Pathophysiology
Clinical meaning
Serotonin syndrome arises from excessive stimulation of central and peripheral serotonin receptors, primarily 5-HT1A and 5-HT2A. Five pharmacological mechanisms can increase synaptic serotonin: (1) increased precursor supply (L-tryptophan), (2) increased serotonin release (MDMA, amphetamines), (3) inhibition of serotonin reuptake (SSRIs, SNRIs, TCAs, tramadol, meperidine), (4) inhibition of serotonin metabolism (MAOIs, linezolid, methylene blue), and (5) direct receptor agonism (buspirone, triptans, LSD). The Hunter Serotonin Toxicity Criteria (sensitivity 84%, specificity 97%) require exposure to a serotonergic agent plus one of: spontaneous clonus, inducible clonus + agitation or diaphoresis, ocular clonus + agitation or diaphoresis, tremor + hyperreflexia, or hypertonia + temperature >38°C + ocular or inducible clonus. The clinician must differentiate from neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic toxicity, and sympathomimetic overdose, then prescribe definitive treatment.