In a phase 4, multicentre, double-blind randomised trial in adults with treatment‑resistant depression, intranasal esketamine monotherapy (56 mg and 84 mg) produced significant reductions in MADRS score versus placebo at day 28 (LS mean differences −5.1 and −6.8; effect sizes 0.48 and 0.63) and demonstrated rapid benefit at 24 hours. The tolerability profile was consistent with prior reports, most commonly nausea, dissociation, dizziness and headache.
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Importance
Esketamine nasal spray, administered in conjunction with an oral antidepressant, is approved for treatment-resistant depression (TRD). However, the efficacy of esketamine nasal spray administered as monotherapy for patients with TRD has not yet been evaluated.
Objective
To assess the efficacy and safety of esketamine monotherapy compared to placebo in reducing depressive symptoms in patients with TRD.
Design, Setting, and Participants
This phase 4, double-blind, placebo-controlled randomized clinical trial was conducted from November 2020 to January 2024 at 51 outpatient centers in the US. Adults with major depressive disorder (DSM-5 criteria) without psychotic features who experienced inadequate response (≤25% improvement) to 2 or more oral antidepressants during the current depressive episode were eligible for inclusion. Data analyses were conducted from March 1, 2024, to July 8, 2024.
Interventions
After a 2-week or longer antidepressant-free period, participants were randomized at a 1:1:2 ratio to fixed-dose intranasal esketamine (56 mg or 84 mg) or matching intranasal placebo, administered twice weekly for 4 weeks.
Main Outcomes and Measures
Change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 28 (primary efficacy end point) and to 24 hours post–first dose (day 2; key secondary efficacy end point) were analyzed by a mixed-effects model using repeated measures.
Results
In this multicenter randomized clinical trial, 378 participants who met prerandomization MADRS severity criteria received 1 or more study drug doses (esketamine, 56 mg [n = 86]; esketamine, 84 mg [n = 95]; or placebo [n = 197]). Mean (SD) participant age was 45.4 (14.1) years, 231 participants (61.1%) were female, and baseline mean (range) MADRS total score was 37.3 (28-50). At day 28, the least-square (LS) mean difference (SE) between esketamine and placebo was −5.1 (1.42) (95% CI, −7.91 to −2.33) for the 56-mg dose and −6.8 (1.38) (95% CI, −9.48 to −4.07) for the 84-mg dose (for each, 2-sided P < .001). Observed effect sizes were 0.48 and 0.63 for the 56-mg and 84-mg dose groups, respectively. At day 2 (approximately 24 hours post–first dose), the between-group difference was significant for both esketamine doses: −3.8 (1.29) (95% CI, −6.29 to −1.22; 2-sided P = .004) for 56 mg and −3.4 (1.24) (95% CI, −5.89 to −1.00; 2-sided P = .006) for 84 mg. The most common treatment-emergent adverse events reported for esketamine (combined doses) were nausea (56 participants [24.8%]), dissociation (55 [24.3%]), dizziness (49 [21.7%]), and headache (43 [19.0%]).
Conclusions and Relevance
According to results of this multicenter, double-blind randomized clinical trial, esketamine monotherapy may expand treatment options for adult patients with TRD by addressing an unmet need of patients experiencing treatment-limiting tolerability concerns and nonresponse with oral antidepressants.
Despite many approved antidepressant options, major depressive disorder (MDD) remains a leading cause of disability and reduced life expectancy, and a substantial proportion of patients fail to respond to standard oral antidepressant (OAD) trials. Patients who meet the common regulatory definition of treatment-resistant depression (TRD)—failing to achieve more than 25% improvement with two or more OADs during the current episode—have markedly higher morbidity and suicide risk and frequently encounter tolerability-related nonadherence with OADs. Earlier phase 2 and 3 trials established that intranasal esketamine administered adjunctively with an OAD produces rapid and durable antidepressant effects, leading to regulatory approval for adjunctive use, but esketamine as monotherapy had not been evaluated in a placebo-controlled trial. Janik and colleagues designed the present study to fill that gap. The trial tested whether fixed-dose intranasal esketamine given alone (56 mg or 84 mg twice weekly for 4 weeks) reduces depressive symptom severity more than placebo in adults with TRD after an antidepressant-free period. The investigators also assessed onset of effect (24 hours after the first dose), safety and tolerability during the double-blind phase, and symptom course in an optional 12-week open-label phase in which participants could receive esketamine.
This was a Phase 4, multicentre, double-blind, placebo-controlled randomised clinical trial conducted at 51 US outpatient centres from November 2020 to January 2024. After a screening period during which any current antidepressants were tapered and discontinued for at least 2 weeks, eligible adults (aged ≥18 years) with DSM-5 major depressive disorder without psychotic features and with TRD (≤25% improvement to two or more prior OADs in the current episode) were randomised in a 1:1:2 ratio to fixed-dose intranasal esketamine 56 mg, esketamine 84 mg, or matching placebo. Dosing occurred twice weekly for 4 weeks under site supervision, with at least 2 hours of postdose observation. Key exclusion criteria included psychotic or bipolar disorders, recent moderate-to-severe substance/alcohol use disorder, recent suicidality, prior exposure to ketamine or esketamine, and nonresponse to neuromodulation (ECT, VNS, DBS) in the current episode. To limit rater unblinding and baseline inflation, entry required an IDS-C30 score ≥34 and the efficacy analysis dataset was defined using site-blinded MADRS severity criteria (MADRS total ≥28 at screening week 1, screening week 2, and prerandomisation day 1, with ≤25% improvement across screening). Participants could opt into a 12-week open-label phase after the double-blind phase; those who entered received esketamine 56 mg on day 28 and dose adjustments thereafter were permitted. Efficacy assessments used the Montgomery–Åsberg Depression Rating Scale (MADRS) administered by raters different from safety assessors (to reduce functional unblinding), plus participant-reported PHQ-9 and investigator-rated CGI-S. Suicidality was monitored with the Columbia Suicide Severity Rating Scale (C-SSRS). The primary efficacy endpoint was change in MADRS total score from baseline to day 28, analysed with a mixed-effects model for repeated measures (MMRM) including treatment, research centre, antidepressant status at screening, day and day-by-treatment interaction, and baseline MADRS as covariate; the key secondary endpoint was change in MADRS at day 2 (approximately 24 hours post-first dose). The safety analysis included all randomised participants receiving at least one dose; adverse events were coded by MedDRA and vital signs were monitored at dosing sessions. Multiplicity control for primary and key secondary hypotheses used a prespecified procedure (including Hochberg).
The study protocol and amendments were approved by institutional review boards (eMethods 1 in Supplement 2). This study was conducted in accordance with the Good Clinical Practice guideline, assuring the rights, safety, and well-being of study participants were protected, consistent with the ethical principles that originated in the Declaration of Helsinki. All individuals provided written informed consent before entering the study. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Efficacy Analyses For the double-blind phase, the efficacy analysis dataset included all randomized participants who received 1 or more doses of study drug and met MADRS-defined severity criteria during screening. The safety analysis dataset included all randomized participants who received 1 or more doses of study drug. The open-label phase dataset included all participants who received 1 or more doses of open-label esketamine. Analyses were performed using SAS version 9.4 (SAS Institute). The statistical approach for sample size determination and significance level with control for multiplicity are provided in eMethods 3 in Supplement 2.
In this first placebo-controlled, monotherapy randomized clinical trial, esketamine demonstrated rapid and robust efficacy at both 56-and 84-mg doses, with a clinically meaningful and statistically significant treatment effect, initially observed 24 hours after the first dose, representing substantial benefit compared to OADs, which typically exhibit a delayed onset of effect.The antidepressant effect was maintained through day 28 of the double-blind phase. Notably, effect size for the primary efficacy end point of 0.48 (56 mg) and 0.63 (84 mg) supports robust efficacy of esketamine monotherapy in a TRD population. The treatment difference for both esketamine doses at days 2 and 28 exceeded the 2-point difference in MADRS score vs placebo established as clinically meaningful.The study had an unique design feature, which used the IDS-C 30 as an entry criterion for depression severity and used the site-blinded MADRS severity criteria to define the efficacy analysis dataset. This design fea- ture was aimed to prevent potential inflation of baseline MADRS score, which in turn would increase the sensitivity of signal detection for the treatment effect.Notably, the results of the primary and key secondary end points from the efficacy analysis dataset were consistent with those from the dataset that included all randomized participants, regardless of meeting MADRS severity criteria. In participants who continued esketamine in the 12-week, single-arm, open-label phase, depressive symptoms remained stable or improved. These findings are consistent with and expand upon efficacy findings in a subgroup of SUSTAIN-3 patients (n = 50) who received esketamine monotherapy for 3 or more months.Response and remission rates were higher in both esketamine groups vs placebo at all double-blind time points. The NNTs with esketamine monotherapy for response (6.5 [56 mg] and 7.1 [84 mg]) and remission (12.3 [56 mg] and 6.7 [84 mg]) after 4-week treatment align with NNTs from phase 3 studies of adjunctive esketamine treatment of TRD.There were no unexpected tolerability findings. Most adverse events commonly observed with esketamine treatment were mild or moderate in severity and transient in duration, occurring on a dosing day and resolving during the 2-hour postdosing, in-clinic observation period. No esketamine-treated participant experienced a treatmentrelated serious adverse event, and few discontinued esketamine due to an adverse event. The latter findings are noteworthy given the relatively high rates of drug-related adverse events, nonadherence, and early discontinuation due to tolerability issues among patients with MDD treated with OADs.Incidences of treatment-emergent suicidal ideation (based on C-SSRS) appear similar to incidences observed in shortterm studies of adjunctive esketamine in TRD (10.4% [esketamine, 56 mg]; 7.1% [esketamine, 84 mg] vs placebo [11.5%] in TRANSFORM-1; 5.4% [esketamine] vs 6.4% [placebo] in TRANSFORM-2).Taken together, the safety profile of esketamine in this monotherapy study is consistent with its safety profile demonstrated in adjunctive treatment trials.
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Chen, X., Hou, X., Bai, D. et al. · American Journal of Psychiatry (2023)
Chen, G., Chen, L., Zhang, Y. et al. · International Journal of Neuropsychopharmacology (2022)
Joshi, K., Pilon, D., Shah, A. et al. · Journal of Medical Economics (2023)
Teeple, A., Zhdanava, M., Pilon, D. et al. · Current Medical Research and Opinion (2023)
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Mallevays, M., Fuet, L., Danon, M. et al. · MedRvix (2026)
Cubała, W. J., Bajbouj, M., Bauer, M. et al. · JAMA Psychiatry (2026)
Jing, R., Tu, Y. · American Journal of Translational Research (2026)
The efficacy analysis dataset comprised 378 participants who met MADRS-defined severity criteria and received at least one dose; the safety dataset included 476 dosed participants. Mean (SD) age was 45.4 (14.1) years, 61.1% were female, and baseline mean MADRS total score was 37.3 (range 28–50). At screening, 65.6% were taking an OAD and 59.3% had failed two antidepressants; lifetime suicidal ideation or behaviour was reported in 46.0% and 24.1% respectively. Primary outcome: From baseline to day 28, both esketamine doses produced significantly greater MADRS reductions than placebo. The least-square mean differences (SE) versus placebo were −5.1 (1.42) for the 56-mg group (95% CI, −7.91 to −2.33; P < .001) and −6.8 (1.38) for the 84-mg group (95% CI, −9.48 to −4.07; P < .001). Corresponding observed effect sizes (Cohen d) were 0.48 (56 mg) and 0.63 (84 mg). Mean (SD) raw changes reported were −12.7 (11.82) for 56 mg and −13.9 (11.89) for 84 mg. Key secondary and other efficacy outcomes: Rapid improvement was evident roughly 24 hours after the first dose: between-group LS mean differences (SE) at day 2 were −3.8 (1.29) for 56 mg (95% CI, −6.29 to −1.22; P = .004) and −3.4 (1.24) for 84 mg (95% CI, −5.89 to −1.00; P = .006). Response (≥50% MADRS reduction) and remission (MADRS ≤10) rates were higher in both esketamine groups than placebo at all double-blind time points, with response rates about twofold higher and remission rates two-to threefold higher at day 28. Number needed to treat (NNT) for response at day 28 was 6.5 (95% CI, 1.8–11.3) for 56 mg and 7.1 (95% CI, 1.7–12.5) for 84 mg; NNTs for remission were 12.3 (95% CI, −0.4 to 25.0) and 6.7 (95% CI, 2.6–10.9), respectively. A post hoc analysis that included all randomised participants regardless of MADRS screening severity produced consistent results. Open-label phase: Participants who continued on or switched to esketamine in the 12-week open-label phase generally maintained or further improved depressive symptoms. Among the 441 participants receiving open-label esketamine, 35.4% received a concomitant OAD at some point. Safety: No deaths occurred. The most common treatment-emergent adverse events in esketamine-treated participants (combined doses) were nausea (24.8%), dissociation (24.3%), dizziness (21.7%), and headache (19.0%). Most adverse events occurred on dosing days and resolved the same day; many nausea and vomiting events clustered in the first three dosing sessions and attenuated thereafter. Serious adverse events were uncommon and included one ankle fracture (56 mg) and two events in the 84-mg group (suicide attempt, ophthalmic migraine); investigators considered these not related to esketamine. Placebo-group serious events included self-injurious ideation, suicidal ideation, and acute myocardial infarction. Discontinuations due to adverse events were infrequent (approximately 1.0% in 56 mg, 4.1% in 84 mg, and 1.2% in placebo). Mean systolic and diastolic blood pressure increased at 40 minutes postdose and returned near predose by 1.5 hours. C-SSRS results showed an increase in the proportion with no suicidal ideation/behaviour from baseline to day 28 across all groups; treatment-emergent suicidal ideation occurred in 6.7% (56 mg), 6.6% (84 mg), and 9.6% (placebo), and two participants (one in each esketamine dose group) exhibited suicidal behaviour. On blinding assessment at day 28, a majority of esketamine-treated participants strongly believed they had received esketamine (71.1% in 56 mg; 78.3% in 84 mg), while 46.9% of placebo-treated participants strongly believed they had received placebo.
Janik and colleagues interpret the findings as demonstrating rapid and robust antidepressant efficacy for intranasal esketamine monotherapy at both 56-mg and 84-mg doses in adults with TRD. The investigators emphasise that improvement began as early as 24 hours after the first dose and was sustained through day 28, with effect sizes of 0.48 and 0.63 and treatment differences exceeding the 2-point MADRS threshold the authors regarded as clinically meaningful. Results in the efficacy analysis dataset were consistent with analyses that included all randomised participants, supporting the observed signal despite the study's careful site-blinded severity criteria. With respect to safety, the authors state there were no unexpected tolerability findings and that most adverse events were transient, mild-to-moderate, occurred on dosing days, and resolved during the in-clinic observation period. No treatment-related serious adverse events were observed and discontinuations for adverse events were uncommon. The overall safety profile in the monotherapy setting is reported to be consistent with prior adjunctive esketamine trials. The authors acknowledge several limitations that temper generalisability: exclusion of patients with substantial psychiatric or medical comorbidity, recent substance dependence, and limited racial and ethnic diversity among participants. They also note the potential for functional unblinding due to esketamine's characteristic psychotomimetic effects but describe mitigation strategies (different raters for efficacy and safety) and report post hoc analyses suggesting dissociation was not associated with greater response rates. Finally, the open-label phase lacked a control arm and is therefore exploratory. The investigators conclude that, given the efficacy and tolerability observed, esketamine monotherapy may represent a useful option for patients with TRD who have inadequate response to or poor tolerability of OADs, with the 84-mg dose showing the larger effect size without new safety concerns.
The study authors conclude that this placebo-controlled trial strengthens evidence for esketamine's antidepressant efficacy when used as monotherapy in adults with treatment-resistant depression. They suggest that esketamine monotherapy could expand treatment options for patients who cannot tolerate or do not respond to oral antidepressants, noting that the 84-mg dose—the most commonly used in clinical practice—produced a larger effect size without new safety signals. The investigators frame esketamine monotherapy as a potential approach to address an unmet need among a vulnerable TRD subpopulation at risk of serious outcomes.