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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Intranasal esketamine spray has shown high efficacy in treating MDD.
“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]
The Conclusions report robust efficacy for intranasal esketamine in treatment-resistant depression, and the Key Points report significant symptom improvement in a trial of 67 adults. The claim broadens that finding to MDD generally; the study evaluated patients with treatment-resistant depression who continued oral antidepressant treatment. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSub-anesthetic doses of racemic ketamine produce rapid antidepressant responses, sometimes within hours, in people whose depression has not responded to monoaminergic drugs.
“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
The Introduction (page unavailable) says several studies have shown antidepressant efficacy with ketamine and notes the limitations of existing antidepressant therapies. It does not establish that sub-anesthetic doses of racemic ketamine work within hours in people resistant specifically to monoaminergic drugs. This trial instead studies intranasal esketamine, the S-enantiomer. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIntranasal esketamine 28 or 84 mg produced a rapid MADRS reduction within two hours and separated from placebo at one week after a single dose.
“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
The Efficacy Assessments section records MADRS measurements two hours after dosing, and the Efficacy section reports rapid improvement and greater MADRS reductions than placebo after one week for the esketamine doses. But the Design section specifies twice-weekly dosing on days 1 and 4; the one-week result was not measured after a single administration. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThere are data demonstrating long-term (greater than 3-year) safety and tolerability for esketamine.
“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]
The Safety section reports adverse events and tolerability during the trial, and the Discussion says the evaluated doses appeared safe. But the study’s treatment phase ended by day 74, with follow-up through day 130; it does not provide safety or tolerability data extending beyond three years. Page numbers are not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIntranasal esketamine spray co-initiated with an antidepressant has demonstrated rapid clinically meaningful efficacy in patients with TRD.
“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]
The Key Points report significant improvement in depressive symptoms after one week in adults with treatment-resistant depression. However, the Study Drug and Administration section says participants continued their existing antidepressant unchanged; esketamine and the antidepressant were not co-initiated in this trial. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Our findings are concordant with the direction and general magnitude of effect reported in pivotal trials of adjunctive intranasal esketamine in treatment-resistant depression and the relapse-prevention study.
“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]
The Abstract reports a placebo-adjusted reduction in depression scores with adjunctive intranasal esketamine in treatment-resistant depression, supporting the claimed direction and providing an effect magnitude. But the Conclusions describe this as an early study supporting larger trials, with a phase 3 study still under way; this source is not itself a pivotal or relapse-prevention trial. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe safety results were consistent with previous findings from completed short-term (4-week) phase 2 and 3 studies.
“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]
The Discussion (page unavailable) says the esketamine doses appeared safe, with no new or unexpected safety concerns. But the Design describes this as a phase 2 study with two one-week double-blind periods; the paper does not compare its safety results with completed four-week phase 2 and 3 studies. (LLM, conf=0.85)
Experimental — accuracy not yet measuredEarlier studies of esketamine in patients with treatment-resistant depression and major depression at imminent risk for suicide, which demonstrated greater magnitude of early response, applied a less stringent definition for response onset and employed site-based raters for efficacy evaluation.
“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]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAmong the 7 RCTs, six were initiation studies and one was a continuation study.
“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 authors verified positive efficacy at 1 week in NCT01998958 but could not compare 4 out of 10 analyses due to unpublished results.
“We verified the positive efficacy at 1 week in NCT01998958 [40] but could not compare 4 out of 10 analyses due to unpublished results.”
The sample size was planned assuming a treatment difference of 6.5 points in MADRS score, a standard deviation of 12, a two-sided significance level of 0.05, and a dropout rate of 25%; 98 individuals per treatment group were required for 90% power.
“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”
The magnitude of postdose blood pressure increases was lower compared with the previous phase 2 study of esketamine nasal spray, possibly because of the risk-mitigation blood pressure guidelines initiated in phase 3 studies.
“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).”
The approvals of esketamine nasal spray were based on efficacy and safety findings from phase 2/3 studies of treatment-resistant depression treatment for 4 weeks to 1 year.
“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].”
Intranasal administration of 28-84 mg (S)-ketamine twice a week for two weeks induced antidepressant actions in treatment-resistant depressed patients as an adjunct treatment.
“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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- 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 · 2017: 1
- 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 › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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