What are the signs of serotonin syndrome?

Signs of Serotonin Syndrome

Serotonin syndrome is characterized by a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities that can be diagnosed using the Hunter criteria, which require the presence of a serotonergic drug within the past 5 weeks plus specific symptoms. 1

Clinical Presentation

The classic triad of serotonin syndrome includes:

1. Mental Status Changes:

   • Agitation
   • Confusion
   • Delirium
   • Restlessness
   • Altered consciousness 1, 2

2. Autonomic Hyperactivity:

   • Hyperthermia (temperature >38°C)
   • Tachycardia
   • Hypertension
   • Diaphoresis (excessive sweating)
   • Dilated pupils
   • Diarrhea 1, 2

3. Neuromuscular Abnormalities:

   • Tremor
   • Hyperreflexia
   • Muscle rigidity
   • Clonus (spontaneous, inducible, or ocular)
   • Muscle jerking
   • "Lead-pipe" rigidity in severe cases 1, 3

Diagnostic Criteria: Hunter Criteria

The Hunter criteria are considered the diagnostic standard for serotonin syndrome. Diagnosis requires:

• Patient has taken a serotonergic drug within the past 5 weeks
• Plus one or more 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 1, 3

Severity Spectrum

Serotonin syndrome presents on a spectrum of severity:

• Mild: Mild symptoms may include tremor, hyperreflexia, and anxiety
• Moderate: More pronounced symptoms with increased vital signs, hyperthermia, hyperactive bowel sounds, and clonus
• Severe: Life-threatening with severe hyperthermia, muscle rigidity, autonomic instability, and altered mental status requiring ICU admission 4, 5

Common Medications Associated with Serotonin Syndrome

Serotonin syndrome is invariably caused by serotonergic medications, including:

• Selective Serotonin Reuptake Inhibitors (SSRIs)
• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
• Monoamine Oxidase Inhibitors (MAOIs)
• Tricyclic Antidepressants
• Opioid analgesics (particularly tramadol, meperidine)
• Antimigraine medications
• Antiemetics
• Herbal supplements (e.g., St. John's Wort)
• Recreational drugs (e.g., MDMA/ecstasy, cocaine) 1, 2

Clinical Pitfalls and Caveats

• Diagnostic confusion: Serotonin syndrome can be confused with neuroleptic malignant syndrome, but NMS typically has "lead-pipe" rigidity and develops more slowly 1
• Overlooked in Parkinson's disease: Tremor in serotonin syndrome may be attributed to underlying Parkinson's disease 5
• Rapid onset: Symptoms typically develop within 24 hours of medication changes or additions 4
• Drug interactions: The most severe cases often involve MAOIs combined with other serotonergic agents 6
• Physician unawareness: Many clinicians are unfamiliar with this condition, leading to missed diagnoses 2

Management Approach

1. Immediate discontinuation of all serotonergic agents
2. Supportive care: IV fluids, cooling measures for hyperthermia
3. Benzodiazepines: For agitation, tremor, and muscle hyperactivity
4. Serotonin antagonists: Cyproheptadine for moderate to severe cases
5. Critical care: Severe cases may require neuromuscular paralysis, sedation, and intubation 1, 3, 4

Early recognition of serotonin syndrome is crucial as most cases resolve within 24-72 hours with prompt discontinuation of the offending agent and appropriate supportive care. Untreated severe cases can progress to rhabdomyolysis, renal failure, disseminated intravascular coagulation, and death, with mortality rates of approximately 11% for untreated cases 1, 4.