Key Facts

Serotonin syndrome results from excessive 5-HT receptor stimulation, usually from drug combinations or overdose. Recognition is critical as it can progress to life-threatening hyperthermia and multiorgan failure.

Epidemiology

Exact incidence unknown — likely underdiagnosed, especially mild cases. Estimated ~15% of SSRI overdoses develop some features. Increasing incidence with rising serotonergic drug prescribing.

Aetiology

Common drug combinations causing serotonin syndrome:

• SSRI + MAOI (most dangerous combination)
• SSRI + tramadol
• SSRI + triptans (5-HT1 agonists)
• SSRI + linezolid (weak MAOI)
• SSRI + St John's wort
• SSRI + lithium
• Combining multiple serotonergic antidepressants
• MDMA (ecstasy) + SSRI

Pathophysiology

• Excess 5-HT stimulation at 5-HT1A and 5-HT2A receptors in brainstem and spinal cord
• 5-HT2A receptor stimulation → hyperthermia, agitation, neuromuscular excitability
• 5-HT1A receptor stimulation → autonomic dysfunction
• Severity depends on degree of serotonergic excess — spectrum from mild tremor to life-threatening hyperthermia

Mild

• Tremor, myoclonus (especially in lower limbs)
• Anxiety, restlessness, insomnia
• Diarrhoea, mydriasis

Moderate

• Agitation, hyperreflexia, inducible clonus
• Diaphoresis, tachycardia
• Temperature 38-40°C

Severe/Life-threatening

• Temperature >41°C, severe clonus/rigidity
• Seizures, delirium, coma
• Rhabdomyolysis, DIC, multiorgan failure

Red Flags

• Temperature >41°C — life-threatening, aggressive cooling needed
• Sustained clonus with rising temperature
• Seizures or loss of consciousness
• Combination of SSRI + MAOI — highest risk combination

Bedside

• Temperature: Core temperature — may be markedly elevated
• Observations: HR, BP, RR, SpO2 — continuous monitoring
• Neurological exam: Clonus (spontaneous and inducible), hyperreflexia, tremor, myoclonus

Bloods

• CK: Elevated in moderate-severe cases (rhabdomyolysis)
• U&Es: AKI from rhabdomyolysis
• LFTs, coagulation: Hepatic injury, DIC
• FBC: WCC may be elevated
• ABG/lactate: Metabolic acidosis

Special Tests

• Drug levels: Serotonergic drug levels may guide management
• ECG: Sinus tachycardia, QTc monitoring
• No specific diagnostic test — diagnosis is clinical (Hunter criteria)

Immediate

1. STOP all serotonergic drugs
2. Supportive care: IV fluids, continuous monitoring
3. Benzodiazepines: Diazepam 5-10mg IV for agitation, myoclonus, seizures

Moderate-Severe

1. Cyproheptadine: 12mg PO/NG loading dose, then 2mg every 2 hours (max 32mg/day) — 5-HT2A antagonist
2. Active cooling: Evaporative cooling, ice packs; avoid antipyretics (ineffective — hyperthermia is muscular, not hypothalamic)
3. Intubation and paralysis: If temperature >41°C with severe rigidity — non-depolarising neuromuscular blocker (e.g., rocuronium)

Post-Recovery

• Symptoms typically resolve within 24-72 hours of drug discontinuation
• Review medication — avoid serotonergic combinations
• If antidepressant needed, choose drug with lower serotonergic potential or different mechanism
• Ensure adequate washout period before starting MAOI (2 weeks for most SSRIs; 5 weeks for fluoxetine)

Referral Criteria

• Moderate-severe serotonin syndrome — ICU/HDU
• Temperature >39°C with neuromuscular symptoms — urgent medical management
• Persistent symptoms >72 hours — investigate for alternative diagnosis

• Mild cases: Resolve within 24 hours with drug withdrawal
• Moderate cases: Resolve within 24-72 hours with supportive care + cyproheptadine
• Severe cases: Mortality <5% with modern management; usually from multiorgan failure
• Most patients recover fully with no long-term sequelae
• Prevention through careful prescribing and awareness of drug interactions is key

Hunter Criteria for Serotonin Syndrome

Requires a serotonergic agent PLUS at least one of:

Key Serotonergic Drug Interactions