Serotonin Syndrome Rare for Patients Treated With Linezolid and Antidepressants


Serotonin syndrome occurred in less than 0.5% of patients, while the number of serotonin syndrome cases was fewer in the antidepressant group.

Serotonin Syndrome Rare for Patients Treated With Linezolid and Antidepressants

Anthony D. Bai, MD

Serotonin syndrome remains extremely rare in patients treated with linezolid and antidepressants.

A team, led by Anthony D. Bai, MD, Division of Infectious Diseases, Department of Medicine, Queen’s University, identified the incidence of serotonin syndrome in patients treated with oral linezolid and how concomitant antidepressant treatment impacts that risk.


Linezolid is a synthetic oxazolidinone antibiotic with activity against resistant gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. However, linezolid can reversibly inhibit monoamine oxidase (MAO)

Linezolid might interact with certain antidepressants, increasing the risk of serotonin syndrome. However, there is not much data supporting warnings for patients treated with antidepressants to avoid linezolid.

Serotonin syndrome presents with a variety of manifestations, including hyperthermia, hypertension, tachycardia, agitation, tremor, myoclonus, hyperreflexia, muscle rigidity, flushed skin, and diaphoresis.

The US Food and Drug Administration (FDA) issued a warning against linezolid use in patients taking antidepressants in 2020.

The Review

In the population-based, retrospective cohort, the investigators examined linked administrative databases at ICES to identify data for 1135 outpatients aged 66 years and older in Ontario who were prescribed oral linezolid between October 1, 2014 and January 1, 2021, with a follow-up of 30 days.

The final analysis included 225 patients aged 66-69 years, 473 patients aged 70-79 years, and 436 patients at least 80 years, of which were prescribed linezolid. In addition, only 19% (n = 215) of the patients were taking antidepressants.

The investigators sought primary outcomes of clinically significant serotonin syndrome based on a physician diagnosis, Sternbach criteria, or the Hunter Serotonin Toxicity Criteria within 30 days of starting oral linezolid treatment. They also sought secondary outcomes of the altered mental status, hospitalization, or death within 30 days of starting linezolid treatment.

Serotonin syndrome occurred in less than 0.5% (n = 6) of patients, while the number of serotonin syndrome cases was fewer in the antidepressant group.

After conducting a propensity score-matched cohort, the adjusted risk difference for serotonin syndrome between the antidepressant group and the cohort who did not take antidepressants was -1.2% (95% CI, -2.9% to 0.5%).

The results also show similar rates of altered mental status, hospitalization, and death between the propensity score-matched groups.

“In this cohort study of older patients who were prescribed linezolid, serotonin syndrome occurred rarely,” the authors wrote. “Concurrent antidepressants did not significantly increase the risk of serotonin syndrome. These findings suggested that linezolid is likely safe for patients receiving antidepressants. Nevertheless, prescribers should remain vigilant for this potential drug interaction.”

The study, “Association of Linezolid With Risk of Serotonin Syndrome in Patients Receiving Antidepressants,” was published online in JAMA Network Open.

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