Editing Neuroleptic malignant syndrome (section)

==Pathophysiology==
The mechanism is commonly thought to depend on decreased levels of [[dopamine]] activity due to:
* [[Dopamine receptor]] blockade
* Genetically reduced function of dopamine receptor [[Dopamine receptor D2|D<sub>2</sub>]]<ref name=pmid12555236>{{cite journal | vauthors = Mihara K, Kondo T, Suzuki A, Yasui-Furukori N, Ono S, Sano A, Koshiro K, Otani K, Kaneko S | display-authors = 6 | title = Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 117B | issue = 1 | pages = 57–60 | date = February 2003 | pmid = 12555236 | doi = 10.1002/ajmg.b.10025 | s2cid = 44866985 }}</ref>
*Sympathoadrenal hyperactivity and autonomic dysfunction

It has been proposed that blockade of D<sub>2</sub>-like (D<sub>2</sub>, D<sub>3</sub> and D<sub>4</sub>) receptors induce massive glutamate release, generating catatonia, [[neurotoxicity]] and myotoxicity.<ref>{{cite journal | vauthors = Kornhuber J, Weller M, Riederer P | title = Glutamate receptor antagonists for neuroleptic malignant syndrome and akinetic hyperthermic parkinsonian crisis | journal = Journal of Neural Transmission. Parkinson's Disease and Dementia Section | volume = 6 | issue = 1 | pages = 63–72 | year = 1993 | pmid = 8105799 | doi = 10.1007/bf02252624 | s2cid = 45530847 }}</ref><ref>{{cite journal | vauthors = Chatterjee A | title = Glutamate-based magnetic resonance spectroscopy in neuroleptic malignant syndrome | journal = Annals of Indian Academy of Neurology | volume = 17 | issue = 1 | pages = 123–124 | date = January 2014 | pmid = 24753679 | pmc = 3992752 | doi = 10.4103/0972-2327.128579 | doi-access = free }}</ref> Additionally, the blockade of diverse serotonin receptors by atypical antipsychotics and activation of 5-HT<sub>1</sub> receptors by certain of them reduces GABA release and indirectly induces glutamate release, worsening this syndrome.<ref>{{cite journal | vauthors = Odagaki Y | title = Atypical neuroleptic malignant syndrome or serotonin toxicity associated with atypical antipsychotics? | journal = Current Drug Safety | volume = 4 | issue = 1 | pages = 84–93 | date = January 2009 | pmid = 19149529 | doi = 10.2174/157488609787354387 | citeseerx = 10.1.1.334.241 }}</ref>

The muscular symptoms are most likely caused by blockade of the [[dopamine receptor D2|dopamine receptor D<sub>2</sub>]], leading to abnormal function of the [[basal ganglia]] similar to that seen in [[Parkinson's disease]].<ref name=uptodate.com>{{Cite web | vauthors = Wijdicks EF | date = 26 May 2022 | veditors = Aminoff MJ, Rabinstein AA, Wilterdink JL |url= https://www.uptodate.com/contents/neuroleptic-malignant-syndrome|title=Neuroleptic malignant syndrome | work = UpToDate }}</ref>

In the past, research and clinical studies seemed to corroborate the D<sub>2</sub> receptor blockade theory in which antipsychotic drugs were thought to significantly reduce dopamine activity by blocking the D<sub>2</sub> receptors associated with this neurotransmitter. The introduction of atypical antipsychotic drugs, with lower affinity to the D<sub>2</sub> dopamine receptors, was thought to have reduced the incidence of NMS. However, recent studies suggest that the decrease in mortality may be the result of increased physician awareness and earlier initiation of treatment rather than the action of the drugs themselves.<ref name=pmid15119907/> NMS induced by atypical drugs also resembles "classical" NMS (induced by "typical" antipsychotic drugs), further casting doubt on the overall superiority of these drugs.<ref>{{cite journal | vauthors = Hasan S, Buckley P | title = Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique | journal = The American Journal of Psychiatry | volume = 155 | issue = 8 | pages = 1113–1116 | date = August 1998 | pmid = 9699705 | doi = 10.1176/ajp.155.8.1113 }}</ref>

However, the failure of D<sub>2</sub> dopamine receptor antagonism, or dopamine receptor dysfunction, do not fully explain the presenting symptoms and signs of NMS, as well as the occurrence of NMS with [[atypical antipsychotic]] drugs with lower D<sub>2</sub> dopamine activity.<ref name=pmid15119907>{{cite journal | vauthors = Ananth J, Parameswaran S, Gunatilake S, Burgoyne K, Sidhom T | title = Neuroleptic malignant syndrome and atypical antipsychotic drugs | journal = The Journal of Clinical Psychiatry | volume = 65 | issue = 4 | pages = 464–470 | date = April 2004 | pmid = 15119907 | doi = 10.4088/JCP.v65n0403 | s2cid = 32752143 }}</ref> This has led to the hypothesis of sympathoadrenal hyperactivity (results from removing tonic inhibition from the [[sympathetic nervous system]]) as a mechanism for NMS.<ref name=pmid9989551>{{cite journal | vauthors = Gurrera RJ | title = Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome | journal = The American Journal of Psychiatry | volume = 156 | issue = 2 | pages = 169–180 | date = February 1999 | pmid = 9989551 | doi = 10.1176/ajp.156.2.169 | s2cid = 31276121 }}</ref> Release of calcium is increased from the sarcoplasmic reticulum with antipsychotic usage. This can result in increased muscle contractility, which can play a role in the breakdown of muscle, muscle rigidity, and hyperthermia. Some antipsychotic drugs, such as [[typical antipsychotics]], are known to block dopamine receptors; other studies have shown that when drugs supplying dopamine are withdrawn, symptoms similar to NMS present themselves.<ref name=Str2007/>

In support of the sympathoadrenal hyperactivity model, it has been hypothesized that a defect in calcium regulatory proteins within the sympathetic neurons may bring about the onset of NMS.<ref>{{cite journal | vauthors = Gurrera RJ | title = Is neuroleptic malignant syndrome a neurogenic form of malignant hyperthermia? | journal = Clinical Neuropharmacology | volume = 25 | issue = 4 | pages = 183–193 | year = 2002 | pmid = 12151905 | doi = 10.1097/00002826-200207000-00001 | s2cid = 29010904 }}</ref> This model of NMS strengthens its suspected association with [[malignant hyperthermia]] in which NMS may be regarded as a neurogenic form of this condition which itself is linked to defective calcium-related proteins.{{citation needed|date=December 2020}}

There is also thought to be considerable overlap between malignant catatonia and NMS in their pathophysiology, the former being idiopathic and the latter being the drug-induced form of the same syndrome.<ref>{{cite journal | vauthors = Northoff G | title = Catatonia and neuroleptic malignant syndrome: psychopathology and pathophysiology | journal = Journal of Neural Transmission | volume = 109 | issue = 12 | pages = 1453–1467 | date = December 2002 | pmid = 12486486 | doi = 10.1007/s00702-002-0762-z | s2cid = 12971112 | citeseerx = 10.1.1.464.9266 }}</ref>

The [[Leukocytosis|raised white blood cell count]] and [[creatine phosphokinase]] (CPK) plasma concentration seen in those with NMS is due to increased muscular activity and [[rhabdomyolysis]] (destruction of muscle tissue).<ref>{{cite journal | vauthors = Latham J, Campbell D, Nichols W, Mott T | title = Clinical inquiries. How much can exercise raise creatine kinase level--and does it matter? | journal = The Journal of Family Practice | volume = 57 | issue = 8 | pages = 545–547 | date = August 2008 | pmid = 18687233 | url = http://www.jfponline.com/home/article/how-much-can-exercise-raise-creatine-kinase-level-and-does-it-matter/86f4f4fd65053888a3d529aca00eb455.html | url-status = live | archive-url = https://web.archive.org/web/20160601202531/http://www.jfponline.com/home/article/how-much-can-exercise-raise-creatine-kinase-level-and-does-it-matter/86f4f4fd65053888a3d529aca00eb455.html | archive-date = 2016-06-01 }}</ref> Someone may experience [[hypertensive crisis]] and [[metabolic acidosis]].

The fever seen with NMS is believed to be caused by hypothalamic dopamine receptor blockade. Antipsychotics cause an increased calcium release from the [[sarcoplasmic reticulum]] of muscle cells which can result in rigidity and eventual cell breakdown. No major studies have reported an explanation for the abnormal [[Electroencephalogram|EEG]], but it is likely also attributable to dopamine blockage leading to changes in neuronal pathways.<ref name=benzer/>