Accelerated High-dose Sequential Bilateral Theta Burst Stimulation for Treatment Resistant Depression

March 30, 2023 updated by: Rajamannar Ramasubbu, University of Calgary

Accelerated High-dose Sequential Bilateral Theta Burst Stimulation for Treatment Resistant Depression: A Randomized Double-Blind Sham-controlled Pilot Study

Repetitive transcranial magnetic stimulation (rTMS) and Theta burst stimulation (TBS) are approved by the US. Food and Drug administration (FDA) for the treatment of refractory major depression. TBS is more efficient than rTMS as it requires shorter stimulation time.Studies suggest that the efficacy of TBS could be enhanced and expedited by accelerated protocols (more than once daily sessions) with higher doses of stimulation (>600 TBS pulses up to 3600 pulses per session) and shorter duration of treatment (4-10days). The main objective of this study is to determine the clinical efficacy and safety of accelerated high dose bilateral TBS treatment for patients with treatment resistant depression in comparison to sham stimulation using a randomized double blind clinical trial design.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Major depressive disorder (MDD) accounts for the highest global burden of all mental health disorders, and approximately 50% of depressed patients meet criteria for treatment resistant of depression. Stimulation based therapies have recently become a promising alternative for patients with treatment resistant depression. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) is approved by the US. Food and Drug administration (FDA) and has been recommended as a viable treatment option for major depression. Recently, a newer form of rTMS called Theta burst stimulation (TBS) is approved by FDA as it has shown comparable clinical efficacy and safety to rTMS in the treatment of depression. TBS is more efficient than rTMS as it requires shorter stimulation time of ≤ 6min compared to 20-40 min required in conventional rTMS protocol and produces equivalent antidepressant responses.

Studies suggest that the efficacy of TBS could be enhanced and expedited by accelerated protocols (more than once daily sessions ranging from 2-10 sessions/day) higher doses of stimulation (>600 TBS pulses up to 3600 pulses per session) with shorter duration of treatment (4-10days). Recently, an accelerated Stanford Neuromodulation Therapy protocol (10 sessions of iTBS a day for 5 days) with high dose stimulation (90,000 pulses in total) was found to be more effective than sham for severe TRD. This protocol yielded robust results with 69.2% response rates compared to 13% in sham during the 4-week outcome period .

The main goal of this project is to determine the clinical efficacy and safety of accelerated high dose bilateral TBS treatment for TRD in comparison to sham stimulation using a randomized double blind clinical trial design. The second objective is to examine the durability of antidepressant effect of this treatment protocol. Our initial open label study of accelerated high dose bilateral TBS demonstrated efficacy in a small cohort of participants with TRD. This proposed study builds on our initial findings whether the antidepressant efficacy of accelerated high dose bilateral TBS would be significantly greater than an identical schedule of sham stimulation. This pilot study will help to examine the feasibility, acceptability, and tolerability of treatment protocol, and estimate the sample size for the next pivotal trial. Hypotheses: Accounting this is a pilot study using small sample size without power size calculations, it is not designed for hypothesis testing. However, it is predicted that the accelerated bilateral TBS would be clinically effective and safe in the treatment of patients with TRD compared to sham stimulation. Additionally, it is anticipated that the antidepressant effects of this treatment may be durable.

Study Type

Interventional

Enrollment (Anticipated)

40

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Diagnosis of MDD (DSM-V)
  • Adults in the age range of 18 - 65
  • Both sex
  • HAMD-17 score of ≥20
  • TRD - failure to two antidepressant trial Stage II (Thase and Rush classification)

Exclusion Criteria:

  • Post traumatic stress disorder,
  • Obsessive compulsive disorder,
  • Psychosis
  • Bipolar disorder,
  • substance abuse disorder,
  • autistic spectrum disorder,
  • active suicidal behavior
  • Epilepsy
  • Dementia,
  • Movement disorders
  • severe head injury
  • Brain metallic implants, cardiac pacemakers
  • Pregnancy .
  • Non-response to prior rTMS, Electroconvulsive treatment, Vagal nerve or Deep brain stimulation or a history of psychosurgery.
  • Borderline personality disorder,
  • Schizotypal, schizoid & paranoid personality disorder
  • Current treatment with anticonvulsants or benzodiazepines

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Active stimulation
Bilateral real TBS
Device: Sequential bilateral theta burst stimulation
Three sessions of active or sham bilateral TBS will be delivered daily for 10 days in 2 weeks (no session on weekend) with a total of 30 sessions for each patient. Daily low intensity (90% resting motor threshold) bilateral sequential continousTBS ( cTBI) will be applied first on the right DLPFC (1800 pulses) and then intermittent TBS (iTBS)on the left DLPFC (1800 pulses) with an intersession interval of 60 minutes. We will adopt 1800 pulse per session based on the previous studies. Patients will receive a stimulation of 3600 pulses a session, 10,800 pulses a day and 108,000 pulses in total. After the study, sham group will receive active stimulation following the same protocol
Sham Comparator: Sham stimulation
Bilateral Sham stimulation
Device: Sequential bilateral theta burst stimulation
Three sessions of active or sham bilateral TBS will be delivered daily for 10 days in 2 weeks (no session on weekend) with a total of 30 sessions for each patient. Daily low intensity (90% resting motor threshold) bilateral sequential continousTBS ( cTBI) will be applied first on the right DLPFC (1800 pulses) and then intermittent TBS (iTBS)on the left DLPFC (1800 pulses) with an intersession interval of 60 minutes. We will adopt 1800 pulse per session based on the previous studies. Patients will receive a stimulation of 3600 pulses a session, 10,800 pulses a day and 108,000 pulses in total. After the study, sham group will receive active stimulation following the same protocol

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Montgomery Asberg Depression Rating Scale (MADRS)
Time Frame: Baseline to week 4 post treatment
Mean change in Montgomery Asberg Depression Rating Scale (MADRS) scores (0-60) from baseline to week 4 post treatment. Higher scores mean worse outcome.
Baseline to week 4 post treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hamilton Depression Rating Scale-17(HDRS-17)
Time Frame: Baseline to week 4 post treatment
Mean change in Hamilton Depression Rating Scale-17(HDRS-17) scores (0-52) from baseline to week 4 post treatment. Higher scores mean worse outcome
Baseline to week 4 post treatment
Quick Inventory of Depressive Symptomatology- Self Report (QIDS-SR)
Time Frame: Baseline to week 4 post treatment
Mean change in Quick Inventory of Depressive Symptomatology- Self Report (QIDS-SR) scores (0-27) from baseline to week 4 post treatment. Higher scores mean worse outcome.
Baseline to week 4 post treatment
Columbia scale of suicidal behavior (CSS)
Time Frame: Baseline to week 4 post treatment
Mean change in Columbia scale of suicidal behavior (CSS) scores (2-25) from baseline to week 4 post treatment. Higher scores mean worse outcome.
Baseline to week 4 post treatment
World Health Organization Quality of Life ( WHOQOL) BREF
Time Frame: Baseline to week 4 post treatment
Mean change in Quality of Life- ( WHOQOL) BREF - scores ( 0-100) from baseline to week 4 post treatment. Higher scores mean better outcome.
Baseline to week 4 post treatment
Clinical Global Impression Scale (CGI)
Time Frame: Baseline to week 4 post treatment
Mean change from Clinical Global Impression Scale (CGI) ( 1-7) baseline to week 4 post treatment. Higher scores mean worse outcome
Baseline to week 4 post treatment
Categorical outcomes
Time Frame: At 4 week post treatment
Response (a reduction ≥ 50% in MADRS from the baseline to 4 weekend point) and remission (MADRS score ≤ 10) rates for each group
At 4 week post treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Calgary

Investigators

  • Principal Investigator: Rajamannar Ramasubbu, MD, University of Calgary

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

May 20, 2023

Primary Completion (Anticipated)

May 20, 2025

Study Completion (Anticipated)

June 30, 2025

Study Registration Dates

First Submitted

January 5, 2023

First Submitted That Met QC Criteria

March 30, 2023

First Posted (Estimate)

April 13, 2023

Study Record Updates

Last Update Posted (Estimate)

April 13, 2023

Last Update Submitted That Met QC Criteria

March 30, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 10021798

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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