Serotonin syndrome

Overview

Serotonin syndrome (SS) = excess serotonergic activity, usually from two serotonergic drugs acting via different mechanisms. Key receptor: 5-HT2A mediates the neuromuscular and autonomic features.

Presentation

Symptoms begin within 6 hours of the precipitating event. Classic triad:

•Autonomic hyperactivity - tachycardia, hypertension, hyperthermia, diaphoresis, mydriasis, hyperactive bowel sounds

•Neuromuscular abnormalities - clonus (hallmark sign, especially inducible ankle clonus), hyperreflexia, tremor, muscle rigidity, ocular clonus

•Altered mental status - agitation, anxiety, confusion, delirium, coma

⚠️

Skin is typically normal in SS. Flushed, hot, dry skin points to anticholinergic toxicity instead.

Investigations

•CK - elevated in rhabdomyolysis (key complication of muscle rigidity/hyperthermia)

•U&Es/creatinine - screen for AKI

•Clotting/LFTs - DIC and hepatic injury in severe hyperthermia

•ECG - tachycardia expected; exclude QTc prolongation

•Serial temperature monitoring - hyperthermia >41°C = severe disease

Management

⚠️

Do NOT use cyproheptadine before benzodiazepines - it is oral only with slower onset. Benzodiazepines are safer and faster in the acute phase.

Prognosis

•Most mild-to-moderate cases resolve within 24-72 hours of stopping the offending drug

•Sustained hyperthermia >41°C carries significant morbidity/mortality without ICU escalation

Causative drugs

•SSRIs (e.g. sertraline, citalopram, fluoxetine)

•SNRIs (e.g. venlafaxine, duloxetine) - inhibit serotonin AND noradrenaline reuptake

•MAOIs (e.g. phenelzine) - prevent serotonin breakdown

•Tramadol - weak opioid but also inhibits serotonin/noradrenaline reuptake; high-risk when added to an SSRI

•Triptans (e.g. sumatriptan) - risk when combined with SSRIs

•St John's Wort

🎯

Most dangerous combination: MAOI + SSRI (prevents breakdown AND reuptake simultaneously). Most commonly tested: SSRI + tramadol (e.g. sertraline + tramadol for pain).

Diagnosis - Hunter Criteria

SS is a clinical diagnosis - no confirmatory blood test. Hunter Serotonin Toxicity Criteria: serotonergic drug exposure PLUS any ONE of:

•Spontaneous clonus

•Inducible clonus + agitation or diaphoresis

•Ocular clonus + agitation or diaphoresis

•Tremor + hyperreflexia

•Hypertonia + temperature >38°C + ocular or inducible clonus