Psychosomatics 42:258-260, June 2001
© 2001 The Academy of Psychosomatic Medicine
Possible Serotonin Syndrome in Association With 5-HT3 Antagonist Agents
Susan Beckwitt Turkel, M.D.,
J. Gary B. Nadala, M.D., and
Michael Z. Wincor, Pharm.D.
Received May 5, 2000; revised July 11, 2000; accepted September 26, 2000. From University of Southern California Schools of Pharmacy and Medicine, Los Angeles, California; University of Southern California Medical Center, Los Angeles, California. Address correspondence and reprint requests to Dr. Turkel Associate Professor of Psychiatry, Pathology and Pediatrics, University of Southern California School of Medicine, Childrens Hospital Los Angeles, 4650 Sunset Boulevard #82, Los Angeles, California 90027; e-mail: sbturkel{at}hsc.usc.edu
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ABSTRACT
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The serotonin syndrome results when serotonergic activity increases to abnormally high levels. It occurs with selective serotonin reuptake inhibitors (SSRIs), opioids, and other serotonergic agents when the serotonin system has been modulated by another serotonergic agent or compromised by illness. Although the symptoms are quite variable, the syndrome is characterized by a triad of altered mental status, neuromuscular abnormalities, and autonomic dysfunction. The authors report the probable occurrence of the serotonin syndrome with serotonin receptor subtype 3 (5-HT3) antagonist therapy when used to control nausea associated with chemotherapy in two seriously ill children. The first case involves combined use with mirtazapine and the second with fentanyl. These agents may pose a potential risk when used in such combination in seriously ill patients.
Key Words: Serotonin • Serotonin Syndrome
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INTRODUCTION
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The serotonin syndrome is a complex condition that results when serotonergic activity increases to abnormally high levels. It is potentially lethal and apparently involves both central and peripheral serotonin receptors.1 It is known to occur with selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and to a lesser extent, opioids, sumatriptan, and other serotonergic agents, usually when used in combination.2–5
The serotonin syndrome was first recognized in laboratory animals and subsequently clinically observed when MAOIs were administered with tryptophan. The syndrome is characterized by a triad of altered mental status, neuromuscular abnormalities, and autonomic dysfunction.6 Its symptoms are quite variable and have included the following: confusion, hypomania, agitation, myoclonus, hyperreflexia, diaphoresis, incoordination, seizures, paresthesias, rhabdomyolysis, myoglobinuric renal failure, diarrhea, nausea, abdominal pain, dyspnea, changes in blood pressure, arrhythmias, disseminated intravascualar coagulopathy, thrombocytopenia and leukopenia.1
We report what we believe to be the occurrence of the serotonin syndrome in two seriously ill children with malignancies. Both children received serotonin receptor subtype 3 (5-HT3) antagonist therapy to control nausea associated with chemotherapy. One child developed the serotonin syndrome in association with the noradrenergic-serotonergic antidepressant, mirtazapine, and the other when the 5-HT3 antagonist was used with the opioid, fentanyl, in the face of veno-occlusive disease. To our knowledge, these are the first such cases reported in the biomedical literature.
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Case Report
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Case 1. S. is a 12-year-old White male patient with disseminated Ewing's sarcoma. He had been previously treated with chemotherapy, radiation, and bone marrow transplantation. His tumor recurred 3 months after transplant, with severe bone pain and pulmonary metastases, and he was treated with chemotherapy and morphine. Psychiatric consultation was requested to evaluate depression. S. was treated with the antidepressant mirtazapine (15 mg) at bedtime to control his depressive symptoms. He was given ondansetron, the routine treatment for nausea, which had been anticipated with the next course of chemotherapy. Mirtazapine and morphine were also continued. The next day S. was confused and tremulous with myoclonus. Ondansetron was discontinued, mirtazapine stopped, and morphine continued. He remained confused the following day with auditory and visual hallucinations, which resolved with a single dose of droperidol (0.25 mg iv). Mirtazapine was resumed several days later without problem. S.'s medical condition continued to worsen and he died 2 weeks later.
Case 2. G. is an 11-year-old Asian female patient with high-risk, Philadelphia chromosome positive, acute lymphoblastic leukemia (ALL), which was diagnosed 2 years before her admission for bone marrow transplantation. She was seen for initial psychiatric consultation because of anxiety before transplantation and her anxiety resolved after the transplant was completed. G. was treated with busulfan and cyclophosphamide, and then she received bone marrow transplantation from her infant brother. She soon developed painful mucositis, and she was treated with continuous infusion of fentanyl. G. was simultaneously given antibacterial, antifungal, and antiviral antibiotics, cyclosporine, and the 5-HT3 antagonist, granisetron.
Two weeks later, G. developed veno-occlusive disease with renal and hepatic involvement. She became irritable and dysphoric with restricted affect, poor eye contact, and impaired attention that was consistent with early delirium, but no changes were made in her treatment. She became acutely confused 5 days later, with visual hallucinations, marked anxiety, tremulousness, ataxia, and myoclonus. Because the serotonin syndrome was suspected, granisetron was discontinued, and fentanyl changed to hydromorphone. G.'s confusion abated by the next day, myoclonus resolved, and her medical condition briefly stabilized, but her condition deteriorated, with progressive renal and hepatic failure. G. died 6 weeks later.
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DISCUSSION
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Serotonergic systems play multiple roles in medical and psychiatric conditions, and serotonergic agents are used to treat emesis, migraines, depression, and anxiety. Serotonergic agents may have peripheral as well as central nervous system (CNS) effects, which, in turn, may contribute to the adverse reactions that characterize the serotonin syndrome. The syndrome often occurs when a serotonin agonist drug is given after the serotonin system has already been modulated by another serotonergic agent or compromised by illness.1
The enterochromaffin cells of the gastrointestinal system synthesize 95% of the serotonin in the body, which then passes through the portal system, to be taken up and stored by platelets, and then metabolized by monoamine oxidase A in the liver and the pulmonary vascular system. Serum serotonin levels are tightly regulated and controlled by endothelial monoamine oxidase inactivation and cellular uptake. Usually any excess serotonin is cleared by the pulmonary or hepatic endothelium or absorbed by the platelets. Neurons and platelets release serotonin when there is increased sympathetic activity. Serotonin interacts with other neurotransmitter systems, which may impact functions regulating vasomotor tone and modulating CNS arousal. Structural damage to the endothelium, in either the peripheral or pulmonary vasculature, will decrease the capacity of the endothelium to metabolize serotonin. If the endothelium is damaged, serotonin can accumulate, and the serotonin syndrome may result with exposure to agents that interfere with its receptor function.1
Numerous drugs have been implicated in the serotonin syndrome. MAOIs result in the serotonin syndrome when used with a variety of other drugs, including meperidine, dextromethorphan, tryptophan, lithium, and tricyclic and SSRI antidepressants. SSRIs have been associated with the serotonin syndrome when used in combination with tryptophan, lithium, or opioids. Some opioids may have serotonin reuptake blocking effects including meperidine and to a lesser extent, dextromethorphan, tramadol, and possibly fentanyl (because it is a phenylpiperidine derivative, which is structurally similar to meperidine).7–9
Diagnosis of the serotonin syndrome is based on finding its characteristic clinical symptoms in association with a suggestive drug history.6 It may be more difficult to recognize the serotonin syndrome when it occurs in severely medically ill patients, and whether the patients' symptoms are wholly due to these complex drug interactions may be uncertain. However, these may be the patients at greatest risk, and the serotonin syndrome should be suspected when the triad of altered mental status, vasomotor instability, and neuromuscular symptoms occurs in patients being treated with medications implicated in producing the serotonin syndrome.
In our first patient, S., the serotonin syndrome occurred once ondansetron and mirtazapine were used together. In our second patient, G., the symptoms of serotonin syndrome did not occur until her worsening medical condition led to compromised endothelial function, coinciding with the use of granisetron and fentanyl.
Multiple serotonin receptors may be involved in producing the symptoms of the syndrome. The serotonin syndrome implies both central and peripheral serotonin dysfunction. Perhaps blocking one type of serotonin receptor and functionally increasing systemic and CNS levels of serotonin simultaneously, hence presenting excessive serotonin to other receptors, increases the risk for serotonin syndrome, especially in severely ill patients with systemic endothelial compromise. Mirtazapine and the 5-HT3 antagonists have been suggested as possible treatments for the serotonin syndrome.10 In light of these two cases, these treatments seem ill advised or should be implemented only with extreme caution. The 5-HT3 antagonists are routinely used in very ill patients with malignancy or transplant, often in conjunction with opioids or other drugs with possible serotonin effects, which may pose a potential and rarely recognized risk. As more serotonergic agents are developed and used in combination, it is inevitable that further cases of the serotonin syndrome will be encountered.
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REFERENCES
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Brown TM, Skop BP, Mareth TR: Pathophysiology and management of the serotonin syndrome. Annals Pharmacother 1996; 30:527–533
-
Mathew NT, Tietjen GE, Lucker C: Serotonin syndrome complicating migraine pharmacotherapy. Cephalalgia 1996; 16:323–327[CrossRef][Medline]
-
Bodner RA, Lynch T, Lewis L, et al: Serotonin syndrome. Neurology 1995; 45:219–223[Abstract]
-
Sporer KA: The serotonin syndrome: implicated drugs, pathophysiology, and management. Drug Safety 1995; 13:94–104[Medline]
-
Sternbach H: The serotonin syndrome. Am J Psychiatry 1991; 148:705–713[Abstract/Free Full Text]
-
Martin TG: Serotonin syndrome. Ann Emerg Med 1996; 28(5):520–526
-
Mason BJ, Blackburn KH: Possible serotonin syndrome associated with tramadol and sertraline coadministration. Ann Pharmacother 1997; 31:175–177[Abstract]
-
Jahr JS, Pisto JD, Gitlin MC, et al: The serotonin syndrome in a patient receiving sertraline after an ankle block. Anesth Analg 1994; 79: 189–191
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Willette RE: Analgesic agents, in Wilson and Gisvold's Textbook of Organic and Medicinal and Pharmaceutical Chemistry, Tenth Edition, edited by Delgado JN, Remers WA. Philadelphia, PA, Lippincott-Raven, 1998, pp 687–726
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Hoes MJAJM, Zeijpveld JHB: Mirtazapine as treatment for serotonin syndrome. Pharmacopsychiatry 1996; 29:81[Medline]
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ABSTRACT
INTRODUCTION
