Serotonin syndrome

Background

• Drug-induced excess serotonergic activity in CNS and peripheral nervous system
• Usually results from combination of serotonergic agents or dose increase of a single agent
• Onset typically within 6-24 hours (usually within 6 hours of medication change)
• Mild cases are common; severe cases can be life-threatening
• Mortality ~2-12% in severe cases

Common Causative Agents

• SSRIs: fluoxetine, sertraline, paroxetine, citalopram, escitalopram
• SNRIs: venlafaxine, duloxetine
• MAOIs: phenelzine, tranylcypromine, selegiline, linezolid, methylene blue
• TCAs: amitriptyline, clomipramine
• Opioids: tramadol, meperidine (Demerol), fentanyl, methadone
• Triptans: sumatriptan (controversial, risk likely low)
• Other: dextromethorphan, lithium, MDMA ("ecstasy"), cocaine, ondansetron (rare)
• Most dangerous combination: MAOI + serotonergic agent

Clinical Features

• Rapid onset (hours) — distinguishes from neuroleptic malignant syndrome (days)
• Hunter Serotonin Toxicity Criteria (most sensitive/specific):
  • In setting of serotonergic agent + any ONE of:
    • Spontaneous clonus (most important finding)
    • Inducible clonus + agitation or diaphoresis
    • Ocular clonus + agitation or diaphoresis
    • Tremor + hyperreflexia
    • Hypertonia + temperature >38°C + ocular or inducible clonus

Clinical Triad

• Neuromuscular excitation: clonus (spontaneous, inducible, or ocular), hyperreflexia, tremor, myoclonus, rigidity (severe)
• Autonomic dysfunction: diaphoresis, tachycardia, hyperthermia, hypertension, mydriasis, hyperactive bowel sounds, diarrhea
• Altered mental status: agitation, anxiety, confusion, delirium

Severity Spectrum

• Mild: tremor, hyperreflexia, tachycardia, diaphoresis
• Moderate: agitation, clonus, mydriasis, hyperthermia (≤40°C)
• Severe: hyperthermia >40°C, rigidity, seizures, rhabdomyolysis, DIC, cardiovascular collapse

Differential Diagnosis

Feature	Serotonin Syndrome	Neuroleptic malignant syndrome	Anticholinergic toxicity	Malignant hyperthermia
Onset	Hours	Days	Hours	Minutes (OR)
Key finding	Clonus/hyperreflexia	Lead-pipe rigidity	Mydriasis, dry	Generalized rigidity
Bowel sounds	Hyperactive	Normal/decreased	Absent	Normal
Skin	Diaphoresis	Diaphoresis	Dry, flushed	Mottled
Pupils	Mydriasis	Normal	Mydriasis	Normal
CK	Mildly elevated	>1000	Normal	Markedly elevated

Evaluation

• Clinical diagnosis based on Hunter criteria — no confirmatory lab test
• CK: mildly elevated (markedly elevated if severe → rhabdomyolysis)
• BMP: electrolytes, creatinine (renal injury), bicarbonate (acidosis)
• CBC, LFTs
• Lactate
• Coagulation studies (DIC in severe cases)
• Core temperature
• Medication reconciliation is essential — identify all serotonergic agents

Management

Immediate

• Discontinue ALL serotonergic agents
• Most mild cases resolve within 24-72 hours after drug cessation

Mild (Tremor, Hyperreflexia)

• Observation, IV fluids, benzodiazepines PRN for agitation
• Supportive care

Moderate (Agitation, Clonus, Hyperthermia <40°C)

• Benzodiazepines for agitation and autonomic instability:
  • Lorazepam 2-4 mg IV q5-10min, or midazolam
• Active cooling for hyperthermia (evaporative cooling, ice packs)
• IV fluid resuscitation

Severe (Hyperthermia >40°C, Rigidity, Seizures)

• Cyproheptadine (serotonin antagonist):
  • 12 mg PO/NG initial dose, then 2 mg q2h until clinical improvement
  • Maintenance: 8 mg PO q6h
  • Only available PO/NG — crush and give via NG if intubated
• Intubation with neuromuscular blockade for severe rigidity/hyperthermia
  • Use non-depolarizing agent (avoid succinylcholine if hyperkalemia/rhabdomyolysis risk)
• Aggressive cooling
• Benzodiazepines for seizures

What to Avoid

• NO antipyretics (not effective — hyperthermia is from muscle activity, not altered setpoint)
• NO bromocriptine (for NMS, not SS)
• NO dantrolene (limited role; rigidity in SS is different from NMS)
• Avoid restraints alone without chemical sedation (isometric muscle contraction worsens hyperthermia)

Disposition

• Mild: observe 6-12 hours; discharge if improving after drug cessation
• Moderate: admit to monitored bed
• Severe: ICU admission
• Symptoms typically resolve within 24-72 hours (longer for fluoxetine/MAOIs — longer half-life)
• Before restarting serotonergic medications: allow washout period (5 half-lives)
  • Fluoxetine: 5 weeks; MAOIs: 2 weeks

See Also

• Neuroleptic malignant syndrome
• Anticholinergic toxicity
• Malignant hyperthermia
• Toxicology
• MAOI toxicity

References

• Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120. PMID 15784664
• Isbister GK, et al. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust. 2007;187(6):361-365. PMID 17874986
• Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010;81(9):1139-1142. PMID 20433130