Effects of repetitive transcranial magnetic stimulation on cognitive function and recurrence of symptoms in individuals with bipolar disorder: a double-blind parallel randomized controlled trial
Kang-Guang Lin, Wan Zeng, Xiong Huang
The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, Guangdong Province, China
|Date of Web Publication||04-Jun-2020|
MD, PhD Kang-Guang Lin
The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, Guangdong Province
MD Xiong Huang
The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, Guangdong Province
Source of Support: None, Conflict of Interest: None
Background and objective: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive nerve stimulation technique that has the potential to improve cognitive function. However, there have been few randomized controlled trials (RCTs) that evaluated the effectiveness of rTMS on cognitive function and the relapse in patients with bipolar disorder.
Participants and methods: This double-blind parallel RCT will be conducted at The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), China. A total of 74 bipolar disorder patients will be recruited and randomly assigned to a trial group (n = 37) and control group (n = 37). Repetitive transcranial magnetic stimulation and sham repetitive transcranial magnetic stimulation will be applied over the left dorsolateral prefrontal cortex in the trial group and control group, respectively. This trial was designed on March 2, 2017 and was approved by the Ethics Committee of The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), China on April 25, 2017 (approval No. 2017022). Patient recruitment began on July 10, 2017 and will be finished in December 2020. The trial will be completed in December 2021. The protocol version is 1.0.
Outcome measures: The primary outcome measure will be the difference between MATRICS Consensus Cognitive Battery scores at post-intervention and at baseline. The secondary outcome measures will be relapse of depressive and/or hypo/mania episode at a one-year follow-up.
Discussion: This clinical trial will provide data regarding effectiveness in long-term cognitive function and relapse of mood episode following repetitive transcranial magnetic stimulation in patients with bipolar disorder.
Trial registration: This trial had been registered in the ClinicalTrials.gov (identifier: NCT03207048) on July 2, 2017.
Keywords: bipolar disorder; clinical trial; Hamilton Depression Scale; long-term cognitive function; MATRICS Consensus Cognitive Battery; psychological disorder; recurrence; repetitive transcranial magnetic stimulation; Young Mania Rating Scale
|How to cite this article:|
Lin KG, Zeng W, Huang X. Effects of repetitive transcranial magnetic stimulation on cognitive function and recurrence of symptoms in individuals with bipolar disorder: a double-blind parallel randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2020;5:27-31
|How to cite this URL:|
Lin KG, Zeng W, Huang X. Effects of repetitive transcranial magnetic stimulation on cognitive function and recurrence of symptoms in individuals with bipolar disorder: a double-blind parallel randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2020 [cited 2021 Jan 27];5:27-31. Available from: https://www.actnjournal.com/text.asp?2020/5/2/27/285358
| Introduction|| |
Bipolar disorder is a common clinical mood disorder that is characterized by a high suicide rate, high comorbidity rate, and low early recognition rate. Patients often have manic and/or depressive symptoms accompanied by cognitive, behavioral, psychophysiological, and interpersonal changes that are compatible with abnormal mood (Grande et al., 2016; Saunders and Geddes, 2016). Anti-manic and antiepileptic drugs are often used clinically to stabilize the mood of patients (Geddes and Miklowitz, 2013). However, these treatments are not known to cure bipolar disorder.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive nerve stimulation technique. rTMS uses an induced magnetic field to modulate excitability in the cerebral cortex, the plasticity of brain neurons, and the release of neurotransmitters such as dopamine (Guo et al., 2017). Transcranial magnetic stimulation has been found to be effective in the treatment of depression (Downaret al., 2016; Reddy and Vijay, 2017), anxiety (Vennewaldet al., 2013), obsessive-compulsive disorder (Jahangardet al., 2016; Donseet al., 2017), schizophrenia (He et al., 2017), substance addiction (Makani et al., 2017), and sleep disorders (Jiang et al., 2013). These have been few randomized conreolled trial (RCT) studies evaluating the effectiveness of rTMS on cognitive function in patients with bipolar disorder and their long-term (12 months) relapse of mood episode [Table 1].
|Table 1: Chinese clinical trials regarding the effect of repetitive transcranial magnetic stimulation on the early cognitive function in the treatment of bipolar disorder|
Click here to view
| Participants and Methods|| |
This parallel double-blind randomized controlled clinical trial will be conducted at the Department of Affective Disorders, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), China. Guangzhou Huiai Hospital is a tertiary-level grade-A psychiatric hospital. All of the members of the research team have a master’s or doctoral degree, a title of associate chief physician or chief physician, and at least 5 years of clinical experience in the Department of Affective Disorders.
Recruitment information will be posted on bulletin boards in the outpatient and inpatient departments of the institute, and simultaneously publicized using the hospital’s official WeChat account and website. Interested individuals will contact the principal investigator via telephone, email, or WeChat.
Patients with bipolar disorder who are currently receiving treatment at Guangzhou Huiai Hospital, China, will be recruited.
Inclusion criteria (determined by members of the research team)
- Accordance with the characteristics of bipolar disorder as defined in The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5; American Psychiatric Association, 2013)
- Hamilton Depression Scale (HAMD) score < 18
- Young Mania Rating Scale (YMRS) score < 12
- Age 18 to 60 years, either sex
Exclusion criteria (determined by members of the research team)
- Other mental conditions according to the DSM-5 diagnostic criteria (mental retardation, organic brain disease, extensive developmental disorder, history of epilepsy)
- Physical disabilities that impede completion of the test of cognitive function
- Implantation of a drug pump or pacemaker
- History of brain surgery
- Metal implants in the head (except for the mouth)
- Diseases associated with increased intracranial pressure
- History of suicide attempts
- Currently undergoing anticoagulant therapy, immunosuppressive therapy, or chemotherapy
- Unstable physical diseases (including infectious diseases)
- Use of psychotropic drugs (except sleeping pills such as benzodiazepines) within the past 4 weeks
- Participation in other clinical trials
Participants in the trial group will receive rTMS over the left dorsolateral prefrontal cortex, conducted using a Rapid2 magnetic stimulator (Magstim, United Kingdom) with a 70-mmdiameter double coil (dynamic air cooling). The stimulation intensity will be 110% of the movement threshold, and the stimulation will be conducted at a frequency of 10 Hz, with 3-second sequences, separated by an interval of 15 seconds. Fifty sequences will be completed during each treatment session (Vion et al., 2018). Each treatment session will be 15 minutes long, and sessions will occur 5 times per week for 4 consecutive weeks.
The control group will receive sham rTMS, where the transcranial magnetic stimulator, the location, and duration of stimulation will be the same as those of the trial group. However, the stimulation will be performed with a pseudo coil that will not cause the depolarization of nerve cells in the cerebral cortex.
Primary outcome measure
Changes in the MATRICS Consensus Cognitive Battery from baseline to post-intervention.
Secondary outcome measures
Relapses of depressive and/or hypomania episode at 12-month follow-up.
[Figure 1] contains a flow chart of the study protocol.
|Figure 1: Trial flow chart.|
Note: MCCB: MATRICS Consensus Cognitive Battery.
Click here to view
The schedule of outcome assessments is shown in [Table 2].
Taking a effect size of 0.4, with a power value of 0.80 at a significance level of α = 0.05, the calculated sample size will be n = 29 per group. Assuming a patient loss rate of 20%, the final sample size will be n = 37 per group, for a total of 74 cases.
The participants will be grouped using a random number table. First, the participants will be numbered according to the order in which they entered the group, starting with a random number selected from the random number table and reading in a randomly-selected direction. Participants assigned an odd number will comprise the trial group and those assigned an even number will comprise the control group.
Each grouping scheme will be placed into an opaque envelope with a code written on the outside. The corresponding numbered envelope will be opened after each patient enters the study. The patient will be intervened according to the scheme in the envelope.
The participants, investigators, and evaluators will be blind to the group allocation. During the trial, except for in the case of serious adverse reactions, the investigators will not conduct unblinding at will. In the case of unblinding, the investigator will immediately inform the supervisor and record the relevant information regarding the unblinding in the case report form, including the time, cause, treatment, and remedy.
This study will be performed in strict accordance with the Declaration of Helsinki formulated by the World Medical Association and relevant national laws and regulations. This trial was approved by the Ethics Committee of The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), China on April 25, 2017 (approval No. 2017022) (Additional file 1 [Additional file 1] ). This trial had been registered in the ClinicalTrials.gov (identifier: NCT03207048) on July 2, 2017. Protocol version is 1.0.
A researcher or designated representative will explain the purpose, methods, risks, and benefits of the study to the patients and their family members, and give them enough time to understand the protocol and decide whether they are willing to participate in this trial. The patients will sign the written informed consent form (Additional file 2 [Additional file 2]) before entering the trial. If new benefits, risks, or side effects are found during the trial, the participants will be informed immediately.
The writing and editing of the study report will be performed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (Additional file 3 [Additional file 3]). 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.
Data will be analyzed using SPSS 23.0 software (IBM, Armork, NY, USA). Normally distributed measurement data will be expressed as the mean ± SD. Non-normally distributed measurement data will be expressed as the lower quartile (q1), median, and upper quartile (q3). Count data will be expressed as percentages. Scores collected at different time points in each group will be compared using a repeated-measures analysis of variance. Scores at the same time point will be compared between the two groups using a one-way analysis of variance and the least significant difference test. The recurrence rate and incidence of adverse events will be compared between the two groups using Pearson’s X2 test or Fisher’s exact test. The significance level (two-sided) will be set at α = 0.05. This trial will be conducted in accordance with the intention-to-treat principle. Interim analysis will be conducted when half of the sample size is met.
Data collection and management
The investigator will timely, completely, correctly, and clearly record the original results/data for each patient into the case report form. After being reviewed and signed by the trial supervisor, all data will be submitted to the data manager in a timely manner. The data will be inputted into the database system by two separate investigators with two computers. If there are any problems with data management, the supervisor will be informed in a timely manner, and the investigator will be required to deal with the problem. Relevant information regarding data management problems will be kept for future reference. After the data entry process has been completed and verified as required, the case report form for each participant will be archived and kept in numeric order in a catalogue for future reference. Electronic data files, including databases, the verification process, the analysis program, analytic results, codebooks, and description documents will be stored in separate categories. Multiple backups will be properly stored on different disks or recording mediums to prevent loss due to damage.
Data quality control
After all of the case report forms have been inputted and verified multiple times, the data manager will write the database inspection report, which includes the list of participants who completed of the study (including the list of participants who dropped out of the study), as well as an inclusion/exclusion criteria inspection, integrity inspection, logical consistency inspection, outlier data inspection, time window inspection, combined medication inspection, and adverse event inspection. Together, the main investigator, representative of the sponsor, inspector, data administrator, and statistician will make decisions regarding the issues raised in the informed consent form signed by the participants, and will write the database inspection report, an audit report, and lock the database. During the trial, the supervisor will regularly visit the research center to examine the progress of the study, and confirm researcher compliance in terms of the research protocols, processes, and regulations by checking the original records and case report forms to ensure that the obtained research data is objective, true, and legal. At the end of the trial, the inspectors will check all of the documents in the research center and archive them.
If the trial protocol or informed consent form needs to be modified, approval will be required from the ethics committee and the details at ClinicalTrials.gov will be updated. The revised informed consent form will need to be authorized by the patient and his or her legal representative.
The clinical trial supervisors at Guangzhou Huiai Hospital will be responsible for checking the trial data, extracting medical records, checking the trial site, and obtaining information from the relevant personnel. Audits will be conducted every six months after the start of the trial. Simultaneously, the trial progress will be reported to the ethics committee, and updated in the registration database.
The research team will strictly protect the privacy of patients. Without authorization, sensitive personal information regarding the patients will not be disclosed.
| Discussion|| |
The results will provide data regarding effectiveness of rTMS on cognitive function and the relapse of mood episode in patients with bipolar disorder.
| Trial Status|| |
Registration time: July 2, 2017
Recruitment time: July 10, 2017–December 30, 2020
Study completed: December 30, 2021
Trial status: Active, recruiting.
Additional file 1: Hospital Ethics Approval (Chinese).
Additional file 2: Informed Consent Form (Chinese).
Additional file 3: SPIRIT checklist.
Study design and manuscript writing: KGL, XH; data collection: WZ. Both authors approved the final version of this manuscript.
Conflicts of interest
The authors declare that the research is conducted in the absence of any commercial or financial relationships that can be construed as a potential conflict of interest.
Institutional review board statement
This study will be performed in strict accordance with the Declaration of Helsinki formulated by the World Medical Association and relevant national laws and regulations. This trial was approved by the Ethics Committee of The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), China on April 25, 2017 (approval No. 2017022).
Declaration of patient consent
The authors certify that they will obtain all appropriate consent forms from the patients or their legal guardians. In the forms, the patients or their legal guardians will give their consent for patients’ images and other clinical information to be reported in the journal. The patients or their legal guardians understand that the patients’ names and initials will not be published and due efforts will be made to conceal their identity.
The writing and editing of the study report will be performed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT).
The statistical methods of this study were reviewed by the biostatistician of Guangzhou Huiai Hospital, China.
Copyright license agreement
The Copyright License Agreement has been signed by the author before publication.
Data sharing statement
Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Data will be available immediately following publication, with no end date. 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.
Checked twice by iThenticate.
Externally peer reviewed.
Open access statement
This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
C-Editor: Zhao M; S-Editors: Yu J, Li CH; L-Editors: Koke S, Stow A, Qiu Y, Wang L; T-Editor: Jia Y
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[Table 1], [Table 2]