Add-on esketamine beneficial to patients with fluctuating antidepressant response

A single dose of esketamine appears to enhance the efficacy of oral antidepressants for treating patients with major depressive disorder (MDD) who are experiencing fluctuating symptoms, as reported in a small study.

“We used the term fluctuating antidepressant response in MDD to refer to the occurrence of fluctuating symptoms, including re-emergence of initial symptoms or episodes or the onset of a new episode during adequate ADT in patients with MDD,” the investigators said.

For the study, the investigators enrolled 30 MDD patients (median age 28.0 years, 56.7 percent women) with fluctuating antidepressant response. These patients were randomly assigned to receive a single infusion of esketamine (0.2 mg/kg; n=15) or midazolam (0.045 mg/kg; n=15) for 40 minutes.

When compared with patients who received midazolam, those who received esketamine had higher response rates at 2 weeks (66.7 percent vs 6.7 percent; p<0.001), the primary study outcome. Adjusted logistic regression analysis showed that the odds of achieving a response, defined as a 50-percent symptom reduction according to MADRS*, were 14 times greater with esketamine than with midazolam (odds ratio [OR], 14.17, 95 percent confidence interval [CI], 1.14–175.96; p=0.04). [JAMA Netw Open   2023;6:e2328817]

Esketamine also showed superiority over midazolam in terms of the secondary outcomes. Specifically, esketamine-treated patients were more likely to achieve remission at the 4-hour (66.7 percent vs 20.0 percent; p=0.01) and the 4-week (53.3 percent vs 6.7 percent; p=0.005) follow-up, as well as experienced a significantly greater reduction in MADRS score from baseline to 2 weeks (mean, –15.7 vs –3.1; p<0.001).

The differences in the reduction in MADRS score between the two treatment groups remained significant at the 6-week follow-up (mean, −5.55, 95 percent CI, −10.08 to −1.03; p=0.02).

According to the investigators, esketamine also had a good safety profile. There were no reports of serious adverse events in the trial, and none of the patients experienced psychotogenic effects or had clinically significant manic symptoms.

Boosting antidepressant efficacy

“In this study, the mean reduction in MADRS score from baseline to 4 weeks was significantly higher in participants treated with esketamine, which contradicts the findings of previous studies showing a loss of efficacy within 4 weeks,” the investigators pointed out. “Furthermore, this effect could last for an extended period, as the mean reduction in MADRS score from 4 to 6 weeks in the esketamine-treated group remained significantly higher than in the control group.”

These data, according to the investigators, indicate that a single subanaesthetic dose of esketamine could boost the efficacy of antidepressants in patients with fluctuating antidepressant response. This effect might be explained by some unidentified interaction that alters antidepressant sensitization and improve tolerance to antidepressants. Already, a previous study has laid out evidence of ketamine acting on the same receptors as antidepressants. [Pharmacol Rev 2018;70:621-660]

“The causes of fluctuating antidepressant response remain unclear, and there is a lack of effective treatments,” the investigators said. [J Affect Disord 2019;245:488-497]

“Available options are limited to increasing the current antidepressant dose, drug holidays, decreasing current antidepressant dose, changing antidepressant drugs, augmenting treatment strategies, and combination treatment strategies. These strategies might be successful after several attempts, but they increase the risk of unanticipated adverse effects in the meantime,” they added. [Innov Clin Neurosci 2014;11:24-28; CNS Drugs 2014;28:601-609]

Also, fluctuating antidepressant response may contribute to treatment-resistant depression development. [J Clin Psychiatry 2007;68:1271-1276; J Affect Disord 2009;115:234-240]

Therefore, the findings of the present study may hold important clinical implications. The investigators believe that patients could continue using their current antidepressant regimen with esketamine therapy and avoid the adverse effects associated with changes in the medication regimen, such as unanticipated adverse effects and a reduced willingness to seek treatment due to repeated attempts.

*Montgomery-Åsberg Depression Rating Scale (range 0-60, with higher scores indicating more severe depressive symptoms)