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Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatr. Nov 19, 2021; 11(11): 981-996
Published online Nov 19, 2021. doi: 10.5498/wjp.v11.i11.981
Agmatine as a novel candidate for rapid-onset antidepressant response
Ana Paula Valverde, Anderson Camargo, Ana Lúcia S Rodrigues
Ana Paula Valverde, Anderson Camargo, Ana Lúcia S Rodrigues, Department of Biochemistry, Campus Universitário, Center for Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC 88040900, Brazil
Author contributions: All the authors performed the literature search and wrote the manuscript.
Supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico, No. 310113/2017-2; and the CNPq Research Productivity Fellowship.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ana Lúcia S Rodrigues, PhD, Full Professor, Department of Biochemistry, Campus Universitário, Center for Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC 88040900, Brazil. alsrodri@gmail.com
Received: March 2, 2021
Peer-review started: March 2, 2021
First decision: June 5, 2021
Revised: June 9, 2021
Accepted: August 23, 2021
Article in press: August 23, 2021
Published online: November 19, 2021
Abstract

Major depressive disorder (MDD) is a disabling and highly prevalent mood disorder as well as a common cause of suicide. Chronic stress, inflammation, and intestinal dysbiosis have all been shown to play crucial roles in the pathophysiology of MDD. Although conventional antidepressants are widely used in the clinic, they can take weeks to months to produce therapeutic effects. The discovery that ketamine promotes fast and sustaining antidepressant responses is one of the most important breakthroughs in the pharmacotherapy of MDD. However, the adverse psychomimetic/dissociative and neurotoxic effects of ketamine discourage its chronic use. Therefore, agmatine, an endogenous glutamatergic modulator, has been postulated to elicit fast behavioral and synaptogenic effects by stimulating the mechanistic target of rapamycin complex 1 signaling pathway, similar to ketamine. However, recent evidence has demonstrated that the modulation of the NLR family pyrin domain containing 3 inflammasome and gut microbiota, which have been shown to play a crucial role in the pathophysiology of MDD, may also participate in the antidepressant-like effects of both ketamine and agmatine. This review seeks to provide evidence about the mechanisms that may underlie the fast antidepressant-like responses of agmatine in preclinical studies. Considering the anti-inflammatory properties of agmatine, it may also be further investigated as a useful compound for the management of MDD associated with a pro-inflammatory state. Moreover, the fast antidepressant-like response of agmatine noted in animal models should be investigated in clinical studies.

Keywords: Agmatine, Fast-acting antidepressants, Ketamine, Major depressive disorder, Microbiota-gut-brain axis, Neuroinflammation

Core Tip: One of the main challenges in the advancement of antidepressant therapy is the establishment of safe and effective fast-acting antidepressants. Ketamine is a prototype for rapid-onset antidepressant responses. Agmatine has been shown to produce fast antidepressant-like effect by stimulating mechanistic target of rapamycin complex 1 signaling pathway, similar to ketamine. Moreover, NLR family pyrin domain containing 3 and microbiota-gut-brain axis may be novel targets for fast antidepressant responses. These targets have also been postulated to play a role in the antidepressant effect of both ketamine and agmatine.