What are the signs and symptoms of serotonin syndrome?

Signs and Symptoms of Serotonin Syndrome

Serotonin syndrome presents with a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities that typically develop within 6-24 hours after starting or increasing a serotonergic medication. 1

Mental Status Changes

The cognitive and psychiatric manifestations include:

• Agitated delirium is a common presentation 2
• Confusion ranging from mild disorientation to severe altered consciousness 2
• Anxiety and restlessness that feels uncontrollable to the patient 3
• Coma may occur in severe cases 2

These mental status changes are part of the diagnostic triad and typically appear within the first 24-48 hours after medication initiation or dose escalation. 3

Neuromuscular Abnormalities (Highly Diagnostic)

The neuromuscular findings are the most specific for serotonin syndrome:

• Clonus (spontaneous, inducible, or ocular) is highly diagnostic when occurring with serotonergic drug use 1, 2
• Hyperreflexia (exaggerated reflexes) is considered highly diagnostic alongside clonus 1, 2
• Myoclonus (muscle twitching) occurs in 57% of cases and is the most common finding 3
• Muscle rigidity or stiffness, especially prominent in the lower extremities 3, 2
• Tremor is a frequent neuromuscular manifestation 2

Clonus and hyperreflexia are the most specific clinical findings and should be actively sought during examination. 1

Autonomic Hyperactivity

The autonomic manifestations include:

• Hyperthermia with temperatures up to 41.1°C (106°F) 2
• Tachycardia (rapid heart rate) 3, 2
• Hypertension or blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic change within 24 hours) 2
• Diaphoresis (profuse sweating) 3, 2
• Mydriasis (dilated pupils) 2
• Tachypnea (rapid breathing) 3
• Shivering 3

Gastrointestinal Symptoms

• Vomiting or diarrhea can occur as part of the syndrome 3

Diagnostic Criteria (Hunter Criteria - Most Accurate)

The Hunter Criteria should be used for diagnosis, requiring a serotonergic agent plus ONE of the following: 1

• Spontaneous clonus
• Inducible clonus with agitation or diaphoresis
• Ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia together
• Hypertonia with temperature >38°C and ocular or inducible clonus

Severity Spectrum

Mild Cases

• May present with subtle serotonergic features that are easily missed 2
• Symptoms may not cause significant distress initially 4

Moderate Cases

• Cause significant distress and warrant treatment 4
• Not immediately life-threatening but require medical attention 4

Severe Cases (Medical Emergency)

• Rapid onset of severe hyperthermia (>41.1°C) 2
• Severe muscle rigidity 2
• Multiple organ failure 2
• Mortality rate is approximately 11% 1, 2
• One-quarter of patients require intubation, mechanical ventilation, and ICU admission 1

Critical Timing

Symptoms typically emerge within minutes to hours, usually 6-24 hours after starting a serotonergic medication, increasing the dose, or adding a second serotonergic agent. 1, 2 The first 24-48 hours represent the highest-risk period requiring vigilant monitoring. 3

Common Pitfalls

• The presentation is extremely variable, and mild cases are easily missed 2
• There are no pathognomonic laboratory or radiographic findings for diagnosis 2
• The condition can be confused with sepsis, neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic syndrome, and withdrawal syndromes 1
• Physical restraints should NEVER be used as they worsen muscle contractions, leading to increased hyperthermia, lactic acidosis, and higher mortality 3

Life-Threatening Complications

Watch for the following severe complications:

• Rhabdomyolysis with elevated creatine kinase 2
• Metabolic acidosis 1, 2
• Renal failure with elevated serum creatinine 1, 2
• Seizures 1, 2
• Disseminated intravascular coagulopathy 1, 2
• Elevated serum aminotransferase 1, 2