Transcriptomic profiles are important indicators for molecular mechanisms and pathways involved in major depressive disorder (MDD) and its different phenotypes, such as immunometabolic depression. We performed whole-transcriptome and pathway analyses on 139 individuals from the observational, case-control, BIOmarkers in DEPression (BIODEP) study, 105 with MDD and 34 controls. We divided MDD participants based on levels of inflammation, as measured by serum high-sensitivity C-reactive protein (CRP), in n = 39 ‘not inflamed’ (CRP < 1 mg/L), n = 31 with ‘elevated CRP’ (1–3 mg/L), and n = 35 with ‘low-grade inflammation’ (>3 mg/L). We performed whole-blood RNA sequencing using Illumina NextSeq 550 and statistical analyses with the Deseq2 package for R statistics (RUV-corrected) and subsequent pathway analyses with Ingenuity Pathway Analysis. Immunometabolic pathways were activated in individuals with CRP > 1 mg/L, although surprisingly the CRP 1–3 group showed stronger immune activation than the CRP > 3 group. The main pathways identified in the comparison between CRP < 1 group and controls were cell-cycle-related, which may be protective against immunometabolic abnormalities in this ‘non-inflamed’ depressed group. We further divided MDD participants based on exposure and response to antidepressants (n = 47 non-responders, n = 37 responders, and n = 22 unmedicated), and identified specific immunomodulatory and neuroprotective pathways in responders (especially vs. non-responders), which could be relevant to treatment response. In further subgroup analyses, we found that the specific transcriptional profile of responders is independent of CRP levels, and that the inhibition of cell-cycle-related pathways in MDD with CRP < 1 mg/L is present only in those who are currently depressed, and not in the responders. The present study demonstrates immunometabolic and cell-cycle-related transcriptomic pathways associated with MDD and different (CRP-based and treatment-based) MDD phenotypes, while shedding light on potential molecular mechanisms that could prevent or facilitate an individual’s trajectory toward immunometabolic depression and/or treatment-non-responsive depression. The recognition and integration of these mechanisms will facilitate a precision-medicine approach in MDD.

转录组谱是重度抑郁症 (MDD) 及其不同表型（例如免疫代谢抑郁）涉及的分子机制和途径的重要指标。我们对来自观察性病例对照抑郁症生物标志物 (BIODEP) 研究的 139 名个体进行了全转录组和通路分析，其中 105 名患有 MDD，34 名对照。我们根据血清高敏 C 反应蛋白 (CRP) 测量的炎症水平对 MDD 参与者进行分组， n = 39 名“未发炎”(CRP < 1 mg/L)， n = 31 名“CRP 升高” ” (1–3 mg/L)， n = 35 例患有“低度炎症”(>3 mg/L)。我们使用 Illumina NextSeq 550 进行全血 RNA 测序，并使用 Deseq2 软件包进行 R 统计（RUV 校正）统计分析，并使用 Ingenuity Pathway Analysis 进行后续通路分析。免疫代谢途径在 CRP > 1 mg/L 的个体中被激活，但令人惊讶的是 CRP 1-3 组比 CRP > 3 组表现出更强的免疫激活。在 CRP < 1 组和对照组之间的比较中确定的主要途径与细胞周期相关，这可能对这个“非炎症”抑郁组的免疫代谢异常具有保护作用。我们根据抗抑郁药物的暴露和反应进一步对 MDD 参与者进行分类（ n = 47 名无反应者、 n = 37 名反应者和n = 22 名未用药者），并确定了反应者中特定的免疫调节和神经保护途径（尤其是与无反应者相比），这可能与治疗反应有关。 在进一步的亚组分析中，我们发现应答者的特定转录谱与 CRP 水平无关，并且 CRP < 1 mg/L 对 MDD 中细胞周期相关途径的抑制仅存在于当前抑郁的患者中，而不是在响应者中。本研究证明了与MDD和不同（基于CRP和基于治疗的）MDD表型相关的免疫代谢和细胞周期相关转录组途径，同时揭示了可以预防或促进个体免疫代谢抑制和/或发展的潜在分子机制。或治疗无反应性抑郁症。这些机制的认识和整合将促进 MDD 的精准医疗方法。