Theta Burst Stimulation for Depression

Overseen By Stacey Shim, MSc

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: The Royal Ottawa Mental Health Centre

Must be taking: Antidepressants

Must not be taking: Illegal drugs, Recreational cannabis

Disqualifiers: Substance abuse, Unstable illness, Suicidality, 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: 20

Duration: 4-6 weeks

256 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for major depression called theta burst stimulation (TBS), a quicker form of repetitive transcranial magnetic stimulation. The researchers aim to determine whether using TBS on both sides of the brain is more effective than on one side and to identify the best method to prevent depression recurrence. This trial includes individuals with major depression that hasn't improved after trying at least one antidepressant and who have been referred for rTMS treatment by their doctor. Participants should adhere to a treatment schedule and maintain stable medication or therapy. As an unphased trial, this study offers a unique opportunity to contribute to innovative research that could enhance future depression treatments.

Will I have to stop taking my current medications?

You will need to stay on your current psychiatric medication or therapy plan for at least four weeks before joining the trial. If you are taking more than 1 mg of lorazepam or equivalent, you may not be eligible to participate.

What prior data suggests that theta burst stimulation is safe for treating depression?

Research shows that theta burst stimulation (TBS) is generally well-tolerated by patients. Studies have found that people who received intermittent theta burst stimulation (iTBS) did not experience significant side effects, and importantly, no serious issues like seizures were reported. This suggests that TBS is a safe treatment option.

TBS is a type of repetitive transcranial magnetic stimulation (rTMS), which is already approved for treating major depression, confirming its safety. While specific studies on using TBS on one side or both sides of the brain are ongoing, current evidence indicates that TBS is a safe choice for managing depression symptoms. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about theta burst stimulation (TBS) for depression because it offers a new approach compared to standard treatments like antidepressant medications and traditional repetitive transcranial magnetic stimulation (rTMS). TBS uses a special pattern of magnetic pulses that can be delivered in a shorter time with potentially faster effects. Unlike most treatments that require weeks to show improvements, TBS could provide quicker relief, making it an appealing option for those who need results sooner. Additionally, the trial is exploring different ways to deliver TBS, such as bilateral and unilateral stimulation, to tailor treatments based on individual needs, which could lead to more personalized and effective depression management.

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

Research shows that theta burst stimulation (TBS) could be a promising treatment for depression. This trial will assign participants to different TBS treatment arms. Some studies found that 42.1% of people responded positively to TBS, and 16.1% experienced complete relief from their symptoms, indicating significant improvements in depression. TBS is more efficient than traditional treatments because it requires shorter sessions. Early findings suggest that TBS can quickly and safely reduce symptoms of depression, even in teenagers. Overall, evidence supports TBS as a potentially effective treatment for depression. ^{3 6 7 8 9}

Who Is on the Research Team?

Sara Tremblay, PhD

Principal Investigator

The Royal Ottawa Mental Health Centre

Are You a Good Fit for This Trial?

This trial is for adults with major depression who haven't improved after 1-7 antidepressant treatments. They must be stable on current medications or therapy for four weeks, have moderate symptoms, and score ≥24 on the MMSE if over 65. Exclusions include substance abuse, unstable medical conditions, pregnancy, TMS contraindications like epilepsy, and recent ECT failure.

Inclusion Criteria

I am willing and able to agree to participate in the study.

I chose to undergo rTMS treatment after my doctor recommended it.

I have been diagnosed with major depression without psychosis.

Exclusion Criteria

I do not have epilepsy, seizures, metallic head implants, or a pacemaker.

I do not have any major uncontrolled illnesses like diabetes or kidney problems.

I am not willing to keep taking my current antidepressants.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TBS treatment 5 days/week for 4 to 6 weeks, with a potential second phase for non-remitters

4-6 weeks

20-30 sessions (in-person)

Maintenance

Responders enter a 6-month maintenance phase with a flexible schedule based on symptom emergence

6 months

Variable visits based on assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Theta burst stimulation

Trial Overview

The study compares two types of Theta burst stimulation (TBS) treatments: unilateral left TBS versus bilateral TBS. It aims to determine which is more effective in treating major depression including cases with comorbid anxiety and establishes an effective maintenance protocol.

How Is the Trial Designed?

Group I: Maintenance Phase: Flexible Active Control 1 Intervention

The flexible maintenance protocol will be based on symptom emergence. Participants will receive a fixed TBS (2x/week) schedule for the first month. For the following months (2-6), they will come in for an assessment (HRSD-17) to determine how many TBS sessions (0, 1, or 2) they receive on a flexible basis.

Group II: Bilateral TBS Active Control 1 Intervention

Intermittent Theta Burst Stimulation (iTBS) will be applied to the left DLPFC and continuous TBS (cTBS) will be applied to the right DLPFC. Participants will receive daily sessions (Mon-Fri) for 4 to 6 weeks (stop at 4 weeks if remission is achieved).

Group III: Unilateral TBS Active Control 1 Intervention

Intermittent Theta Burst Stimulation (iTBS) will be applied to the left DLPFC. Realistic sham continuous TBS (cTBS-sham) will be applied to the right DLPFC. Participants will receive daily sessions (Mon-Fri) for 4 to 6 weeks (stop at 4 weeks if remission is achieved).

Theta burst stimulation is already approved in United States for the following indications:

Approved in United States as iTBS for:

• Major Depressive Disorder

Who Is Running the Clinical Trial?

The Royal Ottawa Mental Health Centre

Lead Sponsor

Trials

24

Recruited

2,300+

Published Research Related to This Trial

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 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]

Intermittent theta-burst stimulation (iTBS) and high-frequency rTMS (HF-rTMS) show similar efficacy in treating treatment-resistant depression (TRD), with response rates of 48.0% for iTBS and 45.5% for HF-rTMS based on two high-quality randomized controlled trials involving 474 participants.

Both iTBS and HF-rTMS have comparable safety profiles, with similar rates of discontinuation and adverse events, such as headaches, indicating that iTBS is a safe alternative to HF-rTMS for patients with TRD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review. Lan, XJ., Yang, XH., Qin, ZJ., et al.[2023]

In a study involving 72 patients with major depressive disorder, two daily sessions of prolonged intermittent theta-burst stimulation (piTBS) over two weeks showed significantly more responders compared to a sham treatment, indicating its efficacy as an antidepressant option.

However, the study found no evidence that longer piTBS sessions led to greater improvements in depression scores compared to other treatments, suggesting that while piTBS is effective, increasing treatment duration does not enhance its antidepressant effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The longer, the better ? Longer left-sided prolonged intermittent theta burst stimulation in patients with major depressive disorder: A randomized sham-controlled study. Li, CT., Cheng, CM., Lin, HC., et al.[2023]

In a study involving 208 participants with treatment-resistant depression, both twice-daily and once-daily intermittent theta burst stimulation (iTBS) protocols showed improvements in depression scores, but there was no significant difference in efficacy between the two schedules after 10 and 30 days.

Response and remission rates were low in both treatment groups, indicating that neither protocol significantly accelerated the improvement of depressive symptoms in patients with treatment-resistant depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: A Canadian rTMS treatment and biomarker network in depression (CARTBIND) study. Blumberger, DM., Vila-Rodriguez, F., Wang, W., et al.[2022]

Continuous theta burst stimulation (cTBS) was found to be safe and well-tolerated in patients with major depressive disorder (MDD) or bipolar depression (BD), with no significant differences in adverse events compared to sham treatment.

However, the meta-analysis of three randomized controlled trials involving 78 participants showed no significant improvement in depression scores or response rates with cTBS compared to sham, indicating that cTBS may not provide a therapeutic advantage for treating major depressive episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive continuous theta burst stimulation for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled studies. Cai, DB., Qin, XD., Qin, ZJ., et al.[2023]

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, 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 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]

In a study of 71 participants with Major Depressive Disorder who had limited response to high-frequency left-sided stimulation, subthreshold intensity intermittent theta-burst stimulation priming (iTBS-P) led to a greater reduction in depressive symptoms compared to suprathreshold intensity stimulation.

The results suggest that iTBS-P may work through homeostatic plasticity mechanisms, indicating that lower intensity stimulation could be more effective for clinical improvement in depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subthreshold stimulation intensity is associated with greater clinical efficacy of intermittent theta-burst stimulation priming for Major Depressive Disorder. Lee, JC., Corlier, J., Wilson, AC., et al.[2021]

Citations

1.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/39761754/

Efficacy study of intermittent theta burst stimulation(iTBS) in ...

The current study suggests that two days of active iTBS to the DLPFC region can rapidly, safely, and effectively improve depressive symptoms in adolescents ...

2.

nature.com

nature.com/articles/s41380-024-02630-5

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 ...

3.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/36841303/

Outcome of transcranial magnetic intermittent theta-burst ...

Results: The response rate was 42.1 % and 16.1 % reached remission. The response rate was significantly larger in the oldest age group compared ...

4.

sciencedirect.com

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

Efficacy and Safety of Accelerated Intermittent Theta-burst ...

In this trial, a-iTBS, administered five sessions per day for ten days, is effective and safe for adolescents with non-treatment-resistant MDD.

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT07033780

NCT07033780 | Theta-Burst Stimulation to Treat Depression

The goal of this clinical trial is to explore the effects of non-invasive brain stimulation protocols using intermittent theta-burst stimulation (iTBS) on ...

6.

pmc.ncbi.nlm.nih.gov

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

Theta burst stimulation for depression: a systematic review ...

A randomized controlled trial (RCT) of SNT demonstrated that iTBS (L-DLPFC) outperformed sham in depressive symptom improvement with a large ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8617062/

A Systematic Review of the Safety and Tolerability of Theta ...

All participants tolerated iTBS without significant adverse events. No complications, such as seizures, occurred in any of the participants. One participant ...

8.

sciencedirect.com

sciencedirect.com/science/article/pii/S0165178123003797

Accelerated intermittent theta burst stimulation in major ...

Four weeks after treatment response rates ranged from 0.0% to 66.7% and remission rates ranged from 0.0% to 57.1%. Three articles described a significant ...

9.

psychiatryonline.org

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

Accelerated Intermittent Theta Burst Stimulation

In terms of the primary outcomes, the authors reported an impressive 69.2% response rate and a 46.2% remission rate 4 weeks after treatment, ...