Esketamine vs Midazolam in Boosting the Efficacy of Oral Antidepressants for Major Depressive Disorder

Depression is common, recurrent and disabling, and pharmacotherapy remains the principal treatment for major depressive disorder (MDD). The authors highlight a clinically important phenomenon distinct from relapse or recurrence: loss of a previously effective response while a patient remains on an adequate antidepressant regimen. This has been variously termed tachyphylaxis or antidepressant tolerance; in this paper the investigators use the term fluctuating antidepressant response in MDD (FAD) to denote re-emergence of prior symptoms or onset of a new episode despite ongoing adequate antidepressant treatment. Causes of FAD are unclear, evidence-based management options are limited and repeated medication changes may increase adverse effects and risk of treatment resistance, so novel approaches are needed to prevent progression to treatment-resistant depression (TRD). Against this background, Xiao and colleagues evaluated whether a single subanesthetic intravenous dose of esketamine could ‘‘boost’’ the efficacy of patients' ongoing oral antidepressants in people with FAD. The study was designed as a pilot, double-blind, midazolam-controlled randomised clinical trial to assess short- and medium-term efficacy and safety over a 6-week follow-up period, with the aim of providing preliminary effect-size data to inform future trials and potential clinical strategies for managing FAD.

This single-centre, double-blind, midazolam-controlled randomised clinical trial was conducted at Beijing Anding Hospital, Capital Medical University. Eligible participants were adults (18 years and older) with MDD who met the investigators' operational definition of fluctuating antidepressant response (FAD), that is, re-emergence of symptoms or a new episode while on adequate antidepressant treatment. Recruitment occurred from August 2021 to January 2022. The trial was approved by a local ethics committee and all participants provided written informed consent. Participants were randomised 1:1 by computer-generated block randomisation (block size 4) to receive either intravenous esketamine or an active control, midazolam. Allocation concealment was handled by an independent assistant who prepared and labelled medication; investigators, staff, participants and outcome assessors were blinded to group assignment. All participants remained on their current oral antidepressant throughout the study. Interventions consisted of a single intravenous infusion administered over 40 minutes: esketamine 0.2 mg/kg or midazolam 0.045 mg/kg, both dissolved in 50 mL normal saline and delivered with a syringe pump. Participants were admitted the day before infusion, observed with safety checks before, during and after infusion, and discharged after a 24-hour follow-up visit. The protocol referenced further safety procedures in a supplement. Efficacy was measured primarily by the Montgomery-Åsberg Depression Rating Scale (MADRS) and Clinical Global Impression–Severity (CGI-S) at multiple time points: 40 minutes; 2, 4 and 24 hours; and 1, 2, 4 and 6 weeks post-infusion. The primary outcome was response at 2 weeks, defined as a 50% reduction in MADRS score; remission was defined as MADRS ≤10. Safety assessments included standard side-effect scales, measures of psychotic symptoms, the Clinician-Administered Dissociative States Scale (CADSS), Young Mania Rating Scale (YMRS) and the Columbia-Suicide Severity Rating Scale. Structured interview guides for early MADRS assessments were used at 4 and 24 hours to improve reliability. As a pilot study, no formal sample size calculation was performed; the investigators planned to enrol 30 participants (15 per group) to generate effect-size estimates. Analyses followed an intention-to-treat approach using the full analysis set (all randomised participants who completed baseline assessment and received medication). Missing MADRS values were imputed by last observation carried forward. Group comparisons used χ2 or Fisher exact tests for categorical data and t tests or Wilcoxon rank-sum tests for continuous data as appropriate. Sensitivity analyses included logistic regression and analysis of covariance adjusting for baseline MADRS and number of MDD episodes, and a two-way repeated-measures analysis of variance examined group-by-time interaction.

Of 43 people screened between August 2021 and January 2022, 30 participants with FAD were enrolled (median age 28.0 years [IQR 24.0–40.0]; 17 [56.7%] female) and all were included in the full analysis set. Twenty-nine participants (96.7%) completed the 6-week trial; one participant randomised to esketamine discontinued after 1 week for relocation related to employment. Baseline characteristics were generally balanced between groups, although the extract indicates differences in the proportion with a first MDD episode, mean number of MDD episodes and mean baseline MADRS score (details in the table referenced in the paper). Primary outcome: At 2 weeks the response rate (≥50% reduction in MADRS) was markedly higher in the esketamine group than in the midazolam control group: 10 of 15 participants (66.7%) versus 1 of 15 (6.7%). The unadjusted odds ratio was 28.00 (95% CI, 2.82–277.96). Sensitivity analysis with logistic regression adjusting for baseline MADRS score and number of MDD episodes confirmed a statistically significant effect (adjusted OR, 14.17; 95% CI, 1.14–175.96; P = .04). Significant between-group differences in response were also observed at 1, 4 and 6 weeks; there was no statistically significant difference at 24 hours (66.7% vs 33.3%; P = .07). Secondary outcomes: Remission rates (MADRS ≤10) were higher in the esketamine group at some early and later time points: at 4 hours 10 of 15 (66.7%) versus 3 of 15 (20.0%) (P = .01), and at 4 weeks 8 of 15 (53.3%) versus 1 of 15 (6.7%) (P = .005). Mean MADRS score reduction from baseline to 2 weeks was substantially greater with esketamine (mean [SD] reduction 15.7 [1.5]) than with midazolam (3.1 [1.3]; P < .001), and this between-group difference was observed at all recorded visits. Analysis of covariance adjusting for baseline MADRS and number of episodes yielded least-squares mean differences in MADRS reduction of −8.74 (95% CI, −13.11 to −4.37; P < .001) at 2 weeks and −5.55 (95% CI, −10.08 to −1.03; P = .02) at 6 weeks. A two-way repeated-measures ANOVA showed a significant time-by-group interaction (F = 8.27; P < .001). The reduction in CGI-S from baseline to 6 weeks was also significantly greater in the esketamine group at each visit. Safety: No serious adverse events were reported. Psychotic symptoms on the Brief Psychiatric Rating Scale and clinically significant manic symptoms on the YMRS were not observed. Dissociation measured by CADSS was zero at 2, 4 and 24 hours for all participants, but at the 40-minute time point the esketamine group had higher dissociation scores (median 6 [IQR 3–13]) compared with the midazolam group (median 0 [IQR 0–0]; P < .001). For general side effects (defined as an increase of at least 1 on each item of the Udvalg for Kliniske Undersogelser scale), 2 participants (13.3%) in the esketamine group reported increased dream activity; in the midazolam group 4 participants (26.7%) reported tension or inner unrest and 3 participants (20.0%) reported increased dream activity. The Columbia-Suicide Severity Rating Scale was monitored throughout the study but no elevated suicide risk events are reported in the extracted text.

Xiao and colleagues interpret their findings as indicating that a single subanesthetic intravenous dose of esketamine given alongside ongoing oral antidepressants produced greater and more durable antidepressant effects in patients with fluctuating antidepressant response than an active midazolam control, with an acceptable safety profile in this small pilot sample. The authors note that prior evidence suggested ketamine's adjunctive benefit often wanes by about 2 to 4 weeks, and they cite trials that found diminished effects by day 28; their current observation of maintained superiority at 4 and 6 weeks contrasts with those earlier reports and suggests a potential ‘‘booster’’ effect when esketamine is administered to patients continuing their antidepressant regimen. In seeking mechanistic explanations, the investigators discuss possible interactions between ketamine (and its enantiomers) and standard antidepressants, including overlapping receptor targets and downstream neuroplastic effects such as restoration of prefrontal synaptic spines. They hypothesise that such effects might restore or enhance antidepressant sensitivity in patients with FAD, though they acknowledge that direct evidence for interaction between ketamine and antidepressants is limited. The authors present their results as preliminary evidence supporting the hypothesis that esketamine may improve antidepressant efficacy in this specific clinical scenario. The extracted Discussion does not include a distinct, detailed limitations paragraph; however, the trial's pilot design, single-centre conduct and small sample are described elsewhere in the paper, and the authors frame the findings as preliminary and hypothesis-generating. They imply that larger, confirmatory randomised trials will be needed to replicate these results, clarify mechanisms, and define longer-term safety and effectiveness, but specific future-study recommendations or policy implications are not elaborated in the provided text.