The DOI matches its Crossref record; 163 of the 163 references it cites were found in a registry or an index.
Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants
Open accessAbstract
For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of ( R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal ideation, occurring within hours following a single administration, with relief from symptoms typically lasting up to a week. The discovery of these actions of ketamine has resulted in a reconceptualization of how depression could be more effectively treated in the future. In this review, we discuss clinical data pertaining to ketamine and other rapid-acting antidepressant drugs, as well as the current state of pharmacological knowledge regarding their mechanism of action. Additionally, we discuss the neurobiological circuits that are engaged by this drug class and that may be targeted by a future generation of medications, for example, hydroxynorketamine; metabotropic glutamate receptor 2/3 antagonists; and N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor modulators.
Overview
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
Verification
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Given that the evidence of PCP, MK-801, and memantine exerting antidepressant-like effects in rodents is mixed, with clinical studies either failing or lacking”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Gould et al., 2019
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It appears that increased strength of excitatory neurotransmission, in particular involving AMPARs, represents a common downstream target that is necessary for antidepressant efficacy among classical and rapid-acting antidepressants (Alt et al., 2006; Gould et al., 2019; Thompson et al., 2015).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Gould et al., 2019
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“NMDAR antagonism may not fully explain the antidepressant effects of ketamine”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Gould et al., 2019
In the citing paper
“Preclinical studies suggest that the beneficial actions of ketamine are mediated by activation of both BDNF-TrkB signaling and endogenous synaptic strengthening mechanisms [114].”
From Beyond the serotonin deficit hypothesis: Communicating a neuroplasticity framework of major depressive disorder (2024) · cites this paper as [114]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,527
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K. R., Rush, A. J., Walters, E. E., & Wang, P. S. (2003) · JAMA · doi:10.1001/jama.289.23.3095 · Cited by 7,988 · cited 1×
“This diagnosis occurs in approximately 16% of the population over the course of a lifetime (1).”
BackgroundRush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., Niederehe, G., Thase, M. E., Lavori, P. W., Lebowitz, B. D., et al. (2006) · American Journal of Psychiatry · doi:10.1176/ajp.2006.163.11.1905 · Cited by 5,643
Antidepressant effects of ketamine in depressed patients
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766 · cited 1×
“5 mg/kg ketamine; at 4, 24, and 72 hours, response rates were 50%, 70%, and 35%, respectively (14, 17).”
Self-citationKrystal, J. H. (1994) · Archives of General Psychiatry · doi:10.1001/archpsyc.1994.03950030035004 · Cited by 3,330 · cited 2×
“Ketamine, even when administered at antidepressant subanesthetic doses, leads to dissociative and psychotomimetic effects, likely mediated by its inhibitory actions at the N-methyl-D-aspartate receptor (NMDAR) (34).”
BackgroundmTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
Li, N., Lee, B., Liu, R.-J., Banasr, M., Dwyer, J. M., Iwata, M., Li, X.-Y., Aghajanian, G., & Duman, R. S. (2010) · Science · doi:10.1126/science.1190287 · Cited by 2,881 · cited 3×
“There is strong evidence that growth-associated signaling cascades converging on the protein mTOR are important in the responses of several rapid-acting antidepressant compounds (71).”
BackgroundParvalbumin neurons and gamma rhythms enhance cortical circuit performance
Sohal, V. S., Zhang, F., Yizhar, O., & Deisseroth, K. (2009) · Nature · doi:10.1038/nature07991 · Cited by 2,606
A molecular and cellular theory of depression
Duman, R. S. (1997) · Archives of General Psychiatry · doi:10.1001/archpsyc.1997.01830190015002 · Cited by 2,129
Nibuya, M., Morinobu, S., & Duman, R. (1995) · The Journal of Neuroscience · doi:10.1523/jneurosci.15-11-07539.1995 · Cited by 2,109
Research works printed but not linked: 6
- 10.1176/appi.ajp.2015.15040465 · DOI · Paper page
- Omranifard V, 2014, J. Res. Med. Sci., 19, 525
- Cerecor., 2016, Cerecor reports top-line data from CERC-301 phase 2 study for major depressive disorder
- Paterson B, 2015, A randomized, double-blind, placebo-controlled, sequential parallel study of CERC-301 in the adjunctive treatment of subjects with severe depression and recent active suicidal ideation despite antidepressant treatment
- Hansen KB, 2017, Methods in Molecular Biology, 1677, 1
- Dong C, 2017, Int. J. Neuropsychopharmacol., 20, 228
Cited by
Sorted by citations
Items 101–133 of 133
Barrutieta-Arberas, I., Ortuzar, N., Vaquero-Rodríguez, A., Picó-Gallardo, M., Bengoetxea, H., Guevara, M., Gargiulo, P. A., & Lafuente, J. V. (2023) · Experimental Biology and Medicine · doi:10.1177/15353702231170007 · Cited by 6
Research trends and hotspots of ketamine from 2014 to 2023: a bibliometric analysis
Wang, Y., Chang, S., & Chen, D. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1407301 · Cited by 6
“The exact mechanism underlying these antidepressant effects remains complex and incompletely understood (Gould et al., 2019).”
BackgroundLa kétamine : un neuropsychotrope au mécanisme d’action innovant
Guilloux, J., Nguyen, T. M. L., & Gardier, A. M. (2023) · Biologie Aujourd hui · doi:10.1051/jbio/2023026 · Cited by 5
Inhibition of SERT and NMDAR synergistically confers rapid antidepressant effects of ketamine
Luo, H., Chen, M., Ning, Y., Ren, L., Lu, Y., Sun, J., Zhu, X., Ran, M., Guo, J., Lu, C., et al. (2025) · National Science Review · doi:10.1093/nsr/nwaf367 · Cited by 4
“As ketamine is a non-competitive NMDAR antagonist and several NMDAR antagonists fail to produce rapid antidepressant effects similar to ketamine [17 ,26 ,3 0 ,3 4 ], this suggests that solely inhibiting NMDAR is insufficient to explain the rapid antidepressant effects of ketamine.”
Gong, X.-N., Zhou, Y.-X., Wang, C.-Y., Wang, T.-T., Gao, Z.-Y., Long, W.-C., Li, R., & Cai, L. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.116065 · Cited by 3
Heifets, B. D., & Airan, R. D. (2026) · Biological Psychiatry · doi:10.1016/j.biopsych.2025.12.001 · Cited by 3
Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions
Nguyen, T. M. L., Guilloux, J., Defaix, C., Mendez‐David, I., Etting, I., Alvarez, J., McGowan, J. C., Highland, J. N., Zanos, P., Lovett, J., et al. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110065 · Cited by 4
Self-citationEffects of ketamine on metabolic parameters in depressive disorders: A systematic review
Wong, S., Le, G. H., Mansur, R. B., Rosenblat, J. D., Kwan, A. T. H., Teopiz, K. M., & McIntyre, R. S. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.08.208 · Cited by 3
Ketamine Infusion (KI) in Treatment Resistant Depression (TRD): Retrospective Clinical Data Analysis
Griffiths, C., O’Neill-Kerr, A., Vai, R. D., Sore, T., & da Silva, K. M. (2019) · Open Journal of Depression · doi:10.4236/ojd.2019.83007 · Cited by 3
“However, a nasal spray cannot deliver as precise a dose as an IV infusion (Gould et al., 2019).”
BackgroundTargum, S. D., Sanacora, G., Formella, A. E., Ceresoli‐Borroni, G., & Owen, R. (2026) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2026.01.006 · Cited by 2
Gould, T. D., Mathew, S. J., D, M. F. M., & Shekhar, A. (2026) · Journal of Psychopharmacology · doi:10.1177/02698811261456206 · Cited by 1
“Instead, the rapid antidepressant effects are better explained through EDP, where the effects are hypothesized to be achieved by direct effects on plasticity (Gould et al., 2019) or a shift in the threshold for induction of synaptic plasticity through metaplas-ticity (Brown et al., 2025b).”
Self-citationEsketamine: the first glutamatergic drug for the management of treatment- resistant depression
Musazzi, L. (2020) · doi:10.36118/pharmadvances.03.2020.02 · Cited by 1
“vated cyclic nucleotide gated (HCN) channels, enhancement of vascular endothelial growth factor (VEGF) action and the role of the gut-brain (34-36).”
BackgroundAssarian, F., Panjehpour, T., Rahmani, A., Ghoreishi, F. S., & Rahimi, H. (2023) · Iranian Journal of Psychiatry and Behavioral Sciences · doi:10.5812/ijpbs-136491 · Cited by 1
“Mood disorders, including major depressive disorder and type I and II bipolar disorder, are among the most important health problems in society and important causes of disability in the world (1).”
BackgroundMethodInfluentialGonzález, C. Á., Zaragozá, C., & Lopez-Munoz, F. J. (2020) · Revista de Investigación y Educación en Ciencias de la Salud (RIECS) · doi:10.37536/riecs.2020.5.2.214 · Cited by 2
Söderqvist, G., & Naessén, S. (2022) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2022.106217 · Cited by 1
“Testosterone seems to affect neurotransmitters, including γ aminobutyric acid (GABA), dopamine, and serotonin (5-HT) which may underlie some of testosterone’s protective benefits on psychological well-being, [22].”
BackgroundThe role of opioid receptors in tianeptine-induced beta oscillations and memory enhancementPreprint
Trigo, M., Knott, T. S., Langston, R. F., Lambert, J. J., & Martin, S. J. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.10.724133 · Cited by 1
Rapid and Sustained Restoration of Astrocytic Functions by Ketamine in Depression Model MicePreprint
Zhang, X., Yang, S., Zhang, Z., Liu, L., Shi, W., Yang, S., Li, S., Cai, X., & Zhou, Q. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3973923
Morilak, D. A. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.737425695.793575858
Oemisch, M., & Seo, H. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.25.501468
“…𝑅𝑅 ) is the probability of animal’s choosing right target at the current trial t, G(t-i), N(t-i), L(t-i) and R(t-i) are regressors encoding gain, neutral, loss and juice reward outcome that occurred after right (left) choice in the i -th trial into the past as 1(-1), and other outcomes as 0,…”
BackgroundTherapeutic doses of ketamine acutely attenuate the aversive effect of losses during decision-making
Oemisch, M., & Seo, H. (2023) · eLife · doi:10.7554/elife.87529 · Cited by 2
Therapeutic doses of ketamine acutely attenuate the aversive effect of losses during decision-makingPreprint
Oemisch, M., & Seo, H. (2023) · eLife · doi:10.7554/elife.87529.1
Therapeutic doses of ketamine acutely attenuate the aversive effect of losses during decision-makingPreprint
Oemisch, M., & Seo, H. (2024) · eLife · doi:10.7554/elife.87529.2
Pham, G. S., & Mathew, S. J. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-18496-3.00014-8
Ketamine’s Multifaceted Neuropharmacological and Neurobiological Actions
Kohtala, S., & Annala, I. (2025) · Neuromethods · doi:10.1007/978-1-0716-4603-8_2
Wang, R., Jin, Y., Zou, B., & Ding, L. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1699304 · Cited by 1
“Other studies have demonstrated that ketamine treatment effectively alleviates depressive symptoms in patients, including those with treatment-resistant depression (Gould and Thompson, 2019).”
Is a new one a well forgotten old? Sleep deprivation as a method of therapy for depression. Part I
Antsyborov, A. V., Dubatova, I. V., & Kalinchuk, A. V. (2021) · Neurology Bulletin · doi:10.17816/nb49755
Brown, K. A., Morris, P. J., Thomas, C. J., & Gould, T. D. (2026) · Journal of Neuroscience · doi:10.1523/jneurosci.0958-25.2026 · Cited by 1
Self-citationImpact of open channel blockers on the surface dynamics and organization of NMDA receptors
Fernandes, A. (2020) · theses.fr (ABES) · doi:10.70675/d12c14b2z7a80z4668z9c48z8e2c0e41c009 · Cited by 1
Exploring the molecular determinants of behavioral changes induced by ketamine at the nanoscale
Uyttersprot, F. (2024) · theses.fr (ABES) · doi:10.70675/df438baaz92d0z488aza38cz4227b46c9acb
Hardy, M. S., Li, S. W., & Wilkinson, S. T. (2026) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.20260001
Sulej, Z., & Zielińska, M. (2026) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2026.1950244
BindingDB Entry 50011888: Repurposing of Drugs-The Ketamine Story.
BindingDB (2022) · UC San Diego · doi:10.7270/q2t15797
Wei, Y., Shi, Z., & Shen, Y. (2026) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2026.2751476
Metadata
- Authors
- Gould, T. D., Zarate, C. A., & Thompson, S. M.
- Affiliations
- University of Maryland, Baltimore (US)
- National Institutes of Health (US)
- Corresponding author
- Gould, Todd D.
- Venue
- Annual Review of Pharmacology and Toxicology
- Publisher
- Annual Reviews
- Published
- 2019-01-06
- Volume
- 59
- Issue
- 1
- Pages
- 213-236
- ISSN
- 0362-1642 (ISSN-L)
- 1545-4304
- PMC
- PMC6364552
- OpenAlex
- W2897395578
- Cited by
- 133
- References
- 163
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 16 · 2023: 21 · 2022: 17 · 2021: 22 · 2020: 24 · 2019: 12
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Annual Review of Pharmacology and Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R01MH086828, R01MH107615, ZIAMH002857)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › 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
- rapid-acting antidepressants, ketamine, depression, mechanism of action, hydroxynorketamine, NMDA receptor modulators, anhedonia, suicidal ideation
- MeSH terms
- Animals, Antidepressive Agents, Brain, Depression, Humans, Ketamine
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
