Phase 4 Data Supports Esketamine 56 mg, 84 mg Monotherapy for TRD

JAMA Psychiatry recently published phase 4 data that supports esketamine monotherapy for treatment-resistant depression (TRD).¹

Back on January 21, 2025, Johnson & Johnson announced that the US Food and Drug Administration (FDA) approved esketamine (SPREVATO) CIII nasal spray as the first monotherapy for adults with TRD.2 The approval followed the FDA’s Priority Review on esketamine for TRD and was based on a phase 4 randomized, double-blind, multicenter, placebo-controlled study that found esketamine alone provided a rapid, superior improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 4 weeks compared with placebo.

Among approximately 21 million US adults who live with major depressive disorder, a third do not respond to oral antidepressants alone.² Patients who do not respond to ≥ 2 oral antidepressants can now try esketamine, a non-selective, non-competitive antagonist of the N-methyl-D-aspartate receptor that targets glutamate.

The phase 4 study, led by Adam Janik, MD, from the department of neuroscience at Johnson & Johnson in San Diego, assessed the efficacy and safety of esketamine monotherapy compared to placebo in reducing depressive symptoms in patients with TRD.¹

“In this first placebo-controlled, monotherapy randomized clinical trial, esketamine demonstrated rapid and robust efficacy at both 56- and 84-mg doses, with a clinically meaningful and statistically significant treatment effect, initially observed 24 hours after the first dose, representing substantial benefit compared to [oral antidepressants], which typically exhibit a delayed onset of effect,” Janik and colleagues wrote.¹

The team conducted this phase 4 study from November 2020 to January 2024 at 51 outpatient centers in the US. Participants (mean age, 45.4 years; 61% females) had major depressive disorder without psychotic features that met DSM-5 criteria. All patients experienced inadequate response (≤ 25% improvement) to ≥ 2 oral antidepressants during the current depressive episode and had a baseline mean MADRS total score of 37.3 (range, 28 – 50).

The primary endpoint was the change in the MADRS total score from baseline to day 28. The secondary endpoint was the change in MADRS total score from baseline to 24 hours post-first dose. Data was analyzed from March 1, 2024, to July 8, 2024.

In total, 378 patients participated in a 2-week antidepressant-free period before getting randomized 1:1:2 to fixed-dose intranasal esketamine (56 mg [n = 86] or 84 mg [n = 95]) or matching intranasal placebo (n = 197). Esketamine or placebo was administered twice weekly for 4 weeks.

At day 28, the least-square (LS) mean difference between esketamine and placebo was -5.1 (95% confidence interval [CI], -7.91 to -2.33) for 56 mg and -6.8 (95% CI, -9.48 to -4.07) for 84 mg (P < .001). Observed effect sizes were 0.48 for 56 mg and 0.63 for 84 mg.¹

Approximately 24 hours post-first dose, investigators observed a significant difference between esketamine and placebo: -3.8 (95% CI, -6.29 to -1.22; P = .004) for 56 mg and -3.4 (95% CI, -5.89 to -1.00; P = .006) for 84 mg.¹

Common treatment-emergent adverse events (TEAEs) for esketamine 56 mg and 84 mg included nausea (24.8%), dissociation (24.3%), dizziness (21.7%), and headache (19%). Most adverse events were mild or moderate and resolved 2 hours post-dose. No patient on esketamine experienced a treatment-related serious adverse event.¹

“Results from this study strengthen the body of evidence for esketamine’s antidepressant efficacy and inform on the monotherapy treatment option for patients with TRD, particularly when [oral antidepressants] have inadequate efficacy but high adverse effect burden,” investigators concluded. “That the 84-mg dose, the most common in real-world practice, conferred a larger effect size without safety concerns supports the potential for starting esketamine monotherapy at this dose.”¹

References

1. Janik A, Qiu X, Lane R, et al. Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. Published online July 02, 2025. doi:10.1001/jamapsychiatry.2025.1317

2. Derman, C. FDA Approves Esketamine as First Monotherapy for Treatment-Resistant Depression. HCPLive. January 21, 2025. https://www.hcplive.com/view/fda-approves-esketamine-first-monotherapy-treatment-resistant-depression. Accessed July 28, 2025.