Serotonin syndrome

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  • Can be produced by any serotonergic medication
  • Majority of cases occur within therapeutic dosages and often from exposure to several different serotonergic drugs, like while switching between antidepressant classes or drugs
  • Most common cause of death is severe hyperthermia
  • Most common cause is ingestion of foods large in L-Tryptophan, along with MAOI, and second is ingestion of SSRI and MAOI[1]

Causative Agents

Clinical Features

  • Altered mental status: Agitated delirium
  • Autonomic Instability: Hyperthermia, tachycardia, hypertension, diaphoresis [2]
    • Often labile blood pressure, HR
  • Neuromuscular Abnormalities: Myoclonus, ocular clonus, rigidity, hyperreflexia, tremor
    • More pronounced in the lower extremities
    • Myoclonus: most common finding
      • Important to identify because it does not occur in other conditions that mimic serotonin syndrome

Differential Diagnosis

Template:Altered mental status and fever DDX


Hunter Toxicity Criteria Decision Rules

Serotonergic agent plus 1 of the following[3]:

  • Spontaneous clonus
  • Inducible clonus AND (agitation or diaphoresis)
  • Ocular Clonus AND (agitation or diaphoresis)
  • Tremor AND hyperreflexia
  • Hypertonia AND temperature >38 AND (ocular clonus or inducible clonus)

84% Sn, 97% Sp

Serotonin syndrome vs Neuroleptic malignant syndrome

  • History of a new serotonergic drug or a dose increase of a serotonergic drug are helpful
  • Serotonin syndrome is usually much more acute in onset than NMS which may develop over days or weeks
  • Presence of ‘lead pipe’ rigidity is typical of NMS, while serotonin syndrome typically manifests with tremor and hyperreflexia
  • Elevations in CK, LFTs, and WBC, coupled with a low iron level, distinguishes NMS from serotonin syndrome among patients taking both neuroleptic and serotonin agonist medications simultaneously


  • Discontinue all serotonergic drugs
  • Aggressive supportive care
    • If pressors required, direct acting (e.g. norepinephrine, epi) preferred, MAO inhibition causes erratic response to dopamine
  • Benzos
    • Goal is to eliminate agitation, neuromuscular abnormalities, elevations in HR/BP
  • Cyproheptadine[4]
    • Give if benzodiazepines and supportive care fail to improve agitation and abnormal vitals
    • Serotonin antagonist
      • Also has antihistamine and anticholinergic properties that may exacerbate other mixed toxicology picture
    • Give 12mg PO/NG; repeat with 2mg q2hr until clinical response is seen (max 32mg/d)
    • Give 4mg q6hr x48hr if patient is responsive to initial dose
  • Chlorpromazine[5]
    • Phenothiazine with antiserotonergic effects
    • 50mg to 100mg IM
    • Avoid in:
      • Hemodynamically unstable patients as can cause serious hypotension[6]
      • Cases in which NMS may still be on the differential
  • Dexmedetomidine[7][8]
    • Small case series found this helpful in adolescent cases refractory to benzos
  • Dantrolene generally not recommended as it can worsen serotonin toxicity[9]
  • Treat hyperthermia
    • Hyperthermia due to increase in muscular activity, not change in set point
    • Intubate and paralyze if temperature > 41.1
    • Standard cooling measures


See Also



  1. Stork CM. Serotonin Reuptake Inhibitors and Atypical Antidepressants. In: Flomenbaum N, Goldfrank L, Hoffman R, Howland MA, et al, eds. Goldfrank’s Toxicologic Emergencies. 8th Ed. New York, NY: McGraw-Hill; 2006: 1070-1082
  2. Boyer, E. W. and Shannon, M. (2005) ‘The Serotonin Syndrome’, New England Journal of Medicine, 352(11), pp. 1112–1120. doi: 10.1056/nejmra041867
  3. Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 2003;96:635-642
  4. Graudins, A., Stearman, A. and Chan, B. (1998) ‘Treatment of the serotonin syndrome with cyproheptadine’, The Journal of Emergency Medicine, 16(4), pp. 615–619. doi: 10.1016/s0736-4679(98)00057-2
  5. Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100-109
  6. Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008 Jul; 54(7): 988–992.
  7. Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014; 48(12):1651-1654.
  8. Duggal HS, Fetchko J. Serotonin syndrome and atypical antipsychotics. Am J Psychiatry. 2002;159(4):672–3.
  9. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17; 352(11):1112-20.