Dorsomedial Prefrontal Neuromodulation in Treatment-resistant Depression

NCT ID: NCT05422417

Last Updated: 2022-08-17

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-07
• Study Completion Date: 2025-12-31

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.

Conditions

Treatment-resistant Depression; Major Depressive Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Prolonged intermittent theta-burst(iTBS)-DMPFC

This active group will receive prolonged intermittent theta-burst(iTBS) on the dorsomedial prefrontal cortex(DMPFC)

Group Type: EXPERIMENTAL

Prolonged intermittent theta burst stimulation (piTBS)

Intervention Type: DEVICE

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.

20Hz rTMS-DMPFC

This active group will receive 20Hz rTMS on the DMPFC

Group Type: EXPERIMENTAL

20Hz rTMS

Intervention Type: DEVICE

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.

Sham prolonged iTBS-DMPFC or 20Hz rTMS-DMPFC

Patients in the sham group will receive the same prolonged iTBS or 20Hz rTMS performed by a sham coil.

Group Type: SHAM_COMPARATOR

sham control

Intervention Type: DEVICE

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

Interventions

Prolonged intermittent theta burst stimulation (piTBS)

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

20Hz rTMS

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

sham control

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

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

1. 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);

2. 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);

3. 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);

4. 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

1. Patients with Bipolar I and II disorder, schizophrenia, organic brain syndromes, or other major physical illnesses;

2. Patients who had received or will receive brain surgery or receive brain metal implantation (for example, neurostimulator) or received cardiac pacemakers;

3. Patients who had strong suicidal ideation within one week ( 3 points for third item of HDRS-suicidality)

4. 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)

5. Pregnancy;

6. Patients who have metal implantation in the body, including cochlear implant, prosthetic heart valve, neurostimulator, clips.. etc

7. 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)

8. Claustrophobia for MRI screening;

9. Those who cannot follow the protocols, and did not sign informed consent proved by the institutional review board (IRB)

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Taipei Veterans General Hospital, Taiwan

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Chih-Ming Cheng, M.D.

Role: PRINCIPAL_INVESTIGATOR

Taipei Veterans General Hospital, Taiwan

Locations

Taipei Veterans General Hospital, Taiwan

Taipei, , Taiwan

Site Status: RECRUITING

Countries

Taiwan

Central Contacts

Chih-Ming Cheng, M.D.

Role: CONTACT

vdodaco@gmail.com

+886 2 28757027

Chih-Ming Cheng, M.D.

Role: CONTACT

886 2 28757027

Facility Contacts

Chih-Ming Cheng, M.D.

Role: primary

vdodaco@gmail.com

886 2 28757027

Other Identifiers

IRB-TPEVGH No.: 2021-08-006A#1

Identifier Type: -

Identifier Source: org_study_id