Intranasal Esketamine in Treatment-resistant Depression: Why Do Real-world Clinical Practice Outcomes Surpass Those of Clinical Trials? a Narrative Review
Year: 2026
Type: review
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.
Source: Boletim de Conjuntura (BOCA)
Authors: 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
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7225178527