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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This work was supported by a National Institutes of Health Grant (MH107615) and a Harrington Discovery Institute Scholar-Innovator Grant to Todd D. Gould, and a National Institutes of Health Grant (MH086828) to Scott M. Thompson.
Conflict of interest
Todd D. Gould has received consulting fees from Janssen Pharmaceuticals, and research funding from Janssen Pharmaceuticals and Roche Pharmaceuticals during the preceding 3 years. Ronald S. Duman has received consulting fees from Janssen Pharmaceuticals and Taisho, and research funding from Janssen Pharmaceuticals and Taisho, Allergan, Naurex, Navitor, and Relmada during the preceding 3 years. Carlos A. Zarate Jr. is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. Panos Zanos, Carlos A. Zarate Jr., and Todd D. Gould are listed as co-authors in patent applications related to the pharmacology and use of (2S,6S)- and (2R,6R)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. Scott M. Thompson is listed as a co-inventor on a patent application for the use of negative allosteric modulators of GABAA receptors containing alpha 5 subunits as fast-acting antidepressants.
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Zanos, P., Thompson, S.M., Duman, R.S. et al. Convergent Mechanisms Underlying Rapid Antidepressant Action. CNS Drugs 32, 197–227 (2018). https://doi.org/10.1007/s40263-018-0492-x
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DOI: https://doi.org/10.1007/s40263-018-0492-x