Why is bupropion (an antidepressant) contraindicated with linezolid (an antibiotic with monoamine oxidase inhibitor (MAOI) properties) despite bupropion's minimal effect on serotonin levels?

Bupropion and Linezolid: Contraindication Mechanism

Bupropion is contraindicated with linezolid because linezolid is a reversible monoamine oxidase inhibitor (MAOI) that can interact with bupropion to increase the risk of hypertensive reactions, despite bupropion's minimal effect on serotonin. 1

Mechanism of Interaction

• Bupropion inhibits the reuptake of dopamine and norepinephrine, and concomitant use with MAOIs like linezolid is contraindicated due to increased risk of hypertensive reactions 2
• Linezolid, while primarily an antibiotic, has MAOI properties that can lead to potentially dangerous drug interactions 3
• The interaction is primarily based on the MAOI properties of linezolid rather than serotonergic effects of bupropion 1, 2

Clinical Manifestations of the Interaction

• The combination can potentially cause hypertensive crisis, which presents with severe headache, increased blood pressure, and other cardiovascular symptoms 2
• Though less common with bupropion than with serotonergic antidepressants, there is still a risk of serotonin syndrome with symptoms including mental status changes, neuromuscular hyperactivity, and autonomic instability 1, 4
• Signs of toxicity may include restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness 2

Evidence from Guidelines and Research

• The British Thoracic Society guidelines explicitly state that linezolid should be avoided with other drugs that inhibit monoamine oxidases A or B 3
• FDA labeling for bupropion specifically contraindicates its use with MAOIs, requiring at least 14 days between discontinuation of an MAOI and initiation of bupropion 2
• The American Thoracic Society guidelines note that linezolid should generally not be administered to patients taking serotonergic agents due to potential for serious CNS reactions 3

Risk Factors and Monitoring

• Patients with uncontrolled hypertension, phaeochromocytoma, carcinoid tumor, thyrotoxicosis, bipolar depression, schizophrenia, or acute confusional states are at higher risk for adverse reactions 3
• Monitoring for signs of hypertensive reactions and serotonin syndrome should begin immediately after co-administration 1
• Recent research suggests that while serotonin syndrome with linezolid may be rare, clinicians should remain vigilant for this potential interaction 5

Management Recommendations

• Ideally, avoid the combination of bupropion and linezolid completely 3, 2
• If linezolid must be used in a patient on bupropion, consider discontinuing bupropion at least 14 days before starting linezolid 2
• If urgent antimicrobial treatment is needed, consider alternative antibiotics without MAOI properties 6
• If no alternatives exist and linezolid must be used, discontinue bupropion and monitor the patient closely for adverse reactions 6

Important Caveats

• The risk of interaction exists even if bupropion has minimal effects on serotonin, as the primary concern is the MAOI property of linezolid interacting with bupropion's effects on dopamine and norepinephrine 2
• The contraindication applies regardless of the indication for either medication 3
• Even though recent research suggests the risk may be lower than previously thought, the potential severity of adverse outcomes warrants caution 5