Esketamine Monotherapy Demonstrates Efficacy in Treatment-Resistant Depression

In a groundbreaking Phase 4 clinical trial, esketamine monotherapy has been shown to significantly reduce symptoms of treatment-resistant depression (TRD) at 28 days compared to a placebo. Conducted across 51 outpatient centers in the United States from 2020 to 2024, this study provides crucial insights into the efficacy of esketamine as a viable treatment option for individuals who have not responded adequately to conventional oral antidepressants.

The trial involved 378 adult participants diagnosed with major depressive disorder and who had failed to respond to two or more oral antidepressants during their current depressive episode. Participants, with a mean age of 45.4 years and including 61% women, underwent a two-week antidepressant-free period before being randomized to receive either intranasal esketamine at doses of 56 mg (n = 86) or 84 mg (n = 95), or a matching placebo (n = 197) twice weekly for four weeks.

According to Dr. Adam Janik, MD, of the Department of Neuroscience at Johnson & Johnson and lead investigator of the study, "Our findings extend previous research and support the use of esketamine monotherapy as a significant treatment option for patients with TRD." The primary outcome measured was the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 28, with secondary outcomes including response and remission rates, and adverse events.

Results indicated that both esketamine doses led to a significant reduction in depressive symptoms at day 28, with p-values less than 0.001 for both dosages. The effect sizes were reported as 0.48 for the 56 mg dose and 0.63 for the 84 mg dose. Additionally, symptoms were significantly alleviated within 24 hours post-first dose, showcasing the rapid action of esketamine. Rates of response and remission were notably higher in both esketamine groups across all time points assessed, compared to the placebo group.

The study also monitored treatment-emergent adverse events, which included nausea (25%), dissociation (24%), dizziness (22%), and headache (19%). Despite these side effects, the trial's investigators emphasized the importance of esketamine as a potential treatment for the vulnerable TRD population.

The significance of this research is underscored by its implications for the treatment landscape of depression. According to Dr. Sarah Johnson, a Professor of Psychiatry at Yale University, "Esketamine provides an alternative for patients who find little relief from traditional antidepressants, addressing a critical gap in mental health treatment options."

However, the study's limitations must be acknowledged. The generalizability of the results was constrained by the exclusion of patients with significant psychiatric or medical comorbidities, as well as limited racial and ethnic diversity among participants. This raises questions about the applicability of findings to broader populations.

The study was funded by Janssen Research & Development, a subsidiary of Johnson & Johnson. Several investigators reported conflicts of interest, including financial ties to various organizations and pharmaceutical companies. Dr. Janik's findings were published online in JAMA Psychiatry on July 2, 2025.

In conclusion, the Phase 4 trial on esketamine monotherapy offers promising evidence for the treatment of TRD, potentially paving the way for new standards in managing this challenging condition. As more research is conducted, there may be further developments in the understanding of esketamine's role in psychiatric care, particularly for individuals facing the dire consequences of untreated depression.