Periodic Reporting for period 2 - MitO2Health (Major depression as a metabolic disorder: The role of oxygen homeostasis and mitochondrial bioenergetics in depression etiology and therapy) Reporting period: 2022-04-01 to 2023-09-30 Summary of the context and overall objectives of the project Major depressive disorder (MDD) is a major contributor to the overall global burden of disease, affecting 5% of the global adult population, and more than 30 million people in Europe. In cases of single MDD episodes, 62% of patients attain remission with therapy. However, a total of up to 80% experience MDD to recur over the course of their lifetime and one third of MDD patients achieve no improvement from therapy. These numbers indicate that the currently applied (pharmacological) treatment concepts of MDD inspired by the 60 years old monoamine hypothesis fall short of both therapy success and recurrence prevention. Emerging research calls forth to conceptualize MDD as a disorder of increased immune system reactivity, decreased mitochondrial energy production in cells, elevated oxidative stress, and alterations in the transport and supply of oxygen in the body, although the precise causes and interplay of these dysfunctional alterations remain elusive and their relevance for therapy response and remission stability is unstudied. In MitO2Health, we will longitudinally assess the clinical and biological status of 100 individuals with MDD receiving 6 months of cognitive behavioral therapy (CBT) in comparison with 100 MDD patients in a waitlist group as well as 100 healthy controls. At four time points over 18 months, the individual course of MDD symptoms as well as individual lifestyle factors, lifetime exposure to traumatic events, personality traits, and coping strategies are comprehensively assessed along with an innovative panel of biological markers to characterize the mitochondrial energy production in immune cells, oxygen homeostasis, markers of oxidative stress, and the inflammatory activity in peripheral immune cells of the blood resp. blood serum/plasma. By providing highly valuable longitudinal evidence on the mutual interplay between biological parameters and individual MDD trajectories, through MitO2Health we contribute cutting-edge evidence on physiological mechanisms underlying MDD. Moreover, CBT is applied as a randomized treatment condition to test whether CBT-related MDD symptom reduction is coupled to a normalization of the investigated biological alterations, and the project will enable us to characterize the biomarker profiles of MDD treatment response and resistance as well as disorder relapse/recurrence. MitO2Health will provide core evidence to establish a modern etiological model of MDD, advance new diagnostic standards, and inspire personalized biologically-founded MDD treatment concepts to improve clinical outcomes. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far With the official project start in 10/2020, the study setup was prepared (ethics, data protection, study registration) and relevant approvals were achieved in 07/ 2021. We submitted a preprint about the biological concept of the trial and published a first review on inflammatory activity in mental health problems. Recruitment of MDD patients and healthy controls started in 08/2021. To date, 281 interested subjects were screened for eligibility, of which 49 MDD patients and 50 healthy controls were enrolled to the study; that is, we have recruited 33% of the final study cohort (200 MDD patients, 100 healthy controls). A psychotherapy manual was developed for the study, and sufficient therapeutic personnel was incorporated at two clinical sites, which enabled us to already complete 15% of the 200 psychotherapies required for the study. Data collection at the post-therapy and the first follow-up timepoint have begun. Efficient procedures of biological specimen collection and processing were established, and a number of time-critical biological analyses are ongoing with specimen collection. Overall, the participants recruitment and data collection run without major problems and could even be increased in efficiency. Nevertheless, the project is behind schedule, as it has already started with a delay and the COVID-19 pandemic has led to a temporary standstill in recruitment, especially during contact restrictions and lockdowns. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) We will characterize the biomarker profiles of MDD treatment response and resistance as well as MDD symptom recurrence during a follow-up period. MitO2Health will not only establish a modern etiological model of MDD, but also identify biomarkers of individual therapy response and relapse. This will lead to new diagnostic standards and inspire biologically well-founded, personalized MDD treatment concepts that will fundamentally improve clinical outcomes in psychotherapy and psychiatry.
