FFinalistSouthampton · 2027
Acute care
AKT · Acute care/Toxicology & overdose

Serotonin syndrome

Excess central and peripheral 5-HT agonism, usually from a drug interaction

Overview

A drug-induced hyperserotonergic state causing the triad of neuromuscular excitation, autonomic instability and altered mental state. It is a prescribing complication, not an idiosyncratic reaction — it comes on within hours of starting, escalating or combining serotonergic drugs, and resolves when they stop.

Recognise

  • Onset is FAST — typically within 6–24 h of a dose change or a second serotonergic drug
  • Neuromuscular: clonus (inducible, spontaneous or ocular), hyperreflexia, tremor, rigidity — classically LOWER limbs more than upper
  • Autonomic: hyperthermia, tachycardia, hypertension, diaphoresis, mydriasis, diarrhoea (gut 5-HT)
  • Mental state: agitation, anxiety, confusion
  • Culprits: SSRIs/SNRIs, MAOIs, tramadol, linezolid, triptans, ondansetron, St John's wort, MDMA — most cases involve TWO agents

Red flags

  • Temperature >38.5 °C, sustained clonus or rigidity → life-threatening; rhabdomyolysis, DIC and multi-organ failure follow quickly. Critical care now.

Differentials & how to tell them apart

Neuroleptic malignant syndromeDAYS not hours; lead-pipe rigidity with HYPOreflexia and bradykinesia; follows a dopamine ANTAGONIST — not clonus
Anticholinergic toxicityDry skin and absent bowel sounds — serotonin syndrome is sweaty with brisk bowel sounds
Malignant hyperthermiaWithin minutes of a volatile anaesthetic or suxamethonium; rising end-tidal CO₂
MeningoencephalitisFever with meningism and no serotonergic drug history; clonus is not a feature
Sympathomimetic toxicity (cocaine, amfetamine)Similar autonomic picture but without clonus/hyperreflexia; the drug history separates them

Investigations

Clinical — the Hunter criteria (a serotonergic agent PLUS spontaneous/inducible/ocular clonus, or tremor with hyperreflexia, or hypertonia with temperature >38 °C). Bloods to find the complications, not the diagnosis: CK (rhabdomyolysis), U&E, LFT, clotting/DIC screen, ABG/lactate. Check paracetamol/salicylate if the exposure was an overdose.

Management

Stop every serotonergic drug, resuscitate ABCDE, and give benzodiazepines with active cooling

  1. 1STOP all serotonergic agents. ABCDE, continuous monitoring, IV access, active external cooling if pyrexial. Benzodiazepines for agitation and rigidity. Consult TOXBASE.
  2. 2Moderate–severe (temperature >38 °C, sustained clonus): add cyproheptadine on specialist advice; IV fluids for rhabdomyolysis.Gate: Temperature >38.5 °C, sustained rigidity or falling GCS → critical care for sedation, paralysis and intubation
  3. 3Never use antipyretics — the fever is muscular, not hypothalamic, so paracetamol does nothing. Avoid physical restraint, which worsens isometric heat production and lactic acidosis.
Benzodiazepines (e.g. lorazepam, diazepam) — First-line for agitation, tremor and to reduce muscle rigidity — treats the hyperadrenergic state and limits heat generation
Cyproheptadine — 5-HT₂A antagonist; oral/NG only. Specialist advice (TOXBASE) — reserved for moderate–severe cases not settling
IV crystalloid — Volume and renal protection where CK is rising

Key points

The discriminator against NMS is the reflexes: serotonin syndrome is HYPERreflexic with clonus, NMS is rigid and HYPOreflexic. Speed is the other tell — hours versus days. Antipyretics do not work because the heat is generated by muscle, and physical restraint makes it worse.

Monitor & prognosis

Continuous temperature, cardiac monitoring, GCS, CK and renal function until improving.

Most mild cases settle within 24 h of stopping the drug. Severe cases carry a real mortality from hyperthermia, rhabdomyolysis and DIC.

Source: NICE CKS · TOXBASE · Hunter serotonin toxicity criteria