Pilot study on esketamine response in treatment-resistant depression: impact of pharmacogenetic, clinical, and demographic variables.
Michaela Krivosova, Matteo Marcatili, Gessica Guerrera, Ranieri Domenico Cornaggia, Federico Luigi Motta, Tommaso Paolini, Beatrice Gamba, Emanuela Giampieri, Francesca Bertola, Beatrice Benatti, Massimo Clerici
Frontiers in pharmacology January 1, 2026 Peer reviewed DOI: 10.3389/fphar.2026.1783538 via PubMed
Summary
In a study of 32 patients with treatment-resistant depression (TRD), no single demographic, clinical, or genetic factor reliably predicted response to esketamine treatment. However, adjunctive psychotherapy was significantly associated with remission rates. The findings suggest that variability in treatment response is influenced more by pharmacologic exposure, biological factors, and psychotherapeutic engagement than by patient selection or dosing alone. The study highlights the need for a multidimensional approach to optimize treatment.
Study at a glance
| Design | observational cohort |
|---|---|
| Sample size | 32 |
| Population | patients with treatment-resistant depression |
| Key finding | Adjunctive psychotherapy was the only factor significantly associated with remission in patients receiving esketamine. |
Abstract
Esketamine, the S-enantiomer of ketamine, is a rapid-acting antidepressant approved for treatment-resistant depression (TRD) when used in combination with an oral antidepressant. Identifying reliable clinical or genetic predictors of treatment response remains a critical unmet need. This study aimed to evaluate the impact of selected clinical and genetic variables on esketamine response in a real-world TRD cohort. Thirty-two TRD patients received intranasal esketamine over 2 months (12 administrations) and underwent pharmacogenetic testing. Depressive symptoms were assessed at baseline and at each session. Response and remission rates were analyzed in relation to clinical, demographic, and genetic variables, including BDNF (rs6265), OPRM1 (rs1799971) polymorphisms, and CYP2B6, CYP2C9, and CYP3A4 metabolizer status. No single demographic, clinical, or genetic variable reliably predicted treatment response. Adjunctive psychotherapy emerged as the only factor significantly associated with remission. Because most patients reached the standard 84 mg dose under the protocol, nominal dosing explained little of the observed variability in outcomes. Exploratory analyses suggested that metabolic phenotype and concomitant pharmacotherapy may contribute to inter-individual differences in treatment response. In real-world TRD care, variability in esketamine response appears to be driven less by patient selection or nominal dose and more by a combination of pharmacologic exposure, biological factors, and psychotherapeutic engagement. These findings support a multidimensional, clinically oriented approach to treatment optimization rather than reliance on a single predictor. Given the limited sample size, the study may have been underpowered to detect modest associations, and the results should be therefore considered exploratory. Future research should prioritize the co-optimization of dosing strategies and psychotherapeutic engagement in routine care, and confirm these findings in larger, prospective studies.