What is serotonin syndrome?

Serotonin Syndrome: Diagnosis and Management

Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonergic activity in the central and peripheral nervous system, characterized by a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. 1

Clinical Presentation

Serotonin syndrome presents with three key categories of symptoms:

1. Neuromuscular Abnormalities:

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

2. Autonomic Hyperactivity:

   • Tachycardia
   • Hypertension (or hypotension in severe cases)
   • Hyperthermia (>38°C)
   • Diaphoresis
   • Mydriasis

3. Mental Status Changes:

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

Diagnostic Criteria

The Hunter criteria are the diagnostic standard for serotonin syndrome, requiring:

• Patient has taken a serotonergic agent within the past 5 weeks
• One or more of the following symptoms 1:
  • 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

Common Causative Medications

Serotonin syndrome is associated with numerous medications 1, 2:

• Antidepressants: SSRIs, SNRIs, TCAs, MAOIs
• Antimigraine drugs: Triptans
• Antiemetics: Ondansetron, metoclopramide
• Antibiotics: Linezolid
• Analgesics: Tramadol, fentanyl
• Over-the-counter medications: Dextromethorphan
• Herbal supplements: St. John's wort
• Drugs of abuse: MDMA, cocaine, LSD

Management Algorithm

1. Immediate discontinuation of all serotonergic agents - This is the most critical first step 1

2. Supportive care:

   • IV fluid administration for dehydration
   • External cooling for hyperthermia
   • Cardiac monitoring
   • Respiratory support if needed

3. Pharmacological management:

   • Mild symptoms: Supportive care and benzodiazepines for agitation
   • Moderate to severe symptoms:
     • Benzodiazepines for agitation control
     • Cyproheptadine (serotonin antagonist) - initial dose of 12 mg orally, followed by 2 mg every 2 hours until symptoms improve 1, 3
     • Consider ICU admission for severe cases 4

4. Monitor for complications:

   • Rhabdomyolysis
   • Renal failure
   • Disseminated intravascular coagulation
   • Seizures

Differential Diagnosis

Important conditions to distinguish from serotonin syndrome 1, 2:

• Neuroleptic Malignant Syndrome (NMS): Associated with dopamine antagonists, presents with "lead-pipe" rigidity, develops more slowly
• Anticholinergic toxicity: Presents with dry mucous membranes, urinary retention, decreased bowel sounds
• Malignant hyperthermia: Associated with anesthetic agents
• Sepsis: May have identifiable source of infection
• Decompensated hyperthyroidism: Thyroid function tests abnormal

Prognosis

• Mortality rate is approximately 11% for untreated serotonin syndrome 1
• Most mild to moderate cases resolve within 24-72 hours after discontinuation of the offending agent 5
• With prompt recognition and appropriate management, the prognosis is generally favorable 3

Prevention

• Avoid combining multiple serotonergic agents
• Be aware of drug interactions, particularly MAOIs with other serotonergic medications
• Educate patients about potential interactions with over-the-counter medications and supplements
• Maintain appropriate washout periods when switching between serotonergic medications

Common Pitfalls

• Misdiagnosis: Serotonin syndrome is frequently misdiagnosed due to its nonspecific symptoms 2
• Delayed recognition: Symptoms may be attributed to the underlying condition being treated
• Medication reconciliation errors: Failing to identify all serotonergic medications a patient is taking
• Confusing with Parkinson's disease symptoms: Tremor in serotonin syndrome may be confused with Parkinsonian tremor 4
• Overlooking mild cases: Not all three components of the clinical triad may be present simultaneously 5