What is serotonin syndrome?

Serotonin Syndrome

Serotonin syndrome is a potentially life-threatening condition characterized by a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities, occurring due to excessive serotonergic activity in the central nervous system when patients take multiple serotonergic medications or have significant exposure to a single serotonin-augmenting drug. 1

Clinical Presentation

Serotonin syndrome manifests through three main categories of symptoms:

1. Mental status changes:

   • Agitation
   • Confusion
   • Hallucinations
   • Delirium
   • Coma (in severe cases)

2. Autonomic hyperactivity:

   • Tachycardia
   • Labile blood pressure
   • Hyperthermia (temperature >38°C)
   • Diaphoresis
   • Flushing
   • Diarrhea

3. Neuromuscular abnormalities:

   • Tremor
   • Muscle rigidity
   • Myoclonus (spontaneous or inducible)
   • Hyperreflexia
   • Incoordination
   • Seizures (in severe cases)

Diagnosis

The Hunter criteria are the recommended diagnostic tool with high sensitivity (84%) and specificity (97%) 1. A diagnosis requires:

• Patient has taken a serotonergic drug within the past 5 weeks
• Presence of one or more of the following:
  • Spontaneous clonus
  • Inducible clonus with agitation or diaphoresis
  • Ocular clonus with agitation or diaphoresis
  • Tremor and hyperreflexia
  • Muscle rigidity with temperature >38°C and ocular or inducible clonus

Common Causative Medications

Serotonin syndrome can be caused by various medications that increase serotonin levels 1, 2, 3:

• Antidepressants: SSRIs, SNRIs, TCAs
• MAOIs: Both psychiatric and others (linezolid, methylene blue)
• Opioids: Particularly tramadol, fentanyl
• Other medications: Triptans, lithium, buspirone
• Herbal supplements: St. John's Wort
• Antibiotics: Certain types with serotonergic properties
• Antiemetics: Some have serotonergic effects

Management

Treatment follows a stepwise approach based on severity:

Immediate Actions:

• Discontinue all serotonergic agents 1
• Provide supportive care with IV fluids

Symptom-Based Management:

• For agitation/tremor: Benzodiazepines are first-line (e.g., diazepam) 1, 4
• For moderate to severe cases: Cyproheptadine (5-HT2A antagonist) at an initial dose of 12 mg orally, maximum daily dose 32 mg 1, 5
• Alternative antiserotonergic agent: Chlorpromazine (use with caution due to side effects) 1

Severe Cases:

• For temperatures >41°C: Consider neuromuscular paralysis with non-depolarizing agents 1
• For respiratory compromise: Intubation and mechanical ventilation (approximately 25% of severe cases require this) 1
• Avoid physical restraints: They can worsen hyperthermia and lactic acidosis 1

Monitoring and Complications

Patients with serotonin syndrome should be monitored for potential complications 1:

• Rhabdomyolysis
• Metabolic acidosis
• Elevated liver enzymes
• Renal failure
• Seizures
• Disseminated intravascular coagulation

Without proper treatment, mortality rate is approximately 11%, emphasizing the importance of prompt recognition and aggressive management 1.

Prevention

Key preventive measures include 1, 2, 3:

• Avoid combining MAOIs with any other serotonergic medications
• Exercise caution when combining two or more non-MAOI serotonergic drugs
• Be vigilant when prescribing opioids with serotonergic effects alongside antidepressants
• Thoroughly review medication lists for potential serotonergic interactions
• Screen patients for risk factors before initiating serotonergic therapy

Prognosis

With prompt recognition and appropriate treatment:

• Fever typically resolves within 1-3 days after removing the offending agent(s) 1
• Most mild to moderate cases resolve completely within 24-72 hours 4
• Severe cases require more intensive management but generally have favorable outcomes if treated promptly 4