Schizophrenia (SCZ), Bipolar Disorder (BD), and Major Depressive Disorder (MDD) are severe psychiatric conditions that share overlapping clinical symptoms, yet they differ in their underlying molecular mechanisms. Despite extensive research, the biological foundations of these disorders remain incompletely understood. In this study, we performed a large-scale transcriptomic analysis by integrating 557 publicly available RNA-seq datasets from post-mortem brain tissues, spanning multiple regions, to better understand the shared and distinct molecular features of these disorders. Using systematic bioinformatic approaches, we identified differentially expressed genes (DEGs) and investigated associated biological pathways, regulatory transcription factors, and drug-gene interactions. Our analysis revealed notable overlap in gene expression profiles, particularly between SCZ and BD, suggesting common molecular pathways underlying these disorders. At the same time, each disorder also demonstrated unique transcriptional patterns, supporting the existence of disorder-specific mechanisms. Brain region-specific analyses further highlighted spatial heterogeneity in gene expression, with significant differences observed in regions such as the hippocampus and dorsolateral prefrontal cortex (DLPFC). The transcription factor enrichment analysis revealed distinct regulatory programs driving each disorder: MDD pathology appears regulated by ASCL3, MYOG, HNF1B, RUNX3, FOXA1 and STAT4; BD exhibited predominant control by immune-regulatory factors including FOSL1, FOSL2, PLSCR1, RELB, BATF3, IRF and NFKB1; while SCZ demonstrated unique regulation through ATF5, CREB3L3, SNAI1, NFIL3, CEBPB, RELB and IRF transcription factors. Moreover, our drug-gene interaction analysis uncovered promising therapeutic targets, with several differentially expressed genes showing potential for drug repurposing, particularly in relation to antipsychotics and immunomodulatory agents. Our comprehensive transcriptomic analysis reveals both shared molecular mechanisms and distinct immune signatures across schizophrenia, bipolar disorder, and major depressive disorder, advancing our understanding of psychiatric pathophysiology while highlighting the heterogeneous nature of these conditions. These findings establish a critical foundation for developing targeted, patient-specific therapeutic interventions that address the underlying biological complexity of major psychiatric disorders.