Distinct pattern in bipolar depression and major depressive disorder: A multiscale imaging-transcriptomic analysis.

AIM: Bipolar depression (BDD) and major depressive disorder (MDD) share similar depressive symptoms but differ in diagnosis, treatment, and prognosis. Clarifying their neurobiological distinctions may improve diagnostic characterization and mechanistic understanding. METHODS: We studied 453 participants, including 85 patients with BDD, 190 with MDD, and 178 healthy controls. Individual morphometric similarity networks (MSN) were constructed using seven structural and diffusion MRI features. Regional MSN differences between BDD and MDD were examined at the parcel level. To characterize the biological relevance of the distinct MSN pattern, we performed imaging-transcriptomic analysis using Allen Human Brain Atlas data, followed by gene enrichment, cell-type enrichment, receptor/transporter dominance analysis, and cognitive meta-analytic decoding. Sensitivity analyses evaluated the effects of medication exposure and demographic imbalance. RESULTS: Compared with MDD, BDD showed distinct MSN alterations mainly in parietal and occipital regions, including higher MSN in the left lateral occipital cortex and lower MSN in the right inferior and superior parietal cortices. The spatial transcriptomic pattern was enriched for ribosomal and protein synthesis/modification pathways. Cell-type enrichment analyses showed that the transcriptomic pattern associated with the MSN differences was enriched for microglial and inhibitory-neuron gene signatures, while receptor dominance analysis identified the 5-HT2A density map as having the largest relative contribution to the explained spatial variance. CONCLUSION: Our findings identify distinct cortical morphometric organization in BDD and MDD, and these differences are linked to transcriptomic, cellular, and neurotransmitter-related annotations, providing multiscale insights into the neurobiological divergence between the two disorders.