Journal Club July 2025

* Major Depressive Disorder (MDD) is a leading cause of disability and shortens life expectancy .

* Approximately 35% of MDD patients do not respond to two or more oral antidepressant (OAD) treatments, which defines TRD .

* TRD patients face increased morbidity and mortality, including a 7-fold higher likelihood of suicide attempts and a 3.6-fold higher suicide-specific mortality rate compared to the general MDD population .

* While esketamine nasal spray is approved for TRD in conjunction with an OAD, its efficacy as monotherapy has not been evaluated, which this study aims to address .

Study Design and Setting: This was a phase 4, double-blind, placebo-controlled randomized clinical trial conducted from November 2020 to January 2024 at 51 outpatient centers in the US .

Participants: Adults aged 18 years or older with recurrent or single-episode MDD (≥2 years) without psychotic features, confirmed by DSM-5 criteria, were eligible . Participants had TRD, defined as ≤25% improvement to two or more different OADs in the current depressive episode, and a minimum Inventory of Depressive Symptomatology–Clinician Rated (IDS-C₃₀) score of ≥34 .

Sample Size: The efficacy analysis dataset included 378 participants, while the safety analysis dataset included 476 participants .

Intervention: After a ≥2-week antidepressant-free period, participants were randomized (1:1:2 ratio) to receive fixed-dose intranasal esketamine (56 mg or 84 mg) or matching intranasal placebo . The study drug was administered twice weekly for 4 weeks .

Main Outcomes: The primary efficacy endpoint was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 28. A key secondary efficacy endpoint was the change in MADRS score at 24 hours post-first dose (day 2) .

Efficacy at Day 28 (Primary Endpoint):

* Both esketamine doses showed statistically significant and clinically meaningful improvement in depressive symptoms compared to placebo .

* LS mean difference (SE) vs placebo: -5.1 (1.42) for 56 mg (95% CI, -7.91 to -2.33; P < .001) and -6.8 (1.38) for 84 mg (95% CI, -9.48 to -4.07; P < .001) .

* Observed effect sizes were 0.48 for 56 mg and 0.63 for 84 mg .

Efficacy at Day 2 (Key Secondary Endpoint):

* Significant between-group differences were observed for both esketamine doses: -3.8 (1.29) for 56 mg (95% CI, -6.29 to -1.22; P = .004) and -3.4 (1.24) for 84 mg (95% CI, -5.89 to -1.00; P = .006) .

* The most common treatment-emergent adverse events for combined esketamine doses were nausea (24.8%), dissociation (24.3%), dizziness (21.7%), and headache (19.0%) .

* Most adverse events were mild or moderate, transient, and occurred on dosing days, resolving within 2 hours post-dose .

* No treatment-related serious adverse events were reported for esketamine-treated participants .

* Incidences of treatment-emergent suicidal ideation were similar across esketamine and placebo groups .

* Esketamine monotherapy offers a new treatment option for TRD patients, especially those with tolerability concerns or nonresponse to OADs .

* The rapid onset of action (within 24 hours) is a significant advantage over traditional OADs .

* The safety profile of esketamine monotherapy is consistent with previous adjunctive treatment trials .

* Esketamine monotherapy demonstrates robust efficacy and a favorable safety profile in adults with TRD .

* The 84-mg dose, commonly used in real-world practice, showed a larger effect size without increased safety concerns, suggesting its potential as a starting dose for monotherapy .

* This treatment option addresses an unmet need for TRD patients who may not tolerate or respond to oral antidepressants .

This study provides strong evidence supporting esketamine nasal spray as a standalone treatment for treatment-resistant depression, offering a valuable alternative for patients with limited options due to efficacy or tolerability issues with conventional oral antidepressants. Its rapid action and consistent safety profile make it a promising therapeutic advancement in the management of this vulnerable patient population.