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Single-dose infusion ketamine and non-ketamine N -methyl- d -aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories
Open accessAbstract
Background: Ketamine and non-ketamine N -methyl- d -aspartate receptor antagonists (NMDAR antagonists) recently demonstrated antidepressant efficacy for the treatment of refractory depression, but effect sizes, trajectories and possible class effects are unclear. Method: We searched PubMed/PsycINFO/Web of Science/clinicaltrials.gov until 25 August 2015. Parallel-group or cross-over randomized controlled trials (RCTs) comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses. Hedges’ g and risk ratios and their 95% confidence intervals (CIs) were calculated using a random-effects model. The primary outcome was depressive symptom change. Secondary outcomes included response, remission, all-cause discontinuation and adverse effects. Results: A total of 14 RCTs (nine ketamine studies: n = 234; five non-ketamine NMDAR antagonist studies: n = 354; MDD = 554, BD = 34), lasting 10.0 ± 8.8 days, were meta-analysed. Ketamine reduced depression significantly more than placebo/pseudo-placebo beginning at 40 min, peaking at day 1 (Hedges' g = −1.00, 95% CI −1.28 to −0.73, p < 0.001), and loosing superiority by days 10–12. Non-ketamine NMDAR antagonists were superior to placebo only on days 5–8 (Hedges' g = −0.37, 95% CI −0.66 to −0.09, p = 0.01). Compared with placebo/pseudo-placebo, ketamine led to significantly greater response (40 min to day 7) and remission (80 min to days 3–5). Non-ketamine NMDAR antagonists achieved greater response at day 2 and days 3–5. All-cause discontinuation was similar between ketamine ( p = 0.34) or non-ketamine NMDAR antagonists ( p = 0.94) and placebo. Although some adverse effects were more common with ketamine/NMDAR antagonists than placebo, these were transient and clinically insignificant. Conclusions: A single infusion of ketamine, but less so of non-ketamine NMDAR antagonists, has ultra-rapid efficacy for MDD and BD, lasting for up to 1 week. Development of easy-to-administer, repeatedly given NMDAR antagonists without risk of brain toxicity is of critical importance.
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“The peak antidepressant effect of ketamine is seen 24 hours post administration, with sustained effects lasting 1-2 weeks 43 .”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [43]
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“The antidepressant effects of an acute dose of ketamine are typically thought to occur within hours, peak around 24 h then gradually decline over a period of 10-12 days [10].”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [10]
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“Ketamine's antidepressant effects peak 1 day following infusion and typically dissipate 1-2 weeks after a single infusion (Kishimoto et al, 2016).”
From Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial (2018) · cites this paper as Kishimoto et al, 2016
In the citing paper
“Multiple meta-analyses55–59 have now concluded that intravenous ketamine is effective as a rapid-acting antidepressant for major depressive episodes in both unipolar and bipolar depression”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [55]
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“While several of these studies have supported claims that ketamine’s antidepressant effect lasts up to 7 days,55,56 other authors have suggested this to be true only for unipolar depression.”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [55]
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“Furthermore, a meta-analysis of single-infusion non-ketamine NMDA receptor antagonists, including traxoprodil, lanicemine and rapastinel (GLYX-13), showed smaller effect sizes in depressive symptom change in comparison with ketamine and non-superiority in remission compared with placebo for unipolar and bipolar depression.55”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [55]
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“A major meta-analysis indicated no difference between ketamine and placebo groups on patient reports of ‘tired/fatigued’ and ‘vivid dreams’.55”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [55]
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Metadata
- Authors
- Kishimoto, T., Chawla, J. M., Hagi, K., Zarate, C. A., Kane, J. M., Bauer, M., & Correll, C. U.
- Affiliations
- Northwell Health (US)
- University Hospital Carl Gustav Carus (DE)
- Corresponding author
- Correll, C. U.
- Venue
- Psychological Medicine
- Publisher
- Cambridge University Press (CUP)
- Published
- 2016-02-12
- Volume
- 46
- Issue
- 7
- Pages
- 1459-1472
- ISSN
- 0033-2917 (ISSN-L)
- 1469-8978
- PMC
- PMC5116384
- OpenAlex
- W2326374493
- Cited by
- 359
- References
- 56
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 26 · 2023: 44 · 2022: 40 · 2021: 56 · 2020: 42 · 2019: 33 · 2018: 39 · 2017: 24 · 2016: 12
- FWCI
- 4.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Psychological Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Foundation for Suicide Prevention
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Teva Pharmaceutical Industries
- Stanley Medical Research Institute
- Sunovion
- National Alliance for Research on Schizophrenia and Depression
- European Commission
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Novo Nordisk
- Astellas Pharma
- Shionogi
- Servier
- H. Lundbeck A/S
- National Institutes of Health
- Genentech
- National Institute of Mental Health (P30MH090590, ZIAMH002857)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Keywords
- ketamine, NMDA receptor antagonists, major depressive disorder, bipolar depression, treatment-resistant depression, antidepressant efficacy, remission, discontinuation, adverse effects, class effect, placebo response, treatment cost-effectiveness
- MeSH terms
- Antidepressive Agents, Bipolar Disorder, Major Depressive Disorder, Humans, Ketamine, Receptors, N-Methyl-D-Aspartate, Outcome Assessment, Health Care, Excitatory Amino Acid Antagonists
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