Systematic review and meta-analysis of intranasal esketamine for treatment-resistant depression: Evidence from real-world studies.
Clara De Oliveira Lapa, Thiago Viola, Rodrigo Delfino, Luiza Dutra, Gabriela Rubira, Rafaela Jung Kurtz Rodrigues, Sayra Catalina Coral, Josep Antoni Ramos‐quiroga, Lucas Spanemberg
Journal of Affective Disorders January 28, 2026 DOI: 10.1016/j.jad.2026.121257 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and meta-analysis Randomized Peer reviewed |
|---|---|
| Sample size | 9 |
| Population | Adults with treatment-resistant depression |
| Intervention | Intranasal esketamine |
| Topics | Depression Esketamine |
| Keywords | Intranasal Meta-analysis Real-world evidence Systematic review |
| Citations | 3 |
| Key findings | Intranasal esketamine was associated with substantial symptom reduction and increasing remission rates over time in real-world treatment of treatment-resistant depression. |
Abstract
Intranasal esketamine has demonstrated efficacy and safety for treatment-resistant depression in randomized controlled trials, however the generalizability of these findings to clinical practice remains unclear. This systematic review and meta-analysis aimed to synthesize real-world evidence of intranasal esketamine in patients with treatment-resistant depression. A systematic search was conducted in PubMed, Embase, and PsycINFO up to April 2025 to identify observational studies reporting clinical outcomes of intranasal esketamine in adults with treatment-resistant depression. Standardized mean changes in depressive symptoms and odds ratios for remission were calculated. Random-effects meta-analyses were performed, followed by meta-regression to explore potential moderators. The study protocol was prospectively registered in PROSPERO (CRD420251025075). Nine studies were included in the final synthesis. The analyses demonstrated that intranasal esketamine showed substantial effectiveness, with an effect size of Hedges' g = -1.98 (95% CI -2.94 to -1.03; p < 0.0001). Patients were about five times more likely to achieve remission at three months compared with the induction phase (OR = 5.1, 95% CI 2.29-11.39). Treatment effectiveness was not influenced by factors such as gender or the presence of comorbidities, such as anxiety, personality, or substance use disorders. The pooled prevalence of any adverse event, based on studies that reported safety data, was 82% (95% CI 69-92). The most frequent was dissociation, reported in 49% of patients (95% CI 37-62). This study provides consistent real-world evidence supporting that Intranasal esketamine was associated with meaningful symptom reduction and rising remission rates over time in real-world settings. Given the observational nature of the evidence and the absence of control groups, effect sizes should be interpreted with caution. Nonetheless, these findings provide valuable insight into esketamine's effectiveness and tolerability in routine practice and highlight the need for controlled comparative studies to guide long-term treatment strategies.
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
Cited by 4
- THE IMPACT OF INTRANASAL ESKETAMINE ON TREATMENT-RESISTANT DEPRESSION: A SYSTEMATIC REVIEW International Journal of Innovative Technologies in Social Science June 25, 2026
- Psilocybin and ayahuasca in treatment-resistant depression: clinical evidence, methodological constraints and ethical challenges: a narrative review Frontiers in Psychiatry September 15, 2026
- Esketamine-based treatment, depression-specific metacognitive training, and their combination in treatment-resistant depression: 6-month trajectories of depressive symptoms and rumination in a multicenter observational study. European Archives of Psychiatry and Clinical Neuroscience August 29, 2026
- [(Es)ketamine: practice update]. Der Nervenarzt August 17, 2026
Cites 17
- 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 of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression The Journal of Clinical Psychiatry April 20, 2020
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
- Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. American Journal of Psychiatry March 1, 2025
and 12 more in the library