What are the signs and symptoms of serotonin syndrome?

Signs and Symptoms of Serotonin Syndrome

Serotonin syndrome presents with a classic triad of neuromuscular excitation, autonomic dysfunction, and altered mental status, with key diagnostic features including muscle rigidity, hyperthermia (>38°C), ocular or inducible clonus, tremor, and hyperreflexia. 1

Clinical Presentation

Serotonin syndrome manifests across three primary domains:

1. Neuromuscular Abnormalities

• Hyperreflexia - Often one of the earliest signs
• Clonus - Can be spontaneous, inducible, or ocular
• Muscle rigidity - Particularly in moderate to severe cases
• Tremor - Often fine and rapid
• Myoclonus - Involuntary muscle jerking 1, 2

2. Autonomic Dysfunction

• Hyperthermia - Temperature >38°C in more severe cases
• Tachycardia - Common finding
• Blood pressure changes - Both hypertension and hypotension can occur
• Diaphoresis - Excessive sweating
• Dilated pupils (mydriasis)
• Diarrhea 1, 3

3. Mental Status Changes

• Agitation - Often prominent
• Confusion - Ranging from mild to severe
• Delirium - Disorganized thinking
• Anxiety
• Coma - In severe cases 2, 3

Diagnostic Criteria

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

1. Patient has taken a serotonergic drug within the past 5 weeks
2. 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, 4

Severity Spectrum

Serotonin syndrome ranges from mild to life-threatening:

Mild

• Mild tachycardia
• Slight hypertension
• Diaphoresis
• Mydriasis
• Tremor
• Hyperreflexia without clonus 5, 4

Moderate

• Tachycardia
• Hypertension
• Hyperthermia (up to 40°C)
• Hyperactive bowel sounds
• Horizontal ocular clonus
• Inducible clonus
• Mild agitation
• Pressured speech 5, 4

Severe

• Hyperthermia (>41.1°C)
• Dramatic swings in pulse rate and blood pressure
• Delirium
• Muscle rigidity
• Sustained clonus
• Rhabdomyolysis
• Metabolic acidosis
• Disseminated intravascular coagulation
• Renal failure
• Seizures
• Coma 1, 4

Important Clinical Considerations

• Symptoms typically develop rapidly, often within hours of medication changes or overdose 3
• All three components of the triad may not occur simultaneously 5
• The condition is often misdiagnosed due to its nonspecific and diverse clinical manifestations 5, 3
• Untreated severe serotonin syndrome has an approximately 11% mortality rate 1

Common Pitfalls in Diagnosis

• Confusing with similar conditions: Particularly neuroleptic malignant syndrome, which presents with "lead-pipe" rigidity rather than clonus and develops more slowly 1, 2
• Overlooking mild cases: Early symptoms may be subtle and attributed to anxiety or other conditions 3
• Failing to obtain medication history: Not recognizing all potential serotonergic agents, including over-the-counter medications and supplements like St. John's Wort 3
• Missing drug interactions: Not recognizing that combinations of serotonergic agents significantly increase risk 6

Risk Factors

• Use of multiple serotonergic medications concurrently
• Recent medication changes or dose increases
• Rapid titration of serotonergic agents
• Combining MAOIs with other serotonergic medications (particularly high risk)
• Use of recreational drugs like MDMA (ecstasy) or cocaine 1, 3, 6

Remember that serotonin syndrome is a predictable and preventable adverse drug reaction rather than an idiosyncratic response, making awareness of its signs and symptoms crucial for early recognition and management 5.