Cognitive Dysfunction in the Addictions Study - Project 4 (P4) (CDiA-P4)

Assessing the Role of Repetitive Transcranial Magnetic Stimulation on Aberrant Executive Function in the Context of Major Depressive Disorder in Adult Outpatients Seeking Treatment for Alcohol Use Disorder

The prefrontal cortex, although well established as an efficacious target for the treatment of major depressive disorder (MDD), has recently come into favour as a therapeutic target for alcohol use disorders (AUD). Depressive symptoms are also highly prevalent in individuals with AUD. A number of cognitive and psychological processes stemming from the prefrontal cortex, a common treatment target for repetitive transcranial magnetic stimulation (rTMS), are disrupted in both MDD and AUD. The proposed study will enhance the development of theta burst stimulation (TBS) as a new intervention for AUD in the context of depressive symptoms and uses integrated TMS-EEG to identify neurophysiological targets of executive dysfunction in this disorder.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder; Alcohol Use Disorder
• Intervention / Treatment: Device: intermittent theta burst stimulation; Device: Sham stimulation

Detailed Description

The prefrontal cortex, although well established as an efficacious target for the treatment of major depressive disorder (MDD), has recently come into favour as a therapeutic target for alcohol use disorders (AUD). Depressive symptoms are also highly prevalent in individuals with AUD. A number of cognitive and psychological processes stemming from the prefrontal cortex, a common treatment target for repetitive transcranial magnetic stimulation (rTMS), are disrupted in both MDD and AUD. The proposed study will enhance the development of theta burst stimulation (TBS) as a new intervention for AUD in the context of depressive symptoms and uses integrated TMS-EEG to identify neurophysiological targets of executive dysfunction in this disorder.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Daphne Voineskos, MD; Phone Number: 30176 416-535-8501; Email: daphne.voineskos@camh.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M6J 1H4
      • Recruiting
      • Centre for Addiction and Mental Health
      • Contact: Daphne Voineskos, MD; Phone Number: 30176 416-535-8501; Email: daphne.voineskos@camh.ca

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. are outpatients;
2. are voluntary and competent to consent to treatment;
3. have a Diagnostic and Statistical Manual for Mental Disorders, 5th edition (DSM-5) diagnosis of AUD based on the MINI;
4. do not exhibit problematic use of any substances (excluding nicotine and caffeine), including alcohol, for >1 month;
5. are male or female between the ages of 18 - 59;
6. screened positive for an MDE based on the MINI without psychotic symptoms
7. are agreeable to keeping their current antidepressant medications and medications for alcohol use disorder constant during the study;
8. are reliably taking SUD agonist therapies if appropriate and managed by their clinical team;
9. are able to adhere to the study schedule;
10. meet the TMS safety criteria.

Exclusion Criteria:

1. have a concomitant major unstable medical illness;
2. are pregnant or intend to get pregnant during the study;
3. have possible or probable dementia (based on the Informant Questionnaire on Cognitive Decline in the Elderly that will be administered to any participant with a baseline total score of < 26 on the Montreal Cognitive Assessment (MoCA);
4. have failed a course of ECT, due to the lower likelihood of response to rTMS;
5. have any significant neurological disorder (e.g., a space occupying brain lesion, a history of stroke, a cerebral aneurysm, a seizure disorder, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant history of head trauma with radiological evidence of intracranial trauma at the time of injury due to risk of possible seizure foci from prior intracranial lesions.
6. present with a medical condition, a medication, or a laboratory abnormality that could cause a major depressive episode or significant cognitive impairment in the opinion of the investigator (e.g., hypothyroidism with low TSH, Cushing's disease);
7. have an intracranial implant (e.g., aneurysm clips, shunts, cochlear implants) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed;
8. require a benzodiazepine with a dose equivalent to lorazepam 2 mg/day or higher or any anticonvulsant due to the potential of these medications to limit the efficacy of rTMS [79];
9. have an inability to communicate in English fluently enough to complete the clinical assessments.
10. have a MINI diagnosis or active symptoms of Bipolar Disorder

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active Bilateral; Bilteral TBS, applied as cTBS over the right DLPFC followed by iTBS over the left DLPFC	Device: intermittent theta burst stimulation; Theta-burst stimulation
Sham Comparator: Sham; Sham TBS	Device: Sham stimulation; Stimulation with double-sided B70-type coil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Executive Function Index - inhibition	Flanker task	baseline and 4 weeks after baseline (after 20 treatments of active/sham rTMS)
Executive Function Index - working memory	N-back task	baseline and 4 weeks after baseline (after 20 treatments of active/sham rTMS)
Executive Function Index - set shifting	switch task	baseline and 4 weeks after baseline (after 20 treatments of active/sham rTMS)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
17-Item Hamilton Depression Rating Scale (HRSD-17)	Decrease in 17-Item Hamilton Depression Rating Scale score, 0 is lowest value, 52 is highest, higher value = more severe depression	baseline and 4 weeks after baseline (after 20 treatments of active/sham rTMS)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Columbia-Suicide Severity Rating Scale	Decrease in Columbia-Suicide Severity Rating Scale score, 0 is lowest score, 25 is highest, higher value = more suicidal ideation	baseline and 4 weeks after baseline (after 20 treatments of active/sham rTMS)

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2022
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: October 13, 2022
• First Submitted That Met QC Criteria: March 1, 2024
• First Posted (Actual): March 8, 2024

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Mood Disorders; Alcohol Drinking; Alcoholism; Depression; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 058-2021

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