The DOI matches its Crossref record; 172 of the 173 references it cites were found in a registry or an index.
The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?
Open accessAbstract
The discovery of the antidepressant effects of ketamine has opened a breakthrough opportunity to develop a truly novel class of safe, effective, and rapid-acting antidepressants (RAADs). In addition, the rapid and robust biological and behavioral effects of ketamine offered a unique opportunity to utilize the drug as a tool to thoroughly investigate the neurobiology of stress and depression in animals, and to develop sensitive and reproducible biomarkers in humans. The ketamine literature over the past two decades has considerably enriched our understanding of the mechanisms underlying chronic stress, depression, and RAADs. However, considering the complexity of the pharmacokinetics and in vivo pharmacodynamics of ketamine, several questions remain unanswered and, at times, even answered questions continue to be considered controversial or at least not fully understood. The current perspective paper summarizes our understanding of the neurobiology of depression, and the mechanisms of action of ketamine and other RAADs. The review focuses on the role of glutamate neurotransmission - reviewing the history of the "glutamate inhibition" and "glutamate activation" hypotheses, proposing a synaptic connectivity model of chronic stress pathology, and describing the mechanism of action of ketamine. It will also summarize the clinical efficacy findings of putative RAADs, present relevant human biomarker findings, and discuss current challenges and future directions.
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 cited source says what the claim attributes to it.
In the citing paper
“A main limitation of previous methods is the lack of distinction between presynaptic glutamate release and postsynaptic activation, the latter has been related to the RAAD effects of ketamine [14,15].”
From The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects (2018) · cites this paper as [15]
In the citing paper
“MDD has been shown to affect, among other areas, the PFC, the hippocampus and the anterior cingulate cortex (ACC), and there is evidence that ketamine affects these areas preferentially.204–206”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [204]
In the citing paper
“MDD has been shown to affect, among other areas, the PFC, the hippocampus and the anterior cingulate cortex (ACC), and there is evidence that ketamine affects these areas preferentially.204–206”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [204]
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 8,525
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
Self-citationA 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
The molecular neurobiology of depression
Krishnan, V., & Nestler, E. J. (2008) · Nature · doi:10.1038/nature07455 · Cited by 2,889
mTOR-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
Self-citationNMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease
Paoletti, P., Bellone, C., & Zhou, Q. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3504 · Cited by 2,523
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
Self-citationNibuya, M., Morinobu, S., & Duman, R. (1995) · The Journal of Neuroscience · doi:10.1523/jneurosci.15-11-07539.1995 · Cited by 2,109
Self-citationSTRESS AND HIPPOCAMPAL PLASTICITY
McEwen, B. S. (1999) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.22.1.105 · Cited by 2,087
Hippocampal atrophy in recurrent major depression
Sheline, Y. I., Wang, P. W., Gado, M. H., Csernansky, J. G., & Vannier, M. W. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.9.3908 · Cited by 1,932
Research works printed but not linked: 1
- Schwarcz, 2017, Endogenous kynurenic acid mediates ketamine- and (2R,6R)-hydroxynorketamine-induced increases in extracellular glutamate and antidepressant actions, Neuropsychopharmacology, 43, S111
Cited by
Sorted by citations
Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial
Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., Finan, P. H., & Griffiths, R. R. (2021) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2020.3285 · Cited by 1,301
Nagy, C., Maitra, M., Tanti, A., Suderman, M., Théroux, J.-F., Davoli, M. A., Perlman, K., Yerko, V., Wang, Y. C., Tripathy, S. J., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0621-y · Cited by 532
Hashimoto, K. (2019) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12902 · Cited by 335
The Mesolimbic Dopamine System in Chronic Pain and Associated Affective Comorbidities
Serafini, R. A., Pryce, K. D., & Zachariou, V. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.10.018 · Cited by 237
Molecular 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
Metadata
- Authors
- Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H.
- Affiliations
- Yale University (US)
- Corresponding author
- Abdallah, Chadi G.
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 190
- Pages
- 148-158
- ISSN
- 0163-7258 (ISSN-L)
- PMC
- PMC6165688
- OpenAlex
- W2803958441
- Cited by
- 219
- References
- 173
- Citations by year
- 2026: 9 · 2025: 29 · 2024: 22 · 2023: 29 · 2022: 25 · 2021: 24 · 2020: 35 · 2019: 31 · 2018: 15
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5k23mh101498-05)
- National Institute of Mental Health (K23MH-101498(, R01MH093897)
- 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
- depression, ketamine, rapid-acting antidepressants, glutamatergic neurotransmission, chronic stress, mechanism of action, biomarkers, antidepressant efficacy
- MeSH terms
- Drug Development, Animals, Antidepressive Agents, Depression, Disease Models, Animal, Humans, Ketamine, Synaptic Transmission, Biomarkers, 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
