What are the symptoms and treatment of serotonin syndrome?

Serotonin Syndrome: Symptoms and Treatment

Serotonin syndrome should be diagnosed using the Hunter criteria and treated by immediately discontinuing all serotonergic agents, providing supportive care, and administering cyproheptadine for moderate to severe cases. 1

Clinical Presentation

Serotonin syndrome presents with a triad of symptoms:

1. Mental Status Changes

   • Agitation
   • Confusion
   • Anxiety

2. Autonomic Instability

   • Hyperthermia (>38°C)
   • Tachycardia
   • Hypertension
   • Diaphoresis (sweating)
   • Flushing
   • Dilated pupils

3. Neuromuscular Abnormalities

   • Tremor
   • Hyperreflexia
   • Muscle rigidity
   • Clonus (spontaneous, inducible, or ocular)
   • Myoclonus

Diagnostic Criteria

The Hunter Serotonin Toxicity Criteria are the gold standard for diagnosis with 84% sensitivity and 97% specificity 1. A diagnosis requires:

• Patient has taken a serotonergic drug within the past 5 weeks
• Plus ONE of the following:
  • Spontaneous clonus
  • Inducible clonus PLUS agitation or diaphoresis
  • Ocular clonus PLUS agitation or diaphoresis
  • Tremor AND hyperreflexia
  • Hypertonia AND temperature >38°C AND ocular or inducible clonus

Treatment Algorithm

Step 1: Discontinue All Serotonergic Agents

• Immediately stop all medications that could contribute to serotonin syndrome 1, 2

Step 2: Supportive Care

• Administer IV fluids for hydration
• Use benzodiazepines for agitation control (first-line) 1
• Implement external cooling measures for hyperthermia 1, 2
• Monitor vital signs and neurological status

Step 3: Pharmacological Intervention

• For moderate to severe cases:
  • Administer cyproheptadine (a 5-HT2A antagonist) 1, 2
    • Initial dose: 12 mg orally
    • Maintenance: 2 mg every 2 hours if symptoms persist
    • Maximum daily dose: 32 mg
  • Alternative: Chlorpromazine (if cyproheptadine unavailable) 1

Step 4: Management of Severe Cases

• For temperatures >41°C or severe symptoms:
  • Consider neuromuscular paralysis with non-depolarizing agents
  • Intubation and mechanical ventilation (required in approximately 25% of severe cases) 1
  • Intensive care unit admission

Complications to Monitor

• Rhabdomyolysis
• Metabolic acidosis
• Elevated liver enzymes
• Renal failure
• Seizures
• Disseminated intravascular coagulation
• Takotsubo cardiomyopathy (rare) 3

Important Considerations

• Avoid physical restraints as they may worsen hyperthermia and lactic acidosis 1
• Recovery timeline: Fever typically resolves in 1-3 days but may take up to 7 days 1
• Prognosis: With prompt treatment, most patients recover completely; without proper treatment, mortality rate is approximately 11% 1
• Common medication triggers: SSRIs, SNRIs, TCAs, MAOIs, opioids, over-the-counter products, antibiotics, antiemetics, and antimigraine drugs 1, 4

High-Risk Drug Combinations

• MAOIs with any other serotonergic medication (highest risk) 1
• Multiple non-MAOI serotonergic drugs 1
• Opioids with serotonergic effects combined with antidepressants 1

The most recent evidence emphasizes that prompt recognition and aggressive treatment are essential to reduce morbidity and mortality, particularly in severe cases 1, 4. Regular education for healthcare providers about this potentially fatal condition is necessary as it is often overlooked 4.