Psychosomatics 46:274-275, June 2005
© 2005 The Academy of Psychosomatic Medicine
Serotonin Syndrome Associated With Linezolid Treatment After Discontinuation of Fluoxetine
Nancy Morales, M.D., and
Heidi Vermette, M.D., UMass Memorial Medical Center, Worcester, Mass.
TO THE EDITOR: Serotonin syndrome is a hyperserotonergic state characterized by the triad of mental status changes, neurologic abnormalities, and autonomic instability.1 Medications with serotonergic activity, including selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, L-tryptophan, amphetamines, and lithium have the potential for causing this condition, especially when used in combination or taken as an overdose.2 Linezolid, an antibiotic of the oxazolidone family, is a reversible, nonselective MAOI used in the treatment of vancomycin-resistant enterococcus and methicillin-resistant staphylococcus aureus.3 Few people are aware about linezolid’s capacity to induce serotonin syndrome. Case reports of serotonin syndrome resulting from the interaction of linezolid and the SSRIs citalopram, sertraline, and paroxetine have recently been published.1,4,5,6 We present a case of suspected serotonin syndrome caused by the administration of linezolid 18 days after the discontinuation of fluoxetine. It presents the possibility of this antibiotic interacting with norfluoxetine (fluoxetine’s active metabolite), an interaction not previously recognized.
Case Report
Ms. A, a 39-year-old Caucasian patient with a history of major depression, two previous suicide attempts, and alcohol dependence was admitted to the hospital after being found unresponsive at home next to a bottle of cyclobenzaprine. Her medications before admission included disulfiram, fluoxetine, buspirone, cyclobenzaprine, and folate.
In the emergency room, she was given two doses of physostigmine for symptoms of anticholinergic syndrome (disorientation, tachycardia, sedation, and dry mucosa) presumed to have been caused by a cyclobenzaprine overdose. After receiving physostigmine, her mental status improved, and she was admitted for further management. Disulfiram, fluoxetine, buspirone, and cyclobenzaprine were held upon admission.
On day two of admission, the patient developed sedation, tachycardia, and intermittent agitation presumed to be due to alcohol withdrawal. She was subsequently transferred to the intensive care unit for closer monitoring. She received lorazepam for alcohol withdrawal and haloperidol for agitation. She was intubated on day five for respiratory depression thought to be due to either increased sputum from aspiration pneumonia or respiratory suppression from lorazepam. The patient was started on a regimen of vancomycin after the sputum cultures grew methicillin-resistant staphylococcus aureus. On day 13, she was extubated. Her mental status improved, and she was transferred to the general medical floor. On day 18 the antibiotic was changed from vancomycin to linezolid. After receiving two doses of linezolid, the patient’s mental status suddenly changed. She developed coarse tremors, diaphoresis, lethargy, bilateral lower extremity sustained clonus, mydriasis, agitation, sialorrhea, and autonomic instability. Her blood pressure was 140/90, her heart rate was 170, her respirations were 18, and her temperature was 98 °F.
Linezolid was discontinued, vancomycin was restarted, and Ms. A was transferred back to the intensive care unit with a differential diagnosis of benzodiazepine withdrawal, neuroleptic malignant syndrome, infection (i.e., sepsis, meningitis), and serotonin syndrome. Benzodiazepine withdrawal, neuroleptic malignant syndrome, and infectious causes were excluded by clinical and laboratory findings.
The toxicology service was consulted, and serotonin syndrome was determined to be the most likely diagnosis secondary to a drug interaction between linezolid and norfluoxetine. A regimen of cyproheptadine was started, and the mydriasis began to improve after 24 hours. The myoclonus and tachycardia began to improve after 48 hours. Unfortunately, the patient experienced respiratory depression requiring intubation, and she was subsequently transferred to another institution for further management.
Discussion
In this case, the diagnosis of serotonin syndrome was demonstrated by the onset of autonomic instability, neurologic symptoms, and alteration in mental status within 24 hours of the administration of linezolid. It is our opinion that the MAOI properties of linezolid combined with fluoxetine’s active metabolite, norfluoxetine, to cause a hyperserotonergic state leading to serotonin syndrome. It is important to note that fluoxetine is special among the SSRIs in that its long elimination half-life potentially creates a longer risk period for patients exposed to other serotonergic drugs.
In summary, it appears that linezolid has the potential to cause serotonin syndrome following the discontinuation of serotonergic agents with long half-lives. When switching from fluoxetine to an MAOI, a washout period of 5 weeks is recommended because of the long elimination half-life of fluoxetine’s active metabolite, norfluoxetine.7 Although further study is needed to determine the risks of interaction between linezolid and norfluoxetine, based on our experience, we would recommend waiting at least 5 weeks after discontinuation of fluoxetine before starting therapy with linezolid.
REFERENCES
- Lavery S, Ravi H, McDaniel WW, Pushkin YR: Linezolid and serotonin syndrome. Psychosomatics 2001; 42: 432–434
- Birmes P, Coppin D, Schmitt L, Lauque D: Serotonin syndrome: a brief review. CMAJ 2003; 168:1439–1442[Free Full Text]
- Zyvox (linezolid) package insert. Kalamazoo, Mich, Pharmacia and Upjohn, 2000
- Bernard L, Stem R, Lew D, Hoffmeyer P: Serotonin syndrome after concomitant treatment with linezolid and citalopram. Clin Infect Dis 2003; 36:1197[CrossRef][Medline]
- Hicks K, Huen A, Raad I: Myelosuppression and serotonin syndrome associated with concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow transplant recipients. Clin Infect Dis 2003; 37:e8–11
- Wigen CL, Goetz MB: Serotonin syndrome and linezolid. Clin Infect Dis 2002; 34:1651–1652[CrossRef][Medline]
- Monoamine oxidase inhibitors, in Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 7th edition. Edited by Sadock BJ, Sadock VA. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 2398–2407
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