Theta Burst Stimulation for Treatment-Resistant Depression

(ciTBS Trial)

Not currently recruiting at 1 trial location

Overseen By Yvette Sheline, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Pennsylvania

Disqualifiers: Pregnancy, Stroke, Epilepsy, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach for individuals with depression that hasn't improved with other treatments. Researchers use a technique called intermittent theta burst stimulation (iTBS), which applies magnetic pulses to a specific brain area over a shorter time. The goal is to determine if this concentrated schedule can effectively reduce depression symptoms. Ideal participants are those diagnosed with major depressive disorder (MDD) who have not responded to at least two previous treatments. As an unphased trial, this study provides a unique opportunity to explore innovative treatments that could potentially enhance quality of life.

Do I have to stop taking my current medications for the trial?

The protocol does not specify if you must stop taking your current medications. However, you may continue your current anti-depressant medication if it doesn't exceed doses that would make TMS an increased risk, at the discretion of the principal investigator.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you may be allowed to stay on your current antidepressant medication if it doesn't increase the risk of the treatment, as decided by the principal investigator.

What prior data suggests that this protocol is safe for treatment-resistant depression?

Research has shown that intermittent theta burst stimulation (iTBS) is generally safe. A review of studies found iTBS to be relatively safe for treating mental health conditions. One study demonstrated that a faster version of iTBS, administered five times a day over ten days, was safe for teenagers with non-resistant depression.

In another trial, researchers used a modified iTBS method on patients with treatment-resistant depression. This approach involved fewer sessions each day and was also found to be safe. These findings suggest that iTBS, even when administered in a shorter time frame, is well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike traditional treatments for depression, such as medications and electroconvulsive therapy, which can take weeks or even months to show effectiveness, Intermittent Theta Burst Stimulation (iTBS) offers a potentially faster approach. iTBS delivers rapid bursts of magnetic pulses to the brain in a compressed schedule, which could lead to quicker symptom relief in just a few days. Researchers are excited about this method because it targets brain activity differently, potentially offering a novel and efficient option for those with treatment-resistant depression.

What evidence suggests that intermittent theta burst stimulation might be an effective treatment for treatment-resistant depression?

Research has shown that intermittent theta burst stimulation (iTBS) can significantly reduce symptoms in individuals with treatment-resistant depression. In this trial, participants will receive iTBS on a compressed schedule. Studies have found that patients often experience noticeable and lasting improvement in their depression after iTBS. This magnetic stimulation works faster than traditional methods, providing quicker relief. In some studies, up to 60% of participants felt better within three months of starting iTBS. The treatment is also considered safe and well-tolerated, making it a promising option for those who haven't found success with other depression treatments. ^{1 2 6 7 8}

What evidence suggests that intermittent theta burst stimulation might be an effective treatment for treatment-resistant depression?

Research has shown that intermittent theta burst stimulation (iTBS), which participants in this trial will receive, can help people with depression that hasn't improved with other treatments. Studies have found that iTBS can significantly reduce depression symptoms, with some patients feeling better in just 1 to 4 weeks. In a national study, about 42.1% of patients responded positively to iTBS, a rate similar to other well-known treatments. iTBS is also considered more efficient and possibly more effective than traditional methods. This evidence suggests that iTBS could be a promising option for those who haven’t found relief with other treatments. ^{1 3 6 7 9}

Who Is on the Research Team?

Yvette Sheline, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for adults aged 18-70 with major depressive disorder who haven't improved after at least two treatments. They must score ≥20 on a depression scale, speak English, and can consent to treatment. Exclusions include MRI contraindications, implanted medical devices like pacemakers, pregnancy, recent substance abuse issues, or certain neurological conditions.

Inclusion Criteria

Patients must be fluent in English

Participants must have the ability to provide consent

My gender does not limit my participation.

Exclusion Criteria

You have a health condition that makes it difficult to get accurate MRI results.

You have been struggling with alcohol or drug addiction in the past three months.

Pregnancy (Female participants)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive compressed intermittent theta-burst stimulation (iTBS) for 5 consecutive days, with 10 treatment sessions per day

1 week

5 visits (in-person)

Follow-up

Participants are monitored for changes in depressive symptoms using MADRS and BDI II scales

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Intermittent Theta Burst Stimulation

Trial Overview The study tests an accelerated form of magnetic brain stimulation called intermittent Theta Burst Stimulation (iTBS), concentrating the usual 6-week protocol into five days for those with treatment-resistant depression.

How Is the Trial Designed?

Group I: Compressed iTBS schedule Experimental Treatment 1 Intervention

Stimulation 3-pulse 50-Hz bursts at 5-Hz for 2-s trains, with trains every 10 s, for 10 minutes, 10 times a day, for 5 consecutive days.

Intermittent Theta Burst Stimulation is already approved in United States, European Union for the following indications:

Approved in United States as iTBS for:

• Treatment-resistant depression

Approved in European Union as iTBS for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

In a study of 22 participants with treatment-resistant depression, the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, which uses high-dose intermittent theta-burst stimulation (iTBS) guided by functional connectivity MRI, showed a remarkable remission rate of 90.5%.

The treatment was well tolerated with no negative cognitive side effects reported, suggesting that SAINT could be a safe and effective option for patients who have not responded to traditional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Cole, EJ., Stimpson, KH., Bentzley, BS., et al.[2020]

Chronic administration of GHB in rats did not lead to tolerance for respiratory depression, indicating that users may remain at high risk for respiratory failure even after repeated use.

The study found changes in the expression of monocarboxylate transporters (MCTs) in the kidneys and intestines, suggesting that chronic GHB use may alter how the body processes this drug, but these changes did not affect the pharmacokinetics or respiratory effects over the treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of chronic γ-hydroxybutyrate (GHB) administration on GHB toxicokinetics and GHB-induced respiratory depression. Morse, BL., Chadha, GS., Felmlee, MA., et al.[2018]

Accelerated intermittent Theta-burst Stimulation (iTBS) applied to the left dorsolateral prefrontal cortex in 50 patients with Treatment Resistant Depression (TRD) was found to be safe and led to significant reductions in depressive symptoms immediately after treatment.

While 28% of patients achieved a 50% reduction in depression scores during the treatment, this response rate increased to 38% two weeks post-treatment, with 30% of responders reaching clinical remission, suggesting delayed therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated intermittent theta burst stimulation treatment in medication-resistant major depression: A fast road to remission? Duprat, R., Desmyter, S., Rudi, de R., et al.[2019]

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, high-dose intermittent theta burst stimulation (iTBS) showed promising results in treating highly treatment-resistant depression, with most patients achieving remission after treatment.

However, the effects were short-lived, as all patients experienced relapse within two weeks, indicating a need for improved treatment strategies that enhance the durability of the therapeutic response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is accelerated, high-dose theta burst stimulation a panacea for treatment-resistant depression? Caulfield, KA.[2021]

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) targeting the left dorsolateral prefrontal cortex significantly decreased the N100 amplitude in participants with treatment-resistant depression, indicating a neurophysiological response to the treatment.

Responders to iTBS showed a notable decrease in N100 amplitude and higher N45 amplitude post-treatment compared to nonresponders, suggesting that these TMS-EEG markers could help predict treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identifying Neurophysiological Markers of Intermittent Theta Burst Stimulation in Treatment-Resistant Depression Using Transcranial Magnetic Stimulation-Electroencephalography. Strafella, R., Momi, D., Zomorrodi, R., et al.[2023]

Three cases of patients who ingested products containing GHB and its precursors (GBL and 1,4-BD) showed severe symptoms but all fully recovered, highlighting the potential dangers of these substances.

Despite the FDA warning leading to the withdrawal of some GBL products, 1,4-butanediol is still available for purchase, raising concerns about its safety and the risks associated with its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Coma and respiratory depression following the ingestion of GHB and its precursors: three cases. Ingels, M., Rangan, C., Bellezzo, J., et al.[2019]

In a randomized, double-blind trial involving 56 patients, intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex showed a significant reduction in negative symptoms for patients with depression, but not for those with schizophrenia.

The treatment was generally safe and well-tolerated, with serious adverse events occurring only in the sham group, indicating that iTBS may be a promising intervention for depressive symptoms in certain patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dorsomedial prefrontal theta burst stimulation to treat anhedonia, avolition, and blunted affect in schizophrenia or depression - a randomized controlled trial. Bodén, R., Bengtsson, J., Thörnblom, E., et al.[2021]

In a study of 60 treatment-refractory patients with major depressive disorder, both intermittent and combined theta-burst stimulation showed significantly better antidepressant responses compared to continuous theta-burst stimulation and sham treatment after 2 weeks.

Theta-burst stimulation is well-tolerated and effective, especially in patients with lower levels of treatment refractoriness, indicating that the severity of refractoriness can influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. Li, CT., Chen, MH., Juan, CH., et al.[2022]

A report on 5 patients in California revealed that illicitly marketed gamma-hydroxybutyrate (GHB) can cause adverse reactions such as drowsiness, dizziness, and nausea, but no deaths were reported, and all patients fully recovered without long-term effects.

Despite being banned by the FDA, GHB remains available in the underground market, particularly among athletes seeking performance enhancement, highlighting the need for physicians to recognize signs of GHB poisoning in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute poisoning from gamma-hydroxybutyrate in California. Chin, MY., Kreutzer, RA., Dyer, JE.[2018]

A study involving 16 participants found that a dose of 50 mg/kg of GHB significantly impaired driving ability one hour after ingestion, leading to more collisions and erratic driving behavior.

However, by three to six hours post-dose, participants showed full recovery from impairment, suggesting that it is safe to drive the next morning after taking GHB for narcolepsy, provided no other substances are involved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of γ-hydroxybutyrate (GHB) on driving as measured by a driving simulator. Liakoni, E., Dempsey, DA., Meyers, M., et al.[2019]

GHB is a drug of abuse that can cause serious health risks, including respiratory and cardiovascular issues, and can lead to incapacitation due to its sedative effects and potential for retrograde amnesia.

Immediate medical attention is crucial in cases of GHB overdose, as the drug's effects can be rapid and its detection in the body is short-lived, making timely reporting essential for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacologic, Pharmacokinetic, and Clinical Assessment of Illicitly Used γ-Hydroxybutyrate. White, CM.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40509535/

Real-World Effectiveness and Tolerability of Prolonged ... Left-sided DLPFC iTBS1800 may be a feasible option for treating older patients with TRD due to its favorable effect and shorter treatment period.

2. 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 ...

3. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2830095

Accelerated Intermittent Theta-Burst Stimulation for ... Within-group improvements for active aiTBS indicated a significant and sustained reduction in depression severity at 1 and 4 weeks. Several ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1935861X22000900

Intermittent theta burst stimulation (iTBS) versus 10 Hz high ... Among responders to an initial course of rTMS, the response rate is ∼60% at 3 months, and approximately 30%–50% at 6 and 12 months [[10], [11], [12]]. This ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40042840/

Accelerated Theta-Burst Stimulation for Treatment ... A pragmatic aTBS protocol using only 3 iTBS sessions per day and a nonexpensive, non-neuronavigated approach was found to be safe and effective for TRD.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10423820/

Efficacy and safety of intermittent theta burst stimulation ... Among the two RCTs, no group differences were found regarding the overall rates of response (iTBS group: 48.0% versus HF-rTMS group: 45.5%) and ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0165032723002604

Outcome of transcranial magnetic intermittent theta-burst ... In this first national register-based cohort study of iTBS for depression we observed a clinician rated response rate of 42.1 %, being on par ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006322325013563

Efficacy and Safety of Accelerated Intermittent Theta-burst ... In this trial, a-iTBS, administered five sessions per day for ten days, is effective and safe for adolescents with non-treatment-resistant MDD.

9. psychiatryonline.org psychiatryonline.org/doi/full/10.1176/appi.ajp.2021.21121221

Accelerated Intermittent Theta Burst Stimulation In terms of the primary outcomes, the authors reported an impressive 69.2% response rate and a 46.2% remission rate 4 weeks after treatment, ...