INTRANASAL ESKETAMINE IN TREATMENT-RESISTANT DEPRESSION: WHY DO REAL-WORLD CLINICAL PRACTICE OUTCOMES SURPASS THOSE OF CLINICAL TRIALS? A NARRATIVE REVIEW
Ana Carmelita Gomes Farias, Maria Laura Vieira Martins Guimarães, Ana Carolina Ferrazi Sampaio, Sandra Lorena Aparecida Alonso Murari Marques, Natan Brito Rigato, Hugo Henrique da Silva Nespolo, Thaís Dos Santos da Silva, João Paulo Cera Albarossi, Pedro Rafael Fracacio, Lisete Horn, Larissa Barbosa Lopes, Rodolfo de Oliveira Medeiros
Boletim de Conjuntura November 3, 2026 DOI: 10.56238/bocav25n84-001 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Randomized Peer reviewed |
|---|---|
| Intervention | Intranasal esketamine |
| Topics | Depression Esketamine Ketamine |
| Key findings | Argues that the larger symptom reductions and increasing remission rates seen with intranasal esketamine in routine practice, compared with modest trial effects, reflect differences in study design and questions rather than greater efficacy. The authors attribute inflated real-world effect sizes to absent control groups, therapeutic expectation, patient selection, dose flexibility, and loss to follow-up, and call for controlled comparative studies and monitoring of functional outcomes. |
Abstract
Intranasal esketamine was approved for the treatment of treatment-resistant depression on the basis of randomized clinical trials whose effects, when pooled in meta-analyses, were of modest magnitude. In contrast, observational studies conducted in routine clinical practice have reported substantial symptom reductions and increasing remission rates over follow-up. This review aimed to critically analyze the discrepancy between the efficacy observed in clinical trials and the effectiveness described in real-world studies, discussing the methodological, clinical and pharmacological factors that may explain it. This is a narrative literature review, with searches in the PubMed/MEDLINE, Scopus, Web of Science and Cochrane Library databases, covering publications from 2019 to 2026 and selecting twelve core references, including pivotal trials, meta-analyses, prospective cohorts and retrospective studies. The evidence shows that clinical trials yielded modest differences relative to the comparator, largely because the control group also received a new oral antidepressant and because placebo response in ketamine and esketamine studies is high. In real-world studies, the absence of a control group, therapeutic expectation, patient selection, dose flexibility and loss to follow-up tend to inflate effect sizes, although these settings also reveal progressive functional gains and benefits in populations excluded from trials. It is concluded that the apparent superiority of clinical practice outcomes should not be interpreted as evidence of greater efficacy, but rather as a reflection of different designs and questions. The critical integration of both sources, combined with controlled comparative studies and the monitoring of functional outcomes, is necessary to guide the rational use of esketamine in treatment-resistant depression.
Comparable studies
Other narrative reviews on esketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Long-term safety of ketamine and esketamine in treatment of depression | 2022 | Review | |
| Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms. | 2024 | Review | |
| Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. Patients with depression | 2024 | Narrative review | |
| The Possible Application of Ketamine in the Treatment of Depression in Alzheimer’s Disease | 2022 | Review |
Citations in the library
Cites 10
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- 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 versus Quetiapine for Treatment-Resistant Depression New England Journal of Medicine October 4, 2023
- Esketamine Treatment for Depression in Adults: A PRISMA Systematic Review and Meta-Analysis. American Journal of Psychiatry March 1, 2025
and 5 more in the library