rTMS for Major Depressive Disorder

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Unity Health Toronto

Must be taking: Antidepressants

Must not be taking: Benzodiazepines

Disqualifiers: Pregnancy, Bipolar, Psychosis, Drug abuse, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 6 weeks

50 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not have started or changed the dose of any psychotropic medication in the four weeks before joining the study.

What data supports the effectiveness of the treatment rTMS for Major Depressive Disorder?

Several studies, including randomized controlled trials, have shown that repetitive transcranial magnetic stimulation (rTMS) can be effective in treating major depression, particularly in the short term. There is also evidence suggesting its potential for long-term maintenance therapy in patients who initially respond well to the treatment. ^{1 2 3 4 5}

Is rTMS safe for treating depression?

Repetitive transcranial magnetic stimulation (rTMS) is generally considered safe for treating depression, with common side effects including temporary headaches and local pain. Rarely, it can cause seizures or mood changes, but these are uncommon. Safety has been studied in both short-term and longer-term treatments, including in older adults. ^{6 7 8 9 10}

How is rTMS treatment different from other treatments for major depressive disorder?

Repetitive Transcranial Magnetic Stimulation (rTMS) is unique because it uses magnetic fields to stimulate nerve cells in the brain, which is different from medications or talk therapy. Unlike electroconvulsive therapy (ECT), rTMS is non-invasive and does not require anesthesia, making it a novel option for treating major depressive disorder. ^{1 3 11 12 13}

What is the purpose of this trial?

Major Depressive Disorder (MDD) is a very common illness that is usually treated with antidepressant medication. Depression can be caused by many things such as childhood experiences, genetics, and changes in the way the body and brain function. For those with depression where medication and psychotherapy have limited benefit, repetitive transcranial magnetic stimulation (rTMS) is an effective treatment. rTMS is a treatment that involves stimulating certain areas of the brain with magnetic field pulses. Over time, the magnetic field pulses can gradually change the activity level of the stimulated brain region. This can be helpful in treating some kinds of psychiatric and neurological disorder, including MDD. It is not fully known how rTMS changes brain activity to improve symptoms of depression. However, certain brain areas responsible for behaviours impacted by depression are underactive in those with depression. One of those brain regions called the dorsolateral prefrontal cortex (DLPFC), and the investigators will target this region using rTMS. By increasing the activity of these regions, rTMS could potentially improve depression symptoms. For participants receiving rTMS, the investigators will be using the participant's brain scan to better understand brain activity of the brain region stimulated by rTMS before and after treatment. In this study, the investigators will be collecting detailed information about participants' psychiatric history and depression symptoms, as well as brain scans and saliva samples. The saliva samples will undergo proteomic (having to do with proteins) analyses to identify biological markers ("biomarkers": biological features (e.g.: gene, protein) that can be measured to indicate factors related to rTMS response. The investigators' goal is to use this information to help us understand whether improvement to rTMS depends on brain activity or proteomic factors localized to two specific behaviours impacted by depression: reward processing and working memory (the capacity to hold information temporarily, such as holding a person's address in mind while listening to instructions about how to get there).

Eligibility Criteria

This trial is for English-speaking adults aged 18-65 with moderate to severe depression, diagnosed as per specific criteria and who haven't responded well to antidepressants. Participants should not have had medication changes or started psychotherapy recently. Pregnant individuals, those at acute suicide risk, with certain psychiatric or major medical conditions, drug abuse history, or contraindications for rTMS or MRI are excluded.

Inclusion Criteria

I have been in stable psychotherapy for depression for at least 3 months with no expected changes.

I have never taken antidepressants.

I have depression and haven't responded well to at least two different antidepressants.

Exclusion Criteria

I do not have major health issues needing immediate treatment, a pacemaker, or an implanted medication pump.

I have never had psychosis, schizophrenia, schizoaffective disorder, or delusional disorder.

I have not had ECT for my current depressive episode.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex (DLPFC) to improve depression symptoms

6 weeks

5 visits per week (in-person)

Follow-up

Participants are monitored for safety and effectiveness after rTMS treatment, including brain scans and saliva sample analyses

4 weeks

Treatment Details

Interventions

• Brain Scan
• Repetitive Transcranial Magnetic Stimulation
• Research Interview, Questionnaires
• Saliva Samples

Trial Overview The study tests if stimulating the brain's dorsolateral prefrontal cortex (DLPFC) using repetitive transcranial magnetic stimulation (rTMS) can improve symptoms of treatment-resistant depression. It involves brain scans before and after treatment to observe changes in DLPFC activity and saliva samples to identify biomarkers related to response.

Participant Groups

Group I: Depression Group Experimental Treatment 4 Interventions

Group II: Control Group Experimental Treatment 3 Interventions

Repetitive Transcranial Magnetic Stimulation is already approved in United States, European Union, Canada for the following indications:

Approved in United States as rTMS for:

• Major depressive disorder
• Obsessive-compulsive disorder
• Migraines

Approved in European Union as rTMS for:

• Major depressive disorder
• Obsessive-compulsive disorder
• Anxiety disorders

Approved in Canada as rTMS for:

• Major depressive disorder
• Obsessive-compulsive disorder

Who Is Running the Clinical Trial?

Unity Health Toronto

Lead Sponsor

Trials

572

Recruited

470,000+

Findings from Research

Repetitive transcranial magnetic stimulation (rTMS) has been shown to have a clear clinical effect in treating major depressive disorder, particularly with left high-frequency rTMS, based on a review of 24 meta-analyses.

The study suggests that rTMS is a justified treatment option for some patients with depression, while also highlighting the need for further research on its efficacy in different stimulation methods and in patients who have not previously received medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A happiness magnet? Reviewing the evidence for repetitive transcranial magnetic stimulation in major depressive disorder. Pridmore, W., Pridmore, S.[2021]

In a study involving 10 adults with major depressive disorder, long-term maintenance therapy using repetitive transcranial magnetic stimulation (rTMS) showed that 7 participants experienced significant benefits, with some maintaining improvement without additional antidepressant medications.

The treatment was found to be safe, with no serious adverse events reported and a zero seizure rate across 1831 rTMS sessions, suggesting that rTMS could be a viable long-term option for managing depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term maintenance therapy for major depressive disorder with rTMS. O'Reardon, JP., Blumner, KH., Peshek, AD., et al.[2022]

In a study involving 59 patients with major depression, repetitive transcranial magnetic stimulation (rTMS) did not show significant effectiveness compared to sham treatment, with no meaningful differences in depression scores between the two groups.

While there were slightly higher response and remission rates in the real rTMS group (32% and 25%, respectively) compared to the sham group (10% for both), these differences were not statistically significant, indicating that rTMS may not provide a clear benefit over placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized controlled trial with 4-month follow-up of adjunctive repetitive transcranial magnetic stimulation of the left prefrontal cortex for depression. Mogg, A., Pluck, G., Eranti, SV., et al.[2022]

A meta-analysis of 24 studies involving 911 patients found that maintenance rTMS can help stabilize mood symptoms for up to 5 months after an initial acute rTMS treatment for depression.

Patients receiving monthly or more frequent maintenance rTMS experienced sustained benefits for up to 6-12 months, while those without maintenance showed only minor changes in mood symptoms over the same period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trajectory of changes in depressive symptoms after acute repetitive transcranial magnetic stimulation: A meta-analysis of follow-up effects. Brian Chen, YC., Chou, PH., Tu, YK., et al.[2023]

Repetitive transcranial magnetic stimulation (rTMS) showed a statistically significant but small improvement in depression scores compared to sham treatment, with a weighted mean difference of 2.31 points, which is below the clinically important threshold of 3.5 points.

In comparison to electroconvulsive therapy (ECT), rTMS was less effective, with ECT showing a greater improvement in depression scores and higher rates of remission and response, indicating that ECT may be a more effective option for treatment-resistant depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. [2022]

Repetitive transcranial magnetic stimulation (rTMS) is generally a well-tolerated treatment for depression, with mild side effects like headaches being the most common, while severe adverse effects are rare.

Special precautions are necessary for certain groups, such as adolescents, pregnant women, and individuals with metal implants, but with proper assessment and monitoring, rTMS can be safely administered to many patients with depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation (TMS) safety: a practical guide for psychiatrists. Taylor, R., Galvez, V., Loo, C.[2019]

A patient with treatment-resistant depression (TRD) showed unexpected improvement after experiencing a seizure during repetitive transcranial magnetic stimulation (rTMS), suggesting a potential link between seizure activity and therapeutic effects in TRD.

While rTMS is generally safe, known adverse events include headaches and seizures; this case highlights an unusual outcome where a seizure may have contributed to the patient's improvement, warranting further investigation into the mechanisms of rTMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-Resistant Depression Entering Remission Following a Seizure during the Course of Repetitive Transcranial Magnetic Stimulation. Kim, JW., Bae, KY., Kim, SW., et al.[2020]

In a study involving 18 subjects with major depression, repetitive transcranial magnetic stimulation (rTMS) for up to 4 weeks was found to be generally safe, with no significant mean deficits in neuropsychologic function or auditory thresholds.

However, two patients experienced mild high-frequency hearing loss, indicating that while rTMS is safe for most, individual responses may vary and warrant further investigation into long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a 2- to 4-week course of repetitive transcranial magnetic stimulation (rTMS) on neuropsychologic functioning, electroencephalogram, and auditory threshold in depressed patients. Loo, C., Sachdev, P., Elsayed, H., et al.[2019]

Repetitive transcranial magnetic stimulation (rTMS) is generally safe for older adults with late-life depression, with only 12.4% reporting any adverse events and serious adverse events occurring in just 1.5% of cases, based on a review of 11 studies involving 353 patients.

The most common adverse events were mild, such as headaches (6.9%) and discomfort at the stimulation site (2.7%), although some serious adverse events, including psychiatric hospitalization and increased suicidal ideation, were noted in case reports, highlighting the need for further research to ensure safety in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events of repetitive transcranial magnetic stimulation in older adults with depression, a systematic review of the literature. Overvliet, GM., Jansen, RAC., van Balkom, AJLM., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) has been shown to be a safe and effective treatment for major depressive disorder (MDD), supported by multiple randomized controlled trials and extensive literature review.

The consensus recommendations from a group of 17 expert clinicians and researchers provide detailed guidance on the clinical application of rTMS, ensuring its safe and effective use in treating MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression. McClintock, SM., Reti, IM., Carpenter, LL., et al.[2022]

A network meta-analysis of 81 studies involving 4233 patients found that priming low-frequency and bilateral rTMS are the most effective and acceptable treatments for major depressive disorder (MDD), significantly outperforming sham treatments.

Novel rTMS interventions, such as accelerated and deep rTMS, did not show any additional efficacy compared to sham, indicating that more traditional methods remain the preferred options for treating MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation for the Acute Treatment of Major Depressive Episodes: A Systematic Review With Network Meta-analysis. Brunoni, AR., Chaimani, A., Moffa, AH., et al.[2022]

In a study of 40 patients with major depressive disorder (MDD), electroconvulsive therapy (ECT) was found to be more effective than repetitive transcranial magnetic stimulation (rTMS), especially in patients with MDD and psychosis.

For patients with MDD without psychosis, rTMS showed similar efficacy to ECT, suggesting that rTMS could be a viable treatment option for this subgroup, but further blinded studies are needed to clarify its role.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: an open study. Grunhaus, L., Dannon, PN., Schreiber, S., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) has shown statistically significant effects in treating major depression, with 29 studies reviewed indicating that factors like high treatment resistance and advanced age negatively predict treatment response.

Effective rTMS treatment parameters include using stimulation intensity above 100% of the motor threshold and more than 1000 stimulations per session, with older patients requiring higher intensity due to cortical atrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Repetitive transcranial magnetic stimulation in major depression: response factor]. Dumas, R., Padovani, R., Richieri, R., et al.[2012]

References

1. England pubmed.ncbi.nlm.nih.gov

A happiness magnet? Reviewing the evidence for repetitive transcranial magnetic stimulation in major depressive disorder. [2021]

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

Long-term maintenance therapy for major depressive disorder with rTMS. [2022]

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

A randomized controlled trial with 4-month follow-up of adjunctive repetitive transcranial magnetic stimulation of the left prefrontal cortex for depression. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Trajectory of changes in depressive symptoms after acute repetitive transcranial magnetic stimulation: A meta-analysis of follow-up effects. [2023]

5. Canada pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. [2022]

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

Transcranial magnetic stimulation (TMS) safety: a practical guide for psychiatrists. [2019]

7. Korea (South) pubmed.ncbi.nlm.nih.gov

Treatment-Resistant Depression Entering Remission Following a Seizure during the Course of Repetitive Transcranial Magnetic Stimulation. [2020]

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

Effects of a 2- to 4-week course of repetitive transcranial magnetic stimulation (rTMS) on neuropsychologic functioning, electroencephalogram, and auditory threshold in depressed patients. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Adverse events of repetitive transcranial magnetic stimulation in older adults with depression, a systematic review of the literature. [2021]

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

Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression. [2022]

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

Repetitive Transcranial Magnetic Stimulation for the Acute Treatment of Major Depressive Episodes: A Systematic Review With Network Meta-analysis. [2022]

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

Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: an open study. [2021]

13. France pubmed.ncbi.nlm.nih.gov

[Repetitive transcranial magnetic stimulation in major depression: response factor]. [2012]