Convergent Mechanisms Underlying Rapid Antidepressant Action

Major depressive disorder is a highly prevalent condition marked by persistent low mood, anhedonia, cognitive and activity disturbances, and elevated suicide risk. Conventional treatments, principally monoamine-based pharmacotherapies and psychotherapies, typically require weeks to months to produce benefit and leave a substantial proportion of patients treatment resistant; they are also frequently associated with undesirable side effects. These limitations have driven interest in therapeutics with a faster onset of action and efficacy in patients who do not respond to classical antidepressants. This review, led by Zanos and colleagues, surveys clinical and preclinical evidence on rapid-acting antidepressant interventions, with a particular focus on ketamine as the prototype. The authors set out to summarise proposed mechanisms that could explain rapid and sustained antidepressant effects, to compare convergent and divergent pathways across candidate agents (including scopolamine, GLYX-13, mGluR2/3 antagonists, GABA A receptor modulators, and ketamine metabolites such as (2R,6R)-HNK), and to indicate how mechanistic insights might guide the development of novel therapeutics with fewer adverse effects.

The extracted text does not present an explicit Methods section describing a systematic search strategy, inclusion criteria, or meta-analytic methods. From the content it is apparent that the paper is a narrative review synthesising preclinical and clinical studies relevant to rapid-onset antidepressant effects, rather than a formal systematic review or pooled meta-analysis. The review integrates findings from animal behavioural paradigms (forced-swim test, novelty-suppressed feeding, learned helplessness, chronic stress models, chronic social defeat, sucrose-preference/anhedonia measures), human clinical trials (including acute single-dose and short-term repeated administration studies), mechanistic in vitro and in vivo electrophysiology and molecular signalling studies, and some early-phase clinical development programmes. Where available, the authors report specific clinical trial regimens and outcomes (for example intranasal (S)-ketamine dosing and trial identifiers) and reference pharmacological probes used in animals and humans to interrogate proposed mechanisms. However, no prespecified criteria, databases searched, date ranges, or risk-of-bias assessment methods are provided in the extracted text.

The review organises evidence around several interrelated domains: clinical efficacy of rapid-acting interventions, predictive animal tests, and candidate molecular and circuit mechanisms. Clinical and translational efficacy: Electroconvulsive therapy (ECT) and sleep deprivation are cited as non-pharmacological examples of relatively rapid antidepressant effects; ECT produces remission rates typically ranging from 50-75% with sustained benefit after multiple sessions, while sleep deprivation produces very rapid but transient benefit. Ketamine is highlighted as the prototype pharmacological rapid-acting antidepressant: a single subanaesthetic intravenous dose can produce antidepressant, anti-suicidal and antianhedonic effects within ~2 h and sustain improvement for around 7 days on average. (S)-ketamine (intranasal, 28–84 mg twice weekly for 2 weeks) has shown dose-dependent effects in treatment-resistant patients and is in advanced clinical development (trial ID NCT02417064). The authors note that many other candidate agents showed promise in preclinical models but have not consistently translated to robust, rapid clinical efficacy—examples include memantine (negative), AZD6765 (transient, modest effects then negative larger trials), CP-101,606/traxoprodil (small study with delayed response at days 5 and 8), and MK-0657 (mixed signals then failed follow-up). Animal tests predictive of rapid-onset antidepressant efficacy: The authors review behavioural paradigms expected to model onset kinetics, emphasising tests assessed at later time points (for example 24 h forced-swim test, novelty-suppressed feeding and chronic stress paradigms) as more predictive of human antidepressant time-course. Ketamine and several other compounds produce rapid behavioural effects in these tests. Notably, (R)-ketamine shows greater potency than (S)-ketamine in many rodent paradigms, and the (2R,6R)-HNK metabolite reproduces several of ketamine’s rapid behavioural effects in animals. NMDAR modulation: The review presents evidence both supporting and challenging an exclusive role for N-methyl-D-aspartate receptor (NMDAR) inhibition in rapid antidepressant action. Preclinical data show that NMDAR antagonists (including GluN2B-selective agents) can produce rapid antidepressant-like behaviours. Conversely, (R)-ketamine—less potent at NMDAR blockade—is more efficacious in rodents than (S)-ketamine, and (2R,6R)-HNK exerts antidepressant effects in animals without inhibiting the NMDAR at relevant concentrations (reported Ki and IC50 >100 μM). Clinical NMDAR antagonists have given mixed results: memantine failed to show efficacy; AZD6765 produced a short-lived effect (~110 min) and ultimately failed larger trials; GluN2B-selective compounds produced inconsistent clinical signals and have not progressed. The authors also describe GLYX-13, a functional partial NMDAR agonist, which produced rapid and sustained antidepressant effects in animals and an initial human trial without dissociative side effects; GLYX-13 is in Phase III according to the extracted text. Modulation of excitatory synaptic transmission and interneuron disinhibition: Ketamine and scopolamine paradoxically increase extracellular glutamate and glutamate cycling in the medial prefrontal cortex (mPFC) at low doses. One proposed mechanism is preferential action on NMDARs or mAChRs located on inhibitory GABAergic interneurons (notably somatostatin-positive and parvalbumin-positive subtypes), causing reduced interneuron firing, cortical disinhibition, increased pyramidal neuron output, and enhanced excitatory neurotransmission. Supporting evidence includes increased cortical gamma oscillations after NMDAR antagonism and experiments where M1-mAChR knockdown in somatostatin interneurons prevents scopolamine’s antidepressant effects. Conversely, some preclinical data argue against simple disinhibition: global GABA A receptor reduction can worsen depressive-like behaviours, and manipulations that increase somatostatin interneuron excitability have produced antidepressant-like effects, indicating complexity and potential cell-type specificity. GABA A receptor negative allosteric modulators (GABA-NAMs): Alpha5-selective GABA-NAMs (e.g., L-655,781, MRK-016, RY-080) produce rapid antidepressant-like responses in several rodent stress paradigms and appear to lack ketamine-like dissociative or abuse-related effects in animal models; clinical data in depressed patients are not yet reported in the extracted text. mGluR2/3 antagonists and presynaptic modulation: Antagonism of group II metabotropic glutamate receptors produces rapid antidepressant effects in multiple preclinical tests, likely by blocking presynaptic autoreceptors and increasing synaptic glutamate release. A large clinical trial of a negative allosteric modulator of mGluR2 (decoglurant; N=310) failed to show benefit compared to placebo, but the authors note that target engagement was not assessed. Synaptic plasticity, LTP/LTD and synaptogenesis: Chronic stress is associated with enhanced LTD, reduced LTP, dendritic atrophy and spine loss in the PFC and hippocampus. Ketamine rapidly reverses stress-induced synaptic deficits and increases mature spine density in PFC within 24 h after a single dose. Similar rapid synaptogenic effects are reported for scopolamine, mGluR2/3 antagonists, GLYX-13 and (2R,6R)-HNK. The authors note some paradoxical findings in slice preparations and attribute differences to metabolism (absence of HNK metabolites in vitro), clearance kinetics in vivo, and differential NMDAR inhibition in slices versus intact brain. AMPAR activation and gamma oscillations: Activation and upregulation of AMPA receptors are emphasised as a convergent requirement for induction and expression of rapid antidepressant responses. Preclinical blockade of AMPARs with NBQX prevents the behavioural and electrophysiological (gamma power) effects of ketamine, (2R,6R)-HNK and several other rapid-acting agents. Ketamine and related compounds increase cell-surface GluA1 and GluA2 subunits and enhance AMPAR-mediated synaptic transmission in mPFC and hippocampus. Increased frontal gamma-band EEG power is reported across many agents with rapid antidepressant effects, and optogenetic cortical activation that increases gamma can produce ketamine-like behavioural effects in rodents. BDNF, eEF2 and mTOR signalling: Rapid antidepressant actions appear to engage BDNF-TrkB signalling, with ketamine’s effects reduced in animals with forebrain Bdnf knockdown and in carriers of the human Val66Met SNP. Ketamine and (2R,6R)-HNK rapidly increase BDNF protein and synaptoneurosomal BDNF levels in hippocampus and/or mPFC. Dephosphorylation of eukaryotic elongation factor 2 (eEF2) following ketamine or (2R,6R)-HNK is proposed to de-suppress protein synthesis and enhance BDNF translation, although eEF2 changes can be induced by other mechanisms as well. Activation of mTORC1 signalling (increased phospho-mTOR, phospho-p70S6K, phospho-4EBP1) is observed rapidly after ketamine and several other agents; mTORC1 inhibition with rapamycin blocks both synaptic and behavioural effects in rodents. Glycogen synthase kinase-3 (GSK-3) inhibition (increased phospho-GSK-3β Ser9) is also implicated: mice with GSK-3 mutations preventing phosphorylation do not show ketamine responses, and lithium coadministration potentiates ketamine-induced mTOR activation and synaptogenesis. Safety and translational gaps: Ketamine’s clinical utility is limited by dissociation, psychotomimetic effects and abuse potential, motivating searches for agents that retain rapid efficacy without these adverse effects (for example (2R,6R)-HNK and GLYX-13). The authors emphasise inconsistent translation from preclinical models to clinical efficacy for many targets and highlight the frequent absence of measures of target engagement in human trials.

Zanos and colleagues interpret the assembled evidence as supporting a convergent model in which distinct pharmacologies can rapidly strengthen excitatory synapses in mood-regulating corticomesolimbic circuits, producing fast-onset and sometimes sustained antidepressant effects. Although NMDAR inhibition was historically central to hypotheses about ketamine’s mechanism, the authors caution that NMDAR blockade alone cannot fully explain the clinical and preclinical data. Instead, they posit that increased glutamatergic drive, AMPAR activation, induction of activity-dependent plasticity, enhanced BDNF-TrkB signalling, eEF2 dephosphorylation and transient activation of mTORC1 converge to promote rapid synaptogenesis and persistent synaptic potentiation. The review positions ketamine’s (2S,6S;2R,6R)-HNK metabolites, GLYX-13, scopolamine, mGluR2/3 antagonists and alpha5-selective GABA-NAMs as mechanistically informative probes and as potential leads for therapeutics that might avoid ketamine’s side-effect profile. Nevertheless, the authors underscore unresolved uncertainties: inconsistent clinical translation for many candidate agents, variability in animal model results (including dose and test dependency), and incomplete understanding of which molecular steps are necessary versus sufficient for rapid antidepressant efficacy. They note specifically the need for clinical studies that include measures of in vivo target engagement to interpret negative trial outcomes and to confirm mechanistic hypotheses. Key limitations acknowledged include gaps in translation from animal models to people, the heterogeneity of depression pathophysiology, the limited data on long-term tolerability and efficacy of rapid-acting agents, and the absence of standardised biomarkers to predict response. The authors recommend further preclinical work to refine mechanistic models and clinical studies designed to assess target engagement, durability of benefit, optimal dosing regimens, and safety with repeated or chronic use.

The authors conclude that research into ketamine’s rapid antidepressant actions has revealed multiple, partially overlapping mechanisms that can produce fast and sustained improvements in mood by restoring synaptic function. They emphasise that AMPAR activation and downstream signalling (BDNF-TrkB, mTORC1, eEF2 modulation) represent common effectors across diverse agents, and that several non-NMDAR strategies—such as (2R,6R)-HNK, GLYX-13, mGluR2/3 antagonists and alpha5-selective GABA-NAMs—offer promising routes to retain rapid efficacy while reducing adverse effects. Further studies are required to delineate precise mechanisms, confirm target engagement clinically, determine long-term safety and durability, and identify agents suitable for routine clinical use. The authors note that (S)-ketamine and GLYX-13 were in Phase III trials at the time of writing, but no rapid-acting antidepressant had yet received regulatory approval.