Peripheral Biomarkers of Response to Ketamine and Esketamine Treatment in Unipolar Depressive Disorder—A Scoping Review

Objectives: A significant problem in the treatment of depressive disorders is the growing number of cases of so-called treatment-resistant depression (TRD). There is evidence of ketamine’s effectiveness in treating TRD, with response rates ranging from 40% to 90%. This review aimed to map available studies on peripheral biomarkers of response to ketamine and esketamine in the treatment of depressive disorders, with particular emphasis on biomarker types, study designs, and identification of gaps in current knowledge.

Methods: A literature review was conducted in accordance with the PRISMA-ScR guidelines for scoping reviews. PubMed and Embase databases were searched from their inception to 1 February 2026. The search terms “ketamine” or “esketamine” were cross-referenced with the terms “depression,” “biomarkers,” and “predictors.” Articles written in languages other than English, unavailable full-text articles, and animal studies were excluded. A manual search of the bibliographies of existing reviews was also conducted to identify additional studies.

Results: Ultimately, 46 articles met the inclusion criteria for the review: 17 randomized controlled trials, 25 non-randomized interventional studies, 2 observational studies, 1 case study, and 1 case series. Most studies focus on BDNF, inflammatory markers, particularly IL-6, TNF-α, IL-10, and IL-8, and kynurenine pathway metabolites. However, the results of these studies are inconsistent. Other areas remain only fragmentarily explored.

Conclusions: Significant heterogeneity was observed in study designs, analytical methods, and definitions of clinical response. No peripheral biomarker has yet demonstrated sufficient consistency for clinical implementation. Future studies should prioritize standardized, adequately powered prospective designs and multimarker approaches integrating neuroplastic, inflammatory, and metabolic pathways, with particular attention to esketamine-treated populations.