What is the difference between Neuroleptic Malignant Syndrome (NMS) and serotonin syndrome?

Distinguishing Neuroleptic Malignant Syndrome from Serotonin Syndrome

The key difference is that NMS presents with lead-pipe rigidity and bradykinesia following dopamine antagonist exposure, while serotonin syndrome presents with hyperreflexia and clonus following serotonergic agent exposure. 1

Medication History: The Critical First Step

NMS occurs after exposure to dopamine antagonists (typical or atypical antipsychotics) or withdrawal of dopaminergic agents (levodopa, amantadine) within 3 days. 1

Serotonin syndrome occurs after exposure to serotonergic agents (SSRIs, SNRIs, MAOIs, tramadol, linezolid, St. John's wort, MDMA) and develops within minutes to hours, typically 6-24 hours after starting, increasing dose, or adding a second serotonergic medication. 1

Neuromuscular Examination: The Most Diagnostic Distinction

NMS Neuromuscular Features:

• Lead-pipe rigidity is the hallmark finding—uniform resistance throughout passive range of motion 2
• Bradykinesia and extrapyramidal signs are prominent 1
• Reflexes are typically normal or decreased 1
• Tremor may occur but is parkinsonian in quality (resting tremor) 1
• Akinesia, dyskinesia, or waxy flexibility may be present 2

Serotonin Syndrome Neuromuscular Features:

• Hyperreflexia and clonus are the most diagnostic features—these are highly specific when occurring with serotonergic drug use 3, 4
• Myoclonus occurs in 57% of cases 1
• Tremor is present but differs from parkinsonian tremor 3
• Muscle rigidity can occur but is accompanied by hyperreflexia (unlike NMS) 3

The presence of clonus (spontaneous, inducible, or ocular) essentially rules out NMS and confirms serotonin syndrome. 3, 1

Mental Status Changes

NMS:

• Mutism is characteristic 1
• Delirium ranging from alert mutism to agitation to stupor to coma 2
• Altered consciousness develops more gradually 1

Serotonin Syndrome:

• Agitated delirium is the typical presentation 1
• Confusion ranging from mild to coma in severe cases 1
• Mental status changes develop rapidly (within hours) 1

Autonomic Instability

Both syndromes share similar autonomic features, making this less useful for differentiation:

NMS:

• Fever up to 41°C or higher 2
• Blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic change within 24 hours) 2
• Diaphoresis, urinary incontinence 1
• Tachycardia, cardiac dysrhythmia 2

Serotonin Syndrome:

• Hyperthermia typically up to 41.1°C 1
• Diaphoresis and mydriasis (dilated pupils) 1
• Tachycardia, hypertension or blood pressure fluctuations 1

Laboratory Findings

NMS:

• Creatine kinase elevation ≥4 times upper limit of normal is a diagnostic criterion 2, 1
• Leukocytosis (15,000-30,000 cells/mm³) 2, 1
• Elevated liver enzymes (alkaline phosphatase, LDH, transaminases) 2, 1
• Low serum iron level may help distinguish NMS from SS 5

Serotonin Syndrome:

• No pathognomonic laboratory findings 3
• Creatine kinase may be elevated in severe cases but typically less dramatically than NMS 3
• Metabolic acidosis and elevated aminotransferases in severe cases 3, 1

Diagnostic Criteria Application

For Serotonin Syndrome - Use Hunter Criteria:

Requires serotonergic agent exposure PLUS one of the following: 3, 1

• Spontaneous clonus, OR
• Inducible clonus with agitation or diaphoresis, OR
• Ocular clonus with agitation or diaphoresis, OR
• Tremor and hyperreflexia, OR
• Hypertonia, temperature >38°C, and ocular or inducible clonus

The Hunter Criteria have 84% sensitivity and 97% specificity, superior to older Sternbach criteria. 2

For NMS - Use Delphi Criteria Point System:

• Dopamine antagonist exposure or dopamine agonist withdrawal within 3 days (20 points) 2
• Hyperthermia >100.4°F on ≥2 occasions (18 points) 2
• Rigidity (17 points) 2
• Mental status alteration (13 points) 2
• Creatine kinase elevation ≥4 times upper limit of normal (10 points) 2
• Sympathetic nervous system lability (10 points) 2

Management Differences

NMS Management:

• Remove the initiating antipsychotic agent 1
• Reintroduce dopaminergic drugs if NMS was triggered by their withdrawal 2
• Benzodiazepines for agitation 2, 1
• IV fluids for dehydration and rhabdomyolysis 2, 1
• External cooling measures 2
• Dantrolene is the most effective evidence-based drug treatment for NMS 5
• Hemodialysis may be necessary for renal failure 2

Serotonin Syndrome Management:

• Discontinue all serotonergic agents immediately 4
• Benzodiazepines for agitation and neuromuscular symptoms 4
• IV fluids for autonomic instability 4
• External cooling for hyperthermia 4
• Cyproheptadine (12 mg initially, then 2 mg every 2 hours) for severe cases 3, 4
• Mortality rate approximately 11% 3, 4

Critical Pitfall to Avoid

Never use bromocriptine (a dopamine agonist) if serotonin syndrome is possible—it can worsen serotonergic symptoms. 6

Never use chlorpromazine (an antipsychotic) if NMS is possible—it can worsen dopamine blockade. 6

In mixed or unclear presentations with polypharmacy, discontinue ALL potentially offending agents and provide supportive care with benzodiazepines and IV fluids while the clinical picture clarifies. 6 Consider treating both syndromes simultaneously with cyproheptadine for SS and dantrolene for NMS if the diagnosis remains uncertain. 6

Timeline Differences

• Serotonin syndrome develops rapidly (minutes to hours, typically 6-24 hours) and is non-idiosyncratic (predictable with excessive serotonergic activity) 1
• NMS develops more gradually and can occur at any point during antipsychotic therapy, not necessarily related to dose or duration 2