Blood transcriptomic analysis reveals a distinct molecular subtype of treatment resistant depression compared to non-treatment resistant depression.

Treatment-resistant depression (TRD) is a severe condition characterized by chronic and recurrent depressive symptoms, leading to significant morbidity and a considerable socio-economic impact. Genetic and biological studies suggest that TRD is associated with distinct biological characteristics. In this study, we analysed whole-transcriptome differences in 293 patients with major depressive disorder (MDD) to compare TRD (N = 150) vs non-TRD (N = 143) cases. We identified 5,746 differentially expressed genes (DEGs), with an adjusted p-value < 0.05. Functional analysis and Weighted Gene Co-expression Network Analysis (WGCNA) revealed that upregulated transcripts in TRD were enriched for non-coding RNAs (ncRNA) and associated with ncRNA processing and ribosomal biogenesis. In contrast, downregulated transcripts in TRD were predominantly protein-coding genes associated with immune system processes, epigenetic regulation, and RNA and DNA processing. Consistently, cell type deconvolution analysis revealed distinct immune cell proportions in TRD patients, with lower levels of neutrophils, mast cells and natural killer (NK) cells, but a higher proportion of CD4 T cells. In a subgroup analysis comparing non-TRD remitters and TRD non-remitters, representing the extreme phenotypes of treatment response, 1,213 DEGs were identified with 96 % overlapping those found in the broader TRD versus non-TRD analysis. This substantial overlap underscores shared molecular features underlying TRD. Overall, the findings suggest that TRD represents a distinct molecular subtype characterized by unique immune and epigenetic signatures. These results indicate that patients with TRD may be identifiable at a molecular level, potentially paving the way for more personalised treatment approaches.