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World J Psychiatry. Jul 19, 2022; 12(7): 884-896
Published online Jul 19, 2022. doi: 10.5498/wjp.v12.i7.884
Genetic variables of the glutamatergic system associated with treatment-resistant depression: A review of the literature
Estela Saez, Leire Erkoreka, Teresa Moreno-Calle, Belen Berjano, Ana Gonzalez-Pinto, Nieves Basterreche, Aurora Arrue
Estela Saez, Leire Erkoreka, Teresa Moreno-Calle, Belen Berjano, Department of Psychiatry, Barrualde-Galdakao Integrated Health Organization, Osakidetza-Basque Health Service, Galdakao 48960, Spain
Leire Erkoreka, Teresa Moreno-Calle, Aurora Arrue, Mental Health Network Group, Biocruces Bizkaia Health Research Institute, Barakaldo 48903, Spain
Leire Erkoreka, Ana Gonzalez-Pinto, Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa 48940, Spain
Ana Gonzalez-Pinto, Department of Psychiatry, Araba Integrated Health Organization, Osakidetza-Basque Health Service, CIBERSAM, Vitoria-Gasteiz 01004, Spain
Ana Gonzalez-Pinto, Severe Mental Disorders Group, Bioaraba Health Research Institute, Vitoria-Gasteiz 01009, Spain
Nieves Basterreche, Zamudio Hospital, Bizkaia Mental Health Network, Osakidetza-Basque Health Service, Zamudio 48170, Spain
Nieves Basterreche, Integrative Research Group in Mental Health, Biocruces Bizkaia Health Research Institute, Barakaldo 48903, Spain
Aurora Arrue, Neurochemical Research Unit, Bizkaia Mental Health Network, Osakidetza-Basque Health Service, Barakaldo 48903, Spain
Author contributions: Saez E, Erkoreka L, Moreno-Calle T, Berjano B, Basterreche N and Arrue A contributed to the literature search and article review; Erkoreka L, Saez E and Moreno-Calle T wrote the draft; Gonzalez-Pinto A contributed to manuscript revision; all authors revised and approved the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest 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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Leire Erkoreka, MD, PhD, Associate Chief Physician, Department of Psychiatry, Barrualde-Galdakao Integrated Health Organization, Osakidetza-Basque Health Service, Labeaga Auzoa 46A, Galdakao 48960, Spain. leire.erkorekagonzalez@osakidetza.eus
Received: January 31, 2022
Peer-review started: January 31, 2022
First decision: April 18, 2022
Revised: April 29, 2022
Accepted: June 26, 2022
Article in press: June 26, 2022
Published online: July 19, 2022
Abstract

Depression is a common, recurrent mental disorder and one of the leading causes of disability and global burden of disease worldwide. Up to 15%-40% of cases do not respond to diverse pharmacological treatments and, thus, can be defined as treatment-resistant depression (TRD). The development of biomarkers predictive of drug response could guide us towards personalized and earlier treatment. Growing evidence points to the involvement of the glutamatergic system in the pathogenesis of TRD. Specifically, the N-methyl-D-aspartic acid receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), which are targeted by ketamine and esketamine, are proposed as promising pathways. A literature search was performed to identify studies on the genetics of the glutamatergic system in depression, focused on variables related to NMDARs and AMPARs. Our review highlights GRIN2B, which encodes the NR2B subunit of NMDAR, as a candidate gene in the pathogenesis of TRD. In addition, several studies have associated genes encoding AMPAR subunits with symptomatic severity and suicidal ideation. These genes encoding glutamatergic receptors could, therefore, be candidate genes for understanding the etiopathogenesis of TRD, as well as for understanding the pharmacodynamic mechanisms and response to ketamine and esketamine treatment.

Keywords: Genetics, N-methyl-D-aspartic acid receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, Treatment-resistant depression, Ketamine, Esketamine

Core Tip: Depression is a common mental disorder and one of the leading causes of disability worldwide. Up to 15%-40% of cases are considered treatment-resistant depression, which seems to be conditioned by environmental and genetic factors. The glutamatergic system, specifically N-methyl-D-aspartic acid receptor (NMDAR) dysfunction, has been proposed to be involved in the pathogenesis of treatment-resistant depression (TRD). A literature search was performed to identify studies on the genetics of the glutamatergic system in depression, focused on NMDAR and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Our review highlights GRIN2B, which encodes the NR2B subunit of NMDAR, as a candidate gene in the pathogenesis of TRD.