Depression is one of the leading causes of disability worldwide; however, no truly mechanistically novel compounds have come to the market in decades.
Ignited by the observation of a rapid antidepressant effect of the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, the glutamate system has emerged as a leading focus for novel drug discovery for depression and other mood disorders.
New basic and clinical research is clarifying the mechanistic relevance and therapeutic feasibility of multiple targets within the glutamate system for novel drug discovery, including NMDA and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, metabotropic glutamate receptors, and other key regulatory proteins such as glycine transporter 1 and excitatory amino acid transporters.
Encouragingly, multiple glutamate-based compounds have entered clinical testing, with some compounds recently advancing to phase III trials.
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.
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In the past 3 years, J.W.M. has provided consultation services for Novartis, Janssen Research and Development, Genentech, ProPhase and Impel Neuropharma, has received research support from Avanir Pharmaceuticals, Inc., and is named on a pending patient for lithium to extend the antidepressant effect of ketamine and for the combination of lithium and ketamine for the treatment of suicidal ideation. The Icahn School of Medicine at Mount Sinai (to which J.W.M. is affiliated) is named on a patent and has entered into a licensing agreement and will receive payments related to the use of ketamine if it is approved for the treatment of depression. J.W.M. is not named on the patent and will not receive any payments. C.G.A. has served as a consultant and/or on advisory boards for Genentech and Janssen. S.J.M. has been receiving consulting fees from Acadia, Cerecor, Otsuka and Valeant, and is on an advisory board for VistaGen Therapeutics. He has received research support from Janssen Research & Development. He is supported by the use of facilities and resources at the Michael E. Debakey VA Medical Center, Houston, Texas, USA.
- Synaptic plasticity
Activity- or experience-dependent changes in synaptic structure and function that are relatively long-lasting (that is, persisting beyond the initial electrochemical event).
- Long-term potentiation
A form of synaptic plasticity in which postsynaptic cellular responses are augmented as a function of recent neuronal activity.
Neurotoxicity through a mechanism at least partially dependent on high Ca2+ influx and subsequent triggering of cell death mechanisms.
- Bipolar disorder
A mood disorder that is characterized by episodes of depression alternating with episodes of mania or hypomania.
- Glial cells
Non-neuronal central nervous system cells, including astrocytes and oligodendrocytes, that function to maintain homeostasis, support neurotransmission and neuronal health, and form myelin.
- Glutamate–glutamine cycling
Biochemical pathway that describes the uptake and conversion of glutamate to glutamine by astrocytes and the subsequent transfer of glutamine back to neurons for conversion to glutamate.
Stereoisomers that are mirror images of each other.
The (S)-stereoisomer of citalopram; a serotonin-selective reuptake inhibitor (SSRI) approved in the United States for the treatment of major depressive disorder and generalized anxiety disorder.
- Chronic variable stress
Procedure used to model depression in rodents that typically consists of subjecting the animal to daily bouts of mild-to-moderate environmental stressors over several weeks.
- Chronic social defeat stress
Procedure used to model depression in rodents that consists of exposing a target rodent to an aggressor daily for 10 days.
- Sucrose preference
Procedure used to assess anhedonia or lack of response to pleasure in rodents that involves measuring the degree to which an animal preferentially selects a solution sweetened with sucrose over a non-sweet solution.
- Global brain connectivity
A seed-free, whole-brain approach to resting-state functional magnetic resonance imaging connectivity analysis.
- Learned helplessness
Behavioural pattern that occurs when animals are repeatedly exposed to aversive stimuli that cannot be controlled or from which the animal cannot escape.
- Forced swimming test
Behavioural despair test in which the degree to which a rodent swims when placed in a cylinder filled with water from which it cannot escape is taken as a measure of antidepressant activity.
- Pseudobulbar affect
Type of affect characterized by episodes of uncontrollable crying or laughing and which typically occurs secondary to a neurological injury.
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Murrough, J., Abdallah, C. & Mathew, S. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov 16, 472–486 (2017). https://doi.org/10.1038/nrd.2017.16
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