Evidence-Based Reviews

Neuroleptic malignant syndrome: Answers to 6 tough questions

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Empiric evidence clarifies risk factors, causes, and first-line interventions.



Diagnosis and treatment of neuroleptic malignant syndrome (NMS) are controversial because this potentially life-threatening syndrome is rare and its presentation varies. These factors make it difficult to evaluate treatments in controlled clinical trials, and data about the relative efficacy of specific interventions are scarce. It may be possible, however, to develop rational treatment guidelines using empiric clinical data.1,2

This article examines the evidence related to 6 controversial aspects of NMS diagnosis and treatment:

  • most-reliable risk factors
  • NMS as a spectrum disorder
  • what causes NMS
  • NMS triggered by first-generation vs second-generation antipsychotics
  • first-line interventions
  • restarting antipsychotics after an NMS episode.

1. Are there reliable risk factors for NMS?

In small case-controlled studies, agitation, dehydration, and exhaustion were the most consistently found systemic factors believed to predispose patients taking antipsychotics to NMS (Table 1).3-5 Catatonia and organic brain syndromes may be separate risk factors.1,6

Preliminary studies also have implicated dopamine receptor abnormalities caused by genetic polymorphisms or effects of low serum iron.1,7,8 Pharmacologic studies have suggested that higher doses, rapid titration, and IM injections of antipsychotics are associated with increased NMS risk.3,5 Some studies suggest that 15% to 20% of NMS patients have a history of NMS episodes.1,2 In addition, high-potency first-generation antipsychotics (FGAs)—especially haloperidol—are assumed to carry higher risk than low-potency drugs and second-generation antipsychotics (SGAs), although this hypothesis remains difficult to prove.9-11

These risk factors, however, are not practical for estimating NMS risk in a given patient because they are relatively common compared with the low risk of NMS occurrence. For the vast majority of patients with psychotic symptoms, the benefits of properly indicated antipsychotic pharmacotherapy will outweigh the risks.

Table 1

Low serum iron concentrations (normal: 60 to 170 mcg/dL)
History of NMS
Organic brain syndromes
Central nervous system
Dopamine receptor dysfunction
Basal ganglia dysfunction
Sympathetic nervous system dysfunction
Pharmacologic treatment*
Intramuscular or intravenous injections
High-potency dopamine antagonists
Rapid dose titration
High doses
FGAs compared with SGAs (?)

*For individual patients, these common risk factors must be weighted again the benefits of antipsychotic therapy FGAs: first-generation antipsychotics; SGAs:second-generation antipsychotics; NMS: neuroleptic malignant syndromeSource: References 1-5

2. Is NMS related to parkinsonism, catatonia, or malignant hyperthermia?

Parkinsonsim. Some researchers have described NMS as an extreme parkinsonian crisis resulting from overwhelming blockade of dopamine pathways in the brain.1,2,12 In this view, NMS resembles the parkinsonian-hyperthermia syndrome that can occur in Parkinson's disease patients following abrupt discontinuation or loss of efficacy of dopaminergic therapy, which can be treated by reinstituting dopaminergic agents.13 Evidence to support this view includes:

  • Parkinsonian signs are a cardinal feature of NMS.
  • Withdrawal of dopamine agonists precipitates the syndrome.
  • All triggering drugs are dopamine receptor antagonists.
  • Risks of NMS correlates with drugs' dopamine receptor affinity.
  • Dopaminergic agonists may be an effective treatment.
  • Lesions in dopaminergic pathways produce a similar syndrome.
  • Patients with NMS have demonstrated low cerebrospinal fluid concentrations of the dopamine metabolite homovanillic acid.14

Catatonia. Fink et al15 and others16-18 have persuasively argued that NMS represents a form of drug-induced malignant catatonia. Evidence supporting this includes:

  • The 2 disorders share neuropsychiatric symptoms.
  • Catalonic signs are common in NMS.19
  • Malignant catatonia and NMS share physiologic and labratory signs.20
  • Reintroduction of antipsychotics can acutely worsen both conditions.
  • Benzodiazepines and electroconvulsive therapy (ECT) are effective treatments for both disorders.15-18

Lee21 examined the relationship between catatonic features and treatment response of 14 NMS patients. Most patients with catatonic symptoms responded to benzodiazepines, whereas none of those did who had an extrapyramidal-hyperthermic presentation without catatonia. Lee concluded that NMS is heterogeneous and may occur in catatonic and noncatatonic forms that differ in treatment response.

Malignant hyperthermia. Some clinicians have compared NMS with malignant hyperthermia caused by inhalational anesthetics and succinylcholine.1,2 Evidence includes

  • similar clinical signs of rigidity, hyperthermia, and hypermetabolism
  • similar psychologic and labratory signs, such as rhabdomyolysis
  • hyperthermia in both responding to dantrolene.

Although the 2 are similar in presentation, malignant hyperthermia occurs intraoperatively and reflects a pharmacogenetic disorder of calcium regulation in skeletal muscle. Additionally, rigidity in malignant hyperthermia does not respond to peripheral-acting muscle relaxants.1,22 Evidence suggests that patients who have previously experienced an NMS episodes are not at risk for malignant hyperthermia.22

3. What is the pathophysiology of NMS?

NMS pathophysiology is complex and likely involves interplay between multiple central and systemic pathways and neurotransmitters. As described above, compelling evidence suggests that dopamine blockade plays a central role.12

Dopamine blockade in the hypothalamus is believed to contribute to thermoregulatory failure, and blockade in the nigrostriatal system likely contributes to muscle rigidity and hypermetabolism. The loss of dopaminergic input to the anterior cingulate-medial orbitofrontal circuit and the lateral orbitofrontal circuit likely con-tributes to the mental status changes and catatonic features seen in NMS.12


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