Mindfulness Neurostimulation for Depression

(MEND Trial)

Overseen By Jyoti Mishra, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Diego

Must be taking: Antidepressants

Disqualifiers: Neurological disorder, Seizure disorder, Psychotic disorder, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 20

Duration: 4 weeks

70 Participants Needed

Trial Summary

What is the purpose of this trial?

Repetitive Transcranial Magnetic stimulation (rTMS) is an FDA-approved therapy for treatment resistant depression (TRD) that involves brief magnetic stimulation pulses on the dorsolateral prefrontal cortex (DLPFC) brain region. But studies of rTMS alone show remission rates of ~30%. Additionally, rTMS has not been shown to improve cognitive functioning that may be an independent factor predicting treatment success. This study will develop a novel multimodal treatment, which combines intermittent theta burst stimulation (iTBS) - a type of rTMS with digital mindfulness training to engage brain plasticity, enhance cognition and alleviate depression symptoms in individuals with TRD.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you should not have started any new antidepressant therapy or increased your dose in the four weeks before joining the trial.

What data supports the effectiveness of the treatment Medi-TBS, Repetitive Transcranial Magnetic Stimulation, rTMS, iTBS, Intermittent Theta Burst Stimulation for depression?

Research shows that intermittent theta burst stimulation (iTBS) and repetitive transcranial magnetic stimulation (rTMS) are effective in treating major depression, with iTBS being as effective and safe as traditional rTMS. Studies also indicate that these treatments can lead to improvements in brain activity patterns associated with depression. ^{1 2 3 4 5}

Is theta burst stimulation (TBS) safe for humans?

Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (rTMS), is generally safe and well-tolerated in humans. Some people may experience mild headaches during or after treatment, but serious side effects are rare. ^{1 6 7 8 9}

How is the treatment Medi-TBS different from other treatments for depression?

Medi-TBS, or intermittent theta burst stimulation (iTBS), is a unique treatment for depression that uses magnetic pulses to stimulate specific areas of the brain, like the dorsolateral prefrontal cortex, which is different from traditional medication or talk therapy. It is a patterned form of repetitive transcranial magnetic stimulation (rTMS) and has shown promise in being as effective and safe as traditional rTMS but with potentially shorter treatment times. ^{1 2 3 4 10}

Research Team

Jyoti Mishra, PhD

Principal Investigator

University of California, San Diego

Eligibility Criteria

This trial is for individuals with treatment-resistant depression, meaning they haven't gotten better with standard treatments. Participants should be able to undergo magnetic brain stimulation and engage in digital mindfulness training.

Inclusion Criteria

I have tried at least one antidepressant that didn't work for me.

I haven't started or increased my antidepressant dose in the last month.

I understand the details of the trial and can consent to participate.

Exclusion Criteria

Patients who are pregnant or breastfeeding

Medically unstable patients

I do not have a psychotic disorder or active symptoms.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a multimodal treatment combining iTBS and digital mindfulness training for 20 sessions over 4 weeks

4 weeks

20 sessions (in-person)

Follow-up

Participants are monitored for changes in depression, anxiety, and cognitive function

4 weeks

Extended Follow-up

Additional monitoring for changes in depressive and anxiety symptoms

4 weeks

Treatment Details

Interventions

• Medi-TBS

Trial Overview The study tests a new approach combining intermittent theta burst stimulation (a form of rTMS) with digital mindfulness exercises aimed at improving brain function and reducing depression symptoms more effectively than current methods.

Participant Groups

Group I: Medi2-TBS Experimental Treatment 1 Intervention

This arm will receive a multimodal treatment with a digital mindfulness training focused on attention to breathing for up to 20 min session dose for up to 20 sessions combined with neuro-navigated iTBS type of rTMS (for 20 treatments over 4 weeks) targeting the left dorsolateral prefrontal cortex (DLPFC) brain region.

Group II: Medi1-TBS Experimental Treatment 1 Intervention

This arm will receive a multimodal treatment with a digital mindfulness training focused on attention to breathing for up to 10 min session dose for up to 20 sessions combined with neuro-navigated iTBS type of rTMS (for 20 treatments over 4 weeks) targeting the left dorsolateral prefrontal cortex (DLPFC) brain region.

Group III: Medi3-TBS Active Control 1 Intervention

This arm will receive a multimodal treatment with a digital mindfulness training focused on intermittent deep breathing for up to 10 min session dose for up to 20 sessions combined with neuro-navigated iTBS type of rTMS (for 20 treatments over 4 weeks) targeting the left dorsolateral prefrontal cortex (DLPFC) brain region.

Medi-TBS is already approved in United States, European Union, Canada for the following indications:

Approved in United States as rTMS for:

• Treatment-resistant depression

Approved in European Union as rTMS for:

• Major depressive disorder
• Treatment-resistant depression

Approved in Canada as rTMS for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

Findings from Research

In a randomized-controlled trial involving 32 patients with major depression, bilateral theta burst stimulation (TBS) to the dorsolateral prefrontal cortex showed a significant increase in treatment response compared to sham stimulation, with 9 responders in the TBS group versus 4 in the sham group.

The study also indicated a trend towards higher remission rates in the TBS group as measured by the Beck Depression Inventory, suggesting that TBS may enhance the effectiveness of ongoing medication and psychotherapy in treating major depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. Plewnia, C., Pasqualetti, P., Große, S., et al.[2018]

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]

A clinical trial involving 96 outpatients with moderate depression will investigate the effectiveness of intermittent theta burst stimulation (iTBS) on reducing depressive symptoms, comparing it to a sham treatment over ten sessions.

The study will also explore various factors, including genetic and neuropsychological measures, that may influence the response to iTBS, ensuring a thorough safety screening and adherence to ethical guidelines throughout the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The antidepressant effect of intermittent theta burst stimulation (iTBS): study protocol for a randomized double-blind sham-controlled trial. Ørbo, MC., Grønli, OK., Larsen, C., et al.[2023]

In a study of 105 patients with major depressive disorder, higher baseline cognition-modulated frontal theta activity (Δfrontalθ) was found to predict the antidepressant response to repetitive transcranial magnetic stimulation (rTMS), but not to prolonged intermittent theta-burst stimulation (piTBS).

Both rTMS and piTBS are effective treatments for depression, but they may operate through different neurobiological mechanisms, as indicated by the differing predictive values of Δfrontalθ for each treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Task-Modulated Brain Activity Predicts Antidepressant Responses of Prefrontal Repetitive Transcranial Magnetic Stimulation: A Randomized Sham-Control Study. Li, CT., Cheng, CM., Juan, CH., et al.[2022]

In a study of 45 antidepressant-free patients with medication-resistant depression, accelerated intermittent Theta Burst Stimulation (aiTBS) led to significant changes in brain perfusion, particularly increasing blood flow in areas like the ventromedial prefrontal cortex, which are linked to mood regulation.

The findings suggest that active aiTBS not only improves depressive symptoms but also alters brain activity in regions associated with depression, while sham treatment showed different effects, indicating that the clinical benefits of aiTBS may be due to both direct stimulation and potential placebo responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated iTBS changes perfusion patterns in medication resistant depression. Wu, GR., Duprat, R., Baeken, C.[2022]

In a study of 27 participants, a prolonged intermittent theta burst stimulation (piTBS) protocol using 1,800 pulses showed limited effectiveness for major depressive disorder, with only 18.2% of participants achieving a response and 9.1% reaching remission.

Safety and tolerability were concerns, as 18.5% of participants experienced issues, suggesting that while piTBS is a promising approach, further research is needed to optimize its parameters and improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. Richard, M., Noiseux, C., Desbeaumes Jodoin, V., et al.[2022]

In a case series of 9 patients with major depressive disorder and bipolar disorder, accelerated theta-burst rTMS treatment over 8 days led to significant reductions in depression symptoms, as measured by the CES-D and CGI scales.

The treatment was well tolerated, with mild headaches being the most common side effect, and five patients achieving at least a 50% reduction in symptoms by the end of the treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated theta-burst repetitive transcranial magnetic stimulation for depression in South Africa. Bröcker, E., van den Heuvel, L., Seedat, S.[2020]

Theta-burst transcranial magnetic stimulation (TBS) is safe and well tolerated in patients with major depression, based on a study involving 33 participants over 10 consecutive days.

The study suggests that TBS may have antidepressant effects, and increasing stimulation parameters does not lead to more side effects, potentially enhancing its therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression. Chistyakov, AV., Rubicsek, O., Kaplan, B., et al.[2019]

In a randomized controlled trial involving 56 patients with moderate to severe depression, bilateral theta-burst stimulation (TBS) and repetitive transcranial magnetic stimulation (rTMS) did not show significant improvements in depression scores compared to sham treatment.

However, there was a noted tendency for both active treatments to increase the responder rate, particularly for the TBS group, suggesting that further research may be needed to explore its potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial. Prasser, J., Schecklmann, M., Poeppl, TB., et al.[2015]

Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex significantly decreased the N100 amplitude in participants with treatment-resistant depression, indicating a neurophysiological response to the treatment.

Responders to iTBS showed a notable decrease in N100 amplitude and higher N45 amplitude post-treatment compared to nonresponders, suggesting that these TMS-EEG markers could help predict treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identifying Neurophysiological Markers of Intermittent Theta Burst Stimulation in Treatment-Resistant Depression Using Transcranial Magnetic Stimulation-Electroencephalography. Strafella, R., Momi, D., Zomorrodi, R., et al.[2023]

References

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

Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. [2018]

2. Netherlands 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. [2021]

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

The antidepressant effect of intermittent theta burst stimulation (iTBS): study protocol for a randomized double-blind sham-controlled trial. [2023]

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

Task-Modulated Brain Activity Predicts Antidepressant Responses of Prefrontal Repetitive Transcranial Magnetic Stimulation: A Randomized Sham-Control Study. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Accelerated iTBS changes perfusion patterns in medication resistant depression. [2022]

6. Ireland pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. [2022]

7. South Africa pubmed.ncbi.nlm.nih.gov

Accelerated theta-burst repetitive transcranial magnetic stimulation for depression in South Africa. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression. [2019]

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

Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial. [2015]

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

Identifying Neurophysiological Markers of Intermittent Theta Burst Stimulation in Treatment-Resistant Depression Using Transcranial Magnetic Stimulation-Electroencephalography. [2023]