with any medication that affects cardiac conduction. 7
• Bradycardia or conduction abnormalities – Significantly increases vulnerability to drug-induced arrhythmias. 7, 6

Pre-Treatment and Monitoring Requirements

For Patients with ANY Risk Factors:

Obtain baseline ECG before initiating bupropion in patients with cardiac risk factors, and correct all electrolyte abnormalities immediately. 7, 6

• Maintain potassium >4.5 mEq/L (not just >4.0 mEq/L). 7, 6
• Normalize magnesium levels before starting therapy. 7, 6
• Review and discontinue other QT-prolonging medications when possible. 7, 6
• Document absence of congenital long QT syndrome (no personal or family history of unexplained syncope or sudden death). 7

During Treatment:

• Repeat ECG 7 days after initiation or any dose change in high-risk patients. 7
• Discontinue bupropion immediately if QTc exceeds 500 ms or increases >60 ms from baseline. 7, 6
• Monitor continuously for symptoms of arrhythmia (palpitations, syncope, dizziness). 7

Management of Bupropion Overdose with QTc Prolongation

Lidocaine bolus and infusion can shorten QTc interval in bupropion overdose, unlike traditional QT-prolonging antiarrhythmics such as amiodarone which should be avoided. 1

Immediate Management:

• Supportive care remains the cornerstone of treatment. 1
• Administer lidocaine bolus followed by continuous infusion for QTc prolongation and ventricular arrhythmias. 1
• Avoid amiodarone and other QT-prolonging antiarrhythmics. 1
• Correct electrolyte abnormalities immediately: potassium >4.5 mEq/L, normalize magnesium. 6
• Administer 2 grams IV magnesium sulfate for torsades de pointes, regardless of serum magnesium level. 7

For Refractory Cases:

• Temporary transvenous pacing is highly effective for recurrent torsades de pointes after electrolyte repletion. 7
• Isoproterenol titrated to heart rate >90 bpm if pacing unavailable. 7
• VA ECMO may be required in severe cases with hemodynamic instability. 1
• Non-synchronized defibrillation for sustained ventricular arrhythmias with hemodynamic collapse. 7

Common Pitfalls and Caveats

The most critical pitfall is misinterpreting QTc prolongation in the setting of bupropion-induced tachycardia. 4

• The Bazett formula overcorrects QTc when heart rate exceeds 100 bpm, which occurs in 76% of bupropion overdoses. 4
• Always examine the uncorrected QT interval alongside QTc—if uncorrected QT is normal, the prolonged QTc may be artifactual. 4
• Do not assume that monitoring alone makes bupropion safe in congenital long QT syndrome—avoidance is the only truly safe approach. 7
• Never combine multiple QT-prolonging medications with bupropion, as this creates exponentially increased risk rather than simply additive effects. 7, 6
• Nausea and vomiting from any cause lead to potassium and magnesium loss that prolongs QTc—correct electrolytes before attributing QTc changes solely to medication. 7

Clinical Decision Algorithm

For Patients WITHOUT Cardiac Risk Factors:

• Bupropion can be initiated at therapeutic doses without baseline ECG. 3, 5
• Standard monitoring for efficacy and side effects is sufficient. 3, 5

For Patients WITH Cardiac Risk Factors (but QTc <500 ms):

• Obtain baseline ECG and correct all electrolyte abnormalities before initiating. 7, 6
• Repeat ECG at 7 days after initiation. 7
• Discontinue if QTc >500 ms or increases >60 ms from baseline. 7, 6

For Patients with Baseline QTc >500 ms or Congenital Long QT Syndrome:

• Bupropion is contraindicated—choose an alternative antidepressant. 7, 6

In Overdose Situations:

• Supportive care with continuous cardiac monitoring. 1
• Lidocaine (not amiodarone) for QTc prolongation and ventricular arrhythmias. 1
• Correct electrolytes aggressively (K+ >4.5 mEq/L, normalize Mg++). 6
• Consider VA ECMO for refractory cases. 1