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.

Inclusion criteria

• Are between 18-75 years old.
• Able to provide voluntary informed consent.
• Diagnosis of MDD or Persistent Depressive Disorder, without psychotic features, confirmed by MINI for DSM-5.
• 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).
• Baseline score of ≥15 on the HRSD-17.
• No change in psychotropic medications or psychotherapy regimen at least 4 weeks prior to entering the trial
• Physically inactive as per the International Physical Activity Questionnaire - Short Form (IPAQ-SF).
• Able to engage in structured exercise as per the Get Active Questionnaire (GAQ).
• Able to adhere to the proposed treatment schedule.

Exclusion criteria

• Diagnosis of bipolar I or II disorder, based on DSM-5 criteria.
• Current or past (<3 months) substance (excluding caffeine or nicotine) or alcohol abuse/dependence, as defined in DSM-5 criteria.
• Current use of illegal substances.
• Current use of cannabis.
• Concomitant major unstable medical or neurologic illness (e.g., uncontrolled diabetes or renal dysfunction).
• Organic cause of the depressive symptoms (e.g. thyroid dysfunctions), determined by the referring physician.
• Acute suicidality or threat to life from self-neglect.
• Pregnant or breastfeeding, or thinking of becoming pregnant during course of treatment.
• Contraindication for TMS and MRI (e.g., personal history of epilepsy or seizure, metallic head implant, pacemaker), confirmed by TMS Adult Safety Scale (TASS) and MRI pre-screener.
• Unwilling to maintain current psychotropic medication and/or psychotherapy regimen for the four weeks prior to and for the duration of the study.
• Taking more than 1 mg/day of lorazepam or equivalent.
• Any other condition that, in the opinion of the investigators which would adversely affect the participant's ability to complete the study.
• Physically active: performing exercise and/or physical activity levels meeting the cut-off for "minimally active" on the IPAQ-SF.