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An Integrated systems biology approach identifies causal pathways and neuronal subtypes associated with phasic changes in major depressive disorder

Rammohan Shukla,

MDD is characterized by heterogeneous symptoms, including low mood, anhedonia and cognitive impairments. The course of the disease often follows a periodic trajectory (Fig1), which includes recurrent episodes of increasing severity, duration, and progressive resistance to antidepressants, separated by gradually shortening partial or full remission phases, often leading to chronic and treatment-resistance depression with deterio functional fitness. Notably, studies so far have majorly focused on the differences between control and MDD subjects. Molecular changes in different phases of the MDD largely remains unknown. Methodology & Theoretical Orientation: To address this issue we performed RNAseq of 90 post-mortem subgenual anterior cingulate cortex tissue samples obtained from one control (n=20) and four MDD cohorts in 1) first episode of depression (n=20); 2) remission state after first episode (n=15); 3) recurrent stages of depressive episode (n=20) and 4) remission stages after recurrent episodes (n=15). Integrating with the available single cell RNAseq and drug based transcriptomic profile using machine learning and network biology approaches we looked for cell specific molecular changes, causal biological pathways, and drug molecules and their targets involved in MDD. Findings: Genes and biological pathways associated with the different phases of MDD and their cellular correlates were first characterized. A subset of CRH and SST positive interneuron neuron showed significant association with the disease trajectory (p-value