What is the difference between serotonin syndrome and neuroleptic malignant syndrome?

Distinguishing Serotonin Syndrome from Neuroleptic Malignant Syndrome

The key differences are: serotonin syndrome presents with hyperreflexia and clonus (especially in lower extremities) with rapid onset (6-24 hours) after serotonergic drug exposure, while neuroleptic malignant syndrome presents with lead-pipe rigidity, slower onset (days to weeks), and occurs after antipsychotic use or dopaminergic drug withdrawal. 1, 2

Medication History: The Critical First Step

Serotonin Syndrome:

• Occurs after exposure to serotonergic agents (SSRIs, SNRIs, MAOIs, tramadol, linezolid, St. John's wort, MDMA) 3, 1
• Develops within minutes to hours, typically 6-24 hours after starting, increasing dose, or adding a second serotonergic medication 1, 4
• Non-idiosyncratic reaction—predictable with excessive serotonergic activity 4

Neuroleptic Malignant Syndrome:

• Follows dopamine antagonist exposure (typical or atypical antipsychotics) or withdrawal of dopaminergic agents (levodopa, amantadine) within 3 days 3
• Develops more gradually over days to weeks 2
• Idiosyncratic drug reaction—unpredictable occurrence 5

Neuromuscular Examination: The Diagnostic Differentiator

Serotonin Syndrome (hyperkinetic):

• Hyperreflexia and clonus are the hallmark findings 1, 6, 4
• Clonus (spontaneous, inducible, or ocular) is highly diagnostic 1, 6
• Myoclonus present in 57% of cases 4
• Tremor common 1
• Muscle rigidity if present is less severe than NMS 5

Neuroleptic Malignant Syndrome (hypokinetic):

• Lead-pipe rigidity is the defining feature 1, 2
• Bradykinesia and extrapyramidal signs 3, 5
• Reflexes typically normal or decreased 2
• Tremor may occur but is parkinsonian in quality 3

Clinical Presentation Patterns

Mental Status Changes:

• SS: Agitated delirium, confusion, ranging from mild confusion to coma in severe cases 1
• NMS: Mutism, delirium, altered consciousness 3

Autonomic Instability:

• SS: Diaphoresis, mydriasis, tachycardia, hypertension or blood pressure fluctuations, hyperthermia typically up to 41.1°C 1
• NMS: Diaphoresis, urinary incontinence, sympathetic lability with blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic within 24 hours), hyperthermia often >100.4°F 3

Fever Characteristics:

• SS: Lower fevers, rapid onset 5
• NMS: Higher fevers, gradual development 5

Laboratory Findings: Supporting Evidence

Serotonin Syndrome:

• No pathognomonic laboratory findings 1
• Severe cases may show elevated creatine kinase (from rhabdomyolysis), metabolic acidosis, elevated aminotransferases 1

Neuroleptic Malignant Syndrome:

• Creatine kinase elevation ≥4 times upper limit of normal (10 points in diagnostic criteria) 3
• Leukocytosis (15,000-30,000 cells/mm³) 3
• Low serum iron level (distinguishing feature) 2
• Elevated liver enzymes (alkaline phosphatase, LDH, transaminases) 3
• Electrolyte abnormalities consistent with dehydration 3

Diagnostic Criteria Application

For Serotonin Syndrome—Use Hunter Criteria: Requires serotonergic agent PLUS one of: 1, 6, 4

• 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

For Neuroleptic Malignant Syndrome—Use Delphi Criteria: Point-based system including: 3

• Dopamine antagonist exposure/dopamine agonist withdrawal within 3 days (20 points)
• Hyperthermia >100.4°F on ≥2 occasions (18 points)
• Rigidity (17 points)
• Mental status alteration (13 points)
• Creatine kinase elevation ≥4× normal (10 points)

Critical Pitfalls to Avoid

Mixed Presentations:

• Patients taking both serotonergic and antipsychotic medications can present with features of both syndromes 7, 8
• In unclear cases, treat for both: discontinue all offending agents, use cyproheptadine for SS and dantrolene for NMS 7
• Avoid bromocriptine initially if SS cannot be excluded (contraindicated in SS) 7
• Avoid chlorpromazine if NMS cannot be excluded (contraindicated in NMS) 7

Gastrointestinal Symptoms:

• More prominent in serotonin syndrome 5

Time Course:

• SS resolves within 24-48 hours after discontinuing serotonergic agents with supportive care 1
• NMS requires longer recovery, often needing a 2-week washout of neuroleptic medication to minimize recurrence 2

Management Differences

Serotonin Syndrome:

• Discontinue all serotonergic agents immediately 1, 6, 4
• Benzodiazepines for agitation and neuromuscular symptoms 6, 4
• External cooling for hyperthermia 6, 4
• Cyproheptadine (12 mg initially, then 2 mg every 2 hours) for severe cases 1, 6
• Mortality approximately 11% 1, 4

Neuroleptic Malignant Syndrome:

• Remove initiating antipsychotic agent 3
• Reintroduce dopaminergic drug if NMS triggered by withdrawal 3
• Benzodiazepines for agitation 3
• IV fluids for dehydration and rhabdomyolysis 3
• Dantrolene is most effective evidence-based treatment 2
• Hemodialysis may be necessary for renal failure 3