Esketamine May Boost Efficacy of Oral Antidepressants in Patients with Fluctuating Response


Researchers sought to find a remedy for the development of treatment-resistant depression in patients whose antidepressant treatment has fluctuated in efficacy.

A single subanesthetic dose of esketamine may boost the efficacy of oral antidepressants in the treatment of fluctuating antidepressant response (FAD) in major depressive disorder (MDD) with a good safety profile, according to the results of a study published in the Journal of the American Medical Association.

Image credit: Kittiphan -

Image credit: Kittiphan -

Currently, the leading strategy in the treatment of MDD is pharmacotherapy. Guidelines recommend that patients who have MDD continue antidepressant therapy for 4 to 9 months after successful acute phase treatment to prevent relapse and recurrence, and 2 years or more of maintenance treatment at a full dose for those with a high risk of recurrence.

Loss of previously effective response differs from relapse and recurrence—which occurs during the continuation or maintenance phase—in that it occurs while receiving adequate antidepressant treatment (ADT) and affects a high proportion of patients with MDD, with rates ranging from 9% to 57%.

There is a lack of effective treatments for FAD, and the causes remain unclear. Available options are limited, and despite the possibility of success, can increase the risk of unanticipated adverse effects (AEs). FAD may also contribute to the development of treatment-resistant depression (TRD). The investigators aimed to find an effective novel treatment strategy to prevent TRD, and conducted a trial focused on the efficacy of esketamine compared to midazolam.

The single-center, double-blind, midazolam-controlled, randomized trial was conducted at a university hospital in China. Patients included in the trial were aged 18 to 60 years and diagnosed with MDD. They were randomized in a 1:1 ratio to receive either 0.2 mg/kg of intravenous (IV) esketamine or 0.045 mg/kg of IV midazolam for 40 minutes.

The primary outcome of the study was the response rate at 2 weeks, in which response was defined as a 50% reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included the response rate at 6 weeks and remission rates at 2 and 6 weeks. Safety outcomes included general AEs, psychotogenic effects, and suicide risk.

From August 2021 to January 2022, 30 participants with FAD were enrolled, of whom 29 participants (96.7%) completed the trial. The median (IQR) duration of ongoing ADT with their current antidepressant was 24.9 (14.9-51.0) weeks, 8.6 (4.0-32.9) weeks stable after symptom relief, and 5.8 (3.1-10.3) weeks with fluctuating symptoms.

At 2 weeks, the response rate was significantly higher in the group treated with esketamine than in participants in the midazolam control group (10 participants [66.7%] versus 1 participant [6.7%]; OR, 28.00; 95% CI, 2.82 to 277.96). There was no significant difference in response rate between the intervention and control groups at 24 hours (10 participants [66.7%] versus 5 participants [33.3%]; P = .07).

Moving on to secondary outcomes, participants in the esketamine-treated group had higher remission rates than the midazolam control group at 4 hours (10 participants [66.7%] versus 3 participants [20.0%]; P = .01) and 4 weeks (8 participants [53.3%] versus 1 participant [6.7%]; P = .005). Interestingly, the mean reduction in MADRS score from baseline to 2 weeks among participants treated with esketamine was significantly greater than among those treated with midazolam (mean [SD] reduction, 15.7 [1.5] versus 3.1 [1.3]; P < .001).

The findings of this study indicate that a single subanesthetic dose of esketamine has a positive effect on oral antidepressants in patients with FAD, and the effect could last for an extended period, the investigators discussed. Esketamine therapy would allow patients to continue using their current antidepressant regimen and avoid AEs associated with changes in medication.

Limitations of the study include potential bias stemming from the definition of FAD, the lack of generalizability of the results due to its small sample size and single center setting, and the COVID-19 pandemic potentially impacting data collection, the investigators wrote.


Xiao C, Zhou J, Li A, et al. Esketamine vs midazolam in boosting the efficacy of oral antidepressants for major depressive disorder: a pilot randomized clinical trial. JAMA Netw Open. 2023;6(8):e2328817. doi:10.1001/jamanetworkopen.2023.28817

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