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Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome is a topic covered in the 5-Minute Clinical Consult.

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  • Neuroleptic malignant syndrome (NMS) is a life-threatening condition that may develop during treatment with neuroleptic medications; 2/3 of cases develop within the first 2 weeks of initiating therapy but can happen at any time during therapy.
  • Nonneuroleptic medications with antidopaminergic activity have also been implicated to a lesser degree.
  • Characterized by muscular rigidity due to dopamine antagonism in the nigrostriatal pathway
  • Signs and symptoms include hyperthermia from antagonism of hypothalamic thermoregulation (more likely in the setting of benzodiazepine withdrawal); autonomic instability, cognitive changes, and elevations of serum creatine phosphokinase (CPK) are other hallmarks.
  • Can be indistinguishable from other causes of drug-induced hyperthermia (e.g., malignant hyperthermia, serotonin syndrome, lethal catatonia, anticholinergic toxins, or sympathomimetic poisoning); detailed history is essential to differentiate between these other conditions.


  • Variably reported as 0.01–3%
  • 2,000 new cases annually in the United States
  • Predominant sex: male > female
  • Predominant age: <40 years

0.15% +/− 0.05% among patients receiving neuroleptics (1)

Etiology and Pathophysiology

  • Exact mechanism: unknown
  • Most likely due to central dopaminergic blockade of nigrostriatal, hypothalamic, mesocortical/limbic pathways
  • Sympathoadrenal hyperactivity and defects in neuronal calcium regulatory proteins may also contribute.
  • Most commonly seen with typical antipsychotics: phenothiazines (e.g., fluphenazine), butyrophenones (e.g., haloperidol), and thiothixene (1)[C]
  • May also be seen with atypical antipsychotics (e.g., clozapine, risperidone, olanzapine) (1)[C]
  • Nonneuroleptic agents with antidopaminergic activity (e.g., metoclopramide, promethazine, and droperidol) have also been implicated.
  • Rare cases have occurred with usage of medications not known to have any central antidopaminergic activity (e.g., lithium, phenelzine, and desipramine).
  • Also associated with withdrawal from dopamine agonists in Parkinson disease, CNS shunt failure, and functional hemispherectomy

  • Some studies show a genetic predisposition to NMS.
  • Polymorphisms: loss of DEL allele in 141C Ins/Del of the dopamine D2 receptor gene and Ser9Gly in the dopamine D3 receptor gene

Risk Factors

  • High-potency neuroleptic medications; newly administered medication or a rapid increase in the dose of an existing agent
  • Intramuscular or depot administration of medications
  • Concurrent use of multiple neuroleptic agents
  • Administration of neuroleptics with other drugs known to cause NMS, such as lithium
  • Previous episodes of NMS
  • Exposure to heat
  • Dehydration/malnutrition
  • Presence of an underlying structural/functional brain disorder (tumor, encephalitis, delirium/dementia)
  • Postpartum women may be at an increased risk for developing NMS.

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Stephens, Mark B., et al., editors. "Neuroleptic Malignant Syndrome." 5-Minute Clinical Consult, 27th ed., Wolters Kluwer, 2019. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/117161/all/Neuroleptic_Malignant_Syndrome.
Neuroleptic Malignant Syndrome. In: Stephens MB, Golding J, Baldor RA, et al, eds. 5-Minute Clinical Consult. 27th ed. Wolters Kluwer; 2019. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/117161/all/Neuroleptic_Malignant_Syndrome. Accessed August 17, 2019.
Neuroleptic Malignant Syndrome. (2019). In Stephens, M. B., Golding, J., Baldor, R. A., & Domino, F. J. (Eds.), 5-Minute Clinical Consult. Available from https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/117161/all/Neuroleptic_Malignant_Syndrome
Neuroleptic Malignant Syndrome [Internet]. In: Stephens MB, Golding J, Baldor RA, Domino FJ, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2019. [cited 2019 August 17]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/117161/all/Neuroleptic_Malignant_Syndrome.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Neuroleptic Malignant Syndrome ID - 117161 ED - Stephens,Mark B, ED - Golding,Jeremy, ED - Baldor,Robert A, ED - Domino,Frank J, BT - 5-Minute Clinical Consult, Updating UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/117161/all/Neuroleptic_Malignant_Syndrome PB - Wolters Kluwer ET - 27 DB - Medicine Central DP - Unbound Medicine ER -