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

Trial Summary

What is the purpose of this trial?

The investigators propose a randomized 3-arm double-blinded parallel experimental trial (20 sessions over 4 weeks) in 75 patients with TRD. The three arms include (1) the combination of a fully Individualized form of intermittent Theta Burst Stimulation (iTBS) (using BOTH the frequency and electric field (E-field) targeting approaches) (Ind-iTBS)), (2) iTBS individualized using E-field targeting only (targeted-iTBS) and (3) Standard iTBS treatment (i.e., typical iTBS localized to the dorsolateral prefrontal cortex (DLPFC) using the Beam F3 method). Electroencephalography (EEG) data will be collected at rest and during a working memory task, at baseline, and at the end of treatment along with clinical assessments of depression severity. The target engagement dependent variable of interest in these three arms will be fronto-parietal theta connectivity measured through resting-state EEG. The investigators hypothesize that stimulation with Ind-iTBS will lead to greater changes in fronto-parietal theta connectivity than that produced with targeted-TBS and standard iTBS. Aim: To evaluate the effects of two individualized forms of iTBS (i.e., using BOTH the frequency and E-field individualization; Ind-iTBS) compared to iTBS individualized for E-field targeting only (targeted-iTBS) and standard iTBS on fronto-parietal theta connectivity. Hypotheses: (1) Ind-iTBS will lead to greater changes in fronto-parietal theta connectivity compared to both targeted-iTBS and standard iTBS. (2) Ind-iTBS will also lead to a greater reduction in depressive symptoms (as defined by the mean reduction in Montgomery Åsberg Depression Rating Scale Scores (MADRS)) compared to both targeted-iTBS and standard iTBS.

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 for depression?

Research shows that intermittent theta burst stimulation (iTBS) is as effective as traditional repetitive transcranial magnetic stimulation (rTMS) for treating depression, with the added benefit of shorter treatment sessions. Studies have demonstrated that iTBS can be effective for treatment-resistant depression, providing similar outcomes to the standard 10 Hz rTMS. ^{1 2 3 4 5}

Is transcranial magnetic stimulation (TMS) using intermittent theta burst stimulation (iTBS) safe for humans?

Intermittent theta burst stimulation (iTBS) is generally considered safe for treating depression, with safety profiles similar to traditional repetitive transcranial magnetic stimulation (rTMS). Some participants may experience tolerability issues, but these are not common. ^{1 2 4 5 6}

How is the treatment of intermittent theta burst stimulation (iTBS) for depression different from other treatments?

Intermittent theta burst stimulation (iTBS) is a newer form of transcranial magnetic stimulation (TMS) that can be delivered in just 3 minutes, compared to the 37.5 minutes required for standard high-frequency TMS sessions, making it a quicker option for treating depression. ^{1 2 4 7 8}

Eligibility Criteria

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.

I am either male or female.

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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) 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 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) 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]

References

1. England 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. [2022]

2. United States 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). [2022]

3. 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]

4. Ireland pubmed.ncbi.nlm.nih.gov

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

5. 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]

6. Ireland 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. [2023]

7. India 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. [2022]

8. Netherlands 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. [2023]