Ketamine/esketamine treatment for resistant depression in children and adolescents: a PRISMA systematic review.
Konstantinos N Fountoulakis, Paraskevi Tatsiopoulou, Athanasios Saitis, Nikolaos K Fountoulakis, Alan F. Schatzberg
European Child & Adolescent Psychiatry February 2026 DOI: 10.1007/s00787-025-02897-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Double-blind Peer reviewed |
|---|---|
| Population | Children and adolescents with treatment-resistant depression |
| Interventions | Ketamine Esketamine |
| Topics | Esketamine Ketamine Depression |
| Keywords | Adolescents Children Resistant depression |
| Key findings | The review identified only two double-blind randomized trials of ketamine or esketamine in pediatric treatment-resistant depression, both reporting positive results: a single ketamine dose's effect lasted at least two weeks without reducing suicidality, and esketamine improved mood and suicidality after three infusions, with mood benefit persisting but suicidality benefit not. The authors conclude that the scarcity of data means there is no definitively convincing evidence for efficacy in this population. |
Abstract
Ketamine and esketamine have been approved as an adjunctive therapy for treatment-resistant major depressive disorder with acute suicidal ideation and behavior in adults. The current paper aimed to systematically review the available data on their efficacy in children and adolescents. The MEDLINE was searched with the keyword 'esketamine' on July 5th, 2024 (by following the PRISMA statement). The review has been registered in PROSPERO for ketamine and esketamine separately (CRD42024552011 and CRD42024516053). Out of 5131 articles originally identified, 29 were included for analysis and discussion. There is only one double-blind RCT with ketamine and another one with esketamine. The ketamine trial tested the effects at 24 h of a single dose with a crossover design and reported that the therapeutic effect lasted for at least two weeks. No effect on suicidality was reported. The esketamine trial reported that mood and suicidality improved after the three infusions were completed. The improvement in depressive symptoms persisted until the end of the study, but the improvement in suicidality did not. ketamine attenuated the negativity bias and reduced depressive cognitive style. Esketamine did not harm cognition, but instead, it improved processing speed. The current systematic review found only positive reports in the literature, but the scarcity of data suggests there is no definitively convincing evidence concerning the usefulness of ketamine and esketamine in the treatment of paediatric resistant depression. More research is needed, both in light of the problematic data in adults as well as in the light of the problems this kind of substance could cause in brain development and maturation.
Comparable studies
Other systematic reviews and meta-analyses on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Adults with unipolar or bipolar major depression | 2020 | Systematic review and meta-analysis | n = 1,877 |
| The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis. Participants in randomized controlled trials of ketamine for suicidal ideation | 2020 | Systematic review and meta-analysis | n = 197 |
| Efficacy of Esketamine Augmentation in Major Depressive Disorder Patients with major depressive disorder who are treatment-resistant or acutely suicidal | 2020 | Systematic review and meta-analysis | n = 774 |
| Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. Patients with treatment-resistant major depressive disorder | 2025 | Systematic review and meta-analysis | |
| EFFICACY AND SAFETY OF RACEMIC KETAMINE AND ESKETAMINE FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS Adults with unipolar or bipolar major depression | 2022 | Systematic review and meta-analysis | n = 2,903 |
Citations in the library
Cites 37
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study American Journal of Psychiatry April 16, 2018
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
and 32 more in the library