Circulating Extracellular Vesicles as Predictors of Antidepressant Response: Monitoring the Mechanism of Novel Therapeutic Approaches in Depression
EVroPAR is a Slovenian-Croatian multidisciplinary research project which combines basic, preclinical and clinical research, including partners from Ruđer Bošković Institute (Croatia), Institute of Biochemistry (Faculty of Medicine in Ljubljana, Slovenia), University Foundation San Pablo CEU (Spain), University Hospital Centre Zagreb (Croatia), University Psychiatric Clinic Ljubljana (Slovenia) and Labena d.o.o. (Slovenia). 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), phototherapy (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. Another goal is to identify specific metabolic and miRNA signatures of depression by comparing patients with an appropriate control group (100 subjects). We expect that new biomarkers identified in this project will help determine treatment efficiency in depression and predict good/poor response to treatment, as a key step towards the inevitable personalized and effective medicine approach.
Stress related (acute stress reaction, posttraumatic stress disorder) and eating disorders, addictions (alcoholism), aggressive/suicidal behavior, and attention deficit hyperactivity disorder are frequent multifactorial and polygenic psychiatric disorders that induce a great suffering in patients and their families, and carry financial burden to the whole society. Molecular basis of these disorders involves the changes in neurotransmitter (primarily serotonin - 5-HT, noradrenalin, dopamine) and neuroendocrine systems, and functional gene polymorphisms controlling the activity of the corresponding proteins.
Serotonergic and catecholaminergic (dopaminergic, noradrenergic) neurotransmitter systems regulate physiological functions and are also connected to the etiology of complex and polygenic neuropsychiatric disorders (Alzheimer’s disease /AD/, frontotemporal dementia, schizophrenia and depression). Etiology and psychobiological mechanisms of neuropsychiatric disorders is not well understood, but could be the result of interaction of genetic factors, specific proteins and environment.
The purpose of the present research is to improve our understanding of the mechanisms of action of neuropshycoactive drugs, especially during their chronic administration and modification by stress. Particular emphasis is placed on the research of benzodiazepines and antidepressants, used to treat anxiety, insomnia and depression, which are acting via GABAergic and serotonergic systems in the brain. Therefore, we investigate the changes in the expression and function of GABA-A receptor in vitro after prolonged exposure to benzodiazepines, known to induce the development of tolerance and dependence. Moreover, by using experimental animals, we have been also investigating the interactions between the effects of stress and benzodiazepines and antidepressants, primarily on the susceptibility to convulsions, as well as the role of the serotonergic system in controlling brain excitability.