Theta Burst Stimulation for Depression

Overseen By Jessica Drodge, MSc

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: The Royal Ottawa Mental Health Centre

Must be taking: Antidepressants

Must not be taking: Benzodiazepines

Disqualifiers: Substance abuse, Psychotic disorders, 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: Unknown

Duration: 6 weeks

22 Participants Needed

Trial Summary

What is the purpose of this trial?

Repetitive Transcranial magnetic stimulation (TMS) uses magnetic fields to modulate brain activity. A novel form of repetitive TMS (rTMS), intermittent theta burst stimulation (iTBS), has emerged as a promising new treatment for depression. This technique may be advantageous due to its very short duration and potentially stronger effect on brain activity in comparison with standard rTMS. However, the exact effect of iTBS on the activity of the brain in clinical populations remains poorly understood. This project aims to improve understanding of the mechanisms of action of iTBS by comparing its neuronal effect to sham treatment in 22 individuals with a diagnosis of major depressive episode, using positron emission tomography (PET) and magnetic resonance imaging (MRI) in a double-blind cross-over experiment, followed by a 6-week daily treatment course of iTBS.

Will I have to stop taking my current medications?

The trial requires participants to have been on a stable antidepressant regimen for at least four weeks before joining, so you will not need to stop taking your current antidepressants.

What data supports the effectiveness of the treatment Theta burst stimulation for depression?

Research shows that intermittent theta burst stimulation (iTBS) is as effective as traditional repetitive transcranial magnetic stimulation (rTMS) for treating depression, even in cases where other antidepressants have failed. It has shown promise in improving symptoms like anhedonia (loss of interest or pleasure) and avolition (lack of motivation) in depression. ^{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. ^{3 6 7 8 11}

Research Team

Sara Tremblay, PhD

Principal Investigator

The Royal Ottawa Mental Health Centre

Eligibility Criteria

This trial is for adults aged 18-55 with major depressive disorder (MDD) who haven't improved after 2-7 antidepressant treatments. They must have a certain depression score, be on stable medication for four weeks, and not have a history of substance abuse or significant medical conditions. Pregnant women and those with metal implants or severe psychiatric disorders are excluded.

Inclusion Criteria

I am between 18 and 55 years old.

Mini-International Neuropsychiatric Interview-confirmed diagnosis of MDD, as a single or recurring episode

A baseline score of ≥ 15 on the 17-item Hamilton Rating Scale for Depression (HRSD-17)

Exclusion Criteria

Pregnancy (confirmed by urine test) and/or lactation

I am currently receiving ECT or rTMS for depression.

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily sessions of intermittent theta burst stimulation (iTBS) on weekdays for 6 weeks

6 weeks

Daily sessions (weekdays)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Theta burst stimulation

Trial Overview The study tests intermittent theta burst stimulation (iTBS), a type of brain stimulation therapy for depression that's quicker than standard treatments. Participants will undergo iTBS compared to sham treatment using PET and MRI scans in a double-blind experiment, followed by six weeks of daily iTBS sessions.

Participant Groups

Group I: Active iTBS Active Control 1 Intervention

Intermittent Theta Burst Stimulation (iTBS) will be applied to the left DLPFC. Participants will receive daily sessions (on weekdays) for 6 weeks.

Group II: Sham iTBS/Active iTBS Placebo Group 1 Intervention

Intermittent Theta Burst Stimulation (iTBS) or realistic sham iTBS will be applied to the left DLPFC. Both sessions will be one week apart.

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]

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]

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]

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. 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]

4. 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]

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

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

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]