Psych · Emergency psychiatry
Serotonin syndrome
Also known as Serotonin toxicity · Serotonergic syndrome · 5-HT syndrome · Hunter criteria serotonin · Sternbach serotonin syndrome
Exam-exhaustive fellowship topic on serotonin toxicity — Hunter criteria (preferred) versus historical Sternbach, toxidrome with neuromuscular hyperreactivity, high-risk combinations (MAOI+SSRI, linezolid, methylene blue, tramadol, pethidine), severity-based management (stop agents, benzodiazepines, cyproheptadine doses, cooling, ICU paralysis), differential from NMS, complications and special populations. FRANZCP-primary, globally tagged.
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Red flags
- MAOI combined with SSRI, SNRI, pethidine, tramadol, or dextromethorphan — catastrophic serotonergic risk
- Spontaneous clonus, ocular clonus with agitation, or hyperthermia with rigidity after a serotonergic agent — treat as serotonin toxicity now
- Temperature rising with increasing muscle tone — stop serotonergics, cool, escalate to ICU; consider paralysis for refractory hyperthermia
- Methylene blue or linezolid plus ongoing antidepressant — perioperative and antimicrobial traps
- Treating presumed NMS with bromocriptine when the syndrome is actually serotonergic — may worsen toxicity
- Prolonged physical restraint of a hyperthermic, rigid patient — amplifies heat generation
Meet the patient
A 58-year-old woman, two years on fluoxetine for depression, is admitted for parathyroidectomy. Theatre gives methylene blue to map the glands. Six hours later she is diaphoretic, tremulous and agitated, and her temperature is climbing. The surgical registrar has written "post-op delirium, for haloperidol."[10][7]
The question that decides everything in the next thirty minutes: is this delirium, or is it serotonin toxicity — and what will you do before the haloperidol arrives? This topic is the disciplined answer: the criteria, the clonus, the traps, and the one drug you must stop.[1][3][12]
References20ShowHide
- [1]Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM, 2003.PMID 12925718
- [2]Sternbach H The serotonin syndrome. Am J Psychiatry, 1991.PMID 2035713
- [3]Boyer EW, Shannon M The serotonin syndrome. N Engl J Med, 2005.PMID 15784664
- [4]Isbister GK, Buckley NA, Whyte IM Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust, 2007.PMID 17874986
- [5]Isbister GK, Buckley NA The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment. Clin Neuropharmacol, 2005.PMID 16239759
- [6]Radomski JW, Dursun SM, Reveley MA, et al. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypotheses, 2000.PMID 10985912
- [7]Volpi-Abadie J, Kaye AM, Kaye AD Serotonin syndrome. Ochsner J, 2013.PMID 24358002
- [8]Perry PJ, Wilborn CA Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Ann Clin Psychiatry, 2012.PMID 22563571
- [9]Sun-Edelstein C, Tepper SJ, Shapiro RE Drug-induced serotonin syndrome: a review. Expert Opin Drug Saf, 2008.PMID 18759711
- [10]Ng BK, Cameron AJ The role of methylene blue in serotonin syndrome: a systematic review. Psychosomatics, 2010.PMID 20484716
- [11]Beakley BD, Kaye AM, Kaye AD Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review. Pain Physician, 2015.PMID 26218943
- [12]Chiew AL, Isbister GK Management of serotonin syndrome (toxicity). Br J Clin Pharmacol, 2025.PMID 38926083
- [13]Cooper J, Duffull SB, Isbister GK Predicting serotonin toxicity in serotonin reuptake inhibitor overdose. Clin Toxicol (Phila), 2023.PMID 36444913
- [14]Chiew AL, Buckley NA The serotonin toxidrome: shortfalls of current diagnostic criteria for related syndromes. Clin Toxicol (Phila), 2022.PMID 34806513
- [15]Prakash S, Patel H, Kumar S, et al. Cyproheptadine in serotonin syndrome: A retrospective study. J Family Med Prim Care, 2024.PMID 38827706
- [16]Evans RW, Tepper SJ, Shapiro RE, et al. The FDA alert on serotonin syndrome with use of triptans combined with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors: American Headache Society position paper. Headache, 2010.PMID 20618823
- [17]Isbister GK, Bowe SJ, Dawson A, et al. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol, 2004.PMID 15362595
- [18]Nisijima K, Yoshino T, Yui K, et al. Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Res, 2001.PMID 11164765
- [19]Lawrence KR, Adra M, Gillman PK Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis, 2006.PMID 16652315
- [20]Gillman PK Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth, 2005.PMID 16051647