Current evidence seems to indicate that an acute reduction in dopamine activity in the brain is the basic mechanism for the development of NMS. Dopamine-antagonist medications have been implicated in the development of NMS. The risk of developing NMS is related to dosage, potency, and rate and route of administration.

An NMS episode may be preceded by a number of rather nonspecific “prodromal” signs (see box on facing page). The onset of an episode typically occurs within 7 to 10 days after the intake of any of the implicated associated medications. Development of an episode of NMS does not indicate an overdose of a medication; rather, NMS seems to develop in reaction to dosages within the therapeutic range. Onset of an episode of NMS mimics the onset of malignant hyperthermia (MH). There are other pathologies that must be considered in the differential process, including local or systemic infection, seizure disorder, thyroid storm, pheochromocytoma, central nervous system tumor,or cerebrovascular accident, as well as ingestion or overdose of a medication or sudden discontinuation of a medication. The box below provides diagnostic criteria for NMS.