Non-invasive Brain Stimulation Normalizes Dopaminergic Transmission in the Frontostriatal Circuit to Alleviate Depression With Metabolic Disorders.

NCT ID: NCT05117983

Last Updated: 2021-11-11

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-08-12
• Study Completion Date: 2024-07-31

Brief Summary

Depression and metabolic disorder (MetD) are two of the most common and debilitating disorders worldwide, occurring with significant rates of comorbidity. This is a major clinical challenge as the outcomes of both conditions are worsened. Studies have uncovered that depression and metabolic disorder are associated with chronic, low-grade inflammation. In brain circuit level, patients with depression are characterized with aberrant frontostriatal (FS) circuit connectivity and reduced activity level that also associated with metabolic comorbidity. In neurotransmitter level, the dopaminergic pathway, that could be feedback regulated by immune and metabolic factors, has long been known to involve in emotional and metabolic homeostasis. More importantly, this dopamine (DA) input is critical to shaping the FS circuit-level dynamic connectivity and plasticity. Therefore, this study hypothesizes that inflammatory and metabolic dysregulations on DA transmission link to the aberrant FS function that cause mood and metabolic syndromes. To clarify the underlying mechanisms, 90 patients who meet the DSM-5 diagnostic criteria of major depressive episode in either major depressive disorder or bipolar disorder are planned to be recruit. FS functional connectivity and activation, before and after receiving 10 Hz repetitive transcranial magnetic stimulation (rTMS) to left dorsolateral prefrontal cortex will be measured. Then systemically analyze participants' clinical symptomology, neurocognitive function, inflammation and metabolic status. Possible correlations between indices, the effects of rTMS and differences between groups will be tested. Results could provide a chance for further understanding the pathophysiology of depression with MetD and comparing between unipolar and bipolar depression, and developing brain circuit based non-invasive brain stimulation personalized treatment for depression with MetD to achieve a better outcome.

Detailed Description

Depression and metabolic disorder (MetD) are two of the most common and debilitating disorders worldwide, occurring with significant rates of comorbidity. This is a major clinical challenge as the outcomes of both conditions are worsened. Studies have uncovered that depression and metabolic disorder are associated with chronic, low-grade inflammation. In brain circuit level, patients with depression are characterized with aberrant frontostriatal (FS) circuit connectivity and reduced activity level that also associated with metabolic comorbidity. BD patients also showed functional anomalies in the VS and FS circuits with reduced neural flexibility of hedonic signaling in response to stress. The dysfunctional FS circuits also link to the metabolic comorbidities in patients with mood disorders. Regarding metabolic control, the FS functional connectivity changes affect food craving. And the altered reciprocal loop from the medial prefrontal cortex could regulate eating behavior and metabolic disturbance. In neurotransmitter level, the dopaminergic pathway, that could be feedback regulated by immune and metabolic factors, has long been known to involve in emotional and metabolic homeostasis. More importantly, this dopamine (DA) input is critical to shaping the FS circuit-level dynamic connectivity and plasticity. Disruptions in the dopamine (DA) system have been observed in psychiatric disorders. MDD might involve DA reductions that could result from either diminished DA release from presynaptic neurons or impaired signal transduction, either due to changes in receptor number or function and/or altered intracellular signal processing. Therefore this study hypothesizes that inflammatory and metabolic dysregulations on DA transmission link to the aberrant FS function that cause depression and MetD. To clarify the underlying mechanisms, unipolar and bipolar depression patients will be enrolled to measure the FS functional connectivity and activation, before and after receiving 10 Hz repetitive transcranial magnetic stimulation (rTMS) to left dorsolateral prefrontal cortex. Then systemically analyze participants' clinical symptomology, neurocognitive function, inflammation and metabolic status. Possible correlations between indices, the effects of rTMS and the possible differences between unipolar and bipolar depression patients will be tested. Results could provide a chance for further understanding the pathophysiology and better treatment of depression with MetD, finding biomarkers for subgrouping depression between unipolar depression and bipolar depression, predicting outcomes to brain circuit based personalized rTMS treatment for depression with MetD.

The specific aims of the project are:

Aim 1: To find the biological homogeneousness among depression with MetD by investigate the associations between (1) FS circuit connectivity and clinical (mood and metabolic) symptoms, and (2) FS circuit activation and clinical (mood and metabolic) symptoms in both unipolar and bipolar depressed individuals.

Aim 2: To confirm the role of FS in depression with MetD by applying rTMS to test its effects on (1) clinical symptoms, (2) FS circuit activation, (3) FS circuit connectivity and (4) find predictors for the rTMS treatment response.

Aim 3: To study the bidirectional inflammatory and metabolic feedback regulations of the DA transmission in FS circuit in depression with MetD by investigate the associations between (1) FS circuit activation, and (2) FS circuit connectivity and systemic inflammatory/ metabolic regulators both before and after rTMS treatments.

Conditions

Depression

Keywords

Depression; Dopamine (DA); Frontostriatal (FS) circuit; Metabolic disorder; Repetitive transcranial magnetic stimulation (rTMS)

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

MDD patient with HRSD score of at least 18

MDD patients who meet the DSM-5 diagnostic criteria of MDD and their current episode show a Hamilton Rating Scale for Depression (HRSD) score of at least 18

Group Type: ACTIVE_COMPARATOR

Repetitive transcranial magnetic stimulation (rTMS)

Intervention Type: DEVICE

Real-time MRI-guided neuronavigation with a Visor neuronavigation system (ANT Neuro, Enschede, Netherlands) will be used for coil positioning. Left dorsolateral prefrontal cortex target is located in each participant.

BD patient with HRSD score of at least 18

BD patients who meet the DSM-5 diagnostic criteria of BD and their current depression episode show a Hamilton Rating Scale for Depression (HRSD) score of at least 18

Group Type: ACTIVE_COMPARATOR

Repetitive transcranial magnetic stimulation (rTMS)

Intervention Type: DEVICE

Real-time MRI-guided neuronavigation with a Visor neuronavigation system (ANT Neuro, Enschede, Netherlands) will be used for coil positioning. Left dorsolateral prefrontal cortex target is located in each participant.

Interventions

Repetitive transcranial magnetic stimulation (rTMS)

Real-time MRI-guided neuronavigation with a Visor neuronavigation system (ANT Neuro, Enschede, Netherlands) will be used for coil positioning. Left dorsolateral prefrontal cortex target is located in each participant.

Intervention Type: DEVICE

Other Intervention Names

Antidepressants

Eligibility Criteria

Inclusion Criteria

• (1)Signed informed consent by patient or legal representative;
• (2) male or female patient aged ≧20 and ≦70 years;
• (3) a diagnosis of MDD or BD according to DSM criteria made by a specialist in psychiatry;
• (4) a total score of at least 18 in the Hamilton Rating Scale for Depression (HDRS) at the screening stage;
• (5) patient or a reliable caregiver can be expected to ensure acceptable compliance and visit attendance for the duration of the study.

Exclusion Criteria

• (1) women of childbearing potential, not using adequate contraception as per investigator judgment or not willing to comply with contraception for the duration of the study;
• (2) females who are pregnant or breast-feeding;
• (3) other major DSM 5 diagnoses other than mood disorders, except for tobacco use disorder and anxiety disorder;
• (4) current evidence of an uncontrolled and/or clinically significant medical condition, e.g. patients with extensive area of ischemic bruise, multiple sclerosis, cardiac, hepatic and renal failure that would compromise patient safety or preclude study participation;
• (5) history of seizure or epilepsy;
• (6) history of neurological diseases or traumatic brain injury;
• (7) history of brain lesion, having received neurosurgery, meningitis or encephalitis;
• (8) exacerbation of symptom severity, presenting severe suicidal ideation or self harm behavior during the screen or study period;
• (9) presence of devices, e.g. pacemakers, cochlear prosthesis, neuro-stimulators, magnetic cochlear prosthesis, intracranial/intraocular metallic fragments;
• (10) patient has received electroconvulsive therapy (ECT) within 3 months prior to the first intervention of the treatment;
• (11) skin lesion at local site receiving rTMS stimulation;
• (12) those who cannot tolerate the side effects or ever developed sleep disorder while receiving rTMS therapy.

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ministry of Science and Technology, Taiwan

OTHER_GOV

Sponsor Role: collaborator

Ministry of Health and Welfare, Taiwan

OTHER_GOV

Sponsor Role: collaborator

National Cheng-Kung University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

National Cheng-Kung University

Tainan City, , Taiwan

Site Status: RECRUITING

Countries

Taiwan

Central Contacts

Po See Chen, MD, PhD

Role: CONTACT

Phone: 06-2353535

Email: chenps@mail.ncku.edu.tw

Facility Contacts

Po See Chen, MD, PhD

Role: primary

Other Identifiers

A-BR-110-005

Identifier Type: -

Identifier Source: org_study_id