Major depressive disorder (MDD) is a brain disorder often characterized by recurrent episode and remission phases. The molecular correlates of MDD have been investigated in case-control comparisons, but the biological alterations associated with illness trait (regardless of clinical phase) or current state (symptomatic and remitted phases) remain largely unknown, limiting targeted drug discovery. To characterize MDD trait- and state-dependent changes, in single or recurrent depressive episode or remission, we generated transcriptomic profiles of subgenual anterior cingulate cortex of postmortem subjects in first MDD episode (n = 20), in remission after a single episode (n = 15), in recurrent episode (n = 20), in remission after recurring episodes (n = 15) and control subject (n = 20). We analyzed the data at the gene, biological pathway, and cell-specific molecular levels, investigated putative causal events and therapeutic leads. MDD-trait was associated with genes involved in inflammation, immune activation, and reduced bioenergetics (q < 0.05) whereas MDD-states were associated with altered neuronal structure and reduced neurotransmission (q < 0.05). Cell-level deconvolution of transcriptomic data showed significant change in density of GABAergic interneurons positive for corticotropin-releasing hormone, somatostatin, or vasoactive-intestinal peptide (p < 3 × 10-3). A probabilistic Bayesian-network approach showed causal roles of immune-system-activation (q < 8.67 × 10-3), cytokine-response (q < 4.79 × 10-27) and oxidative-stress (q < 2.05 × 10-3) across MDD-phases. Gene-sets associated with these putative causal changes show inverse associations with the transcriptomic effects of dopaminergic and monoaminergic ligands. The study provides first insights into distinct cellular and molecular pathologies associated with trait- and state-MDD, on plasticity mechanisms linking the two pathologies, and on a method of drug discovery focused on putative disease-causing pathways.
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.