The Role of Glutamate Underlying Treatment-resistant Depression

Overview

Journal Clin Psychopharmacol Neurosci

Specialty Psychiatry

Date 2023 Jul 10

PMID 37424412

Authors

Jeongseop Kim

Tae-Eun Kim

Seung-Hwan Lee

Ja Wook Koo

Affiliations

Soon will be listed here.

Abstract

The monoamine hypothesis has significantly improved our understanding of mood disorders and their treatment by linking monoaminergic abnormalities to the pathophysiology of mood disorders. Even 50 years after the monoamine hypothesis was established, some patients do not respond to treatments for depression, including selective serotonin reuptake drugs. Accumulating evidence shows that patients with treatment-resistant depression (TRD) have severe abnormalities in the neuroplasticity and neurotrophic factor pathways, indicating that different treatment approaches may be necessary. Therefore, the glutamate hypothesis is gaining attention as a novel hypothesis that can overcome monoamine restrictions. Glutamate has been linked to structural and maladaptive morphological alterations in several brain areas associated with mood disorders. Recently, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has shown efficacy in TRD treatment and has received the U.S. Food and Drug Administration approval, revitalizing psychiatry research. However, the mechanism by which ketamine improves TRD remains unclear. In this review, we re-examined the glutamate hypothesis, bringing the glutamate system onboard to join the modulation of the monoamine systems, emphasizing the most prominent ketamine antidepressant mechanisms, such as NMDAR inhibition and NMDAR disinhibition in GABAergic interneurons. Furthermore, we discuss the animal models used in preclinical studies and the sex differences in the effects of ketamine.

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References

Khan A, Fabre L, Rudolph R . Venlafaxine in depressed outpatients. Psychopharmacol Bull. 1991; 27(2):141-4. View

Duman R, Aghajanian G, Sanacora G, Krystal J . Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016; 22(3):238-49. PMC: 5405628. DOI: 10.1038/nm.4050. View

McEwen B, Gianaros P . Stress- and allostasis-induced brain plasticity. Annu Rev Med. 2010; 62:431-45. PMC: 4251716. DOI: 10.1146/annurev-med-052209-100430. View

ZELLER E, BARSKY J . In vivo inhibition of liver and brain monoamine oxidase by 1-Isonicotinyl-2-isopropyl hydrazine. Proc Soc Exp Biol Med. 1952; 81(2):459-61. DOI: 10.3181/00379727-81-19910. View

Corral R, Alessandria H, Agudelo Baena L, Ferro E, Duque X, Quarantini L . Suicidality and Quality of Life in Treatment-Resistant Depression Patients in Latin America: Secondary Interim Analysis of the TRAL Study. Front Psychiatry. 2022; 13:812938. PMC: 8924115. DOI: 10.3389/fpsyt.2022.812938. View

Gould T, Zarate Jr C, Thompson S . Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants. Annu Rev Pharmacol Toxicol. 2018; 59:213-236. PMC: 6364552. DOI: 10.1146/annurev-pharmtox-010617-052811. View

Widman A, McMahon L . Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. Proc Natl Acad Sci U S A. 2018; 115(13):E3007-E3016. PMC: 5879689. DOI: 10.1073/pnas.1718883115. View

Rasmussen N . Making the first anti-depressant: amphetamine in American medicine, 1929-1950. J Hist Med Allied Sci. 2006; 61(3):288-323. DOI: 10.1093/jhmas/jrj039. View

Dua D, Agarwal A, Dalal P . Imipramine in schizophrenia with depressive symptomatology. Indian J Psychiatry. 2011; 32(3):229-34. PMC: 2990171. View

10.

Denomme B.S N . The Domino Effect: Ed Domino's early studies of Psychoactive Drugs. J Psychoactive Drugs. 2018; 50(4):298-305. DOI: 10.1080/02791072.2018.1506599. View

11.

Fuchs T, Jefferson S, Hooper A, Yee P, Maguire J, Luscher B . Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state. Mol Psychiatry. 2016; 22(6):920-930. PMC: 5422144. DOI: 10.1038/mp.2016.188. View

12.

Fuller R, Hemrick-Luecke S, Snoddy H . Effects of duloxetine, an antidepressant drug candidate, on concentrations of monoamines and their metabolites in rats and mice. J Pharmacol Exp Ther. 1994; 269(1):132-6. View

13.

Kew J, Kemp J . Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl). 2005; 179(1):4-29. DOI: 10.1007/s00213-005-2200-z. View

14.

Maeng S, Zarate Jr C, Du J, Schloesser R, McCammon J, Chen G . Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2007; 63(4):349-52. DOI: 10.1016/j.biopsych.2007.05.028. View

15.

Endler N . The Origins of Electroconvulsive Therapy (ECT). Convuls Ther. 1988; 4(1):5-23. View

16.

Freeman M, Papakostas G, Hoeppner B, Mazzone E, Judge H, Cusin C . Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression. J Psychiatr Res. 2019; 110:166-171. PMC: 6360121. DOI: 10.1016/j.jpsychires.2019.01.010. View

17.

Nieto-Gonzalez J, Holm M, Vardya I, Christensen T, Wiborg O, Jensen K . Presynaptic plasticity as a hallmark of rat stress susceptibility and antidepressant response. PLoS One. 2015; 10(3):e0119993. PMC: 4350919. DOI: 10.1371/journal.pone.0119993. View

18.

Bisgaard C, Jayatissa M, Enghild J, Sanchez C, Artemychyn R, Wiborg O . Proteomic investigation of the ventral rat hippocampus links DRP-2 to escitalopram treatment resistance and SNAP to stress resilience in the chronic mild stress model of depression. J Mol Neurosci. 2007; 32(2):132-44. DOI: 10.1007/s12031-007-0025-4. View

19.

LAPORTA M, Chouinard G, Goldbloom D, Beauclair L . Hypomania induced by sertraline, a new serotonin reuptake inhibitor. Am J Psychiatry. 1987; 144(11):1513-4. DOI: 10.1176/ajp.144.11.1513. View

20.

Trullas R, Skolnick P . Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990; 185(1):1-10. DOI: 10.1016/0014-2999(90)90204-j. View