Theta Burst Stimulation for Depression and Autism

(RETSORE-RCT Trial)

Overseen By Jennifer Combs, Masters

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Children's Hospital Medical Center, Cincinnati

Must not be taking: Anticonvulsants, Barbiturates, Lithium, Benzodiazepines

Disqualifiers: Substance use disorder, Epilepsy, 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: 9

Duration: 1 week

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called theta burst stimulation (aTBS) to determine its effectiveness in reducing depression symptoms in people with autism spectrum disorder (ASD). Participants will receive either the active treatment or a sham (fake) version for comparison. The trial suits individuals with ASD who experience moderate to severe depression and have not responded well to at least one antidepressant. Participants must be fluent in English and able to discuss the study details. As an unphased trial, this study offers a unique opportunity to contribute to pioneering research that could lead to new treatment options for ASD-related depression.

Will I have to stop taking my current medications?

You don't have to stop taking your current medications, but you should try to keep them stable during the study. However, if you are currently using anticonvulsant, barbiturate, lithium, or benzodiazepine medications, you cannot participate in the trial.

What prior data suggests that theta burst stimulation is safe for treating depression and autism?

Research has shown that theta burst stimulation (TBS) is generally safe when used according to current guidelines. Studies have found that TBS can be a safe treatment option for conditions like depression. Although all medical treatments can have side effects, TBS has a safety record similar to repetitive transcranial magnetic stimulation (rTMS).

Some studies tested high-dose TBS in children with autism spectrum disorder (ASD) to assess its safety and effectiveness. These studies suggest that TBS is both feasible and safe for this group. However, because TBS involves brain stimulation, following safety guidelines closely is crucial to minimize potential risks. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Theta Burst Stimulation (TBS) is unique because it offers a rapid and non-invasive approach to treating depression and autism by targeting the brain's left dorsolateral prefrontal cortex. Unlike traditional treatments like medication or electroconvulsive therapy, which can take weeks to show effects and may have significant side effects, TBS can potentially show benefits in just days with fewer adverse reactions. Researchers are excited about TBS because it uses brief magnetic pulses to modulate brain activity, potentially providing a quicker and safer alternative for those who haven't responded well to existing therapies.

What evidence suggests that theta burst stimulation is effective for reducing depressive symptoms in autism?

This trial will compare active theta burst stimulation (TBS) with a sham-controlled treatment. Studies have shown that TBS can help reduce symptoms of depression. Research on TBS targeting the left dorsolateral prefrontal cortex, a brain area involved in mood regulation, has demonstrated significant improvements in depression symptoms. One study showed that this treatment quickly and safely reduced depression symptoms in teenagers. Another study found TBS more effective than a placebo for depression. In individuals with autism spectrum disorder (ASD), TBS has also shown potential benefits for easing depression symptoms. ^{3 4 6 7 8}

Who Is on the Research Team?

Rana Elmaghraby, MD

Principal Investigator

Cincinnati Childrens Hospital Medical Center

Are You a Good Fit for This Trial?

This trial is for individuals with Autism Spectrum Disorder (ASD) who are also experiencing hard-to-treat depression. Participants should be diagnosed with both conditions and have not found relief from standard treatments.

Inclusion Criteria

Fluent in English and able to volunteer in the informed consent process and provide spontaneous narrative description of key elements, risks, and benefits of the study

Full-scale intelligence quotient ≥ 70

I am between 13 and 26 years old.

Exclusion Criteria

Actively suicidal (i.e., suicidal ideation with plan and intent) or deemed at high risk for suicide

For female subjects of childbearing potential, a positive urine pregnancy test

I have previously undergone rTMS treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Treatment

Participants receive either active or sham accelerated theta burst stimulation (aTBS) targeting the left dorsolateral prefrontal cortex, 5 sessions per day for 5 days

1 week

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments at 2-week, 6-week, and 12-week intervals

12 weeks

3 visits (in-person)

Open-label extension (optional)

Participants in the sham group who do not show a significant treatment response by the 12-week follow-up are eligible for active, open-label treatment

What Are the Treatments Tested in This Trial?

Interventions

• Theta Burst Stimulation

Trial Overview The study is testing the effectiveness of a technique called accelerated theta burst stimulation (aTBS), which uses magnetic fields to stimulate certain areas of the brain, in reducing symptoms of depression in people with ASD.

How Is the Trial Designed?

Group I: Active TBS Treatment Active Control 1 Intervention

Active aTBS targeting the left dorsolateral prefrontal cortex, 5 sessions per day for 5 days.

Group II: Sham controlled Placebo Group 1 Intervention

Sham aTBS targeting the left dorsolateral prefrontal cortex, 5 sessions per day for 5 days. If participants in the sham group do not show a significant treatment response by the 12-week follow-up - defined as a 50% reduction from baseline on the HDRS- they will then become eligible for and offered active, open-label treatment.

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

Approved in United States as Theta Burst Stimulation for:

• Major Depressive Disorder

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Published Research Related to This Trial

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) 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]

In a study of 27 participants, a prolonged intermittent theta burst stimulation (piTBS) protocol using 1,800 pulses showed limited effectiveness for major depressive disorder, with only 18.2% of participants achieving a response and 9.1% reaching remission.

Safety and tolerability were concerns, as 18.5% of participants experienced issues, suggesting that while piTBS is a promising approach, further research is needed to optimize its parameters and improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. Richard, M., Noiseux, C., Desbeaumes Jodoin, V., et al.[2022]

Repeated applications of Theta Burst stimulation (TBS) in rats showed complex effects on neuronal activity markers, with some markers increasing while others decreased, indicating that the response to TBS is not simply accumulative.

Specifically, while the expression of the vesicular glutamate transporter (VGLUT1) increased with stimulation, markers for inhibitory activity like GAD67 and calcium-binding proteins decreased, suggesting a nuanced interaction between excitatory and inhibitory neuronal responses to repeated TBS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-dependence of changes in cortical protein expression induced with repeated transcranial magnetic theta-burst stimulation in the rat. Volz, LJ., Benali, A., Mix, A., et al.[2016]

In a study of 165 pediatric participants aged 6 to 18, theta-burst TMS (TBS) demonstrated a similar safety profile to single- and paired-pulse TMS (sp/ppTMS), with no severe adverse effects reported.

The overall rate of adverse effects was 10.5% for TBS and 12.4% for sp/ppTMS, with most effects rated as minimal or mild, indicating that TBS is a safe option for further investigation in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of theta burst stimulation vs. single and paired pulse transcranial magnetic stimulation: a comparative study of 165 pediatric subjects. Hong, YH., Wu, SW., Pedapati, EV., et al.[2020]

In a study involving 36 participants, it was found that the intensity of transcranial magnetic stimulation (TMS) significantly affects the plasticity response in the primary motor cortex, with higher intensities (150% of resting motor threshold) yielding greater depression effects from continuous theta burst stimulation (cTBS).

For intermittent theta burst stimulation (iTBS), the most effective probing intensity was at 110% of resting motor threshold, indicating that different intensities are crucial for accurately assessing neuroplasticity responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Probing changes in corticospinal excitability following theta burst stimulation of the human primary motor cortex. Goldsworthy, MR., Vallence, AM., Hodyl, NA., et al.[2017]

Theta-burst transcranial magnetic stimulation (TBS) is safe and well tolerated in patients with major depression, based on a study involving 33 participants over 10 consecutive days.

The study suggests that TBS may have antidepressant effects, and increasing stimulation parameters does not lead to more side effects, potentially enhancing its therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability and preliminary evidence for antidepressant efficacy of theta-burst transcranial magnetic stimulation in patients with major depression. Chistyakov, AV., Rubicsek, O., Kaplan, B., et al.[2019]

In a randomized-controlled trial involving 32 patients with major depression, bilateral theta burst stimulation (TBS) to the dorsolateral prefrontal cortex showed a significant increase in treatment response compared to sham stimulation, with 9 responders in the TBS group versus 4 in the sham group.

The study also indicated a trend towards higher remission rates in the TBS group as measured by the Beck Depression Inventory, suggesting that TBS may enhance the effectiveness of ongoing medication and psychotherapy in treating major depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. Plewnia, C., Pasqualetti, P., Große, S., et al.[2018]

Accelerated intermittent theta burst stimulation (TBS) was found to be safe and well tolerated in 12 suicidal therapy-resistant depressed patients, showing a significant decrease in suicidal ideation over time.

However, the reduction in suicidal thoughts was not definitively linked to the active TBS treatment compared to sham stimulation, indicating that further research is needed to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The acute effects of accelerated repetitive Transcranial Magnetic Stimulation on suicide risk in unipolar depression: preliminary results. Desmyter, S., Duprat, R., Baeken, C., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9867406/

A Case Series of Intermittent Theta Burst Stimulation ... TMS therapy in the form of iTBS may have some beneficial therapeutic effects on depressive symptoms in individuals with ASD.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11995711/

Feasibility, safety, and efficacy of high-dose intermittent ... Applying rTMS over the left dorsolateral prefrontal cortex (DLPFC) has been demonstrated to significantly improve various symptom domains in neuropsychiatric ...

3. nature.com nature.com/articles/s41380-024-02630-5

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

4. link.springer.com link.springer.com/article/10.1007/s10803-024-06244-2

Accelerated Theta Burst Transcranial Magnetic Stimulation ... Depression: Primary and Secondary Outcomes ... There is considerable existing evidence that TMS treatment in depression is superior to sham ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165032725000023

Efficacy study of intermittent theta burst stimulation(iTBS) in ... The current study suggests that two days of active iTBS to the DLPFC region can rapidly, safely, and effectively improve depressive symptoms in adolescents ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3260517/

Safety of Theta Burst Transcranial Magnetic Stimulation TMS is considered quite safe if applied within current safety guidelines, however, TMS does pose some risk for adverse side effects (Rossi et al., 2009). The ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1094715923007420

Review Articles Efficacy and Safety of Theta Burst Versus ... The aim of this meta-analysis was to compare TBS therapy with standard rTMS treatment regarding their safety and therapeutic effect on individuals with ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT07033780

NCT07033780 | Theta-Burst Stimulation to Treat Depression The goal of this clinical trial is to explore the effects of non-invasive brain stimulation protocols using intermittent theta-burst stimulation (iTBS) on ...