Neuromodulation for Treatment-Resistant Depression

Overseen By David Spiegel, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Stanford University

Must be taking: Antidepressants

Must not be taking: Ketamine, ECT

Disqualifiers: Pregnancy, Psychotic disorder, Substance use, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 4-8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new brain stimulation approach for individuals with depression that hasn't improved with usual treatments. The treatment, called accelerated intermittent theta burst stimulation (aiTBS), aims to reduce anhedonia, or the lack of enjoyment in life. Participants will receive either the actual aiTBS treatment or a sham (fake) version for comparison. This trial is best suited for those experiencing a current major depressive episode who have tried other treatments without success, are not currently facing substance abuse issues, and have not undergone extensive past treatments like ECT (electroconvulsive therapy). As an unphased trial, this study offers a unique opportunity to explore a novel treatment option for depression.

Will I have to stop taking my current medications?

No, you will not have to stop taking your current medications. Participants must be on a stable antidepressant regimen for 6 weeks before joining the study and agree to continue it throughout the study.

What prior data suggests that this neurostimulation strategy is safe for treatment-resistant depression?

Research has shown that accelerated intermittent theta burst stimulation (aiTBS) is generally safe for people. In past studies, patients with treatment-resistant depression (TRD) who received aiTBS experienced positive outcomes. These studies found that aiTBS was well-tolerated, with no serious side effects.

One study found that a specific aiTBS method was both safe and effective for TRD. Another study highlighted its promising effects in quickly reducing depression symptoms. Additionally, those who received aiTBS showed more improvement in anxiety and depression than those who received a placebo treatment.

Overall, evidence suggests that aiTBS is a safe option for people with TRD, with participants usually handling the treatment well. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about Accelerated Intermittent Theta Burst Stimulation (aiTBS) because it offers a fresh approach to tackling treatment-resistant depression. Unlike standard treatments like antidepressant medications and Electroconvulsive Therapy (ECT), aiTBS uses a non-invasive technique called Transcranial Magnetic Stimulation (TMS) to deliver rapid bursts of magnetic fields to specific brain areas associated with mood regulation. This method has the potential to work faster and with fewer side effects compared to traditional options. By targeting the brain more precisely and efficiently, aiTBS could offer new hope for those who haven't found relief with existing therapies.

What evidence suggests that accelerated intermittent theta burst stimulation (aiTBS) is effective for treatment-resistant depression?

Research has shown that Accelerated Intermittent Theta Burst Stimulation (aiTBS) can help individuals with treatment-resistant depression. In this trial, participants may receive active theta-burst TMS stimulation, which studies have found significantly reduces depression symptoms compared to sham treatments. It provides rapid relief from depression. This method is a type of non-invasive brain stimulation, meaning it doesn't involve surgery or implants. aiTBS is gaining recognition for its potential to help when other treatments have failed. ^{1 2 3 6 7}

Who Is on the Research Team?

David Spiegel, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with treatment-resistant depression, defined by a specific score on the Maudsley Staging Method. Participants must be in good health, have ongoing psychiatric care, and women of childbearing age should use effective contraception. Exclusions include substance abuse issues, recent suicide attempts or ideation, certain neurological diseases or head trauma, metal implants incompatible with MRI or rTMS treatments.

Inclusion Criteria

MADRS score of ≥20 at screening (Visit 1)

I have been diagnosed with MDD or Bipolar II and am currently experiencing a major depressive episode.

In good general health, as evidenced by medical history

Exclusion Criteria

Active suicidal ideation (defined as an MSSI > 8) or a suicide attempt within the past 90 days

I have used ketamine or had ECT for depression recently.

I don't have metal in my head, a seizure history, or known brain lesions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive theta-burst TMS stimulation or sham stimulation for 4-8 weeks

4-8 weeks

5 visits per week (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Accelerated Intermittent Theta Burst Stimulation (aiTBS)

Trial Overview The study tests an innovative neurostimulation approach called accelerated intermittent theta burst stimulation (aiTBS) targeting different brain regions to alleviate symptoms of severe depression that hasn't responded to standard treatments. It compares active aiTBS at two brain sites versus sham (placebo-like) treatment.

How Is the Trial Designed?

Group I: Active TBS-DLPFC Active Control 1 Intervention

The active group will receive theta-burst TMS stimulation.

Group II: Active TBS-DMPFC Active Control 1 Intervention

The active group will receive theta-burst TMS stimulation.

Group III: Sham Comparator: Sham TBS-DLPFC or DMPFC Placebo Group 1 Intervention

The sham group will receive sham theta-burst TMS stimulation.

Accelerated Intermittent Theta Burst Stimulation (aiTBS) is already approved in United States for the following indications:

Approved in United States as aiTBS for:

• Treatment-resistant depression
• Major depressive disorder

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Published Research Related to This Trial

In a randomized, double-blind trial involving 56 patients, intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex showed a significant reduction in negative symptoms for patients with depression, but not for those with schizophrenia.

The treatment was generally safe and well-tolerated, with serious adverse events occurring only in the sham group, indicating that iTBS may be a promising intervention for depressive symptoms in certain patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dorsomedial prefrontal theta burst stimulation to treat anhedonia, avolition, and blunted affect in schizophrenia or depression - a randomized controlled trial. Bodén, R., Bengtsson, J., Thörnblom, E., et al.[2021]

In a study involving 50 patients with treatment-resistant depression (TRD), accelerated intermittent theta burst stimulation (aiTBS) significantly reduced depression symptoms over time, indicating its potential efficacy as a noninvasive treatment option.

The treatment was associated with changes in brain network organization, specifically a reduction in modularity of structural networks, suggesting that aiTBS may promote beneficial neuroplasticity effects in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated intermittent theta burst stimulation in major depression induces decreases in modularity: A connectome analysis. Caeyenberghs, K., Duprat, R., Leemans, A., et al.[2023]

Accelerated, high-dose intermittent theta burst stimulation (iTBS) showed promising results in treating highly treatment-resistant depression, with most patients achieving remission after treatment.

However, the effects were short-lived, as all patients experienced relapse within two weeks, indicating a need for improved treatment strategies that enhance the durability of the therapeutic response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is accelerated, high-dose theta burst stimulation a panacea for treatment-resistant depression? Caulfield, KA.[2021]

In a study of 26 patients with bipolar depression, active intermittent theta burst stimulation (iTBS) showed a high response rate of 72% and a remission rate of 42%, indicating its potential efficacy in treating this condition.

No adverse events were reported, demonstrating that iTBS is safe and well-tolerated, but further research with larger sample sizes is needed to confirm its superiority over sham treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Twice-daily neuronavigated intermittent theta burst stimulation for bipolar depression: A Randomized Sham-Controlled Pilot Study. Bulteau, S., Beynel, L., Marendaz, C., et al.[2020]

Accelerated intermittent Theta-burst Stimulation (iTBS) applied to the left dorsolateral prefrontal cortex in 50 patients with Treatment Resistant Depression (TRD) was found to be safe and led to significant reductions in depressive symptoms immediately after treatment.

While 28% of patients achieved a 50% reduction in depression scores during the treatment, this response rate increased to 38% two weeks post-treatment, with 30% of responders reaching clinical remission, suggesting delayed therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated intermittent theta burst stimulation treatment in medication-resistant major depression: A fast road to remission? Duprat, R., Desmyter, S., Rudi, de R., et al.[2019]

In a study of 22 participants with treatment-resistant depression, the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, which uses high-dose intermittent theta-burst stimulation (iTBS) guided by functional connectivity MRI, showed a remarkable remission rate of 90.5%.

The treatment was well tolerated with no negative cognitive side effects reported, suggesting that SAINT could be a safe and effective option for patients who have not responded to traditional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Cole, EJ., Stimpson, KH., Bentzley, BS., et al.[2020]

In a study of 50 depressed patients undergoing accelerated intermittent theta burst stimulation (aiTBS), baseline cortical thickness in the right caudal part of the anterior cingulate cortex (cACC) was found to significantly correlate with immediate clinical responses to treatment.

Longitudinal changes in cortical thickness in the right cACC also predicted delayed clinical responses, suggesting that this brain region could serve as a biomarker for determining the effectiveness of aiTBS in treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cortical Thickness in the Right Anterior Cingulate Cortex Relates to Clinical Response to Left Prefrontal Accelerated Intermittent Theta Burst Stimulation: An Exploratory Study. Baeken, C., van Beek, V., Vanderhasselt, MA., et al.[2022]

Citations

1. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2830095

Accelerated Intermittent Theta-Burst Stimulation for ... They found that active aiTBS was significantly more effective than sham stimulation for depressive symptoms, supporting the clinical efficacy of ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40042840/

Accelerated Theta-Burst Stimulation for Treatment ... A pragmatic aTBS protocol using only 3 iTBS sessions per day and a nonexpensive, non-neuronavigated approach was found to be safe and effective for TRD.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05849402

Accelerated Intermittent Theta-Burst Stimulation (aiTBS) in ... The aim of this study is to assess the efficacy of aiTBS applied to the left dorsolateral prefrontal cortex (L-DLPFC) in reducing depressive symptoms in ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0165178123003797

Accelerated intermittent theta burst stimulation in major ... aiTBS is a promising form of non-invasive brain stimulation [NIBS] with rapid antidepressant and antisuicidal effects in major depressive disorder [MDD].

5. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.2021.21121221

Accelerated Intermittent Theta Burst Stimulation First, the severity of treatment-resistant depression and level of treatment resistance in the study sample appears to be moderate, not severe, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11238064/

Accelerated Intermittent Theta-Burst Stimulation and ... This randomized clinical trial assesses the effectiveness of accelerated intermittent theta-burst stimulation for depressive symptom reduction

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006322325013563

Efficacy and Safety of Accelerated Intermittent Theta-burst ... The a-iTBS group showed significantly greater improvements in anxiety and self-reported depression at all time points compared to the sham group ...