The Role of iTBS in Bipolar II Depression

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.

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.

Eligibility Criteria:
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.