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
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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.
“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]
The Results (‘Change in depressive symptoms’; page not supplied) show that ketamine’s effect peaked at day 1, supporting the 24-hour peak. The effect remained significantly greater than placebo through days 5–8, but not at days 10–12 or 14–15, so sustained effects lasting up to two weeks are not supported. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAfter an acute ketamine dose, antidepressant effects usually begin within hours, peak near 24 hours, and then decline over about 10 to 12 days.
“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]
Ketamine's antidepressant effects peak 1 day following infusion and typically dissipate 1-2 weeks after a single infusion.
“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
Multiple meta-analyses have concluded that intravenous ketamine is effective as a rapid-acting antidepressant for major depressive episodes in both unipolar and bipolar depression.
“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]
Several studies have supported that ketamine's antidepressant effect lasts up to 7 days, while other authors have suggested this is true only for unipolar depression.
“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]
A meta-analysis of single-infusion non-ketamine NMDA receptor antagonists showed smaller effect sizes in depressive symptom change compared with ketamine and non-superiority in remission compared with placebo for unipolar and bipolar depression.
“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]
A major meta-analysis indicated no difference between ketamine and placebo groups on patient reports of 'tired/fatigued' and 'vivid dreams'.
“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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- 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 › 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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