Evaluation of Intranasal Esketamine and Oral Midazolam for Rapid Symptom Reduction in Adolescent Major Depressive Disorder with Acute Suicidal Ideation

The primary objective is to evaluate the efficacy of a single 84 mg dose of esketamine administered intranasally, in combination with comprehensive standard of care, compared to a psychoactive placebo (oral midazolam) for the rapid reduction of symptoms associated with major depressive disorder in adolescents aged 12 to <18 years presenting with acute suicidal ideation or behavior. The study also assesses the safety of the intervention.

This clinical trial involves a total of 162 participants. The study population consists of adolescents between the ages of 12 and <18 years, including both male and female individuals. Participants are diagnosed with major depressive disorder according to DSM-5 criteria, specifically without psychotic features. The cohort is characterized by acute suicidal ideation or behavior, requiring clinical necessity for psychiatric hospitalization. Inclusion requires a CGI-SS-R score of “Markedly suicidal” or greater and a CDRS-R total score of ≥58, indicating moderate to severe depression. All subjects must be medically stable and receive standard of care, which includes voluntary hospitalization and the administration of an SSRI antidepressant such as fluoxetine, escitalopram, or sertraline.

This Phase 3, double-blind, randomized, placebo-controlled study evaluates the efficacy and safety of a single 84 mg dose of intranasal esketamine compared to a psychoactive placebo, specifically oral midazolam, in addition to comprehensive standard of care. The study is designed for adolescents aged 12 to <18 years diagnosed with major depressive disorder presenting with acute suicidal ideation or behavior. Following a screening visit to confirm eligibility via DSM-5 diagnostic criteria and clinical assessments, participants undergo a baseline predose visit. The investigation focuses on the change from baseline in depressive symptoms, measured by the CDRS-R total score, at 24 hours post-administration. Participants are required to undergo voluntary psychiatric hospitalization for a minimum of five days to receive standard care, which includes prescribed SSRI antidepressants such as fluoxetine, escitalopram, or sertraline. The clinical trial is expected to conclude recruitment by September 2031.

The experimental treatment consists of esketamine administered as a nasal spray solution. The formulation is provided in 28 mg concentrations for intranasal use.

The comparator treatment involves midazolam provided as an oral solution with a concentration of 2 mg/ml. This substance serves as a psychoactive placebo.

The study also utilizes an intranasal placebo and an oral placebo to maintain the blinding of the protocol in addition to standard of care for major depressive disorder.

The efficacy of a single dose of 84 mg esketamine, administered intranasally in addition to comprehensive standard of care, is evaluated in adolescents with Major Depressive Disorder presenting with acute suicidal ideation or behavior. The primary endpoint is the change from baseline in depressive symptoms, as assessed by the Children's Depression Rating Scale-Revised (CDRS-R) total score.

Measurements for this primary endpoint are performed at 24 hours following the first dose, using the baseline assessment conducted on Day 1 prior to dosing.