Exercise + TMS for Treatment Resistant Depression

Overseen By Ana M. Abrantes, Ph.D.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Butler Hospital

Disqualifiers: Pregnancy

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 30

Duration: 6 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

Given the growing evidence that aerobic increases cortical excitability and promotes neuroplasticity, the scientific premise for its potential priming effect on the brain is strong. Combining AE with rTMS may produce a neural environment optimized for a robust physiological effect of rTMS, thereby leading to improved depression outcomes. With positive findings, this study would provide preliminary support for an innovative, safe and feasible approach for improving outcomes for this significant public health problem.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the treatment Exercise + TMS for Treatment Resistant Depression?

Research shows that aerobic exercise can significantly reduce depression symptoms, and transcranial magnetic stimulation (TMS) has been effective in treating major depressive disorder, especially when other treatments haven't worked. Combining these approaches may offer a promising option for those with treatment-resistant depression. ^{1 2 3 4 5}

Is exercise safe for people with depression?

Exercise, including aerobic exercise, is generally considered safe for people with depression and can be an effective addition to other treatments. While more high-quality studies are needed, current research suggests that exercise can be safely integrated into treatment plans for depression. ^{2 6 7 8 9}

How does the Exercise + TMS treatment differ from other treatments for treatment-resistant depression?

The Exercise + TMS treatment is unique because it combines physical exercise with transcranial magnetic stimulation (TMS), a non-invasive technique that uses magnetic fields to stimulate nerve cells in the brain. This combination may offer a novel approach by potentially enhancing the effects of TMS, which is already used for treatment-resistant depression, through the added benefits of exercise. ^{3 4 5 10 11}

Eligibility Criteria

This trial is for adults over 18 with treatment-resistant depression who are approved for standard TMS therapy at Butler Hospital's clinic and can safely do moderate-intensity exercise.

Inclusion Criteria

Able to safely engage in moderate-intensity aerobic exercise (determined by a study physician)

I am over 18 and approved for TMS therapy at Butler Hospital.

Exclusion Criteria

Currently pregnant or plans to become pregnant in the next 6 weeks

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 30 sessions of rTMS treatment, with either aerobic exercise or video watching prior to each session

6 weeks

30 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Aerobic Exercise
• Video Watching

Trial Overview The study tests if doing aerobic exercise before receiving repetitive Transcranial Magnetic Stimulation (rTMS) improves outcomes in treating major depressive disorder compared to just watching videos.

Participant Groups

Group I: Video Condition Experimental Treatment 1 Intervention

In this condition, participants will be asked to sit and watch various documentaries or educational videos on topics NOT related to physical activity. These will last approximately 20 minutes and will occur before each TMS session.

Group II: Aerobic Exercise Experimental Treatment 1 Intervention

Exercise sessions will be 20 minutes of moderate-intensity aerobic exercise on a treadmill. A treadmill is located on D1A within the space shared by the Butler Hospital TMS Clinic and the COBRE-support Neuromodulation Research Facility. A research staff member will monitor their heart rate and blood pressure to ensure safety and that activity is occurring at a moderate intensity (i.e., 64-76% of age predicted maximal heart rate). Participants will be asked to rate their affect and rating of perceived exertion (RPE) during exercise sessions. Sessions will include a 5-min warm-up and a 5-min cool-down to ensure safe exercise procedures. Participants will be asked to answer questions about affect before, during, and after exercise. These sessions will be supervised (i.e., they provide onsite coverage) by an exercise physiologist or medical staff member (e.g., nurse or physician) to ensure safety.

Who Is Running the Clinical Trial?

Butler Hospital

Lead Sponsor

Trials

133

Recruited

16,700+

National Institute of General Medical Sciences (NIGMS)

Collaborator

Trials

315

Recruited

251,000+

Findings from Research

In an open-label extension study of trans-cranial magnetic stimulation (TMS) involving patients with medication-resistant major depressive disorder, those who previously received sham treatment showed a significant mean reduction in depression scores (MADRS) of -17.0 after 6 weeks of active TMS, with 42.4% achieving a response and 20.0% reaching remission.

Patients who had not responded to initial active TMS also benefited from continued treatment, showing a mean reduction of -12.5 in MADRS scores, with 26.0% responding and 11.0% remitting, indicating that longer courses of TMS may enhance therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation in the acute treatment of major depressive disorder: clinical response in an open-label extension trial. Avery, DH., Isenberg, KE., Sampson, SM., et al.[2019]

Aerobic exercise (AE) has been shown to have a significant antidepressant effect in clinically depressed adults, with a large effect size (g = -0.79) based on a meta-analysis of 11 trials involving 455 patients.

The study found that AE was effective across various settings and formats, and it worked similarly for both outpatients and inpatients, regardless of the severity of their symptoms, suggesting its broad applicability as a treatment for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerobic exercise for adult patients with major depressive disorder in mental health services: A systematic review and meta-analysis. Morres, ID., Hatzigeorgiadis, A., Stathi, A., et al.[2019]

This study is a large-scale, multicenter clinical trial involving 360 Veterans with treatment-resistant major depression (TRMD) to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) compared to sham treatment over 30 sessions.

The trial uniquely includes Veterans with posttraumatic stress disorder (PTSD) and substance abuse histories, aiming to assess a wide range of predictors for treatment response, with the primary outcome being the remission rate measured by the Hamilton Rating Scale for Depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depression (TRMD) Veteran patients: study protocol for a randomized controlled trial. Mi, Z., Biswas, K., Fairchild, JK., et al.[2018]

This study is the largest to investigate the use of 10-Hz transcranial magnetic stimulation (TMS) for treating treatment-resistant depression (TRD) in adolescents, involving 103 participants aged 12-21 over 6 weeks.

While TMS showed a clinically meaningful reduction in depression symptoms, the results were not significantly better than those from the sham treatment, indicating that further research is needed to enhance its efficacy and understand the placebo effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Left prefrontal transcranial magnetic stimulation for treatment-resistant depression in adolescents: a double-blind, randomized, sham-controlled trial. Croarkin, PE., Elmaadawi, AZ., Aaronson, ST., et al.[2022]

An accelerated transcranial magnetic stimulation (TMS) protocol using intermittent theta burst stimulation (iTBS) was safely administered to 19 veterans, with 17 completing the treatment, showing significant reductions in depression symptoms.

The remission and response rates were 47.1% and 64.7%, respectively, indicating that this accelerated protocol is as effective as traditional TMS treatments that last 6 to 9 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An accelerated course of TMS using intermittent theta burst for veterans with major depressive disorder: A case series. Zuschlag, ZD., Bajor, L., Van Trees, K., et al.[2023]

This systematic review aims to evaluate how different types of exercise—specifically aerobic, resistance, and meditative movement—affect sleep quality in patients with unipolar depression, using a comprehensive search of multiple databases and rigorous methodology.

The study will assess not only sleep quality but also secondary outcomes like sleep duration, daytime functioning, and the use of sleep medications, providing a thorough understanding of the potential benefits and risks of exercise interventions for improving sleep in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of aerobic, resistance, and meditative movement exercise on sleep in individuals with depression: protocol for a systematic review and network meta-analysis. Brupbacher, G., Gerger, H., Wechsler, M., et al.[2023]

A 24-week study involving 40 individuals with major depression showed that both aerobic exercise (AE) and aerobic exercise with motor complexity (AEMC) significantly reduced feelings of hopelessness and improved emotional responses, indicating their efficacy in treating depression.

Only AE was found to increase the volumes of brain regions associated with emotional control, such as the amygdala, thalamus, and nucleus accumbens, suggesting that AE may promote brain plasticity in addition to its clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and neuroimaging correlates in a pilot randomized trial of aerobic exercise for major depression. Moreira-Neto, A., Neves, LM., Miliatto, A., et al.[2023]

A systematic review of 22 randomized controlled trials found that exercise and various complementary and alternative medicine (CAM) treatments showed similar efficacy to second-generation antidepressants (SGAs) for major depressive disorder, but the evidence quality was low or insufficient due to bias in the studies.

The risk of adverse events and treatment discontinuation was higher for selective serotonin reuptake inhibitors compared to St. John's wort, suggesting that some CAM options may have a better safety profile than traditional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Benefits and Harms of Complementary and Alternative Medicine Therapies for Initial Treatment of Major Depressive Disorder: Systematic Review and Meta-Analysis. Asher, GN., Gartlehner, G., Gaynes, BN., et al.[2022]

Exercise combined with antidepressants shows strong effectiveness in treating major depressive disorder, according to a systematic review of 13 studies, despite some methodological weaknesses.

This adjunctive treatment strategy could be safely implemented in clinical practice, offering a potential alternative for patients who do not respond well to standard antidepressant therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review. Mura, G., Moro, MF., Patten, SB., et al.[2022]

Transcranial magnetic stimulation (TMS) is an effective treatment for treatment-resistant depression (TRD) and has gained FDA approval, but many new psychiatry residents lack exposure to it.

A self-learning module (SLM) significantly improved residents' understanding of TMS, with agreement on educational objectives rising from 64-86% before the module to 79-93% after completion, indicating its efficacy as an educational tool.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial Magnetic Stimulation for Treatment-Resistant Depression: An Interactive Self-Learning Module. Wang, J., Nelson, B.[2020]

Repetitive transcranial magnetic stimulation (rTMS) has been shown to be an effective and safe treatment for treatment-resistant depression (TRD), with 16 out of 17 studies indicating positive outcomes in reducing depressive symptoms.

The review included 17 randomized controlled trials published in the last five years, highlighting the need for further research to establish standardized protocols for rTMS application, including factors like frequency and intensity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation for the Treatment of Resistant Depression: A Scoping Review. Adu, MK., Shalaby, R., Chue, P., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation in the acute treatment of major depressive disorder: clinical response in an open-label extension trial. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Aerobic exercise for adult patients with major depressive disorder in mental health services: A systematic review and meta-analysis. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depression (TRMD) Veteran patients: study protocol for a randomized controlled trial. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Left prefrontal transcranial magnetic stimulation for treatment-resistant depression in adolescents: a double-blind, randomized, sham-controlled trial. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

An accelerated course of TMS using intermittent theta burst for veterans with major depressive disorder: A case series. [2023]

6. England pubmed.ncbi.nlm.nih.gov

The effects of aerobic, resistance, and meditative movement exercise on sleep in individuals with depression: protocol for a systematic review and network meta-analysis. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical and neuroimaging correlates in a pilot randomized trial of aerobic exercise for major depression. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Comparative Benefits and Harms of Complementary and Alternative Medicine Therapies for Initial Treatment of Major Depressive Disorder: Systematic Review and Meta-Analysis. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Transcranial Magnetic Stimulation for Treatment-Resistant Depression: An Interactive Self-Learning Module. [2020]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation for the Treatment of Resistant Depression: A Scoping Review. [2022]