Cell-resolved cortical architecture and intercellular communication distinguish bipolar and major depressive disorders

Bipolar disorder (BD) and major depressive disorder (MDD) overlap clinically, particularly during depressive episodes, yet diverge in longitudinal course, treatment response, and underlying neurobiology. Whether this overlap reflects graded disruption along a shared depressive axis or distinct cortical organization remains unclear, underscoring the need to distinguish shared from disorder-specific neurobiological features beyond symptom-based categories. We created a harmonized cross-cohort dlPFC single-nucleus transcriptomic resource from PsychENCODE and GEO datasets, comprising 715 077 nuclei from 34 BD, 41 MDD, and 73 control donors, enabling direct comparison of BD and MDD across cell-type composition, transcriptional dysregulation, co-expression networks, and intercellular communication. MDD was associated with broader transcriptomic dysregulation, vascular-associated compositional shifts, and compartment-specific glial and stress-response alterations involving astrocytes, oligodendrocyte precursor cells, endothelial cells, microglia and perivascular macrophages. By contrast, BD was associated with fewer global changes but exhibited a prominent oligodendroglial signature involving membrane excitability, adhesion, signaling, and neuron–glia interactions. Network and communication analyses identified additional differences: BD showed reduced neuronal biosynthetic programs and broader attenuation of inferred neuronal communication, whereas MDD showed heterogeneous remodeling of glial, immune/perivascular, vascular-interface, extracellular matrix, OPC-associated, and endocannabinoid-related pathways. These findings support partly divergent patterns of cortical cellular architecture and intercellular coordination in BD and MDD. Cell-resolved cortical organization may therefore provide candidate features for future biological stratification of mood disorders.