Dorsomedial Prefrontal Cortex and the Antidepressant Efficacy of Theta Burst Stimulation in Depressed Patients

Study Overview
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Brief Summary
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This study evaluates an association between different dosage and the antidepressant efficacy of theta burst stimulation in patients with treatment-resistant depression. In a double-blind design, All patients are randomized to three groups, i.e. standardized dosage intermittent theta-burst stimulation treatment, high dosage intermittent theta-burst stimulation treatment or sham treatment.

Official Title
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Dorsomedial Prefrontal Cortex and the Antidepressant Efficacy of Theta Burst Stimulation in Depressed Patients and Its Predictors

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Device: Active standardized iTBS-DMPFC
* Device: Active high-dosage iTBS-DMPFC
* Device: Sham standardized iTBS-DMPFC or high-dosage iTBS-DMPFC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 21 to 70 years of age. Diagnosed with the recurrent Major depressive disorder (MDD) and currently having a Major Depressive Episode (MDE) Participants failed to respond to at least one adequate antidepressant treatment in their current episode Participants have a Clinical Global Impression - Severity score of at least 4 and a total score of at least 18 on the Hamilton Depression Rating Scale (HDRS-17) at both screening and baseline visits ( Day -14 and Day 0) Participants must discontinue their antidepressant medications at least for one week ( at least two weeks if Fluoxetine) prior to the TMS intervention and keep antidepressant-free during the study duration. Participants also failed to respond to one complete left-sided DLPFC 10Hz rTMS/piTBS treatment course. Exclusion Criteria: a lifetime psychiatric history of bipolar disorder, schizophrenia, psychotic disorders, or organic mental disorder including substance abuse and dependence (based on DSM-IV criteria) Participants with a lifetime medical history of major systemic illness and clinically significantly abnormal screening examination that might affect safety, study participation, or confound interpretation of study results. Participants with a lifetime medical history of neurological disorder records (e.g., stroke, seizure, traumatic brain injury, post brain surgery), brain implants (neurostimulators), cardiac pacemakers Women with breastfeeding or pregnancy Participants with a current strong suicidal risk (i.e., a score of 4 on item 3 of the HDRS-17)

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active standardized iTBS-DMPFC<br>This active group will receive standardized dosage of intermittent theta-burst on dorsomedial prefrontal cortex(DMPFC) | Device: Active standardized iTBS-DMPFC<br>* Participants in the standardized dosage(600 pulse) of intermittent TBS(iTBS) active stimulation group will receive 3-week three-pulse 50-Hz bursts administered every 200 milliseconds (at 5 Hz) at an intensity of 80% active motor threshold (MT) to bilateral DMPF, twice a day. Bilateral side DMPFC will be targeted by MRI-neuronavigation system. Stimulation will be delivered to the DMPFC using a Magstim stimulator.<br>|
| Experimental: Active high-dosage iTBS-DMPFC<br>This active group will receive high dosage of intermittent theta-burst on dorsomedial prefrontal cortex(DMPFC) | Device: Active high-dosage iTBS-DMPFC<br>* Participants in the standardized dosage(1800pulse) of intermittent TBS(iTBS) active stimulation group will receive 3-week three-pulse 50-Hz bursts administered every 200 milliseconds (at 5 Hz) at an intensity of 80% active motor threshold (MT) to bilateral DMPF, twice a day. Bilateral side DMPFC will be targeted by MRI-neuronavigation system. Stimulation will be delivered to the DMPFC using a Magstim stimulator.<br>|
| Sham Comparator: Sham standardized iTBS-DMPFC or high-dosage iTBS-DMPFC<br>Patients in the sham group will receive the same standardized or high-dosage iTBS performing by a sham coil | Device: Sham standardized iTBS-DMPFC or high-dosage iTBS-DMPFC<br>* Half of the patients in the sham group received 3-week the same standardized iTBS parameter stimulation (standardized sham-iTBS), and the other half received the same high dosage iTBS parameter stimulation using a sham coil (high dosage sham-rTMS), which also improved the blinding process<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change in 17-item Hamilton Depression Rating Scale | the altered percentage of 17-item Hamilton Depression Rating Scale (range, 0 to 52, with higher scores indicating more depression) | Baseline, Week 1, Week 2, Week 3, Week 15(three-month after brain stimulation), Week 27(Six-month after brain stimulation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate after 3-week treatment at the end of iTBS sessions and three and six month after. | improvement > 50 % of 17-item Hamilton Depression Rating Scale (range, 0 to 52, with higher scores indicating more depression) | Baseline, Week 1, Week 2, Week 3, Week 15(three-month after brain stimulation), Week 27(Six-month after brain stimulation) | 
| Remission rate after 3-week treatment | 17-item Hamilton Depression Rating Scale ≤7 (range, 0 to 52, with higher scores indicating more depression) | Baseline, Week 1, Week 2, Week 3, Week 15(three-month after brain stimulation), Week 27(Six-month after brain stimulation) | 
| Changes in Clinical Global Index | Clinical Global Index | Baseline, Week 1, Week 2, Week 3 | 
| Changes in depression severity, rated by self-reported | Depression and Somatic Symptoms Scale, range from 0 to 66 with higher scores indicating more depressive and somatic symptom. | Baseline, Week 1, Week 2, Week 3 | 
| Changes in Young Mania Rating Scale | Young Mania Rating Scale, range from 0 to 60 with higher scores indicating more severe manic symptoms. | Baseline, Week 1, Week 2, Week 3 | 
| Baseline treatment refractory level and the further antidepressant efficacy of brain stimulation | Maudsley staging method | Baseline, Week 3 | 
| Baseline brain connectivity and the further antidepressant efficacy of brain stimulation | baseline functional MRI | Baseline, Week 3 | 
| the change of brain connectivity after 3-week iTBS treatment | the change in brain connectivity | Baseline, Week 3 | 
| Baseline Life event stress scale and the further antidepressant efficacy of brain stimulation | Life event stress scale,range from 0 to 1467 with higher scores indicating more life event stress. | Baseline, Week 3 | 
| Changes in EEG band before and after brain stimulation | Perform rostral anterior cingulate cortex(rACC)-engaging cognitive task(RECT) before 1-st treatment | Day 1(pre-RECT, post RECT, post 1st treatment, pre-30th treatment) | 
| Baseline single-pulse stimulation and the further antidepressant efficacy of brain stimulation | baseline single-pulse stimulation | Baseline, Week 3 | 
| Changes in single-pulse stimulation before and after brain stimulation | the change in single-pulse stimulation | Baseline, Week 3 | 
| Baseline paired-pulse stimulation and the further antidepressant efficacy of brain stimulation | baseline paired-pulse stimulation | Baseline, Week 3 | 
| Changes in paired-pulse stimulation before and after brain stimulation | the change in paired-pulse stimulation | Baseline, Week 3 | 
| Change in anxiosomatic cluster symptoms derived 17-item Hamilton Depression Rating Scale | the altered anxiosomatic cluster symptoms (range, 0 to 26, with higher scores indicating more severe anxiosomatic symptoms).The anxiosomatic cluster symptoms comprised nine items derived from HDRS-17: early insomnia, middle insomnia, slowness or retardation, psychic anxiety, autonomic anxiety, gastrointestinal symptoms, somatic symptoms, genital symptoms, and hypochondriasis. | Baseline, Week 1, Week 2, Week 3 |