Management of Serotonin Syndrome
Immediately discontinue all serotonergic agents and provide aggressive supportive care with benzodiazepines as first-line treatment; for severe cases with hyperthermia and rigidity, add cyproheptadine 12 mg orally initially, then 2 mg every 2 hours until symptoms improve. 1, 2
Initial Recognition and Diagnosis
Diagnose serotonin syndrome using the Hunter Criteria, which require exposure to a serotonergic agent plus one of the following: 1, 3
- Spontaneous clonus
- Inducible clonus with agitation or diaphoresis
- Ocular clonus with agitation or diaphoresis
- Tremor and hyperreflexia
- Hypertonia, temperature >38°C, and ocular or inducible clonus
The Hunter Criteria have higher sensitivity (84%) and specificity (97%) compared to older Sternbach criteria. 4 Clonus and hyperreflexia are the most diagnostic features when occurring with serotonergic drug use. 1, 3
Symptoms typically develop within 6-24 hours of starting, increasing, or combining serotonergic medications. 1, 3 The clinical triad consists of mental status changes (confusion to coma), autonomic hyperactivity (hyperthermia up to 41.1°C, tachycardia, diaphoresis, hypertension), and neuromuscular abnormalities (myoclonus, hyperreflexia, clonus, rigidity). 4, 1
Severity-Based Treatment Algorithm
Mild Cases
- Discontinue all serotonergic agents immediately 2, 3
- Provide IV fluids for dehydration and autonomic instability 2, 3
- Administer benzodiazepines for agitation, tremor, and neuromuscular symptoms 2, 3
- Implement external cooling measures (cooling blankets) for hyperthermia 2, 3
- Avoid antipyretics—they are ineffective because fever results from muscular hyperactivity, not hypothalamic dysregulation 1, 2
- Most mild-to-moderate cases resolve within 24-48 hours with these measures alone 1, 5
Moderate to Severe Cases
Hospitalization with continuous cardiac monitoring is required. 1, 2 In addition to the above measures:
- Add cyproheptadine (serotonin antagonist at 5-HT2A receptors): 1, 2
- Adults: 12 mg orally initially, then 2 mg every 2 hours until symptom improvement
- Maintenance: 8 mg every 6 hours after initial control
- Pediatrics: 0.25 mg/kg per day
- Continue cyproheptadine until the complete clinical triad resolves (mental status normalizes, neuromuscular hyperactivity ceases, autonomic instability resolves) 1
- Avoid physical restraints—they worsen isometric contractions, exacerbating hyperthermia and lactic acidosis 2, 3
Severe/Life-Threatening Cases (Hyperthermia >41.1°C, Severe Rigidity, Organ Failure)
This is a medical emergency with 11% mortality rate. 1, 2 Approximately 25% of patients require intubation and ICU admission. 2
- ICU admission with aggressive interventions: 1, 2
- Intubation and mechanical ventilation
- Paralysis with non-depolarizing agents only (avoid succinylcholine due to hyperkalemia and rhabdomyolysis risk) 1
- Aggressive external cooling
- Cyproheptadine via nasogastric tube if unable to take orally
- For hemodynamic instability, use direct-acting sympathomimetics (phenylephrine, norepinephrine) rather than indirect agents like dopamine 1
- Monitor for complications: rhabdomyolysis with elevated creatine kinase, metabolic acidosis, renal failure, seizures, disseminated intravascular coagulopathy 1, 2
Critical Monitoring Parameters
Monitor these specific findings to guide treatment duration: 1
- Resolution of clonus and hyperreflexia
- Normalization of vital signs (temperature, heart rate, blood pressure)
- Return to baseline mental status
- Cessation of diaphoresis and tremor
Important Pitfalls to Avoid
Distinguish from neuroleptic malignant syndrome (NMS): 1
- NMS: Lead-pipe rigidity, antipsychotic exposure, slower onset
- Serotonin syndrome: Hyperreflexia/clonus, serotonergic agent exposure, rapid onset (hours)
Be aware of cyproheptadine side effects: sedation and hypotension may occur. 1, 2
Patients can deteriorate rapidly—close observation and preparation for rapid escalation of care is essential. 1
The presentation is highly variable, and mild cases are easily missed. 4, 1 Maintain high clinical suspicion in any patient on serotonergic medications presenting with the triad of symptoms.