Major depressive disorder (MDD) is highly prevalent among adolescents and strongly associated with suicidal behavior. Adolescents with depression have approximately a fivefold increased risk of suicide attempts, and up to 80% of adolescents who attempt suicide meet diagnostic criteria for depression at the time of the attempt. However, current treatments—including antidepressants, hospitalization, and psychotherapy—often require weeks to achieve therapeutic benefit, leaving a critical need for interventions that rapidly reduce depressive symptoms and suicide risk. Esketamine nasal spray, an NMDA receptor antagonist, has demonstrated rapid antidepressant effects in adults with MDD and suicidal ideation. This study evaluated the efficacy, safety, and tolerability of esketamine nasal spray in adolescents with MDD who were at imminent risk for suicide.

This phase 2b, randomized, double-blind, double-dummy, psychoactive-controlled multicenter trial enrolled adolescents aged 12 to <18 years with DSM-5–diagnosed MDD and imminent suicide risk who required acute psychiatric hospitalization. Participants had moderate-to-severe depressive symptoms (Children’s Depression Rating Scale–Revised [CDRS-R] score =58) and active suicidal ideation with intent. A total of 147 participants were randomized (1:1:1:2) to receive intranasal esketamine (28 mg, 56 mg, or 84 mg) or oral midazolam (psychoactive placebo) twice weekly for four weeks. All participants also received comprehensive standard-of-care treatment, including hospitalization, initiation or optimization of oral antidepressants (fluoxetine, escitalopram, or sertraline), and evidence-based psychotherapy. The primary efficacy endpoint was change in CDRS-R total score from baseline to 24 hours after the first dose. Secondary outcomes included changes in suicidality, response and remission rates, and safety outcomes. Participants were followed for six months after the treatment phase.

Participants were moderately to severely depressed at baseline, and approximately 95% were rated as moderately to extremely suicidal, where about half had attempted suicide within the previous month. Pooled esketamine doses of 56 mg and 84 mg demonstrated statistically significant superiority over midazolam in reducing depressive symptoms at 24 hours after the first dose (least-squares mean difference -5.8 on the CDRS-R; p = .037). A significant dose-response relationship was also observed. Individual dose comparisons with midazolam did not reach statistical significance, likely due to smaller sample sizes, but treatment effects were directionally consistent.

All treatment groups—including the midazolam group—showed improvement in suicidality scores during the study, with no statistically significant between-group differences at 24 hours. This improvement likely reflected the comprehensive standard-of-care interventions provided to all participants. Esketamine was generally well-tolerated. The most common adverse events included dizziness, nausea, dissociation, headache, dysgeusia, somnolence, vomiting, and hypoesthesia. Dissociative symptoms were transient and typically resolved within 1.5 hours. No new safety concerns were identified compared with adult studies.

In adolescents with MDD at imminent risk for suicide, intranasal esketamine combined with comprehensive standard-of-care treatment produced rapid and clinically meaningful reductions in depressive symptoms within 24 hours. Although improvements in suicidality were observed across all treatment groups, the rapid antidepressant effects of esketamine suggest potential utility as an acute intervention in this high-risk population. The safety profile was consistent with previous studies. Larger trials are warranted to further evaluate the efficacy and long-term safety of esketamine for adolescents with severe depression and suicidal risk.

Reference: Kosik-Gonzalez C, et al. J Am Acad Child Adolesc Psychiatry 2026;65(1):42-55. Abstract