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, administering benzodiazepines for agitation, and using cyproheptadine for moderate to severe cases. 1

Clinical Presentation

Serotonin syndrome presents with a characteristic triad of symptoms:

1. Mental Status Changes

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

2. Autonomic Instability

   • Tachycardia
   • Hypertension (or hypotension)
   • Hyperthermia (temperature >38°C)
   • Diaphoresis
   • Dilated pupils
   • Diarrhea

3. Neuromuscular Abnormalities

   • Tremor
   • Hyperreflexia
   • Muscle rigidity
   • Spontaneous clonus
   • Inducible clonus
   • Ocular clonus

Diagnostic Criteria

The Hunter criteria are the gold standard for diagnosis with high sensitivity (84%) and specificity (97%) 1:

• 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 AND temperature >38°C AND ocular or inducible clonus

Treatment Algorithm

Step 1: Immediate Discontinuation

• Stop all serotonergic medications immediately 1, 2

Step 2: Supportive Care

• Intravenous fluids
• External cooling measures for hyperthermia
• Vital sign monitoring 1

Step 3: Symptom Management

• For agitation/tremor: Benzodiazepines (first-line) 1, 3
• For moderate to severe cases: Cyproheptadine (serotonin antagonist)
  • Initial dose: 12 mg orally
  • Maximum daily dose: 32 mg 1
  • Alternative: Chlorpromazine (use with caution due to side effects) 1

Step 4: Management of Severe Cases

• For temperatures >41°C:
  • Consider neuromuscular paralysis with non-depolarizing agents
  • Intubation and mechanical ventilation (required in ~25% of severe cases) 1
• Monitor for complications:
  • Rhabdomyolysis
  • Metabolic acidosis
  • Elevated liver enzymes
  • Renal failure
  • Seizures
  • Disseminated intravascular coagulation 1, 4

Severity Classification

• Mild: Tremor, hyperreflexia, mild agitation, diaphoresis

  • Management: Discontinuation of agent, supportive care

• Moderate: Tachycardia, hypertension, hyperthermia (38-40°C), clonus, agitation

  • Management: Above plus benzodiazepines and cyproheptadine

• Severe: Temperature >41°C, severe hypertension/tachycardia, delirium, muscle rigidity

  • Management: ICU admission, possible paralysis and intubation 1, 3

Common Pitfalls and Caveats

• Avoid physical restraints as they may worsen hyperthermia and lactic acidosis 1
• Don't substitute diphenhydramine for cyproheptadine as it lacks antiserotonergic effects 1
• Fever resolution may take 1-3 days (up to 7 days in some cases) after removing the offending agent 1
• Differential diagnosis must include neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic toxicity, and sepsis 5
• Medication awareness is critical as serotonin syndrome can be caused by numerous medications including:
  • SSRIs, SNRIs, TCAs, MAOIs
  • Certain opioids (particularly tramadol, meperidine, fentanyl)
  • Over-the-counter products containing dextromethorphan
  • Antibiotics (linezolid)
  • Antiemetics (ondansetron)
  • Antimigraine drugs (triptans)
  • Recreational drugs (MDMA/ecstasy, cocaine) 1, 4

Prognosis

With prompt recognition and appropriate treatment, most patients recover completely from serotonin syndrome. However, without proper treatment, the mortality rate is approximately 11%, emphasizing the importance of rapid intervention 1. Early recognition and management significantly improve outcomes in this potentially life-threatening but highly preventable condition 2, 3.