What are the symptoms and treatment of serotonin syndrome?

Serotonin Syndrome: Symptoms and Treatment

Clinical Presentation

Serotonin syndrome presents with a classic triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities that typically develop within 6-24 hours of starting or increasing a serotonergic medication. 1, 2

Mental Status Changes

• Agitated delirium and confusion are the most common presentations 2
• Altered consciousness ranging from mild confusion to coma in severe cases 2
• Anxiety and restlessness may occur in milder presentations 3

Neuromuscular Abnormalities (Most Diagnostic)

• Clonus (spontaneous, inducible, or ocular) and hyperreflexia are the most specific findings and highly diagnostic when occurring with serotonergic drug use 1, 2
• Myoclonus occurs in 57% of cases 4
• Muscle rigidity and tremor are common 2, 3
• Hyperreflexia is a key distinguishing feature 2, 5

Autonomic Hyperactivity

• Hyperthermia (temperature can reach 41.1°C or higher in severe cases) 2
• Tachycardia and tachypnea 2
• Hypertension or blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic change within 24 hours) 2
• Profuse diaphoresis 2, 5
• Mydriasis (dilated pupils) 2

Diagnostic Approach

Use the Hunter Criteria for diagnosis, which requires a serotonergic agent plus ONE of the following: 1, 2, 5

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

Important diagnostic pitfall: The presentation is extremely variable and mild cases are easily missed, so maintain high clinical suspicion in any patient on serotonergic agents with neuromuscular hyperactivity 2

Differential Diagnosis

• Neuroleptic malignant syndrome (NMS): Distinguished by lead pipe rigidity (not clonus/hyperreflexia), delirium, and history of antipsychotic use rather than serotonergic agents 2
• Malignant hyperthermia, anticholinergic syndrome, and withdrawal syndromes must also be excluded 1, 4

Treatment Algorithm

Step 1: Immediate Actions

Discontinue ALL serotonergic agents immediately—this is the cornerstone of treatment 1, 4

Step 2: Supportive Care (All Cases)

• Administer benzodiazepines as first-line treatment for agitation, neuromuscular symptoms, and tremor 1, 4
• Provide IV fluids for dehydration and autonomic instability 1, 4
• Implement external cooling measures (cooling blankets) for hyperthermia 1
• Avoid physical restraints as they worsen hyperthermia and lactic acidosis through isometric muscle contractions 1, 4
• Antipyretics are ineffective because hyperthermia results from muscular hyperactivity, not hypothalamic dysregulation 1

Step 3: Severity-Based Management

Mild Cases:

• Supportive care alone with benzodiazepines 4, 5
• Most resolve within 24-48 hours after discontinuing serotonergic agents 2

Moderate to Severe Cases:

• Hospitalization with continuous cardiac monitoring is required 1, 2
• Administer cyproheptadine (serotonin antagonist): 12 mg orally initially, then 2 mg every 2 hours until symptom improvement 1, 2
• Maintenance dose: 8 mg every 6 hours after initial symptom control 1, 2
• Pediatric dosing: 0.25 mg/kg per day 2
• Warning: Cyproheptadine may cause sedation and hypotension 1, 2

Severe Cases (Medical Emergency):

• ICU admission for severe hyperthermia (>41.1°C), muscle rigidity, and autonomic instability 2, 4
• Approximately 25% of patients require intubation and mechanical ventilation 1
• Consider intubation with paralysis using non-depolarizing agents (avoid succinylcholine due to hyperkalemia and rhabdomyolysis risk) 2
• For hemodynamic instability, use direct-acting sympathomimetics (phenylephrine, norepinephrine) rather than indirect agents like dopamine 2

Step 4: Monitor for Complications

• Rhabdomyolysis with elevated creatine kinase 2
• Metabolic acidosis 1, 2
• Renal failure with elevated creatinine 2
• Elevated serum aminotransferases 1, 2
• Seizures and disseminated intravascular coagulopathy 1, 2
• The mortality rate is approximately 11%, emphasizing the need for prompt recognition 1, 2, 4

Step 5: Treatment Duration

Continue cyproheptadine until the complete clinical triad resolves: mental status normalizes, neuromuscular hyperactivity (clonus, hyperreflexia) disappears, and autonomic instability (vital signs, diaphoresis) resolves 2

Critical Clinical Pearls

• Symptoms develop rapidly, typically within 6-24 hours of medication initiation or dose increase 1, 2, 6
• 74% of patients present within 24 hours of the precipitating event 6
• Serotonin syndrome is NOT idiosyncratic—it is predictable and preventable, occurring with new drugs, dose increases, or drug combinations 2, 4, 7
• Most mild-to-moderate cases resolve within 24-48 hours with appropriate management 2, 6
• With prompt recognition and treatment, the prognosis is favorable even in severe cases 7, 5