Description

• 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

Epidemiology

• 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

Prevalence
0.15% ± 0.05% among patients receiving neuroleptics

Risk Factors

• 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
• Dehydration/Malnutrition
• 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

Pathophysiology

• 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.

Etiology

• 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)