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

  • SSRIs
  • MAOIs (should have washout period of 2+ wks prior to starting a SSRI)
  • TCAs
  • Drugs of Abuse: Cocaine, Ecstasy, Marijuana, Methamphetamine
  • Analgesics: Demerol, fentanyl
  • Antiemetics
  • Triptans
  • Bromocriptine
  • OTC: Cough meds like Dextromethorphan, herbal products, St John’s Wort

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

Altered mental status and fever


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 temp >38 AND (ocular clonus or inducible clonus)

84% Sn, 97% Sp

Template:Serotonin syndrome vs Neuroleptic malignant syndrome


  • Discontinue all serotonergic drugs
  • Aggressive supportive care
    • If pressors required, direct acting (e.g. norepi, 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 benzos and supportive care fail to improve agitation and abnormal vitals
    • Serotonin antagonist
    • Give 12mg PO/NG; repeat with 2mg q2hr until clinical response is seen (max 32mg/d)
    • Give 4mg q6hr x48hr if pt is responsive to initial dose
  • Chlorpromazine[5]
    • Phenothiazine with antiserotonergic effects
    • 50mg to 100mg IM
    • Can consider in severe cases
  • Dexmedetomidine[6]
    • Small case series found this helpful in adolescent cases refractory to benzos
  • Treat hyperthermia
    • Hyperthermia due to increase in muscular activity, not change in set point
    • Intubate and paralyze if temp > 41.1
    • Standard cooling measures


  • Severe cases may require intubation and ventilation in ICU
  • 24hr admission for AMS or abnormal vital signs requiring further supportive care
  • Discharge mild cases with minimal intervention required after 6 hrs of observation

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. Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014; 48(12):1651-1654.