Effect of Esketamine on Depressive Symptoms in Adolescents With Major Depressive Disorder at Imminent Suicide Risk: A Randomized Psychoactive-Controlled Study - 26/12/25
, Dong-Jing Fu, MD, PhD a, Li Nancy Chen, PhD a, Rosanne Lane, MAS a, Michael H. Bloch, MD, MS b, Melissa DelBello, MD, MS c, Carmen Moreno, MD, PhD d, Wayne C. Drevets, MD e, Carla M. Canuso, MD aAbstract |
Objective |
To evaluate the efficacy, safety, and tolerability of esketamine nasal spray vs psychoactive placebo (oral midazolam) in rapidly reducing depressive symptoms in adolescents with major depressive disorder at imminent risk for suicide.
Method |
This double-blind, double-dummy, phase 2b study randomized (1:1:1:2) 147 adolescents (12 to <18 years old) to esketamine (28, 56, or 84 mg) or midazolam twice weekly for 4 weeks. Participants concomitantly received comprehensive standard of care, including initial hospitalization, oral antidepressant, and evidenced-based psychotherapy. The primary efficacy end point—change in Children’s Depression Rating Scale–Revised (CDRS-R) total score from baseline to 24 hours post first dose—was analyzed using analysis of covariance, according to a pooled sequential multiple testing procedure.
Results |
All participants were moderately to severely depressed at enrollment; approximately 95% were moderately to extremely suicidal. Pooled esketamine doses (56 and 84 mg) showed superiority over midazolam in reducing CDRS-R total score at 24 hours post first dose (between-group difference of least squares means [95% CI]: −5.8 [−11.19, −0.35], p = .037). The between-group differences for individual esketamine 84 mg and 56 mg doses vs midazolam were −5.7 ([−12.91, 1.55], p = .123) and −5.9 ([−12.25, 0.53], p = .072), respectively. Severity of suicidality, per Clinical Global Impression of Severity of Suicidality–revised (CGI-SS-R), improved in all 4 groups (between-group difference of least squares means [95% CI]: −0.2 [−0.90, 0.41], −0.3 [−0.93, 0.31], 0.0 [−0.69, 0.72] for esketamine 28, 56, and 84 mg, respectively, at 24 hours post first dose). Common adverse events (incidence ≥20%) reported for esketamine were dizziness, nausea, dissociation, headache, dysgeusia, somnolence, vomiting, hypoesthesia, and intentional self-injury.
Conclusion |
The primary efficacy end point of the study was met for the pooled esketamine doses (56 and 84 mg). Esketamine in conjunction with comprehensive standard of care rapidly improved depressive symptoms among adolescents at imminent risk for suicide.
Plain language summary |
This double-blind randomized controlled clinical trial compared the effects of esketamine nasal spray (28, 56, or 84 mg) to a psychoactive placebo (midazolam) in 147 adolescents with major depressive disorder who were at imminent risk for suicide. All participants also received standard-of-care treatment, including initial hospitalization, oral antidepressant treatment, and evidenced-based psychotherapy. Combined 56- and 84-mg doses of esketamine were superior to midazolam in reducing depressive symptoms at 24 hours following the first dose; all 4 treatment groups showed continued improvement in depressive symptoms and severity of suicidality after 4 weeks of treatment. The most common side effects reported for esketamine-treated participants were dizziness, nausea, dissociation, headache, bitter taste, and sleepiness.
Clinical trial registration information |
Study to Evaluate the Efficacy and Safety of 3 Fixed Doses of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Pediatric Participants Assessed to Be at Imminent Risk for Suicide; NCT03185819
Le texte complet de cet article est disponible en PDF.Key words : esketamine, major depressive disorder, RCT, suicide
Plan
| This article was reviewed under and accepted by Consulting Editor Samuele Cortese, MD, PhD. |
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| This project was funded by Janssen Research & Development, LLC , a Johnson & Johnson company. |
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| The Independent Review Board or Ethics Committee at each research site approved the study protocol and its amendments. |
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| Data Sharing: The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at transparency . As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu . |
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| Rosanne Lane served as the statistical expert for this research. |
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| The authors acknowledge Sandra Norris, PharmD (Norris Communications Group, LLC), supported by Janssen Research & Development LLC, a Johnson & Johnson company, for medical writing assistance and Ellen Baum, PhD (Johnson & Johnson) for additional editorial support. The authors acknowledge Gahan Pandina, PhD and Dawn Ionescu, MD of Janssen Research & Development, LLC, a Johnson & Johnson company, as well as Kathleen Kelly, MD, an employee of Janssen Research & Development, LLC, a Johnson & Johnson company, at the time the study was conducted (currently retired), for their involvement in the study design or conduct of the study. The authors also acknowledge Randall L. Morrison, PhD, an employee of Janssen Research & Development, LLC, a Johnson & Johnson company, at the time the study was conducted (currently retired), for his contributions to the approach taken for cognitive testing and the interpretation of cognitive testing results, and Matthijs van Hoogdalem, PhD, an employee of Janssen Research & Development, LLC, a Johnson & Johnson company, for his contributions to address pharmacology comments from peer reviewers. |
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| Study Investigators: All investigators contributed to the data collection for the study and approve acknowledgement. The following investigators enrolled patients from whom safety and efficacy data were reported: Brazil: Lucas Quarantini, MD, PhD, of Federal University of Bahia, Cintia Azevedo Perico, MD, PhD, of University of São Paulo, Luiz Petry, MD, of Trial Tech Technology in Drug Research; France: Olivier Bonnot, MD, PhD, of University of Paris-Saclay, David Cohen, MD, PhD, of University Hospital Pitié-Salpêtrière, Pierre Fourneret, MD, PhD, of Claude Bernard University of Lyon and University Hospital of Lyon, Renaud Jardri, MD, PhD, of the Lille University Medical Center, Pierre De Maricourt, MD, of Sainte Anne Hospital, Valerie Vantalon, MD, of University Hospital Robert Debré; Hungary: Krisztina Kapornai, MD, PhD, of University of Szegedi, Nikolett Szolnoki, MD, of Vadaskert Psychiatric Hospital; Italy: Lorenzo Bassani, MD, of Psychiatry Hospital of Merano, Carmela Bravaccio, MD, PhD, of University of Naples, Sara Carucci, MD, of the University of Cagliari, Giuseppina Pustorino, MD, PhD, of Foggia University Hospital; Poland: Maciej Pilecki, MD, PhD, of Jagiellonian University Medical College; Spain: Hilario Blasco, MD, PhD, of the Puerta de Hierro-Majadahonda University Hospital, Montserrat Dolz, MD, of Sant Joan de Déu Hospital in Barcelona, Luisa Lázaro, MD, PhD, of Hospital Clinic University of Barcelona, Carmen Moreno, MD, PhD, of the Complutense University School of Medicine, Maria Goretti Moron, MD, PhD, of the Complutense University School of Medicine, Montserrat Pamias, MD, PhD, of Corporació Sanitària Parc Tauli of Sabadell (Barcelona), Elisa Seijo, MD, PhD, of the University Institute of Neurosciences, Asturias; United States, Connecticut: Michael Bloch, MD, MS, of Yale School of Medicine, Mirjana Domakonda, MD, of Hartford Hospital/Institute of Living; Georgia: Suneel Katragadda, MD, of Atlanta Behavioral Research; Illinois: Adrienne Adams, MD, of Rush University Medical Center; Indiana: Ahmed Elmaadawi, MD, of Clinical Research-Beacon Medical Group; Louisiana: Kashinath Yadalam, MD, of Lake Charles Clinical Trials; Maryland: Elia Acevedo-Diaz, MD, of CenExel CBH Health; North Carolina: Shahzad Ali, MD, of University of North Carolina School of Medicine, Matthew Hough, DO, of Wake Forest Baptist Medical Center; Ohio: Melissa DelBello, MD, MS, of the University of Cincinnati College of Medicine, Ghada Lteif, MD, of Ohio State University College of Medicine and Nationwide Children’s Hospital, Sarah Lytle, MD, of University Hospitals Cleveland Medical Center; Tennessee: Margaret Benningfield, MD, MSc, of Vanderbilt University Medical Center. |
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| Disclosure: Colette Kosik-Gonzalez, Dong-Jing Fu, Li Nancy Chen, Rosanne Lane, Wayne C. Drevets, and Carla M. Canuso are employees of Janssen Research & Development, LLC, a Johnson & Johnson company, and all hold company equity/options in Johnson & Johnson. Michael H. Bloch has received research support from Janssen, Emalex, Neurocrine, and SciSparc, as well as the National Institutes of Health . Melissa DelBello has received research support from the National Institutes of Health, the Patient-Centered Outcomes Research Institute (PCORI), AbbVie, Alkermes, Eli Lilly and Company, Intracellular, Janssen, Johnson & Johnson, Lundbeck, Myriad, Novartis, Otsuka, Pfizer, Sage, Shire, Sunovion, Supernus, and Vanda and has provided consultation or advisory board services for Alkermes, Allergan, CMEology, Janssen, Johnson & Johnson, Lundbeck, Medscape, Myriad, Neuronetics, Pfizer, Sunovion, and Sage. Carmen Moreno has received grants by the Spanish Ministry of Science and Innovation , Instituto de Salud Carlos III (ISCIII, PI21/01929), Consorcio Centro de Investigación Biomédica en Red (CIBER) (CB/07/09/0023), cofinanced by the European Union and European Regional Development Fund (ERDF) Funds from the European Commission, “A way of making Europe,” financed by the European Union, Madrid Regional Government, European Union Structural Funds, EU Seventh Framework Program, H2020 Program, and Horizon Europe, National Institute of Mental Health of the National Institutes of Health, Fundación Familia Alonso, and Fundación Alicia Koplowitz. She has received honoraria as a consultant and/or advisor and/or for lectures from Angelini, British Association for Psychopharmacology, Compass, Esteve, Exeltis Janssen, Lundbeck, Neuraxpharm, Nuvelution, Otsuka, Pfizer, Servier and Sunovion. |
Vol 65 - N° 1
P. 42-55 - janvier 2026 Retour au numéro
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