Transcranial Magnetic Stimulation for Depression

(FREED Trial)

Recruiting at 1 trial location

Overseen By Interventional Psychiatry

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of California, San Diego

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

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

Compensation: Varies

Number of Visits: 21

Duration: 4 weeks

75 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a brain stimulation treatment called transcranial magnetic stimulation (TMS) for individuals with treatment-resistant depression. It compares three types of TMS: Fully Individualized iTBS, Standard-iTBS, and targeted-iTBS, to determine which best enhances brain activity and reduces depression symptoms. The trial is open to those diagnosed with major depression who have not responded to at least one antidepressant. Participants should not have started or changed their depression medication in the past month. As an unphased trial, this study provides a unique opportunity to explore innovative treatment options for depression.

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.

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

Research has shown that intermittent Theta Burst Stimulation (iTBS) is generally safe for treating depression. Many studies suggest that iTBS, when applied to the dorsolateral prefrontal cortex (DLPFC), is well-tolerated by patients. One study indicated that fully personalized iTBS offers a favorable balance between benefits and risks for treating depression, with benefits outweighing potential risks.

Standard iTBS is also considered safe, with research demonstrating its ability to quickly and effectively improve depression symptoms without major side effects. It has been used safely in teenagers, providing fast results and confirming its safety across different age groups.

For targeted-iTBS, which employs a specific method to focus the treatment, safety remains similar. Studies have shown it to be both safe and effective, with no major negative effects reported.

Overall, these types of iTBS have demonstrated good safety in previous research, indicating they are unlikely to cause harm and are considered safe options for treating depression. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the transcranial magnetic stimulation (TMS) techniques being tested for depression because they offer a personalized approach that could enhance treatment effectiveness. Unlike standard TMS treatments that use general targeting methods, these investigational treatments use individualized E-field modeling to tailor coil placement and current amplitude specifically for each patient. The fully individualized iTBS also customizes the stimulation frequency based on EEG data, potentially optimizing therapeutic outcomes. These advancements might lead to more effective and faster relief from depressive symptoms compared to conventional methods.

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

Research has shown that theta burst stimulation (TBS) can effectively treat depression. In this trial, participants will receive one of three different iTBS treatments. The fully individualized iTBS adjusts both the frequency and the specific brain areas targeted, potentially improving results by tailoring the treatment to each person's brain activity. Another group will receive standard iTBS, which quickly and safely reduces symptoms of depression, with about 42% of people responding positively. The targeted-iTBS, focusing more precisely on certain brain areas, has demonstrated similar effectiveness in reducing depressive symptoms. Overall, these treatments offer hope for people with depression that hasn't improved with other treatments. ^{1 2 3 4 5}

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with major depressive disorder who haven't improved after trying at least one antidepressant. They must be able to consent, have a moderate to severe depression score, and not have started new antidepressants recently.

Inclusion Criteria

I haven't started or increased my antidepressant dose in the last 4 weeks.

I have been diagnosed with a major depressive episode.

Montgomery-Asberg Depression Rating Scale (MADRS) Score of >19 (moderate - severe depression)

Exclusion Criteria

I do not have a psychotic disorder or active symptoms.

I have a neurological condition or a history of seizures.

Inability to provide informed consent

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 20 sessions of iTBS over 4 weeks, with EEG data collected at rest and during a working memory task

4 weeks

20 sessions (in-person)

Follow-up

Participants are monitored for changes in fronto-parietal theta connectivity and depressive symptoms

1-2 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Fully Individualized iTBS
• Standard-iTBS
• targeted-iTBS

Trial Overview The FREED study tests three types of Transcranial Magnetic Stimulation (TMS) treatments over four weeks: fully individualized iTBS targeting frequency and E-field, iTBS targeting only E-field, and standard iTBS. It measures changes in brain connectivity and depression severity.

How Is the Trial Designed?

Group I: iTBS individualized using E-field targeting only (targeted-iTBS) Active Control 1 Intervention

In the targeted-iTBS, the coil placement and current amplitude will be provided using individualized E-field modeling and coordinate-based cortical targeting.

Group II: The fully individualized form of iTBS (BOTH the frequency and E-field targeting approaches) Active Control 1 Intervention

In the Ind-iTBS, the coil placement and current amplitude will be provided using individualized E-field modeling and coordinate-based cortical targeting. The stimulation frequency will also be individualized according to EEG-derived TGC.

Group III: Standard iTBS treatment (i.e., typical iTBS localized to the DLPFC using the Beam F3 method) Active Control 1 Intervention

The standard iTBS will be delivered with the typical 5Hz/50Hz patterned frequencies used in the FDA-approved treatment protocol and stimulation will be delivered according to the Beam F3 targeting.

Fully Individualized iTBS is already approved in United States, European Union for the following indications:

Approved in United States as iTBS for:

• Major Depressive Disorder

Approved in European Union as iTBS for:

• Major Depressive Disorder

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

Intermittent theta-burst stimulation (iTBS) targeting the left visual cortex (VC) was found to be non-inferior to targeting the left dorsolateral prefrontal cortex (DLPFC) in improving depressive symptoms in patients with major depressive disorder (MDD), based on a study of 75 participants over 14 days.

The VC group experienced lower rates of suicidal ideation and fewer adverse events, such as eye discomfort and pain, suggesting that VC-targeted iTBS may be a safer option for treating MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-inferiority of intermittent theta burst stimulation over the left V1 vs. classical target for depression: A randomized, double-blind trial. Kong, Y., Zhou, J., Zhao, M., et al.[2023]

In a study of 54 patients with major depression, the combination of intermittent theta burst stimulation (iTBS) and low-frequency rTMS (LF-rTMS) significantly improved depression and anxiety symptoms more than high-frequency rTMS (HF-rTMS).

The results suggest that iTBS combined with LF-rTMS may be a promising alternative therapy for major depression, offering both efficacy and time-saving benefits compared to traditional methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Left intermittent theta burst stimulation combined with right low-frequency rTMS as an additional treatment for major depression: A retrospective study. Mi, Y., Ji, Y., Lou, Z., et al.[2022]

Intermittent theta burst stimulation (iTBS) and high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) are equally effective and safe for treating patients with treatment-resistant major depressive disorder, based on a comprehensive meta-analysis.

iTBS may be a more practical option in clinical settings because it requires less stimulation intensity and shorter treatment times compared to HF-rTMS, making it potentially more accessible for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent theta burst stimulation vs. high-frequency repetitive transcranial magnetic stimulation for major depressive disorder: A systematic review and meta-analysis. Kishi, T., Sakuma, K., Matsuda, Y., et al.[2023]

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 study of 60 patients with treatment-resistant unipolar depression, both intermittent theta burst stimulation (iTBS) and conventional 10 Hz rTMS showed similar efficacy in reducing depression scores and improving quality of life over a 6-month follow-up, with response rates of 36.7% for iTBS and 33.3% for rTMS.

iTBS is highlighted as a more time-efficient and cost-effective option compared to rTMS, suggesting it could be a valuable treatment alternative for patients with severe depression who have not responded to multiple antidepressant trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent theta burst stimulation (iTBS) versus 10 Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) to alleviate treatment-resistant unipolar depression: A randomized controlled trial (THETA-DEP). Bulteau, S., Laurin, A., Pere, M., et al.[2022]

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]

Intermittent theta burst stimulation (iTBS) is as effective as standard high-frequency (10 Hz) rTMS for treating treatment-resistant depression, showing non-inferiority in improving depression scores over 4-6 weeks in a study with 414 participants.

Both iTBS and 10 Hz rTMS had similar safety profiles and dropout rates, with headaches being the most common side effect, indicating that iTBS can be a viable alternative that allows for more patients to be treated in a shorter time without losing effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Blumberger, DM., Vila-Rodriguez, F., Thorpe, KE., et al.[2022]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11609094/

Theta burst stimulation for depression: a systematic review ... Theta burst stimulation (TBS) presents as a more efficient and potentially more effective therapeutic modality than conventional repetitive transcranial ...

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

Efficacy and Safety of Accelerated Intermittent Theta-burst ... Evidence suggests that increasing the number of treatment sessions and the total pulse dose substantially improves clinical outcomes(13, 14).

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12047393/

The effects of intermittent theta burst stimulation (iTBS) on ... This research highlights the crucial role of stimulation intensity in modulating brain activity and lays the groundwork for future clinical studies focused on ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT07033780

NCT07033780 | Theta-Burst Stimulation to Treat Depression This trial will compare the effects of the compressed iTBS (iTBS-c) protocol, which is commonly used to treat depression, and the spaced iTBS ( ...

5. nature.com nature.com/articles/s41591-023-02764-z

Connectivity-guided intermittent theta burst versus ... - Nature Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton ...