An interventional study of Theta burst stimulation in Major Depressive Disorder (MDD) and Treatment Resistant Depression (TRD), sponsored by The Royal Ottawa Mental Health Centre. Recruiting at 1 site in Canada. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2026-09-29.
Sponsored by The Royal Ottawa Mental Health Centre · Not applicable, Interventional, and Treatment
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.
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.
Exclusion Criteria:
4-weeks of exercise (moderate-to-vigorous intensity) followed by 6 weeks of iTBS combined with exercise.
Device: Theta burst stimulation
Standard care of 4 weeks of stable treatment (i.e. no changes to antidepressant regimen or physical activity) followed by 6 weeks of iTBS alone.
Device: Theta burst stimulation
Cool B70 cooled-coil (left DLPFC) with X100 MagPro rTMS Device (Magventure A/S, Farum, Denmark)
Also known as: rTMS
Assessing feasibility on combining structured exercise and intermittent Theta Burst Stimulation (iTBS) in participants with treatment-resistant depression (TRD)
Feasibility outcomes are crucial metrics that will guide the refinement of our protocols, thereby enhancing our preparedness for future design endeavors. These will include: 1) recruitment, 2) adherence, 3) compliance, 4) retention, 5) satisfaction, and 6) adverse events.
Time frame: Assessed at the end of the study once all participants have completed the study.
Compare the effects on clinical response of exercise on enhancing iTBS treatment efficacy vs. iTBS alone
Clinical response will be defined as a ≥ 50% reduction in the 17-item Grid Hamilton Rating Scale for Depression (Grid-HRSD-17). The Grid HRSD is a clinician-rated instrument with seventeen items used to measure the severity of depressive episodes. The overall score ranges from 0 to 52, where scores of 0 to 7 are considered as being normal, 8 to 16 suggest mild depression, 17 to 23 moderate depression, and scores ≥ 24 indicate severe depression.
Time frame: Administered at screening, before iTBS treatment course (week 4), at the end of the treatment course (week 10), then at the 6-week follow-up (week 16)
Change in self-reported depression symptoms as measured by Beck Depression Inventory (BDI-II).
As a secondary measure of depressive symptoms. Score scale from 0 (better outcome, no depression) to 63 (worst outcome, extreme depression).
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)
As a secondary measure of anxiety symptoms. Score scale from 0 (better outcome, no depression) to 63 (worst outcome, extreme anxiety).
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)
To assess the effect of treatment on suicidal thoughts that may be improved by iTBS. Score scale from 0 (better outcome, no desire for suicide) to 38 (worst outcome, extreme desire for suicide).
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)
To assess the effect of treatment on self-report symptoms and perceptions of stress that may be improved by iTBS. 6-item measure where responses are rated on an 8-point Likert scale. Score scale from 1 (Definitely True) to 8 (Definitely False).
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)
To assess the effect of treatment on biomarkers. Greater improvements in these biomarkers will also be associated with greater reductions in depressive symptoms.
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
To assess the effect of treatment on biomarkers. Greater improvements in these biomarkers will also be associated with greater reductions in depressive symptoms.
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
To assess the effect of the intervention on physical health.
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)
Incidence of Treatment-Emergent Adverse Events
Adverse events will be tracked and recorded.
Time frame: Daily Monday-Friday throughout study (16 weeks).
Side Effects
Side effects will be tracked and recorded on any TMS visits, using the TMS side effects questionnaire.
Time frame: Daily Monday-Friday throughout study (16 weeks).
Plan to share: Yes — All Individual Participant Data collected from this study (IPD) will be de-identified for all parties who have permission to access it. This de-identified data may be shared with other researchers at the Royal's Institute of Mental Health Research. De-identified may be shared with the public only upon request. Please note that all data that has the potential of revealing participants' identity will NOT be used to share.
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