Serotonin syndrome: Preventing, recognizing, and treating it

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FIGURE 1
Algorithm for clinical diagnosis of serotonin based on Hunter serotonin toxicity criteria (based on information in reference 9).

TABLE 1

Drug mechanisms associated with serotonin syndrome

Mechanism	Specific agents
Decreased serotonin breakdown	Monoamine oxidase inhibitors^a: phenelzine, tranylcypromine, isocarboxazid, moclobemide, selegiline, rasagiline Antibiotics: linezolid, tedizolid Others: methylene blue, procarbazine, Syrian rue
Decreased serotonin reuptake	Antidepressants: Selective serotonin reuptake inhibitors^a : fluoxetine, fluvoxamine, paroxetine, citalopram, sertraline, escitalopram Serotonin-norepinephrine reuptake inhibitors^a: venlafaxine, duloxetine, milnacipran Tricyclic antidepressants^a: clomipramine, imipramine St. John’s wort Opioids^a: meperidine, buprenorphine, tramadol, tapentadol, dextromethorphan Antiepileptics: valproate, carbamezapine Antiemetics: ondansetron, granisetron, metoclopramide
Increased serotonin precursors or agonists	Tryptophan, lithium, fentanyl, lysergic acid diethylamide (LSD)
Increased serotonin release	Central nervous system stimulants: amphetamines^a Anorectics^a: fenfluramine, dexfenfluramine, phentermine Drugs of abuse: methylenedioxymethamphetamine (ecstasy),^a cocaine
CYP2D6 and CYP3A4 inhibitors	Antibiotics: erythromycin, ciprofloxacin Antifungal: fluconazole Antiretroviral: ritonavir

↵a Confirmed to precipitate serotonin syndrome. The others have not been reliably confirmed and are based on case reports or expert opinion.

TABLE 2

Spectrum of symptoms of serotonergic toxicity

Severity	Neuromuscular excitation	Altered mental status	Autonomic dysfunction
Mild	Hyperreflexia Tremor Myoclonus	Anxiety Restlessness Insomnia	Diaphoresis Mydriasis Tachycardia
Moderate	Opsoclonus Spontaneous or inducible clonus	Agitation	Hypertension Hyperthermia (< 40°C, < 104°F) Hyperactive bowel sounds Diarrhea, nausea, vomiting
Severe	Rigidity Respiratory failure Tonic-clonic seizure	Coma Delirium Confusion	Severe hyperthermia (≥ 40°C, ≥ 104°F) Dynamic blood pressure

TABLE 3

Differential diagnosis of serotonin syndrome

	Serotonin syndrome	Neuroleptic malignant syndrome	Anticholinergic toxicity
Causative agent	Serotonergic agent	Dopamine antagonist Withdrawal from dopamine agonist	Anticholinergic agent
Onset	Within 24 hours	Within days to weeks	Within 1–2 hours
Resolution	Within 24 hours	In approximately 9 days	Within hours to days
Features similar to those of serotonin syndrome	—	Hyperthermia Altered mental state Diaphoresis Autonomic instability	Mydriasis Hyperthermia Agitation, delirium Visual hallucinations
Distinct features	Myoclonus Hyperreflexia Mydriasis Tremor Diarrhea Nausea, vomiting	Bradyreflexia Lead pipe rigidity Extrapyramidal features Absence of neuromuscular excitation	Dry skin and mucous membranes Urinary retention Decreased bowel sounds Normal muscle tone and reflexes