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RESEARCH ARTICLE
Asia Pac J Clin Trials Nerv Syst Dis 2018,  3:102

Deep-brain magnetic stimulation as add-on treatment to lithium carbonate in the treatment of bipolar depression: study protocol for a randomized, double-blind, sham-controlled trial


Beijing Anding Hospital, Capital Medical University, Beijing, China

Date of Web Publication27-Aug-2018

Correspondence Address:
Le Xiao
Beijing Anding Hospital, Capital Medical University, Beijing
China
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Source of Support: This study was funded by Beijing Municipal Administration of Hospitals Incubating Program, No. PX2017048; Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, No. ZYLX201607; and Beijing Municipal Administration of Hospitalsí Ascent Plan, No. DFL20151801., Conflict of Interest: None


DOI: 10.4103/2542-3932.238436

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  Abstract 

Background and objectives: Bipolar disorder is a highly prevalent mental disorder. In clinical practice, mood stabilizers such as lithium carbonate are the conventional treatment for bipolar disorder. However, these drugs have slow onset of action and are not sufficiently effective in the acute phase. Deep-brain magnetic stimulation was hypothesized to have significant therapeutic effects in patients with major depressive disorder by entrainment of neural oscillations. In previous clinical trials, deep-brain magnetic stimulation showed good outcomes in the treatment of unipolar depression. However, randomized controlled trials that verify these results are lacking. Therefore, the current proposal intends to address this issue.
Design: A single-center, randomized, double-blind, sham-controlled trial.
Methods: Sixty patients aged 18–60 years who have been diagnosed with bipolar disorder at Beijing Anding Hospital, Capital Medical University of China, will be included and randomly divided into experimental and control groups (n = 30 per group). Patients in the experimental group will be treated with deep-brain magnetic stimulation plus lithium carbonate for 2 weeks followed by subsequent treatment with only lithium carbonate for 4 weeks. Patients in the control group will be treated with the same protocol, except they will receive sham stimulation.
Outcome measures: The primary outcome measure is the change in score on the 17-Item Hamilton Rating Scale for Depression at weeks 2 and 6. The secondary outcome measures include response rate, complete remission rate (clinical cure rate), and changes in scores on the Hamilton Anxiety Rating Scale, 16-Item Quick Inventory of Depressive Symptomatology Self-Report, Generalized Anxiety Disorder-7, 9-Item Patient Health Questionnaire, Young Mania Rating Scale, Clinical Global Impression-Bipolar Disorder, and Montreal Cognitive Assessment at visit points relative to baseline scores. The safety evaluation indicators are the incidence of adverse events and the rate of manic switch.
Discussion: The trial will verify the effectiveness of deep-brain magnetic stimulation with lithium carbonate in the treatment of bipolar disorder, providing evidence as to whether this combined therapy has the potential to be new alternative treatment for bipolar disorder.
Ethics and dissemination: The trial was approved by the Ethics Committee of Beijing Anding Hospital, Capital Medical University in China (approval No. 201777FS-2) on October 27, 2017. Design of the trial was completed on June 28, 2017, and the trial registration was completed at the Chinese Clinical Trial Registry on November 10, 2017. Recruitment was initiated in January 2018 and it is expected to be completed in December 2018. Follow-up visit will end in June, 2019. Data analysis will be completed in December 2019. The results of the study will be disseminated through presentations at scientific meetings and/or in peer-reviewed publications. Anonymized trial data will be available indefinitely at www.figshare.com.
Trial registration: The trial has been registered with the Chinese Clinical Trial Registry (Registration No. ChiCTR-INR-17013338) and the version number is 2.1.

Keywords: bipolar disorder; deep-brain magnetic stimulation; lithium carbonate; 17-item Hamilton Rating Scale for Depression; Hamilton Anxiety Rating Scale; 16-item Quick Inventory of Depressive Symptomatology Self-Report; Generalized Anxiety Disorder-7; 9-Item Patient Health Questionnaire; Young Mania Rating Scale; Clinical Global Impression-Bipolar Disorder; randomized controlled trial


How to cite this article:
Xiao L, Wang G, Feng L. Deep-brain magnetic stimulation as add-on treatment to lithium carbonate in the treatment of bipolar depression: study protocol for a randomized, double-blind, sham-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:102-11

How to cite this URL:
Xiao L, Wang G, Feng L. Deep-brain magnetic stimulation as add-on treatment to lithium carbonate in the treatment of bipolar depression: study protocol for a randomized, double-blind, sham-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2018 Oct 23];3:102-11. Available from: http://www.actnjournal.com/text.asp?2018/3/3/102/238436


  Introduction Top


Research background

Bipolar disorder (BD) is a mood disorder with a lifetime prevalence of approximately 5% in which people cycle between mania and depression (Ferrari et al., 2011; Farren et al., 2012). The dominant state of the disorder is depression, which on average, consumes over 30% of a patient’s lifetime. Moreover, the risk of suicide and self-injury is highest during depressive episode in BD patient among general population, with 15–19% of patients committing suicide (Barnett and Smoller, 2009; Baldessarini et al., 2013). BD causes more difficult problems than mania alone, and is very difficult to treat. It has become a major public health problem that urgently needs to be resolved.

Although mood stabilizers such as lithium carbonate are currently used to treat BD (Leibenluft and Rich, 2008), they have slow onset of actions and are not effective enough in the acute phase (Post, 2016). Indeed, whether antidepressant drugs should be used in BD treatment at all is highly controversial. While clinical experience has suggested that antidepressants are effective, an increasing number of clinical studies do not support this view (Post, 2016). Some scholars even believe that in addition to being ineffective for BD treatment and presenting a problem of withdrawal, antidepressants can actually increase the risk of phase inversion and rapid circulation (Tak and Stevens, 2013). Although electrical shock therapy in patients with severe symptoms has a rapid onset of action, consequential cognitive impairment cannot be ignored (Zhao, 2015). Therefore, exploring non-drug treatments for BD is of great clinical significance.

Transcranial magnetic stimulation (TMS) has been shown to have an antidepressant effect in patients with BD (Best et al., 2015), but TMS requires to be located to certain brain regions and the movement threshold should be determined before treatment. Effect and efficacy of TMS is closely related to stimulation regions and adopted frequency, and high intensity magnetic fields of TMS might induce seizures, which greatly limits its clinical application (Rossi et al., 2009). In recent years, low-field magnetic stimulation (LFMS) has been successful in improving depressive symptoms in BD (Rohan et al., 2004; Carlezon et al., 2005; Rohan et al., 2014). Antidepressant-like effects of LFMS were also demonstrated by reducing immobility in the forced swim test of depressive animal model (Carlezon et al., 2005). LFMS can produce an evenly diffused magnetic stimulation without targeting to a specific region. Additionally, the intensity of LFMS is only a few hundred percent of traditional TMS and this cannot induce seizures (Rohan et al., 2004, 2014). Clinical studies conducted at Harvard Medical School showed that LFMS treatment alone can rapidly improve the depressive symptoms of patients with unipolar depression (Rohan et al., 2004, 2014).

It is hypothesized that antidepressant mechanism of TMS is related to reestablishing intrinsic cortical oscillatory activity (Leuchter et al., 2013). Based on the rationale and supportive findings of low-field synchronized transcranial magnetic stimulation in major depressive disorder (MDD) patients (Leuchter et al., 2015), deep-brain magnetic stimulation (DMS) has been developed by Beijing Aldans Biotech Company LTD and Tianjin ANTIS medical device company LTD, Certified by Beijing medical device quality supervision and inspection center with diverse rhythmic stimuli including alpha, theta, and gamma rhythms and demonstrated to be effective for neuropsychiatric disorders (Peng et al., 2012; Zhang et al., 2014; Xiao et al., 2015, 2018; Zhen et al., 2017). DMS produces synchronized rhythmic stimuli which is supposed to couple with specific oscillatory rhythms in the neural network and increase long-term potentiation which strengthening signal transmission between two neurons (Cooke and Bliss, 2006).

Animal experiments at the cellular and molecular levels have demonstrated that DMS with alpha-gamma rhythms can promote adult rodent hippocampal neurogenesis under stress, facilitate the development of newborn neurons, and upregulate brain-derived neurotrophic factor (BDNF), thereby alleviating depression and stress responses in model animals (Zhang, 2014). Small-scale clinical studies have also confirmed that DMS can improve depressive symptoms and increase serum BDNF levels in patients with treatment-resistant depression (Xiao et al., 2015). A randomized controlled trial of 22 patients with depression showed that the DMS with alpha and delta rhythms significantly improved depressive symptoms after 6 weeks of treatment (Xiao et al., 2018). Compared with delta rhythms (0.5 Hz), alpha rhythms (8–12 Hz) were better at improving depressive symptoms, while delta rhythms were superior at improving anxiety symptoms. Additionally, alpha rhythms were also better than delta rhythms in terms of response and complete remission rates. Increased BDNF levels were highly associated with the response rate, and increases in BDNF levels at the 2nd week strongly predicted effective outcomes at the 6th week (Xiao et al., 2018). DMS was also proved to promote neural development in mouse models of Alzheimer’s disease (Zhen et al., 2017). Findings from a clinical trial show that DMS combined with nootropic drugs achieves better outcomes than drug therapy alone in recovering the cognitive function of patients with Alzheimer’s disease (Peng et al., 2012).



In addition, gamma oscillations can facilitate synaptic plasticity and regulate neural networks, which are involved in advanced cognitive activities such as selective attention and memory. Patients with depression present with abnormal gamma band activity: resting-state gamma activity is lower than normal, and gamma activity is higher after experiencing negative stimuli than positive stimuli, indicating that the abnormal gamma band activity reflects the negative bias of emotional processing in patients with depression (Wang et al., 2011). Patients with BD have abnormal resting-state gamma connectivity in the frontal lobe, and BD is intimately associated with cognitive impairment (Jia et al., 2016). [Table 1] shows the results of recent clinical studies on the use of DMS in the BD treatment.
Table 1: Clinical results of deep-brain magnetic stimulation (DMS) in the treatment of major depression in recent years

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Features and objectives

DMS based on specific rhythms is expected to increase the overall efficacy of treatment for depression, and the EEG index associated with the gamma band may serve as a predictor of the efficacy. Synchronous DMS based on the gamma rhythm might improve treatment efficacy in patients with bipolar depression in the acute phase of treatment and the objective evaluation indicators for BD will be discussed in this study. This trial is intended to determine the efficacy and safety of DMS combined with lithium carbonate in the treatment of BD, providing a theoretical basis for the development of new treatment options.


  Methods/Design Top


Study design

This will be a randomized, double-blind, parallel-controlled, sham stimulation trial at Capital Medical University Beijing Anding Hospital in China. The study population will comprise 60 patients diagnosed with BD who will be randomly assigned into an experimental group or a control group (n = 30 per group). The treatment period will be 6 weeks in both groups. Patients in the experimental group will be treated with DMS plus lithium carbonate for 2 weeks followed by treatment with only lithium carbonate for 4 weeks. The same protocol with be used for the control group, except that the DMS will use sham stimulation. The primary outcome measure is change in scores on the 17-Item Hamilton Rating Scale for Depression (HAMD-17) at the end of the 2nd and 6th weeks. The secondary outcome measures will include response rate, complete remission rate (clinical cure rate), and changes in scores on the Hamilton Anxiety Rating Scale (HAMA), 16-Item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), Generalized Anxiety Disorder-7 (GAD-7), 9-Item Patient Health Questionnaire (PHQ-9), Young Mania Rating Scale (YMRS), Clinical Global Impression-Bipolar Disorder (CGI-BD), and Montreal Cognitive Assessment (MoCA) at each visit point relative to baseline. The safety evaluation indicators are the incidence of adverse events and the rate of manic switch.

Recruitment

Potential patients will be informed of the upcoming trial through a recruitment poster at the clinic and admitting office of Capital Medical University Beijing Anding Hospital or recommended by clinicians. Patients or their families interested in participating will contact the study sponsor via telephone or email.

Study population

BD patients will be enrolled from Capital Medical University Beijing Anding Hospital in China.

Inclusion criteria

Patients will be required to meet all of the following conditions to be included in this trial:

  • A diagnosis of BD (ICD-10), experiencing a current depression episode without psychotic features (Organization, 2016) as determined by Mini-International Neuropsychiatric Interview (MINI) 6.0.0
  • HAMD-17 total score ≥ 14
  • Primary school or above level of education, having the ability to understand the content of the questionnaire
  • Inpatients/outpatients, aged 18 to 60 years (inclusive)
  • Provision of written informed consent


Exclusion criteria

The following patients will be excluded from this trial:

  • Those who have been diagnosed with schizophrenia, schizoaffective disorder, or other mental disorders associated with diseases
  • Those with alcohol/drug dependence or acute poisoning within 1 year
  • Pregnant or lactating women
  • Those at serious risk for suicide
  • Those with severe physical illnesses
  • Those with a history of intolerance to lithium carbonate
  • Those who have been continuously treated with lithium carbonate for at least 14 days at a daily dose > 0.75 g
  • Those having been treated with fluoxetine or antipsychotic long-acting injection within 30 days
  • Those currently with a kidney disease
  • Those with thyroid dysfunction or receiving hormone therapy before enrollment
  • Those with a history of craniocerebral injury, nervous system injury, or repeated episodes of headache
  • Those who have had electroconvulsive therapy within 1 year
  • Those who have irremovable metal objects embedded in their bodies, such as dentures, artery clips, pacemakers, or metal fixtures


Withdrawal criteria

After initially being included, patients will be withdrawn from the study in the following situations:

  • Presence of severe adverse events.
  • Serious violations of the research program, such as unscheduled treatment or poor compliance.
  • Suicide, suicide attempt, or serious self-injury during the trial
  • Experience of manic or light manic episodes during the trial
  • Inability to complete the follow-up


Randomization and blindness

The test device is controlled by an authorization card with a chip. By adjusting chip settings, some authorization cards will order the device to produce real stimulation, while other cards will generate sham stimulation. The authorization cards will be issued to the enrolled patients and the labels on the card, including card number, participant number, and initials, will be produced by a person independent of the research team. This person will prepare a random number table and edit the cards.

The random number table will be generated by a statistician not involved in the study, using SAS 9.4 software (SAS Institute Inc., Cary, North Carolina, USA) block method. The random number of seeds and random number table will be saved as the blind. Each random number will have a corresponding emergency letter. Eligible patients will be randomized into experimental and control groups with a 1:1 assignment ratio.

All cards will look the same so that the experimenters cannot know who is in which group. The card will be issued to each participant by the authorized investigator in the order of enrollment. From the start of randomization until the locking of the database, participants, researchers, assessors, and data analysts will all be unaware of grouping information.

Interventions

Eligible patients will be required to refrain from using antidepressants, mood stabilizers, and antipsychotics at least for 5 days before enrollment, but will not be required to terminate the use of lithium carbonate (as long as the dosage does not exceed 0.75 g/d).

Two groups of participants will be given lithium carbonate (Shanghai New Yellow River Pharmaceutical Co., Ltd., approval No. H31021756, specifications: 0.25 g/tablet), 0.2 g per oral dose, 3 times per day, for 6 weeks. Participants who had not been using lithium carbonate will be tested for serum levels of lithium at the 2nd and 6th weeks. Those who were taking lithium carbonate before the start of the trial will have their serum levels tested before enrollment. If serum lithium levels exceed 1.2 mM during the trial or patients cannot tolerate the side effects related to lithium, we will reduce the dosage. We must be alert to the possibility of lithium carbonate poisoning. Thus, we will monitor for abnormal body temperature, drowsiness, confusion, tremors, convulsions, tendon reflexes, weak muscle strength, hypertonicity, ataxia, nausea, vomiting, and diarrhea. If lithium poisoning is certain and removing lithium from the body becomes urgent, intravenous administration of sodium chloride solution or glucose and sodium chloride solution will be given to promote the excretion of lithium via the kidneys. Patients presenting no vomiting will also drink sodium chloride solution to promote the excretion of lithium.

Patients in the experimental group will be given gamma (30–40 Hz) rhythmic LFMS treatment. Stimulation will initiate at 30 Hz, and will be automatically raised about 2 Hz every 4 minutes of a 20-minute session (finally reaching 40 Hz). Sessions will be given twice a day for two weeks, with an interval of at least 6 hours between 2 sessions (28 sessions in all).

Patients in the control group will be given sham stimulation with simulated gamma rhythm (30–40 Hz) in terms of frequency and sound. The treatment time, frequency, and number of sessions will be the same as those of the experimental group.

The DMS transcranial magnetic stimulator (model No. ADTIS Z1, batch No. 01012014110001-01012014110072) is provided by Tianjin ADTIS Medical Devices Co., Ltd., China. Participants will be asked to be in supine or lateral position with their heads in the middle of the device. After the power is turned on, the device will be started by pushing the star button after reading twice the patients’ authorization cards. The device will stop automatically after 20 minutes of treatment [Figure 1].
Figure 1: Treatment with deep-brain magnetic stimulation.
Note: (A) The device of deep-brain magnetic stimulation. (B) During treatment, the patient is in the supine or lateral position with his/her head in the middle of the stimulator.


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All antidepressants, antipsychotics, and other mood stabilizers other than lithium carbonate will be banned during the study. It will be forbidden to use any other physiological therapy during the study, such as electrotherapy, TMS, phototherapy, electroacupuncture, biofeedback, or vagal nerve stimulation. Systematic psychotherapy (psychoanalysis, cognitive comprehension, desensitization therapy, hypnosis therapy, Morita therapy) will also be prohibited during the study, although general supportive psychotherapy will be allowed.

Restricted use of concomitant drugs: Specific drugs may be used in the following conditions if the investigator confirms that it is necessary:

  • For severe insomnia, the use of benzodiazepines (estazolam ≤ 2 mg/night, alprazolam ≤ 0.8 mg/night, lorazepam ≤ 1 mg/night, oxazepam ≤ 30 mg/night) or non-benzodiazepines (zolpidem ≤ 10 mg/night, zopiclone ≤ 7.5 mg/night) will be permitted, but these drugs cannot be used continuously over 2 weeks. Additionally, these drugs should be withdrawn 8 hours before the assessment.
  • For anxiety or agitation, oral lorazepam (≤ 3 mg⁄d) or oxazepam (≤ 45 mg/d) will be used only temporarily. Continual use and prophylactic use are not recommended, and the use of these drugs should be terminated at 8 hours before the assessment.
  • Symptomatic treatment will be provided for common physical diseases and therapeutic drugs in type and dose are recommended to remain unchanged during the study.


The type and dose of the drug used must be recorded in detail, and the exact start and stop time must be indicated.

Outcome measures

Primary outcome measure

The primary outcome measure is the change in total score on the HAMD-17 at the 2nd and 6th weeks. The HAMD-17 is a universal clinical assessment tool that rates the severity of depressive symptoms with 17 items, and a higher score indicates greater depression severity (Williams, 1988).

Secondary outcome measures

  • Response rate: the proportion of patients with HAMD-17 total scores that are reduced by at least 50% from baseline at endpoint (the 6th week).
  • Remission rate: the proportion of patients with HAMD-17 total scores ≤ 7 at endpoint.
  • Changes in HAMA scores (relative to baseline) at each follow-up visit. The HAMA contains 14 items, including anxious mood, tension, fears, insomnia, intellectual, depressed mood, somatic (muscular), somatic (sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary symptoms, autonomic symptoms, and behavior at interview (Hamilton, 1959). A higher score indicates more severe anxiety.
  • Changes in QIDS-SR scores (relative to baseline) at each follow-up visit. The QIDS-SR has 16 items involving 9 dimensions with a full score being 27, with higher scores indicating greater severity of depression (Rush et al., 2003).
  • Changes in the GAD-7 scores (relative to baseline) at each follow-up visit. The GAD-7 scale comprises seven questions, with higher scores indicating more serious anxiety (Spitzer et al., 2006).
  • Changes in the PHQ-9 scores (relative to baseline) at each follow-up visit. The PHQ-9 contains nine items, with higher scores indicating more serious anxiety (Löwe et al., 2004).
  • Changes in the YMRS scores (relative to baseline) at each follow-up visit. The YMRS measures the severity of manic episodes using 11 items. Higher scores indicate more serious mania (Young et al., 1978).
  • Changes in the severity and improvement scale scores on the CGI-BD (relative to baseline) at each follow-up visit. The CGI-BD evaluates the severity of illness, overall improvement of illness. The severity scale is a 7-point scale with higher scores indicating a more serious mental disorder. The improvement scale is also a 7-point scale with lower score indicating a better outcome (Spearing et al., 1997).
  • Changes in the total and dimensional scores on the MoCA (relative to baseline) at each visit point. The MoCA is a 30-point scale, with lower scores indicating more severe cognitive impairment (Li et al., 2018).
  • Laboratory tests include routine blood and urine tests, urine pregnancy test, biochemistry, and thyroid function analysis.


Safety assessment

Adverse events and response rate

An adverse event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Existing diseases that have deteriorated during the study will be reported as adverse events.

Adverse events can be categorized as mild (discomforts that do not affect daily activities), moderate (discomforts that reduce or affect daily activities), and severe (unable to work or perform daily activities).

The collection of adverse events will start from the signing of informed consent and screening until the 28th day after the withdrawal of treatment. During the trial, the adverse event will be accurately recorded in the adverse event list of a case report form (CRF), including the occurrence time, severity, duration, measures taken and outcomes.

Generally, the relationship between an adverse event and the medical device will be categorized as the following five grades: (1) Definitely related: The adverse event will appear at a reasonable time after medication and be consistent with one of the known adverse events of the suspected drug. The adverse event will disappear after discontinuation of the suspected drug, which cannot result from the patient’s clinical status or other reasons. (2) Probably related: The adverse event will appear in line with the law of medication time, and belong to one of the known adverse events of the suspected drug. An obvious relief will be detected after withdrawal of the suspected drug, and it cannot result from the patient’s clinical status or other reasons. (3) Possibly related: The adverse event will occur in line with the law of medication time, and also belong to one of the known adverse events of the suspected drug. The adverse event will be reduced after withdrawal of the drug, but this phenomenon may result from the patient’s clinical status or other reasons. (4) Possibly unrelated: The emergence of the adverse event will be contradictory to the law of medication time, and this event will also not belong to one of the known adverse events of the suspected drug. No relief will be detected after withdrawal of the drug, and a reduction in symptoms due to the adverse event will be observed after improvement of patient’s clinical status or elimination of other reasons. (5) Definitely unrelated: The emergence of the adverse event will not meet the law of medication time, and it will also not belong to one of the known adverse events of the suspected drug. The adverse event will result from the patient’s clinical status and other reasons rather than the suspected drug, and the symptoms will disappear or relieve after improvement of patient’s clinical status or elimination of other reasons.

A serious adverse event (SAE) in human drug trials is defined as any untoward medical condition that at any dose: (1) is fatal (death is an adverse event outcome, but not an event), (2) is life-threatening (it refers to an event that result in an immediate risk of death rather than leads to death if the event becomes serious), (3) requires or prolongs inpatient hospitalization, (4) results in persistent or significant disability/incapacity, (5) constitutes a congenital anomaly/birth defect, or (6) is of great medical significance or requires intervention to prevent one or more of the above results.

At the beginning of the study (after signing informed consent), any serious adverse events that occur during the study (including long-term follow-up) must be reported within one working day to the ethics committee of the branch center and medical administrative department. Researchers must complete the report form of serious adverse events and send them to the person in charge of serious adverse events, and record it at the Ethics Committee of Beijing Anding Hospital, Capital Medical University.

If any emergency medical events that occur during the study are identified as serious adverse events, we will terminate the trial. The principal investigator will ensure that the emergency medical events during the study can be given proper measures by experts. In case of requiring any emergency medical treatment, the subject can contact the principal investigator to initiate an emergency plan, stop the trial immediately, give appropriate medical treatment, and arrange for referral treatment in case of inability to deal with any condition in our hospital to ensure the safety of the subject.

Rate of manic switch

Manic switch is defined as the total score of YMRS ≥ 8 during the trial.

Flow chart of the trial

The trial flow chart is shown in [Figure 2], and the time for outcome measurements is shown in [Table 2].
Figure 2: Flow chart of the trial.
Note: HAMD-17: The 17-Item Hamilton Rating Scale for Depression; HAMA: Hamilton Anxiety Rating Scale; QIDS-SR: Quick Inventory of Depressive Symptomatology Self-Report; GAD-7: Generalized Anxiety Disorder-7; PHQ-9: 9-Item Patient Health Questionnaire; YMRS: Young Mania Rating Scale; CGI-BD: Clinical Global Impression-Bipolar Disorder; MoCA: Montreal Cognitive Assessment.


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Table 2: Time schedule for outcome measurements

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Sample size

The trial was designed as a superiority study. Based on the findings of Rohan et al. (2004, 2014) and our preliminary work of DMS in the treatment of depression, the mean improvement mean of the symptoms in the acute phase was about 8 in the control group and 10 in the experimental group, and the pooled standard deviation was 2.2. Taking a statistically significant level of 0.05 and a power of 0.9, the calculated sample size was about 48 cases (n = 24 per group). Assuming a 20% dropout rate in the longitudinal observation study, the sample size was finally set as 60 cases.

Statistical analysis

Statistical analysis of the population

  • Full Analysis Set (FAS): According to the principle of intention to treat analysis, efficacy analysis will be performed at least once on all cases taking medication once. To deal with missing data, observation data at the last available visit will be carried forward and assumed to be the final results for the missing data point at the end of the trial according to the last observation carried forward analysis (LOCF).
  • Per Protocol Set (PPS): This analysis is restricted to the patients who are eligible for inclusion criteria but ineligible for exclusion criteria. The treatment plan at the observation period will last for at least 2 weeks. No drugs or treatment measures that may affect the efficacy will be used during the trial. The efficacy evaluation of this study will be performed based on the FAS and PPS data sets.
  • Safety Set (SS): All enrolled subjects will be given the test drug at least once and safety records from all the subjects after administration will be included in the SS data set, which will be used for safety analysis.


Statistical methods

General principle: Statistical analysis will be performed using SAS 9.4 software. Unless otherwise stated, all numerically archiving.

  • Design of CRFs: Data collection forms will be designed according to the requirements of the protocol. Flow chart of the trial, data modules and data items collected will be defined and corresponding data collection guidelines will be drafted and reviewed and finalized by the principal investigator.
  • Data entry: The researchers will complete a medical record for each subject. Completed medical records will be reviewed by the researchers themselves and a quality monitor, and then promptly and accurately input by an entry clerk.
  • Data audit: The data administrator will compile a logical verification plan based on the study protocol and research medical records. After being reviewed and approved by the principal investigator, it will be then finalized and used to logically audit the data and issue system queries in real time. Except for system queries, the data administrator will be responsible for manual verification of research data and posing questions if there are any questions.
  • Data locking and output: After all the subjects complete the trial, all the medical records will be input into the system. Collected data and established databases will be reviewed and confirmed by the principal investigator, statistical analyst, and data administrator. And then, the data will be locked by the data administrator. Locked data will be exported by the data administrator to a designated database for statistical analysis. Locked data will not be edited but can be corrected in the statistical analysis program if there are some questions confirmed. Unlocking the data, if really necessary, will be approved by the principal investigator.


Data monitoring

  • Trial implementation, management, quality control, data management and statistical analysis will be completed at the Beijing Anding Hospital, Capital Medical University.
  • The study protocol was drafted by the principal investigator on the basis of a full review of the literature, and was approved by the ethics committee. Without the consent of the principal investigator, the flow chart of the trial cannot be altered.
  • A fixed quality control system will be established, and assigned inspectors responsible for quality control will develop a quality control plan, carry out the quality control during the trial, make the trial to follow the protocol and comply with the relevant regulations, and audit the trial records for the correctness and completeness. Any conditions that do not conform to the study protocol during the trial should be reported promptly and corrective measures should be taken. Each phase of the trial should be implemented in accordance with standard operating procedures for the quality management and quality assurance of the clinical trial to ensure that the data is reliable and the study process is correct.
  • If any emergency medical events are identified as serious adverse events during the trial, we will terminate the trial. The principal investigator will ensure the proper measures for the events from the experts. In case of requiring any emergency medical treatment, an emergency plan will be initiated via contacting the principal investigator to stop the trial immediately, give appropriate medical treatment, and arrange for referral treatment in case of inability to deal with any condition in our hospital to ensure the safety of the subject.
  • Before the start of clinical trial, a research start-up meeting attended by researchers will be held to perform uniform trainings for Good Clinical Practice of China and study protocol, filling in the CRFs, and operational procedures. Scale training and consistency testing will be performed on the researchers participating in the scale evaluation. These trainings will ensure that all researchers conduct research under uniform standards and requirements, and ensure that every researcher will be familiar with the trial protocol and flow chart.
  • Clinical data collected during the trial will be recorded in CRFs. All researchers who receive the CRF’s authorization will be trained by the principal investigator or coordinator.


Compensation

During the trial, the subjects included will receive a transportation allowance and have their appointment and follow-up examination fees waived. The researchers should provide insurance coverage for subjects participating in the trial and cover the costs of treatment and financial compensation for subjects suffering damage or death associated with the trial.

Ethics and dissemination

  • This trial will follow the relevant laws and regulations of the Declaration of Helsinki and relevant clinical trial principles in China. Study protocol, informed consent and investigator’s brochure were approved by the Ethics Committee of the Beijing Anding Hospital, Capital Medical University in China (approval No. 201777FS-2; Additional file 1 [Additional file 1]).
  • Any change or correction made to the study protocol and informed consent during the trial will be reported to and approved by the Ethics Committee of the Beijing Anding Hospital, Capital Medical University. Any serious adverse events must be reported to the hospital’s ethics committee.
  • All the subjects and their legal representatives will be fully informed of the study objective, procedures and possible benefits and risks. All the subjects will be aware that they have the right to decide whether to participate in the trial and have the right to request withdrawal from the trial. Written informed consent will be provided by all the subjects prior to the commencement of the trial and archived.
  • In accordance with the guidelines of individual privacy and data defense stated in the informed consent, patients will give their consent for their information related to the trial that will be used and reported by the researchers and relevant persons. Research data will be stored in a computer database and kept confidential according to the corresponding laws in China.
  • Corrected protocol, amendments and/or new versions of the protocol (corrected) must be submitted to the hospital’s ethics committee for approval before implementation. If there is a non-significant change, this change must be submitted to the hospital’s ethics committee or obtain its written consent in accordance with the relevant requirements. Any change or correction made to the informed consent provided by the research center must be informed to the research center’s ethics committee. Amended informed consent must be approved in writing by the ethics committee.
  • In strict accordance with the requirements of the State Food and Drug Administration and the Good Clinical Practice of China, clinical data should be kept by all clinical units for 5 years, including medical records, CRF and various original records (including all original, signed informed consent of patients) and detailed records of drug acceptance, distribution and recycling.
  • This study was reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (Additional file 2 [Additional file 2]). The results of this trial will be disseminated through presentations at scientific meetings or by publications in peer-reviewed journals. Anonymized trial data will be published at www.figshare.com.



  Discussion Top


Past findings

DMS has been confirmed to improve the symptoms of depression and anxiety in patients with unipolar depression (Xiao et al., 2015, 2018), but sham-stimulation controlled trials are lacking, and the efficacy of DMS in BD patients has yet to be validated. Therefore, current evidence is insufficient for providing a clinical basis for DMS in the treatment of BD.

Study novelty

Outside of China, although devices using a similar LFMS principal have been used in the study of unipolar and bipolar depression, the inclusion criteria for patients are not strict. A previous study has included both patients with unipolar and bipolar depression (Rohan et al., 2014). Our previous study only compared two active stimulations in the treatment of MDD and there was lack of sham control (Xiao et al., 2018). Additionally, the observation times have only been from 1dayto up to 4 weeks (Rohan et al., 2004, 2014; Jin and Phillips, 2014), the long-term effect of LFMS is not clear (Xiao et al., 2018).This randomized controlled study will be better to explain the efficacy of DMS in the treatment of bipolar depression and duration of antidepressant effect when DMS stops.

Study limitations

This trial will have a small sample size and will only cover 6-week efficacy of DMS in BD patients. Therefore, further studies of the long-term effect will still be warranted.

Study significance

The trial will verify the effectiveness of independently developed DMS combined with lithium carbonate, and potentially provide a new choice for BD patients.


  Trial Status Top


The trial was approved by the Ethics Committee of Beijing Anding Hospital, Capital Medical University in China (approval No. 201777FS-2) on October 27, 2017. Design of the trial was completed on June 28, 2017, and the trial registration was completed at the Chinese Clinical Trial Registry on November 10, 2017. Recruitment was initiated in January 2018 and was expected to be completed in December 2018. Follow-up visit will end in June, 2019. Data analysis will be completed in December 2019. Currently, recruitment of participants is ongoing.

Additional files

Additional file 1: Hospital’s ethical approval form.

Additional file 2: SPIRIT checklist.

Author contributions

Design and execution of the study protocol: LX and LF. Guidance of the study protocol: GW. All the authors approved the final version of the manuscript for publication.

Conflicts of interest

Although the transcranial magnetic stimulator for DMS will be used as an intervention, the authors declare that the trial will be conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Financial support

This study was funded by Beijing Municipal Administration of Hospitals Incubating Program, No. PX2017048; Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, No. ZYLX201607; Beijing Municipal Administration of Hospitals’ Ascent Plan, No. DFL20151801. The conception, design, execution, and analysis of experiments, as well as the preparation of and decision to publish this manuscript were made independent of any funding organization.

Institutional review board statement

The protocol has been approved by the Ethics Committee of the Beijing Anding Hospital of Capital Medical University in China (approval No. 201777FS-2). All the patients and their families will voluntarily participate in the trial, and provide written informed consent with the premise of fully understanding the treatment plan. Clinicians and the research institute involved in the trial will follow the relevant laws and regulations of the Declaration of Helsinki and relevant hospital’s ethical principles.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient and their legal guardian consent forms. In the form the patients and their legal guardian will give their consent for patients’ images and other clinical information to be reported in the journal. The patients will understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Reporting statement

This study follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of Beijing Anding Hospital, Capital Medical University, China.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this article after deidentification (text, tables, figures, and appendices) will be shared. Study protocol, informed consent form and clinical study report will be promulgated within 6 months after the completion of the trial. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Funding: This study was funded by Beijing Municipal Administration of Hospitals Incubating Program, No. PX2017048; Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support, No. ZYLX201607; and Beijing Municipal Administration of Hospitals’ Ascent Plan, No. DFL20151801. [34]

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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