Targeting glutamate signalling in depression: progress and prospects

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.

The extracted text does not include a formal Methods section describing search strategy, eligibility criteria or systematic review procedures. The paper is presented as a narrative, conceptual review that integrates findings from animal models, human translational studies (neuroimaging, spectroscopy, PET) and clinical trials, and that evaluates both mechanistic and clinical evidence for glutamate-targeting antidepressants. Within this framework, the authors considered preclinical lines of evidence (behavioural models such as chronic variable stress, chronic social defeat, sucrose preference and forced swim tests), clinical randomised controlled trials (RCTs) and open-label studies of ketamine and other agents, and biomarker studies measuring metabolites (1H-MRS Glx/GABA), functional MRI connectivity, PET metabolism and peripheral BDNF. The review also summarises phase I–III trial results and early-phase programmes for a range of compounds (for example, GLYX-13, d-cycloserine, NRX-1074, CERC-301, AV-101, dextromethorphan combinations, sarcosine, AMPAR potentiators and mGluR modulators) as reported in the available literature and company-sponsored studies cited by the authors.

Evidence for glutamatergic dysfunction in depression includes elevated glutamate in some biofluids and brain regions, altered expression or function of NMDAR subunits in post-mortem studies, reductions in glial elements (which regulate synaptic glutamate), and neuroimaging findings such as reduced Glx and GABA in prefrontal cortex (PFC) by 1H-MRS and reduced mGluR5 binding by PET. Chronic stress in animals produces dendritic atrophy, reduced synapse density and impairments in AMPAR and NMDAR availability; these microstructural changes are proposed to underlie volumetric and connectivity abnormalities seen in MDD. Ketamine clinical effects: Low-dose intravenous (i.v.) ketamine produces rapid reductions in core depressive symptoms within hours, with antidepressant effects that generally wane over days to about a week after a single infusion. RCTs, including comparisons with saline and the active control midazolam, consistently show rapid antidepressant effects in TRD; a meta-analysis of seven RCTs reported that ketamine was ~9.9-fold more likely to induce an antidepressant response and ~14.5-fold more likely to induce remission versus control. Another meta-analysis of eight RCTs found large effects, and a Cochrane Review reported increased likelihood of response but noted small samples and risk of bias. The total number of patients randomised across controlled trials remains small. Repeated i.v. dosing regimens (two or three times weekly over 15 days) have shown maintenance of efficacy over the short assessment period in industry-sponsored trials. Intranasal (S)-ketamine (esketamine) is under development; i.v. (S)-ketamine showed rapid antidepressant effects in a 30-patient trial, while (R)-ketamine has no published human data in the extracted text. Mechanistic and biomarker findings: Preclinical data implicate synaptic plasticity as a central downstream mechanism. Ketamine and several rapid-acting agents increase synaptic protein translation (for example GluR1 and PSD95) via BDNF–TRKB–AKT–ERK–mTORC1 pathways and disinhibit protein translation through eEF2 regulation. AMPAR activation is repeatedly required for ketamine’s antidepressant-like effects in animals; AMPAR antagonism blocks these effects. Some studies indicate that a ketamine metabolite—(2R,6R)-hydroxynorketamine (HNK)—may produce antidepressant effects independently of NMDAR blockade but still requiring AMPAR activation, raising the possibility of NMDAR-independent mechanisms. Non-ketamine NMDAR antagonists such as memantine generally lacked robust antidepressant efficacy, suggesting that simple NMDAR blockade is not sufficient. Human translational biomarkers show acute increases in cortical Glx and GABA after ketamine, and task and resting fMRI studies report rapid changes in regional BOLD and connectivity; for example, ketamine normalised caudate responses to positive stimuli and partially reversed PFC hypoconnectivity 24 hours post-infusion. PET studies found mixed metabolic changes correlated with symptom improvement in regions including PFC, temporal cortex and habenula. Peripheral BDNF studies yield inconsistent results: some reports of post-treatment increases correlating with response, others negative, and a tentative influence of the Val66Met polymorphism on treatment response. Other glutamate modulators: Early-phase and company-sponsored trials of varied agents produced mixed outcomes. d-Cycloserine (high-dose) showed some adjunctive benefit in a 6-week trial; GLYX-13 (rapastinel) had dose-dependent effects in a 120-patient RCT where intermediate doses separated from placebo while the highest and lowest did not; NRX-1074 is an oral analogue anticipated for phase II. The NR2B-selective antagonist CERC-301 (MK-0657) had mixed efficacy in small studies. AV-101 (4-Cl-KYN), a prodrug of a glycine-site antagonist, showed antidepressant-like effects in mice but no human data in the extracted text. Dextromethorphan-containing combinations and next-generation formulations were in phase II–III development. Sarcosine (a GlyT1 inhibitor) showed superiority to citalopram in a small 6-week RCT. AMPAR potentiators had encouraging early-phase biomarker and safety signals (for Org 26576), but clinical data were limited. mGluR2/3 and mGluR5 modulators produced ketamine-like effects in preclinical models; however, a phase IIb adjunctive trial of the mGluR5 negative allosteric modulator basimglurant failed its primary end point, though post-hoc or secondary analyses suggested possible dose-related effects. Safety and trial-design findings: Acute ketamine causes transient dissociation, psychotomimetic symptoms and haemodynamic changes that complicate masking in trials. Preclinical neurotoxicity has been observed at high doses or during development. Reported short-term clinical trials using low doses and limited infusions did not find persistent psychological or substance-abuse sequelae in pooled analyses, but long-term safety and effects of repeated or chronic exposure remain inadequately studied. Trial design challenges include heterogeneity of depressed samples, expectancy effects with parenteral administration, potential functional unblinding when active drugs have distinctive acute effects, sensitivity of standard outcome measures to rapid changes, and uncertainty about optimal dosing frequency.

Murrough and colleagues interpret the assembled evidence as indicating substantial progress: ketamine has established itself as a prototype rapid-acting antidepressant and has catalysed translational work that links glutamate signalling to synaptic plasticity pathways. The authors frame synaptic plasticity—engaging AMPARs, BDNF–TRKB signalling, mTORC1 and related intracellular translation machinery—as a plausible common pathway for rapidly acting antidepressant effects, supported by convergent animal and human imaging data. At the same time, the authors highlight important uncertainties. They caution that NMDAR antagonism per se may not be necessary or sufficient for clinical efficacy, given differential results with memantine and the emerging data implicating active ketamine metabolites (such as (2R,6R)-HNK) and AMPAR-dependent mechanisms. The possibility that ketamine’s effects engage non-glutamatergic systems—monoaminergic, opioid, inflammatory or epigenetic pathways—is acknowledged, and disentangling these contributions remains an open question. Key limitations of the current literature are emphasised: small total sample sizes in randomized ketamine trials, risk of bias from imperfect masking, scarcity of long-term safety and efficacy data, heterogeneity in patient selection, and a lack of validated biomarkers for diagnosis and treatment prediction. The authors note that many candidate glutamate modulators have shown promising preclinical results but mixed clinical outcomes, and that some programmes have stalled or failed in mid-stage trials. For future research and clinical translation, the authors advocate careful dose- and frequency-finding, improved trial designs to mitigate expectancy and unblinding (for example, using plausible active comparators), enriched patient selection strategies beyond simple counts of prior treatment failures, and multimodal translational studies to validate imaging and molecular surrogate markers. Safety assessment of repeated or chronic dosing is described as a crucial unmet need before broader clinical adoption can be recommended. Finally, they stress the importance of clarifying how glutamate-based pharmacotherapies might interface with existing pharmacological, neurostimulatory and psychotherapeutic approaches.

The review concludes that while glutamate-modulating therapies—exemplified by ketamine—represent a major advance in the understanding and potential treatment of depression, significant gaps remain. There is compelling translational evidence linking glutamate signalling to synaptic plasticity and rapid mood improvement, yet long-term safety and efficacy data are largely absent, mechanisms remain incompletely characterised (and may extend beyond direct NMDAR blockade), and no glutamate-targeting agent has been approved for depression at the time of the review. The authors call for more rigorous, longer-term clinical trials, refined biomarker development and cautious assessment of risk–benefit before widespread clinical use.