Exploration of Novel Biomarkers Through a Precision Medicine Approach Using Multi‐Omics and Brain Organoids in Patients With Atypical Depression and Psychotic Symptoms

Abstract Major depressive disorder (MDD) with atypical features accompanied by psychotic symptoms represents a severe and under‐researched subtype of depression and severe mental illness, characterized by significant personal and social impact. This study aims to explore novel biomarkers through a precision medicine approach by combining clinical data, white blood cell (WBC) single‐cell RNA sequencing (scRNA‐seq), plasma proteomics, and brain organoid models to uncover immunological and neurological alterations in patients with this condition. Patients exhibited elevated stress, anxiety, depression, and increased WBC counts, although the difference in WBC count is not significant after adjusting for age. Plasma proteomic profiling identified an upregulation of proteins implicated in synaptic formation, including Doublecortin‐Like Kinase 3 (DCLK3) and Calcyon (CALY), as well as immune‐related proteins such as Complement Component 5 (C5). WBC scRNA‐seq revealed significant neutrophil and monocyte transcriptomic alterations, suggesting increased inflammation and immune dysregulation. Patient‐derived brain organoids display reduced growth and distinct gene expression patterns compared to controls, particularly under dexamethasone‐induced stress conditions. Combining WBC scRNA‐seq, plasma proteomics, and brain organoid models offers a novel framework for understanding the pathophysiology of psychiatric disorders, which is one of the most complex disorders.