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Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression.
Open accessAbstract
OBJECTIVE: The authors conducted a systematic review and meta-analysis of ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists in the treatment of major depression. METHOD: Searches of MEDLINE, PsycINFO, and other databases were conducted for placebo-controlled, double-blind, randomized clinical trials of NMDA antagonists in the treatment of depression. Primary outcomes were rates of treatment response and transient remission of symptoms. Secondary outcomes included change in depression symptom severity and the frequency and severity of dissociative and psychotomimetic effects. Results for each NMDA antagonist were combined in meta-analyses, reporting odds ratios for dichotomous outcomes and standardized mean differences for continuous outcomes. RESULTS: Ketamine (seven trials encompassing 147 ketamine-treated participants) produced a rapid, yet transient, antidepressant effect, with odds ratios for response and transient remission of symptoms at 24 hours equaling 9.87 (4.37-22.29) and 14.47 (2.67-78.49), respectively, accompanied by brief psychotomimetic and dissociative effects. Ketamine augmentation of ECT (five trials encompassing 89 ketamine-treated participants) significantly reduced depressive symptoms following an initial treatment (Hedges' g=0.933) but not at the conclusion of the ECT course. Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, d-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects. CONCLUSIONS: The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine's mechanism of action. The fleeting nature of ketamine's therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.
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“Of note, however, rapastinel, another drug that reverses synaptic plasticity deficits and exhibits antidepressant-like effects in rodent models 36,37 , has been studied in 3 clinical trials to date with relatively weak evidence for its efficacy 38 .”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [38]
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“Ketamine, an antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor (an ionotropic glutamate receptor), was shown to exhibit rapid onset and robust, short-term antidepressant effect in patients with treatment-resistant depression (TRD) [1–3].”
From Cardiac Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: Results from the Clinical Development Program (2020) · cites this paper as [1]
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“Racemic ketamine was obtained from the Yale-New Haven Hospital Pharmacy and administered intravenously by constant infusion over 40 minutes at a dose of 0.5mg/kg, which has consistently been shown to have robust and rapid antidepressant effects 7,8 , and is typically used clinically.”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [8]
In the citing paper
“This is supported by the finding that other NMDA receptor antagonists such as memantine, lanicemine and nitrous oxide do not exert a consistent antidepressant effect in RCTs.90”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [90]
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“Ketamine's antidepressant effects compared to placebo controls are further supported by several thorough meta-analyses [134-136].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [134]
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“This literature leads to the conclusion that while alternative NMDAR channel-blocking antagonists may exert clinical antidepressant actions, such actions are not of the same time frame or magnitude as those exerted by ketamine.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [99]
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“However, clinical trials indicate that these alternative NMDAR antagonists, lack the rapid, robust and/or long-lasting antidepressant actions of ketamine in humans 99.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [99]
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Metadata
- Authors
- Newport, D. J., Carpenter, L. L., McDonald, W. M., Potash, J. B., Tohen, M., Nemeroff, C. B., & The APA Council of Research Task Force on Novel Biomarkers and Treatments
- Affiliations
- University of Miami (US)
- University of Iowa (US)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2015-10-01
- Volume
- 172
- Issue
- 10
- Pages
- 950-966
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- OpenAlex
- W2111728433
- Semantic Scholar
- 1554f1974f06fcabaaf6be07d58e1ebf23572172
- Cited by
- 598
- References
- 177
- Citations by year
- 2026: 27 · 2025: 36 · 2024: 37 · 2023: 50 · 2022: 53 · 2021: 65 · 2020: 62 · 2019: 65 · 2018: 71 · 2017: 64 · 2016: 62 · 2015: 5
- FWCI
- 8.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Foundation for Suicide Prevention
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Teva Pharmaceutical Industries
- Brown University
- Celgene
- University of Miami
- Emory University
- Sunovion
- National Alliance for Research on Schizophrenia and Depression
- OPKO Health
- University of Oxford
- Mitsubishi Tanabe Pharma Corporation
- H. Lundbeck A/S
- National Institutes of Health
- Health Resources and Services Administration
- School of Medicine, Emory University
- Allergan
- Leonard M. Miller School of Medicine
- Roy J. and Lucille A. Carver College of Medicine, University of Iowa
- National Institute of Mental Health
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Keywords
- ketamine, NMDA receptor antagonists, major depressive disorder, antidepressant efficacy, rapid-acting antidepressants, D-cycloserine, psychotomimetic effects, dissociative effects, glutamate modulation, treatment response, remission
- MeSH terms
- Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Humans, Ketamine, Receptors, N-Methyl-D-Aspartate, Excitatory Amino Acid Antagonists
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