Theta-Burst Stimulation for Bipolar Disorder

(TRIBE Trial)

Recruiting at 1 trial location

Overseen By Mawahib Semeralul

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Centre for Addiction and Mental Health

Must be taking: Mood stabilizers

Must not be taking: Anticonvulsants, High-dose lorazepam

Disqualifiers: Substance use disorder, Schizophrenia, Psychotic symptoms, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

The purpose of this trial is to determine if intermittent theta-burst stimulation (iTBS) can reduce the symptoms of depression in treatment-resistant bipolar disorder. To do this, some of the participants in this study will receive treatment with active iTBS stimulation, while others will receive sham iTBS stimulation. Participants will come for 30 days of either active iTBS or sham iTBS, with a 6-week follow-up period. Symptoms of depression (for determining treatment efficacy) and mania (for determining treatment safety) will be assessed using the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Young Mania Rating Scale (YMRS) every five treatments during the treatment course, and at 1 week and 6 week after treatment completion.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not start or increase any psychotropic medications for depression 4 weeks before screening. You must also be on a non-anticonvulsant mood stabilizer like lithium or quetiapine, and you cannot take anticonvulsants or more than 2 mg of lorazepam daily.

What data supports the effectiveness of the treatment Theta-Burst Stimulation for Bipolar Disorder?

Research shows that intermittent theta burst stimulation (iTBS) can be effective for bipolar depression, with high response and remission rates in a small study. This suggests that iTBS might help improve symptoms in people with bipolar disorder, but more research is needed to confirm these findings. ^{1 2 3 4 5}

Is theta-burst stimulation safe for humans?

Research shows that theta-burst stimulation, including intermittent theta-burst stimulation (iTBS) and accelerated intermittent theta-burst stimulation (aiTBS), is generally safe and well-tolerated in humans, with no adverse events reported in studies involving patients with bipolar depression. ^{3 4 6 7 8}

How is Theta-Burst Stimulation treatment different from other treatments for bipolar disorder?

Theta-Burst Stimulation (TBS) is a non-invasive brain stimulation technique that uses magnetic fields to stimulate nerve cells in the brain, which is different from traditional drug treatments that involve medication. This method is unique because it targets specific brain areas involved in mood regulation, potentially offering a new approach for those who do not respond well to medications like lithium or anticonvulsants. ^{9 10 11 12 13}

Eligibility Criteria

This trial is for individuals with bipolar disorder who have not responded well to standard treatments for depression. Participants must be able to attend 30 treatment sessions and follow-up visits. Specific criteria will determine eligibility.

Inclusion Criteria

Not currently experiencing a mixed or manic episode (YMRS ≤10)

Pass the TMS adult safety screening questionnaire

I am between 18 and 65 years old.

Exclusion Criteria

Have a MINI anxiety disorder, trauma-related disorder, obsessive compulsive disorder, or personality disorder assessed by a study investigator to be primary and/or causing greater impairment than BD-DE

Have active suicidal intent (assessed during HRSD-17 Item 3 and SSRS as imminent intent to act on specific plan, confirmed by psychiatric staff)

I have never received rTMS treatment before.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either active or sham iTBS stimulation once daily over 30 days

4 weeks

30 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 weeks

2 visits (in-person)

Treatment Details

Interventions

• Theta-Burst Stimulation (Behavioural Intervention)

Trial Overview The study tests if iTBS, a brain stimulation technique, can alleviate depression in those with treatment-resistant bipolar disorder. Half receive real iTBS; the other half get sham (fake) treatment, decided randomly.

Participant Groups

Group I: Active iTBS Stimulation Experimental Treatment 1 Intervention

Administered once daily over 30 days. Each session will deliver 600 pulses of active iTBS in triplet 50Hz bursts, repeated at 5Hz 2s on 8s off for a total time of \~3 minutes, 9 seconds at a target intensity of 120% of the subject's resting motor threshold.

Group II: Sham iTBS Stimulation Placebo Group 1 Intervention

Administered once daily over 30 days, using a sham coil that reproduces auditory and tactile sensations of stimulation and has an identical external appearance. Each session will deliver 600 pulses of sham iTBS in triplet 50Hz bursts, repeated at 5Hz 2s on 8s off for a total time of \~3 minutes, 9 seconds at a target intensity of 120% of the subject's resting motor threshold.

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

University Health Network, Toronto

Collaborator

Trials

1,555

Recruited

526,000+

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]

Intermittent theta-burst stimulation (iTBS) significantly improves hand function in stroke patients, particularly in those with higher baseline motor function and the presence of motor-evoked potentials (MEPs).

The study of 72 stroke patients showed that those with MEPs and better grip strength (Group A) had the greatest improvement in motor function, suggesting that iTBS effectiveness can be predicted by these factors, allowing for more tailored neurostimulation strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Corticospinal integrity and motor impairment predict outcomes after excitatory repetitive transcranial magnetic stimulation: a preliminary study. Lai, CJ., Wang, CP., Tsai, PY., et al.[2016]

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]

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 involving 19 patients with acute-phase bipolar depression, continuous theta burst stimulation (cTBS) was found to be safe and well-tolerated, with no major adverse effects reported.

Despite the treatment being safe, the efficacy of cTBS in significantly improving depression symptoms was inconclusive, as no statistically significant differences were observed between the active and sham treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Continuous Theta Burst "Intensive" Stimulation in Acute-Phase Bipolar Depression: A Pilot, Exploratory Study. Mallik, G., Mishra, P., Garg, S., 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]

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]

Accelerated intermittent theta burst stimulation (aiTBS) has shown promising efficacy in treating major depressive episodes in patients with major depressive disorder (MDD) or bipolar depression (BD), outperforming sham stimulation in a meta-analysis of five randomized controlled trials involving 239 patients.

The results suggest that aiTBS could be a beneficial treatment option for individuals experiencing major depressive episodes, indicating its potential as an effective intervention for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated intermittent theta burst stimulation for major depressive disorder or bipolar depression: A systematic review and meta-analysis. Cai, DB., Qin, ZJ., Lan, XJ., et al.[2023]

Hippocampal neurons derived from induced pluripotent stem cells (iPSCs) of bipolar disorder (BD) patients exhibit hyperexcitability, which is confirmed across different patient cohorts, indicating a consistent cellular characteristic of the disorder.

The study identifies two sub-populations of BD neurons based on lithium responsiveness, with lithium treatment effectively reducing hyperexcitability in lithium-responsive patients but not in non-responsive patients, highlighting the potential for personalized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium. Stern, S., Santos, R., Marchetto, MC., et al.[2019]

Recent research suggests that voltage-gated ion channels play a significant role in bipolar disorder (BD), affecting various neurobiological mechanisms such as synaptic plasticity and energy regulation, which may contribute to the disorder's complex symptoms.

The proposed model indicates that genetic variations in ion channel proteins can lead to endophenotypes like poor impulse control and cognitive deficits, suggesting that these neurobiological changes may underlie the mood episodes experienced by BD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains. Balaraman, Y., Lahiri, DK., Nurnberger, JI.[2021]

Rapid-cycling bipolar disorder is linked to a worse treatment response and higher suicide risk, with patients experiencing more depressive episodes that are often harder to treat compared to those without rapid cycling.

Effective management of rapid cycling involves a three-part approach: reducing cycle-promoting agents, optimizing mood stabilizers, and considering experimental treatments, with established options including lithium and atypical antipsychotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of rapid-cycling bipolar disorder. Schneck, CD.[2013]

Research into bipolar disorder has shifted from focusing solely on traditional antidepressants and antipsychotics to understanding the role of intracellular calcium signaling and its impact on neural circuits, particularly in the paraventricular thalamic nucleus.

The study highlights the potential for individualized treatment approaches that combine pharmacological and psychosocial therapies, based on the biological mechanisms underlying each patient's condition, including genetic vulnerabilities and circadian rhythm abnormalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies. Kato, T.[2020]

Patients with rapid cycling bipolar disorder experience more severe mood swings and are more likely to have recurrences despite treatment, highlighting the need for careful diagnosis and management.

Lithium and lamotrigine are supported by controlled studies as effective prophylactic treatments, and combinations of mood stabilizers may enhance maintenance therapy, although antidepressants have not consistently shown benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid cycling bipolar disorder: clinical characteristics and treatment options. Coryell, W.[2018]

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

Corticospinal integrity and motor impairment predict outcomes after excitatory repetitive transcranial magnetic stimulation: a preliminary study. [2016]

3. France pubmed.ncbi.nlm.nih.gov

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

4. 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]

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

Safety and Efficacy of Continuous Theta Burst "Intensive" Stimulation in Acute-Phase Bipolar Depression: A Pilot, Exploratory Study. [2023]

6. 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]

7. 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]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Accelerated intermittent theta burst stimulation for major depressive disorder or bipolar depression: A systematic review and meta-analysis. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium. [2019]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains. [2021]

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

Treatment of rapid-cycling bipolar disorder. [2013]

12. Australia pubmed.ncbi.nlm.nih.gov

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies. [2020]

13. New Zealand pubmed.ncbi.nlm.nih.gov

Rapid cycling bipolar disorder: clinical characteristics and treatment options. [2018]