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

Trial Summary

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 data supports the effectiveness of the treatment Theta Burst Stimulation for Depression?

Research shows that intermittent theta burst stimulation (iTBS) is effective for treating major depressive disorder and is comparable to traditional repetitive transcranial magnetic stimulation (rTMS). It has shown promise in improving symptoms of depression, even in cases where other antidepressant treatments have failed. ^{1 2 3 4 5}

Is theta burst stimulation safe for humans?

Research shows that intermittent theta burst stimulation (iTBS) is generally safe and well-tolerated in humans, with studies reporting no adverse events in patients with bipolar depression and treatment-resistant depression. ^{6 7 8 9 10}

How is Theta Burst Stimulation different from other treatments for depression?

Theta Burst Stimulation (iTBS) is a newer form of repetitive transcranial magnetic stimulation (rTMS) that can be delivered in just over 3 minutes, compared to the 37.5 minutes required for standard high-frequency rTMS sessions. This makes it a quicker option for patients with treatment-resistant depression, potentially allowing for faster remission. ^{5 6 7 8 11}

What is the purpose of this trial?

Repetitive transcranial magnetic stimulation (rTMS) is a Health Canada approved treatment for major depression. Theta burst stimulation (TBS) is a very promising new treatment for major depression that allows a 15-fold reduction in duration of daily sessions. However, no large scale naturalistic study has assessed the superiority of bilateral TBS in comparison with unilateral left TBS. In fact, no TBS study thus far has included both unipolar and bipolar depression, or other psychiatric comorbidities such as anxiety. Maintenance has yet to be studied with TBS, along with an effective maintenance protocol to prevent relapse. Our study aims to explore and address these gaps.

Research Team

Sara Tremblay, PhD

Principal Investigator

The Royal Ottawa Mental Health Centre

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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) 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 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]

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]

References

1. 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]

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

Is accelerated, high-dose theta burst stimulation a panacea for treatment-resistant depression? [2021]

5. Netherlands 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. [2023]

6. 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]

7. Switzerland 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. [2023]

8. United States 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. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Adjunctive continuous theta burst stimulation for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled studies. [2023]

10. France pubmed.ncbi.nlm.nih.gov

Twice-daily neuronavigated intermittent theta burst stimulation for bipolar depression: A Randomized Sham-Controlled Pilot Study. [2020]

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

Subthreshold stimulation intensity is associated with greater clinical efficacy of intermittent theta-burst stimulation priming for Major Depressive Disorder. [2021]