Circulating Extracellular Vesicles as Predictors of Antidepressant Response: Monitoring the Mechanism of Novel Therapeutic Approaches in Depression

Proposed project is a Slovenian-Croatian multidisciplinary research project which combines basic, preclinical and clinical research, including partners from the academic community (Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Slovenia, and University Foundation San Pablo CEU, Spain), research institute (Ruđer Bošković Institute, Croatia), and public health facilities (University Psychiatric Clinic Ljubljana, Slovenia, and University Hospital Centre Zagreb, Croatia). Project incorporates cutting-edge metabolomics approach and miRNA profiling in order to identify novel biomarkers that could help clinicians to tailor treatment strategies in depression for individual patients. Currently available therapy for depression involves pharmacotherapy combined with psychotherapy, while dealing with poor response/nonresponse and a frequent discontinuation of treatment. The objective of the study is to give better insights into the efficacy and molecular mechanisms behind the effects of a widely used antidepressant (duloxetine), and compare this to the mechanism behind the effects of alternative methods of treatment in patients with treatment-resistant depression (Transcranial Magnetic Stimulation (TMS), Bright light Therapy (BTL), esketamine treatment). The study will focus on circulating extracellular vesicles (EVs) as easily obtainable and non-invasive biomarkers. We aim to measure the dysregulation of epigenetic markers - the EV miRNA expression, and to determine metabolic alterations in four groups of patients (duloxetine vs. BLT vs. TMS vs. esketamine), by sampling 50 patients per group before and after the treatment intervention. Another goal is to identify specific metabolic and miRNA signatures of depression by comparing groups of patients diagnosed with depression (non-treatment resistant and treatment resistant depression) with an appropriate healthy control group (100 subjects). We expect that new biomarkers identified in this project will help determine treatment efficiency in depression and predict good or poor response to treatment, as a key step towards the inevitable personalized and effective medicine approach. As this is a bilateral project, we would like to emphasize that we have combined complementary expertise of two research institutions. Namely, metabolomics will be performed at the Ruđer Bošković Institute, Croatia (in cooperation with the San Pablo University Foundation CEU, Spain) and epigenetics at the Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana. Also the included health institutions also have expertise in various approaches to treatment, namely, the University Hospital Center Zagreb, Croatia for BLT, the University Psychiatric Clinic Ljubljana, Slovenia for TMS and esketamine.