Serotonin Syndrome

BASICS

Definition: Potentially life-threatening drug-induced syndrome due to increased synaptic serotonin (5-HT) with stimulation of CNS/peripheral serotonin receptors.
Classic Triad: Mental status changes, neuromuscular hyperactivity, autonomic instability.
Onset: Usually within 24 hours (often within 6 hours) of serotonergic agent exposure, dose increase, or drug interaction.
Settings: Therapeutic use (mild/moderate), overdose (moderate), or drug interaction (often severe).
High-Risk Agents/Combinations: SSRIs, SNRIs, MAOIs, TCAs, buspirone, lithium, tramadol, fentanyl, linezolid, dextromethorphan, St. John’s wort, MDMA, triptans, others.
Incidence: ~14–16% of SSRI overdose patients.

Increased Risk: Polypharmacy (elderly), drug interactions, dose increases, intentional/accidental overdose.
Children: Similar presentation; consider accidental ingestion.
Neonates: Tremor, hypertonia, irritability, feeding/sleep disturbances, increased reflexes.

Careful review of drug–drug interactions before prescribing multiple serotonergic agents.
Avoid unnecessary serotonergic medications for nonpsychiatric indications (e.g., tramadol).
Warn patients to check with a physician before starting OTC/herbal agents (e.g., St. John’s wort).

Neuromuscular: Hyperreflexia (esp. lower limbs), clonus (spontaneous, inducible, ocular), myoclonus, rigidity, bilateral Babinski, tremor.
Autonomic: Diaphoresis, tachycardia, hypertension, hyperthermia (severe: >40°C), mydriasis, hyperactive bowel sounds, diarrhea.
Mental status: Agitation, anxiety, insomnia, confusion, delirium, coma (severe).
Severe cases: Muscle rigidity, respiratory failure, tonic-clonic seizures, DIC, ARDS, rhabdomyolysis, metabolic acidosis.

Discontinue offending agent(s) immediately.
Supportive care is the mainstay:
Oxygen, IV fluids, cardiac monitoring, urine output.
Monitor for complications (rhabdomyolysis, DIC, ARDS).
Benzodiazepines for agitation, tremor, mild ↑BP/HR.
Cyproheptadine (serotonin antagonist) if not controlled with benzos/supportive care.
Antipyretics not effective (hyperthermia is due to muscle activity, not hypothalamic set-point).
Avoid restraints (may worsen hyperthermia/lactic acidosis).
Severe cases: Immediate sedation, intubation, paralysis (with nondepolarizing paralytics only).

Adult: 12 mg PO (or NG), then 2 mg q2h until response (max 32 mg/24h).
Pediatrics: <2 years: 0.06 mg/kg q6h; 2–6 years: 2 mg q6h; 7–14 years: 4 mg q6h.

ICU admission for severe cases.
Referral: Psychiatry (for med management), toxicology, poison control.
Discharge: Only after full clinical recovery and stable vital/neurologic signs.

Address risk/benefit of restarting serotonergic meds (generally not advised after severe syndrome).
Titrate any reinitiated serotonergic medications slowly with close monitoring.

Most cases resolve within 24 hours after discontinuation, but may persist longer for drugs with long half-lives (SSRIs, MAOIs).
Complications/death most commonly due to uncontrolled hyperthermia.

Renal failure, ARDS, arrhythmia, coma, DIC, seizure, metabolic acidosis, multiorgan failure, myoglobinuria, respiratory arrest, rhabdomyolysis.

Suspect serotonin syndrome in patients on serotonergic agents with unexplained agitation, clonus, hyperreflexia, tachycardia, hypertension, and hyperthermia.
Severity ranges from mild (tremor, anxiety, tachycardia) to life-threatening (rigidity, delirium, hyperthermia, organ failure).
Combination therapy (SSRIs + MAOIs or others) is the most dangerous risk factor.
Hunter Criteria are most useful for diagnosis.
Cyproheptadine is the serotonin antagonist of choice if benzodiazepines/supportive measures fail.