The DOI matches its Crossref record, with a small difference in title or year; 50 of the 51 references it cites were found in a registry or an index.
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial
Open accessAbstract
Importance: Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. Objective: To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). Design, Setting, and Participants: This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. Interventions: In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. Main Outcomes and Measures: The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Results: Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 [2.09], P = .02; 56 mg: -6.3 [2.07], P = .001; 84 mg: -9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy). Conclusions and Relevance: In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials. Trial Registration: clinicaltrials.gov identifier: NCT01998958.
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“Moreover, formulations of ketamine are also being developed, and intranasal esketamine spray has shown high efficacy in treating MDD. 484”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [484]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“A breakthrough in the treatment of depression was the discovery that the anesthetic (R,S)-ketamine (ketamine), when administered at sub-anesthetic doses, elicits rapid (sometimes within hours) antidepressant effects in humans that are otherwise resistant to monoaminergic-acting therapies.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Daly et al., 2018
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This study observed a similar rapid reduction (within two hours) in depression symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) following an intranasal (S)-ketamine treatment (28 or 84 mg), which separated from placebo even at one week following a single administration.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Daly et al., 2018
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Unlike IV ketamine, there are also data demonstrating long- term (i.e., greater than 3- year) safety and tolerability for esketamine 194,195 .”
From Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions (2023) · cites this paper as [194]
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In the citing paper
“Intranasal esketamine spray co- initi ated with an antidepressant has also demonstrated rapid clinically meaningful efficacy in patients with TRD.”
From Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions (2023) · cites this paper as [194]
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“Our findings are concordant with the direction and general magnitude of effect reported in pivotal trials of adjunctive intranasal esketamine in TRD and the relapse-prevention study (18–23)”
From Intranasal esketamine plus oral antidepressant for treatment-resistant depression: acute induction and maintenance relapse-prevention outcomes in a systematic review and meta-analysis (2026) · cites this paper as [18]
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“Results were consistent with previous findings from completed short-term (4-week) phase 2 and 3 studies.10,12,15”
From Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial (2019) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Earlier studies of esketamine in patients with treatmentresistant depression (10,11) and major depression at imminent risk for suicide (12), which demonstrated greater magnitude of early response, applied a less stringent definition for response onset and employed site-based raters for efficacy evaluation.”
From Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study (2019) · cites this paper as [11]
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“Among these, six were initiation studies (1 with a 1-week duration [40], five with a 4-week duration [9–11, 41, 42] and one was a continuation study [12].”
The cited source says what the claim attributes to it.
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“We verified the positive efficacy at 1 week in NCT01998958 [40] but could not compare 4 out of 10 analyses due to unpublished results.”
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“The sample size planned for this study was calculated assuming a treatment difference for the double-blind treatment phase of 6.5 points in MADRS score between the esketamine plus antidepressant group and the antidepressant plus placebo group and a standard deviation of 12, based on the results of a phase 2 study of esketamine nasal spray for treatment-resistant depression (11) and clinical”
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“The magnitude of postdose blood pressure increases was lower compared with the previous phase 2 study of esketamine nasal spray (11), possibly because of the riskmitigation blood pressure guidelines initiated in phase 3 studies (see the online supplement).”
In the citing paper
“The approvals of esketamine nasal spray were based on efficacy and safety findings from phase 2/3 studies of TRD treatment for 4 weeks to 1 year [9–14].”
In the citing paper
“In addition, intranasal administration of 28–84 mg (S)-ketamine twice a week for a total period of two weeks induced antidepressant actions in treatment-resistant depressed patients as an adjunct treatment 119.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [119]
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Cites
A Brief Measure for Assessing Generalized Anxiety Disorder: The GAD-7
Spitzer, R. L., Kroenke, K., Williams, J. B. W., & Löwe, B. (2006) · Archives of Internal Medicine · doi:10.1001/archinte.166.10.1092 · Cited by 31,765
Diagnostic and Statistical Manual of Mental Disorders.
Widiger, T. A. (2000) · Oxford University Press eBooks · doi:10.1037/10518-009 · Cited by 19,766
A new depression scale designed to be sensitive to change
Montgomery, S. A., & Åsberg, M. (1979) · British Journal of Psychiatry · doi:10.1192/bjp.134.4.382 · Cited by 13,962
The Brief Psychiatric Rating Scale.
Overall, J. E., & Gorham, D. R. (1962) · Psychological Reports · doi:10.2466/pr0.1962.10.3.799 · Cited by 11,090
Cook, R. J., Dickens, B. M., & Fathalla, M. F. (2003) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780199241323.003.0025 · Cited by 10,825
(1976) · Medical Entomology and Zoology · Cited by 8,899
Vos, T., Barber, R. M., Bell, B., Bertozzi-Villa, A., Biryukov, S., Bolliger, I., Charlson, F., Davis, A., Degenhardt, L., Dicker, D., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(15)60692-4 · Cited by 6,414
Antidepressant effects of ketamine in depressed patients
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856
Rush, A. J., Trivedi, M. H., Ibrahim, H. M., Carmody, T. J., Arnow, B., Klein, D. N., Markowitz, J. C., Ninan, P. T., Kornstein, S., Manber, R., et al. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01866-8 · Cited by 3,829
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Fármacos de uso más habitual en la patología psiquiátrica infanto-juvenil
Aparicio, T. J. (2026) · Boletín de Pediatría · doi:10.63788/b3pzty92
Barlattani, T., Sernia, G., D’Amelio, C., Maritato, S., Gabriele, D., Bologna, A., Trebbi, F., Ricci, V., Tomasetti, C., Martiadis, V., et al. (2026) · Psychiatry International · doi:10.3390/psychiatryint7050207
He, L., Sun, Z., Guo, Q., Wang, E., Li, L., & Shenxiayu, L. (2026) · Journal of Investigative Surgery · doi:10.1080/08941939.2026.2712673
Macaluso, M. (2026) · Journal of Psychiatric Practice · doi:10.1097/pra.0000000000000947
Civardi, S. C., Besana, F., Durbano, F., Toscano, M. O. M., Raffone, F., Dell’Osso, B. M., & Olivola, M. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1858319
Kim, Y. B., Yun, C.-O., & Yoon, A. R. (2026) · Drug Delivery · doi:10.1080/10717544.2026.2738285
Hua, Z., Shu, Y., Li, L., Xia, S., Xiao, J., Li, J., Ji, Y., Li, H., Peng, D., Wan, A., et al. (2026) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2026.112148
Psychometric Properties of the 3-Item Clinician Administered Dissociative States Scale (CADSS)
Bremner, J. D., & Vaccarino, V. (2026) · Chronic Stress · doi:10.1177/24705470261497666
Szawarnoga, D., Fojcik, J., Górski, M. K., & Krzystanek, M. (2026) · Pharmaceuticals · doi:10.3390/ph19101644
Xiao, C., Xu, X., Yao, W., Pan, Y., Wan, S., Wei, J., & Xu, L. (2026) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2026.10.038
Ghumman, U., Shafee, C., Altarawneh, L. N., Iorini, M., Kandel, H., Anand, N., Lopez, A., Mendoza, J., Romero, E., Dang, A., et al. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1906750
Vasudeva, S., Orsini, D. K., Lovell, G. F. M., Luch, S. D. D., Le, G. H., Wong, S., McIntyre, R. S., & Rosenblat, J. D. (2026) · Psychiatry Research · doi:10.1016/j.psychres.2026.117556
Metadata
- Authors
- Daly, E. J., Singh, J. B., Fedgchin, M., Cooper, K., Lim, P., Shelton, R. C., Thase, M. E., Winokur, A., Van Nueten, L., Manji, H., & Drevets, W. C.
- Affiliations
- Janssen Research & Development (United States) (US)
- Department of Neuroscience, Janssen Research & Development LLC, San Diego, California
- University of Alabama (US)
- University of Pennsylvania (US)
- UConn Health (US)
- Department of Neuroscience, Janssen Research & Development, Beerse, Belgium
- Corresponding author
- Daly, Ella J.
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2018-02-01
- Volume
- 75
- Issue
- 2
- Pages
- 139
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC5838571
- OpenAlex
- W2779386549
- Semantic Scholar
- b920d61a3ab10c4fbf2f123dd93cb19a9c3872f9
- Cited by
- 718
- References
- 51
- Citations by year
- 2026: 71 · 2025: 99 · 2024: 92 · 2023: 80 · 2022: 75 · 2021: 86 · 2020: 105 · 2019: 70 · 2018: 38
- FWCI
- 40.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- esketamine, treatment-resistant depression, major depressive disorder, intranasal administration, adjunctive therapy, antidepressant resistance, dose-response relationship, antidepressant efficacy, antidepressant safety, adverse events, NMDA receptor antagonists, ketamine derivatives, open-label extension, relapse prevention, treatment-emergent adverse events
- MeSH terms
- Administration, Intranasal, Administration, Oral, Adult, Antidepressive Agents, Major Depressive Disorder, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Ketamine, Male, Middle Aged, Treatment Outcome, Young Adult, Depressive Disorder, Treatment-Resistant
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