What are the symptoms and treatment of serotonin syndrome?

Serotonin Syndrome: Symptoms and Treatment

Clinical Presentation

Serotonin syndrome presents as a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities that typically develop within 6-24 hours of starting, increasing, or combining serotonergic medications. 1

Mental Status Changes

• Agitated delirium and confusion are the most common presentations 1
• Altered consciousness ranging from mild confusion to coma in severe cases 1
• Restlessness and agitation 2

Autonomic Hyperactivity

• Hyperthermia (temperature up to 41.1°C or higher) 1
• Tachycardia and tachypnea 1
• Hypertension or blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic change within 24 hours) 1
• Profuse diaphoresis 1
• Mydriasis (dilated pupils) 1

Neuromuscular Abnormalities

• Clonus (spontaneous, inducible, or ocular) and hyperreflexia are the most diagnostic features 1, 3
• Myoclonus (present in 57% of cases) 4
• Muscle rigidity 1
• Tremor 1

Diagnostic Approach

Use the Hunter Criteria for diagnosis, which requires exposure to a serotonergic agent plus ONE of the following: 1, 3

• Spontaneous clonus, OR
• Inducible clonus with agitation or diaphoresis, OR
• Ocular clonus with agitation or diaphoresis, OR
• Tremor and hyperreflexia, OR
• Hypertonia with temperature >38°C and ocular or inducible clonus

Key Diagnostic Considerations

• No laboratory or imaging findings are pathognomonic for serotonin syndrome 1
• The presentation is extremely variable, and mild cases are easily missed 1
• Distinguish from neuroleptic malignant syndrome (NMS), which shows lead pipe rigidity and history of antipsychotic use rather than hyperreflexia and clonus 1

Treatment Algorithm

Immediate Management (All Cases)

Discontinue all serotonergic agents immediately—this is the cornerstone of treatment 3, 4

Mild Cases

• Supportive care with IV fluids for dehydration and autonomic instability 3
• Benzodiazepines as first-line treatment for agitation, neuromuscular symptoms, and tremor 3, 4
• External cooling measures (cooling blankets) for hyperthermia 3, 4
• Avoid antipyretics—they are ineffective because hyperthermia results from muscular hyperactivity, not hypothalamic dysregulation 1, 3
• Most mild-to-moderate cases resolve within 24-48 hours 1, 5

Moderate to Severe Cases

Hospitalization with continuous cardiac monitoring is required 3

Administer cyproheptadine (serotonin antagonist): 1, 3

• Initial dose: 12 mg orally
• Followed by 2 mg every 2 hours until symptom improvement
• Maintenance: 8 mg every 6 hours after initial control
• Pediatric dosing: 0.25 mg/kg per day 1
• Continue cyproheptadine until the complete clinical triad resolves (mental status changes, neuromuscular hyperactivity, and autonomic instability) 1

Important caveat: Cyproheptadine may cause sedation and hypotension 1, 3

Severe/Life-Threatening Cases

Severe serotonin syndrome is characterized by hyperthermia >41.1°C, severe muscle rigidity, and multiple organ failure—this is a medical emergency with an 11% mortality rate 1, 3

• ICU admission required 1, 3
• Aggressive cooling measures 1
• Intubation and mechanical ventilation (approximately 25% of patients require this) 3
• Paralysis with non-depolarizing agents if needed 1
• Avoid succinylcholine due to risks of hyperkalemia and rhabdomyolysis 1
• Avoid physical restraints—they exacerbate isometric contractions, worsening hyperthermia and lactic acidosis 3, 4

Hemodynamic Instability

Use direct-acting sympathomimetic amines (phenylephrine, norepinephrine) rather than indirect agents like dopamine 1

Monitoring for Complications

Watch for the following complications in severe cases: 3

• Rhabdomyolysis with elevated creatine kinase 1
• Metabolic acidosis 1
• Renal failure with elevated serum creatinine 1
• Elevated serum aminotransferases 1
• Seizures 1
• Disseminated intravascular coagulopathy 1

Clinical Monitoring Parameters for Treatment Response

Monitor these parameters to guide cyproheptadine discontinuation: 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

Critical Pitfalls to Avoid

• Patients can deteriorate rapidly—close observation and preparation for rapid intervention is essential 1
• The condition is non-idiosyncratic and predictable, occurring with new drugs, dose increases, or drug combinations 1, 4
• Mild cases are frequently misdiagnosed as flu or other benign conditions 6