287 - Ketamine and Esketamine Versus Midazolam in Adolescents with Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials

Publication Number: 3276.287

Isabela Hartmann Rost, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil; Claudio Cesar Silva Pereira, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil; Lara Cappelletti Beneti Branco, São Camilo University Center, São Paulo, Sao Paulo, Brazil; Isabela Borja de Oliveira, University of São Paulo, São Paulo, Sao Paulo, Brazil; Mariana Veiga e Silva, Faculdade de Medicina de Petropolis, Petrópolis, Rio de Janeiro, Brazil; Anna Victoria de Vasconcelos, Afya College of Medical Sciences of Santa Inês, Santa Inês, Maranhao, Brazil; Alessandra Lemos de. Carvalho, Boston Children's Hospital, Brookline, MA, United States

Background: Major depressive disorder (MDD) in adolescents is a significant public health concern, often associated with suicidal ideation and poor response to first-line treatments. Ketamine and its S-enantiomer esketamine have shown promising rapid-acting antidepressant effects in adults, but their efficacy and safety in adolescents remain uncertain.

Objective: We aimed to assess the short-term efficacy and safety of esketamine/ketamine versus midazolam in reducing depressive symptoms in adolescents with MDD. Our study seeks to clarify the therapeutic value of these agents in youth and to provide insights to optimize treatment strategies and guide future trials.

Design/Methods: Following PRISMA guidelines, we searched PubMed, Embase, Cochrane Library, Scopus, PsycINFO, and Web of Science up to July 2025 for randomized controlled trials (RCTs) comparing ketamine or esketamine to midazolam in adolescents with MDD. Mean differences (MDs) and risk ratios (RRs) were pooled using a random-effects model. Heterogeneity was calculated using the I² statistic. R software 4.5.0 was used for statistical analysis.

Results: Of 2,345 records, three RCTs (n=218) met inclusion criteria; two on esketamine and one on ketamine. Females predominated in all trials (>75%), and the mean age was 15 years. Ketamine/esketamine significantly reduced depressive symptoms compared to midazolam within 24 hours (MD=-5.57; p=0.03; I²=78%), as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Esketamine alone did not show a significant effect. Adverse events included dissociation (RR=3.41; p< 0.001; I²=13.7%) and altered time perception (RR=7.45; p=0.003; I²=0%), which were transient and did not lead to discontinuation. No serious adverse events occurred. Significant heterogeneity was observed in depression scores. Sensitivity analysis excluding the intranasal (IN) study removed heterogeneity and increased the effect size for intravenous (IV) administration.

Conclusion(s): Ketamine/esketamine demonstrated greater short-term efficacy than midazolam in reducing depressive symptoms among adolescents with MDD, though esketamine alone did not. Both drugs exhibited a favorable safety profile. The analysis excluding the IN study enhanced the effect size, suggesting IV delivery may be more effective. This is the first meta-analysis to evaluate ketamine/esketamine in adolescents with MDD and, despite the limited number and size of available trials, our findings support the time-sensitive antidepressant potential of these agents and underscore the urgent need for larger, long-term studies to define their role in this vulnerable population.

Reduction in Depressive Symptoms with Ketamine/Esketamine
Forest plot showing the pooled mean difference (MD) in MADRS score reduction after 24 hours. Ketamine/esketamine demonstrated significantly greater improvement than midazolam. SD: standard deviation. IV: inverse variance. CI: confidence interval.

Increased Risk of Dissociation with Ketamine/Esketamine
Forest plots summarizing the incidence of dissociation events within 24 hours. A significant increase was observed both when analyzing only the 28 mg dose (A) and when pooling all investigated doses (B). CI: confidence interval. MH: Mantel-Haenszel. RR: risk ratio.

PRISMA Flow Diagram of Study Screening and Selection
Of 2,345 records screened, 944 were evaluated by title and abstract, 64 underwent full-text review, and 3 randomized controlled trials met the inclusion criteria after exclusion of duplicates, non-randomized designs, overlapping populations, and studies without relevant outcomes.