Editing Ketamine (section)

==== Mechanism of action ====
Ketamine is a mixture of equal amounts of two [[enantiomer]]s: [[esketamine]] and [[arketamine]]. Esketamine is a far more [[potency (pharmacology)|potent]] NMDA receptor pore blocker than arketamine.<ref name="Hashimoto2019" /> Pore blocking of the [[NMDA receptor]] is responsible for the anesthetic, analgesic, and psychotomimetic effects of ketamine.<ref name="pmid29945898">{{cite journal |vauthors=Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, Pereira EF, Albuquerque EX, Thomas CJ, Zarate CA, Gould TD |title=Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms |journal=Pharmacol Rev |volume=70 |issue=3 |pages=621–660 |date=July 2018 |pmid=29945898 |pmc=6020109 |doi=10.1124/pr.117.015198 }}</ref><ref name="pmid27028535">{{cite journal |vauthors=Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI |title=Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy |journal=Clin Pharmacokinet |volume=55 |issue=9 |pages=1059–77 |date=September 2016 |pmid=27028535 |doi=10.1007/s40262-016-0383-6 |s2cid=5078489 }}</ref> Blocking of the NMDA receptor results in analgesia by preventing [[central sensitization]] in [[posterior horn of spinal cord|dorsal horn]] neurons; in other words, ketamine's actions interfere with pain transmission in the [[spinal cord]].<ref name="Quibell2011">{{cite journal | vauthors = Quibell R, Prommer EE, Mihalyo M, Twycross R, Wilcock A | title = Ketamine* | journal = Journal of Pain and Symptom Management | volume = 41 | issue = 3 | pages = 640–9 | date = March 2011 | pmid = 21419322 | doi = 10.1016/j.jpainsymman.2011.01.001 | url = http://www.jpsmjournal.com/article/S0885-3924%2811%2900046-7/fulltext | type = Therapeutic Review | doi-access = free | title-link = doi | access-date = 28 July 2014 | archive-date = 16 September 2018 | archive-url = https://web.archive.org/web/20180916035324/https://www.jpsmjournal.com/article/S0885-3924%2811%2900046-7/fulltext | url-status = live }}</ref>

The mechanism of action of ketamine in alleviating depression is not well understood, but it is an area of active investigation. Due to the hypothesis that NMDA receptor antagonism underlies the antidepressant effects of ketamine, esketamine was developed as an antidepressant.<ref name="Hashimoto2019" /> However, multiple other [[NMDA receptor antagonist]]s, including [[memantine]], [[lanicemine]], [[rislenemdaz]], [[rapastinel]], and [[4-chlorokynurenine]], have thus far failed to demonstrate significant effectiveness for depression.<ref name="Hashimoto2019" /><ref name="GarayZarate2018">{{cite journal | vauthors = Garay R, Zarate CA, Cavero I, Kim YK, Charpeaud T, Skolnick P | title = The development of glutamate-based antidepressants is taking longer than expected | journal = Drug Discovery Today | volume = 23 | issue = 10 | pages = 1689–1692 | date = October 2018 | pmid = 29501913 | pmc = 6211562 | doi = 10.1016/j.drudis.2018.02.006 }}</ref> Furthermore, animal research indicates that arketamine, the enantiomer with a weaker NMDA receptor antagonism, as well as [[(2R,6R)-hydroxynorketamine|(2''R'',6''R'')-hydroxynorketamine]], the [[metabolite]] with negligible affinity for the NMDA receptor but potent [[alpha-7 nicotinic receptor]] antagonist activity, may have antidepressant action.<ref name="Hashimoto2019" /><ref name="pmid23183107"/> This furthers the argument that NMDA receptor antagonism may not be primarily responsible for the antidepressant effects of ketamine.<ref name="Hashimoto2019" /><ref name="AdisInsight-HR-071603">{{cite web | url=https://adisinsight.springer.com/drugs/800056158 | title=Arketamine – Jiangsu Hengrui Medicine – AdisInsight | access-date=13 November 2019 | archive-date=13 April 2021 | archive-url=https://web.archive.org/web/20210413141717/https://adisinsight.springer.com/drugs/800056158 | url-status=live }}</ref><ref name="GarayZarate2018" /> Acute inhibition of the [[lateral habenula]], a part of the brain responsible for inhibiting the [[mesolimbic reward pathway]] and referred to as the "anti-reward center", is another possible mechanism for ketamine's antidepressant effects.<ref name="pmid29532791" /><ref name="pmid29879390">{{cite journal | vauthors = Kim D, Cheong E, Shin HS | title = Overcoming Depression by Inhibition of Neural Burst Firing | journal = Neuron | volume = 98 | issue = 5 | pages = 878–879 | date = June 2018 | pmid = 29879390 | doi = 10.1016/j.neuron.2018.05.032 | doi-access = free | title-link = doi }}</ref><ref name="pmid29446381">{{cite journal | vauthors = Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, Hu H | title = Ketamine blocks bursting in the lateral habenula to rapidly relieve depression | journal = Nature | volume = 554 | issue = 7692 | pages = 317–322 | date = February 2018 | pmid = 29446381 | doi = 10.1038/nature25509 | s2cid = 3334820 | bibcode = 2018Natur.554..317Y }}</ref>

Possible biochemical mechanisms of ketamine's antidepressant action include direct action on the [[N-Methyl-D-aspartic acid|NMDA]] receptor and downstream effects on regulators such as [[Brain-derived neurotrophic factor|BDNF]] and [[mTOR]].<ref name="pmid29532791"/> It is not clear whether ketamine alone is sufficient for antidepressant action or its metabolites are also important; the active metabolite of ketamine, [[hydroxynorketamine]], which does not significantly interact with the NMDA receptor but nonetheless indirectly activates AMPA receptors, may also or alternatively be involved in the rapid-onset antidepressant effects of ketamine.<ref name="pmid29945898" /><ref name="pmid29532791">{{cite journal | vauthors = Zanos P, Gould TD | title = Mechanisms of ketamine action as an antidepressant | journal = Molecular Psychiatry | volume = 23 | issue = 4 | pages = 801–811 | date = April 2018 | pmid = 29532791 | pmc = 5999402 | doi = 10.1038/mp.2017.255 }}</ref><ref name="pmid29516301">{{cite journal | vauthors = Zanos P, Thompson SM, Duman RS, Zarate CA, Gould TD | title = Convergent Mechanisms Underlying Rapid Antidepressant Action | journal = CNS Drugs | volume = 32 | issue = 3 | pages = 197–227 | date = March 2018 | pmid = 29516301 | pmc = 6005380 | doi = 10.1007/s40263-018-0492-x }}</ref> In NMDA [[receptor antagonist|receptor antagonism]], acute blockade of NMDA receptors in the brain results in an increase in the release of [[Glutamate (neurotransmitter)|glutamate]], which leads to an activation of [[α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor]]s (AMPA receptors), which in turn modulate a variety of downstream [[signaling pathway]]s to influence [[neurotransmission]] in the [[limbic system]] and mediate antidepressant effects.<ref name="pmid29736744" /><ref name="pmid29532791" /><ref name="pmid29668918">{{cite journal |vauthors=Gilbert JR, Yarrington JS, Wills KE, Nugent AC, Zarate CA |title=Glutamatergic Signaling Drives Ketamine-Mediated Response in Depression: Evidence from Dynamic Causal Modeling |journal=The International Journal of Neuropsychopharmacology |volume=21 |issue=8 |pages=740–747 |date=August 2018 |pmid=29668918 |pmc=6070027 |doi=10.1093/ijnp/pyy041}}</ref> Such downstream actions of the activation of AMPA receptors include [[upregulation]] of [[brain-derived neurotrophic factor]] (BDNF) and activation of its signaling receptor [[tropomyosin receptor kinase B]] (TrkB), activation of the [[mammalian target of rapamycin]] (mTOR) pathway, deactivation of [[glycogen synthase kinase 3]] (GSK-3), and inhibition of the [[phosphorylation]] of the [[eukaryotic elongation factor 2]] (eEF2) [[kinase]].<ref name="pmid29736744" /><ref name="pmid29532791" /><ref name="pmid26519901">{{cite journal | vauthors = Björkholm C, Monteggia LM | author-link2 = Lisa Monteggia | title = BDNF – a key transducer of antidepressant effects | journal = Neuropharmacology | volume = 102 | pages = 72–79 | date = March 2016 | pmid = 26519901 | pmc = 4763983 | doi = 10.1016/j.neuropharm.2015.10.034 }}</ref><ref name="pmid27425886">{{cite journal | vauthors = Castrén E, Kojima M | title = Brain-derived neurotrophic factor in mood disorders and antidepressant treatments | journal = Neurobiology of Disease | volume = 97 | issue = Pt B | pages = 119–126 | date = January 2017 | pmid = 27425886 | doi = 10.1016/j.nbd.2016.07.010 | hdl-access = free | s2cid = 644350 | hdl = 10138/311483 }}</ref>