Neural Mechanisms of Intermittent Theta Burst Stimulation in the Core Depression Network

Major Depressive Disorder Clinical Trial

Official title:

Neural Mechanisms of Intermittent Theta Burst Stimulation in the Core Depression Network

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05224206
• Other study ID #: 2021013
• Status: Recruiting
• Phase: N/A
• Start date: April 26, 2023
• Est. completion date: June 1, 2025

Study information

• Verified date: September 2023
• Source: The Royal Ottawa Mental Health Centre
• Contact: Stacey Shim, MSc
• Phone: 613-722-6521
• Email: stacey.shim[@]theroyal.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Repetitive Transcranial magnetic stimulation (TMS) uses magnetic fields to modulate brain activity. A novel form of repetitive TMS (rTMS), intermittent theta burst stimulation (iTBS), has emerged as a promising new treatment for depression. This technique may be advantageous due to its very short duration and potentially stronger effect on brain activity in comparison with standard rTMS. However, the exact effect of iTBS on the activity of the brain in clinical populations remains poorly understood. This project aims to improve understanding of the mechanisms of action of iTBS by comparing its neuronal effect to sham treatment in 22 individuals with a diagnosis of major depressive episode, using positron emission tomography (PET) and magnetic resonance imaging (MRI) in a double-blind cross-over experiment, followed by a 6-week daily treatment course of iTBS.

Description:

Repetitive transcranial magnetic stimulation (rTMS) is a Health Canada approved treatment for major depression. Typical clinical rTMS treatment is delivered on the left dorsolateral prefrontal cortex (DLPFC) at a 10 Hz frequency for 30-45 minutes to increase cortical excitability which will outlast the duration of stimulation. The treatment involves daily sessions that are applied over a four to six-week period. Intermittent theta burst stimulation (iTBS) is a novel refinement of conventional rTMS. iTBS consists of bursts of 3 stimulations at 50 Hz at theta frequency (5 Hz). However, instead of 30-min treatment sessions, iTBS has comparable clinical efficacy with only 3 minutes treatment sessions. Because iTBS is a novel technique, much of its effects on the brain are currently unknown. However, since it is a modified rTMS protocol, it is assumed that its neuronal effects are comparable.

Therapeutic effects of rTMS are thought to be related to its effects on the subgenual anterior cingulate cortex (sgACC; Broadman area 25). In depression, metabolic activity of the sgACC is increased (measured as increase of 18F-labeled fluorodeoxyglucose ([18F]FDG) uptake with positron emission tomography (PET)). Importantly, the metabolic activity of the sgACC appears to be a general marker for treatment response, e.g. [18F]FDG uptake is decreased in response to antidepressant medications or deep brain stimulation. In addition to resting state functional MRI, diffusion weighted imaging has been used to study TMS targets, but this technique has never been used for testing targets for treating depression.

Currently, the system level mechanisms of action of iTBS in depression patients are completely unexplored. Based on prior research the investigators hypothesize that 1) a single session of iTBS will decrease [18F]FDG uptake in the sgACC and 2) the magnitude of decrease is related to the connectivity between the target site and the sgACC. This study will establish the system level mechanisms of action of iTBS, paving a way to improve clinical treatment. This study will also develop connectivity measures that can be used to improve iTBS targeting (i.e. choose iTBS target based on sgACC connectivity) and predict treatment response (i.e. predict iTBS treatment response in patients based on sgACC connectivity).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 22
• Est. completion date: June 1, 2025
• Est. primary completion date: June 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Men or women aged 18 to 55 years of age

• Mini-International Neuropsychiatric Interview-confirmed diagnosis of MDD, as a single or recurring episode

• Symptoms of MDD have not improved after = 1 but = 7 adequate dose(s) of antidepressant trial(s) in the current depressive episode

• A baseline score of = 15 on the 17-item Hamilton Rating Scale for Depression (HRSD-17)

• Have received a stable antidepressant regimen for at least four weeks prior to entering trial

• Are voluntary and competent to consent to study

• Can speak and read English

Exclusion Criteria:

• Current or past (< 3 months) substance (including nicotine) or alcohol abuse/dependence, as defined in DSM-5 criteria

• Positive urine test for illegal substances, cannabis, or cotinine

• Suicide attempt in the past three months and/or active suicidal intent

• Pregnancy (confirmed by urine test) and/or lactation

• Psychotic features in the current episode

• Any comorbid mental health disorders (including, but not limited to lifetime history of psychotic disorders, OCD, PTSD and/or bipolar I or II disorder) with the exception of anxiety/panic disorders and ADHD

• Significant unstable medical or neurologic illness confirmed by medical history and blood test at baseline (e.g. uncontrolled diabetes, or renal dysfunction)

• Organic cause to the depressive symptoms (e.g. thyroid dysfunctions), as ruled out by the referring physician

• Contraindication for TMS (e.g., personal history of epilepsy or convulsion, metallic head implant, pacemaker)

• Contraindication for MRI (e.g. metallic implant, claustrophobia)

• Have undergone a prior PET or SPECT research study

• ECT or rTMS treatment in the current depressive episode

• Benzodiazepine use

• Have a body mass index (BMI) higher then 35 or lower then 18

• Any other condition that, in the opinion of the investigators, would adversely affect the participant's ability to complete the study

Related Conditions & MeSH terms

• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Intervention

Device:
• Theta burst stimulation
Cool B65 active/placebo coil (left DLPFC) with X100 MagPro rTMS Device (Magventure A/S, Farum, Denmark)
• Theta burst stimulation
Cool B70 coil (left DLPFC), with X100 MagPro rTMS Device (Magventure A/S, Farum, Denmark)

Locations

Country	Name	City	State
Canada	The Royal Ottawa Mental Health Centre	Ottawa	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
The Royal Ottawa Mental Health Centre

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Neural mechanisms of iTBS measured by [18F]FDG uptake in the sgACC	The primary outcome measure for Part I is the change in [18F]FDG uptake in the sgACC after iTBS.	40 minutes after iTBS
Primary	Neuroimaging predictors of iTBS response to treatment - primary measures	The primary clinical outcome measures will be response to treatment and remission. Response to treatment will be defined as at least a 50% reduction in pre-treatment symptoms severity as measured by the mean HRSD-17 score at week 6. Remission will be defined as a HRSD-17 score lower or equal to 7 at week 6.	6 weeks
Secondary	Neuroimaging predictors of iTBS response to treatment - QIDS-SR16	For secondary analyses, improvement in symptoms will be defined as the percentage of change of symptoms at week 6 in comparison with pre-treatment symptoms severity. Response to treatment will be defined as a 50% reduction in pre-treatment symptoms severity as measured by the mean of the Quick Inventory of Depressive Symptomatology (16-item) (Self-Report) (QIDS-SR16). Remission will be defined as a QIDS-SR score = 6.	6 weeks
Secondary	Neuroimaging predictors of iTBS response to treatment - Beck Anxiety Inventory (BAI)	For secondary analyses, improvement in symptoms will be defined as the percentage of change of symptoms at week 6 in comparison with pre-treatment symptoms severity. Response to treatment will be defined as a 50% reduction in pre-treatment symptoms severity. The Beck Anxiety Inventory (BAI) will be used to assess severity of patient anxiety. It is a structured 21-item self-report measure using a likert scale of 0-3. A total score of 0 - 7 is interpreted as a "Minimal" level of anxiety; 8 - 15 as "Mild"; 16 - 25 as "Moderate", and; 26 - 63 as "Severe".	6 week
Secondary	Neuroimaging predictors of iTBS response to treatment - Quality of life (Q-LES-Q-SF)	For secondary analyses, improvement in symptoms will be defined as the percentage of change of symptoms at week 6 in comparison with pre-treatment symptoms severity. Response to treatment will be defined as a 50% reduction in pre-treatment symptoms severity. The Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) will be used to assess response to iTBS treatment. The Q-LES-Q-SF is used to obtain sensitive measures of the degree of enjoyment and satisfaction experienced by subjects in various areas of daily functioning. It's a structured 16-item self-report measure where items are scored on a 5-point Likert scale, from Very Poor to Very Good.	6 week
Secondary	Neuroimaging predictors of iTBS response to treatment - Well-being (WEMWBS)	For secondary analyses, improvement in symptoms will be defined as the percentage of change of symptoms at week 6 in comparison with pre-treatment symptoms severity. Response to treatment will be defined as a 50% reduction in pre-treatment symptoms severity. The Short Warwick Edinburgh Mental Well-Being Scale (SWEMWBS) will be used to assess general overview of mental well-being. It's a self-rated; 7 questions; rated over the past 2 weeks. Scored: 1 (none of the time) to 5 (all of the time).	6 week