<p>Bipolar disorder (BD) and major depressive disorder (MDD) are severe and chronic mood disorders which impairs the psychosocial functioning of patients. Besides manic or hypomanic episodes, many patients with BD also experience depressive episodes similar to those seen in MDD, suggesting the similarities and differences between the two diseases. However, the shared and distinct abnormalities of gene expression and cellular function in the brain underlying the disorders remain to be elucidated. Here we analyzed publicly available single-nucleus and bulk RNA expression datasets of postmortem brain samples from BD patients, MDD patients, and healthy donors. For single-nucleus gene expression profiling of postmortem orbitofrontal cortex (OFC), differential abundance testing, differential gene expression analysis and gene set enrichment analysis performed on each cell type showed abnormal gene expression profiles in both neuronal and non-neuronal cells. Cell-cell communication inference revealed the dysfunction of parvalbumin interneurons, as well as enhanced interactions among certain subtypes of neurons, in both diseases. Gene co-expression network analysis identified the overall alterations in both diseases, as well as the differences in co-expression modules between BD and MDD. Compared to MDD, most neurons in BD exhibited particularly downregulated expression of modules related to translation and mitochondrial ATP production. Transcription factor network analysis revealed the regulatory relationships among the modules. Further analyses of two additional datasets supported the main findings of the postmortem OFC analyses. Overall, our findings clarified the molecular mechanisms underlying BD and MDD, which highlight distinct molecular pathways that may inform therapeutic strategies for mood disorders.</p>