What is the pathophysiology of neuroleptic malignant syndrome (NMS)?

Pathophysiology of Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome results primarily from dopamine D2 receptor blockade in the hypothalamus and nigrostriatal pathways, which simultaneously disrupts thermoregulation and produces severe muscle rigidity, leading to a cascade of hyperthermia, rhabdomyolysis, and autonomic instability. 1

Central Dopaminergic Blockade Mechanism

The core pathophysiologic mechanism involves antipsychotic-induced dopamine receptor antagonism at multiple critical sites:

• Hypothalamic dopamine blockade increases the temperature set point and impairs heat-dissipating mechanisms, directly causing hyperthermia 1
• Nigrostriatal pathway blockade produces extrapyramidal dysfunction, manifesting as the characteristic "lead pipe" muscle rigidity 1
• The potency of dopamine blockade in these pathways correlates with the risk of developing NMS, though this relationship is not absolute 2

Muscle-Level Pathophysiology

The dopaminergic blockade triggers a peripheral cascade at the muscle level:

• Increased calcium release from the sarcoplasmic reticulum causes sustained muscle contractility and rigidity 1
• This sustained contraction generates excessive heat production, compounding the centrally-mediated hyperthermia 1
• Muscle cell breakdown (rhabdomyolysis) occurs from prolonged contraction, releasing creatine kinase into the bloodstream and potentially causing renal failure 1

Autonomic Dysfunction

• Dopaminergic blockade disrupts autonomic regulation, producing tachycardia, blood pressure fluctuations, diaphoresis, and other dysautonomic features 1
• The autonomic instability contributes to the life-threatening nature of the syndrome 3

Alternative and Contributing Mechanisms

While dopamine blockade is the primary mechanism, additional pathways may contribute:

• Serotonergic and noradrenergic receptor involvement may play a role, particularly given that NMS can occur with atypical antipsychotics like clozapine that have relatively low D2 receptor affinity 2
• Enhanced synthesis and action of prostaglandin E1 and E2 has been suggested as a contributing factor 4
• Alterations in calcium-mediated signal transduction throughout the body may amplify the syndrome 4

Clinical Implications of the Pathophysiology

Understanding the mechanism explains the clinical presentation:

• Hyperthermia reaching 41°C or higher results from both central thermoregulatory dysfunction and peripheral heat generation from muscle rigidity 1
• Elevated creatine kinase (≥4 times upper limit of normal) directly reflects muscle breakdown from sustained contraction 1
• Altered mental status ranging from alert mutism to coma results from hypothalamic and cortical dopaminergic disruption 1
• Leukocytosis (15,000-30,000 cells/mm³) and electrolyte abnormalities reflect the systemic stress response and dehydration 1

Important Caveats

• NMS can occur with atypical antipsychotics despite their lower D2 receptor affinity, indicating the pathophysiology is more complex than simple dopamine blockade alone 2
• The syndrome is not related to malignant hyperthermia, which involves a distinct skeletal muscle defect triggered by anesthetic agents rather than central dopaminergic mechanisms 5
• Risk factors that facilitate NMS—including dehydration, exhaustion, rapid dose escalation, and concurrent medications—likely lower the threshold for dopaminergic blockade to trigger the syndrome 3, 6