Back to resultsDorsomedial Prefrontal Neuromodulation in Treatment-resistant Depression
Primary Purpose
Treatment-resistant Depression, Major Depressive Disorder
Status
Recruiting
Phase
Not Applicable
Locations
Taiwan
Study Type
Interventional
Intervention
Prolonged intermittent theta burst stimulation (piTBS)
20Hz rTMS
sham control
Sponsored by
About this trial
This is an interventional treatment trial for Treatment-resistant Depression focused on measuring rTMS, prolonged iTBS, brain stimulation, intermittent theta burst stimulation
Eligibility Criteria
Inclusion Criteria:
- Diagnosed with a recurrent major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Diagnoses were established after taking a thorough medical history and conducting a semistructured interview by administering the Mini International Neuropsychiatric Interview (MINI);
- Recruited participants had to have a Clinical Global Impression - Severity score of at least four and a total score of at least 18 on the 17-items Hamilton Depression Rating Scale (HDRS-17);
- Patients were qualified if they failed to respond to at least one adequate antidepressant treatment in their current episode (for example, failed to achieve 50% improvement of depression to an equivalent daily dose of 10 to 20 mg of escitalopram for at least eight weeks);
- Stabilized treatment: keeping current antidepressant drug treatment, including the dose at least for four weeks before this trial and during the trial period; keep the stabilized psychotherapy at least for three months and no anticipated adjustment of types of psychotherapy and the frequency.
Exclusion Criteria:
- Patients with Bipolar I and II disorder, schizophrenia, organic brain syndromes, or other major physical illnesses;
- Patients who had received or will receive brain surgery or receive brain metal implantation (for example, neurostimulator) or received cardiac pacemakers;
- Patients who had strong suicidal ideation within one week ( 3 points for third item of HDRS-suicidality)
- Patients who had abnormal finding in the brain ( for example, brain tumor or arteriovenous malformation) or neurological disease ( for example, history of meningitis, encephalitis, epilepsy, stroke or neurodegenerative disease)
- Pregnancy;
- Patients who have metal implantation in the body, including cochlear implant, prosthetic heart valve, neurostimulator, clips.. etc
- Patients who also failed to respond after receiving one completed course of electroconvulsive therapy (ECT) treatment or left dorsolateral prefrontal brain stimulation (adequate dose and adequate duration of ECT or DLPFC-rTMS and had followed up to monitor the efficacy at least for three months)
- Claustrophobia for MRI screening;
- Those who cannot follow the protocols, and did not sign informed consent proved by the institutional review board (IRB)
Sites / Locations
- Taipei Veterans General Hospital, TaiwanRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Sham Comparator
Arm Label
Prolonged intermittent theta-burst(iTBS)-DMPFC
20Hz rTMS-DMPFC
Sham prolonged iTBS-DMPFC or 20Hz rTMS-DMPFC
Arm Description
This active group will receive prolonged intermittent theta-burst(iTBS) on the dorsomedial prefrontal cortex(DMPFC)
This active group will receive 20Hz rTMS on the DMPFC
Patients in the sham group will receive the same prolonged iTBS or 20Hz rTMS performed by a sham coil.
Outcomes
Primary Outcome Measures
Change in 17-item Hamilton Depression Rating Scale
the altered 17-item Hamilton Depression Rating Scale (range, 0 to 52, with higher scores indicating more depression)
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.
Secondary Outcome Measures
Response rate after 2-week treatment at the end of the trial, one month and three months after.
Improvement ≥ 50 % of 17-item Hamilton Depression Rating Scale (range, 0 to 52, with higher scores indicating more depression)
Remission rate after 2-week treatment at the end of the trial, one month and three months after.
17-item Hamilton Depression Rating Scale ≤7 (range, 0 to 52, with higher scores indicating more depression)
Changes in Clinical Global Index
Clinical Global Index, range from 1 to 7 with higher scores indicating worse clinical severity of illness.
Changes in depression severity, rated by self-reported
including Depression and Somatic Symptoms sub-scales, range from 0 to 66 with higher scores indicating more depressive and somatic symptom.
Changes in Young Mania Rating Scale
Young Mania Rating Scale, range from 0 to 60 with higher scores indicating more severe manic symptoms.
Baseline treatment refractory level and the further antidepressant efficacy of brain stimulation
Maudsley staging method(MSM),, range from 3 to 15 with higher scores indicating higher treatment resistance.
Baseline treatment refractory level(TRDSS) and the further antidepressant efficacy of brain stimulation
Treatment-resistant depression severity scale(TRDSS), range from 3 to 20 with higher scores indicating higher treatment resistance.
Baseline Life event stress scale and the further clinical efficacy of brain stimulation
Life event stress scale,range from 0 to 1467 with higher scores indicating more life event stress.
Changes in depression severity, rated by Montgomery-Asberg Depression Rating Scale (MADRS)
the altered MADRS (range, 0 to 60 , with higher scores representing greater severity of depressive symptoms.
Change in Hamilton Anxiety Scale (HAMA)
the altered Hamilton Anxiety Scale (HAMA) (range, 0 to 56, with higher scores indicating more anxiety)
Baseline Rumination response scale (RRS) and the further clinical efficacy of brain stimulation
RRS,range from 22 to 88 with higher scores indicating more rumination.
Change in Rumination response scale (RRS)
RRS,range from 22 to 88 with higher scores indicating more rumination.
Baseline Snaith-Hamilton Pleasure Scale and the further clinical efficacy of brain stimulation
The 14-item Snaith-Hamilton Pleasure Scale is a self-administered instrument. Each of the items has a set of four response categories--Definitely Agree, Agree, Disagree, and Strongly Disagree, with either of the Disagree responses receiving a score of 1 and either of the Agree responses receiving a score of 0. Thus, the SHAPS was scored as the sum of the 14 items so that total scores ranged from 0 to 14. A higher total SHAPS score indicated higher levels of present state of anhedonia.
Change in Snaith-Hamilton Pleasure Scale
The 14-item Snaith-Hamilton Pleasure Scale is a self-administered instrument. Each of the items has a set of four response categories--Definitely Agree, Agree, Disagree, and Strongly Disagree, with either of the Disagree responses receiving a score of 1 and either of the Agree responses receiving a score of 0. Thus, the SHAPS was scored as the sum of the 14 items so that total scores ranged from 0 to 14. A higher total SHAPS score indicated higher levels of present state of anhedonia.
Changes in EEG band before and after brain stimulation
The value changes of prefrontal alpha, beta, theta, delta wave before and after 2 weeks treatment
Changes in brain connectivity before and after brain stimulation
the change in resting-state functional connectivity
Changes in TMS-EEG/paired-pulse stimulation before and after brain stimulation
the change in TMS-EEG/paired-pulse stimulation
Changes in cognitive performance of Taiwan Cognition Questionnaire
Evaluate by Taiwan Cognition Questionnaire, range from 0 to 15 with higher scores indicating higher cognitive impairment
Changes in cognitive performance of word list recall.
Evaluate by word list recall.
Changes in cognitive performance of Trail-Making Test
Evaluate by Trail-Making Test
Changes in cognitive performance of Go/No-Go task
Evaluate by Go/No-Go task
Changes in cognitive performance of Wisconsin Card Sorting Test
Evaluate by Wisconsin Card Sorting Test
Full Information
NCT ID
NCT05422417
First Posted
June 7, 2022
Last Updated
August 15, 2022
Sponsor
Taipei Veterans General Hospital, Taiwan
1. Study Identification
Unique Protocol Identification Number
NCT05422417
Brief Title
Dorsomedial Prefrontal Neuromodulation in Treatment-resistant Depression
Official Title
New Form of Brain Stimulation Targeting Dorsomedial Prefrontal Cortex in Treating Refractory Depression and the Predictive Biomarkers of Antidepressant Efficacy
Study Type
Interventional
2. Study Status
Record Verification Date
August 2022
Overall Recruitment Status
Recruiting
Study Start Date
June 7, 2022 (Actual)
Primary Completion Date
September 30, 2025 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Taipei Veterans General Hospital, Taiwan
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Major depressive disorder (MDD) is a common and troublesome disorder, with high risk of physical and psychiatric comorbidity. At least one-third of patients could not achieve a response after several antidepressant trials, so-called treatment-refractory depression (TRD). The high-frequency repetitive transcranial magnetic stimulation (rTMS) or intermittent theta-burst stimulation (iTBS) at left-sided dorsolateral prefrontal cortex (DLPFC) have a response rate of 40-60%. Obviously, not all TRD patients achieve the remitted state after treatment with antidepressants or DLPFC-rTMS, which may result from the heterogeneity of MDD. More and more evidence, such as brain lesion studies, deep brain stimulation, open-labeled rTMS case series, and neuroimaging studies, suggests that dorsomedial prefrontal cortex (DMPFC) might play a more central role in the pathophysiology of major depression. The DMPFC demonstrated as a "dorsal nexus" phenomenon in depression, which means a unique brain region where cortical networks for affect regulation, default mode control and cognitive control coverage in depressed subjects but not in healthy persons. In addition, another meta-analysis of resting-state functional MRI (fMRI) demonstrated the abnormal functional connectivity from DMPFC. These abnormalities of networks were highly associated with several depressive symptoms such as anhedonia, emotional regulation, somatic markers, rumination, self-reflection, poor attention and poor decision-making. However, only a handful of studies investigated the brain stimulation targeting DMPFC and the further changes in brain functional connectivity. The clinical efficacy and the fMRI changes of prolonged intermittent theta-burst stimulation (piTBS) and 20Hz- rTMS targeting bilateral DMPFC were investigated, and the predictive value of baseline networks by fMRI for antidepressant responses was also assessed to find a reliable approach to gauge treatment response prospectively.
Detailed Description
Several open label studies showed the preliminary clinical efficacy of DMPFC stimulation, but there was no randomized sham-control trial to confirm the clinical efficacy in Asian people. In addition, there were also few fMRI studies to express the brain circuit changes after DMPFC stimulation. The clinical efficacy and the fMRI changes of prolonged intermittent theta-burst stimulation (piTBS) and 20Hz- rTMS targeting bilateral DMPFC were investigated, and the predictive value of baseline networks by fMRI for antidepressant responses was also assessed to find a reliable approach to gauge treatment response prospectively. All patients with TRD who failed at least one antidepressant trial are randomized to three groups (Group-A: piTBS treatment; Group-B: 20Hz-rTMS treatment; Group-C: sham treatment). Before and after 20 sessions targeting bilateral DMPFC over ten days, structural and functional magnetic resonance imaging (MRI) is arranged for each participant. In addition, pre- and post-treatment fMRI data are analyzed for each patient to investigate the networks and local brain activity changes between groups.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Treatment-resistant Depression, Major Depressive Disorder
Keywords
rTMS, prolonged iTBS, brain stimulation, intermittent theta burst stimulation
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
75 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Prolonged intermittent theta-burst(iTBS)-DMPFC
Arm Type
Experimental
Arm Description
This active group will receive prolonged intermittent theta-burst(iTBS) on the dorsomedial prefrontal cortex(DMPFC)
Arm Title
20Hz rTMS-DMPFC
Arm Type
Experimental
Arm Description
This active group will receive 20Hz rTMS on the DMPFC
Arm Title
Sham prolonged iTBS-DMPFC or 20Hz rTMS-DMPFC
Arm Type
Sham Comparator
Arm Description
Patients in the sham group will receive the same prolonged iTBS or 20Hz rTMS performed by a sham coil.
Intervention Type
Device
Intervention Name(s)
Prolonged intermittent theta burst stimulation (piTBS)
Intervention Description
Participants in the prolonged dosage (1800 pulse) of intermittent TBS (iTBS) active stimulation group will receive 2-week three-pulse 50-Hz bursts administered every 200 milliseconds (at 5 Hz) at an intensity of 80% active motor threshold (MT) to the bilateral DMPFC, twice a day. Stimulation will be delivered to the DMPFC using a stimulator.
Intervention Type
Device
Intervention Name(s)
20Hz rTMS
Intervention Description
Participants in the 20 Hz rTMS (2000 pulse) active stimulation group will receive 2-week 2s- and-10s off, total 50 cycles at each hemisphere/session, at an intensity of 100% resting motor threshold (MT) to the bilateral DMPFC, twice a day. Stimulation will be delivered to the DMPFC using a stimulator.
Intervention Type
Device
Intervention Name(s)
sham control
Intervention Description
Half of the patients in the sham group received 2-week the same prolonged iTBS parameter stimulation (sham- prolonged iTBS), and the other half received the same 20 Hz rTMS parameter stimulation using a sham coil (sham-20 Hz rTMS), which also improved the blinding process
Primary Outcome Measure Information:
Title
Change in 17-item Hamilton Depression Rating Scale
Description
the altered 17-item Hamilton Depression Rating Scale (range, 0 to 52, with higher scores indicating more depression)
Time Frame
Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
Title
Change in anxiosomatic cluster symptoms derived 17-item Hamilton Depression Rating Scale
Description
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.
Time Frame
Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
Secondary Outcome Measure Information:
Title
Response rate after 2-week treatment at the end of the trial, one month and three months after.
Description
Improvement ≥ 50 % of 17-item Hamilton Depression Rating Scale (range, 0 to 52, with higher scores indicating more depression)
Time Frame
Time Frame: Week 2, Week 6(one month after brain stimulation), Week 14(three-month after brain stimulation)
Title
Remission rate after 2-week treatment at the end of the trial, one month and three months after.
Description
17-item Hamilton Depression Rating Scale ≤7 (range, 0 to 52, with higher scores indicating more depression)
Time Frame
Time Frame: Week 2, Week 6(one month after brain stimulation), Week 14(three-month after brain stimulation)
Title
Changes in Clinical Global Index
Description
Clinical Global Index, range from 1 to 7 with higher scores indicating worse clinical severity of illness.
Time Frame
Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
Title
Changes in depression severity, rated by self-reported
Description
including Depression and Somatic Symptoms sub-scales, range from 0 to 66 with higher scores indicating more depressive and somatic symptom.
Time Frame
Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
Title
Changes in Young Mania Rating Scale
Description
Young Mania Rating Scale, range from 0 to 60 with higher scores indicating more severe manic symptoms.
Time Frame
Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
Title
Baseline treatment refractory level and the further antidepressant efficacy of brain stimulation
Description
Maudsley staging method(MSM),, range from 3 to 15 with higher scores indicating higher treatment resistance.
Time Frame
Baseline and Week 2
Title
Baseline treatment refractory level(TRDSS) and the further antidepressant efficacy of brain stimulation
Description
Treatment-resistant depression severity scale(TRDSS), range from 3 to 20 with higher scores indicating higher treatment resistance.
Time Frame
Baseline and Week 2
Title
Baseline Life event stress scale and the further clinical efficacy of brain stimulation
Description
Life event stress scale,range from 0 to 1467 with higher scores indicating more life event stress.
Time Frame
Baseline and Week 2
Title
Changes in depression severity, rated by Montgomery-Asberg Depression Rating Scale (MADRS)
Description
the altered MADRS (range, 0 to 60 , with higher scores representing greater severity of depressive symptoms.
Time Frame
Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
Title
Change in Hamilton Anxiety Scale (HAMA)
Description
the altered Hamilton Anxiety Scale (HAMA) (range, 0 to 56, with higher scores indicating more anxiety)
Time Frame
Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
Title
Baseline Rumination response scale (RRS) and the further clinical efficacy of brain stimulation
Description
RRS,range from 22 to 88 with higher scores indicating more rumination.
Time Frame
Baseline and Week 2
Title
Change in Rumination response scale (RRS)
Description
RRS,range from 22 to 88 with higher scores indicating more rumination.
Time Frame
Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
Title
Baseline Snaith-Hamilton Pleasure Scale and the further clinical efficacy of brain stimulation
Description
The 14-item Snaith-Hamilton Pleasure Scale is a self-administered instrument. Each of the items has a set of four response categories--Definitely Agree, Agree, Disagree, and Strongly Disagree, with either of the Disagree responses receiving a score of 1 and either of the Agree responses receiving a score of 0. Thus, the SHAPS was scored as the sum of the 14 items so that total scores ranged from 0 to 14. A higher total SHAPS score indicated higher levels of present state of anhedonia.
Time Frame
Baseline and Week 2
Title
Change in Snaith-Hamilton Pleasure Scale
Description
The 14-item Snaith-Hamilton Pleasure Scale is a self-administered instrument. Each of the items has a set of four response categories--Definitely Agree, Agree, Disagree, and Strongly Disagree, with either of the Disagree responses receiving a score of 1 and either of the Agree responses receiving a score of 0. Thus, the SHAPS was scored as the sum of the 14 items so that total scores ranged from 0 to 14. A higher total SHAPS score indicated higher levels of present state of anhedonia.
Time Frame
Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
Title
Changes in EEG band before and after brain stimulation
Description
The value changes of prefrontal alpha, beta, theta, delta wave before and after 2 weeks treatment
Time Frame
Baseline and Week 2
Title
Changes in brain connectivity before and after brain stimulation
Description
the change in resting-state functional connectivity
Time Frame
Baseline and Week 2
Title
Changes in TMS-EEG/paired-pulse stimulation before and after brain stimulation
Description
the change in TMS-EEG/paired-pulse stimulation
Time Frame
Baseline and Week 2
Title
Changes in cognitive performance of Taiwan Cognition Questionnaire
Description
Evaluate by Taiwan Cognition Questionnaire, range from 0 to 15 with higher scores indicating higher cognitive impairment
Time Frame
Baseline and Week 2
Title
Changes in cognitive performance of word list recall.
Description
Evaluate by word list recall.
Time Frame
Baseline and Week 2
Title
Changes in cognitive performance of Trail-Making Test
Description
Evaluate by Trail-Making Test
Time Frame
Baseline and Week 2
Title
Changes in cognitive performance of Go/No-Go task
Description
Evaluate by Go/No-Go task
Time Frame
Baseline and Week 2
Title
Changes in cognitive performance of Wisconsin Card Sorting Test
Description
Evaluate by Wisconsin Card Sorting Test
Time Frame
Baseline and Week 2
10. Eligibility
Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosed with a recurrent major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Diagnoses were established after taking a thorough medical history and conducting a semistructured interview by administering the Mini International Neuropsychiatric Interview (MINI);
Recruited participants had to have a Clinical Global Impression - Severity score of at least four and a total score of at least 18 on the 17-items Hamilton Depression Rating Scale (HDRS-17);
Patients were qualified if they failed to respond to at least one adequate antidepressant treatment in their current episode (for example, failed to achieve 50% improvement of depression to an equivalent daily dose of 10 to 20 mg of escitalopram for at least eight weeks);
Stabilized treatment: keeping current antidepressant drug treatment, including the dose at least for four weeks before this trial and during the trial period; keep the stabilized psychotherapy at least for three months and no anticipated adjustment of types of psychotherapy and the frequency.
Exclusion Criteria:
Patients with Bipolar I and II disorder, schizophrenia, organic brain syndromes, or other major physical illnesses;
Patients who had received or will receive brain surgery or receive brain metal implantation (for example, neurostimulator) or received cardiac pacemakers;
Patients who had strong suicidal ideation within one week ( 3 points for third item of HDRS-suicidality)
Patients who had abnormal finding in the brain ( for example, brain tumor or arteriovenous malformation) or neurological disease ( for example, history of meningitis, encephalitis, epilepsy, stroke or neurodegenerative disease)
Pregnancy;
Patients who have metal implantation in the body, including cochlear implant, prosthetic heart valve, neurostimulator, clips.. etc
Patients who also failed to respond after receiving one completed course of electroconvulsive therapy (ECT) treatment or left dorsolateral prefrontal brain stimulation (adequate dose and adequate duration of ECT or DLPFC-rTMS and had followed up to monitor the efficacy at least for three months)
Claustrophobia for MRI screening;
Those who cannot follow the protocols, and did not sign informed consent proved by the institutional review board (IRB)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Chih-Ming Cheng, M.D.
Phone
+886 2 28757027
Email
vdodaco@gmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Chih-Ming Cheng, M.D.
Phone
886 2 28757027
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chih-Ming Cheng, M.D.
Organizational Affiliation
Taipei Veterans General Hospital, Taiwan
Official's Role
Principal Investigator
Facility Information:
Facility Name
Taipei Veterans General Hospital, Taiwan
City
Taipei
Country
Taiwan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chih-Ming Cheng, M.D.
Phone
886 2 28757027
Email
vdodaco@gmail.com
12. IPD Sharing Statement
Learn more about this trial
Dorsomedial Prefrontal Neuromodulation in Treatment-resistant Depression
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