JAMA Psychiatry

More evidence for esketamine monotherapy in treatment-resistant depression

July 7, 2025

Study details: This phase 4, double-blind, placebo-controlled randomized trial (NCT04599855) enrolled 378 adults with major depressive disorder and inadequate response to ≥2 oral antidepressants. After a ≥2-week antidepressant-free period, participants were randomized to fixed-dose intranasal esketamine (56 mg or 84 mg) or placebo, administered twice weekly for 4 weeks. Primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 28; a key secondary endpoint was change at 24 hours post–first dose.

Results: Both esketamine doses produced statistically significant and clinically meaningful reductions in MADRS scores vs. placebo at day 28 (LS mean difference: −5.1 for 56 mg, −6.8 for 84 mg; both P < 0.001), with effect sizes of 0.48 and 0.63, respectively. Significant improvement was observed as early as 24 hours post–first dose. Common adverse events included nausea (24.8%), dissociation (24.3%), dizziness (21.7%), and headache (19.0%).

Clinical impact: The findings support use of esketamine nasal spray as a monotherapy option for adults with TRD, particularly for those unable to tolerate or not responding to oral antidepressants. The rapid onset and sustained efficacy through 4 weeks may expand therapeutic options in this population.

Source:

Janik A, et al. (2025, July 2). JAMA Psychiatry. Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial. https://pubmed.ncbi.nlm.nih.gov/40601310/