Role of Genetic and Epigenetic Biomarkers in Treatment-Resistant Depression: A Literature Review.

Abstract

<h4>Background</h4>Treatment-resistant depression (TRD) affects up to 30-40% of patients with major depressive disorder and remains a major therapeutic challenge. Genetic and epigenetic factors are increasingly recognized as key contributors to both vulnerability and treatment response.<h4>Methods</h4>We conducted a narrative review of studies published between 2021 and 2025, focusing exclusively on DNA- and RNA-based biomarkers of TRD. Twelve studies met the inclusion criteria, covering candidate gene analyses, genome-wide association studies (GWAS), neuroimaging-genetic approaches, and microRNA profiling.<h4>Results</h4>Genetic investigations consistently implicate neuroplasticity-related genes (<i>BDNF</i>, <i>NTRK2</i>, <i>PTEN</i>, <i>SYN1</i>, <i>MAPK1</i>, and <i>GSK3B</i>) in the risk of TRD and its relapse. Variants in glutamatergic receptor genes (<i>GRIN2A</i>, <i>GRIN2B</i>, <i>GRIA2</i>, <i>GRIA3</i>) were predicted to result in a rapid and sustained response to ketamine. Genomic approaches further demonstrated that composite genetic panels outperform single-variant predictors. In parallel, microRNAs such as miR-1202, miR-16, miR-135, miR-124, miR-223, and miR-146a emerged as dynamic biomarkers of treatment response, particularly in cohorts treated with ketamine or electroconvulsive therapy.<h4>Conclusions</h4>DNA- and RNA-based biomarkers provide promising avenues for improving the understanding and management of TRD. Their integration into clinical frameworks could support patient stratification, individualized treatment selection, and real-time monitoring of therapeutic efficacy. Future research should prioritize replication, methodological harmonization, and longitudinal validation to facilitate the translation of findings into precision psychiatry.

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