Pharmacogenetic variability and response to intranasal esketamine in treatment-resistant depression: insights from a real-world study

Background: Intranasal esketamine is a novel, rapid-acting antidepressant approved for use in combination with orally administered antidepressants in patients with treatment-resistant depression (TRD). Despite its promising clinical efficacy, determinants of interindividual variability in treatment response remain poorly understood. Pharmacogenetic variability, particularly in genes involved in drug metabolism and neurobiological pathways, may contribute to these differences. The aim of this study was to evaluate the impact of pharmacogenetic variants involved in esketamine biotransformation, as well as other selected polymorphisms.

Methods: A total of 32 TRD patients initiating esketamine at the Vademecum Fa.Re (Unit for treatment resistant psychiatric disorders) were included. Patients followed a standardized protocol consisting of a one-month induction phase (two administrations weekly) followed by a maintenance phase (weekly administrations). Symptom severity was assessed at each administration using validated psychometric scales including Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), and Brief Psychiatric Rating Scale (BPRS). Treatment response and remission were evaluated after two months of therapy. Pharmacogenetic profiling included determination of metabolizer status for key enzymes involved in esketamine metabolism (CYP2B6, CYP3A4, CYP2C9), as well as genotyping of selected polymorphisms in BDNF (rs6265) and OPRM1 (rs1799971). Associations between genetic variants and treatment outcomes were subsequently analyzed.

Results: At baseline, the mean MADRS score was 25.3, indicating moderate depression severity, while the mean HAM-A score was 15.6, corresponding to mild anxiety. The cohort consisted predominantly of women (59.4%), with a mean age of 57.6 years. Following two months of treatment, a significant improvement in both depressive and anxiety symptoms was observed across the cohort; however, remission was achieved in 43.8% of patients. No statistically significant associations were identified between metabolizer status of CYP2B6, CYP3A4, or CYP2C9 and treatment outcomes. Genotype distributions for BDNF and OPRM1 were consistent with Hardy–Weinberg equilibrium and similarly, no significant associations were found. Although no overall association between BDNF genotype and MADRS score was detected, pairwise comparison suggested a difference between Val/Val and Met/Met carriers, with Met/Met carriers exhibiting lower baseline MADRS scores. A non-significant trend towards greater symptom improvement was observed in patients with predicted slower metabolic capacity, potentially reflecting higher drug exposure. In addition, patients receiving fluvoxamine, a moderate inhibitor of CYP2C9 and CYP3A4, demonstrated a similar trend, suggesting a possible effect of phenoconversion.

Conclusions: Although no statistically significant pharmacogenetic predictors of treatment response were identified, the observed trends suggest a potential influence of metabolic capacity and drug–drug interactions on esketamine efficacy. These findings highlight the complexity of treatment response in TRD and underscore the potential relevance of pharmacokinetic variability, including phenoconversion, in clinical practice. Given the limited sample size, the results should be interpreted with caution; however, they support further investigation in larger, well-powered studies aimed at elucidating the role of pharmacogenetics in optimizing esketamine therapy and advancing personalized treatment strategies in psychiatry.

This project was supported by the EU NextGenerationEU through the Recovery and Resilience Plan for Slovakia under the project No. 09I03-03-V04-00207.

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