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
Hashimoto, K. (2019) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12902 · Cited by 335
Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor
Wei, Y., Chang, L., & Hashimoto, K. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01121-1 · Cited by 248
“It has been recognized that the rapid-acting antidepressantlike effects of (R,S)-ketamine are mediated through blockade of NMDARs located on γ-aminobutyric acid (GABA) ergic inhibitory interneurons, and that subsequent activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is required…”
BackgroundMolecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine
Hashimoto, K. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113935 · Cited by 241
The role of dissociation in ketamine’s antidepressant effects
Ballard, E. D., & Zarate, C. A. (2020) · Nature Communications · doi:10.1038/s41467-020-20190-4 · Cited by 231
Self-citationMicroglial ERK-NRBP1-CREB-BDNF Signaling in Sustained Antidepressant Actions of (R)-Ketamine
Yao, W., Cao, Q., Luo, S., He, L., Yang, C., Chen, J., Qi, Q., Hashimoto, K., & Zhang, J.-C. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01377-7 · Cited by 216
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
