While its pathophysiology is not completely understood, NMS appears to be related to blockade of dopamine receptors in the brain. The dopamine theory attributes this syndrome to depletion of CNS dopamine. More specifically, the decreased transmission in the nigrostriatal tracts and mesocortical tracts is responsible for the hyperthermia, rigidity, and alteration in mental status associated with this disorder. Another theory receiving attention concerns abnormalities in the skeletal muscle system, similar to those observed in patients who develop malignant hyperthermia secondary to general anesthesia. This skeletal muscle involvement could also contribute to the hyperthermia and muscle rigidity observed in many patients.
Numerous theories exist, but the exact mechanism continues to be speculative.
Onset of NMS can occur very early-within one hour of an injection of an antipsychotic agent. While the mean time to onset of NMS after exposure to an antipsychotic agent is five days, most cases occur within 10 days of initiation of therapy. The syndrome usually develops progressively over the first three days. In most cases, the initial syndrome manifests as either muscle rigidity or mental status change. Occasionally patients will not present with all the classical symptoms of the syndrome.