Serotonin Syndrome

Serotonin syndrome is a potentially life-threatening state of excess serotonergic activity (mostly through 5-HT2A and 5-HT1A receptors) in the central and peripheral nervous system. It results from therapeutic doses, drug interactions or overdose. Spectrum: mild (tremor, hyperreflexia, tachycardia) to fatal (hyperthermia over 41 degrees Celsius, rigidity, rhabdomyolysis, disseminated intravascular coagulation).

Causative drugs

• Selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants
• Monoamine oxidase inhibitors (the most dangerous, including linezolid and methylene blue)
• Opioids (tramadol, meperidine, fentanyl, methadone)
• Triptans, ondansetron, lithium, buspirone, dextromethorphan, St John's wort
• Amphetamines, MDMA, cocaine and linezolid

The most dangerous combination is an irreversible monoamine oxidase inhibitor with a serotonergic agent, and a washout of 2 weeks (5 weeks after fluoxetine) is needed between them.

Onset is within 6 hours of a new drug or dose change in about 60% of cases, and within 24 hours in most. Resolution is usually within 24 to 72 hours with removal of the drug, but longer with long-acting agents.

Mortality is under 1% with prompt care, and complications are rhabdomyolysis, renal failure, seizures, disseminated intravascular coagulation, respiratory failure and aspiration.

• Triad: altered mental status (agitation, restlessness, confusion), autonomic hyperactivity (diaphoresis, tachycardia, hypertension, hyperthermia, mydriasis, diarrhea, flushing) and neuromuscular excitation
• Neuromuscular signs, which are the most useful: inducible clonus, spontaneous clonus, ocular clonus (slow horizontal eye movements), tremor, hyperreflexia (greater in the legs) and rigidity
• Severe: temperature over 41 degrees Celsius, muscle rigidity (more in the lower limbs), seizures, delirium and shock
• Features distinguishing it from neuroleptic malignant syndrome: onset within hours, hyperreflexia and clonus, normal or increased bowel sounds, and rapid resolution
• Red flags: temperature over 38.5 degrees Celsius, rigidity, a heart rate over 140 beats a minute and a fall in conscious level

1. Clinical diagnosis: a serotonergic drug within the past 5 weeks, plus one of: spontaneous clonus; inducible clonus with agitation or diaphoresis; ocular clonus with agitation or diaphoresis; tremor with hyperreflexia; or hypertonia with temperature over 38 degrees Celsius and ocular or inducible clonus.
2. Laboratory tests: creatine kinase, creatinine, electrolytes, bicarbonate, lactate, liver tests, coagulation studies and blood count. Findings are nonspecific and mainly define complications.
3. ECG and cultures or lumbar puncture and neuroimaging where infection or another cause is suspected.
4. Toxicology screen and a medication review including herbal products and recreational drugs.

Differentials: neuroleptic malignant syndrome, anticholinergic toxicity, malignant hyperthermia, sympathomimetic toxicity, withdrawal states, thyroid storm, encephalitis, heat stroke.

1. Stop all serotonergic drugs and give supportive care: IV crystalloid, oxygen, cardiac monitoring, correction of electrolytes.
2. Mild disease: observation for 6 to 12 hours, benzodiazepines for agitation (diazepam 5 to 10 mg IV or lorazepam 1 to 2 mg IV).
3. Moderate disease:
   • Diazepam 5 to 10 mg IV every 5 to 10 minutes as needed.
   • Cyproheptadine 12 mg orally (or crushed through a nasogastric tube) as the first dose, then 2 mg every 2 hours while symptoms continue, followed by maintenance 8 mg every 6 hours (maximum 32 mg daily). Expect sedation and anticholinergic effects.
   • Children: cyproheptadine 0.25 mg/kg a day in divided doses.
   • Chlorpromazine 50 to 100 mg IM is an alternative if oral therapy is impossible (hypotension and neuroleptic malignant syndrome risk).
4. Severe disease (temperature over 41.1 degrees Celsius): immediate sedation, intubation and neuromuscular paralysis with a non-depolarizing agent (rocuronium 1 mg/kg IV). Avoid succinylcholine because of hyperkalemia from rhabdomyolysis. Active external cooling.
5. Hypertension and tachycardia: short-acting titratable agents (esmolol 500 micrograms/kg IV load then 50 to 200 micrograms/kg/min, or nitroprusside 0.5 to 10 micrograms/kg/min). Hypotension: norepinephrine or phenylephrine. Avoid dopamine and long-acting beta blockers.
6. Rhabdomyolysis: IV crystalloid at 200 to 300 mL/h to keep urine output above 1 mL/kg/h.
7. Avoid antipyretics (they do not work because the fever is muscular), bromocriptine and dantrolene (no benefit and may harm), and physical restraints.

Follow-up: observation for 24 hours after symptoms resolve, review of the indication for all serotonergic drugs, and counsel on interactions (including over-the-counter dextromethorphan and herbal products).