Clinical trial NCT06152705: Comparing the Efficacy of FMRI-Guided Vs. Standard ITBS in Treating Depression
Official title: Triple-blind Randomized Trial Comparing the Efficacy of FMRI-Guided Vs. Standard ITBS in Treating Depression
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Depression
Depressive Disorder, Major
Depressive Episode
Keywords: fMRI
iTBS
neuronavigation
Lead sponsor: The Royal Ottawa Mental Health Centre
Sponsor class: OTHER
First posted: 2023-12-01
Enrollment: 210
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In this triple-blind randomized controlled trial, we ask if targeting intermittent theta burst stimulation (iTBS) based on individual resting state connectivity improves treatment outcomes in major depressive disorder (MDD). For the trial, we will recruit 210 patients with major depressive disorder. Each patient will undergo a 30-40-minute MRI scan, after which they will receive a 6-week standard iTBS treatment. Participants will be randomized to receive iTBS either to the standard neuronavigated target (a technique for treatment location targeting, based on group-average connectivity) or to a personalized connectivity-guided target selected based on individual functional connectivity scans. The main outcome of this trial is response rate as determined by ≥ 50% reduction in Grid HRSD-17 scores. Secondary outcomes include remission rate, change in depression, anxiety and anhedonia symptoms, quality of life, and biological measures of heart rate variability, objective sleep measures and daily activity as a proxy of anhedonia - defined as a reduced ability to experience pleasure.

Detailed description: Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved and widely used focal, safe, well-tolerated, and non-invasive brain stimulation method for the treatment of depression, and has been approved in Canada. Typical clinical rTMS is delivered on the left dorsolateral prefrontal cortex (DLPFC) at a 10 Hz frequency over 30-45 minutes to induce an increase in cortical excitability, which outlasts the duration of 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 minute treatment sessions, iTBS has comparable clinical efficacy with only 3 minute treatment sessions. Currently roughly 50% of the people receiving rTMS treatment for depression respond to the treatment. One of the main goals of current research in rTMS is to find improvements in the protocol to increase the number of responders.

One of the potential ways to improve rTMS is to select the target based on individual resting state functional connectivity. Within the DLPFC, there are still several possible targets for the rTMS. Functional magnetic resonance imaging (fMRI) studies have shown that therapeutic effects of rTMS are related to its effects on the subgenual anterior cingulate cortex (sgACC; Broadman area 25). Past literature has shown that in MDD the effectiveness of a target is related to its connectivity with the sgACC. A recent study showed in a retrospective sample of MDD patients that response to rTMS correlates with the distance from the personalized connectivity-guided target rather than a group average target, opening the door for individualized connectivity-guided rTMS targeting. Yet, the question whether individualized connectivity-guided rTMS targeting improves rTMS outcomes in a prospective sample has never been investigated. In this two-arm triple-blind randomized parallel assignment clinical trial we will test if 6-week treatment using individualized connectivity-guided iTBS targeting leads to better outcomes in MDD compared to conventional neuronavigated iTBS.

Eligibility criteria: Inclusion criteria:

For inclusion in the study, participants must fulfill all the following criteria:

1. voluntary and competent to consent to study,
2. Adults aged 18 years old or older,
3. can speak and read English,
4. primary and/or predominant diagnosis of major depressive episode without psychotic features in the current episode (confirmed by a Mini-International Neuropsychiatric Interview),
5. depressive symptoms have not improved after ≥ 1 adequate dose of antidepressant trial in the current depressive episode,
6. moderate symptoms in the current depressive episode as indexed by a score of at least 15 on the Grid 17-item Hamilton Rating Scale for Depression (Grid HRSD-17),
7. have been referred to rTMS treatment by their treating physician, and took a free and informed decision to follow this treatment,
8. are able to adhere to treatment schedule,
9. have stable psychotropic medications (including prescribed cannabis) or psychotherapy regimen for at least four weeks prior to entering the trial,
10. have an education-adjusted score of ≥ 24 at the Mini-Mental State Evaluation (MMSE) if they are aged ≥ 65.

Exclusion criteria:

Participants fulfilling any of the following criteria will be excluded from the study:

1. diagnosis of bipolar I or II disorder, based on the DSM-5 criteria
2. current or past (\< 3 months) substance (excluding caffeine or nicotine) or alcohol use disorder, as defined in DSM-5 criteria. Based on the DSM-5 criteria, mild cannabis or alcohol use disorder would be permissible in the past 3 months, moderate to severe would be an exclusion.
3. current use of illegal substances or cannabis (unless medical use, see note below), confirmed by urine drug screen
4. have a concomitant major unstable medical or neurologic illness (e.g. uncontrolled diabetes or renal dysfunction),
5. organic cause to the depressive symptoms (e.g. thyroid dysfunctions), as ruled out by the referring physician
6. acute suicidality or threat to life from self-neglect,
7. are pregnant or breastfeeding, or thinking of becoming pregnant during course of treatment (pregnancy will be assessed by a urine test),
8. have a specific contraindication for TMS (e.g., personal history of epilepsy or seizure, metallic head implant, pacemaker),
9. unwilling to maintain current antidepressant regimen,
10. are taking more than 1 mg of lorazepam per day or equivalent,
11. any other condition that, in the opinion of the investigators, would adversely affect the participant's ability to complete the study,
12. any contraindications for MRI
13. have failed a course of ECT within the current depressive episode due to the lower likelihood of response to rTMS (if they have had failed ECT in the past, this does not exclude them)

Primary outcomes:
measure: Compare the efficacy of fMRI guided TMS and conventional neuronavigated TMS on clinical response.
timeFrame: Administered at baseline (prior to first iTBS treatment) and every 2 weeks after that for 6 weeks (week 2, week 4, and week 6).
Secondary outcomes:
measure: Change in severity of clinician-rated depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS).
timeFrame: Administered at screening, before the first iTBS, week 2, week 4 and after iTBS treatment (week 6).
measure: Change in self-reported depression symptoms as measured by Beck Depression Inventory (BDI-II).
timeFrame: Administered at baseline (prior to first iTBS treatment) and every week after that for 6 weeks (week 1, week 2, week 3, week 4, week 5, week 6).]
measure: Change in self-reported anxiety symptoms as measured by Beck Anxiety Inventory (BAI)
timeFrame: Administered at baseline (prior to first iTBS treatment) and every week after that for 6 weeks (week 1, week 2, week 3, week 4, week 5, week 6).]
measure: Change in self-reported suicidal thoughts symptoms as measured by Beck Scale for Suicidal Ideation (BSS).
timeFrame: Administered at baseline (prior to first iTBS treatment) and every week after that for 6 weeks (week 1, week 2, week 3, week 4, week 5, week 6).]
measure: Change in self-reported sleep quality as measured by Leeds Sleep Evaluation Questionnaire (LSEQ)
timeFrame: Administered at baseline (prior to first iTBS treatment) and every week after that for 6 weeks (week 1, week 2, week 3, week 4, week 5, week 6).]
measure: Change in self-reported sleep patterns as measured by Pittsburgh Sleep Quality Index (PSQI)
timeFrame: Before the first iTBS and after treatment (6 weeks).
measure: Change in quantity of sleep as measured with Empatica EmbracePlus Smartwatch
timeFrame: Start 2 weeks before the planned start date. Continuous measurement throughout study until the 2-week follow-up visit
measure: Change in perceived stress as measures with Perceived stress scale (PSS)
timeFrame: Administered at baseline before first iTBS treatment and after treatment completion (week 6).
measure: Change in physiological stress based on pulse rate and electrodermal activity response as measured with Empatica EmbracePlus Smartwatch
timeFrame: Start 2 weeks before the planned start date. Continuous measurement throughout study until the 2-week follow-up visit
measure: Change in self-reported anhedonia as measured by Snaith-Hamilton Pleasure Scale (SHAPS)
timeFrame: Administered at baseline (prior to first iTBS treatment) and every week after that for 6 weeks (week 1, week 2, week 3, week 4, week 5, week 6).]
measure: Change in motion intensity (based on number of steps and total activity) as measured with Empatica EmbracePlus Smartwatch
timeFrame: Start 2 weeks before the planned start date. Continuous measurement throughout study until the 2-week follow-up visit.
measure: Change in motion heart rate variability as measured with Empatica EmbracePlus Smartwatch
timeFrame: Start 2 weeks before the planned start date. Continuous measurement throughout study until the 2-week follow-up visit.
measure: Change in self-reported hopelessness as measured by Beck Hopelessness Scale (BHS)
timeFrame: Administered at baseline (prior to first iTBS treatment) and every week after that for 6 weeks (week 1, week 2, week 3, week 4, week 5, week 6).
measure: Change in quality of life as measured with Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF)
timeFrame: Time Frame: Administered at baseline (prior to first iTBS treatment) and every week after that for 6 weeks (week 1, week 2, week 3, week 4, week 5, week 6).
measure: Change in well-being as measured with Short Warwick Edinburgh Mental Well-Being Scale (SWEMWBS)
timeFrame: Administered before the first iTBS, week 2, week 4 and after iTBS treatment (week 6).
Other outcomes:
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: Daily Monday-Friday throughout study (6 weeks).
measure: Side Effects
timeFrame: Daily Monday-Friday throughout study (6 weeks).
Locations:
city: Ottawa
country: Canada
facility: The Royal's Institute of Mental Health Research
state: Ontario
Study officials:
affiliation: The Royal&#39;s Institute of Mental Health Research
name: Sara Tremblay, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Royal&#39;s Institute of Mental Health Research
name: Lauri Tuominen, MD PhD
role: PRINCIPAL_INVESTIGATOR
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citation: Avery DH, Holtzheimer PE 3rd, Fawaz W, Russo J, Neumaier J, Dunner DL, Haynor DR, Claypoole KH, Wajdik C, Roy-Byrne P. A controlled study of repetitive transcranial magnetic stimulation in medication-resistant major depression. Biol Psychiatry. 2006 Jan 15;59(2):187-94. doi: 10.1016/j.biopsych.2005.07.003. Epub 2005 Sep 1.
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