Putative role of glial cells in treatment resistance depression: An updated critical literation review and evaluation of single-nuclei transcriptomics data.

Major depressive disorder (MDD) is a prevalent global mental illness with diverse underlying causes. Despite the availability of first-line antidepressants, approximately 10-30 % of MDD patients do not respond to these medications, falling into the category of treatment-resistant depression (TRD). Our study aimed to elucidate the precise molecular mechanisms through which glial cells contribute to depression-like episodes in TRD. We conducted a comprehensive literature search using the PubMed and Scopus electronic databases with search terms carefully selected to be specific to our topic. We strictly followed inclusion and exclusion criteria during the article selection process, adhering to PRISMA guidelines. Additionally, we carried out an in-depth analysis of postmortem brain tissue obtained from patients with TRD using single-nucleus transcriptomics (sn-RNAseq). Our data confirmed the involvement of multiple glia-specific markers (25 genes) associated with TRD. These differentially expressed genes (DEGs) primarily regulate cytokine signaling, and they are enriched in important pathways such as NFκB and TNF-α. Notably, DEGs showed significant interactions with the transcription factor CREB1. sn-RNAseq analysis confirmed dysregulation of nearly all designated DEGs; however, only Cx30/43, AQP4, S100β, and TNF-αR1 were significantly downregulated in oligodendrocytes (OLGs) of TRD patients. With further exploration, we identified the GLT-1 in OLGs as a hub gene involved in TRD. Our findings suggest that glial dysregulation may hinder the effectiveness of existing therapies for TRD. By targeting specific glial-based genes, we could develop novel interventions with minimal adverse side effects, providing new hope for TRD patients who currently experience limited benefits from invasive treatments.

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Declaration of competing interest The authors declare that they ate no conflicts of interest.