Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial

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 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.