Exercise priming before rTMS (iTBS) for difficult-to-treat depression

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

This will test whether adding a 4-week structured exercise program before and during intermittent theta-burst stimulation (iTBS) helps physically inactive adults with treatment-resistant depression feel better.

Quick facts

• Phase: Not applicable
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: The Royal Ottawa Mental Health Centre (Academic / other)
• Locations: 1 site (Ottawa, Ontario)
• Trial ID: NCT06773949 on ClinicalTrials.gov

What this trial studies

This is a randomized, two-arm pilot feasibility trial enrolling physically inactive adults with treatment-resistant major depressive disorder. One group completes 4 weeks of moderate-to-vigorous exercise (≈1 hour, 3x/week) followed by 6 weeks of iTBS with ongoing exercise, while the control group has 4 weeks of stable treatment followed by 6 weeks of iTBS alone. The priming phase aims to increase fitness and neuroplasticity to improve responsiveness to iTBS, and the synergetic phase integrates neuromodulation with maintained exercise. Feasibility measures and changes in depressive symptoms will be collected to inform larger future trials.

Who should consider this trial

Good fit: Adults 18–75 with MDD or persistent depressive disorder who have not improved after at least one adequate antidepressant trial, score ≥15 on the HRSD-17, are physically inactive, medically able to exercise, and on a stable psychotropic/psychotherapy regimen are ideal candidates.

Not a fit: People with bipolar disorder, psychotic features, recent substance dependence, an inability to safely engage in structured exercise, unstable psychiatric medication/therapy, or those already physically active may not benefit from this approach.

Why it matters

Potential benefit: If successful, combining structured exercise with iTBS could boost antidepressant response and improve physical fitness and daily functioning in people with difficult-to-treat depression.

How similar studies have performed: Mechanistic and pilot data suggest exercise can enhance neuroplasticity and that active people may respond better to TBS, but the specific approach of priming iTBS with a structured exercise program is novel and only preliminarily tested.

Eligibility criteria

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.

Where this trial is running

Ottawa, Ontario

• Royal Ottawa Mental Health Centre — Ottawa, Ontario, Canada (Recruiting)

Study contacts

• Principal investigator: Sara Tremblay, PhD — Royal Ottawa Mental Health Centre
• Study coordinator: Stacey Shim, MSc

Conditions Major Depressive Disorder; Treatment Resistant Depression; iTBS; rTMS; Exercise; Physical inactivity