A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder
Open accessAbstract
Background The N-methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. Methods In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. Results Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. Conclusions This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.
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Ketamine can produce remission in patients who do not respond to monoamine-targeted treatments, which is why the FDA approved it.
“In the population of patients that are resistant to monoamine system targeting therapies, ketamine has been shown to facilitate remission, hence the current indication by the FDA (Lapidus et al., 2014).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Lapidus et al., 2014
The Results > Efficacy report a rapid antidepressant response in patients who had failed prior treatment, but do not report that ketamine produced remission. More decisively, the Discussion describes treatment of refractory depression as a potential use “should it gain approval for this indication,” contrary to the claim that it already had an FDA indication. Page numbers were not available in our copy. (LLM, conf=0.86)
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Experimental — accuracy not yet measuredLapidus et al. (2014) showed significant improvement in depressive symptoms within 24 hours with intranasal ketamine in treatment-resistant depression.
“Significant improvement in depressive symptoms within 24 hours”
From Virtual reality and psychedelics for the treatment of psychiatric disease: A systematic literature review (2020) · cites this paper as Lapidus et al. (2014)
Intranasally administered ketamine has a rapid antidepressant effect.
“demonstrating the rapid antidepressant effect of intranasally administered ketamine.”
From Virtual reality and psychedelics for the treatment of psychiatric disease: A systematic literature review (2020) · cites this paper as Lapidus et al. (2014)
Intranasal ketamine was well tolerated, with almost no psychotomimetic or dissociative side effects or visible hemodynamic changes.
“being well tolerated, with almost no psychotomimetic or dissociative side effects or visible hemodynamic changes”
From Virtual reality and psychedelics for the treatment of psychiatric disease: A systematic literature review (2020) · cites this paper as Lapidus et al. (2014)
In patients with treatment-resistant depression in a major depressive episode, intranasal ketamine (50 mg) produced significant improvement in depressive symptoms within 24 hours compared to placebo.
“Significant improvement in depressive symptoms were observed within 24 hours after ketamine administration compared to placebo”
From Virtual reality and psychedelics for the treatment of psychiatric disease: A systematic literature review (2020) · cites this paper as Lapidus et al. (2014)
One RCT on intranasal ketamine suggested intranasal administration may be a viable alternative, while another study was aborted early due to poor tolerance to the intranasal formulation.
“While one RCT on intranasal ketamine63 suggested that intranasal administration may be a viable alternative, another study64 was aborted early due to poor tolerance to the intranasal formulation.”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [63]
In clinical trials, one subanesthetic ketamine dose gives rapid symptom relief-within 24 hours-in MDD and treatment-resistant depression, but the benefit is short-lived.
“In contrast to the slow therapeutic actions of typical antidepressants, a single subanesthetic dose of ketamine produces rapid (within 24 h of administration) symptomatic relief in MDD and treatment resistant depression in clinical trials, though the effects are transient [108].”
From Beyond the serotonin deficit hypothesis: Communicating a neuroplasticity framework of major depressive disorder (2024) · cites this paper as [108]
A single sub-anesthetic dose of ketamine induces rapid and sustained antidepressant actions in treatment-resistant patients.
“Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions in treatment-resistant patients.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [8]
Several other clinical trials demonstrated rapid antidepressant actions of ketamine in treatment-refractory patients.
“Following these initial reports, several other clinical trials demonstrated rapid antidepressant actions of ketamine in treatment-refractory patients (e.g. 8, 18).”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [8]
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“A recent doubleblind, placebo-controlled trial on the efficacy of intranasal ketamine in MDD observed a fast antidepressant effect and good tolerability, with a response rate of 44% in the ketamine group and 6% in the placebo group after 24 hours [102].”
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“Another placebo-controlled study with crossover design with the use of ketamine was conducted by Lapidus et al. (2014), but in this case, it was administered intranasally, in order to facilitate therapeutic delivery.”
MethodFrom psychache to neuroplasticity: A unified rescue-repair model of Ketamine’s anti-suicidal action
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- Authors
- Lapidus, K. A. B., Levitch, C. F., Perez, A. M., Brallier, J. W., Parides, M. K., Soleimani, L., Feder, A., Iosifescu, D. V., Charney, D. S., & Murrough, J. W.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- James J. Peters VA Medical Center (US)
- Corresponding author
- Murrough, James W.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 76
- Issue
- 12
- Pages
- 970-976
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4185009
- OpenAlex
- W1996780673
- Cited by
- 480
- References
- 37
- Citations by year
- 2026: 14 · 2025: 33 · 2024: 38 · 2023: 40 · 2022: 42 · 2021: 44 · 2020: 48 · 2019: 39 · 2018: 40 · 2017: 33 · 2016: 43 · 2015: 46 · 2014: 19
- FWCI
- 32.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000067, K23MH094707)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- intranasal ketamine, major depressive disorder, treatment-resistant depression, rapid antidepressant effects, NMDA receptor antagonists, antidepressant efficacy, adverse effects, psychotomimetic effects, dissociative effects, hemodynamic effects
- MeSH terms
- Administration, Intranasal, Adult, Aged, Antidepressive Agents, Major Depressive Disorder, Double-Blind Method, Female, Follow-Up Studies, Humans, Ketamine, Male, Middle Aged, Psychiatric Status Rating Scales, Time Factors, Treatment Outcome, Cross-Over Studies, Young Adult
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