Targeting glutamate signalling in depression: progress and prospects
This review (2017) examines the history, rationale, and efficacy of glutamate-modulating agents in treating depression. Ketamine has emerged as the prototypical fast-acting antidepressant and has yielded compelling hypotheses about the role of glutamate, although the role of its effects on NMDA receptor inhibition still remains unclear as to whether it alleviates depression. Preliminary evidence also suggests that ketamine-like drugs exert antidepressant properties by regulating monoamine signaling, opioid signaling, inflammatory systems, or even epigenetic mechanisms.
Authors
- Sanjay Mathew
- James Murrough
- Chadi Abdallah
Published
Abstract
Major depressive disorder (MDD) is severely disabling, and current treatments have limited efficacy. The glutamate N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine was recently repurposed as a rapidly acting antidepressant, catalysing the vigorous investigation of glutamate-signalling modulators as novel therapeutic agents for depressive disorders. In this Review, we discuss the progress made in the development of such modulators for the treatment of depression, and examine recent preclinical and translational studies that have investigated the mechanisms of action of glutamate-targeting antidepressants. Fundamental questions remain regarding the future prospects of this line of drug development, including questions concerning safety and tolerability, efficacy, dose-response relationships and therapeutic mechanisms.
Research Summary of 'Targeting glutamate signalling in depression: progress and prospects'
Introduction
Major depressive disorder (MDD) is a leading cause of global disability and a large minority of patients fail to respond adequately to existing monoamine-based treatments; up to ~20% of patients have treatment-resistant depression (TRD), commonly defined as failure of two or more antidepressant trials. Conventional antidepressants also have a delayed onset of benefit, prompting interest in alternative biological systems. Glutamate signalling has emerged as a prominent target because of its pervasive role in synaptic plasticity and its regulation of mood, cognition and reward, but its ubiquity creates drug-discovery challenges related to tolerability and the potential for excitotoxicity. Murrough and colleagues set out to review progress in developing glutamate-modulating agents for depressive disorders, using ketamine as a prototype rapid-acting antidepressant to frame translational and clinical evidence. The review synthesises preclinical, translational and clinical studies of diverse glutamatergic targets (including NMDARs, AMPARs, mGluRs, GlyT1 and glutamate-release regulators), evaluates proposed mechanisms—especially whether NMDAR engagement is necessary for clinical benefit—and discusses unresolved questions about safety, dosing, efficacy and future directions for drug development.
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Murrough, J. W., Abdallah, C. G., & Mathew, S. J. (2017). Targeting glutamate signalling in depression: progress and prospects. Nature Reviews Drug Discovery, 16(7), 472-486. https://doi.org/10.1038/nrd.2017.16
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Hashimoto, K. · Psychiatry and Clinical Neurosciences (2019)
Abdallah, C. G., Sanacora, G., Duman, R. S. et al. · Chronic Stress (2018)
Jones, J. L., Mateus, C. F., Malcolm, R. J. et al. · Frontiers in Psychiatry (2018)
Grunebaum, M. F., Galfalvy, H. C., Choo, T. H. et al. · American Journal of Psychiatry (2018)
Zanos, P., Thompson, S. M., Duman, R. S. et al. · CNS Drugs (2018)
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