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

This is a randomized, two-arm, pilot feasibility clinical trial design involving physically inactive individuals diagnosed with treatment-resistant depression (TRD). Participants will be randomly assigned to either: 1) 4-weeks of exercise (moderate-to-vigorous intensity; \~1h session, 3x/week) followed by 6 weeks of iTBS combined with exercise (intervention group), or 2) 4 weeks of stable treatment (i.e. no change in psychotropic medication/psychotherapy regimen or physical activity) followed by 6 weeks of iTBS alone (control group). The intervention group is divided into two phases: the priming phase and the synergetic phase. Due to the neuroplasticity-enhancing effects of exercise and fitness, and based on pilot results demonstrating superior antidepressant effects of TBS in physically active participants, the main objective of the priming phase is to enhance brain plasticity mechanisms through increases in fitness from the 4 weeks of exercise training. In other words, this phase aims to build capacity for a better response to TBS treatment. The synergetic phase (interventional group) follows the priming and involves integrating TBS treatment into the exercise training regimen. Participants in the interventional group will maintain their exercise routine to enhance and sustain gains while undergoing TBS treatment for 6 weeks. In accordance with the recommended guidelines for both exercise and TBS treatment for depression, participants in the interventional group will engage in exercise sessions lasting approximately 1 hour, three times per week. In both interventional and control groups, TBS treatment will be administered five times per week, with treatment delivery lasting 3 minutes. We hypothesize that all aspects of this project will be feasible, that is the exercise and iTBS delivery and outcomes assessment. Additionally, we expect participants to show high levels of adherence and compliance with the strategy. The ultimate goal, to be investigated in a larger-scale study following this one, is to determine whether exercise acts as an active ingredient that enhances the effectiveness of iTBS.

• Change in self-reported depression symptoms as measured by Beck Depression Inventory (BDI-II). [Time frame: Administered at screening, before the first iTBS treatment (week 4) and every week after that for 6 weeks (week 5, week 6, week 7, week 8, week 9, week 10), and at the 6-week follow-up assessment (week 16)]
• Change in self-reported anxiety symptoms as measured by Beck Anxiety Inventory (BAI) [Time frame: Administered at screening, before the first iTBS treatment (week 4) and every week after that for 6 weeks (week 5, week 6, week 7, week 8, week 9, week 10), and at the 6-week follow-up assessment (week 16)]
• Change in self-reported suicidal thoughts symptoms as measured by Beck Scale for Suicidal Ideation (BSS) [Time frame: Administered at screening, before the first iTBS treatment (week 4) and every week after that for 6 weeks (week 5, week 6, week 7, week 8, week 9, week 10), and at the 6-week follow-up assessment (week 16)]
• Change in self-reported hopelessness as measured by State Hope Scale (SHS) [Time frame: Administered at screening, before the first iTBS treatment (week 4) and every week after that for 6 weeks (week 5, week 6, week 7, week 8, week 9, week 10), and at the 6-week follow-up assessment (week 16)]
• Change in neuroplasticity as measured by neurophysiology (TMS) and MRI (Arterial Spin Labelling measures of brain blood flow) [Time frame: Administered at pre-assessment (baseline), before iTBS treatment course (week 4), end of iTBS treatment course (week 10)]
• Change in grip strength as measured by dynamometer [Time frame: Administered at pre-assessment (baseline), before iTBS treatment course (week 4), end of iTBS treatment course (week 10), and at 6-week follow-up assessment (week 16)]
• Change in physical measures as assessed by anthropometrics [Time frame: Administered at pre-assessment (baseline), before iTBS treatment course (week 4), end of iTBS treatment course (week 10), and at 6-week follow-up assessment (week 16)]