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Linezolid and Serotonin Syndrome

Received March 21, 2001; accepted March 29, 2001. From Eastern Virginia Medical School, Department of Psychiatry and Behavioral Sciences, 825 Fairfax Avenue, Norfolk, Virginia 23507. Address correspondence and reprint requests to Dr. Pushkin, Associate Professor of Clinical Psychiatry, Director Consultation & Liaison Psychiatry, EVMS; E-mail address: pushkiyr{at}evms.edu

Key Words: Linezolid • Serotonin Syndrome • MAO Inhibitors

Serotonin syndrome is a potentially severe adverse drug interaction characterized by the sudden onset of the triad of altered mental status, autonomic dysfunction, and neuromuscular abnormalities.¹ It can be a serious complication of treatment with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and other serotonergic medications.² Serotonin syndrome is idiosyncratic in nature. It has been reported in association with single-drug therapy, combination-drug therapy, single-drug overdose, polydrug overdose, and recreational drugs of abuse.³

Linezolid is a new antibiotic of the oxazolidinone class and is the only one that has progressed to clinical trials.⁴ Its major clinical indication is for the treatment of vancomycin-resistant enterococcus (VRE).⁵ Linezolid has been shown to be a relatively weak nonspecific reversible inhibitor of human monoamine oxidase.⁶ Linezolid has the potential for interaction with adrenergic, serotonergic, and dopaminergic agents. However, no demonstrated clinical evidence of adverse reactions as a result of monoamine oxidase inhibition has been reported.⁷ Coadministration of linezolid and serotonergic agents was not associated with serotonin syndrome in phase 1, 2 or 3 studies.⁸ The interactions of sertraline and other serotonin re-uptake inhibitors with linezolid have not been studied to date.⁸ This article reports a case of suspected serotonin syndrome caused by the interaction between linezolid and sertraline.

Case Report

Mr. S., a 45-year-old white male with a long history of probable schizoaffective disorder and three previous suicide attempts was admitted to the trauma service after an acute suicide attempt. The most recent attempt involved jumping out of a two-story building resulting in a T6-level spinal cord injury and paraplegia. The consultation-liaison psychiatry service was consulted on admission. Psychiatric consultation assessment revealed an acutely depressed patient complaining of depressive thought content as well as psychosis. Pharmacotherapy was initiated with sertraline and risperidone and titrated to 200 mg qd and 1 mg bid, respectively. Mr. S. subsequently underwent T4–T6 fixation and spent 2 months on the rehabilitation unit. When medically stable, he was transferred to the psychiatric ward, where his medications were adjusted. Bupropion up to the dosage of 75 mg bid was added owing to partial treatment response and trazodone 50 mg qhs was added for sleep disturbance. Mr. S. continued to exhibit refractory depressive symptoms after these medication adjustments. Therefore, lithium carbonate 300 mg bid was added.

Mr. S. developed a deep sacral decubitus ulcer and was transferred to the plastic surgery service. He underwent sacral flap closure with a bilateral gluteal myocutaneous flap. After surgery, his temperature and white blood cell count remained elevated for several days. Culture of serosanguinous drainage from his myocutaneous flap revealed a vancomycin-resistant enterococcus fecalis. Computed tomography scan with contrast confirmed the diagnosis of abscess formation. Mr. S. was subsequently started on intravenous (IV) linezolid 600 mg q 12 hours and metronidazole 500 mg po q 6 hours.

Prior to the addition of linezolid and metronidazole, Mr. S. had manifested a fine resting tremor and dry mouth, which were thought to be side effects of lithium carbonate. The lithium carbonate level was found to be elevated at 1.1 mEq/L. Consequently, the lithium carbonate was discontinued owing to apparent toxicity, lack of therapeutic response and in anticipation of possible electroconvulsive therapy. One week after discontinuation of lithium and 10 days after initiation of linezolid, the patient complained of increasing tremor, nausea, vomiting, diarrhea, and dry mouth. At that time, the sertraline, buproprion, and trazodone were discontinued because of the possibility of drug interactions with linezolid. Concurrent medications included baclofen 10 mg qd, promethazine 12.5 mg IV prn for nausea, docusate sodium 100 mg bid, bisacodyl 5 mg bid, megestrol 800 mg qd, lansoprazole 30 mg qd, and risperidone 1 mg qd.

The next day, Mr. S. became delirious marked by acute confusion, visual hallucinations, and delusions. Temperature was elevated to 100.1°F, pulse was 101, respirations were 20/ min, and blood pressure was 100/71mm Hg. He exhibited coarse tremor and myoclonus. His pupils were dilated to 6 mm and minimally reactive. Laboratory findings revealed a white blood count of 14,200/mm3 and hemoglobin and hematocrit of 8.1 mg/dl and 26.1 mg/dl respectively, which reflected no change from values of prior months. Urinalysis was normal. A chemistry panel revealed the following: sodium 132 mmol/L, potassium 3.4 mmol/L, chloride 103 mmol/L, CO2 15 mmol/L, BUN 5 mg/dL, Creatinine 0.6 mg/dL, glucose 189 mg/dL, calcium 7.7 mg/dL, magnesium 1.6 mg/dL, phosphorus 3.5 mg/ dL. Liver function studies revealed Albumin 2 g/dl, total bilirubin 0.2 mg/dl, total protein 5.4 g/dl, SGOT 29 IU/L, SGPT 5 IU/L, alkaline phosphatase 100 IU/L, Globulin 3.4 g/dl.

Differential diagnosis of the delirium included hypotension, infection, and medication interactions. Acute metabolic disturbance was ruled out as lab data showed no marked difference from previous recordings. The hypotension was chronic, caused by autonomic dysreflexia secondary to paraplegia. Earlier in the course, Mr. S. had been septic with significant temperatures above 104°F; however, he had been treated with 13 days of antibiotics and the fevers had resolved several days prior to his delirium. He had been on his current polydrug regimen for 2 months, excluding linezolid and metronidazole. While metronidazole, if given concurrently with lithium carbonate, can cause signs of lithium carbonate toxicity,⁹ Mr. S. had not had a dose of lithium carbonate for 1 1/2 weeks prior. The diagnosis of serotonin syndrome was considered because of the possible interactions between linezolid and sertraline in light of the symptoms of altered mental status, nausea, vomiting, diarrhea, myoclonus, dilated pupils, tremor, dry mouth, and temperature elevations. Subsequently, Mr. S. was started on cyproheptadine, a serotonin antagonist. Cyproheptadine was administered in an initial po dose of 8 mg, followed by 8 mg q 8 hours for 72 hours. Within 60 minutes of administration of the first dose, the pupil size decreased to 4 mm. After 48 hours of treatment with cyproheptadine, the altered mental status, tremor, gastrointestinal symptoms, myoclonus, pupil dilatation, and fever resolved.

DISCUSSION

The diagnosis of serotonin syndrome was based on the abrupt onset of symptoms with the addition of linezolid, the rapid recovery with cessation of the interacting psychotropics, the response to adjunctive therapy with cyproheptadine, and the exclusion of other medical causation. This case illustrates the potentially complicated way in which patients may present with serotonin syndrome, as well as the abrupt onset and rapid recovery that is often seen.

The diagnosis of serotonin syndrome is made on a clinical basis. The characteristic manifestations of this syndrome include confusion, agitation, lethargy, coma, seizure, hyperthermia, hyperreflexia, tachycardia, diaphoresis, nausea, vomiting, diarrhea, dilated pupils, myoclonus, rigidity, trismus, and death.¹ Laboratory abnormalities such as increased total white blood cell count and creatine phosphokinase levels and a decreased serum bicarbonate level may occur; however, they are nonspecific.¹⁰ A strong clinical suspicion, known exposure to serotonergic agents, demonstration of specific signs and symptoms, and exclusion of other medical and psychiatric conditions is required for the diagnosis.¹

Although there are differences in the selectivity of inhibition and the duration of action of MAOIs, all of them have demonstrated an ability to produce serotonin syndrome.³ One of the most common precipitating events is the combination of an MAOI and an SSRI. In most cases, two or more types of medications known to increase the activity of serotonin at the 5-HT 1A receptor are required to produce the syndrome, and it frequently begins soon after the initiation of a new treatment regimen.¹⁰

The above case apparently involved an interaction between sertraline, an SSRI, and linezolid, an antibiotic with MAOI properties. The presence of bupropion, a noradrenergic and dopaminergic agent, as well as trazodone, a serotonergic agent, may have also played a role in the patient's presentation, in light of potential theoretical interactions with linezolid. Though the patient did not have seizures or a hypertensive crisis symptomatic of bupropion toxicity, many of the symptoms of serotonin syndrome overlap with those of bupropion toxicity. However, high-dose bupropion (450 mg/day) has been used in combination with a MAOI without any adverse effects.¹¹ The diagnosis of serotonin syndrome appears to have been more likely, given the high dosage of sertraline compared with bupropion, and the prompt resolution with cyproheptadine administration.

Management of serotonin syndrome is largely supportive. Identification and removal of the offending agent is paramount.² Most cases resolve within 24 to 36 hours with supportive care and conventional symptomatic therapy. Appropriate supportive care may require external cooling, sedatives, paralytics, mechanical ventilation, anticonvulsants, and antihypertensives. Animal studies and isolated case reports have shown that nonspecific serotonergic antagonists that block both 5-HT 1A and 5-HT 2 receptors, such as cyproheptadine, methysergide, and propanolol, are effective in treating serotonin syndrome. Cyproheptadine appears to be the most consistently effective antiserotonergic agent in humans. It usually ameliorates the symptoms after the first dose, but it can be given every 1–4 hours (up to a maximum daily dose of 32 mg) until a therapeutic response is obtained.¹² However, it should be considered only an adjunct to supportive care.

In summary, it appears that linezolid, a weak MAOI has the potential for causing serotonin syndrome in combination with SSRIs and possibly other toxic reactions with psychotropics. Caution should be exercised when administering linezolid as part of a polydrug regimen.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the assistance of Jerry H. Morewitz, M.D., Chairman of the Department of Psychiatry at EVMS, for his helpful comments during the preparation of this case report.

REFERENCES

1. Martin TG: Review: serotonin syndrome. Ann Emerg Med 1996; 28:520-526[CrossRef][Medline]
2. Mason JP, Morris AV, Balcezak JT: Serotonin syndrome: presentation of two cases and review of the literature. Medicine 2000; 79:201-209[CrossRef][Medline]
3. Mills KC: Medical Toxicology: serotonin syndrome, a clinical update. Crit Care Clin 1997; 13:763-783[CrossRef][Medline]
4. Lundstrom T, Sobel J: Antibiotics for gram positive infections. Vancomycin, teicoplanin, quinopristin/daltopristin and linezolid. Infect Dis Clin North Am 2000; 14:463-474[CrossRef][Medline]
5. Murray BE: Problems and perils of vancomycin resistant enterococci, The Brazilian Journal of Infectious Diseases: an official publication of the Brazilian Society of Infectious Diseases 2000; 4:9-14
6. Mandell LG, Bennett EJ, Dolin R: Principles and Practice of Infectious Diseases, 5th edition Churchill Livingstone, Inc., 2000. pp. 392-393
7. Clemett D, Markham A: Linezolid. Drugs 2000; 59:815-827[CrossRef][Medline]
8. Mosby's GenRx, 11th edition, 2001; Linezolid (003479)
9. Mosby's GenRx, 10th ed., 2000; Metronidazole (001803)
10. LoCurto M: Neurologic emergencies: the serotonin syndrome. Emerg Med Clin North Am 1997; 15:665-675[CrossRef][Medline]
11. Ginsberg dL: Combination bupropion-tranylcypromine for refractory depression. Primary Psychiatry 2000; 7:22
12. Graudins A: Treatment of the serotonin syndrome with cyproheptadine. J Emerg Medi 1998; 16:615-619[CrossRef][Medline]

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