rTMS for Depression

Overseen By Corey Keller, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Stanford University

Must not be taking: Olanzapine, chlorpromazine, lithium

Disqualifiers: Neurological disease, substance abuse, psychotic, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 4 sessions, each lasting 30 minutes

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach for treating major depression using rTMS (Repetitive Transcranial Magnetic Stimulation), which involves magnetic stimulation of the brain. The focus is on personalizing the treatment by precisely targeting the brain's central executive network (CEN). The trial will compare this personalized method to other rTMS techniques to determine which is most effective. Individuals with major depression who experience persistent low mood and energy might be suitable candidates, provided they do not have conditions like neurological disorders or a history of seizures.

As an unphased trial, this study offers an opportunity to contribute to innovative research that could lead to more personalized and effective treatments for major depression.

Will I have to stop taking my current medications?

The trial requires that you do not take any 'as needed' medications within 24 hours of your study appointment and you cannot be on medications that lower the seizure threshold, like olanzapine, chlorpromazine, or lithium.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that repetitive transcranial magnetic stimulation (rTMS) is generally safe for treating depression. Research indicates that a personalized approach with rTMS is safe and may alleviate depression. Most people tolerate it well, though some might experience mild side effects like headaches or scalp discomfort.

For neuronavigated rTMS, studies have demonstrated its effectiveness in improving depression symptoms. While side effects may occur, they are usually mild and resolve on their own.

Scalp-targeted rTMS has also proven to be a safe treatment for depression. It is non-invasive, meaning it doesn't involve surgery or anything entering the body. Mild side effects like headaches might occur, but they typically resolve quickly.

Overall, rTMS is considered a safe option for many people dealing with depression, with minor side effects that don't last long. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores how individualized CEN-targeted rTMS can be a game-changer for treating depression. Unlike traditional rTMS, which usually targets the dlPFC in a more generalized way, this approach uses advanced neuronavigation and TMS-EEG to pinpoint the exact part of the brain's dlPFC that connects most strongly with the CEN. This precision aims to make the treatment more effective by directly influencing the brain's network involved in depression, potentially offering faster and more robust relief than current options like standard rTMS, medications, or psychotherapy. The trial also includes different rTMS methods like neuronavigated and scalp-targeted rTMS, allowing researchers to compare their effectiveness and safety, offering hope for more personalized and efficient depression therapies.

What evidence suggests that this trial's treatments could be effective for depression?

Studies have shown that rTMS, or repetitive transcranial magnetic stimulation, effectively treats depression. This trial will compare different rTMS approaches. Participants may receive Individualized CEN-targeted rTMS, which customizes treatment to each person's brain, potentially enhancing effectiveness. Another group will receive Neuronavigated rTMS, guided by MRI images. Research suggests this method can significantly reduce depression symptoms, with a success rate of up to 62%. Additionally, some participants will receive Scalp-targeted rTMS, which has proven effective, showing clear improvements in depression compared to Sham rTMS, a fake treatment used for comparison. Overall, these methods show promise in reducing depression symptoms. ^{5 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with major depression, as confirmed by a clinical interview. Participants must understand English, have no seizure risk or neurological disorders, not be using certain medications or substances, and not be pregnant. They should also have a significant level of depression severity.

Inclusion Criteria

PHQ9 > 10 for disease severity

Must comprehend English well to ensure adequate comprehension of the EEG and TMS instructions, and of clinical scales

Right-handed

Exclusion Criteria

Active substance abuse

I am taking medication that could make it easier for me to have seizures.

I have been diagnosed with a psychotic or bipolar disorder.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Diagnostic Session

Participants undergo a diagnostic session including a Structured Clinical Interview for DSM5 (SCID-I62) and a PHQ9 assessment

1 session

MRI Session

Participants undergo a 30-minute MRI session to record structural brain data

30 minutes

Treatment

Participants receive rTMS targeting the dlPFC using different methods including individualized CEN targeting, structural MRI, and standard scalp targeting

4 sessions, each lasting 30 minutes

4 visits (in-person)

Sham rTMS

Participants receive a sham rTMS session to control for off-target effects

1 session, lasting 30 minutes

Follow-up

Participants are monitored for changes in TMS-EEG measures and behavioral changes in attention and working memory

Up to 2 hours

What Are the Treatments Tested in This Trial?

Interventions

• Individualized CEN-targeted rTMS
• Neuronavigated rTMS
• Scalp-targeted rTMS
• Sham rTMS

Trial Overview The study tests whether personalized rTMS targeting the central executive network can better improve symptoms in those with depression compared to standard approaches. It's a randomized and double-blind experiment involving different types of rTMS including sham (placebo) treatment.

How Is the Trial Designed?

Group I: Individualized CEN-targeted rTMS Experimental Treatment 2 Interventions

Individualized CEN-targeted rTMS will combine neuronavigated rTMS and single pulse TMS-EEG to identify the region of the dlPFC making the strongest connection with the parietal node of the CEN. First, regions of the dlPFC strongly connected to the parietal CEN will be identified by applying single TMS pulses in grid-like fashion to ROIs within the dlPFC. For each anatomical dlPFC subunit probed with TMS, the TMS-EEG response will be quantified in the parietal region of the CEN. The dlPFC subunit that demonstrates the strongest TMS-EEG response in parietal cortex will be chosen for rTMS. rTMS will last approximately 30 minutes (3000 pulses total) and will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the rTMS session for adverse events and/or side effects.

Group II: Neuronavigated rTMS Active Control 2 Interventions

Neuronavigated rTMS will be delivered using neuro-navigation based on participants' own MRI images to target the dlPFC. rTMS will last approximately 30 minutes (3000 pulses total) and will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the rTMS session for adverse events and/or side effects.

Group III: Scalp-targeted rTMS Active Control 2 Interventions

Scalp-targeted rTMS will be delivered using standard BEAM F3 targeting methodology to target the dlPFC. rTMS will last approximately 30 minutes (3000 pulses total) and will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the rTMS session for adverse events and/or side effects.

Group IV: Sham rTMS Placebo Group 1 Intervention

Sham rTMS will be delivered for one session to mimic active rTMS conditions. To maximize sham validity, both 1) a direction- sensor TMS coil will alert the operators to flip the coil if the wrong side is being used, and 2) low-intensity electrical stimulation to match the active rTMS frequency will be applied to scalp electrodes under the coil for sham and placed but not activated in the active arm. The rTMS coil will be positioned using neuro-navigation based on participants' own MRI images, mimicking active rTMS. Sham rTMS will last approximately 30 minutes (3000 pulses total) and will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the sham rTMS session for adverse events and/or side effects.

Individualized CEN-targeted rTMS 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
• Smoking Cessation

Approved in European Union as rTMS for:

• Major Depressive Disorder
• Obsessive-Compulsive Disorder

Approved in Canada as rTMS for:

• Major Depressive Disorder
• Obsessive-Compulsive Disorder

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

A case study of a 40-year-old woman with drug-resistant depression showed that using a navigation system to accurately target the prefrontal cortex during rTMS led to more significant antidepressant effects compared to the standard targeting method.

The standard method for locating the prefrontal cortex may misidentify the target area, as it incorrectly stimulated Broca's area instead, highlighting the importance of precise targeting in rTMS for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The value of navigation-guided rTMS for the treatment of depression: an illustrative case. Lefaucheur, JP., Brugières, P., Ménard-Lefaucheur, I., et al.[2007]

Recent studies on repetitive transcranial magnetic stimulation (rTMS) for depression have demonstrated significantly improved clinical outcomes, with a pooled effect size of -0.76 from 5 studies involving 274 patients, compared to -0.35 from earlier studies.

The findings indicate that new parameters of rTMS stimulation may enhance its antidepressant effects, suggesting a potential advancement in treatment strategies for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and meta-analysis comparing the recent vs. the earlier rTMS studies. Gross, M., Nakamura, L., Pascual-Leone, A., et al.[2018]

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]

Repetitive transcranial magnetic stimulation (rTMS) can be more effective for treating major depressive disorder if personalized to individual patients' brain characteristics and specific symptoms, rather than using a one-size-fits-all approach.

A proposed three-step process for optimizing rTMS involves identifying the patient's symptom pattern, determining the precise brain target using neuroimaging, and adjusting coil positioning through computational modeling, although further randomized clinical trials are needed to confirm the benefits of these personalized protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personalizing Repetitive Transcranial Magnetic Stimulation Parameters for Depression Treatment Using Multimodal Neuroimaging. Klooster, DCW., Ferguson, MA., Boon, PAJM., et al.[2022]

In a study involving 41 patients with medication-refractory depression, the effectiveness of repetitive transcranial magnetic stimulation (rTMS) was significantly predicted by stimulation sites that were more anterolateral and had negative connectivity with the subgenual cingulate.

The strongest predictor of response to active rTMS was the functional connectivity between the stimulation site and the subgenual cingulate, suggesting that targeting this connectivity could enhance treatment outcomes for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective Validation That Subgenual Connectivity Predicts Antidepressant Efficacy of Transcranial Magnetic Stimulation Sites. Weigand, A., Horn, A., Caballero, R., et al.[2019]

This study demonstrates that individualized TMS (transcranial magnetic stimulation) coil placement can effectively activate deeper brain regions, specifically Brodmann area 25 (BA25), by targeting the right frontal pole, based on structural imaging data from ten subjects.

The results showed a significant increase in brain activation in BA25 in nine out of ten subjects, indicating that TMS can influence deeper brain structures in a dosage-dependent manner, potentially enhancing its therapeutic applications for psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Using diffusion tensor imaging to effectively target TMS to deep brain structures. Luber, B., Davis, SW., Deng, ZD., et al.[2023]

Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment for major depressive disorder (MDD), particularly for patients who do not respond to traditional therapies, and may be tailored to individual patient characteristics.

The review emphasizes the importance of identifying and validating patient-specific factors, such as genetic and neuroimaging biomarkers, to optimize rTMS treatment and move towards a personalized medicine approach in depression care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of Clinical Features and Biomarkers that may inform a Personalized Approach to rTMS for Depression. Garnaat, SL., Fukuda, AM., Yuan, S., et al.[2021]

In a pilot study involving 19 medication-resistant depressed subjects, bilateral prefrontal repetitive transcranial magnetic stimulation (rTMS) did not show superior efficacy compared to sham treatment over 3 weeks, as both groups experienced similar improvements in mood.

Despite the lack of significant differences in mood improvement, rTMS was found to be safe, with no neuropsychological impairments reported in either the active or sham treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression. Loo, CK., Mitchell, PB., Croker, VM., et al.[2019]

Transcranial Magnetic Stimulation (TMS), particularly repetitive TMS (rTMS) over the frontal cortex, has been shown to be clinically effective in treating depression, with numerous trials supporting its therapeutic potential over the past two decades.

Despite its effectiveness, there is currently no widely accepted 'gold standard' protocol for rTMS treatment, highlighting the need for further research to optimize factors such as localization, frequency, and intensity for better efficacy and tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

UNANSWERED QUESTIONS IN THE TRANSCRANIAL MAGNETIC STIMULATION TREATMENT OF PATIENTS WITH DEPRESSION. Morvai, S., Nagy, A., Kovács, A., et al.[2019]

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]

In a study of 26 patients with major depressive disorder, a personalized, connectome-guided approach to repetitive transcranial magnetic stimulation (rTMS) resulted in a 62% remission rate, indicating its potential efficacy in treating depression.

Patients showed significant improvements in quality of life and depression symptoms, with 68% achieving significant remission at follow-up, suggesting that this tailored rTMS method may be more effective than standard one-size-fits-all strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personalized, parcel-guided rTMS for the treatment of major depressive disorder: Safety and proof of concept. Tang, SJ., Holle, J., Dadario, NB., et al.[2023]

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) has shown statistical superiority over sham therapy for treating depression, particularly with left-prefrontal high frequency stimulation, but the actual clinical benefits are often marginal.

Factors such as younger age, absence of treatment-resistant depression, and no psychotic features are associated with a better response to rTMS, highlighting the need for further research to optimize treatment parameters and confirm its clinical utility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation for depression. Mitchell, PB., Loo, CK.[2017]

Citations

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A sequential dual-site repetitive transcranial magnetic ... Repetitive transcranial magnetic stimulation (rTMS) is approved for major depressive disorder (MDD), but it is limited by variable efficacy.

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Efficacy and Safety of Magnetic Resonance Imaging ... This study aims to assess the feasibility, safety, acceptability, and preliminary efficacy trends of a Magnetic Resonance Imaging-guided ...

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Repetitive Transcranial Magnetic Stimulation as ... This randomized clinical trial of 75 participants with TRD showed that rTMS and lithium had comparable efficacy in preventing TRD relapse.