rTMS Therapy for Depression

(SUNSET Trial)

Overseen By Tien Dam

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of California, San Francisco

Disqualifiers: Psychotic disorders, Neurological conditions, Substance 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: 33

Duration: 6-8 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is a stratified, parallel-group, single-center study utilizing multimodal imaging techniques to identify biomarkers for Major Depressive Disorder (MDD). The study goal is to identify biomarkers for MDD and treatment response that can be implemented in clinical diagnosis and care as valid and reliable measures, through monitoring neurophysiological and electrophysiological changes across the course of transcranial magnetic stimulation (TMS) treatment.

Will I have to stop taking my current medications?

The trial does not require you to stop taking your current medications. If you are on a regimen of psychotropic medication, you should not make any changes to it during the study.

What data supports the effectiveness of the treatment rTMS therapy for depression?

Repetitive transcranial magnetic stimulation (rTMS) has been shown to be effective in treating depression, with over 20 years of clinical trials supporting its use. It has been particularly beneficial for patients who have not responded well to traditional drug treatments, and studies suggest it is effective for both younger and older patients with depression. ^{1 2 3 4 5}

Is rTMS therapy safe for humans?

Repetitive transcranial magnetic stimulation (rTMS) is generally considered safe for treating depression, with common side effects including mild headaches and local pain. Rarely, it can cause seizures, but this is uncommon. Safety has been studied in both short-term and longer courses of treatment. ^{6 7 8 9 10}

How is rTMS therapy different from other treatments for depression?

rTMS therapy is unique because it uses magnetic fields to stimulate nerve cells in the brain, which is different from medications that work through chemical changes. It is a non-invasive treatment, meaning it doesn't require surgery or medication, and has been shown to be effective for people who haven't responded to other treatments. ^{1 4 11 12 13}

Research Team

Andrew Krystal, MD, MS

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for adults aged 18-70 with Major Depressive Disorder currently experiencing a depressive episode without psychotic features. Participants must have moderate to severe depression, have tried 1-4 antidepressants without success, and be stable on current medications if any. They should be able to undergo non-invasive brain stimulation and commit to research visits for about 8 weeks.

Inclusion Criteria

I am willing and able to have a treatment that involves stimulating my brain without surgery.

I've tried 1-4 antidepressants without success in this episode.

Has MADRS of > 19 at baseline, corresponding with moderate to severe depression

Exclusion Criteria

Presence of an implanted magnetic-sensitive medical device in or near the head, including but not limited to pacemaker, vagus nerve stimulator, or metal aneurysm clips or coils, staples, or stents

Inability to comply with study daily visits

Inability to speak and/or read English

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline Evaluation

Participants undergo baseline evaluation including resting-state fMRI, DTI, and EEG scans prior to TMS treatment

1 week

1 visit (in-person)

Treatment

Participants receive 30-40 daily sessions of rTMS to the dorsolateral prefrontal cortex, with mid- and post-treatment fMRI, DTI, and EEG scans

6-8 weeks

30-40 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including post-treatment evaluations

4 weeks

1-2 visits (in-person)

Treatment Details

Interventions

• rTMS therapy

Trial Overview The study tests the effectiveness of rTMS therapy in treating Major Depressive Disorder by monitoring changes in brain activity through imaging techniques. It aims to identify reliable biomarkers that can predict treatment response and aid clinical diagnosis.

Participant Groups

Group I: Morning rTMS treatment Experimental Treatment 1 Intervention

Eligible participants will be assigned to the afternoon treatment group. Prior to the onset of rTMS treatment, EEG scans and magnetic resonance imaging (MRI) sessions including diffusion weighted imaging will be recorded as baseline measures. These measures will also be repeated at treatment midpoint and within one month of rTMS discontinuation in order to track structural and functional changes that occur over the course of treatment. Participants will complete an initial screening followed by 30-40 daily sessions of repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC), completed with their TMS provider.

Group II: Afternoon rTMS treatment Experimental Treatment 1 Intervention

Eligible participants will be assigned to the afternoon treatment group. Prior to the onset of rTMS treatment, EEG scans and magnetic resonance imaging (MRI) sessions including diffusion weighted imaging will be recorded as baseline measures. These measures will also be repeated at treatment midpoint and within one month of rTMS discontinuation in order to track structural and functional changes that occur over the course of treatment. Participants will complete an initial screening followed by 30-40 daily sessions of repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC), completed with their TMS provider.

rTMS therapy is already approved in United States, European Union, Canada for the following indications:

Approved in United States as rTMS therapy for:

• Major Depressive Disorder (MDD)
• Treatment-resistant depression

Approved in European Union as rTMS therapy for:

• Major Depressive Disorder (MDD)
• Treatment-resistant depression

Approved in Canada as rTMS therapy for:

• Major Depressive Disorder (MDD)
• Treatment-resistant depression

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Findings from Research

High-frequency rTMS targeting the left dorsolateral prefrontal cortex is an effective treatment for acute episodes of major depressive disorder, supported by over 20 years of clinical trials.

While rTMS is effective for unipolar and likely bipolar depression, there is limited evidence for its effectiveness in the maintenance phase of treatment, indicating a need for ongoing research and practitioner education.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the clinical use of repetitive transcranial magnetic stimulation in the treatment of depression. Fitzgerald, PB.[2021]

A systematic review of 98 randomized controlled trials on repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder revealed that none of the interventions were fully described, which hinders their implementation in clinical practice.

After contacting authors for additional information, only 10.4% of interventions were completely described, highlighting the need for better adherence to reporting guidelines like the TIDieR checklist to ensure clarity and efficacy in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Completeness of Descriptions of Repetitive Transcranial Magnetic Stimulation Intervention: A Systematic Review of Randomized Controlled Trials of rTMS in Depression. Chantebel, R., Chesneau, A., Tavernier, E., et al.[2019]

Repetitive transcranial magnetic stimulation (rTMS) has shown effectiveness in treating depression, particularly in patients who have not responded well to conventional drug treatments.

A case study highlighted in the report demonstrates that a patient who experienced multiple relapses with standard medications responded positively to rTMS at three different times, suggesting its potential as a reliable alternative treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation is effective following repeated courses in the treatment of major depressive disorder--a case report. Dannon, PN., Grunhaus, L.[2014]

Repetitive Transcranial Magnetic Stimulation (rTMS) shows potential efficacy in treating depression in older patients, with some studies indicating a decrease in depression scores, although only about 25% of patients experienced significant remission.

rTMS is generally safe and does not lead to cognitive deficits, even in elderly patients with cerebrovascular disease, but factors like older age and reduced frontal gray matter volume may negatively impact treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapeutic efficacy and safety of repetitive Transcranial Magnetic Stimulation in depressions of the elderly: a review]. Jalenques, I., Legrand, G., Vaille-Perret, E., et al.[2010]

Accelerated rTMS treatment, involving 15 sessions over 3 days, led to a more rapid improvement in depressive symptoms compared to sham treatment, indicating its efficacy for patients with major depressive disorder (MDD).

The safety profile of accelerated rTMS was comparable to that of conventional rTMS, suggesting that it is a viable and more accessible treatment option for MDD patients, without increased adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid Symptom Improvement in Major Depressive Disorder Using Accelerated Repetitive Transcranial Magnetic Stimulation. Kim, SJ., Son, SJ., Jang, M., et al.[2022]

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]

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]

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]

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]

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]

Repetitive transcranial magnetic stimulation (rTMS) has been primarily used to treat major depressive disorder (MDD), highlighting its importance in addressing a significant global health challenge.

Recent advancements in rTMS include exploring new stimulation patterns, targets, and personalized treatment approaches, which aim to enhance the effectiveness and response rates of rTMS in treating MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation treatment for depressive disorders: current knowledge and future directions. Baeken, C., Brem, AK., Arns, M., et al.[2020]

High-frequency rTMS targeting the left dorsolateral prefrontal cortex is an effective treatment for major depressive disorder, supported by over 15 years of research and the authors' 10 years of clinical experience.

While other rTMS techniques, such as low-frequency stimulation to the right prefrontal cortex, show potential, they need further evaluation in larger trials to confirm their efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A practical guide to the use of repetitive transcranial magnetic stimulation in the treatment of depression. Fitzgerald, PB., Daskalakis, ZJ.[2022]

A study involving 145 first-time patients with treatment-resistant depression found that 15-minute rTMS sessions were as effective as 30-minute sessions in achieving response and remission rates over 6 weeks.

Both treatment durations resulted in similar outcomes, with the 15-minute sessions showing a partial response rate of 28.2% and a remission rate of 21.8%, indicating that shorter sessions could allow for more patients to be treated with the same resources.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of 15 minute vs 30 minute repetitive transcranial magnetic stimulation sessions for treatment resistant depression - are longer treatment sessions more effective? Ford, H., Hahn, L., Clarke, P., et al.[2021]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

An update on the clinical use of repetitive transcranial magnetic stimulation in the treatment of depression. [2021]

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

Completeness of Descriptions of Repetitive Transcranial Magnetic Stimulation Intervention: A Systematic Review of Randomized Controlled Trials of rTMS in Depression. [2019]

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

Repetitive transcranial magnetic stimulation is effective following repeated courses in the treatment of major depressive disorder--a case report. [2014]

4. France pubmed.ncbi.nlm.nih.gov

[Therapeutic efficacy and safety of repetitive Transcranial Magnetic Stimulation in depressions of the elderly: a review]. [2010]

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

Rapid Symptom Improvement in Major Depressive Disorder Using Accelerated Repetitive Transcranial Magnetic Stimulation. [2022]

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

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

8. 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]

9. 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]

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

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

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

Repetitive transcranial magnetic stimulation treatment for depressive disorders: current knowledge and future directions. [2020]

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

A practical guide to the use of repetitive transcranial magnetic stimulation in the treatment of depression. [2022]

13. Netherlands pubmed.ncbi.nlm.nih.gov

A comparison of 15 minute vs 30 minute repetitive transcranial magnetic stimulation sessions for treatment resistant depression - are longer treatment sessions more effective? [2021]