Esketamine Monotherapy Effective for Treatment-Resistant Depression
Esketamine monotherapy significantly reduced depressive symptoms in adult patients with treatment-resistant depression (TRD) compared to placebo, according to randomized clinical trial results published in JAMA Psychiatry.
“In the context of well-characterized treatment-limiting tolerability concerns and limited efficacy of first-line oral antidepressants (OADs) for some patients, as well as well-known noncompliance in patients with major depressive disorder (MDD), this study supports esketamine monotherapy as an important option in the management of patients for whom OADs or other pharmacological treatments are no longer appropriate or acceptable,” wrote Adam Janik, MD, Department of Neuroscience, Johnson & Johnson, San Diego, California, and study coauthors.
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The phase 4 trial included 378 adults with MDD without psychotic features who experienced inadequate response to 2 or more oral antidepressants during the current depressive episode. Participants were randomized to receive either 56 mg of esketamine (n=86), 84 mg of esketamine (n=95), or an intranasal placebo (n=197), which were administered twice weekly for 4 weeks. Changes in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) scores were compared to scores 24 hours post–first dose and at day 28.
Researchers found that patients receiving either dose of esketamine demonstrated statistically significant improvement in depressive symptoms compared to placebo. After 24 hours post–first dose, the least-square mean difference between the 56 mg group and placebo was −3.8 (1.29) (95% CI, −6.29 to −1.22; 2-sided P = .004). Between the placebo and 84 mg group, the least-square mean difference was −3.4 (1.24) (95% CI, −5.89 to −1.00; 2-sided P = .006). These significant reductions were maintained through day 28: at this timepoint, the mean difference compared to placebo was −5.1 (1.42) (95% CI, −7.91 to −2.33) (2-sided P < .001) for the 56-mg dose and −6.8 (1.38) (95% CI, −9.48 to −4.07) (2-sided P < .001) for the 84-mg dose. Effect sizes were 0.48 and 0.63 for the 56-mg and 84-mg dose groups, respectively, at day 28.
Common treatment-emergent adverse events in the esketamine group included nausea, dissociation, dizziness, and headache.
While the study was limited by its exclusion of patients with significant psychiatric comorbidities and a lack of racial and ethnic diversity among its participants, the results suggest a broadening in treatment options for TRD patients. “Esketamine monotherapy can potentially address a significant unmet need for the especially vulnerable untreated TRD subpopulation at risk of serious outcomes,” the authors concluded.
Reference
Janik A, Qiu X, Lane R, et al. Esketamine monotherapy in adults with treatment-resistant depression. JAMA Psychiatry. Published July 2, 2025. Accessed August 7, 2025. doi:10.1001/jamapsychiatry.2025.1317