Neuroleptic Malignant Syndrome
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- Life-threatening condition that may develop anytime during therapy with neuroleptics; most cases develop within the 1st 2 weeks of starting 1 of these medications.
- Non-neuroleptic medications that have antidopaminergic activity have also been implicated.
- Characterized by muscular rigidity due to dopamine antagonism in the nigrostriatal pathway
- Hyperthermia from the blockage of hypothalamic thermoregulation (more likely in the setting of benzodiazepine withdrawal)
- Autonomic dysfunction
- Altered mental status
- May be indistinguishable from other causes of drug-induced hyperthermia (e.g., malignant hyperthermia, serotonin syndrome, lethal catatonia, anticholinergic toxins, or sympathomimetic poisoning); detailed history can help differentiate between these causes
- Variably reported from prospective studies as 0.01–3%
- 2,000 new cases annually in the US
- Predominant sex: Male > Female
- Predominant age: <40 years
0.15% ± 0.05% among patients receiving neuroleptics
- Newly administered medication/rapid increase in the dose of an existing agent
- IM or depot administration of medications
- Concurrent use of multiple neuroleptic agents
- Administration of neuroleptics with other drugs known to cause neuroleptic malignant syndrome (NMS), such as lithium
- Previous episodes of NMS
- Exposure to heat
- Use of psychoactive agents
- Presence of an underlying structural/functional brain disorder (tumor, encephalitis, delirium/dementia)
- Postpartum women may be at an increased risk of developing NMS.
- 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
- Exact mechanism unknown
- Most likely due to central dopaminergic blockade of nigrostriatal, hypothalamic, mesocortical/limbic pathways
- Certain theories suggest a role of sympathoadrenal hyperactivity; defects in neuronal calcium regulatory proteins may also contribute to the pathogenesis.
- Most commonly seen in treatment with typical neuroleptics: Phenothiazines (e.g., fluphenazine), butyrophenones (e.g., haloperidol), and thiothixene
- May also be seen with atypical antipsychotics (e.g., clozapine, risperidone, olanzapine) (1,2)
- Nonneuroleptic agents with anti–dopaminergic 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 anti-dopaminergic activity (e.g., lithium, phenelzine and desipramine).
- Also associated with withdrawal from dopamine agonists in Parkinson disease, CNS shunt failure, and functional hemispherectomy (3)