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

Differences Between Serotonin Syndrome and Neuroleptic Malignant Syndrome

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are distinct clinical entities with different pathophysiology, causative agents, clinical presentations, and management approaches, despite their overlapping features.

Causative Agents

• Serotonin Syndrome (SS):

  • Caused by excessive serotonergic activity
  • Associated with serotonergic medications including:
    • SSRIs
    • Other antidepressants
    • Antibiotics
    • Opiate analgesics
    • Antiemetics
    • Anticonvulsants
    • Antimigraine drugs
    • Anti-Parkinsonism drugs
    • Muscle relaxants
    • Weight-reduction medications
    • Over-the-counter medications
    • Herbal supplements
    • Drugs of abuse 1

• Neuroleptic Malignant Syndrome (NMS):

  • Caused by dopamine blockade or withdrawal of dopaminergic agents
  • Associated with:
    • Antipsychotic medications
    • Withdrawal of anti-Parkinsonism drugs 1, 2

Clinical Presentation

Serotonin Syndrome:

• Onset: Typically rapid (within hours)
• Clinical triad:
  • Mental status changes
  • Autonomic hyperactivity
  • Neuromuscular abnormalities 1
• Specific features:
  • Tremor
  • Hyperreflexia
  • Ocular clonus
  • Inducible clonus
  • Muscle rigidity
  • Hyperthermia (>38°C) 2

Neuroleptic Malignant Syndrome:

• Onset: Typically slower (days to weeks)
• Key features:
  • Hyperthermia
  • "Lead-pipe" muscle rigidity
  • Mental status alteration
  • Autonomic instability 1, 2
• Additional findings:
  • Elevated creatine kinase (≥4 times upper limit of normal)
  • Leukocytosis (15,000-30,000 cells/mm³)
  • Sympathetic nervous system lability
  • Hypermetabolism 1

Diagnostic Criteria

Serotonin Syndrome:

• Hunter Criteria (diagnostic standard):
  • Requires patient to have taken a serotonergic drug within past 5 weeks
  • Must exhibit specific symptoms including:
    • Muscle rigidity with temperature >38°C, OR
    • Ocular clonus, OR
    • Inducible clonus, OR
    • Tremor and hyperreflexia, OR
    • Other combinations of these symptoms 2

Neuroleptic Malignant Syndrome:

• Delphi Panel Criteria (point system):
  • Exposure to dopamine antagonist or withdrawal of dopamine agonist 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 of normal) (10 points)
  • Sympathetic nervous system lability (10 points)
  • Hypermetabolism (5 points)
  • Negative workup for other causes (7 points) 1

Laboratory Findings

Serotonin Syndrome:

• Less pronounced laboratory abnormalities
• May have mild CK elevation

Neuroleptic Malignant Syndrome:

• Marked elevation in creatine kinase
• Leukocytosis
• Elevated liver enzymes (alkaline phosphatase, LDH, transaminases)
• Electrolyte abnormalities consistent with dehydration 1, 3

Management Approaches

Serotonin Syndrome:

• Immediate discontinuation of serotonergic agents
• Supportive care
• Benzodiazepines for agitation
• Cyproheptadine for moderate to severe cases
• External cooling for hyperthermia 2, 4

Neuroleptic Malignant Syndrome:

• Discontinuation of the offending antipsychotic
• Supportive care
• IV fluids for dehydration
• External cooling for hyperthermia
• Dantrolene for severe rigidity and hyperthermia
• Benzodiazepines for agitation
• Consider electroconvulsive therapy in refractory cases 1, 2, 4

Prognosis

Serotonin Syndrome:

• Approximately 11% mortality rate if untreated
• Typically resolves within 24-72 hours after discontinuation of the offending agent 2

Neuroleptic Malignant Syndrome:

• Current mortality rates <10-15% with early recognition
• Slower resolution (1-2 weeks) even after discontinuation of the offending agent 2

Potential Pitfalls in Diagnosis

• Both syndromes can present similarly with hyperthermia, altered mental status, and autonomic instability
• Patients on both serotonergic and antipsychotic medications can present with overlapping features
• Pediatric and elderly patients may present atypically
• Avoid using bromocriptine in suspected SS (can worsen symptoms)
• Avoid using chlorpromazine in suspected NMS (can worsen symptoms) 5, 6

When faced with a patient with features of both syndromes, a practical approach is to:

1. Provide supportive care and withdraw all potentially offending agents
2. Treat for both disorders initially if diagnosis is unclear
3. Refine treatment as the clinical picture becomes clearer 6