Fast-acting antidepressant activity of ketamine: Highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies
Open accessAbstract
Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, displays a fast antidepressant activity in treatment-resistant depression and in rodent models of anxiety/depression. A large body of evidence concerning the cellular and molecular mechanisms underlying its fast antidepressant-like activity comes from animal studies. Although structural remodeling of frontocortical/hippocampal neurons has been proposed as critical, the role of excitatory/inhibitory neurotransmitters in this behavioral effect is unclear. Neurochemical and behavioral changes are maintained 24h after ketamine administration, well beyond its plasma elimination half-life. Thus, ketamine is believed to initiate a cascade of cellular mechanisms supporting its fast antidepressant-like activity. To date, the underlying mechanism involves glutamate release, then downstream activation of AMPA receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis in the medial prefrontal cortex (mPFC), a brain region strongly involved in ketamine therapeutic effects. However, these mPFC effects are not restricted to glutamatergic pyramidal cells, but extend to other neurotransmitters (GABA, serotonin), glial cells, and brain circuits (mPFC/dorsal raphe nucleus-DRN). It could be also mediated by one or several ketamine metabolites (e.g., (2R,6R)-HNK). The present review focuses on evidence for mPFC neurotransmission abnormalities in major depressive disorder (MDD) and their potential impact on neural circuits (mPFC/DRN). We will integrate these considerations with results from recent preclinical studies showing that ketamine, at antidepressant-relevant doses, induces neuronal adaptations that involve the glutamate-excitatory/GABA-inhibitory balance. Our analyses will help direct future studies to further elucidate the mechanism of action of fast-acting antidepressant drugs, and to inform development of novel, more efficacious therapeutics.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Ketamine produces a brief but robust glutamate surge that drives enhanced AMPAR throughput and calcium influx.
“The result is a brief but robust glutamate surge that drives enhanced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) throughput and calcium influx, including through calcium permeable AMPA channels [20,42,47].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [47]
Section 1, “Glutamate release,” describes quick glutamate bursts after ketamine, and §4.3.3.4.3 links increased glutamate release to AMPAR activation and enhanced excitatory synaptic function. The cited passages do not establish that this sequence increases calcium influx, including through calcium-permeable AMPA channels; the copy’s discussion of calcium influx concerns NMDA receptors (§4.3.3.3). Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEsketamine provides a more NMDAR-centered entry into the induction pathway, producing rapid clinical effects but also transient dissociation and sympathomimetic effects.
“Esketamine provides a more NMDAR-centered entry into the induction pathway described above, producing rapid clinical effects but also transient dissociation and sympathomimetic effects [45,46,47,49,52,55,56].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [47]
Section 2 (page not available) reports that (S)-ketamine has four times the NMDA-receptor affinity of (R)-ketamine, supporting a more NMDAR-centered description of esketamine. The Introduction and Section 3 discuss ketamine’s clinical antidepressant efficacy and possible dissociative effects, but the copy does not establish rapid clinical effects, transient dissociation, or sympathomimetic effects specifically for esketamine. (LLM, conf=0.86)
Experimental — accuracy not yet measuredStabilization of presynaptic architecture indexed by SV2A helps restore synaptic density in patients with low baseline SV2A.
“stabilization of presynaptic architecture indexed by SV2A helps restore synaptic density in patients with low baseline SV2A”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [47]
Section 4.3.1 discusses reduced synapse density after chronic stress, and section 4.3.3.4.2 discusses AMPA receptors and synaptic plasticity. Searches for SV2A, presynaptic stabilization, and low baseline SV2A did not find a passage linking them to restored synaptic density in patients. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 392 · Cited by 186
Research works printed but not linked: 1
- [307]307. Romeo, B., Choucha, W., Fossati, P., & Rotge, J. Y. (2017). [Clinical and biological predictors of ketamine response in treatment-resistant major depression: Review]. Encephale, 43, 354-362.
- Authors
- Pham, T. H., & Gardier, A. M.
- Affiliations
- Inserm (FR)
- Corresponding author
- Gardier, Alain M.
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 199
- Pages
- 58-90
- ISSN
- 0163-7258 (ISSN-L)
- OpenAlex
- W2921641141
- Cited by
- 186
- References
- 392
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 28 · 2023: 38 · 2022: 34 · 2021: 21 · 2020: 23 · 2019: 10
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Pharmacology & Therapeutics (acceptedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- ketamine, rapid-acting antidepressants, treatment-resistant depression, major depressive disorder, NMDA receptor antagonism, glutamatergic neurotransmission, GABAergic neurotransmission, serotonergic neurotransmission, medial prefrontal cortex, dorsal raphe nucleus, AMPA receptors, mTOR, brain-derived neurotrophic factor, excitation-inhibition balance, ketamine metabolites, glial cells, neural circuits
- MeSH terms
- Animals, Antidepressive Agents, Brain, gamma-Aminobutyric Acid, Humans, Ketamine, Synaptic Transmission, Serotonin, Glutamic Acid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
