The Role of iTBS in Bipolar II Depression

October 2, 2023 updated by: Sheng Yu Lee, Kaohsiung Veterans General Hospital.

Changes in Serum miRNA and BDNF Levels in Bipolar II Depression Treated by Theta-burst Stimulation: A Randomized Sham-controlled Exploratory Study

There is a paucity of evidence-supported treatment choices for bipolar II depression (BD-II depression), hindered by multiple comorbidity and manic switch. In addition, a slower response also burdens the patients. Intermittent theta-burst stimulation (iTBS) is a new form of Repetitive transcranial magnetic stimulation (rTMS) which is more powerful and requires less time of operation (i.e., about 1/3 of traditional treatment time) compared to traditional rTMS protocols. The antidepressant effect of iTBS for major depressive disorder is well established; however, its effect for BD-II depression is still undetermined with few investigations. In the current study, the investigators plan to conduct a randomized, controlled study to directly compare antidepressant effects of iTBS (n=30) versus sham (n=30) for BD-II depression under treatment of quetiapine monotherapy. The participants will receive 10 times of iTBS sessions in 2 weeks (daily from Monday to Friday and off on the weekends for 2 weeks), followed on the end of week 2 (right after treatment,), week 6 and week 12. The investigators hypothesize that iTBS is effective for BD-II depression and may improve cognitive decline associated with BD-II. In addition, the investigators have identified several microRNAs (miRNAs) (miR-7-5p, miR-142-3p, miR-221-5p, and miR-370-3p) which may aid the diagnosis of BD-II and such diagnostic model was patented in Taiwan. The investigators further found significant correlations with these miRNAs with peripheral levels of brain derived neurotrophic factor (BDNF). The investigators inferred that these miRNAs may be associated with susceptibility with BD-II thru modulation of BDNF. Because modulation of BDNF level is one of the anti-depression mechanism for rTMS, the investigators plan to monitor the changes of these candidate miRNAs and BDNF levels in serum before and after iTBS treatment (week 0, 2,6,12), in attempt to clarify whether these miRNAs may be treatment biomarker as well. The investigators believe that the current study result may be a great addition for predictor for therapeutic assessment and precision treatment of BD-II depression.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

In this 2-year prospective, randomized, and controlled study, the investigators plan to recruit a total of 60 patients with BD-II depression. According to a random distribution table, the participants will be randomly divided into the two subgroups, respectively: the real iTBS group (n=30) and the sham iTBS group (n=30). Patients with BD-II depression between 20 and 65 years old will be recruited in 2 years. Patients will be evaluated by research psychiatrists after a thorough medical and neurological workup. The Chinese Version of Modified Schedule of Affective Disorder and Schizophrenia-Life Time (SADS-L) will be conducted for confirmation of the diagnosis. Although DSM-IV-TR criteria require a minimum duration of 4 days of hypomania, current epidemiologic data suggest that a 2-day duration is more prevalent in community samples; therefore, the investigators will use the 2-day minimum for hypomania in the diagnosis of BD-II. Eligible participants, aged 20-65, need to have a DSM-IV-TR diagnosis of BD-II. HDRS and YMRS will be used to evaluate severity of mood symptoms. Only patients in depressive state (HDRS≧18) will be recruited. Inclusion criteria are those with diagnosis of BD-II either first-onset or with previous episodes. Exclusion criteria are (i) any DSM-IV-TR Axis I diagnosis, including organic mental disorders, substance use disorder, and other major and minor mental illnesses other than BD-II, (ii) any significant medical illness, (iii) any neurological disorders, and (iv) any poorly controlled physical illness that might influence the interview and study results; (v) any form of metal implants; (iv) any history of seizures, or medications known to lower seizure threshold; (vii) history of exposure to rTMS or electroconvulsive therapy.

During the course of the follow-up, all patients will receive open-label quetiapine adjusted individually according to the clinical response and side effects in the first two weeks and will be maintained till the end of the trial, with the final dose ranging from 200 to 700 mg/d. Concomitant benzodiazepine medication (lorazepam < 4 mg) may be used for insomnia during the study. No other antidepressants, mood stabilizers, first or second-generation antipsychotics will be allowed during the study.

Twenty milliliters of whole blood will be withdrawn from the antecubital vein of each participant and prepared as serum for the purpose of total RNA extraction and for level of BDNF analysis.

The patients will be followed for 12 weeks and blood samples (20cc whole blood) and clinical symptoms will be examined at week0, the end of week 2, 6 and week 12.

Clinical severity will be assessed by the HDRS and YMRS and Clinical ratings will be performed by research psychiatrists who are trained and experienced in the rating scales. Assessments will be performed after recruitment, week 0 and on the end of week 2, 6, and 12. RNA extraction Serum will be isolated from the whole blood and stored at -80°C immediately.

The miRNeasy kit (Qiagen, CA) will be implemented for total RNA extraction using serum from all patients and controls.

Total RNAs will be isolated from 250-µL serum of clinical samples and subjected to quantitative detection of miRNA by using the cDNA TaqMan Advanced miRNA cDNA synthesis kit (Applied Biosystems, Inc., USA). Synthesized cDNA samples will then be subjected to qRT-PCR by using the TaqManR Universal PCR Master Mix II and TaqMan Advanced miRNA assays according to manufacturer's instructions (Applied Biosystems). Expression levels of miRNAs in serum will be normalized with miR-16. The following IDs of miRNA will be used: hsa-miR-7-5p (483061_mir), hsa-miR-142-3p (477910_mir), hsa-miR-370-3p (478326_mir), and hsa-miR-221-5p (478778_mir), and has-miR-16 (481312_mir).

The level of plasma BDNF will be measured by a BDNF kit (Quantikine Human BDNF kit; R&D Systems, Minneapolis, MN) and an enzyme-linked immunosorbent assay (ELISA) reader (SpectraMax-M2; Molecular Devices, Sunnyvale, CA) which has a minimum detectable dose of 80 pg/ml.

All iTBS procedures will be conducted in the Department of Psychiatry in Kaohsiung Veterans General Hospital. An Magstim Rapid2 stimulator with eight-figure coil was used for stimulation. The resting motor threshold (MT) will be determined by the minimum intensity of magnetic stimulation on the primary motor cortex to elicit five visible muscle contractions out of ten consecutive stimuli in the contralateral abductor pollicis brevis muscle . Because a recent meta-analysis found that low stimulation intensities, high number of pulses per session, short treatment periods (less or equal to 2 weeks), and intermittent TBS (iTBS) might be the optimal parameters of TBS protocols, investigators adopted the iTBS protocol which follows the standard TBS protocols, with 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) and an intensity of 80% motor threshold. In each session, a 2-s train of bursts will be repeated every 10 s for a total of 570 s (1800 pulses) to the left dorsolateral prefrontal cortex (DLPFC). TBS sessions will be scheduled daily in a 5-day sequence, for a total of 10 sessions in 2 weeks. The figure-eight coil will be positioned in a para-sagittal plane 5.5 cm anterior to the site of MT determination and magnetic stimulation will be consequently delivered to the brain region of left DLPFC. Finally, after the 2-week double-blind phase of active or sham iTBS treatment, each patient will be followed at week 6 and week 12 to evaluate the response to the iTBS treatment.

Neuropsychological function assessment Brief Assessment of Cognition in Affective Disorders (BACA) Investigators will adopt the BACA to evaluate objective cognitive functioning in patients with mood disorders. This instrument consists of seven subtests, including Verbal Memory (List Learning), Working Memory (Digit Sequencing), Processing Speed (Verbal Fluency; Token Motor Task; Symbol Coding), Reasoning and Problem Solving (Tower of London [TOL]), and tests of affective interference (emotional distractibility and affective memory) and emotional disinhibition, which are then summed up as affective composite scores. This assessment takes approximately 45 minutes.

Study Type

Interventional

Enrollment (Estimated)

60

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. The Chinese Version of Modified Schedule of Affective Disorder and Schizophrenia-Life Time (SADS-L) and DSM-IV-TR will be conducted for confirmation of the diagnosis of BD-II.
  2. Aged 20-65.
  3. HDRS and YMRS will be used to evaluate severity of mood symptoms. Only patients in deressive state (HDRS≧18) will be recruited.

Exclusion Criteria:

  1. Any DSM-IV-TR Axis I diagnosis, including organic mental disorders, substance use disorder, and other major and minor mental illnesses other than BD-II.
  2. Any significant medical illness.
  3. Any neurological disorders.
  4. Any poorly controlled physical illness that might influence the interview and study results.
  5. Any form of metal implants.
  6. Any history of seizures, or medications known to lower seizure threshold.
  7. History of exposure to TMS or electroconvulsive therapy.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: experimental (iTBS group)
device: Magstim Rapid2 Stimulator
Device: repetitive transcranial magnetic stimulation (rTMS)
Investigators adopted the iTBS protocol which follows the standard TBS protocols, with 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) and an intensity of 80% motor threshold. In each session, a 2-s train of bursts will be repeated every 10 s for a total of 570 s (1800 pulses) to the left dorsolateral prefrontal cortex (DLPFC). TBS sessions will be scheduled daily in a 5-day sequence, for a total of 10 sessions in 2 weeks.
Sham Comparator: sham group
device shame Magstim Rapid2 Stimulator
Device: sham repetitive transcranial magnetic stimulation (rTMS)
no stimulation, Sham TBS sessions will be scheduled daily in a 5-day sequence, for a total of 10 sessions in 2 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hamilton Depression Rating Scale (HDRS)
Time Frame: Baseline, week 2 (after rTMS intervention), week6, week 12 (endpoint).
Clinical depression severity will be assessed by the HDRS. The total score range is from 0 to 52. Higher scores (>=18) indicate a greater degree of depression. A significant change in the score is considered a response to rTMS. HDRS will be assessed from baseline, week2, week 6,and week12.
Baseline, week 2 (after rTMS intervention), week6, week 12 (endpoint).

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Young Mania Rating Scale (YMRS)
Time Frame: Baseline, week 2 (after rTMS intervention), week6, week 12 (endpoint).
Clinical manic severity will be assessed by the YMRS. The total score range is from 0 to 44. Higher scores (>29) indicate a greater degree of maina. YMRS will be used to assess mood severity at baseline, week2, week6,and week12..
Baseline, week 2 (after rTMS intervention), week6, week 12 (endpoint).

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Brief Assessment of Cognition in Affective Disorders (BACA)
Time Frame: Baseline, endpoint (week 12)
The BACA is used to evaluate objective cognitive functioning in patients with mood disorders. A T-score of 50 demonstrates average functioning with regard to the healthy population with the same age and gender; the standard deviation is 10 points.
Baseline, endpoint (week 12)
plasma miRNA
Time Frame: Baseline, week 2 (after rTMS intervention), week6, week 12 (endpoint).
The following plasma miRNA levels: miR-7-5-p, miR-142-3p, miR-370-3p, miR221-5p (miRNA unit: delta Ct).
Baseline, week 2 (after rTMS intervention), week6, week 12 (endpoint).
plasma BDNF level
Time Frame: Baseline, week 2 (after rTMS intervention), week6, week 12 (endpoint).
Plasma BDNF levels.
Baseline, week 2 (after rTMS intervention), week6, week 12 (endpoint).

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Kaohsiung Veterans General Hospital.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 23, 2022

Primary Completion (Estimated)

March 31, 2024

Study Completion (Estimated)

March 31, 2024

Study Registration Dates

First Submitted

July 1, 2021

First Submitted That Met QC Criteria

August 9, 2021

First Posted (Actual)

August 10, 2021

Study Record Updates

Last Update Posted (Actual)

October 4, 2023

Last Update Submitted That Met QC Criteria

October 2, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 21-CT3-23(210303-1)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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