Serotonin syndrome

(Redirected from Serotonin Syndrome)


  • Can be produced by any serotonergic medication
  • 1 in 6 U.S. adults take at least one psychoactive medication[1]
  • Majority of cases occur within therapeutic drug dosages
  • Most common cause is ingestion of foods high in L-Tryptophan while taking an MAOI. Second most common is ingestion of both SSRI and MAOI[2]
  • Most common cause of death is severe hyperthermia

Causative Agents[3]


Drugs of Abuse



Over the counter Medications

Herbal products

  • St John’s Wort, Ginseng, Nutmeg, Yohimbe

Other Medications

Clinical Features

  • Altered mental status: Agitated delirium. Patients generally hyperactive.
  • Autonomic Instability: Hyperthermia, tachycardia, hypertension, diaphoresis, gastrointestinal illness [5]
    • Often labile blood pressure, HR
  • Neuromuscular Abnormalities: Clonus, ocular clonus, myoclonus, rigidity, hyperreflexia, tremor, seizures
    • More pronounced in the lower extremities
    • Clonus (inducible or spontaneous): most common finding[6]
      • Important to identify because it does not occur in other conditions that mimic serotonin syndrome
    • Hyperactivity as opposed to rigidity in neuroleptic malignant syndrome

Differential Diagnosis

Movement Disorders and Other Abnormal Contractions

Altered mental status and fever


Hunter Toxicity Criteria Decision Rules

Serotonergic agent plus 1 of the following[7]:

  • 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
    • In severe cases, large doses are required (diazepam IV 10-20 mg, titrated with 10 mg increments)
  • Cyproheptadine[8]
    • 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[9]
    • Phenothiazine with antiserotonergic effects
    • 50mg to 100mg IM
    • Avoid in:
      • Hemodynamically unstable patients as can cause serious hypotension[10]
      • Cases in which NMS may still be on the differential
  • Dexmedetomidine[11][12]
    • Small case series found this helpful in adolescent cases refractory to benzos
  • Dantrolene generally not recommended as it can worsen serotonin toxicity[13]
  • Treat hyperthermia
    • Hyperthermia due to increase in muscular activity, not change in set point
    • Intubate and paralyze if temperature > 41.1
    • Standard cooling measures
      • Fans, water sprays, ice packs, cooled crystalloids, cooling blankets


See Also


  1. Moore TJ and Mattison DR. Adult Utilization of Psychiatric Drugs and Differences by Sex, Age, and Race. JAMA Intern Med. Published online December 12, 2016. doi:10.1001/jamainternmed.2016.7507.
  2. 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
  3. Brown CH. Drug-induced Serotonin Syndrome. US Pharm. 2010;35(11):HS-16-HS-21.
  4. Thorpe EL, Pizon AF, Lynch MJ, Boyer J. Bupropion induced serotonin syndrome: a case report. J Med Toxicol. 2010;6(2):168-171. doi:10.1007/s13181-010-0021-x
  5. Boyer, E. W. and Shannon, M. (2005) ‘The Serotonin Syndrome’, New England Journal of Medicine, 352(11), pp. 1112–1120. doi: 10.1056/nejmra041867
  6. Farkas, J. Serotonin Syndrome. The Internet Book of Critical Care. Published June 13th, 2019. Accessed December 31st, 2020.
  7. 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
  8. 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
  9. Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100-109
  10. Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008 Jul; 54(7): 988–992.
  11. Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacother. 2014; 48(12):1651-1654.
  12. Duggal HS, Fetchko J. Serotonin syndrome and atypical antipsychotics. Am J Psychiatry. 2002;159(4):672–3.
  13. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17; 352(11):1112-20.