Background: Major Depressive Disorder (MDD) is frequently associated with reduced levels of physical activity, altered circadian rhythms, and sleep–wake disturbances, all of which contribute to symptom severity, functional impairment, and poor treatment outcomes. Objective, continuous monitoring of motor activity and rest–activity cycles may provide sensitive behavioral markers of disease severity and treatment response, overcoming the limitations of self-reported measures.

Objectives: This study aims to investigate changes in objectively measured physical activity and circadian rhythm parameters in patients with MDD undergoing a structured physical activity intervention in addition to standard antidepressant treatment. Secondary aims include exploring the relationship between actigraphy-derived metrics, depressive symptom severity, and functional outcomes over time.

Methods: In this multicenter randomized controlled trial, 110 patients with MDD receiving stable antidepressant therapy are recruited across three clinical centers and randomized (1:1) to a 12-week individualized physical activity program or treatment as usual. Wrist-worn actigraphy (ActiGraph LEAP or wGT3X-BT) is used to continuously monitor motor activity and sleep–wake patterns for seven consecutive days at baseline (T0), post-intervention (T3), and six-month follow-up (T6). (Study number: PNRR-MCNT2-2023-12377777). Actigraphy-derived parameters include total activity counts, time spent in sedentary, light, moderate, and vigorous physical activity, step count, sleep duration, sleep onset latency, nocturnal awakenings, and rest–activity rhythm regularity. Data are processed using standardized algorithms and analyzed longitudinally to capture within-subject changes and between-group differences over time.

Expected Impact: This actigraphy-based approach is expected to provide objective behavioral signatures of physical activity engagement and circadian regulation in MDD. The identification of actigraphy-derived markers associated with clinical improvement may support the use of wearable technologies for monitoring treatment adherence and response, and for guiding personalized physical activity interventions in depressive disorders.

Raffaella Zanardi, MD, PhD is a psychiatrist, psychotherapist, and specialist in criminology. She has served for over 25 years as Head of the Functional Unit for Mood Disorders within the Department of Psychiatry at IRCCS San Raffaele Turro, Milan. She has extensive experience in clinical research on mood disorders, with a primary focus in recent years on treatment-resistant depression and innovative antidepressant strategies, including both pharmacological and non-pharmacological approaches. Her research interests also include the role of inflammation and metabolic dysfunction in the pathophysiology of depression. She has acted as Principal Investigator in numerous interventional clinical studies involving patients with mood disorders and is the author of several dozen peer-reviewed publications in international journals (h-index: 43).