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Ketamine Inside Neurons?

Lester, Henry A. and Lavis, Luke D. and Dougherty, Dennis A. (2015) Ketamine Inside Neurons? American Journal of Psychiatry, 172 (11). pp. 1064-1066. ISSN 0002-953X. PMCID PMC6107348. doi:10.1176/appi.ajp.2015.14121537.

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Clinically used antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), aid only a fraction of patients. Furthermore, even successful use of SSRIs takes 2 to 6 weeks of maintained medication. Depressed patients need faster help. Since 2000, several clinical studies report that depressed patients given subanesthetic doses of ketamine showed improvement within 2 hours. Trials continue for various dosing regimens, formulations, and populations. It is not understood what causes the therapeutic action of the SSRIs, and it is also not clear how ketamine exerts its effects. The best-known behavioral effect of ketamine is dissociative anesthesia. The drug retains Food and Drug Administration (FDA) approval for anesthesia in special populations as well as for veterinary use. The dissociative effects presumably arise from ketamine’s action to block N-methyl-D-aspartate (NMDA) receptor channels that have been opened by glutamate. The kinetics, equilibrium, and voltage sensitivity of open-channel blockers is a well-studied topic, and recent work shows how ketamine becomes trapped within the channel pore of NMDA receptors at local concentrations of ∼1 µM, which are expected to occur at the clinically effective antidepressant human doses. How might blockade of NMDA receptors lead to the antidepressant effects? Most studies emphasize signal transduction pathways that could be modulated by the locally decreased Ca^(2+) flux through NMDA receptors, especially extrasynaptic GluN2B subunit-containing NMDA receptors. In one series of experiments, the decreased Ca^(2+) flux led to decreased activity of eukaryotic elongation factor 2 kinase, which in turn desuppressed eukaryotic elongation factor 2. This ribosome-binding protein then increased translation of brain-derived neurotrophic factor (BDNF). Many other experiments show that BDNF is released during antidepressant action.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Lester, Henry A.0000-0002-5470-5255
Lavis, Luke D.0000-0002-0789-6343
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2015 American Psychiatric Association. Accepted: March 1, 2015. The authors report no financial relationships with commercial interests.
Issue or Number:11
PubMed Central ID:PMC6107348
Record Number:CaltechAUTHORS:20150728-082757273
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:59022
Deposited By: Tony Diaz
Deposited On:28 Jul 2015 16:23
Last Modified:10 Nov 2021 22:13

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