Serotonin Syndrome

Key considerations: NMS (differentiate: SS has rapid onset/clonus vs NMS has slow onset/lead-pipe rigidity), Anticholinergic toxicity, Malignant hyperthermia

Cannot miss

NMS (differentiate: SS has rapid onset/clonus vs NMS has slow onset/lead-pipe rigidity)
Anticholinergic toxicity
Malignant hyperthermia

Likely diagnoses

SSRI/SNRI overdose
Drug interaction (SSRI + tramadol, linezolid, or MAOI)
Serotonergic agent combination
Transition between serotonergic medications without washout

Red flags

Hyperthermia >41C (life-threatening)
Clonus (pathognomonic — especially inducible ocular clonus)
Agitation + diaphoresis + tachycardia after starting/increasing serotonergic agent
Recent addition of linezolid, tramadol, or fentanyl to SSRI

Workup

history: All serotonergic medications, recent changes or additions, timeline of symptom onset (rapid — within 24 hours); exam: Hunter Criteria assessment: clonus (spontaneous, inducible, ocular), hyperreflexia, tremor, agitation, diaphoresis, hypertonia, temperature; labs: CK (rhabdomyolysis), BMP, LFTs, CBC, drug screen; imaging: Not typically indicated unless alternative diagnosis suspected; bedside: Temperature, continuous monitoring, clonus assessment

Management

immediate: Discontinue all serotonergic agents immediately; Benzodiazepines for agitation and muscle hyperactivity; Cyproheptadine 12mg PO/NG then 2mg q2h (serotonin antagonist); general: Active cooling if hyperthermia; Intubation and paralysis for severe hyperthermia/rigidity; Do NOT use succinylcholine (hyperkalemia risk from rhabdomyolysis); IV fluids for rhabdomyolysis prevention

Disposition

admit: ICU for severe cases (hyperthermia, hemodynamic instability); discharge: Mild cases may be observed in ED with close monitoring — discharge if resolving; consults: Toxicology, psychiatry for medication management

Clinical pearls

Clonus is the key differentiator from NMS — sustained rhythmic muscle contractions, especially ankle clonus
NMS has lead-pipe rigidity WITHOUT clonus, develops over 1-3 days; SS develops within 24 hours
Hunter Criteria: serotonergic agent + one of: spontaneous clonus, inducible clonus + agitation/diaphoresis, ocular clonus + agitation/diaphoresis, tremor + hyperreflexia, hypertonia + temp >38C + clonus

Source and review

Hunter Criteria 2003, UpToDate Serotonin Syndrome 2024. Last reviewed: 2024-11-01