What is the management of serotonin syndrome?

Management of Serotonin Syndrome

Immediately discontinue all serotonergic agents and administer benzodiazepines as first-line treatment for agitation and neuromuscular symptoms, with cyproheptadine reserved for severe cases. 1

Initial Recognition and Diagnosis

Use the Hunter Criteria for diagnosis, which requires a serotonergic agent plus one of the following: 1, 2

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

Clonus and hyperreflexia are the most diagnostic features when occurring with serotonergic drug use. 1, 3 Symptoms typically develop within 6-24 hours after starting or increasing a serotonergic medication. 1

Immediate Management Algorithm

Step 1: Discontinue All Serotonergic Agents

Stop every medication with serotonergic activity immediately—this is the cornerstone of treatment. 1, 2

Step 2: Supportive Care

• Administer IV fluids for dehydration and autonomic instability 1
• Give benzodiazepines as first-line treatment for agitation, neuromuscular symptoms, and tremor 1, 2
• Implement external cooling measures (cooling blankets) for hyperthermia 1, 2
• Avoid physical restraints—they worsen hyperthermia and lactic acidosis through isometric muscle contractions 1, 2

Step 3: Severity-Based Treatment Escalation

Mild Cases:

• Discontinue offending agents
• Benzodiazepines for symptom control
• Outpatient monitoring may be appropriate 1

Moderate Cases:

• Hospitalization with continuous cardiac monitoring 1
• IV benzodiazepines for agitation
• Aggressive cooling measures
• Monitor for complications (rhabdomyolysis, metabolic acidosis, renal failure) 1

Severe Cases (hyperthermia >41.1°C, muscle rigidity, autonomic instability):

• ICU admission immediately 1, 2
• Cyproheptadine 12 mg orally initially, then 2 mg every 2 hours until symptom improvement 1
• Maintenance dose: 8 mg every 6 hours after initial control 1
• Consider intubation with non-depolarizing paralytic agents (avoid succinylcholine due to hyperkalemia and rhabdomyolysis risk) 1
• For hemodynamic instability, use direct-acting sympathomimetics (phenylephrine, norepinephrine) rather than indirect agents like dopamine 1

Critical Pitfalls to Avoid

Do not use antipyretics—hyperthermia results from muscular hyperactivity, not hypothalamic dysregulation, making acetaminophen and NSAIDs ineffective. 1

Do not use succinylcholine in severe cases due to risks of hyperkalemia and worsening rhabdomyolysis. 1

Do not apply physical restraints—these exacerbate muscle contractions, worsening hyperthermia and lactic acidosis. 1, 2

Watch for rapid deterioration—approximately 25% of patients require intubation and mechanical ventilation, and mortality is approximately 11%. 1, 2

Cyproheptadine Dosing Specifics

The American Academy of Pediatrics recommends cyproheptadine as the antidote of choice for severe serotonin syndrome. 1

Adult dosing: 1

• Initial: 12 mg orally
• Continuation: 2 mg every 2 hours for ongoing symptoms
• Maintenance: 8 mg every 6 hours after symptom control
• Maximum: 12-24 mg over 24 hours

Pediatric dosing: 0.25 mg/kg per day 1, 4

Side effects: Cyproheptadine may cause sedation and hypotension. 1

Monitoring for Complications

Watch for: 1

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

Differential Diagnosis Considerations

Distinguish serotonin syndrome from: 1, 2

• Neuroleptic malignant syndrome (slower onset, lead-pipe rigidity without clonus)
• Malignant hyperthermia (requires anesthesia exposure)
• Anticholinergic syndrome (dry skin, absent bowel sounds, mydriasis without clonus)
• Withdrawal syndromes

Myoclonus is present in 57% of serotonin syndrome cases and helps differentiate it from these conditions. 2