What are the symptoms of serotonin syndrome?

Symptoms of Serotonin Syndrome

Serotonin syndrome is characterized by a classic triad of neuromuscular excitation, autonomic instability, and altered mental status, with specific diagnostic features including muscle rigidity, hyperthermia (>38°C), ocular clonus, inducible clonus, tremor, and hyperreflexia. 1

Diagnostic Criteria

According to the American Academy of Pediatrics, the Hunter criteria are considered the diagnostic standard for serotonin syndrome, requiring:

1. Patient must have taken a serotonergic drug within the past 5 weeks
2. At least one of the following symptoms or combinations:
   • Spontaneous clonus
   • Inducible clonus with agitation or diaphoresis
   • Ocular clonus with agitation or diaphoresis
   • Tremor and hyperreflexia
   • Hypertonia, temperature above 38°C (100.4°F), and ocular or inducible clonus 1, 2

Symptom Categories

Neuromuscular Symptoms

• Muscle rigidity
• Tremor
• Hyperreflexia
• Clonus (spontaneous, inducible, or ocular)
• Myoclonus
• Muscle fasciculations 1, 3

Autonomic Symptoms

• Hyperthermia (>38°C/100.4°F)
• Tachycardia
• Hypertension
• Diaphoresis (excessive sweating)
• Dilated pupils
• Flushing 1, 4

Mental Status Changes

• Agitation
• Confusion
• Altered consciousness
• Anxiety
• Hallucinations
• Delirium 1, 2, 4

Gastrointestinal Symptoms

• Diarrhea
• Nausea
• Vomiting 4

Severity Spectrum

Serotonin syndrome presents on a spectrum of severity:

• Mild cases: Mild tachycardia, shivering, diaphoresis, mydriasis, intermittent tremor
• Moderate cases: Increased heart rate and blood pressure, hyperthermia (up to 40°C), hyperactive bowel sounds, hyperreflexia, clonus, mild agitation
• Severe cases: Severe hyperthermia (>41.1°C), dramatic fluctuations in pulse rate and blood pressure, delirium, muscle rigidity 2, 4

Common Pitfalls and Caveats

1. Diagnostic challenges: Serotonin syndrome is a diagnosis of exclusion and can be underrecognized, making the true incidence unknown 3, 4

2. Headache as presenting symptom: Headache may be an overlooked early symptom of serotonin syndrome, especially in patients recently started on serotonergic medications 5

3. Differentiation from other conditions: Serotonin syndrome can be confused with neuroleptic malignant syndrome, anticholinergic toxicity, or sympathomimetic toxidromes 1

4. Rapid onset: Symptoms typically develop rapidly, often within hours of medication changes or additions 2, 6

5. Recognition of drug combinations: The most dangerous combinations include MAOIs with SSRIs, MAOIs with tricyclic antidepressants, MAOIs with tryptophan, and MAOIs with pethidine (meperidine) 6

If left unrecognized and untreated, serotonin syndrome carries a mortality rate of approximately 11% according to the American Academy of Pediatrics and the National Institute of Mental Health 1, 3.