Hype or hope? High placebo response in major depression treatment with ketamine and esketamine: a systematic review and meta-analysis
This meta-analysis of 14 RCTs (1,100 participants) found large antidepressant effects for ketamine and esketamine. However, the pooled placebo response accounted for up to 72% of the overall treatment effect (66% at seven days), indicating a major contribution of placebo to observed benefits and implications for clinical practice.
Authors
- Matsingos, A.
- Wilhelm, M.
- Noor, L.
Published
Abstract
Background
Ketamine and esketamine offer a novel approach in the pharmacological treatment of major depressive disorder (MDD). This meta-analysis aimed to investigate the placebo response in double-blind, randomized controlled studies (RCTs) on patients with MDD receiving ketamine or esketamine.
Methods
For this systematic review and meta-analysis Medline (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), PsycInfo and Embase databases were systematically searched for citations published up to March 17, 2023. A total number of 5017 abstracts was identified. Quality of the included trials was assessed with the Cochrane risk-of-bias tool. The meta-analysis was performed using a restricted maximum likelihood model. This study is registered with PROSPERO, number CRD42022377591.
Results
A total number of 14 studies and 1100 participants (593 in the medication group and 507 in the placebo group) meeting the inclusion criteria were selected. We estimated the pooled effect sizes of the overall placebo (dpl = -1.85 [CI 95%: -2.9 to -0.79] and overall treatment (dtr = -2.57; [CI 95% -3.36 to -1.78]) response. The overall placebo response accounts for up to 72% of the overall treatment response. Furthermore, we performed subgroup analysis of 8 studies for the for the 7 days post-intervention timepoint. Seven days post-intervention the placebo response (dpl 7d = -1.98 [CI 95%: -3.26 to -0.69]) accounts for 66% of the treatment response (dtr 7d = - 3.01 [CI 95%, -4.28 to -1.74]).
Conclusion
Ketamine and esketamine show large antidepressant effects. However, our findings suggest that the placebo response plays a significant role in the antidepressant response and should be used for the benefit of the patients in clinical practice.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022377591.
Research Summary of 'Hype or hope? High placebo response in major depression treatment with ketamine and esketamine: a systematic review and meta-analysis'
Introduction
Placebo response contributes substantially to the measured effect of antidepressant treatments and has been estimated in earlier work to account for a large proportion of apparent benefit in randomised controlled trials. Previous meta-analyses of oral antidepressants suggested that only a minority of participants derive benefit beyond placebo, and commentators have called for novel trial designs that better control expectation and blinding. Ketamine and esketamine, NMDA-receptor antagonists that can produce rapid reductions in depressive symptoms, have emerged as promising treatments for major depressive disorder (MDD), but the magnitude of placebo response in trials of these agents has not been systematically quantified. Matsingos and colleagues set out to estimate the placebo response in double-blind, randomized, placebo-controlled trials of subanaesthetic ketamine or intranasal esketamine for MDD. The study aims to quantify pooled effect sizes for change from baseline in placebo and active arms, to compare those effects across time points and interventions, and to examine potential moderators and the role of adverse events as indicators of insufficient blinding. This meta-analysis therefore addresses a gap in the literature on psychoactive, non-oral antidepressants and assesses how much of reported treatment response may be attributable to placebo mechanisms rather than drug-specific effects.
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Study Details
- Study Typemeta
- Journal
- Compounds
- Topics
- APA Citation
Matsingos, A., Wilhelm, M., Noor, L., Yildiz, C., Rief, W., Hofmann, S. G., Falkenberg, I., & Kircher, T. (2024). Hype or hope? High placebo response in major depression treatment with ketamine and esketamine: a systematic review and meta-analysis. Frontiers in Psychiatry, 15. https://doi.org/10.3389/fpsyt.2024.1346697
References (9)
Papers cited by this study that are also in Blossom
Alnefeesi, Y., Chen-Li, D., Jawad, M. Y. et al. · Journal of Psychiatric Research (2022)
Price, R., Kissel, N., Baumeister, A. et al. · Molecular Psychiatry (2022)
Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)
Ionescu, D. F., Qiu, X., Lane, R. et al. · International Journal of Neuropsychopharmacology (2020)
Ionescu, D. F., Bentley, K. H., Eikermann, M. et al. · Journal of Affective Disorders (2019)
Li, C. T., Chen, M. H., Lin, W. C. et al. · Human Brain Mapping (2016)
Singh, J. B., Fedgchin, M., Daly, E. J. et al. · American Journal of Psychiatry (2016)
Chen, X., Hou, X., Bai, D. et al. · American Journal of Psychiatry (2019)
Aday, J. S., Heifets, B. D., Pratscher, S. D. et al. · Psychopharmacology (2021)
Cited By (1)
Papers in Blossom that reference this study
Earleywine, M., Falabella, G. S., Oliva, A. B. et al. · Journal of Psychoactive Drugs (2024)
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