Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome.
OBJECTIVE
The author's goal was to develop a pathophysiological model for neuroleptic malignant syndrome with greater explanatory power than the alternative hypotheses of hypothalamic dopamine antagonism (elevated set point) and direct myotoxicity (malignant hyperthermia variant).


METHODS
Published clinical findings on neuroleptic malignant syndrome were integrated with data from human and animal studies of muscle physiology, thermoregulation, and autonomic nervous system function.


RESULTS
The data show that the sympathetic nervous system's latent capacity for autonomous activity is expressed when tonic inhibitory inputs from higher central nervous system centers are disrupted. These tonic inhibitory inputs are relayed to preganglionic sympathetic neurons by way of dopaminergic hypothalamospinal tracts. The sympathetic nervous system mediates hypothalamic coordination of thermoregulatory activity and is a primary regulator of muscle tone and thermogenesis, augmenting both of these when stimulated. In addition, the sympathetic nervous system modulates all of the other end-organs that function abnormally in neuroleptic malignant syndrome.


CONCLUSIONS
There is substantial evidence to support the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most, if not all, features of neuroleptic malignant syndrome. A predisposition to more extreme sympathetic nervous system activation and/or dysfunction in response to emotional or psychological stress may constitute a trait vulnerability for neuroleptic malignant syndrome, which, when coupled with state variables such as acute psychic distress or dopamine receptor antagonism, produces the clinical syndrome of neuroleptic malignant syndrome. This hypothesis provides a more comprehensive explanation for existing clinical data than do the current alternatives.
Gurrera
R J
RJ
Department of Psychiatry, Harvard Medical School, Brockton-West Roxbury DVA Medical Center, Brockton, MA 02301, USA. rgurrera@world-net.att.net
D000313:Adrenal Medulla / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000633:toxicity; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology; D004198:Disease Susceptibility / Q000503:physiopathology; D004837:Epinephrine / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D008959:Models, Neurological; D009459:Neuroleptic Malignant Syndrome / Q000209:etiology* / Q000503:physiopathology; D009638:Norepinephrine / Q000502:physiology*; D013315:Stress, Psychological / Q000235:genetics / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology