Glutamatergic Modulators for Major Depression from Theory to Clinical Use

Abstract

Major depressive disorder (MDD) is a chronic, burdensome, highly prevalent disease that is characterized by depressed mood and anhedonia. MDD is especially burdensome as approved monoamine antidepressant treatments have weeks-long delays before clinical benefit and low remission rates. In the past 2 decades, a promising target emerged to improve patient outcomes in depression treatment: glutamatergic signaling. This narrative review provides a high-level overview of glutamate signaling in synaptogenesis and neural plasticity and the implications of glutamate dysregulation in depression. Based on this preclinical evidence implicating glutamate in depression and the rapid improvement of depression with ketamine treatment in a proof-of-concept trial, a range of N-methyl-D-aspartate (NMDA)-targeted therapies have been investigated. While an array of treatments has been investigated in registered phase 2 or 3 clinical trials, the development of most of these agents has been discontinued. Multiple glutamate-targeted antidepressants are actively in development, and two are approved. Nasal administration of esketamine (Spravato^®) was approved by the US Food and Drug Administration (FDA) in 2019 to treat adults with treatment-resistant depression and in 2020 for adults with MDD with acute suicidal ideation or behavior. Oral combination dextromethorphan-bupropion (AXS-05, Auvelity^® extended-release tablet) was FDA approved in 2022 for the treatment of MDD in adults. These approvals bolster the importance of glutamate in depression and represent an exciting breakthrough in contemporary psychiatry, providing new avenues of treatment for patients as first-line therapy or with either poor response or unacceptable side effects to monoaminergic antidepressants.

Fig. 1

Glutamate signaling in neuroplasticity and synaptogenesis. Akt protein kinase B, AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, BDNF brain-derived neurotrophic factor, EAAT excitatory amino acid transporter, EF2 eukaryotic elongation factor 2, ERK extracellular signal-regulated kinases, Gln glutamine, Glu glutamate, mGluR metabotropic glutamate receptor, mTOR mammalian target of rapamycin, NMDAR N-methyl-d-aspartate receptor, P phosphorylated, TrkB tropomyosin receptor kinase B, vGLUT vesicular glutamate transporter. Modified from Lener et al. 2017 [162] and Henter et al. 2021 [14]. Figure illustration elements modified from Servier Medical Art (2022) by Servier (https://smart.servier.com, used under a Creative Commons Attribution 4.0 License)

Fig. 2

Timeline of registered trials of glutamate-targeted drugs for treatment of depression^a. ^aFigure includes phase 2, 3, and 4 trials registered on ClinicalTrials.gov for the treatment of MDD or TRD as detailed in Online Resource 1, Supplementary Table 1. ^bThe first placebo-controlled, double-blind trial of ketamine in seven people with depression, conducted in 2000, was not registered on ClinicalTrials.gov [64]. ^cIntranasal esketamine is approved by the FDA, TPD, EMA, and TGA as an adjunctive treatment for TRD and/or for MDD with suicidal ideation/behavior or psychiatric emergency. ^dAXS-05 is approved to treat MDD in adults by the FDA. EMA European Medicines Agency, FDA US Food and Drug Administration, MDD major depressive disorder, NMDA N-methyl d-aspartate, TGA Australia’s Therapeutic Goods Administration, TPD Canada’s Therapeutic Products Directorate, TRD treatment-resistant depression

Fig. 3

Response and remission rates with adjunctive intranasal esketamine in TRANSFORM-2 trial^a,b. ^aTRANSFORM-2 (NCT02418585) investigated adjunctive flexibly dosed intranasal esketamine versus adjunctive placebo with a newly initiated oral SNRI or SSRI antidepressant, in patients with TRD in a 28-day double-blind treatment phase. ^bPercentages shown are the proportion of patients remaining at visit [127]. ADT antidepressant, IN intranasal, MADRS Montgomery-Åsberg Depression Rating Scale, SNRI serotonin-norepinephrine reuptake inhibitor, SSRI selective serotonin reuptake inhibitor, TRD treatment-resistant depression, NR not reported

Fig. 4

Antidepressant mechanisms of sigma-1 receptors^a. ^aActivated sigma-1 receptors may: translocate from the ER to ion channels, GPCR, or NMDAR at the cell membrane to modulate receptor activity; stabilize IP₃R to maintain Ca²⁺ flow and ATP production; and modulate ER stress to enable downstream BDNF expression. ASIC1a acid-sensing ion channel, ATP adenosine triphosphate, BDNF brain-derived neurotrophic factor, CaMKII calmodulin-dependent protein kinase II, ER endoplasmic reticulum, ERK extracellular signal-regulated kinase, GPCR G-protein coupled receptor, IP3R inositol 1,4,5-trisphosphate receptor, IRE1 inositol-requiring enzyme 1, mTOR mammalian target of rapamycin, NMDAR N-methyl-d-aspartate receptor, P phosphorylated, XBP1 X-box-binding protein 1. Figure illustration elements modified from Servier Medical Art (2022) by Servier (https://smart.servier.com, under a Creative Commons Attribution 4.0 License)

Fig. 5

Response and remission rates with oral AXS-05 in GEMINI trial. ***P < 0.001 versus control; analyzed via χ² test. ^a GEMINI (NCT04019704) investigated AXS-05 versus placebo in patients with MDD for a 6-week double-blind treatment period. MADRS Montgomery-Åsberg Depression Rating Scale, MDD major depressive disorder, PO oral