SSRId

Major depressive disorder (MDD) affects between 6.4-10.1% of the population and despite its prevalence and considerable burden, our understanding of the pathophysiology remains rudimentary. Several molecules reported to be dysregulated in MDD have been signaled as potential biomarkers, however, a validated biomarker has yet to be identified. Antidepressants are the most common treatment for MDD, yet roughly one third of patients experience an inadequate response to treatment after several attempts. This affects patient care, economic and social outcomes of MDD, and the development of new medication, as it occludes efficiency data of new molecules in clinical trials. Thus, there is a great need in not only identifying biomarkers of MDD but also those that can predict response to antidepressant treatment. As onset of MDD is commonly associated with an environmental trigger, and the contribution of environmental factors to MDD is substantial, the investigation of dynamic epigenetic factors in the onset of MDD and its treatment is of significant interest. Here, we propose to investigate how small non-coding RNAs (ncRNAs) may regulate MDD and evaluate their ability as biomarkers for MDD and predicting response to antidepressants. We focus on small ncRNAs as it was recently reported that one particular type, miRNAs are transported by exosomes, which may act in communication between cells, suggesting that these molecules can act as feasible biomarkers. We will first conduct small RNA-sequencing in human post-mortem brain samples to identify small ncRNAs that show differential expression according to presence of MDD. This screening study will generate a list of candidate small ncRNAs associated with MDD. Using two well-characterized animal models of depression, we will investigate expression of small ncRNAs in brain and blood and identify small ncRNAs associated with depression models. We will then carry out a series of in vivo and in vitro experiments including genetic manipulation studies to follow-up on these candidate small ncRNAs to study their involvement in the mechanism of MDD and in the effects of antidepressants. We will then use this information to develop, test and validate a molecular biomarker panel predicting response to antidepressant treatment. We will evaluate the generalizability of the biomarker panel to predict response in samples collected from a large representative group of patients (N>3000) from different time points of placebo-controlled or prospective clinical trials investigating the effects of different antidepressant drugs. This project brings together leading researchers working on MDD neurobiology and treatment to combine their expertise to investigate small ncRNAs associated with depression. The goal is to identify biomarkers of MDD and predictors of antidepressant response. The information that will be generated from this project is expected to have substantial impact on the treatment of MDD.