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This study examined postmortem brain tissue (subgenual anterior cingulate cortex) using RNA sequencing to identify molecular changes that accumulate progressively across clinical stages of Major Depressive Disorder, distinguishing them from changes specific to discrete episodes or remissions. Progressive changes were linked to superficial-layer neurons and extracellular matrix disruptions during episodes, while metabolic and catalytic pathways showed partial restoration during remission. Anhedonia emerged as a trait-like feature associated with both acute episode and progressive remission signatures, and pharmacological analysis identified molecular targets with context-dependent effects depending on disease state and dosage.
Why it matters
Understanding how molecular alterations accumulate across repeated depressive episodes could help explain why treatment resistance develops over time and may point toward more targeted interventions for patients with recurrent or chronic depression.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Major Depressive Disorder (MDD) frequently follows a recurrent trajectory of episodes and remissions, often culminating in treatment-resistance. Molecular differences defining state-specific changes during episode and remission have been explored. However, progressive differences–defined here as cross-sectional linear trends across clinical stages from first to recurrent episodes or remissions, reflecting increasing illness burden over time–remain poorly understood, limiting sustained therapeutic outcomes. Here, we analyzed RNA-seq data from postmortem sgACC to identify progressive differences across MDD episodes or remission relative to state-specific differences, using an integrative assessment of molecular and cellular specificity, genetic-risk, disease-comorbidity and potential therapeutic targets. Differential expression analysis showed greater overlap between progressive and state-specific differences during remission than episode. Pathway enrichment highlighted disruptions in extracellular-matrix pathways shared by state-specific and progressive episodes, while metabolic and catalytic pathways were restored during remission. Cell-type-specific analyses showed that progressive changes were linked to superficial-layer intra-telencephalic neurons, whereas state-specific changes were enriched in pyramidal neuron subtypes and deeper layer SST-positive interneurons. Genome-wide association-informed enrichment analysis further linked these transcriptomic changes to genetic risk factors and symptom dimensions. Anhedonia was associated with both state-specific episode and progressive-remission signatures, suggesting that it is a persistent trait-like feature of MDD. Finally, an integrative pharmacological analysis revealed shared molecular mechanisms between pro-disease and therapeutic targets, highlighting pleiotropic effects of key pathways depending on disease state and dosage. Together, these findings provide a novel perspective on biological underpinnings of MDD progression over episodes or remissions and identify pharmacological targets that account for pathological and/or compensatory/therapeutic processes.
Source: Molecular Characterization of the Progressive Landscape of Depression