Neuroleptic malignant syndrome

Last updated: September 11, 2023

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Summarytoggle arrow icon

Neuroleptic malignant syndrome (NMS) is a rare, life-threatening adverse drug event associated with dopamine blocking agents (e.g., antipsychotic medications). The clinical presentation often comprises a constellation of fever, autonomic instability, leukocytosis, tremor, elevated enzymes, and rigidity. While NMS is a diagnosis of exclusion, laboratory studies to support the diagnosis may show elevated creatine kinase (CPK), myoglobinuria, leukocytosis, and metabolic acidosis. Numerous diagnostic criteria have been proposed, but their clinical utility is debated. Management includes discontinuation of the culprit medication, supportive measures, and, in some cases, pharmacotherapy (e.g, dantrolene, bromocriptine, lorazepam).

Definitiontoggle arrow icon

NMS is an adverse drug event associated with dopamine blocking agents.

Etiologytoggle arrow icon

Standard therapeutic doses of antipsychotics or other dopamine receptor antagonists can cause NMS. [4]

Pathophysiologytoggle arrow icon

Clinical featurestoggle arrow icon

Symptom progression [3]

  • Onset: insidious, within 2–4 weeks of initiation of medication
  • Sequence: cognitive changes precede systemic manifestations
  • Resolution: gradually, within 7–10 days of stopping the culprit medication

The clinical presentation of NMS is heterogenous and varies widely; e.g., fulminant symptoms that develop over hours, and catatonia lasting > 1 month have both been described in case reports. [3]

Typical presentation [2][3]

In contrast to serotonin syndrome, patients with NMS do not present with clonus or hyperreflexia. [2]

FALTER: Fever, Autonomic instability, Leukocytosis, Tremor, Elevated enzymes (creatine kinase, transaminases), and Rigidity are common findings in neuroleptic malignant syndrome.

Diagnosticstoggle arrow icon

General principles

  • NMS is a diagnosis of exclusion.
  • Obtain a focused clinical evaluation including a comprehensive medication history.
  • Obtain diagnostic studies to support the diagnosis or identify an alternative cause.
  • Consider the use of diagnostic criteria. [2]

The diagnosis of neuroleptic malignant syndrome is primarily clinical and based on typical signs and symptoms of NMS (e.g., hyperthermia, rigidity, autonomic dysfunction), supportive laboratory findings (e.g., elevated creatine kinase), and the exclusion of differential diagnoses.

Laboratory studies [2][3]

Additional studies [3]

Obtain as needed to rule out differential diagnoses of NMS.

Differential diagnosestoggle arrow icon

The differential diagnoses listed here are not exhaustive.

Treatmenttoggle arrow icon


Supportive measures [5]

Pharmacotherapy [3][5]

Evidence of the benefits of pharmacotherapy is primarily based on small, retrospective studies.

Antipsychotic medications should only be resumed under specialist care and after informed consent has been given about the risk of recurrent NMS with continued use of antipsychotics. [5]

Coadministration of dantrolene and calcium channel blockers can cause cardiovascular collapse. [3]

Complicationstoggle arrow icon

We list the most important complications. The selection is not exhaustive.

Referencestoggle arrow icon

  1. Tse L, Barr A, Scarapicchia V, Vila-Rodriguez F. Neuroleptic Malignant Syndrome: A Review from a Clinically Oriented Perspective. Curr Neuropharmacol. 2015; 13 (3): p.395-406.doi: 10.2174/1570159x13999150424113345 . | Open in Read by QxMD
  2. Strawn JR, Keck PE, Caroff SN. Neuroleptic Malignant Syndrome. Am J Psychiatry. 2007; 164 (6): p.870-876.doi: 10.1176/ajp.2007.164.6.870 . | Open in Read by QxMD
  3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association ; 2013
  4. Pileggi DJ, Cook AM. Neuroleptic Malignant Syndrome. Ann Pharmacother. 2016; 50 (11): p.973-981.doi: 10.1177/1060028016657553 . | Open in Read by QxMD
  5. $Contributor Disclosures - Neuroleptic malignant syndrome. All of the relevant financial relationships listed for the following individuals have been mitigated: Jan Schlebes (medical editor, is a shareholder in Fresenius SE & Co KGaA). None of the other individuals in control of the content for this article reported relevant financial relationships with ineligible companies. For details, please review our full conflict of interest (COI) policy.

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