Neuromodulation of Different Doses to Treat TRD Guided by pBFS Technique

Study Overview
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Brief Summary
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The aim of this study is to explore the effectiveness and safety of different doses of neural regulation under the guidance of pBFS technology in improving symptoms in patients with moderate to severe depressive disorders.

Detailed Description
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In 2022, the FDA cleared a large dosage of repetitive transcranial magnetic stimulation for treatment-resistant depression (TRD), which requires 10 sessions per day of 1,800 pulses per session for a total of 18,000 pulses per day. The inter-session interval is 50 min, and it costs patients 9 hours for the intervention. The investigators assume that patients with moderate to severe depression may not need 10 sessions per day, patients may achieve response or remission with a less amount of dosage, which will save the cost of treatment. Hence, the investigators try to find the optimal treatment dosage for patients with moderate to severe depression. After being informed about the study and potential risks. All patients giving written informed consent will undergo a screening period to determine eligibility for study entry. At week 0, patients who meet the eligibility requirements will be randomized in a double-blind manner in a 1:1:1:1:1 ratio to each active rTMS group with different pulses (4×1800 pulses, 6×1800 pulses, 8×1800 pulses, 10×1800 pulses) and sham-control group. And then all participants will undergo a 5-day rTMS treatment followed by four- and eight weeks follow-up visits. Participants will keep a stable treatment regime during treatment and the four-week follow-up.

Official Title
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The Dosage Effect of Personalized Brain Functional Sectors(pBFS) Guided rTMS Treatment for Treatment-resistance Depression： a Randomized， Double-Blind， Sham-controlled Trial

Conditions
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Moderate Depression, Major Depressive Disorder, Severe Depression

Intervention / Treatment
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* Device: 4 session rTMS
* Device: 6 session rTMS
* Device: 8 session rTMS
* Device: 10 session rTMS
* Device: sham rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized/outpatient patients aged 18-65 years (inclusive), male or female. Meet the diagnostic criteria of DSM-5(Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) for depression disorder without psychotic symptoms, and currently experiencing a recurrence episode. Total HAMD-17 score ≥20 and MADRS ≥20 before randomization. The Maudsley Staging Method (MSM) is used to assess patients as having at least a moderate level of treatment-resistant condition (MSM score ≥ 7 points). Participants currently are on stable drug use for at least 4 weeks before randomization. Antidepressants used are selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Combined use of two types of antidepressants is allowed. Voluntarily participate in the trial and able to provide informed consent. Able to comply with the planned visit, examination and treatment plan, and other study procedures. Exclusion Criteria: Meet DSM-5 diagnostic criteria for other mental disorders (such as schizophrenia spectrum disorders, bipolar and related disorders, neurodevelopmental disorders, neurocognitive disorders, or depressive disorders due to substances and/or medications, depressive disorders due to other medical problems, etc.); Patients with a cardiac pacemaker, cochlear implant, or other metal foreign body and any electronic equipment implanted in the body, patients with claustrophobia and other contraindications to magnetic resonance scanning, and patients with contraindications to rTMS treatment; Patients with serious or unstable diseases of the cardiovascular, liver, kidney, blood, endocrine, neurological system, and other systems or organs, especially those with organic brain diseases (such as ischemic stroke, cerebral hemorrhage, brain tumor, etc.) and a history of severe brain trauma as judged by the researcher; History of epilepsy (presence of at least 2 uninduced seizures more than 24 hours apart, or diagnosis of the epileptic syndrome, or seizures within the past 12 months); Or currently received medications or other treatments that will lower the seizure threshold; History of ECT, rTMS, VNS, DBS, tDCS, light therapy, or other physical therapy related to mental illness within 3 months; Currently receiving or plan to start formal cognitive or behavioral therapy, or systemic psychological therapy (interpersonal therapy, dynamic therapy, cognitive behavioral therapy, etc.) during the trial; Substance abuse or dependence (including alcohol, drugs, and other psychoactive substances) in the past 1 year; Female of childbearing potential who plans to become pregnant during the trial. Female that is pregnant or breastfeeding. Patients in any clinical trials of other drugs or physical therapy within 1 month before the screening. Investigators think that was inappropriate to participate.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 4 session rTMS<br>Four sessions of active rTMS would be delivered to the left DLPFC daily, with a session of 1800 pulse. | Device: 4 session rTMS<br>* Participants will receive 4 sessions per day of 1800 pulses per session, lasting for 5 days. Individualized targets will be generated using the pBFS method.<br>|
| Active Comparator: 6 session rTMS<br>Six sessions of active TMS would be delivered to the left DLPFC daily, with a session of 1800 pulse. | Device: 6 session rTMS<br>* Participants will receive 6 sessions per day of 1800 pulses per session, lasting for 5 days. Individualized targets will be generated using the pBFS method.<br>|
| Active Comparator: 8 session rTMS<br>Eight sessions of active rTMS would be delivered to the left DLPFC daily, with a session of 1800 pulse. | Device: 8 session rTMS<br>* Participants will receive 8 sessions per day of 1800 pulses per session, lasting for 5 days. Individualized targets will be generated using the pBFS method.<br>|
| Active Comparator: 10 session rTMS<br>Ten sessions of active rTMS would be delivered to the left DLPFC daily, with a session of 1800 pulse. | Device: 10 session rTMS<br>* Participants will receive 10 sessions per day of 1800 pulses per session, lasting for 5 days. Individualized targets will be generated using the pBFS method.<br>|
| Sham Comparator: sham rTMS<br>Subjects were randomized to receive 4 sessions or 6 sessions or 8 sessions or 10 sessions of sham rTMS to the left DLPFC daily in a 1:1:1:1 ratio. | Device: sham rTMS<br>* The parameters in the sham arms are the same as the active stimulation groups. Stimulation was delivered by the same device as the active group fitted with a sham coil.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) scores from baseline to Immediate Post-treatment | The MADRS is a validated instrument stratifying the severity of depressive episodes in adults. The MADRS has an overall score ranging from 0 (no depression) to 60 (worst depression). | Baseline, Day 5(Immediate Post-treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MADRS | A provider-administered questionnaire was used to assess remission and recovery from depression. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. The MADRS has an overall score range from 0-60, with higher scores corresponding to higher levels of depression. | Baseline, Day 5 (Immediate Post-treatment), 14 days Post-treatment, 28 days Post-treatment, 56 days Post-treatment | 
| Change in Hamilton Depression Scale (HAMD-17) | A provider-administered questionnaire was used to assess remission and recovery from depression. The Hamilton Depression Rating Scale (HAMD-17) is the most widely used clinician-administered depression assessment scale. The HAMD-17 version consists of 17 items assessing mood, guilt, general somatic symptoms, work and activities, anxiety, and slowness of thought and speech. Each item is scored on a scale of 0 to 4, except for the somatic, sleep, and insight items which are scored 0 to 2. On the HAM-17 there can be a total score of 22. Higher scores represent higher depression severity. | Baseline, Day 5 (Immediate Post-treatment), 14 days Post-treatment, 28 days Post-treatment, 56 days Post-treatment | 
| Change in Quick Inventory of Depressive Symptomatology Self-Report (QIDS_SR) | A provider-administered questionnaire was used to assess remission and recovery from depression. The 16-item QIDS_SR is a widely used self-report instrument covering depressive symptoms incorporating nine Diagnostic and Statistical Manual of Mental Disorder-IV (DSM-IV) diagnostic criteria for major depressive disorders. Each item is scored on a scale of 0 to 4. Higher scores represent higher depression severity. | Baseline, Day 5 (Immediate Post-treatment), 14 days Post-treatment, 28 days Post-treatment, 56 days Post-treatment | 
| Safety estimated using SSI, YMRS | Scale for Suicide Ideation (SSI) measures suicide ideation, Young Mania Rating Scale(YMARS) measures mania | Baseline, Day 5 (Immediate Post-treatment), 14 days Post-treatment, 28 days Post-treatment, 56 days Post-treatment | 
| cognitive change in Digit Symbol Substitution Test (DSST） | Cognitive scores are measured using Chinese brief cognitive test (C-BCT), the DSST equires a subject to match symbols to numbers according to a key located on the top of the page | Baseline, Day 5 | 
| cognitive change in continuous performance test (CPT） | CPT from the C-BCT measures a person's sustained and selective attention | Baseline, Day 5 | 
| cognitive change in Trail-Making Test (TMT) | The TMT test from the C-BCT can provide information about visual search speed, scanning, speed of processing, mental flexibility, and executive functioning | Baseline, Day 5 | 
| cognitive change in Digit Span Test (DST) | DST from the C-BCT is a measure of verbal short term and working memory that can be used in two formats, Forward Digit Span and Reverse Digit Span | Baseline, Day 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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transcranial magnetic stimulation, rTMS, Major Depression, Moderate Depression, MDD, personalized neuromodulation