Serotonin syndrome


A toxic drug effect characterised by mental state changes and a variety of autonomic and neuromuscular manifestations.

Causes are usually

  1. Intentional self-poisoning with serotonergic agents or
  2. When drugs that inhibit the cytochrome P450 are added to therapeutic regimens of SSRIs

Specific agents that may be implicated in serotonin syndrome include:

  • amphetamines and their derivatives (ecstasy, dextroamphetamine, methamphetamine, and sibutramine)
  • analgesics (cyclobenzaprine, fentanyl, meperidine, tramadol)
  • antidepressants/mood stabilizers (buspirone, lithium)
  • MAOIs (such as phenelzine)
  • SSRIs (such as fluoxetine) & serotonin-norepinephrine reuptake inhibitors (e.g. venlafaxine)
  • St. John's wort
  • TCADs
  • antiemetics (metoclopramide, ondansetron)
  • antimigraine drugs (carbamazepine, ergot alkaloids, triptans, valproic acid)

Diagnostic criteria for serotonin syndrome

  • Coincident with increase in known serotinergic agent
  • Features not integral part of underlying psychiatric disorder
  • A neuroleptic not started or increased prior to symptoms
  • Four major or three major plus two minor signs
  • Other aetiologies ruled out

Major criteria

  • Impaired consciousness
  • Elevated mood
  • Myoclonus
  • Hyperreflexia
  • Diaphoresis
  • Shivering
  • Tremor
  • Rigidity (especially legs)
  • Fever

Minor criteria

  • Restlessness
  • Insomnia
  • Incoordination
  • Mydriasis
  • Akathesia
  • Tachycardia
  • Tachypnoea
  • Diarrhoea
  • Changes in blood pressure

At the severe end of the spectrum there may be seizures, rhabdomyolysis and ventricular arrhythmias.

DDx of serotonin syndrome

  • Neuroleptic malig synd
  • Sympathomimetic overdose
  • Anticholinergic toxicity
  • Delerium tremens
  • Sepsis
  • Heat stroke
  • Hepatic encephalopathy

Serotonin Syndrome

  • Onset Sudden
  • Within 24 hrs of intro of serotonergic agent
  • Agitation, diarrhoea
  • Dilated pupils, myoclonus, hyperreflexia
  • Mortality Rare


  • Slower onset
  • Within 7 days intro of neuroleptic agent
  • Dysphagia hypersalivation incontinence
  • Hyperthermia (>38.5°c), akinesia
  • Extrapyramidal "lead pipe" rigidity
  • Rhabdomyolysis
  • Mortality - 5% - 20%


  • Discontinue or decrease suspected medication according to the severity
  • Supportive care: hydration, control physiology (esp. fever & BP)
  • Basic Ix should include U&E, CK, & urine for myoglobin
  • Clonazepam if myoclonus
  • Diazepam if seizures
  • If severe hyperpyrexia consider:
    • Dantrolene (1 mg/kg over 15 minutes, repeated every 15 mins to a max of 10 mg/kg in 24 hours)
    • Propanolol or cyproheptadine (after toxicological advice)
    • CUH: Cyproheptidine is located in the antidotes press (DDA press) in Resus
  • Paralysis/ventilation or dialysis may be required

Last review Dr ÍOS 5/12/23.