Accelerated vs. Conventional Theta Burst Stimulation for Late-life Depression (ACT-LLD)

The purpose of this trial is to compare the treatment efficacy (improvement in depressive symptoms) of accelerated TBS protocol (where participants receive multiple TBS treatments daily) to conventional TBS protocol (where participants receive a single TBS treatment daily) in late life depression. In addition, the study also aims to determine if specific patterns of stimulation are more or less effective. To do this, all participants will receive active treatments, but some of the participants in this study will receive accelerated TBS and some will receive once daily TBS.

Study Overview

• Status: Recruiting
• Conditions: Mood Disorders; Depressive Disorder, Treatment-Resistant; Late Life Depression (LLD); Depression - Major Depressive Disorder
• Intervention / Treatment: Device: TBS

Detailed Description

The purpose of this trial is to compare the treatment efficacy (change in MADRS scores) of accelerated TBS to conventional TBS in participants with moderate to severe LLD at 4-weeks following accelerated TBS or following 30 once daily treatments of conventional TBS. Accelerated TBS group will receive 5 treatment sessions per day at approximately 1 hour intervals for 4 consecutive days on week 1 and 2 non-consecutive days on week 2. Conventional TBS group will receive 30 once daily treatment (approximately 6 weeks). Each treatment will consist of either 1) cTBS of right DLPFC followed by iTBS of left DLPFC; or 2) iTBS of left DLPFC.

• Study Type: Interventional
• Enrollment (Estimated): 280
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Recruiting
      • Sunnybrook Health Sciences Centre
      • Contact: Donguk Jo; Phone Number: 61518 416-480-6100; Email: donguk.jo@sri.utoronto.ca
      • Principal Investigator: Sean M Nestor
    • Toronto, Ontario, Canada, M6J 1H1
      • Recruiting
      • Centre for Addiction and Mental Healh
      • Contact: Elizabeth Clancy; Phone Number: 416-535-8501; Email: elizabeth.clancy@camh.ca
      • Principal Investigator: Hyewon (Helen) Lee
      • Principal Investigator: Daniel Blumberger

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. are voluntary and competent to consent to treatment
2. are an outpatient
3. are ≥ 60 years old
4. have a Mini International Neuropsychiatric Interview (MINI 7.0) confirmed diagnosis of MDD, with a current MDE
5. have failed to achieve a clinical response to an adequate dose of an antidepressant based on an Antidepressant Treatment History Form (ATHF) score of ≥ 3 in the current episode or have failed to tolerate two separate trials of an antidepressant
6. have a score ≥ 10 on the Patient Health Questionnaire (PHQ-9)
7. have had no increase or initiation of any antidepressant or antipsychotic medication in the 4 weeks prior to screening
8. are able to adhere to the treatment schedule
9. pass the TMS adult safety screening (TASS) questionnaire

Exclusion Criteria:

1. have a Mini International Neuropsychiatric Interview (MINI 7.0) confirmed diagnosis of substance dependence or abuse within the last 3 months
2. have a concomitant major unstable medical illness as determined by one of the study physicians
3. have active suicidal intent
4. have presumed or probable dementia or clinical evidence of dementia as assessed by Short Blessed Test score ≥ 10
5. have a lifetime MINI diagnosis of bipolar I or II disorder, or primary psychotic disorder
6. have current psychotic symptoms
7. have a diagnosis of obsessive compulsive disorder, post-traumatic stress disorder (current or within the last year), anxiety disorder (generalized anxiety disorder, social anxiety disorder, panic disorder), or dysthymia, assessed by a study investigator to be primary and causing greater impairment than MDD
8. have a diagnosis of any personality disorder as assessed by a study investigator to be primary and causing greater impairment than MDD
9. did not respond to a course of ECT in the current depressive episode
10. have received rTMS in the current episode; patients who have had rTMS in a previous episode would be eligible
11. have a history of a primary seizure disorder or a seizure associated with an intracranial lesion
12. have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed
13. have an implanted electronic device that is currently in function such as a defibrillator
14. have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with interview)
15. have clinically significant laboratory abnormality, in the opinion of a study investigator
16. currently take more than lorazepam 2 mg daily (or equivalent) or any dose of an anticonvulsant
17. if participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Accelerated TBS; Multiple treatments a day (5 treatments/day) for 4 consecutive days in the first week and 2 non-consecutive days in the second week.	Device: TBS; Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive neurostimulation that uses focused magnetic field pulses to directly stimulate cortical neurons. Theta burst stimulation (TBS) is a briefer form of patterned rTMS that has been shown to be effective against major depressive disorder. Each treatment will consist of either 1) cTBS of right DLPFC followed by iTBS of left DLPFC; or 2) iTBS of left DLPFC.
Active Comparator: Conventional TBS; Treatment once a day for 30 days (e.g., 5 days a week for 6 weeks)	Device: TBS; Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive neurostimulation that uses focused magnetic field pulses to directly stimulate cortical neurons. Theta burst stimulation (TBS) is a briefer form of patterned rTMS that has been shown to be effective against major depressive disorder. Each treatment will consist of either 1) cTBS of right DLPFC followed by iTBS of left DLPFC; or 2) iTBS of left DLPFC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Depression severity	Montgomery Asberg Depression Rating Scale (MADRS) Change	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Depression severity	17 item Hamilton Depression Rating Scale (HDRS-17) Change	up to 10 weeks
Depression severity	The Beck Depression Inventory (BDI-II) Change	up to 10 weeks
Anxiety severity	General Anxiety Disorder-7 (GAD-7) Change	up to 10 weeks
Suicidal ideation	The Beck Scale for Suicide Ideation (BSS) Change	up to 10 weeks
Global cognition	Montreal Cognitive Assessment (MoCA) Change	up to 10 weeks
Executive function	Delis-Kaplan Executive Function System (D-KEFS) Change	up to 10 weeks
Executive function	NIH Toolbox Flanker Inhibitory Control and Attention Test	up to 10 weeks
Memory	California Verbal Learning Test- third edition (CVLT-3) Change	up to 10 weeks
Disability and Functional Impairment	Sheehan Disability Scale (SDS) Change	up to 10 weeks
Quality of Life Measure	Quality of Life Enjoyment and Satisfaction Scale (Q-LES-Q) change	up to 10 weeks
Quality of Life Measure	World Health Organization Quality of Life Short Version (WHOQOL-BREF) Change	up to 10 weeks
Participant Expectancy of Improvement and Preference	Modified Stanford Expectations of Treatment Scale (SETS)	Baseline

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Collaborators: Sunnybrook Health Sciences Centre

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2025
• Primary Completion (Estimated): November 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: February 21, 2025
• First Submitted That Met QC Criteria: February 25, 2025
• First Posted (Actual): March 3, 2025

Study Record Updates

• Last Update Posted (Actual): January 28, 2026
• Last Update Submitted That Met QC Criteria: January 27, 2026
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: rTMS; Brain stimulation; Theta burst stimulation; Accelerated theta burst stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Depressive Disorder; Mood Disorders; Depressive Disorder, Treatment-Resistant
• Other Study ID Numbers: CTO4933

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No