What is the treatment for serotonin fever or serotonin syndrome?

Treatment of Serotonin Syndrome

Immediately discontinue all serotonergic agents and administer benzodiazepines as first-line treatment, with cyproheptadine reserved for moderate-to-severe cases requiring additional serotonin antagonism. 1

Immediate Management Steps

Discontinue all serotonergic medications as the absolute first priority—this is the cornerstone of treatment and must be done without delay. 1, 2

Administer benzodiazepines as the primary pharmacologic intervention for:

• Agitation control 1
• Neuromuscular symptoms including tremor and clonus 1
• Prevention of complications from muscle hyperactivity 3

Supportive Care Algorithm

Provide aggressive supportive measures including:

• IV fluids for dehydration and autonomic instability 1
• External cooling measures (cooling blankets) for hyperthermia—note that antipyretics are ineffective because fever results from muscular hyperactivity rather than hypothalamic dysregulation 1
• Continuous cardiac monitoring for moderate-to-severe cases requiring hospitalization 1

Avoid physical restraints as they exacerbate isometric muscle contractions, worsening hyperthermia and lactic acidosis. 1

Cyproheptadine Administration

Use cyproheptadine (a 5-HT2A receptor antagonist) for moderate-to-severe cases with specific dosing: 1, 4

• Initial dose: 12 mg orally
• Repeat dosing: 2 mg every 2 hours until symptom improvement
• Maintenance: 8 mg every 6 hours after initial symptom control 1

Be aware of cyproheptadine side effects: sedation and hypotension, which may complicate management. 1

The evidence supporting cyproheptadine is consistent across multiple sources 3, 5, 6, though it functions as an adjunct rather than primary treatment.

Severity-Based Treatment Escalation

Mild cases resolve with drug withdrawal and supportive care within hours. 3, 6

Moderate-to-severe cases require hospitalization with:

• Continuous monitoring 1
• Approximately 25% of patients require intubation, mechanical ventilation, and ICU admission 1

Severe cases with hyperthermia demand aggressive intervention:

• External cooling 1
• Neuromuscular paralysis and sedation for critically ill patients 3
• Intubation as needed 1

Critical Monitoring Parameters

Watch for life-threatening complications including:

• Rhabdomyolysis 1
• Metabolic acidosis 1
• Elevated serum aminotransferases 1
• Renal failure 1
• Seizures 1
• Disseminated intravascular coagulopathy 1

The mortality rate is approximately 11%, emphasizing the urgency of prompt recognition and treatment. 1

Common Pitfalls to Avoid

Do not confuse serotonin syndrome with neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic syndrome, or withdrawal syndromes—these require different management approaches. 1

Do not rely on antipyretics for fever management, as they are ineffective in this context. 1

Do not underestimate rapid progression—symptoms typically develop within 6-24 hours of medication initiation or dose increase, and severe cases can progress to seizures, respiratory failure, and death within 24-48 hours. 1, 2

Diagnostic Confirmation

Use the Hunter Criteria for diagnosis, requiring a serotonergic agent plus one of:

• 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 1, 3

Clonus and hyperreflexia are highly diagnostic when occurring with serotonergic drug use. 1, 7