Theta Burst Stimulation for Bipolar Disorder

Overseen By Fabio Ferrarelli, MD, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Mary Phillips, MD MD (Cantab)

Must be taking: Mood stabilizers

Must not be taking: SNRI antidepressants

Disqualifiers: Head injury, Neurological disorder, Epilepsy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 3 weeks

134 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a brain treatment called Continuous Theta Burst Stimulation (cTBS) to assess its effects on brain activity and emotions in individuals with and without bipolar disorder (BD). Researchers believe that cTBS might reduce negative emotions by altering brain activity, particularly in those with BD. Participants will receive various types of brain stimulation, including a sham version, to compare results. The trial seeks adults diagnosed with bipolar disorder or those without a history of the condition, excluding individuals with major psychiatric disorders or a history of head injuries. As an unphased study, this trial offers a unique opportunity to contribute to groundbreaking research on brain stimulation and emotional health.

Will I have to stop taking my current medications?

The trial does not require you to stop taking your current medications if you have Bipolar Disorder, as long as you are not on SNRI antidepressants or bupropion. You can continue with other medications like anxiolytics, atypical antipsychotics, lithium, mood stabilizers, and non-SNRI antidepressants.

What prior data suggests that this technique is safe for use in adults with and without bipolar disorder?

Research has shown that continuous theta burst stimulation (cTBS) is generally safe and well-tolerated. Studies have found that cTBS does not cause serious side effects in individuals experiencing major depressive episodes, including those with bipolar disorder. Most participants in these studies managed the treatment well without major problems.

Another source notes that repetitive transcranial magnetic stimulation (rTMS), a similar method, is FDA-approved for treating major depression and has been specially recognized for use in bipolar disorder, indicating a strong safety record.

Overall, while cTBS is not yet specifically approved for bipolar disorder, existing evidence suggests it is safe for individuals. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about Continuous Theta Burst Stimulation (cTBS) for bipolar disorder because it offers a novel, non-invasive way to potentially alleviate symptoms by targeting specific brain regions. Unlike typical medications like mood stabilizers and antipsychotics, which can take weeks to show effects and often come with significant side effects, cTBS uses rapid magnetic pulses to stimulate the brain, aiming for faster results with fewer side effects. By focusing on the ventrolateral prefrontal cortex and somatosensory areas, this method could provide targeted relief, making it a promising alternative to traditional drug therapies.

What evidence suggests that continuous theta burst stimulation could be an effective treatment for bipolar disorder?

This trial will evaluate the effectiveness of Theta Burst Stimulation (TBS) for managing bipolar depression. Participants will receive different sequences of Continuous Theta Burst Stimulation (cTBS) and Sham Continuous Theta Burst Stimulation (Sham cTBS) to assess their effects. Studies have shown that TBS is emerging as a promising and safe method for managing bipolar depression. TBS, a type of brain stimulation, may work better and more efficiently than traditional methods. The FDA has approved repetitive transcranial magnetic stimulation (rTMS), which includes TBS, for treating major depression, and it shows potential for helping with bipolar disorder as well. TBS alters brain activity, which might help reduce symptoms like negative emotions in people with bipolar disorder. While researchers continue to study TBS, early findings suggest it could be beneficial for those with bipolar disorder. ^{2 4 6 7 8}

Who Is on the Research Team?

Fabio Ferrarelli, MD, PhD

Principal Investigator

University of Pittsburgh

Mary L Phillips, MD, MD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for adults aged 18-35 with Bipolar Disorder I/II in remission or mild-moderate hypomania. They must score low on depression and mania scales, can be unmedicated or on certain stable medications (excluding antidepressant monotherapy), and have no severe psychiatric disorders, substance abuse issues, head injuries, neurological diseases, or family history of epilepsy.

Inclusion Criteria

You have been diagnosed with bipolar disorder.

You do not have a condition that causes hallucinations or delusions.

You have a score of less than 15 on the Young Mania Rating Scale, which measures symptoms of mania.

Exclusion Criteria

You are left-handed or use both hands interchangeably.

I am currently experiencing a depressive episode.

My diagnosis is not bipolar I or II disorder.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Baseline MRI

Participants undergo a baseline MRI scan to assess initial brain activity

1 day

1 visit (in-person)

Treatment

Participants receive transcranial brain stimulation (TBS) and undergo fMRI scanning at each of the 3 cTBS study visits, including one sham session

3 weeks

3 visits (in-person)

Follow-up

Participants are monitored for changes in brain activity and clinical symptoms after the treatment phase

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Continuous Theta Burst Stimulation (cTBS)
• Sham Continuous Theta Burst Stimulation (Sham cTBS)

Trial Overview The study tests the effects of Theta Burst Stimulation (TBS) on brain activity and emotions in people with Bipolar Disorder. It compares Continuous TBS (cTBS), which is an active treatment, to a sham version that mimics the procedure without real stimulation to see if cTBS reduces symptoms like negative emotions.

How Is the Trial Designed?

Group I: Left vlPFC/Left vlPFC sham/Left SS Experimental Treatment 2 Interventions

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Group II: Left vlPFC sham/Left vlPFC/Left SS Experimental Treatment 2 Interventions

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Group III: Left vlPFC sham/Left SS/Left vlPFC Experimental Treatment 2 Interventions

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Group IV: Left ventrolateral prefrontal cortex (vlPFC)/Left SS/Left vlPFC sham Experimental Treatment 2 Interventions

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Group V: Left SS/Left vlPFC/Left vlPFC sham Experimental Treatment 2 Interventions

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Group VI: Left SS/Left vlPFC sham/Left vlPFC Experimental Treatment 2 Interventions

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Continuous Theta Burst Stimulation (cTBS) is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Transcranial Magnetic Stimulation (TMS) for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)

Approved in European Union as Transcranial Magnetic Stimulation (TMS) for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)

Approved in Canada as Transcranial Magnetic Stimulation (TMS) for:

• Major Depressive Disorder (MDD)
• Obsessive-Compulsive Disorder (OCD)

Who Is Running the Clinical Trial?

Mary Phillips, MD MD (Cantab)

Lead Sponsor

Trials

4

Recruited

180+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

Theta-burst stimulation (TBS) was found to be safe for children, with no serious adverse events reported among 40 participants aged under 18, including those with Tourette syndrome and typically developing children.

Only 11.6% of participants experienced mild, self-limited side effects, such as finger twitching and headaches, indicating that TBS is well tolerated in this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta-burst transcranial magnetic stimulation in children. Wu, SW., Shahana, N., Huddleston, DA., et al.[2012]

In a double-blind, six-week clinical trial involving 100 patients with acute mixed depression, bilateral theta-burst stimulation (TBS) did not show significant efficacy compared to sham treatment, indicating it may not be an effective add-on therapy for this condition.

Response and remission rates for TBS were similar to those of the sham group, suggesting that TBS targeting the dorsolateral prefrontal cortex does not provide additional benefits for patients with bipolar or unipolar mixed depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of mixed depression with theta-burst stimulation (TBS): results from a double-blind, randomized, sham-controlled clinical trial. Tavares, DF., Suen, P., Rodrigues Dos Santos, CG., et al.[2023]

Theta burst stimulation (TBS) appears to be safe and tolerable for children and adolescents, with reported adverse events mostly being mild, such as headaches, similar to those seen in adults.

Despite the promising safety profile, there is a lack of long-term studies on TBS in younger populations, highlighting the need for further research to better understand its effects and potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review of the Safety and Tolerability of Theta Burst Stimulation in Children and Adolescents. Elmaghraby, R., Sun, Q., Ozger, C., et al.[2023]

In a case series of 9 patients with major depressive disorder and bipolar disorder, accelerated theta-burst rTMS treatment over 8 days led to significant reductions in depression symptoms, as measured by the CES-D and CGI scales.

The treatment was well tolerated, with mild headaches being the most common side effect, and five patients achieving at least a 50% reduction in symptoms by the end of the treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated theta-burst repetitive transcranial magnetic stimulation for depression in South Africa. Bröcker, E., van den Heuvel, L., Seedat, S.[2020]

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 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]

Theta-burst stimulation (TBS) shows promise as a rapid and effective treatment for psychiatric disorders, particularly treatment-resistant depression and auditory hallucinations, with studies indicating mild adverse effects but no severe complications like seizures or mania.

The current research on TBS is varied in design and outcomes, highlighting the need for more rigorous sham-controlled studies to better assess its long-term safety and efficacy in treating various psychiatric conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Theta-Burst Stimulation in the Treatment of Psychiatric Disorders: A Review of the Literature. Rachid, F.[2019]

In a study involving 300 patients with treatment-resistant depression, accelerated bilateral theta burst stimulation (TBS) was found to be effective and safe, with a treatment response rate of 43.7% and a remission rate of 28.2%.

The study revealed no significant differences in efficacy between different TBS intensities or when compared to traditional unilateral 10 Hz rTMS, indicating that the accelerated TBS does not provide faster antidepressant effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial. Chen, L., Thomas, EHX., Kaewpijit, P., et al.[2022]

Theta burst stimulation (TBS) is a promising technique for altering brain excitability, with a review of studies showing that adverse events were mostly mild and occurred in only 5% of subjects, indicating a generally safe profile.

Despite its safety, TBS carries a theoretical higher risk of seizures compared to other stimulation methods, necessitating cautious application and further research into its dosing parameters to better understand seizure risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. Oberman, L., Edwards, D., Eldaief, M., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11572496/

Efficacy of Theta Burst Stimulation in Bipolar Depression Theta Burst Stimulation (TBS) a novel variant of rTMS is currently evolving as an effective and safe therapeutic tool in the management of bipolar depression.

2. sciencedirect.com sciencedirect.com/science/article/pii/S2667174325001727

Efficacy, effectiveness and safety of transcranial magnetic ... Repetitive transcranial magnetic stimulation (rTMS) is FDA-approved for major depression and recently received breakthrough status for bipolar ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04696471?term=bipolar&aggFilters=funderType:nih,status:rec%20not&rank=6

Effects of Theta Burst Stimulation on the Brain, Behavior ... Bipolar Disorder (BD) is a common and highly debilitating psychiatric disorder, however, the predisposing brain mechanisms are poorly understood.

4. 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 ...

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2777422

Efficacy of Active vs Sham Intermittent Theta Burst ... iTBS targeting the left dorsolateral prefrontal cortex is not efficacious in the treatment of acute bipolar depression and can result in mood episode switches.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35815855/

Safety and Efficacy of Continuous Theta Burst "Intensive ... Our trial concludes that although safe and well tolerated, the therapeutic efficacy of intensive intermittent TBS in acute-phase bipolar depression is ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37924984/

A meta-analysis of randomized controlled studies Although cTBS appeared to be a safe and well-tolerated option for treating major depressive episodes in MDD or BD patients, no advantage in treatment effects ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S3050529124000825

A double-blind, randomized, sham-controlled clinical trial ... This randomized, double-blind, sham-controlled clinical trial evaluated the safety, tolerability, and efficacy of applying 10 sessions of iTBS, delivered twice ...