The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?

Abdallah and colleagues open by situating ketamine's discovery within a longer history of serendipitous psychopharmacology, noting prior unexpected findings that ultimately led to major drug classes. They highlight that a single subanesthetic dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects, an observation that stimulated interest in targeting glutamate neurotransmission for rapid-acting antidepressants (RAADs). Early efforts emphasised glutamate inhibition (either by reducing release or blocking NMDARs) because of concerns about glutamate-mediated excitotoxicity in depression, but subsequent evidence raised the contrasting possibility that transient glutamate activation underlies RAAD effects. This perspective paper aims to synthesise preclinical and clinical data to clarify that debate. Specifically, the authors review the history of the “glutamate inhibition” versus “glutamate activation” hypotheses, propose a synaptic connectivity model of chronic stress pathology (CSP), describe ketamine’s putative mechanisms, summarise clinical efficacy of candidate RAADs, present relevant human biomarker findings, and discuss current challenges and future directions for the field.

The extracted text presents this work as a narrative perspective rather than a systematic review; no explicit search strategy, inclusion criteria, or formal methods for study selection are reported in the provided material. Instead, the authors synthesise experimental and clinical findings from animal models, human imaging and spectroscopy studies, and randomized and proof-of-concept clinical trials to build a conceptual model. Evidence types integrated throughout include preclinical rodent studies (behavioural models, microdialysis, molecular assays), human neuroimaging (functional MRI, structural MRI), carbon-13 magnetic resonance spectroscopy (13C MRS), receptor binding studies, and clinical trials of ketamine and several other investigational agents (for example scopolamine, traxoprodil, rapastinel, esketamine, lanicemine). Where mechanistic inferences are made, the authors draw on pharmacokinetic data (timing of ketamine and metabolite concentrations), receptor pharmacology, and intervention studies that manipulate downstream signalling (for example AMPA receptor antagonists) to infer causal steps in the pathway from transient glutamate effects to sustained synaptic changes.

The historical literature reviewed shows initially mixed interpretations: 1990s data suggested that downregulating NMDAR function might be common to antidepressant action, and inhibiting NMDARs or glutamate release could block stress-related dendritic atrophy in animals. However, more recent evidence indicates that subanesthetic ketamine produces a transient prefrontal glutamate ‘‘surge’’ (activation) rather than sustained inhibition, and that acute glutamate activation is associated with upregulation of brain-derived neurotrophic factor (BDNF) and other neurotrophins. The authors present a synaptic chronic stress pathology (CSP) model in which repeated or traumatic stress produces region-specific synaptic remodelling: hypoconnectivity (reduced dendritic length, spine/synapse density and synaptic strength) in the prefrontal cortex (PFC) and hippocampus, but hyperconnectivity in the nucleus accumbens (NAc) and some amygdala nuclei. Glial deficits and dysregulated glucocorticoid signalling are implicated in reduced glutamate reuptake and paradoxically elevated extrasynaptic glutamate despite reduced resting synaptic transmission. Preclinical work links these synaptic changes to depressive-like behaviours, and both slow-acting antidepressants (SAADs) and RAADs reverse PFC hypoconnectivity while reducing NAc hyperconnectivity. Mechanistically, two ketamine-induced changes are emphasised as critical to RAAD effects: a transient postsynaptic activation of glutamate neurotransmission in the PFC (a ‘‘surge’’) and a sustained restoration of PFC synaptic connectivity within about 24 hours. The transient activation triggers activity-dependent BDNF release, engages mTORC1 signalling (mechanistic target of rapamycin complex 1), increases protein synthesis and synaptic strength. Evidence supporting the necessity of postsynaptic activation includes blockade of ketamine’s synaptic and behavioural effects by AMPA receptor (AMPAR) antagonists, and the dependence on postsynaptic depolarisation and L-type voltage-dependent calcium channel activity. Pharmacokinetic notes: ketamine rapidly reaches the brain (within about 1 minute) and shows a brain/plasma concentration ratio of about 6.5 for roughly 10 minutes in rodents; plasma ketamine and norketamine peak ~10 minutes, while hydroxynorketamine (HNK) peaks ~30 minutes. (2R,6R)-HNK has been reported to show RAAD-like effects without NMDAR blockade, but preliminary data indicate it also induces a glutamate surge. A range of other putative RAADs appear to act via transient glutamate activation, including scopolamine (muscarinic antagonist), rapastinel (NMDAR partial agonist candidate), selective GluN2B antagonists (e.g. traxoprodil), mGluR2/3 antagonists, and AMPAR potentiators (ampakines). By contrast, agents aimed at inhibiting glutamate release (for example lamotrigine, riluzole) have shown at best slow-acting antidepressant properties and inconsistent RAAD effects; chronic administration of some of these drugs may ultimately increase BDNF and PFC glutamate activity rather than sustain inhibition. The authors also distinguish synaptic versus extrasynaptic NMDARs, noting that extrasynaptic activation is linked to cell death pathways and that selective blockade of extrasynaptic NMDARs produced RAAD-like effects in rodents, although existing studies often assessed behaviour immediately after dosing rather than at 24 hours. Clinical efficacy synthesis emphasises robust replication that a single intravenous ketamine infusion (commonly 0.5 mg/kg over 40 minutes) yields rapid antidepressant effects in major depressive disorder (MDD). Relapse commonly occurs within 1–2 weeks after a single infusion, but repeated dosing (for example twice weekly) can maintain effects. Intranasal administration shows pilot promise. Safety considerations include transient psychotomimetic effects (generally lasting 1–2 hours), addiction liability, and limited data on chronic safety; heavy daily ketamine use is associated with bladder, hepatic and neurotoxic harms. Other clinical candidates reviewed: scopolamine has shown efficacy in small trials; traxoprodil had signal but development halted due to QT prolongation; esketamine demonstrates early RAAD properties; d-cycloserine has retrospective signals; rapastinel showed proof-of-concept efficacy; lanicemine had mixed results across trials. The authors note that confirmatory trials are still needed for many candidates. On biomarkers, several lines support a ketamine-induced prefrontal glutamate surge in humans: alterations in PFC glucose metabolism and blood flow, increased BOLD signal, increased total glutamate, changes in mGluR5 binding, and in vivo/ex vivo 13C MRS evidence. Resting-state functional MRI work has repeatedly identified reduced PFC global brain connectivity (GBC) in disorders with chronic stress, and ketamine increases PFC GBC during infusion and normalises deficits within 24 hours in MDD, with the magnitude of GBC increase predicting clinical response. Structural MRI pilot data indicate that ketamine can increase hippocampal volume and reduce NAc volume within 24 hours in responders. The authors caution that many human mechanistic studies are preliminary and that most imaging work in healthy subjects limits direct linkage to antidepressant response.

Abdallah and colleagues interpret the assembled evidence as increasingly consistent with a model in which rapid antidepressant effects arise from transient postsynaptic glutamate activation in the prefrontal cortex that triggers BDNF and mTORC1-dependent protein synthesis and synaptogenesis, producing sustained restoration of synaptic connectivity. They acknowledge that earlier data and some treatments point to antidepressant effects of glutamate inhibition, but emphasise that such effects have been primarily associated with slow-acting antidepressant outcomes rather than rapid responses. Key limitations the authors acknowledge include the relative paucity of reproducible, translatable biomarkers for target engagement (transient postsynaptic glutamate activation) and target validation (sustained synaptic remodelling) in humans. This gap hinders the development and optimisation of RAAD candidates, partly explaining why several agents with plausible in vitro profiles have failed in clinical trials. Translational complexity is compounded by inverted U-shaped dose–response relationships, differences between presynaptic release and postsynaptic activation, and the need to avoid excitotoxicity from chronic or frequent glutamate activation. The authors also stress pharmacologic and safety concerns for ketamine, including addiction potential and uncertain long-term safety. For future work, the paper urges development of robust in vivo biomarkers of prefrontal glutamate activation and synaptic connectivity, and proposes using ketamine as a tool compound to establish these measures because of its rapid, robust and reproducible effects. Additional recommended directions include testing whether selective blockade of extrasynaptic NMDARs can produce RAAD effects without inducing a postsynaptic glutamate surge, exploring optimal dosing schedules that balance efficacy and safety (for example infrequent dosing to avoid excitotoxicity), and investigating the mechanisms of the apparent homeostatic reversal of synaptic changes within about two weeks. The authors conclude that ketamine studies have substantially advanced understanding of CSP and RAAD mechanisms, but that important mechanistic and translational challenges remain before reliably generalisable, safe RAADs can be developed.