How do you differentiate between serotonin syndrome and neuroleptic malignant syndrome in a patient presenting with agitation, confusion, and muscle rigidity, with a history of taking antidepressants (e.g. selective serotonin reuptake inhibitors (SSRIs)) and antipsychotics?

Differentiating Serotonin Syndrome from Neuroleptic Malignant Syndrome

The key distinguishing features are: serotonin syndrome presents with hyperreflexia and clonus (especially inducible and ocular clonus) developing within 6-24 hours of serotonergic drug exposure, while neuroleptic malignant syndrome presents with lead pipe rigidity, bradykinesia, and develops over days to weeks after antipsychotic exposure. 1, 2

Critical Diagnostic Features

Serotonin Syndrome Characteristics

Neuromuscular findings:

• Hyperreflexia and clonus are the most diagnostic features - these are highly specific when occurring with serotonergic drug use 1, 3
• Myoclonus occurs in 57% of cases 3
• Inducible clonus (ankle or patellar) with agitation or diaphoresis 1
• Ocular clonus (spontaneous horizontal eye movements) 1
• Tremor is common 1

Timing:

• Symptoms develop rapidly within 6-24 hours (sometimes minutes to hours) after starting, increasing dose, or adding a second serotonergic agent 1, 3

Autonomic features:

• Hyperthermia up to 41.1°C 1
• Tachycardia, tachypnea, hypertension 1
• Diaphoresis and mydriasis 1

Mental status:

• Agitated delirium and confusion are typical 1

Neuroleptic Malignant Syndrome Characteristics

Neuromuscular findings:

• Lead pipe rigidity is the hallmark finding - this is the most common neurologic sign 2
• Akinesia (reduced movement) rather than hyperkinetic movements 2
• Bradykinesia and waxy flexibility may be present 2
• Tremors are intermittent, not continuous 2

Timing:

• Develops over days to weeks after antipsychotic exposure 2
• Can occur within 3 days of dopamine antagonist exposure or dopamine agonist withdrawal 2

Autonomic features:

• Fever up to 41°C or higher 2
• Blood pressure instability 2
• Tachycardia, diaphoresis, pallor 2
• Autonomic dysfunction may occur before other symptoms 2

Mental status:

• Delirium varying from alert mutism to stupor to coma 2
• Less agitated than serotonin syndrome 2

Laboratory Differentiation

NMS laboratory profile:

• Markedly elevated creatine kinase (often >1000 U/L, typically 4 times upper limit of normal) 2, 4
• Leukocytosis (15,000-30,000 cells/mm³) 2, 4
• Elevated liver enzymes (LDH, AST, alkaline phosphatase) 2, 4
• Low serum iron level 4
• Metabolic acidosis 2

Serotonin syndrome laboratory profile:

• Creatine kinase may be elevated but typically less dramatically than NMS 1
• No pathognomonic laboratory findings 1
• Complications in severe cases: rhabdomyolysis, metabolic acidosis, elevated aminotransferases, renal failure 1

Diagnostic Criteria Application

Use Hunter Criteria for Serotonin Syndrome (84% sensitivity, 97% specificity): 1, 3 Requires serotonergic agent PLUS one of:

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

Use Delphi Criteria for NMS: 2 Point-based system including:

• Dopamine antagonist exposure 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 times upper limit (10 points)
• Sympathetic nervous system lability (10 points)

Medication History Assessment

For Serotonin Syndrome, look for:

• SSRIs, SNRIs, tricyclic antidepressants 2
• MAO inhibitors 2
• Tramadol, fentanyl, meperidine 2
• Linezolid (antibiotic with MAO inhibitor properties) 5
• Ondansetron, metoclopramide 2
• Recent dose increase or addition of second serotonergic agent 1

For NMS, look for:

• First or second-generation antipsychotics 2
• Metoclopramide 2, 5
• Withdrawal of dopamine agonists (levodopa, amantadine) 2
• Concomitant use of multiple psychotropic agents (increases risk) 2
• Long-acting depot antipsychotics 2

Critical Pitfalls to Avoid

Overlapping syndromes can occur when patients take both antipsychotics and antidepressants simultaneously - you may see features of both 5, 6, 7

Physical examination focus:

• Check for clonus systematically - test ankle clonus by dorsiflexing the foot rapidly, check for ocular clonus 1
• Assess reflexes bilaterally - hyperreflexia points to serotonin syndrome 1
• Test muscle tone - lead pipe rigidity throughout range of motion suggests NMS 2
• Clonus is typically more prominent in lower extremities in serotonin syndrome 1

Do not rely on antipyretics for hyperthermia in either condition - fever results from muscular hyperactivity, not hypothalamic dysregulation 1, 8

Avoid physical restraints as they worsen isometric muscle contractions, exacerbating hyperthermia and lactic acidosis in both conditions 8, 3

Management Implications

For Serotonin Syndrome:

• Discontinue all serotonergic agents immediately 8, 3
• Benzodiazepines for agitation and neuromuscular symptoms 8, 3
• For severe cases: cyproheptadine 12 mg initially, then 2 mg every 2 hours until improvement 1, 8
• External cooling measures 8, 3

For NMS:

• Discontinue antipsychotic immediately 2
• Supportive care with IV fluids 2
• Dantrolene is the most effective evidence-based treatment 4
• Bromocriptine (dopamine agonist) may be beneficial 4
• Do not use cyproheptadine for NMS - it can worsen symptoms 1

Both conditions have approximately 11% mortality rate and require aggressive management 1, 8