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

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 (<3 months) substance (excluding caffeine or nicotine) or alcohol abuse/dependence, as defined in DSM-5 criteria.
3. Current use of illegal substances.
4. Current use of cannabis.
5. Concomitant major unstable medical or neurologic illness (e.g., uncontrolled diabetes or renal dysfunction).
6. Organic cause of the depressive symptoms (e.g. thyroid dysfunctions), determined by the referring physician.
7. Acute suicidality or threat to life from self-neglect.
8. Pregnant or breastfeeding, or thinking of becoming pregnant during course of treatment.
9. 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.
10. Unwilling to maintain current psychotropic medication and/or psychotherapy regimen for the four weeks prior to and for the duration of the study.
11. Taking more than 1 mg/day of lorazepam or equivalent.
12. Any other condition that, in the opinion of the investigators which would adversely affect the participant's ability to complete the study.
13. Physically active: performing exercise and/or physical activity levels meeting the cut-off for "minimally active" on the IPAQ-SF.