What is the treatment for serotonin syndrome?

Treatment of Serotonin Syndrome

The treatment of serotonin syndrome requires immediate discontinuation of all serotonergic agents, supportive care, benzodiazepines for agitation and muscle hyperactivity, and cyproheptadine as a serotonin antagonist in moderate to severe cases. 1

Diagnosis Confirmation

Before initiating treatment, confirm the diagnosis using the Hunter Serotonin Toxicity Criteria, which have superior sensitivity (84%) and specificity (97%):

• Patient must have taken a serotonergic drug within the past 5 weeks
• Plus one of the following:
  • 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 1, 2

Treatment Algorithm Based on Severity

Mild Serotonin Syndrome

• Immediately discontinue all serotonergic agents 1, 2
• Provide supportive care and close monitoring 2
• Administer benzodiazepines for agitation and tremor 2
• Most mild cases resolve within 24-72 hours with these measures 3

Moderate Serotonin Syndrome

• All measures for mild syndrome plus:
• Hospital admission for close monitoring 3
• Intravenous fluids for hydration 1
• External cooling measures for temperature >38°C 1
• Cyproheptadine (5-HT2A antagonist): Initial dose 12 mg orally, followed by 2 mg every 2 hours until clinical improvement (maximum daily dose: 32 mg) 1, 3

Severe Serotonin Syndrome

• Immediate ICU admission 3
• Aggressive cooling measures for hyperthermia 1, 4
• Benzodiazepines for severe agitation 1, 2
• Cyproheptadine administration as above 1
• In critically ill patients: neuromuscular paralysis, sedation, and intubation may be required 2
• Avoid physical restraints as they may worsen hyperthermia and lactic acidosis 1

Important Clinical Considerations

• The mortality rate for untreated serotonin syndrome is approximately 11%, highlighting the need for prompt intervention 1
• About 25% of severe cases require intubation and mechanical ventilation 1
• Monitor for complications including rhabdomyolysis, metabolic acidosis, elevated liver enzymes, renal failure, seizures, and disseminated intravascular coagulation 1
• Benzodiazepines are the first-line agents for controlling agitation and neuromuscular hyperactivity 1, 2
• Diphenhydramine should NOT be used as a substitute for cyproheptadine due to its lack of specific serotonin antagonist properties 1

Prognosis

With prompt recognition and appropriate management, the prognosis for serotonin syndrome is generally favorable 2, 3. Most cases resolve completely within 24 hours after discontinuation of the serotonergic agent and initiation of supportive care 5.

Prevention Strategies

• Avoid combining MAOIs with any other serotonergic medications 1
• Exercise caution when combining two or more non-MAOI serotonergic drugs 1
• Be aware of common culprits: SSRIs, SNRIs, TCAs, MAOIs, opioids, and over-the-counter products such as dextromethorphan and St. John's wort 1
• Educate patients about potential drug interactions and symptoms of serotonin syndrome 3