How to diagnose serotonin syndrome in a patient with a history of depression, anxiety, hyperthyroidism, or menopause, taking Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), or Monoamine Oxidase Inhibitors (MAOIs)?

How to Test for Serotonin Syndrome

Serotonin syndrome is diagnosed clinically using the Hunter Criteria—there are no laboratory tests or imaging studies that can confirm the diagnosis. 1

Diagnostic Approach Using Hunter Criteria

The diagnosis requires exposure to a serotonergic agent (SSRIs, SNRIs, MAOIs, or other serotonergic drugs) plus ONE of the following clinical findings: [1, 2

• Spontaneous clonus (most specific finding)
• Inducible clonus (ankle or patellar) PLUS agitation or diaphoresis
• Ocular clonus (horizontal eye movements) PLUS agitation or diaphoresis
• Tremor AND hyperreflexia together
• Hypertonia (muscle rigidity) PLUS temperature >38°C (100.4°F) PLUS ocular or inducible clonus

The Hunter Criteria have 84% sensitivity and 97% specificity, making them superior to older diagnostic criteria. 1

Key Clinical Features to Assess

Neuromuscular Examination (Most Diagnostic)

• Check for clonus: Test ankle clonus by rapidly dorsiflexing the foot; test patellar clonus by rapidly pushing the patella downward. Sustained rhythmic contractions indicate positive clonus. [1, 3
• Assess hyperreflexia: Test deep tendon reflexes, particularly in lower extremities where findings are typically more pronounced. [1, 3
• Evaluate for myoclonus: Look for brief, involuntary muscle jerks. 4
• Check muscle tone: Assess for rigidity or hypertonia. 1

Autonomic Signs

• Temperature: Measure core temperature (can reach 41.1°C in severe cases). 1
• Vital signs: Document tachycardia, tachypnea, and blood pressure (may show hypertension or fluctuations ≥20 mmHg diastolic or ≥25 mmHg systolic). 1
• Diaphoresis: Observe for excessive sweating. 4
• Pupil examination: Check for mydriasis (dilated pupils). 4

Mental Status Changes

• Assess for agitation, confusion, or agitated delirium—these are common presenting features. 1
• In severe cases, altered consciousness can range from confusion to coma. 1

Timeline Considerations

Symptoms typically develop within 6-24 hours after starting a serotonergic medication, increasing the dose, or adding a second serotonergic agent. 1 This rapid onset is a key diagnostic clue distinguishing serotonin syndrome from other conditions.

Laboratory Testing (For Complications, Not Diagnosis)

While no lab test diagnoses serotonin syndrome, obtain the following to assess for complications in moderate-to-severe cases: 1

• Creatine kinase: To detect rhabdomyolysis
• Basic metabolic panel: To identify metabolic acidosis and renal failure (elevated creatinine)
• Liver function tests: Elevated aminotransferases may occur
• Coagulation studies: To screen for disseminated intravascular coagulopathy

Critical Differential Diagnoses to Exclude

Neuroleptic Malignant Syndrome (NMS)

• Key distinguishing features: NMS presents with "lead pipe" rigidity (versus hyperreflexia/clonus in serotonin syndrome), history of antipsychotic use (not serotonergic agents), and slower onset over days to weeks. 1

Anticholinergic Toxicity

• Look for dry skin (versus diaphoresis in serotonin syndrome), decreased bowel sounds, and urinary retention—features absent in serotonin syndrome. 5

Malignant Hyperthermia

• Requires exposure to volatile anesthetics or succinylcholine, not serotonergic medications. 5

Common Diagnostic Pitfalls

• Missing mild cases: The presentation is highly variable, and mild cases with subtle hyperreflexia or minimal clonus are easily overlooked. 1
• Failing to check for clonus: This is the most specific finding but requires active testing—it won't be apparent on casual observation. [1, 3
• Not obtaining medication history: Always ask specifically about over-the-counter medications (dextromethorphan), herbal supplements (St. John's Wort), and illicit drugs (MDMA, cocaine), as patients often don't volunteer this information. 6
• Lower extremity focus: Hyperreflexia and clonus are typically more pronounced in the lower extremities than upper extremities. 1

Severity Classification After Diagnosis

Once diagnosed, classify severity to guide treatment intensity: 1

• Mild: Hyperreflexia, tremor, mild agitation—outpatient management may be possible after observation
• Moderate: Significant autonomic instability, temperature elevation, prominent clonus—requires hospitalization with continuous cardiac monitoring
• Severe: Hyperthermia >41.1°C, severe rigidity, altered consciousness—medical emergency requiring ICU admission with mortality rate of approximately 11%