Feasibility Trial of Exercise as a Priming Strategy for rTMS Treatment in Difficult-to-Treat Depression

The goal of this study is to collect feasibility data on combining structured exercise aimed to improve physical fitness, and intermittent TBS (iTBS) in treating individuals diagnosed with difficult-to-treat depression who are physically inactive. By conducting this trial, we will compare the therapeutic benefits of the combined approach against the standard treatment of iTBS alone (without exercise). These findings will be used to inform future large-scale projects in which we will investigate, in a larger sample size, whether structured exercise aimed to improve fitness as recommended by most public exercise guidelines (i.e., ≥3x/week, moderate-to-vigorous intensity) serves as an active ingredient that amplifies the effectiveness of iTBS. Ultimately, the insights gained from this study will be valuable for clinicians seeking to alleviate depressive symptoms in MDD through neuromodulation techniques such as iTBS.

Inclusion Criteria: 1. Are between 18-75 years old. 2. Able to provide voluntary informed consent. 3. Diagnosis of MDD or Persistent Depressive Disorder, without psychotic features, confirmed by MINI for DSM-5. 4. Depressive symptoms have not improved after ≥ 1 adequate antidepressant trial in the current episode (i.e., difficult-to-treat MDD), based on the Antidepressant Treatment History Form (ATHF). 5. Baseline score of ≥15 on the HRSD-17. 6. No change in psychotropic medications or psychotherapy regimen at least 4 weeks prior to entering the trial 7. Physically inactive as per the International Physical Activity Questionnaire - Short Form (IPAQ-SF). 8. Able to engage in structured exercise as per the Get Active Questionnaire (GAQ). 9. Able to adhere to the proposed treatment schedule. Exclusion Criteria: 1. Diagnosis of bipolar I or II disorder, based on DSM-5 criteria. 2. Current or past (\