Theta Burst Stimulation for Schizophrenia

(REDOCS Trial)

Overseen by Fabio Ferrarelli, MD, PhD

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Fabio Ferrarelli

Disqualifiers: Intellectual disorder, Neurologic disorder, Epilepsy, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial will test if a special type of brain stimulation called iTBS can improve brain activity and memory in people with early-stage schizophrenia. The treatment uses magnetic pulses to boost brain rhythms in a specific area linked to memory. Researchers will compare the effects of different treatments to see if iTBS makes a difference. Intermittent theta burst stimulation (iTBS) is a noninvasive brain stimulation technique that has shown promise in treating various psychiatric and neurological conditions, including treatment-resistant depression and cognitive impairments.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Intermittent Theta Burst Stimulation (iTBS) for schizophrenia?

Research indicates that iTBS can significantly reduce negative symptoms of schizophrenia, with effects lasting up to 6 months after treatment. Additionally, iTBS has shown potential in improving brain connectivity, which may help alleviate symptoms. ^{1 2 3 4 5}

Is theta burst stimulation safe for humans?

Theta burst stimulation, including intermittent theta burst stimulation (iTBS), is generally considered safe and well-tolerated in humans, with studies showing no major side effects in conditions like depression and schizophrenia. ^{6 7 8 9 10}

How does intermittent theta burst stimulation (iTBS) differ from other treatments for schizophrenia?

Intermittent theta burst stimulation (iTBS) is a unique treatment for schizophrenia as it uses magnetic pulses to stimulate specific brain areas, potentially improving negative symptoms by enhancing dopamine transmission. Unlike traditional treatments, iTBS sessions are short, lasting just over 3 minutes, and can be administered twice daily over a short period, offering a non-invasive alternative to medication. ^{4 6 7 10 11}

Research Team

Fabio Ferrarelli, MD, PhD

Principal Investigator

University of Pittsbrugh

Eligibility Criteria

This trial is for individuals aged 18-40 with early-course schizophrenia, having experienced psychosis for less than three years. Participants must have a diagnosis within the Schizophrenia Spectrum and be able to give informed consent. It's not open to those who are pregnant or recently postpartum, have diabetes with certain complications, significant neurological disorders, substance dependence (except cannabis/alcohol), or a history of severe head injury.

Inclusion Criteria

I have been diagnosed with a schizophrenia spectrum disorder.

Duration of less than three years from beginning of psychosis, defined by report of symptoms and/or history of treatment, based on clinical guidelines employed in UPMC psychoses clinics in Pittsburgh.

I am between 18 and 40 years old.

Exclusion Criteria

DSM intellectual developmental disorder

Inability to provide informed consent

I have a medical condition that affects my brain.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intermittent Theta Burst Stimulation (iTBS) and sham TBS over the dorsolateral prefrontal cortex (DLPFC) to assess changes in oscillatory activity and working memory performance

1 week

2 visits (in-person)

Follow-up

Participants are monitored for changes in DLPFC oscillatory activity and working memory performance post-treatment

1 week

Treatment Details

Interventions

• Intermittent Theta Burst Stimulation (iTBS) (Behavioural Intervention)

Trial Overview The study tests if Theta Burst Stimulation (iTBS) can improve brain function and memory in people with early schizophrenia. iTBS uses magnetic pulses on the brain while EEG tracks activity changes. Participants will receive either real iTBS or a sham treatment without active stimulation to compare effects on working memory.

Participant Groups

Group I: sham, then active intermittent Theta Burst Stimulation (iTBS) over DLPFC Experimental Treatment 2 Interventions

This arm will first receive sham iTBS (i.e., with the TMS coil in the placebo orientation) and then active iTBS stimulation over the left dorsolateral prefrontal cortex (DLPFC).

Group II: active, then sham Intermittent Theta Burst Stimulation (iTBS) over DLPFC Experimental Treatment 2 Interventions

This arm will first receive active iTBS stimulation and then sham iTBS over the left dorsolateral prefrontal cortex (DLPFC).

Who Is Running the Clinical Trial?

Fabio Ferrarelli

Lead Sponsor

Trials

2

Recruited

280+

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 study of 105 patients with treatment-resistant depression undergoing theta-burst stimulation, those taking antipsychotics did not have worse outcomes compared to those not on these medications, and some results even suggested better response and remission rates.

The findings indicate that the use of antipsychotics may not hinder the effectiveness of theta-burst stimulation, which is promising for patients who are on these medications, warranting further research into combined treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of antipsychotic pharmacotherapy on clinical outcomes of intermittent theta-burst stimulation for refractory depression. Schulze, L., Remington, G., Giacobbe, P., et al.[2018]

This study is a randomized, sham-controlled, double-blind trial involving 86 patients with schizophrenia spectrum disorder, testing the efficacy of continuous theta burst stimulation (cTBS) on reducing auditory verbal hallucinations (AH).

The primary goal is to measure the reduction in AH symptoms using the PSYRATS-AH score after treatment, with follow-up assessments at 1, 3, and 6 months, which will help determine the effectiveness of cTBS compared to sham treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of auditory hallucinations with bilateral theta burst stimulation (cTBS): protocol of a randomized, double-blind, placebo-controlled, multicenter trial. Plewnia, C., Brendel, B., Schwippel, T., et al.[2018]

This clinical trial will compare the effects of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) and intermittent theta burst stimulation (iTBS) on negative symptoms of schizophrenia in 90 patients, aiming to provide a new treatment option for this challenging condition.

The study will also explore the impact of these treatments on depressive symptoms, cognitive performance, and smoking behavior, while using MRI and EEG to identify potential neural markers for treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and study design of a trial to assess rTMS add-on value for the amelioration of negative symptoms of schizophrenia (RADOVAN). Hebel, T., Langguth, B., Schecklmann, M., et al.[2022]

In a study involving 22 patients with treatment-resistant negative symptoms of schizophrenia, intermittent theta burst transcranial magnetic stimulation (iTBS) significantly reduced symptom severity compared to a sham treatment, with effects lasting up to 6 months after the sessions ended.

Neuroimaging results indicated that iTBS increased functional connectivity in the brain regions associated with dopamine transmission, suggesting that the therapeutic effects of iTBS may be linked to enhanced dopamine activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent theta burst stimulation for negative symptoms of schizophrenia-A double-blind, sham-controlled pilot study. Bation, R., Magnin, C., Poulet, E., et al.[2021]

Theta burst stimulation (TBS) is a promising therapeutic approach for schizophrenia, showing potential benefits in treating specific symptoms and improving patient insight, based on a review of 30 studies that utilized various neuroimaging techniques.

TBS is well-tolerated and has few adverse effects, making it a feasible option for augmenting traditional pharmacotherapy in patients with schizophrenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of theta burst stimulation in patients with schizophrenia - A systematic review. Poorganji, M., Goeke, K., Zomorrodi, R., et al.[2023]

Intermittent theta-burst stimulation (iTBS) and high-frequency rTMS (HF-rTMS) show similar efficacy in treating treatment-resistant depression (TRD), with response rates of 48.0% for iTBS and 45.5% for HF-rTMS based on two high-quality randomized controlled trials involving 474 participants.

Both iTBS and HF-rTMS have comparable safety profiles, with similar rates of discontinuation and adverse events, such as headaches, indicating that iTBS is a safe alternative to HF-rTMS for patients with TRD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review. Lan, XJ., Yang, XH., 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]

In a study involving 36 patients with treatment-resistant schizophrenia, intermittent theta burst stimulation (iTBS) targeting the midline cerebellum did not show significant improvements in schizophrenia symptoms compared to sham stimulation, indicating limited efficacy for this approach.

The iTBS treatment was found to be safe and well tolerated, with no major side effects reported, suggesting that while it may not be effective, it does not pose significant risks to patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Intensive Cerebellar Intermittent Theta Burst Stimulation (iCiTBS) in Treatment-Resistant Schizophrenia: a Randomized Placebo-Controlled Study. Chauhan, P., Garg, S., Tikka, SK., et al.[2021]

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]

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]

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]

References

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

Effect of antipsychotic pharmacotherapy on clinical outcomes of intermittent theta-burst stimulation for refractory depression. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

Treatment of auditory hallucinations with bilateral theta burst stimulation (cTBS): protocol of a randomized, double-blind, placebo-controlled, multicenter trial. [2018]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Rationale and study design of a trial to assess rTMS add-on value for the amelioration of negative symptoms of schizophrenia (RADOVAN). [2022]

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

Intermittent theta burst stimulation for negative symptoms of schizophrenia-A double-blind, sham-controlled pilot study. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

The use of theta burst stimulation in patients with schizophrenia - A systematic review. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review. [2023]

7. England 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. [2022]

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

Efficacy of Intensive Cerebellar Intermittent Theta Burst Stimulation (iCiTBS) in Treatment-Resistant Schizophrenia: a Randomized Placebo-Controlled Study. [2021]

9. Ireland pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. [2022]

10. United States 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. [2022]

11. United States 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). [2022]