What are the most common medications involved in Neuroleptic Malignant Syndrome (NMS)?

Most Common Medications Involved in Neuroleptic Malignant Syndrome

First-generation (typical) antipsychotics, particularly high-potency agents like haloperidol, are the most frequently implicated medications in neuroleptic malignant syndrome, though all antipsychotics including atypical agents can cause this potentially life-threatening condition. 1

Medication Classes Associated with NMS

First-Generation (Typical) Antipsychotics

• Highest risk agents:
  • Haloperidol (most frequently reported) 2
  • Phenothiazines (e.g., chlorpromazine)
  • Thioxanthenes
  • Butyrophenones 2

Second-Generation (Atypical) Antipsychotics

Despite their lower propensity for extrapyramidal symptoms, atypical antipsychotics can also cause NMS:

• Clozapine (often presents with less rigidity) 3, 4
• Olanzapine 5, 4
• Risperidone 4
• Quetiapine 4
• Ziprasidone 4
• Aripiprazole 3

Other Medications

• Withdrawal of dopaminergic agents (e.g., sudden discontinuation of antiparkinsonian medications) 1
• Metoclopramide and other non-psychiatric medications with dopamine-blocking properties

Risk Factors for NMS Development

• Concomitant use of multiple psychotropic agents 1
• Use of long-acting depot antipsychotics 1
• Rapid dose escalation of antipsychotics 1
• Male gender 1
• Young adults 1
• Dehydration 1
• Physical exhaustion 1
• Preexisting organic brain disease 1

Clinical Presentation and Diagnosis

NMS is characterized by four hallmark features:

1. Hyperthermia (often severe)
2. Altered mental status (ranging from confusion to coma)
3. Muscle rigidity (lead-pipe rigidity, though may be less prominent with clozapine)
4. Autonomic instability (tachycardia, blood pressure fluctuations, diaphoresis) 1

Laboratory findings typically include:

• Elevated creatine kinase (CK) levels
• Leukocytosis
• Electrolyte disturbances
• Elevated liver enzymes
• Metabolic acidosis
• Myoglobinuria 1

Clinical Implications

The mortality rate for NMS has decreased from 76% in the 1960s to less than 15% currently with proper recognition and treatment 1. Early identification is crucial as prompt discontinuation of the offending agent and supportive care significantly reduce morbidity and mortality.

When reintroducing antipsychotics after an episode of NMS:

• Wait at least 2 weeks after complete resolution of symptoms
• Start with low-potency agents
• Use gradual dose increases
• Consider alternative medication classes when possible 1

Key Distinctions from Similar Syndromes

NMS must be differentiated from other conditions with similar presentations:

• Serotonin syndrome (hyperreflexia, clonus, diarrhea)
• Malignant hyperthermia (exposure to anesthetics)
• Lethal catatonia
• CNS infections
• Heat stroke (environmental exposure) 1

Understanding which medications most commonly cause NMS helps clinicians maintain appropriate vigilance when prescribing these agents, particularly in patients with multiple risk factors for this potentially fatal condition.