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 2026 DOI: 10.3389/fphar.2026.1783538 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Pilot study Peer reviewed |
|---|---|
| Sample size | 32 |
| Population | Patients with treatment-resistant depression |
| Intervention | Esketamine |
| Dose | 84 mg |
| Duration | 2 months (12 administrations) |
| Topics | Depression Esketamine Ketamine |
| Keywords | Bdnf Cyp2b6 Oprm1 Trd Pharmacogenetics Psychotherapy |
| Key findings | Adjunctive psychotherapy was the only factor significantly associated with remission; no single demographic, clinical, or genetic variable reliably predicted esketamine treatment response. |
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.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.
Citations in the library
Cited by 2
- Esketamine and Acceptance and Commitment Therapy (ACT) for Treatment-Resistant Depression: An Intervention-Development Framework and Treatment Manual Psychedelics October 1, 2026
- Non-randomized rapamycin augmentation of chronic self-administered ketamine provides subjective improvement in diverse phenotypes Frontiers in Psychiatry August 26, 2026
Cites 12
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- Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression Psychotherapy and Psychosomatics 2017
- Effects of Mu-Opiate Receptor Gene Polymorphism rs1799971 (A118G) on the Antidepressant and Dissociation Responses in Esketamine Nasal Spray Clinical Trials The International Journal of Neuropsychopharmacology May 5, 2020
- Personalized use of ketamine and esketamine for treatment-resistant depression. Translational Psychiatry November 29, 2024
and 7 more in the library