Serotonin Syndrome

Serotonin Syndrome

Take home messages

  • Serotonin does lots of different things, in the CNS, gut and platelets
  • If you have too much of it, you get a triad of autonomic hyperactivity, neuromuscular abnormalities and mental status change
  • It's a clinical diagnosis, and there has to be a trigger
  • Treatment is mainly supportive and it usually resolves in 24 hours


  • Monoamine neurotransmitter made from L-tryptophan
  • Plays a role in bronchospasm, platelet aggregation, pain, nausea and vomiting
  • Metabolised by monoamine oxidase (MAO)
  • Primary metabolite is 5-hydroxyindole acetic acid (5-HIAA), excreted in urine

In what three locations is serotonin made?

  • Serotoninergic neurons in the CNS
  • Enterochromaffin cells in the GI tract
  • Platelets

Serotonin receptors

  • 7 classes 5HT1–7 with different subtypes e.g. 5-HT2a
  • All act via G-Proteins and cAMP, apart from 5HT-3, which acts via a ligand-gated ion channel
  • 5HT-3 receptors act in GI tract and CNS to generate emetic response, hence inhibitors of 5HT-3 receptors (like ondansetron) are effective antiemetics

Serotonin Specific Reuptake Inhibitors

  • Commonly used medications to boost synaptic serotonin levels
  • Best not to stop in perioperative period, but a few missed doses not significant
  • Anaesthesia can trigger hypotension, arrhythmias, shivering, and postoperative confusion, albeit rarely
  • Probably decrease platelet aggregation but not thought to be clinically significant in perioperative setting

Serotonin syndrome

  • Mixture of mental status change, neuromuscular abnormalities, and autonomic hyperactivity
  • Occurs within 24 - 48 hours of trigger, usually a change in medications
  • Thought to be from hyperstimulation of 5-HT1a and 5-HT2 receptors in medulla and central grey nuclei
  • Classic triggers are a combination of drugs that boost serotonin levels, including SSRIs, tricyclic antidepressants, MAO inhibitors, and St. John's Wort
  • Previously diagnosed according to the Sternbach criteria, either four major or three major plus two minor features must be present

Sternbach Criteria - Major symptoms

  • Confusion
  • Elevated mood
  • Coma
  • Fever
  • Sweating
  • Clonus
  • Hyperreflexia
  • Tremor
  • Rigidity
  • Shivering

Sternbach Criteria - Minor symptoms

  • Hyperactivity
  • Agitation
  • Restlessness
  • Insomnia
  • Tachycardia
  • Tachypnoea
  • Labile blood pressure
  • Flushing
  • Incoordination
  • Mydriasis
  • Akathisia
  • Ataxia
  • But Hunter criteria probably better, and so are used more frequently nowadays:


  • Stop any drugs that increase serotonin
  • Supportive therapy
  • Self-resolves within 24 hours - rarely fatal - usually good prognosis if spotted early
  • Benzodiazepines for anxiolysis and seizures
  • Noradrenaline if severely hypotensive
  • Cyproheptadine has also been used (antihistamine that also has anti-serotonin activity)

References and Further Reading:

  • Sadasivan Chinniah, FRCA, James L.H. French, FRCA, David M. Levy, FRCA, Serotonin and anaesthesia, Continuing Education in Anaesthesia Critical Care & Pain, Volume 8, Issue 2, April 2008, Pages 43–45,
  • Bartakke A, Corredor C, van Rensburg A. Serotonin syndrome in the perioperative period. BJA Educ. 2020 Jan;20(1):10-17. doi: 10.1016/j.bjae.2019.10.003. Epub 2019 Dec 4. Erratum in: BJA Educ. 2020 Apr;20(4):139. PMID: 33456910; PMCID: PMC7807833.

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