Intron retention can be an excellent marker for evaluating the depressed state and useful for discovering new pathways in the recovery of depression by a drug.

BACKGROUND: Peripheral inflammation is often associated with depressive disorders, and immunological biomarkers of depression remain a focus of investigation. METHODS: We performed RNA-seq analysis of human peripheral blood mononuclear cell (PBMC) RNA transcripts from a case-control study including subjects with self-reported depression in the pre-symptomatic state of major depressive disorder (MDD), and analysed differential expression of genes (DEGs) and intron retention (IR) using rMats. RESULTS: Among the DEGs with a statistically significant value, both 651 up-regulated and 820 down-regulated genes were enriched in GO (gene ontology) terms of innate and adaptive immunity. The former was particularly enriched in bacterial infection and phagocytosis, while the latter was enriched in genes related to antigen presentation and T cell proliferation and maturation. Genes with the 158 increased and 211 decreased IRs (termed IncIR and DecIR genes, respectively) in the depressed subjects were analysed. Their GO terms were very similar to those of the up- and down-regulated genes, with an emphasis on ciliary assembly and function in the DecIR. The results also showed that a Japanese herbal medicine partially reversed the depression in these subjects after recovering the DecIR and IncIR genes. By imposing the recovered genes on the network of depressed subjects, several new pathways for recovery from depression were successfully discovered. CONCLUSION: Depression was associated with activation of the innate immune response and relative inactivation of T cell signalling. DEGs reflect physiological demands at the transcriptional level, whereas IRs are a mechanism for fine-tuning cytoplasmic homeostasis. Accordingly, IR is a stress response and IR genes are sensors of the physiological state in the cytoplasm. In particular, where ciliary genes were detected by IR analysis, it is expected that there is a defect in ciliary function or immune synaptogenesis in depression. We demonstrate the potential of IR biomarkers in the immunological stratification of depressed patients and their utility in the discovery of novel pathways involved in recovery from depression.