Theta Burst Stimulation for Bipolar Disorder

Recruiting in Palo Alto (17 mi)

Overseen by Mary L Phillips, MD, MD

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

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

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

Bipolar Disorder (BD) is a common and highly debilitating psychiatric disorder, however, the predisposing brain mechanisms are poorly understood. Here, the investigators aim to examine the immediate effect of transcranial brain stimulation (TBS) on brain activity and emotions in adults with and without BD as a first stage toward understanding the predisposing brain mechanisms of BD. The investigators hypothesize that TBS will reduce brain activity while playing a game with rewards in all adults, but the TBS will reduce brain activity more in the adults with BD compared to adults without BD. Furthermore, the investigators hypothesize that this reduced brain activity will be associated with reduced BD symptoms, such as negative emotions.

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 data supports the effectiveness of the treatment Continuous Theta Burst Stimulation (cTBS) for Bipolar Disorder?

Research shows that continuous theta burst stimulation (cTBS) has mixed results for treating bipolar depression, with some studies indicating modest improvements. Additionally, accelerated theta-burst repetitive transcranial magnetic stimulation (rTMS), a similar treatment, has shown significant symptom reduction in depression, suggesting potential benefits for bipolar disorder as well. ^{1 2 3 4 5}

Is theta burst stimulation (TBS) safe for humans?

Theta burst stimulation (TBS) is generally considered safe for humans, with most studies reporting only mild side effects. However, there is a theoretical risk of seizures, so it should be used with caution, especially since it is a relatively new technique. ^{3 6 7 8 9}

How does continuous theta burst stimulation (cTBS) differ from other treatments for bipolar disorder?

Continuous theta burst stimulation (cTBS) is a unique treatment for bipolar disorder because it uses magnetic pulses to stimulate specific brain areas, potentially offering faster and longer-lasting effects compared to traditional repetitive transcranial magnetic stimulation (rTMS). It is particularly notable for its shorter delivery time and potential to target brain connectivity issues specific to bipolar disorder. ^{1 3 4 9 10}

Research Team

Fabio Ferrarelli, MD, PhD

Principal Investigator

University of Pittsburgh

Mary L Phillips, MD, MD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

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 either younger than 18 or older than 35.

I am currently experiencing a depressive episode.

Trial Timeline

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

Treatment Details

Interventions

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

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.

Participant Groups

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 Canada for the following indications:

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+

Dr. Joshua A. Gordon

National Institute of Mental Health (NIMH)

Chief Executive Officer since 2016

MD, PhD

Dr. Shelli Avenevoli

National Institute of Mental Health (NIMH)

Chief Medical Officer

PhD

Findings from Research

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]

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 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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Treatment of mixed depression with theta-burst stimulation (TBS): results from a double-blind, randomized, sham-controlled clinical trial. [2023]

2. France pubmed.ncbi.nlm.nih.gov

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

3. 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]

4. 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]

5. South Africa pubmed.ncbi.nlm.nih.gov

Accelerated theta-burst repetitive transcranial magnetic stimulation for depression in South Africa. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta-burst transcranial magnetic stimulation in children. [2012]

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

Safety of theta burst transcranial magnetic stimulation: a systematic review of the literature. [2022]

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

A Systematic Review of the Safety and Tolerability of Theta Burst Stimulation in Children and Adolescents. [2023]

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

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

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

Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial. [2022]