Transcranial Magnetic Stimulation for Depression

(FREED Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: University of California, San Diego

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

No Placebo Group

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 between 18 and 80 years old.

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

Trial 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)

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of California, San Diego La Jolla, CA

Who Is Running the Clinical Trial?

University of California, San Diego Lead Sponsor

National Institutes of Health (NIH) Collaborator

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] Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression.

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] Recently intermittent theta burst stimulation (iTBS) proved to be non-inferior to conventional repetitive transcranial magnetic stimulation (10 Hz rTMS) in unipolar depression after failure of one antidepressant trial, but to date no randomized control trial assessed the ability of iTBS to improve depression level and quality of life in more resistant features of depression with a long-term (6 month) follow-up in comparison to 10 Hz rTMS.

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] Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex is effective for treatment-resistant depression, but the effects of iTBS on neurophysiological markers remain unclear. Here, we indexed transcranial magnetic stimulation-electroencephalography (TMS-EEG) markers, specifically, the N45 and N100 amplitudes, at baseline and post-iTBS, comparing separated and contiguous iTBS schedules. TMS-EEG markers were also compared between iTBS responders and nonresponders.

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

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. [2022] Intermittent theta burst stimulation (iTBS) using 600 pulses is an effective and FDA-cleared transcranial magnetic stimulation (TMS) protocol for major depressive disorder (MDD). Prolonged iTBS (piTBS) using 1,800 pulses could increase the effectiveness of TMS for MDD, but its real-world effectiveness is still debated. We assessed the safety, tolerability, and preliminary effectiveness of a 3x daily piTBS 1,800 pulses protocol delivered over 2 weeks in 27 participants. Only four participants (18.2%) achieved response, two of them achieving remission (9.1%). Five participants (18.5%) experienced tolerability issues. Future studies should focus on the neurophysiological effects of TBS protocols to determine optimal parameters.

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] Intermittent theta burst stimulation (iTBS) when applied over the left dorsolateral prefrontal cortex (DLPFC) has been shown to be equally effective and safe to treat depression compared to traditional repetitive transcranial magnetic stimulation (rTMS) paradigms. This protocol describes a funded single-centre, double-blind, randomized placebo-controlled, clinical trial to investigate the antidepressive effects of iTBS and factors associated with an antidepressive response.

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] Our meta-analysis demonstrated that intermittent theta burst stimulation (iTBS)/bilateral-TBS (Bi-TBS) and high-frequency repetitive transcranial magnetic stimulation (HF-rTMS)/bilateral-rTMS (Bi-rTMS) had similar efficacy, acceptability, and safety profiles for antidepressant treatment-resistant major depressive disorder (AD-TRD). In our sensitivity analysis that excluded a study that compared Bi-TBS with Bi-rTMS for older adults, all efficacy outcomes were also comparable between iTBS and HF-rTMS. Because iTBS does not require higher stimulation intensity and a longer stimulus time than conventional HF-rTMS protocols, we speculated that for those with AD-TRD, iTBS/Bi-TBS is a more helpful therapeutic modality in clinical practice than HF-rTMS/Bi-rTMS.

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] Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depression (MD). We retrospectively analyzed the efficacy of intermittent theta burst stimulation (iTBS) on the left dorsolateral prefrontal cortex (DLPFC) combined with low-frequency rTMS (LF-rTMS) on the right DLPFC as an additional therapy to standard medication treatment.

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] Repetitive transcranial magnetic stimulation (rTMS) targeting the visual cortex (VC) has shown antidepressant effects for major depressive disorder (MDD) in sham-controlled trials, but comparisons with rTMS targeting the left dorsolateral prefrontal cortex (DLPFC) are lacking. We aimed to determine the non-inferiority of intermittent theta-burst stimulation (iTBS) over VC vs DLPFC for MDD.