Temperature above 38.5 C, rigidity, or autonomic instability: this is severe serotonin syndrome. Stop all serotonergic drugs, cool aggressively, sedate with benzodiazepines, and involve critical care.
Clinical triad (Hunter criteria)
- Neuromuscular: clonus (especially lower limb, inducible or spontaneous), hyperreflexia, tremor, rigidity
- Autonomic: fever, tachycardia, sweating, dilated pupils, diarrhoea
- Mental state: agitation, confusion
- Onset is usually rapid (within 24 h of a new or increased serotonergic drug)
Triggers
- SSRI or SNRI plus another serotonergic drug
- MAOIs, tramadol, pethidine, triptans, linezolid, methylene blue
- St John's wort, MDMA, amfetamines
- Recent dose increase or overdose
Mild
- Tremor, diaphoresis, tachycardia
- Stop serotonergic drugs
- Supportive care, observe
Moderate
- Clonus, hyperreflexia, agitation
- Benzodiazepines, IV fluids
- Active cooling
Severe
- Temp over 38.5, rigidity, autonomic instability
- Cyproheptadine, critical care
- Consider intubation and paralysis
Management
1
1. Stop the drugs
Identify and stop all serotonergic agents. Resuscitate and support ABC.
Identify and stop all serotonergic agents. Resuscitate and support ABC.
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2
2. Sedate and cool
Benzodiazepines for agitation, rigidity and to lower temperature. Active cooling; IV fluids; monitor CK (rhabdomyolysis) and renal function.
Benzodiazepines for agitation, rigidity and to lower temperature. Active cooling; IV fluids; monitor CK (rhabdomyolysis) and renal function.
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3
3. Severe cases
Consider cyproheptadine (a serotonin antagonist) on specialist advice. Severe hyperthermia may need paralysis, intubation and active cooling in critical care.
Consider cyproheptadine (a serotonin antagonist) on specialist advice. Severe hyperthermia may need paralysis, intubation and active cooling in critical care.
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4
4. Differentiate
Distinguish from neuroleptic malignant syndrome (slower onset, lead-pipe rigidity, bradyreflexia), malignant hyperthermia and sepsis.
Distinguish from neuroleptic malignant syndrome (slower onset, lead-pipe rigidity, bradyreflexia), malignant hyperthermia and sepsis.
Clues vs NMS
- Serotonin syndrome: fast onset, clonus and hyperreflexia
- NMS: slower onset, rigidity with hyporeflexia, after antipsychotics
- Both can cause hyperthermia and raised CK
Pitfalls
- Missing inducible clonus (a key sign)
- Attributing fever to infection and continuing the drug
- Using antipyretics alone (ineffective)
- Not escalating severe hyperthermia to critical care
MedPrep - www.medprep.uk - Educational revision aid only. Not clinical guidance. Doses are adult examples; check the BNF, current guidelines and local policy, and seek senior advice. Nov 2026