Background: Major Depressive Disorder (MDD) is a highly prevalent and heterogeneous psychiatric condition and a leading cause of disability worldwide. Despite the proven efficacy of antidepressant treatments, a substantial proportion of patients show partial or no response and experience frequent relapses, often accompanied by metabolic and cardiovascular comorbidities. In this context, non-pharmacological interventions such as physical activity represent a promising adjunctive strategy, potentially enhancing treatment response while targeting underlying biological mechanisms.

Objectives: The present study aims to investigate whether a structured physical activity intervention exerts a synergistic effect with standard antidepressant therapy in patients with MDD. Primary objectives focus on changes in depressive symptom severity, subjective well-being, psychosocial functioning, and quality of life. Secondary objectives aim to elucidate the neurophysiological, epigenetic, transcriptomic, and metabolic mechanisms underlying the effects of physical activity on depressive symptoms.

Methods: This is a multicenter, randomized controlled trial involving 110 patients with MDD receiving stable antidepressant treatment, recruited across three Italian clinical centers. Participants are randomized (1:1) to either a 12-week individualized physical activity program (150 minutes/week) or treatment as usual without structured exercise. Clinical assessments and actigraphy-based physical activity monitoring are conducted at baseline, post-intervention (3 months), and follow-up (6 months). A subgroup undergoes quantitative EEG recordings to assess functional connectivity changes. Peripheral blood samples are collected for epigenomic, transcriptomic, and metabolic analyses. In parallel, longitudinal analyses are conducted in the population-based Moli-sani cohort to investigate metabolic and epigenetic mediators of the association between physical activity and depressive symptoms.

Expected Impact: By integrating clinical, neurophysiological, and multi-omics data, this study aims to identify biological signatures associated with response to physical activity in depression. The findings are expected to contribute to the development of personalized, mechanism-based, non-pharmacological interventions for patients with MDD.

Matteo Carminati completed his psychiatry residency at the age of 31 at Vita-Salute San Raffaele University in Milan. He works as a psychiatrist in the Italian NHS and as a Clinical Researcher at San Raffaele Scientific Institute in Milan, with a specific interest in Mood Disorder, Treatment Resistant Depression and immunopsychiatry. He published several scientific papers on Internation Journals and participated in national and international congresses.