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CNS Drugs
Erschienen in: CNS Drugs 3/2018

01.03.2018 | Review Article

Convergent Mechanisms Underlying Rapid Antidepressant Action

verfasst von: Panos Zanos, Scott M. Thompson, Ronald S. Duman, Carlos A. Zarate Jr., Todd D. Gould

Erschienen in: CNS Drugs | Ausgabe 3/2018

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Abstract

Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-d-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.
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Metadaten
Titel
Convergent Mechanisms Underlying Rapid Antidepressant Action
verfasst von
Panos Zanos
Scott M. Thompson
Ronald S. Duman
Carlos A. Zarate Jr.
Todd D. Gould
Publikationsdatum
01.03.2018
Verlag
Springer International Publishing
Erschienen in
CNS Drugs / Ausgabe 3/2018
Print ISSN: 1172-7047
Elektronische ISSN: 1179-1934
DOI
https://doi.org/10.1007/s40263-018-0492-x

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