What non‑serotonergic antidepressant can be used safely with linezolid?

Alternate Antidepressant with Linezolid

Bupropion is the preferred non-serotonergic antidepressant that can be used with linezolid, though it requires careful monitoring for hypertensive reactions due to linezolid's monoamine oxidase inhibitor properties. 1, 2

Understanding the Interaction Risk

Linezolid acts as a reversible, nonselective monoamine oxidase (MAO) inhibitor, which creates serious interaction risks with serotonergic antidepressants. 3 The American Thoracic Society explicitly recommends that linezolid should generally not be administered to patients taking serotonergic agents such as SSRIs or SNRIs because the combination can lead to serotonin syndrome or neuroleptic malignant syndrome-like reactions. 3

Bupropion as the Preferred Alternative

Bupropion is mechanistically distinct from serotonergic antidepressants—it inhibits the reuptake of dopamine and norepinephrine rather than serotonin. 2 This makes it the most suitable antidepressant option when linezolid is required. However, the combination is not without risk:

• The British Thoracic Society guidelines note that linezolid should be avoided with drugs that inhibit monoamine oxidases A or B, which technically includes bupropion due to potential interactions. 2
• The primary concern is hypertensive reactions rather than serotonin syndrome, as both drugs affect catecholamine pathways. 2
• The FDA label for bupropion includes specific warnings about use with reversible MAOIs such as linezolid. 4

Clinical Management When Using Bupropion with Linezolid

If bupropion must be continued with linezolid, implement the following monitoring protocol:

• Obtain baseline vital signs, particularly blood pressure, before initiating the combination. 1
• Monitor blood pressure closely for hypertensive reactions, especially during the first 24-48 hours. 2, 5
• Watch for signs of autonomic hyperactivity including tachycardia, diaphoresis, and agitation. 2, 5
• Patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, bipolar depression, schizophrenia, or acute confusional states are at higher risk and should avoid this combination. 1, 2

Alternative Approach: Discontinuing Antidepressants

The safest approach is to discontinue the antidepressant entirely during linezolid therapy if clinically feasible. 6 When this strategy is chosen:

• SSRIs should be discontinued before starting linezolid, with monitoring for serotonin syndrome even after discontinuation. 6
• The risk of serotonin syndrome can persist due to the long half-lives of some SSRIs and their metabolites. 6
• Bupropion can be discontinued without the same washout concerns as SSRIs, though abrupt discontinuation should be avoided per standard practice. 4

Evidence on Actual Risk with Serotonergic Agents

While guidelines strongly warn against combining linezolid with serotonergic antidepressants, recent research suggests the actual risk may be lower than previously thought:

• A 2022 population-based study of 1,134 older patients found serotonin syndrome occurred in fewer than 6 patients (<0.5%), with no significant increase in risk among those taking antidepressants concurrently. 7
• A retrospective Mayo Clinic review of 72 patients receiving linezolid and SSRIs found only 2 patients (3%) had high probability of serotonin syndrome, both of which resolved rapidly upon discontinuation. 8
• However, case reports document serious adverse reactions including cardiopulmonary arrest in patients receiving linezolid with sertraline. 6

Despite these reassuring data, guidelines appropriately maintain conservative recommendations because serotonin syndrome, when it occurs, can be life-threatening with an 11% mortality rate in severe cases. 5

Practical Algorithm for Antidepressant Management

When linezolid is required in a patient on antidepressants:

1. First choice: Discontinue the antidepressant if the patient's psychiatric condition allows and linezolid duration is short (typically ≤28 days). 3

2. Second choice: Switch to bupropion if ongoing antidepressant therapy is essential, with close blood pressure monitoring. 2

3. Last resort: Continue SSRI/SNRI only if both the infection requiring linezolid and the psychiatric condition are life-threatening, with intensive monitoring for serotonin syndrome symptoms (confusion, myoclonus, hyperreflexia, fever, tachycardia, hypertension). 5, 8

Critical Monitoring Parameters

For any patient receiving linezolid, regardless of antidepressant status, monitor for:

• Mental status changes, agitation, or confusion (present in most serotonin syndrome cases). 5
• Muscle twitching (myoclonus), which occurs in 57% of serotonin syndrome cases. 5
• Hyperreflexia and clonus, which are highly specific findings. 5
• Autonomic instability: fever, tachycardia, hypertension, diaphoresis. 5
• Symptoms typically emerge within 24-48 hours of starting the combination. 5

If serotonin syndrome is suspected, immediately discontinue all serotonergic agents and linezolid, provide supportive care with benzodiazepines and IV fluids, and consider cyproheptadine as an antidote. 5, 6

Common Pitfalls to Avoid

• Do not overlook other serotonergic medications beyond antidepressants, including tramadol, methadone, fentanyl, dextromethorphan, ondansetron, and St. John's Wort. 1, 5
• Do not assume a 14-day washout period is always necessary for SSRIs before starting linezolid—clinical judgment based on infection severity is required. 8
• Do not use physical restraints if serotonin syndrome develops, as this worsens muscle contractions and increases mortality risk. 5
• Do not forget that linezolid itself carries significant toxicity risks (myelosuppression, peripheral neuropathy, optic neuritis) requiring weekly CBC monitoring and monthly neurological assessments. 3, 1