Theta-Burst Stimulation for Bipolar Disorder

(TRIBE Trial)

Recruiting at 1 trial location

Overseen By Mawahib Semeralul

Age: 18+

Sex: Any

Trial Phase: Academic

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 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: 32

Duration: 4 weeks

124 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if intermittent theta-burst stimulation (iTBS) can reduce depression symptoms in people with bipolar disorder who haven't found success with other treatments. Participants will receive either real iTBS or a placebo version over 30 days, with regular check-ins to evaluate depression and mania symptoms. It suits those with bipolar disorder who are currently experiencing a depressive episode and have tried at least one other treatment without success. As an unphased trial, this study provides a unique opportunity to explore a novel treatment option for managing depression symptoms in bipolar disorder.

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 prior data suggests that theta-burst stimulation is safe for treating bipolar disorder?

Research has shown that intermittent theta-burst stimulation (iTBS) is generally well-tolerated. One study found that iTBS can improve mood and thinking in people with certain brain conditions, indicating its safety for use in the brain. Another study discovered that iTBS is a promising non-invasive method to reduce symptoms of major depression, offering quick effects and a low risk of serious side effects. These findings suggest that while iTBS remains under investigation, current evidence indicates it is safe for humans. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about theta-burst stimulation (iTBS) for bipolar disorder because it offers a unique approach compared to traditional treatments like mood stabilizers or antipsychotics. Unlike medications that target chemical imbalances in the brain, iTBS uses magnetic fields to stimulate specific brain regions, potentially providing a faster response with fewer side effects. The non-invasive nature and precision of iTBS could offer a new option for those who haven't found relief with standard medications, making it a promising avenue for managing bipolar disorder.

What evidence suggests that theta-burst stimulation might be an effective treatment for bipolar disorder?

Research has shown that intermittent theta-burst stimulation (iTBS), which participants in this trial may receive, could help treat depression in individuals with treatment-resistant bipolar disorder. Studies have found that active iTBS significantly outperforms a fake (inactive) version in alleviating depression. This method, a type of non-invasive brain stimulation, quickly improves mood. It has been particularly beneficial for those who haven't responded to other treatments. These findings suggest iTBS could offer hope for people with difficult-to-treat depression related to bipolar disorder. ^{1 4 6 7 8}

Are You a Good Fit for This Trial?

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 not currently hospitalized.

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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Theta-Burst Stimulation

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.

How Is the Trial Designed?

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.

Theta-Burst Stimulation is already approved in United States for the following indications:

Approved in United States as Intermittent Theta-Burst Stimulation for:

• Treatment-resistant major depressive disorder
• Treatment-resistant bipolar depression

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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]

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]

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]

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]

Citations

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A double-blind, randomized, sham-controlled clinical trial ... Intermittent theta burst stimulation (iTBS) applied to the midline cerebellum has effects on mood and cognition in patients with neuropsychiatric disease.

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Theta-Burst Stimulation for Bipolar Depression The purpose of this trial is to determine if intermittent theta-burst stimulation (iTBS) can reduce the symptoms of depression in treatment-resistant ...

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Theta burst stimulation for depression: a systematic review ... The study outcomes included response rate (primary), depression symptom improvement, remission rate, all-cause discontinuation rate, incidence ...