Aetiology
All antipsychotic medications have been associated with NMS, presumably through their antagonism of dopamine D2 receptors.[21] A syndrome indistinguishable from NMS occurs in Parkinson's disease in the context of abrupt dopamine agonist withdrawal.[22][23] Generally, any rapid reduction in dopamine/dopamine agonist availability at post-synaptic receptors increases the risk of NMS, but even long-term dopamine antagonism increases NMS risk.
Predisposing structural brain abnormalities and central nervous system disorders of dopamine (e.g., Parkinson's disease, Wilson's disease) raise the risk of NMS on exposure to antipsychotic medications.[13][24][25][26][27] The idiosyncratic nature of its occurrence, and the lack of a reproducible dose-dependent relationship between agent and syndrome, even in individuals known to be at risk for the disorder, has led to speculation that risk is genetic.[28] A number of reports have found statistical associations between NMS and a variety of polymorphisms, but no pattern has emerged.
NMS is also associated with exposure to dopamine antagonists/modulators other than antipsychotics, including metoclopramide, lithium, tolcapone, amantadine, and certain (particularly tricyclic) antidepressants.[1][2][3][29]
Pathophysiology
The pathophysiology of NMS has not been established, but an acute imbalance or dysregulation of central nervous system neurotransmitters is strongly suspected.
The ubiquitous dopamine-blocking effects of antipsychotic medications clearly implicate dopamine systems, and it is generally believed that acute, centrally mediated hypodopaminergia leads to muscle rigidity, impaired hypothalamic thermoregulation, and autonomic dysfunction.[13][21] Limited circumstantial evidence (e.g., alterations in cerebrospinal fluid homovanillic acid in patient case series and reduced dopamine in brain neuro-imaging case reports) supports this premise, although these findings are not well replicated.[30][31]
Abrupt hypoferraemia is often present during or immediately preceding the most severe phase of illness, but its significance is not yet clear.[32][33] Elevated peripheral catecholamines (in particular, noradrenaline) also appear to be relevant to the pathophysiology of NMS, but whether increased sympathetic nervous system activity plays a primary or a secondary role has not been established.[34]
Evidence is less strong for involvement of other neurotransmitters, although occurrence of NMS (as well as serotonin syndrome) with exposure to antidepressant medications has been reported. The involvement of lithium suggests that serotonergic imbalance may perhaps contribute.[3][12][24]
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