Correspondence
The Serotonin Syndrome
N Engl J Med 2005; 352:2454-2456June 9, 2005
- Article
To the Editor:
The review of the serotonin syndrome by Boyer and Shannon (March 17 issue)1 raises some questions. First, how many features make a diagnosis of the serotonin syndrome? This is especially relevant when a patient presents with nonspecific symptoms (agitation, tachycardia, tremor, diarrhea, or a combination) that are often early and transient side effects of selective serotonin-reuptake inhibitors (SSRIs). An overenthusiastic diagnosis of the serotonin syndrome at this stage may actually deprive the patient of the benefits of SSRI treatment for depression.
Second, SSRIs and other proserotonergic agents act, by definition, by raising serotonergic activity in the brain. How and when does one decide that this activity is excessive? As Boyer and Shannon rightly point out, “No laboratory tests confirm the diagnosis of the serotonin syndrome.” Hence, the term “serotonin syndrome” might be a misnomer, because we do not know whether it is an excess of serotonin that causes the syndrome, even in its full-blown form.
1 ReferencesDebasish Basu, M.D.
Mersey Care NHS Trust, Southport PR9 0LT, United Kingdom
db_sm2002@yahoo.com 1
Boyer EW ,Shannon M . The serotonin syndrome. N Engl J Med 2005;352:1112-1120
Full Text | Web of Science | Medline
To the Editor:
Boyer and Shannon appropriately note Whyte's work describing 2222 overdoses of serotonergic drugs. This work strongly reinforces the value of the spectrum concept of serotonin toxicity1,2 and demonstrates that mild serotonin toxicity occurs in only 15 percent of SSRI-alone overdoses but that severe and potentially fatal serotonin toxicity occurs in 50 percent of cases in which monoamine oxidase inhibitors (MAOIs) and SSRIs are mixed. It is important to understand that it is only these patients who are at high risk and who may need urgent lifesaving treatment with 5-hydroxytryptamine type 2A receptor antagonists. Intravenous chlorpromazine has been used in 20 such cases, with rapid improvement of symptoms. It is better to think of serotonin toxicity as a form of poisoning (inevitable, if enough is ingested), not as a syndrome, because it is not idiosyncratic. This is why an accurate list of which drugs are actually serotonin-reuptake inhibitors or MAOIs is vital — for example, mirtazapine and nefazodone do not pose a risk with MAOIs.1
2 ReferencesPeter K. Gillman, M.D.
Pioneer Valley Private Hospital, Mackay 4740, Australia
kg@matilda.net. au 1
Gillman PK, Whyte IM. Serotonin syndrome. In: Haddad P, Dursun S, Deakin B, eds. Adverse syndromes and psychiatric drugs. Oxford, England: Oxford University Press, 2004:37-49.
2
Whyte IM. Serotonin toxicity (syndrome). In: Dart RC, ed. Medical toxicology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2004:103-6.
To the Editor:
One drug interaction is not included in Table 1 of Boyer and Shannon's review. The authors do mention opiates and meperidine, fentanyl, tramadol, and pentazocine in Table 1, but oxycodone and hydrocodone, administered with SSRIs, are also reported causes of the serotonin syndrome.1 We have reported four cases from a long-term care facility.2
In addition, we surveyed 49 long-term care residents who were given oxycodone or hydrocodone with SSRIs and found 10 cases of possible or probable serotonin syndrome. Since nitroglycerin is a suggested treatment for the serotonin syndrome,3 we performed an analysis to determine whether nitroglycerin use protected patients against the development of the syndrome. Unexpectedly, nitroglycerin use was associated with a higher risk of the serotonin syndrome (odds ratio, 5.3; P=0.02). Nitroglycerin use may be a surrogate indicator of vascular disease, which is known to be associated with decreased monoamine oxidase A activity, which in turn may increase the risk of the serotonin syndrome.
Frail elderly persons may be at high risk for the serotonin syndrome because of the use of multiple medications and associated vascular disease. Characterization of the serotonin syndrome in this population is lacking and merits further study.
3 ReferencesNallini Gnanadesigan, M.D., M.P.H.
Jewish Home for the Aging, Reseda, CA 91335
nallini@pacbell.net Randall T. Espinoza, M.D., M.P.H.
Geffen School of Medicine at UCLA, Los Angeles, CA 90095Rick L. Smith, M.D.
Jewish Home for the Aging, Reseda, CA 913351
Rosebraugh CJ ,Flockhart DA ,Yasuda SU ,Woosley RL . Visual hallucination and tremor induced by sertraline and oxycodone in a bone marrow transplant patient. J Clin Pharmacol 2001;41:224-227
CrossRef | Web of Science | Medline2
Gnanadesigan N, Espinoza RT, Smith R, Israel M, Reuben DB. Interaction of serotonergic antidepressants and opioid analgesics: is serotonin syndrome going undetected? J Am Med Dir Assoc (in press).
3
Brown TM ,Skop BP . Nitroglycerin in the treatment of the serotonin syndrome. Ann Pharmacother 1996;30:191-192
Web of Science | Medline
To the Editor:
The serotonin syndrome can occur in a broad range of clinical settings; however, experience with its management is scarce.1 Severe cases require immediate and effective therapy and leave little time for expert consultation. Treatment with cyproheptadine, olanzapine, or chlorpromazine is recommended1 but seems imprudent in inexperienced hands. Furthermore, these drugs may not be readily available, causing unnecessary delay in treatment.
Recently, we successfully managed a life-threatening presentation of the serotonin syndrome without these drugs. A 72-year-old man using tranylcypromine (60 mg a day) accidentally ingested venlafaxine (300 mg); severe muscular rigidity, delirium, hyperthermia, and respiratory failure developed rapidly. We used propofol2 to induce sedation and rocuronium, a nondepolarizing agent, to induce muscular paralysis, followed by intubation and ventilation.3 Within two hours, his temperature returned to 37.0°C. His further recovery was uneventful, and he was discharged 48 hours later. This widely practiced method of inducing anesthesia can be used safely and quickly in any hospital setting with an intensive care unit and does not require expertise with the serotonin syndrome.
3 ReferencesJurgen A.H.R. Claassen, M.D.
Harry P.M.M. Gelissen, M.D.
Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands
j.claassen@ger. umcn. nl 1
Boyer EW ,Shannon M . The serotonin syndrome. N Engl J Med 2005;352:1112-1120
Full Text | Web of Science | Medline2
Hyde RA ,Mortimer AJ . Safe use of propofol in a patient receiving tranylcypromine. Anaesthesia 1991;46:1090-1090
CrossRef | Web of Science | Medline3
Brubacher JR ,Hoffman RS ,Lurin MJ . Serotonin syndrome from venlafaxine-tranylcypromine interaction. Vet Hum Toxicol 1996;38:358-361
Medline
Author/Editor Response
Dr. Basu questions the point at which signs of serotonergic activity become serotonin toxicity. As we suggest in our article, the diagnosis of the serotonin syndrome depends on a clustering of clinical findings, described in Figure 4 of the article. We do not believe that the semantic changes proposed by Dr. Basu are as important as the need for clinicians to respond to the serotonin syndrome or to recognize that the administration of serotonergic drugs in any person with even one of the clinical signs listed can provoke clinical deterioration.
Dr. Gillman correctly highlights the plurality of signs and symptoms seen in the serotonin syndrome and the presumed effectiveness of treatment with chlorpromazine. We would caution clinicians against dismissing a specific agent as incapable of producing the serotonin syndrome. The condition has occurred in surprising clinical situations and, because of phenotypic variations among individual persons, has been associated with unexpected drugs, including mirtazapine.1
Drs. Claassen and Gelissen relate the aggressive action needed to manage severe serotonin syndrome, and the strategy they describe of using sedation (with propofol), control of hyperthermia (with rocuronium), and supportive care (orotracheal intubation) is in line with our recommendations. We disagree, however, that the safe and effective use of antihistamines and antipsychotic agents is beyond the grasp of clinicians, especially since extensive clinical experience with the disease and its treatment is available from toxicology consultation services and poison-control centers.
We agree with Dr. Gnanadesigan and colleagues that opiate and opioid drugs can result in serotonergic excess, but the leading reference they cite involves a transplant recipient receiving maintenance treatment with cyclosporine and other drugs in whom tremor and hallucinations developed — both classic signs of cyclosporine toxicity.2 In any case, the serotonin syndrome, as well as many pharmacologic factors and drug interactions, is poorly described in the elderly. We have always regarded nitroglycerin as a poorly conceived treatment for the serotonin syndrome, and we are glad that these authors are gathering clinical evidence of its potential dangers.
2 ReferencesEdward W. Boyer, M.D., Ph.D.
Michael Shannon, M.D., M.P.H.
Children's Hospital, Boston, MA 02115
edward.boyer@tch. harvard. edu 1
Duggal HS ,Fetchko J . Serotonin syndrome and atypical antipsychotics. Am J Psychiatry 2002;159:672-673
CrossRef | Web of Science | Medline2
Rosebraugh CJ ,Flockhart DA ,Yasuda SU ,Woosley RL . Visual hallucination and tremor induced by sertraline and oxycodone in a bone marrow transplant patient. J Clin Pharmacol 2001;41:224-227
CrossRef | Web of Science | Medline
- Citing Articles (5)
Citing Articles
1
Michelle Fleurat, Craig Smollin. (2012) Case Files of the University of California San Francisco Medical Toxicology Fellowship: Lamotrigine Toxicity. Journal of Medical Toxicology
CrossRef2
Lisa Wilson, Thomas Rooney, Reginald F. Baugh, Belinda Millington. (2011) Recognition and management of perioperative serotonin syndrome. American Journal of Otolaryngology
CrossRef3
J.L. Pilgrim, D. Gerostamoulos, Olaf H. Drummer. (2010) Deaths involving serotonergic drugs. Forensic Science International 198:1-3, 110-117
CrossRef4
Sven Armbrust, Werner Nikischin, Gertrud Rochholz, Cornelia Franzelius, Andreas Bielstein, Hans-Heiner Kramer. (2010) Hypothermia in a combined intoxication with doxepin and moclobemide in an adolescent. Forensic Science International 195:1-3, e1-e3
CrossRef5
S. Cassens, E. A. Nickel, M. Quintel, P. Neumann. (2006) Das Serotoninsyndrom. Der Anaesthesist 55:11, 1189-1196
CrossRef
