Neuroleptic Malignant Syndrome

Basics

Uncommon, but life-threatening disorder associated with antipsychotic (dopamine antagonist) medications, or with dopamine agonist withdrawal
Mortality can be as high as 20%
May develop any time during therapy–from days to years
Most often occurs in the 1st month of therapy, or after a dosage increase, or with parenteral (IV/IM) depot administration
Muscular rigidity and tremor result from dopamine blockade in the nigrostriatal pathway
Fever, delirium, and/or dysautonomia, due to dopamine receptor blockade in the hypothalamus
May be indistinguishable from other causes of drug-induced hyperthermia (malignant hyperthermia, serotonin syndrome, anticholinergic or sympathomimetic toxicity)
May have a waxing and waning course
Most episodes resolve 3–14 d after stopping the offending agent
Diagnostic criteria:
- Fever + severe muscle rigidity in association with use of antipsychotic/neuroleptic medication
- 2 or more of the following:
  - Diaphoresis
  - Dysphagia
  - Tremor
  - Incontinence
  - Altered mental status
  - Mutism
  - Tachycardia
  - Nystagmus
  - Elevated labile BP
  - Leukocytosis
  - Lab evidence of muscle injury
- Symptoms not caused by another disease process

Rare complication of treatment with neuroleptics:
- Phenothiazines:
  - Chlorpromazine (Thorazine)
  - Fluphenazine (Modecate)
  - Prochlorperazine (Compazine)
  - Promethazine (Phenergan)
  - Metoclopramide (Reglan)
- Butyrophenones:
  - Haloperidol
  - Droperidol
- Atypical antipsychotics:
  - Risperidone (Risperdal),most common of the atypical medications to cause neuroleptic malignant syndrome (NMS)
  - Olanzapine (Zyprexa)
  - Quetiapine (Seroquel)
  - Clozapine (Clozaril)
  - Aripiprazole (Abilify)
Occurs in ∼1 in 1000 patients treated with neuroleptics
Has also been associated with abrupt withdrawal from dopamine agonists in Parkinson disease
SSRIs, TCAs, carbamazepine, metoclopramide, and lithium may also precipitate NMS; however, it is difficult to distinguish from serotonin syndrome
Patients taking 2nd-generation antipsychotics can have atypical presentation (lacking fever/rigidity)
Risk factors:
- Rapid drug loading
- High-dose antipsychotics
- High-potency antipsychotics
- IV/IM administration of drug
- Depot preparations
- Dehydration
- Prior NMS
- Preceding extreme psychomotor agitation
- Infection or surgery
- Physical restraints
- History of catatonia
- Low iron level
- Fever
- Lithium use
- Withdrawal of dopamine agonist (such as L-Dopa)
- Genetic predisposition