Editing Serotonin syndrome (section)

==Pathophysiology==

Serotonin is a [[neurotransmitter]] involved in multiple complex biological processes including aggression, pain, sleep, appetite, anxiety, depression, migraine, and vomiting.<ref name="Dunkley"/> In humans the effects of excess serotonin were first noted in 1960 in patients receiving an MAOI and [[tryptophan]].<ref>{{cite journal|vauthors=Oates JA, Sjoerdsma A |title=Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor |journal=Neurology |volume=10 |issue=12 |pages=1076–8 |date=December 1960 |pmid=13730138 |doi=10.1212/WNL.10.12.1076 |s2cid=40439836 }}</ref> The syndrome is caused by increased serotonin in the CNS.<ref name=Boy2005/> It was originally suspected that [[Agonist|agonism]] of [[5-HT receptor|5-HT<sub>1A</sub> receptors]] in [[central grey]] nuclei and the [[medulla oblongata]] was responsible for the development of the syndrome.<ref name="Whyte"/> Further study has determined that overstimulation of primarily the [[5-HT2A receptor|5-HT<sub>2A</sub> receptors]] appears to contribute substantially to the condition.<ref name="Whyte">{{cite book|last=Whyte |first=Ian M. |chapter=Serotonin Toxicity/Syndrome |title=Medical Toxicology |publisher=Williams & Wilkins |location=Philadelphia |year=2004 |pages=103–6 |isbn=978-0-7817-2845-4}}</ref> The 5-HT<sub>1A</sub> receptor may still contribute through a [[pharmacodynamic]] interaction in which increased synaptic concentrations of a serotonin agonist saturate all receptor subtypes.<ref name=Boy2005/> Additionally, noradrenergic CNS hyperactivity may play a role as CNS [[norepinephrine]] concentrations are increased in SS and levels appear to correlate with the clinical outcome. Other neurotransmitters may also play a role; [[NMDA receptor]] antagonists and [[γ-aminobutyric acid]] have been suggested as affecting the development of the syndrome.<ref name=Boy2005/> Serotonin toxicity is more pronounced following supra-therapeutic doses and [[overdose]]s, and they merge in a continuum with the toxic effects of overdose.<ref name="Isbister-JToxClinTox">{{cite journal|vauthors=Isbister G, Bowe S, Dawson A, Whyte I |title=Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose |journal=J Toxicol Clin Toxicol |volume=42 |issue=3 |pages=277–85 |year=2004 |pmid=15362595 |doi=10.1081/CLT-120037428|s2cid=43121327 }}</ref><ref>{{cite journal|vauthors=Whyte I, Dawson A, Buckley N |title=Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants |journal=QJM |volume=96 |issue=5 |pages=369–74 |year=2003 |pmid=12702786 |doi=10.1093/qjmed/hcg062|doi-access= }}</ref>

===Spectrum concept===
A postulated "spectrum concept" of serotonin toxicity emphasises the role that progressively increasing serotonin levels play in mediating the clinical picture as side effects merge into toxicity. The [[dose-response relationship]] is the effect of progressive elevation of serotonin, either by raising the dose of one drug, or combining it with another serotonergic drug which may produce large elevations in serotonin levels.<ref>{{cite journal|author=Gillman PK |title=The spectrum concept of serotonin toxicity |journal=Pain Med |volume=5 |issue=2 |pages=231–2 |date=June 2004 |pmid=15209988 |doi=10.1111/j.1526-4637.2004.04033.x|doi-access= }}</ref><ref name="Gillman PK-2006" /> Some experts prefer the terms serotonin toxicity or serotonin toxidrome, to more accurately reflect that it is a form of [[poisoning]].<ref name="Isbister Buckley"/><ref name="Gillman PK-2006">{{cite journal|author=Gillman PK |title=A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action |journal=Biol Psychiatry |volume=59 |issue=11 |pages=1046–51 |date=June 2006 |pmid=16460699 |doi=10.1016/j.biopsych.2005.11.016 |s2cid=12179122 }}</ref>