What causes neuroleptic malignant syndrome (NMS)?

From the Guidelines

Neuroleptic malignant syndrome (NMS) is primarily caused by the blockade of dopamine D2 receptors in the central nervous system, particularly in the hypothalamus and basal ganglia, leading to a lack of dopaminergic activity. This blockade is most commonly associated with the use of antipsychotic medications, including both first-generation (typical) antipsychotics like haloperidol, fluphenazine, and chlorpromazine, and second-generation (atypical) antipsychotics such as risperidone, olanzapine, and quetiapine 1. The syndrome can develop at any time during treatment with these medications, but it typically occurs within the first two weeks of starting an antipsychotic or after increasing the dosage. Other medications that affect dopamine levels, including metoclopramide, lithium, and the sudden withdrawal of dopaminergic drugs like levodopa in Parkinson's disease patients, can also precipitate NMS.

The pathophysiology of NMS involves the antagonism of D2 receptors, which leads to an increased set point in the hypothalamus and a loss of heat-dissipating mechanisms, resulting in hyperthermia. Additionally, the blockade of D2 receptors in the nigrostriatal pathways and spinal cord via extrapyramidal pathways produces muscle rigidity and tremor. In the periphery, the increased release of calcium from the sarcoplasmic reticulum causes increased contractility, leading to muscle rigidity, increased heat production, and muscle cell breakdown 1.

Key risk factors for NMS include rapid dose escalation, high-potency antipsychotics, parenteral administration, dehydration, agitation, and previous episodes of NMS. The condition presents with a tetrad of symptoms: high fever, muscle rigidity, altered mental status, and autonomic instability, which can include fluctuating blood pressure, tachycardia, and diaphoresis 1. Given the severity of NMS and its potential for high morbidity and mortality, it is crucial to recognize the condition early and manage it promptly, especially in patients with risk factors or those who are taking medications known to precipitate NMS.

The diagnosis of NMS is clinical, relying on the identification of the characteristic symptoms and a history of exposure to dopamine antagonist or withdrawal of dopamine agonist within a relevant timeframe. Diagnostic criteria have been proposed to aid in the identification of NMS, including the presence of hyperthermia, rigidity, mental status alteration, and elevated creatine kinase, among others 1. Given the complexity and variability of NMS presentations, a high index of suspicion is necessary for early detection and effective management.

From the FDA Drug Label

Antipsychotic drugs including RISPERIDONE can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs Neuroleptic Malignant Syndrome (NMS): NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including ZYPREXA.

Neuroleptic Malignant Syndrome (NMS) Causes:

• Antipsychotic drugs, including risperidone, haloperidol, and olanzapine, can cause NMS.
• The exact cause of NMS is not fully understood, but it is believed to be related to the use of antipsychotic medications.
• Key Factors:
  • Use of antipsychotic drugs
  • Unknown mechanisms, possibly related to dopamine blockade
• Important Considerations:
  • NMS is a rare but potentially fatal condition
  • Immediate discontinuation of antipsychotic drugs and intensive symptomatic treatment are necessary if NMS is suspected 2, 3, 4

From the Research

Causes of Neuroleptic Malignant Syndrome

The causes of neuroleptic malignant syndrome (NMS) are complex and multifactorial. Some of the key factors that contribute to the development of NMS include:

• Dopamine blockade: NMS is presumptively linked to dopamine blockade, particularly in the nigrostriatal tract, mesocortical pathway, and hypothalamic nuclei 5, 6, 7.
• Use of antipsychotic medications: NMS is a rare but potentially fatal complication of antipsychotic medications, including both typical and atypical antipsychotics 5, 6, 8, 9, 7.
• Risk factors: Risk factors for NMS include previous episodes, dehydration, agitation, and the rate and route of neuroleptic administration 6.
• Individual susceptibility: Some individuals may be more susceptible to developing NMS due to underlying medical conditions, such as organic brain disorders or mood disorders 6.

Pathophysiology of NMS

The pathophysiology of NMS is not fully understood, but it is thought to involve an acute reduction in brain dopamine activity 6. Other factors, such as serotoninergic and noradrenergic receptors, may also play a role in the development of NMS 7.

Triggers for NMS

NMS can be triggered by a variety of factors, including:

• Sudden increase in dose of neuroleptic medication 7
• Dehydration 6
• Agitation 6
• Use of high-potency typical antipsychotics 6
• Use of atypical antipsychotics, such as olanzapine 8, 9, 7