Brain-derived Neurotrophic Factor and the Antidepressant Efficacy of Brain Stimulation

Study Overview
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Brief Summary
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This study evaluates an association between brain-derived neurotrophic factor(BDNF) polymorphisms and the antidepressant efficacy of transcranial magnetic stimulation device in patients with treatment-resistant depression. In a double-blind design, All patients are randomized to three groups, i.e.repetitive transcranial magnetic stimulation treatment, intermittent theta-burst stimulation treatment or sham treatment.

Official Title
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Different Forms of Prefrontal Transcranial Stimulation and Brain-derived Neurotrophic Factor in the Prediction of Antidepressant Efficacy of Brain Stimulation

Conditions
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Treatment Resistant Depression

Intervention / Treatment
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* Device: Active rTMS-DLPFC
* Device: Active iTBS-DLPFC
* Device: Sham TBS-DLPFC or Sham rTMS-DLPFC


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. 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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No

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 rTMS-DLPFC<br>This active group will receive high-frequency repetitive TMS stimulation. | Device: Active rTMS-DLPFC<br>* Participants in the rTMS active stimulation group will receive 4-week 10 Hz 120% of RMT to left DLPFC. Left side DLPFC will be targeted by MRI-neuronavigation system. Stimulation will be delivered to the L-DLPFC using a Magstim stimulator.<br>|
| Experimental: Active iTBS-DLPFC<br>This active group will receive intermittent theta-burst TMS stimulation. | Device: Active iTBS-DLPFC<br>* Participants in the intermittent TBS(iTBS) active stimulation group will receive 4-week three-pulse 50-Hz bursts administered every 200 milliseconds (at 5 Hz) at an intensity of 80% active motor threshold (MT) to left DLPFC. Left side DLPFC will be targeted by MRI-neuronavigation system. Stimulation will be delivered to the L-DLPFC using a Magstim stimulator.<br>|
| Sham Comparator: Sham TBS-DLPFC or Sham rTMS-DLPFC<br>Patients in the sham group will receive the same iTBS or rTMS parameter stimulation, performing by a sham coil. | Device: Sham TBS-DLPFC or Sham rTMS-DLPFC<br>* Half of the patients in the sham group received 4-week the same iTBS parameter stimulation (sham-iTBS), and the other half received the same rTMS parameter stimulation using a sham coil (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 4(day 20) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate after 4-week treatment at the end of TMS sessions and three 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 4, week 16 (day 80) | 
| Remission rate after 4-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 4, week 16 (day 80) | 
| Changes in Clinical Global Index | Clinical Global Index | Baseline, Week 1, Week 2, Week 3, Week 4(day 20) | 
| 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, Week 4(day 20) | 
| 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, Week 4(day 20) | 
| The association between BDNF Polymorphism genotype and the antidepressant efficacy of brain stimulation | Val/Val, Met/Met, Val/Met genotype and the efficacy after receiving 4-week treatment. The antidepressant efficacy defined by the altered percentage of 17-item Hamilton Depression Rating Scale | Baseline, Week 4(day 20) | 
| The association between the value of baseline brain metabolism and the antidepressant efficacy of brain stimulation | baseline PET/MRI.The antidepressant efficacy defined by the altered percentage of 17-item Hamilton Depression Rating Scale. | Baseline, Week 4(day 20) | 
| The association between the value of Baseline treatment refractory level and the antidepressant efficacy of brain stimulation | Maudsley staging method. The antidepressant efficacy defined by the altered percentage of 17-item Hamilton Depression Rating Scale. | Baseline, Week 4(day 20) | 
| The association between the value pf baseline Life event stress scale and the antidepressant efficacy of brain stimulation | Life event stress scale,range from 0 to 1467 with higher scores indicating more life event stress. The antidepressant efficacy defined by the altered percentage of 17-item Hamilton Depression Rating Scale. | Baseline, Week 4(day 20) | 
| Changes in EEG band before and after brain stimulation | Perform rACC-engaging cognitive task(RECT) before 1-st treatment | Day 1(pre-RECT, post RECT, post 1st treatment, pre-20th treatment) |