Deep rTMS for Depression in Older Adults (DIVINE)

DIfferential Feasibility and Tolerability of Deep repetitiVe transcranIal MagNEtic Stimulation for Depression in Older Adults (DIVINE Trial): A Pilot Study

This study aims to: (1) assess the feasibility and tolerability of two active dTMS coils - H4 and H7 - in older adults with depression; and (2) clinical response measured by change from baseline on the Hamilton Depression Rating Scale- 24 item; changes in cognitive function through neuropsychological assessment; and changes in regional electrophysiological activity and functional connectivity indexed by EEG. Through a parallel design, participants will complete a four-week course of five dTMS sessions per week, for a total of 20 stimulation sessions. Participants will be randomly assigned to either coil (H4 or H7) and will complete questionnaires examining side effects, mental health symptoms, and cognition. Participant EEG data will be measured and collected at baseline and at the end of each week. Collectively, the study will address the absolute and differential feasibility and tolerability of the two active coils to provide preliminary data for a future randomized controlled trial comparing one or both of these novel interventions to the established H1-coil and a sham stimulation (placebo) control.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Device: Brainsway H4-Coil Deep TMS System; Device: Brainsway H7-Coil Deep TMS System

Detailed Description

Transcranial magnetic stimulation (TMS) is a non-invasive therapeutic technique used to stimulate regions of the brain using magnetic pulses. Repeated TMS delivers sequences of pulses for multiple days in a row and is an approved treatment for several psychiatric conditions. Deep TMS (dTMS) is a new technique that uses modified magnetic Hesed coils (H-coils) to stimulate deeper regions of the brain and has been FDA- and Health Canada-approved for major depressive disorder (MDD), obsessive-compulsive disorder, smoking cessation, and anxious-depression in adults. For older adults (60+), traditional rTMS has also shown efficacy for MDD (60+) and one RCT has found benefit for the H1 dTMS coil, but no trials have examined the H4 and H7 coils in this population. This innovative pilot study will explore dTMS feasibility and tolerability (i.e., side effects, impacts on mental health and cognition) of these two dTMS coils (H4, targeting insula and H7, targeting anterior cingulate cortex) in older adults with depression. The pilot will provide critical preliminary data for a future trial comparing these novel interventions to the H1-coil and a sham stimulation control. There is sparse literature examining the effects of dTMS on cognition, as measured by neuropsychological testing, and brain activity, as measured by electroencephalogram (EEG), while comparing different dTMS H-coils. Therefore, a second feature of the design includes assessing both domains over the course of treatment. The results will lay the foundation for a future randomized controlled trial examining the efficacy and mechanisms of one or both of these novel forms of neurostimulation for MDD in older adults.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jane De Jesus, BSc; Phone Number: 905-522-1155; Email: dejesuj@mcmaster.ca
• Study Contact Backup: Name: Dante Duarte, MD, MSc, PhD; Phone Number: 36782 905 522-1155; Email: duartedante@mcmaster.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L9C 0E3
      • Recruiting
      • Peter Boris Centre for Addictions Research, St. Joseph's Healthcare Hamilton

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

A) 60 - 85 years old

B) Able to provide informed consent to participate in the study

C) MDD diagnosis, single or recurrent episode, assessed using Evaluation of the Diagnostic Assessment Research Tool (DART) Screener for DSM-5 Mood Disorder Module

D) Total score of at least 20 on the 24-item Hamilton Depression Rating Scale (HDRS-24) at screening visit

E) Treatment resistance to antidepressant pharmacotherapy during the current episode as indexed by Antidepressant Treatment History Form - Short Form (ATHF - SF). Specifically, participants will be required to have failed at least one or to have had an inadequate trial (including intolerance) to at least two antidepressants in the current episode

F) Participants will be required to be on stable dosages of other psychotropic medications for at least 4 weeks prior to screening

Exclusion Criteria:

A) Primary diagnosis of bipolar I or II disorder; psychotic disorder; obsessive-compulsive, post-traumatic stress, anxiety, or personality disorder; participants with anxiety or personality disorders will be eligible if is not their primary diagnosis

B) Active suicidal behavior

C) Substance dependence/abuse in the past 3 months before entering the study (this will be screened via self-report and verified by urine screening test)

D) Possible dementia diagnosis based on a Mini Mental Status Exam (MMSE) score of <24 and clinical presentation of dementia

E) Unsuccessful ECT treatment on the current episode

F) Traditional contraindications to rTMS: Intracranial or metal implants in the head or nearby regions, excluding the mouth, that cannot be safely removed; History of epilepsy or seizures; Active unstable medical condition (recent laboratory and neuroimaging alterations); Pacemaker and/or implantable cardioverter-defibrillators; current use of bupropion >300 mg/day as it is associated with risk of seizures, treatment with equivalent benzodiazepine dose to lorazepam >2 mg/day

G) People with severe literacy, visual, or hearing issues that affect their ability to engage in the interviews

H) People with recurring migraines or headaches (weekly or more).

I) Individuals residing beyond the borders of the Greater Hamilton Area and its neighbouring vicinities.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active H4-coil dTMS treatment	Device: Brainsway H4-Coil Deep TMS System; Participants assigned to this arm will complete a 4-week course of 5 dTMS sessions per week (using the Brainsway H4-coil), for a total of 20 stimulation sessions. We will follow the standard Health Canada and FDA-approved protocol for depression: 18 Hz and 55 trains, for a total of 1980 pulses.
Experimental: Active H7-coil dTMS treatment	Device: Brainsway H7-Coil Deep TMS System; Participants assigned to this arm will complete a 4-week course of 5 dTMS sessions per week (using the Brainsway H7-coil), for a total of 20 stimulation sessions. We will follow the standard Health Canada and FDA-approved protocol for depression: 18 Hz and 55 trains, for a total of 1980 pulses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility criteria 1: Protocol completion	Percentage of intervention sessions completed	4 weeks
Feasibility criteria 2: Retention rate	Percentage of participants who complete study once enrolled	4 weeks
Feasibility criteria 3: Screening rates and capacity	Number of participants (n) screened; n enrolled as a percentage of n screened monthly	4 weeks
Feasibility criteria 4: Recruitment rate and capacity	Total number of participants recruited and enrolled per month.	4 weeks
Feasibility criteria 5: Duration of intervention and assessment processes	Compared to estimated times, the actual mean times (in min) from start to finish for each dTMS intervention session and mean time (in hours) from start to finish for each visit.	4 weeks
Feasibility criteria 5: Safety of H-coil dTMS treatment	Total number of adverse events reported during the treatment sessions assessed by the Side Effects Questionnaire for dTMS (custom-developed for study). At each dTMS stimulation session, participants will complete a questionnaire to evaluate potential adverse effects of dTMS (headache, neck pain, itching and redness at the site of stimulation) according to a 4-point scale.	4 weeks
Tolerability of H-coil dTMS treatment	Percentage of participants withdrawn or terminated following enrollment due to adverse events	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes from baseline in resting-state EEG	Using electroencephalography (EEG), we will assess alpha, theta and gamma rhythms in fronto-temporo-parietal region, including assessment of connectivity and coherence. We will additionally measure cross-frequency coupling named theta (4-8Hz)-gamma (>25Hz) phase-amplitude coupling (PAC). We will also investigate phase synchronization in upper theta frequency band between prefrontal and temporal areas. Changes in these EEG parameters will be correlated with changes in mood severity and cognitive status, with a focus on working memory improvements. EEG will be performed before dTMS sessions at baseline (V1) and at the end of each week (V5, V10, V15 and V20) by using a wireless dry electrode portable EEG system (CGX Quick 20r). Resting state connectivity, coherence, PAC, and synchronization assessed by EEG will use standardized data processing pipelines in EEG Lab.	4 weeks
Changes from baseline in neurocognitive functioning (Repeatable Battery of Neuropsychological Status [RBANS])	Neurocognitive performance will be assessed with the Repeatable Battery of Neuropsychological Status. Assessments will be completed at baseline (V1) and at post-treatment (V20).	4 weeks
Change from baseline on the Hamilton Depression Rating Scale- 24 item (HDRS-24).	The Hamilton Depression Rating Scale (24 item) will be used as the primary measure of depression. Symptoms of depression will be assessed with the HDRS- 24 item (a 24-item depression checklist) at multiple visits: the in-person screen (V0), baseline (V1), end-of-week dTMS sessions (V5, V10, V15, V20), and the 2-week follow-up. Scores range from 0 (min) to 75 (max), with a score of ≥ 20 indicating a moderate-to-severe depression. Lower scores may indicate mild depression or remission.	4-weeks + 2-week follow-up
Changes from baseline on the Geriatric Depression 30-item Scale (GDS-30)	The Geriatric Depression 30-item Scale (GDS-30) will be used as a second measure of depression, a 30-item checklist, at the baseline (V1), midpoint (V10) and endpoint (V20) visits and at the 2-week follow-up. Scores of 0-4 are considered normal, 5-8 indicate mild depression; 9-11 indicate moderate depression; and 12-15 indicate severe depression.	4-weeks + 2-week follow-up
Change from baseline on the General Anxiety Disorder- 7 item (GAD-7)	Symptoms of anxiety will be assessed using this 7-item questionnaire at the baseline (V1), midpoint (V10) and endpoint (V20) visits and at the 2-week follow-up. Scores of 0-4 indicate minimal anxiety; 5-9: mild anxiety; 10-14: moderate anxiety; and 15 or greater: severe anxiety.	4-weeks + 2-week follow-up
Change from baseline on the Pittsburgh Sleeping Quality Index (PSQI)	Sleep will be monitored and assessed using the Pittsburgh Sleeping Quality Index (PSQI) at the baseline (V1), midpoint (V10) and endpoint (V20) visits and at the 2-week follow-up. Each of component of the PSQI is issued a score ranging from 0 to 3, with 3 indicating the greatest dysfunction.	4-weeks + 2-week follow-up
Change from baseline on the Patient Health Questionnaire (PHQ - Somatic Symptoms)	Somatic symptoms will be evaluated using the Patient Health Questionnaire (PHQ) somatic inventory at the baseline (V1), midpoint (V10) and endpoint (V20) visits and at the 2-week follow-up. Scores range from 0 to 30: ≥ 5 = mild, ≥ 10 = moderate, and ≥ 15 = severe levels of somatization.	4-weeks + 2-week follow-up

Collaborators and Investigators

• Sponsor: St. Joseph's Healthcare Hamilton
• Collaborators: Peter Boris Centre for Addictions Research (PBCAR)
• Investigators: Principal Investigator: Dante Duarte, MD, MSc, PhD, Peter Boris Centre for Addictions Research at St. Joseph's Healthcare, Hamilton; Study Director: James MacKillop, PhD, Peter Boris Centre for Addictions Research at St. Joseph's Healthcare, Hamilton; Study Chair: Emily MacKillop, PhD, ABPP-CN, Peter Boris Centre for Addictions Research at St. Joseph's Healthcare, Hamilton

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2023
• Primary Completion (Estimated): June 28, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: February 6, 2023
• First Submitted That Met QC Criteria: May 9, 2023
• First Posted (Actual): May 12, 2023

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: older adults; depression; MDD; Major Depressive Disorder; mood disorders; depressive disorder; dTMS; deep transcranial magnetic stimulation; late-life depression; deep TMS; H coil; H-coil; H4-coil; H7-coil
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 15344

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