What is serotonin syndrome?

What is Serotonin Syndrome?

Serotonin syndrome is a potentially life-threatening drug-induced condition caused by excessive serotonergic activity in the central and peripheral nervous systems, characterized by a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. 1

Pathophysiology

Serotonin syndrome results from overstimulation of serotonin receptors, particularly the 5-HT1A and 5-HT2A subtypes, due to increased intrasynaptic serotonin levels. 2, 3 The severity of symptoms correlates directly with the concentration of free serotonin in the synaptic cleft. 2

Clinical Presentation

The syndrome manifests through three key domains:

Mental Status Changes

• Agitated delirium 1
• Confusion 1
• Hallucinations 4
• Coma in severe cases 4

Autonomic Hyperactivity

• Hyperthermia (up to 41.1°C in severe cases) 1
• Tachycardia and tachypnea 1
• Hypertension or labile blood pressure 4
• Diaphoresis (profuse sweating) 1
• Mydriasis (dilated pupils) 1

Neuromuscular Abnormalities

• Clonus (spontaneous, inducible, or ocular) - highly diagnostic 1, 5
• Hyperreflexia - highly diagnostic 1, 5
• Myoclonus (present in 57% of cases) 6
• Muscle rigidity 1
• Tremor 1

Timing and Onset

Symptoms typically develop within 6-24 hours after starting a serotonergic medication, increasing the dose, or adding a second serotonergic agent. 1, 5 The condition is non-idiosyncratic, meaning it is predictable and dose-related rather than an allergic reaction. 6, 7

Causative Medications

Serotonin syndrome occurs with numerous drug classes: 8

• SSRIs and SNRIs (sertraline, fluoxetine, etc.) 4, 9
• MAOIs (especially dangerous in combination) 4, 2
• Tricyclic antidepressants 4
• Triptans (migraine medications) 4
• Opioids (particularly tramadol and fentanyl) 4
• Linezolid (antibiotic with MAOI properties) 4
• Methylene blue (intravenous) 4
• St. John's Wort 4
• Lithium, buspirone, tryptophan 4

Critical pitfall: Life-threatening cases most commonly occur when MAOIs are combined with serotonin reuptake inhibitors. 2, 3

Diagnostic Criteria

Hunter Criteria (Recommended by American Academy of Pediatrics)

Requires a serotonergic agent plus one of the following: 1, 5

• Spontaneous clonus
• Inducible clonus + (agitation OR diaphoresis)
• Ocular clonus + (agitation OR diaphoresis)
• Tremor + hyperreflexia
• Hypertonia + temperature >38°C + (ocular clonus OR inducible clonus)

Key diagnostic point: There are no pathognomonic laboratory or radiographic findings for serotonin syndrome—diagnosis is purely clinical. 1

Severity Classification

Mild

• Mild tremor, hyperreflexia, tachycardia 7
• Resolves with supportive care 7

Moderate

• Requires hospitalization 5
• Prominent autonomic symptoms 10

Severe (Medical Emergency)

• Hyperthermia >41.1°C 1
• Severe muscle rigidity 1
• Multiple organ failure 1
• Mortality rate approximately 11% 1, 5
• Approximately 25% require intubation and ICU admission 6, 5

Complications of Severe Cases

• Rhabdomyolysis with elevated creatine kinase 1
• Metabolic acidosis 1
• Renal failure 1
• Elevated liver enzymes 1
• Seizures 1
• Disseminated intravascular coagulopathy 1

Differential Diagnosis

Serotonin syndrome must be distinguished from: 6, 5

• Neuroleptic malignant syndrome (slower onset, "lead pipe" rigidity without hyperreflexia)
• Malignant hyperthermia (occurs with anesthesia)
• Anticholinergic syndrome (dry skin, absent bowel sounds, mydriasis without hyperreflexia)
• Withdrawal syndromes

Distinguishing features: Myoclonus and hyperreflexia strongly favor serotonin syndrome over these alternatives. 6

Management Principles

Immediate Actions

1. Discontinue all serotonergic agents immediately 6, 5
2. Administer benzodiazepines as first-line treatment for agitation, neuromuscular symptoms, and tremor 6, 5
3. Provide IV fluids for dehydration and autonomic instability 6, 5
4. Implement external cooling measures (cooling blankets) for hyperthermia 6, 5

Severe Cases

• Cyproheptadine 12 mg initially, then 2 mg every 2 hours until symptom improvement (maintenance 8 mg every 6 hours) 1
• ICU admission with aggressive cooling 1, 6
• Consider intubation with non-depolarizing paralytic agents (avoid succinylcholine due to hyperkalemia risk) 1
• Use direct-acting vasopressors (phenylephrine, norepinephrine) if needed 1

Critical Pitfalls to Avoid

• Do not use physical restraints (worsens isometric contractions, hyperthermia, and lactic acidosis) 6, 5
• Antipyretics are ineffective (fever results from muscular hyperactivity, not hypothalamic dysregulation) 1, 5
• Avoid succinylcholine in severe cases 1

Prevention

The condition is highly preventable through careful medication reconciliation and avoiding dangerous drug combinations, particularly MAOIs with serotonin reuptake inhibitors. 4, 7 When switching from an SSRI to an MAOI, appropriate washout periods are essential (5 weeks for fluoxetine due to its long half-life). 4