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This is a clinician-written, evidence-based summary aligned to the USMLE Step 2 CK Content Outline. It is intended for medical students preparing for USMLE Step 2 CK. Management reflects current ACC/AHA, USPSTF, and APA guidelines. Always cross-reference with UpToDate, institutional protocols, and clinical judgment.
The Bottom Line
- NMS: dopamine blockade or dopamine agonist withdrawal; days-weeks; fever, AMS, autonomic instability, lead-pipe rigidity, high CK
- Serotonin syndrome: serotonergic excess; within hours; agitation, diaphoresis, diarrhea, hyperreflexia, clonus, tremor, fever
- Both require immediate discontinuation of offending agents and supportive care
- NMS severe cases: ICU, cooling/fluids, dantrolene and/or bromocriptine/amantadine
- Serotonin syndrome: benzodiazepines, cooling, cyproheptadine
Overview
NMS and serotonin syndrome can mimic sepsis, malignant hyperthermia, anticholinergic toxicity, catatonia, heat stroke, or withdrawal. NMS follows dopamine blockade or dopamine agonist withdrawal; serotonin syndrome follows serotonergic drugs/combinations such as SSRI/SNRI/MAOI, linezolid, tramadol, meperidine, MDMA, triptans, lithium, or St. John’s wort.
Epidemiology
NMS is rare but fatal risk rises with dehydration, agitation, high-potency/parenteral antipsychotics, rapid dose escalation, and illness. Serotonin syndrome is more common and often iatrogenic after initiation, dose increase, overdose, or drug interaction.
Clinical Features
Symptoms
NMS: fever, confusion, mutism, severe rigidity, autonomic instability after antipsychotic
NMS timing: gradual onset over days after dopamine antagonist or dopamine agonist withdrawal
Serotonin syndrome: agitation, diaphoresis, tremor, diarrhea, mydriasis after serotonergic change
Serotonin syndrome: inducible/spontaneous clonus, ocular clonus, hyperreflexia
Seizures, hyperthermia, rhabdomyolysis, renal failure, coma
Signs
NMS: lead-pipe rigidity, high fever, labile BP, tachycardia, diaphoresis
Serotonin: clonus, hyperreflexia, tremor, hyperactive bowel sounds, mydriasis
Both: altered mental status, autonomic instability, dehydration, rhabdomyolysis
Anticholinergic toxicity has dry skin, urinary retention, ileus; malignant hyperthermia follows anesthesia
Investigations
First-line
Medication timelineAntipsychotic/dopamine blocker, dopamine agonist withdrawal, SSRI/SNRI/MAOI, linezolid, tramadol, MDMA, lithium, triptan, overdose
Core labsCK, CMP/Cr, K/Ca/phosphate, CBC, LFTs, coagulation, urinalysis for myoglobin
Vitals/ECGTemperature, BP instability, arrhythmias, QT/QRS issues
Second-line
Toxicology/drug levelsAcetaminophen/salicylate, lithium, valproate, other levels based on ingestion
Infectious/neurologic workupCultures, CXR, LP, CT/MRI only if sepsis/CNS disease plausible
Diagnostic criteriaHunter criteria support serotonin syndrome; NMS is clinical
Specialist
ICUSevere hyperthermia, rigidity, rhabdomyolysis, renal failure, autonomic instability, respiratory failure, seizures
Toxicology/psychiatry/neurologyMedication reversal, future treatment, catatonia differential, rechallenge
1
Immediate care
- Stop offending medications immediately
- ABCs, IV fluids, external cooling, electrolytes, urine output, CK/renal monitoring
- ICU for severe hyperthermia, autonomic instability, rigidity, rhabdomyolysis, renal failure, seizures, respiratory compromise
2
NMS
- Stop dopamine blocker; avoid restart until full recovery and specialist review
- Dantrolene for severe rigidity/hyperthermia; bromocriptine/amantadine restore dopaminergic tone
- Benzodiazepines for agitation/catatonia; ECT for refractory NMS/catatonia overlap
3
Serotonin syndrome
- Benzodiazepines for agitation/tremor/muscle activity
- Cyproheptadine PO/NG for moderate-severe cases
- Avoid precipitating serotonergic combinations and observe MAOI washout periods
Complications
- Rhabdomyolysis and AKI:
- Hyperthermia causing DIC/hepatic injury/death:
- Arrhythmias:
- Respiratory failure:
- Recurrence with premature rechallenge:
USMLE Step 2 CK Exam Tips
- 1NMS = lead-pipe rigidity + high CK after antipsychotic
- 2Serotonin syndrome = clonus/hyperreflexia + diarrhea after serotonergic drug
- 3NMS evolves over days; serotonin syndrome within hours
- 4Dantrolene/bromocriptine = NMS; cyproheptadine = serotonin syndrome
- 5Linezolid can precipitate serotonin syndrome with SSRIs
- 6Anticholinergic toxicity has dry skin/urinary retention/ileus/no clonus
- 7Malignant hyperthermia follows anesthetic exposure and uses dantrolene
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