Clinical trial NCT05422417: 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
Overall status: RECRUITING
Phase: NA
Conditions: Treatment-resistant Depression
Major Depressive Disorder
Keywords: rTMS
prolonged iTBS
brain stimulation
intermittent theta burst stimulation
Lead sponsor: Taipei Veterans General Hospital, Taiwan
Sponsor class: OTHER_GOV
First posted: 2022-06-16
Enrollment: 75
Sex: ALL
Minimum age (years): 21
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Change in 17-item Hamilton Depression Rating Scale
timeFrame: Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
measure: Change in anxiosomatic cluster symptoms derived 17-item Hamilton Depression Rating Scale
timeFrame: Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
Secondary outcomes:
measure: Response rate after 2-week treatment at the end of the trial, one month and three months after.
timeFrame: Time Frame: Week 2, Week 6(one month after brain stimulation), Week 14(three-month after brain stimulation)
measure: Remission rate after 2-week treatment at the end of the trial, one month and three months after.
timeFrame: Time Frame: Week 2, Week 6(one month after brain stimulation), Week 14(three-month after brain stimulation)
measure: Changes in Clinical Global Index
timeFrame: Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
measure: Changes in depression severity, rated by self-reported
timeFrame: Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
measure: Changes in Young Mania Rating Scale
timeFrame: Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
measure: Baseline treatment refractory level and the further antidepressant efficacy of brain stimulation
timeFrame: Baseline and Week 2
measure: Baseline treatment refractory level(TRDSS) and the further antidepressant efficacy of brain stimulation
timeFrame: Baseline and Week 2
measure: Baseline Life event stress scale and the further clinical efficacy of brain stimulation
timeFrame: Baseline and Week 2
measure: Changes in depression severity, rated by Montgomery-Asberg Depression Rating Scale (MADRS)
timeFrame: Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
measure: Change in Hamilton Anxiety Scale (HAMA)
timeFrame: Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
measure: Baseline Rumination response scale (RRS) and the further clinical efficacy of brain stimulation
timeFrame: Baseline and Week 2
measure: Change in Rumination response scale (RRS)
timeFrame: Time Frame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
measure: Baseline Snaith-Hamilton Pleasure Scale and the further clinical efficacy of brain stimulation
timeFrame: Baseline and Week 2
measure: Change in Snaith-Hamilton Pleasure Scale
timeFrame: Baseline, Week 1, Week 2, Week 3 (one week after brain stimulation), Week 6, Week 14(three-month after brain stimulation)
measure: Changes in EEG band before and after brain stimulation
timeFrame: Baseline and Week 2
measure: Changes in brain connectivity before and after brain stimulation
timeFrame: Baseline and Week 2
measure: Changes in TMS-EEG/paired-pulse stimulation before and after brain stimulation
timeFrame: Baseline and Week 2
measure: Changes in cognitive performance of Taiwan Cognition Questionnaire
timeFrame: Baseline and Week 2
measure: Changes in cognitive performance of word list recall.
timeFrame: Baseline and Week 2
measure: Changes in cognitive performance of Trail-Making Test
timeFrame: Baseline and Week 2
measure: Changes in cognitive performance of Go/No-Go task
timeFrame: Baseline and Week 2
measure: Changes in cognitive performance of Wisconsin Card Sorting Test
timeFrame: Baseline and Week 2
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital, Taiwan
Study officials:
affiliation: Taipei Veterans General Hospital, Taiwan
name: Chih-Ming Cheng, M.D.
role: PRINCIPAL_INVESTIGATOR
References: