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Role of the Pharmacogenomics in the Treatment-Resistant Depression: A Literature Review

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28 September 2025

Posted:

30 September 2025

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Abstract
Background: 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. Methods: We conducted a narrative review of studies published between 2021 and 2025, focusing exclusively on DNA- and RNA-based biomarkers of TRD. Thirteen studies met the inclusion criteria, covering candidate gene analyses, genome-wide association studies (GWAS), neuroimaging–genetic approaches, and microRNA profiling. Results: Genetic investigations consistently implicate neuroplasticity-related genes (BDNF, NTRK2, PTEN, SYN1, MAPK1, and GSK3B) in the risk of TRD and its relapse. Variants in glutamatergic receptor genes (GRIN2A, GRIN2B, GRIA2, GRIA3) 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. Conclusions: 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.
Keywords: 
treatment-resistant depression
;  
major depressive disorder
;  
pharmacogenetics
;  
GWAS
;  
BDNF
;  
NTRK2
;  
GRIN2A
;  
GRIN2B
;  
microRNA
;  
epigenetics
;  
ketamine
;  
electroconvulsive therapy
Subject: 
Medicine and Pharmacology  -   Psychiatry and Mental Health

1. Introduction

Major depressive disorder (MDD) remains one of the leading causes of disability worldwide [1], affecting more than 300 million people, with lifetime prevalence estimates ranging between 12% and 20% depending on region [2,3]. MDD has been ranked as the third greatest cause of disease burden worldwide and is projected to rank first within the next decade [1,4]. It frequently follows a chronic and relapsing course, with recurrence observed in approximately 50% of patients after a first episode, 70% after a second, and up to 90% after a third [1,5]. Although standard antidepressants achieve remission in a subset of patients, up to 30–40% fail to respond to at least two adequate treatment trials, meeting criteria for treatment-resistant depression (TRD) (Rush [6,7,8,9,10,11,12,13]. This subpopulation carries a disproportionate burden, including chronic course, economic costs, high relapse rates, and elevated suicide risk [14,15,16,17,18,19,20,21,22].
For decades, depression research was dominated by the monoaminergic hypothesis, which attributed pathophysiology to reduced serotonergic, noradrenergic, and dopaminergic signaling [23,24,25]. While this framework contributed to the development of SSRIs and SNRIs, its explanatory power is limited, as only one-third of patients achieve remission after first-line therapy, and effect sizes remain modest in TRD [26,27,28]. These shortcomings have prompted a paradigm shift toward alternative mechanisms, including neuroplasticity impairment [29,30,31,32,33].
Genomic research provides mounting evidence for neuroplasticity-related pathways as determinants of treatment outcome. Candidate gene analyses associate polymorphisms in BDNF, NTRK2, PTEN, SYN1, MAPK1, and GSK3B with TRD and relapse [34]. Neuroimaging–genetic studies link NTRK2 variants with reduced hippocampal volume, a structural correlate of poor antidepressant response [35]. Broader glutamatergic contributions have also been documented, with GRIN2B polymorphisms linked to TRD risk, suicidality, and anterior cingulate glutamate levels [36]. Genome-wide approaches identify variants in BDNF, NTRK2, and GRIN2A that predict rapid and sustained ketamine effects, alongside associations with serum ketamine/norketamine levels [37]. Large-scale, multi-center analyses from the Predictors Consortium further validated these associations, demonstrating consistent signals in BDNF–TrkB and glutamatergic pathways across heterogeneous cohorts [38].
Epigenetic regulation provides another layer of insight. Multiple microRNAs, including miR-30a, miR-133b, miR-16, miR-1202, and the let-7 family, are dysregulated in TRD and normalize with treatment [33,39]. Electroconvulsive therapy (ECT)-focused studies report downregulation of inflammatory miRNAs such as miR-223 and miR-146a in responders, with non-responders showing no changes [40,41]. Importantly, both ketamine and ECT converge on overlapping networks, including the miR-29 family and the miR-132/212 cluster, which regulate apoptotic signaling, neuroprotection, and hippocampal neurogenesis [42].
To date, systematic reviews and meta-analyses have investigated select genetic and RNA biomarkers of treatment-resistant depression, often focusing on glutamatergic genes, neurotrophic pathways, and microRNAs. However, no prior review has comprehensively synthesized both DNA and RNA biomarkers across pharmacological (ketamine, esketamine) and somatic (ECT, TMS) interventions. This narrative review addresses this gap by integrating findings from 12 recent studies published between 2021 and 2025, highlighting candidate genes, GWAS findings, and microRNA regulation as promising predictors of treatment outcomes in TRD.

2. Materials and Methods

This narrative review was conducted by systematically searching the electronic databases PubMed (https://pubmed.ncbi.nlm.nih.gov) and Scopus (https://www.scopus.com). The search covered the period from 1 January 2021 to 1 June 2025, corresponding to the publication years of the included studies. The search strategy combined terms related to depression, treatment resistance, pharmacogenetics, and molecular biomarkers: “treatment-resistant depression,” “major depressive disorder,” “pharmacogenomics,” “genetics,” “RNA,” “microRNA,” “epigenetics,” “ketamine,” “esketamine,” “ECT,” and “TMS.”
Inclusion criteria were:
  • Peer-reviewed original research articles or reviews published in English.
  • Human studies or translational studies with direct relevance to major depressive disorder or treatment-resistant depression.
  • Investigations of DNA variants (candidate gene studies, GWAS, multi-omic models with genetic focus) or RNA-based biomarkers (gene expression, microRNAs).
Exclusion criteria included conference abstracts, case reports, animal-only studies without a translational link, and studies that focused solely on proteomic or metabolomic biomarkers.
A total of 12 studies fulfilled these criteria. The characteristics of the studies (authors, year, methodology, and biomarker domain) are summarized in Table 1. These included candidate gene analyses, neuroimaging–genetic association studies, GWAS of ketamine response, systematic reviews of glutamatergic and neurotrophic genes, and multiple investigations of microRNA expression in TRD and ECT cohorts.
Limitations of this approach include its non-systematic design, restriction to English-language studies, and the heterogeneity of methods and outcome measures, which reduce comparability across studies.
Table 1. Summary of included studies.
Table 1. Summary of included studies.
Reference Full Title Methodology / Biomarker Domain
[33] Cai et al. (2024) miRNAs in treatment-resistant depression: a systematic review Systematic review; Epigenetics (microRNAs)
[39] Cătană et al. (2025) MicroRNAs: a novel approach for monitoring treatment response in major depressive disorder? Review; Epigenetics (microRNAs)
[37] Chen et al. (2021) Treatment response to low-dose ketamine infusion for treatment-resistant depression: a gene-based genome-wide association study Candidate gene–based GWAS in TRD; Genetics
[44] Franklin et al. (2025) Genetics of Response to ECT, TMS, Ketamine and Esketamine Systematic review of candidate genes, GWAS, and PRS; Genetics
[41] Galbiati et al. (2025) Plasma microRNA levels after electroconvulsive therapy in treatment-resistant depressed patients Clinical plasma miRNA profiling; Epigenetics
[43] Kang et al. (2025) Genetic predictors of ketamine/esketamine response in treatment-resistant depression Pharmacogenomic association study; Genetics
[40] Kaurani et al. (2023) MicroRNA modulation after electroconvulsive therapy: markers of response in treatment-resistant depression Clinical study of plasma miRNAs pre/post ECT; Epigenetics
[35] Paolini et al. (2023) Association between NTRK2 polymorphisms, hippocampal volumes and treatment resistance in major depressive disorder Neuroimaging–genetic study (3T MRI + genotyping); Genetics
[34] Santos et al. (2023) BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 genetic polymorphisms in antidepressant treatment response phenotypes Candidate gene analysis in MDD/TRD; Genetics
[36] Saez et al. (2022) Genetic variables of the glutamatergic system associated with treatment-resistant depression: a review of the literature Narrative/systematic review; Genetics (NMDA/AMPA pathways)
[42] Statharakos et al. (2023) Towards precision ECT: a systematic review of epigenetic biomarkers in treatment-resistant depression Systematic review; Epigenetics
[38] Zelada et al. (2025) Genetics of response to electroconvulsive therapy, TMS, ketamine and esketamine: insights from the Gen-ECT-ic consortium Multi-center, multi-omic integration; machine learning; Genetics (PRS/consortium)

3. Results

3.1. Genetic Predictors of TRD

Santos et al. [34] investigated polymorphisms in neuroplasticity-related genes in 80 patients with MDD treated under the Texas Medication Algorithm over 27 months. Three independent signals were identified for TRD: PTEN rs12569998 (TG genotype/G allele ≈ fourfold higher risk), SYN1 rs1142636 (GG genotype ≈ sixfold, G allele ≈ threefold higher risk), and BDNF rs6265 (CT genotype ≈ 3.2-fold higher risk). For relapse, two loci emerged: MAPK1 rs6928, where C-allele carriers showed reduced relapse risk and longer time-to-relapse compared with GG homozygotes, and GSK3B rs6438552, where G-allele carriers had a substantially higher relapse risk. Gene-set analyses converged on synaptic and glutamatergic signaling, implicating glutamate receptor activity and ionotropic receptor complexes as central pathways.
Saez et al. [36] synthesized evidence implicating the glutamatergic system—particularly NMDA and AMPA receptor genes—in the pathogenesis of TRD and the response to ketamine and esketamine. GRIN2B polymorphisms (rs1805502, rs1806201, rs890) were linked to TRD risk, suicidality, and reduced anterior cingulate glutamate. GRIN2A rs16966731 was associated with rapid and sustained ketamine response, while GRIA2 and GRIA3 variants correlated with earlier MDD onset and suicidal ideation. Preclinical studies demonstrated that the deletion of NR2B in GABAergic interneurons abolished ketamine’s antidepressant-like effects, and AMPAR activation was essential for sustained efficacy, underscoring the NMDA/AMPA genes as critical contributors across various depression phenotypes.
Paolini et al. [35] examined 121 MDD inpatients with structural MRI and targeted genotyping, identifying an NTRK2 variant (rs1948308) with over-dominant effects. Heterozygotes exhibited smaller bilateral hippocampal volumes and higher odds of TRD compared with homozygotes. Mediation analysis showed that hippocampal volume partially explained the effect of rs1948308, while the direct effect remained significant. No associations were found for BDNF variants, including Val66Met.
Chen et al. [37] performed a candidate gene–based GWAS in 65 TRD patients treated with low-dose ketamine. Predictors of rapid (≤240 min) and sustained (up to 14 days) response included BDNF rs2049048, multiple NTRK2 variants (rs10217777, rs10868590, rs77918527), and NMDAR subunits such as GRIN2A, GRIN2B, GRIN2C, and GRIN3A. Pharmacogenomic analyses linked GRIN2A/2B polymorphisms to circulating ketamine/norketamine levels and NTRK2 variants to ketamine plasma concentrations at 80–120 minutes. Pathway enrichment confirmed glutamatergic signaling and activity-dependent plasticity as central mechanisms.
Kang et al. [43] analyzed genetic predictors of ketamine response in patients with TRD, reporting novel associations in genes regulating synaptic vesicle trafficking (SYNGR1, VAMP2) and immune regulation (IL6R, TNFAIP3). Enrichment analyses highlighted pathways related to synapse organization, neurotransmitter release, and cytokine signaling. Gene–gene interaction models suggest that inflammatory gene variants modulate ketamine efficacy through their effects on glutamatergic neurotransmission, indicating that combined synaptic–immune signatures may better stratify responders.
Zelada et al. [38] conducted a large-scale, multi-center study (Predictors Consortium) that integrated genomic, transcriptomic, proteomic, and clinical data using machine learning. Composite biomarker panels incorporating BDNF, NTRK2, GRIN2A/2B, IL6, and TNFAIP3 achieved AUCs above 0.80, significantly outperforming single-variant or purely clinical models. Interaction analyses revealed that combining glutamatergic and immune-related loci enhanced the prediction of ketamine response, supporting the feasibility of multi-omic precision psychiatry frameworks in TRD.
Franklin et al. [44] systematically reviewed genetic studies examining predictors of treatment response across ECT, TMS, ketamine, and esketamine. Candidate gene investigations most frequently evaluated variants in BDNF and COMT, with mixed and largely non-replicated associations reported for somatic treatments. For ketamine and esketamine, earlier reports had linked the BDNF Val66Met polymorphism to synaptic plasticity and treatment response; however, subsequent studies did not confirm these consistent effects. Genome-wide association studies remain underpowered, though several novel signals have been reported, including variants in genes related to immune regulation and synaptic function. Extensive registry-based studies of ECT demonstrated that polygenic risk scores for depression predicted poorer outcomes, while higher polygenic risk for bipolar disorder predicted better response. Overall, the review concluded that no single genetic variant has yet emerged as a reliable predictor of treatment outcomes.
Results are summarized in Table 2.

3.2. Epigenetic Regulation in TRD

Cătană et al. [39] reviewed the role of microRNAs (miRNAs) as biomarkers for treatment-resistant depression, highlighting their ability to regulate genes associated with immune responses, synaptic plasticity, and stress signaling. Candidate markers included miR-30a, miR-133b, miR-16, let-7 family, and drug-specific changes such as miR-1202 (citalopram) and miR-146a-5p (duloxetine). Several miRNAs normalized following successful treatment, suggesting their use as dynamic blood-based markers for monitoring antidepressant response.
Kaurani et al. [40] investigated miRNA expression in patients undergoing ECT and identified differential regulation of miR-146a, miR-223, and miR-126. These were linked to immune system modulation and neuronal plasticity pathways, supporting their role as biomarkers of ECT response.
Galbiati et al. [41] measured plasma miRNA levels before and after ECT in TRD patients, finding that miR-223-3p and miR-146a-5p decreased significantly in responders, while non-responders showed no significant changes. This suggests that these inflammatory miRNAs track therapeutic efficacy and could guide stratification for somatic treatments.
Cai et al. [33] conducted a systematic review of the involvement of miRNA in MDD and TRD. They highlighted consistent evidence for miR-1202, miR-16, miR-135, miR-124, and miR-146a as central regulators of synaptic plasticity, serotonergic signaling, and neuroinflammatory responses. The review proposed that these conserved miRNAs could form the foundation of standardized biomarker panels.
Statharakos et al. [42] examined epigenetic changes associated with somatic therapies, particularly ECT and ketamine, focusing on circulating miRNAs as biomarkers. They identified overlapping regulation of miR-29 family, miR-132, and miR-212, all of which are linked to synaptic plasticity, stress response, and neuronal survival. Notably, both ECT and ketamine were found to modulate miR-29a and miR-29c, which influence apoptotic and neuroprotective pathways, suggesting a shared mechanism of resilience induction. Furthermore, alterations in the miR-132/212 cluster were associated with improved cognitive performance and hippocampal neurogenesis following treatment. While the study emphasized the promise of miRNAs as cross-modality biomarkers, the authors highlighted several limitations, including small sample sizes, heterogeneous patient cohorts, and a lack of longitudinal validation. Nonetheless, their findings support the hypothesis that ECT and ketamine converge on common miRNA-mediated regulatory networks involved in antidepressant efficacy.
Results are summarized in Table 3.

4. Discussion

4.1. Genetic Predictors and Convergent Signaling

The strongest and most consistent genetic findings converge on BDNF–TrkB signaling and glutamatergic receptor biology. Candidate gene studies have identified polymorphisms in BDNF, NTRK2, PTEN, and SYN1 as risk factors for TRD, while MAPK1 and GSK3B variants predicted relapse [34]. These findings underscore the contribution of intracellular cascades—particularly Akt, ERK, and mTOR—that mediate synaptic plasticity, long-term potentiation, and dendritic remodeling. Neuroimaging–genetic work extends this evidence, with NTRK2 rs1948308 carriers exhibiting smaller hippocampal volumes and increased resistance; mediation analyses confirm hippocampal atrophy as a biological pathway linking genotype to clinical outcome [35].
Genome-wide association studies have further strengthened these associations. BDNF rs2049048 and NTRK2 rs10217777 predicted rapid and sustained ketamine effects, while GRIN2A and GRIN2B variants were associated with both clinical outcomes and ketamine/norketamine pharmacokinetics [37]. GRIN2B polymorphisms have also been tied to suicidality, stress-related vulnerability, and anterior cingulate glutamate concentrations, while AMPAR variants (GRIA2/3) contribute to disease onset and suicidality [36]. Integrative reviews suggest that these glutamatergic loci are relevant across modalities, including ECT and TMS, implying common neurobiological substrates across somatic and pharmacological treatments [44].
Beyond these core pathways, novel associations have been reported in calcium channel genes (CACNA1C), circadian regulators (CLOCK, ARNTL), and immune modulators (IL6R, TNFAIP3) [43]. Zelada et al. demonstrated that composite biomarker panels integrating glutamatergic, neurotrophic, and immune loci outperform single-variant models [38]. Together, these findings emphasize that TRD has a polygenic architecture, where converging synaptic, circadian, and immune pathways shape treatment trajectories.

4.2. RNA-Based Biomarkers and Epigenetic Modulation

Epigenetic regulation through microRNAs (miRNAs) provides additional insight into treatment outcomes. Multiple miRNAs, including miR-30a, miR-133b, miR-16, miR-1202, and the let-7 family, are consistently dysregulated in TRD and show normalization with successful treatment [33,39].
ECT-focused studies have identified inflammatory miRNAs (miR-223, miR-146a) as markers of response, with responders showing downregulation and non-responders showing no significant changes [40,41]. These results indicate that blood-based miRNAs may serve as dynamic biomarkers of treatment engagement.
Systematic reviews confirm reproducibility for miR-1202, miR-16, miR-135, and miR-124, implicating them in serotonergic signaling, synaptic plasticity, and immune regulation [33]. Importantly, both ketamine and ECT converge on overlapping miRNA networks, specifically the miR-29 family (apoptosis and neuroprotection) and the miR-132/212 cluster (hippocampal neurogenesis and cognition) [42]. This suggests a shared mechanism across treatments where miRNAs act as both biomarkers and mechanistic mediators of antidepressant efficacy.

4.3. Translational and Clinical Implications

The convergence of DNA and RNA biomarkers in TRD has several important implications:
1. Patient stratification – Combining pre-treatment genetic markers (e.g., BDNF rs6265, GRIN2B polymorphisms) with circulating miRNAs could help identify patients most likely to benefit from ketamine or ECT.
2. Response monitoring – Longitudinal profiling of miRNAs offers real-time indicators of treatment efficacy, particularly for ECT and ketamine.
3. Drug development – Pathways such as TrkB signaling, NMDA/AMPA receptor balance, and miRNA-regulated immune–neuroplastic crosstalk represent promising therapeutic targets.
4. Cross-treatment biomarkers – The overlap of DNA and miRNA predictors across ketamine, ECT, and TMS suggests that unified biomarker panels may guide multimodal treatment strategies.

4.4. Limitations and Future Directions

Despite encouraging findings, current research faces several challenges. Many studies are constrained by small sample sizes, heterogeneous cohorts, and variable treatment protocols, which limit reproducibility [34,35,36]. Moreover, methodological heterogeneity in genetic sequencing and miRNA quantification complicates comparability [33,39]. Most studies remain cross-sectional, leaving the exploration of longitudinal biomarker trajectories unexplored.
Future research should prioritize multi-center replication, standardization of biomarker pipelines, and integration of DNA and RNA markers with neuroimaging and clinical predictors. Longitudinal designs will be crucial for capturing biomarkers relevant to both the acute response and sustained remission.

5. Conclusion

Treatment-resistant depression is increasingly understood as a disorder shaped by convergent genetic and epigenetic mechanisms that regulate synaptic plasticity, neurotransmission, and immune–neurobiological cross-talk. Recent evidence highlights consistent associations between variants in BDNF, NTRK2, GRIN2A/2B, SYN1, PTEN, and MAPK1 with antidepressant outcomes, implicating neuroplasticity and glutamatergic signaling as central pathways. Complementing this, microRNAs such as miR-1202, miR-16, miR-135, miR-124, miR-223, and miR-146a have emerged as dynamic circulating biomarkers that both reflect and potentially modulate treatment response, particularly in the context of ketamine and electroconvulsive therapy. Together, these findings underscore that a single locus or molecular signal cannot explain TRD; instead, outcomes are determined by the interaction of multiple DNA- and RNA-based regulatory systems. From a translational standpoint, integrating candidate gene variants, GWAS findings, and miRNA profiles offers a promising route toward precision psychiatry, facilitating pre-treatment stratification, real-time monitoring, and mechanism-based drug development. Future studies should prioritize multi-center replication, harmonized methodologies, and longitudinal designs to validate these biomarkers across diverse populations. Incorporating DNA and RNA signatures into clinical care could shift TRD management away from empirical prescribing and toward biologically informed, patient-tailored interventions.

Author Contributions

All authors have read and agreed to the published version of the manuscript.

Funding

This study is supported by the Croatian part of the ERA PerMed project “Artificial intelligence for personalised medicine in depression - analysis and harmonization of clinical research data for robust multimodal patient profiling for the prediction of therapy outcome – ArtiPro (accepted 2021).

Informed Consent Statement

Not applicable

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
Abbreviation Definition
ACC Anterior Cingulate Cortex
AKT Protein kinase B, intracellular signaling pathway
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
BDNF Brain-Derived Neurotrophic Factor
COMT Catechol-O-methyltransferase
ECT Electroconvulsive Therapy
FT3 Free Triiodothyronine
GSK3B Glycogen Synthase Kinase 3 Beta
GWAS Genome-Wide Association Study
IL6 Interleukin 6
IL6R Interleukin 6 Receptor
MAPK1 Mitogen-Activated Protein Kinase 1
MDD Major Depressive Disorder
miRNA microRNA
MTOR Mechanistic Target of Rapamycin
NMDA N-methyl-D-aspartate receptor
NTRK2 Neurotrophic Receptor Tyrosine Kinase 2 (TrkB)
PRS Polygenic Risk Score
PTEN Phosphatase and Tensin Homolog
SYN1 Synapsin I
TMS Transcranial Magnetic Stimulation
TNFAIP3 Tumor Necrosis Factor Alpha Induced Protein 3
TRD Treatment-Resistant Depression
TrkB Tropomyosin receptor kinase B
VAMP2 Vesicle-Associated Membrane Protein 2

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Table 2. Genetic Predictors of TRD.
Table 2. Genetic Predictors of TRD.
Author (Year) Sample / Methodology Key Findings
[34] Santos et al. (2023) 80 MDD patients, Texas Medication Algorithm; candidate gene analysis TRD risk: PTEN rs12569998, SYN1 rs1142636, BDNF rs6265. Relapse: MAPK1 rs6928 (protective), GSK3B rs6438552 (higher relapse risk). Pathways: synaptic transmission, glutamatergic signaling.
[36] Saez et al. (2022) Systematic review of glutamatergic genetics GRIN2B polymorphisms (rs1805502, rs1806201, rs890) linked to TRD, suicidality, low ACC glutamate. GRIN2A rs16966731 linked to ketamine response. GRIA2/GRIA3 variants linked to MDD onset and suicidal ideation.
[35] Paolini et al. (2023) 121 MDD inpatients; 3T MRI + genotyping NTRK2 rs1948308 heterozygotes → smaller hippocampal volumes, higher TRD risk. Effect partly mediated by hippocampal volume. No BDNF associations (including Val66Met).
[37] Chen et al. (2021) 65 TRD patients, low-dose ketamine; candidate gene-based GWAS Predictors: BDNF rs2049048, NTRK2 variants (rs10217777, rs10868590, rs77918527). GRIN2A, GRIN2B, GRIN2C, GRIN3A linked to rapid/sustained response. GRIN2A/2B variants associated with ketamine/norketamine levels.
[43] Kang et al. (2025) TRD patients treated with ketamine/esketamine; pharmacogenomic analysis Novel associations: SYNGR1, VAMP2 (synaptic vesicle trafficking); IL6R, TNFAIP3 (immune regulation). Pathways: synapse organization, cytokine signaling. Gene–gene interactions: inflammatory variants modulate ketamine efficacy.
[38] Zelada et al. (2025) Multi-center; genomic, transcriptomic, proteomic, clinical data; machine learning Composite panels (BDNF, NTRK2, GRIN2A/2B, IL6, TNFAIP3) → AUC >0.80. Combined glutamatergic + immune loci improved prediction of ketamine response.
[44] Franklin et al. (2025) Systematic review of 34 candidate gene and 9 GWAS studies across ECT, TMS, ketamine, and esketamine No single variant consistently predicted outcomes. BDNF and COMT findings were mixed; GWAS remain underpowered but point to glutamatergic and immune processes. Registry-based studies showed depression PRS predicted poorer ECT response, while bipolar PRS predicted better response. Polygenic and integrative approaches show greatest promise.
Table 3. Epigenetic regulation in TRD.
Table 3. Epigenetic regulation in TRD.
Author (Year) Sample / Methodology Key Findings
[39] Cătană et al. (2025) Review of blood-based miRNA biomarkers Highlighted miR-30a, miR-133b, miR-16, let-7 family; drug-specific modulation (miR-1202 with citalopram, miR-146a-5p with duloxetine); normalization after effective treatment.
[40] Kaurani et al. (2023) ECT patients, miRNA profiling Differential regulation of miR-146a, miR-223, miR-126; linked to immune modulation and neuronal plasticity; proposed as ECT-response biomarkers.
[41] Galbiati et al. (2025) Plasma miRNA in TRD patients before/after ECT Responders showed ↓miR-223-3p, ↓miR-146a-5p; non-responders showed no change; supports use as response-tracking markers.
[33] Cai et al. (2024) Systematic review of MDD/TRD miRNAs Consistent evidence for miR-1202, miR-16, miR-135, miR-124, miR-146a; central roles in plasticity, serotonergic signaling, and neuroinflammation.
[42] Statharakos et al. (2023) Review of ECT and ketamine miRNA studies Overlap in regulation of miR-29 family, miR-132, miR-212; both ECT and ketamine modulated miR-29a/c; linked to neuroprotection and plasticity; preliminary evidence for cross-modality biomarkers.
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