Edited by: Toru Takahata, Zhejiang University, China
Reviewed by: Xuan Yin, Shanghai University of Traditional Chinese Medicine, China; Fang Zeng, Chengdu University of Traditional Chinese Medicine, China
*Correspondence: Yongjun Chen,
This article was submitted to Mood and Anxiety Disorders, a section of the journal Frontiers in Psychiatry
†ORCID: Haixiong Lin,
‡These authors have contributed equally to this work
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Sub-threshold depression is common and could impair function, as well as increase the risk of developing major depression. Despite evidence of efficacy for electroacupuncture (EA) and counseling in the treatment of sub-threshold depression, the sample size is insufficient and the level of evidence remains low. This study aims to evaluate the effectiveness of sub-threshold depression treatments by comparing the treatment effects among EA, counseling, and combination therapy, as well as to further study their mechanism.
This study is a multicenter, randomized, single blind clinical trial that will be conducted in settings at four clinical centers in China. The randomized controlled trial (RCT) will examine the effectiveness of EA intervention, compared with counseling and combination therapy. A total of 138 sub-threshold depression patients (18 to 55 years of age with Beck Depression Inventory (BDI-II) score ≥ 14 points and Hamilton Depression Scale (HAMD-17) score: 7 points ≤ HAMD total score <17 points) will be recruited. The participants will be randomly assigned to receive the above treatments. The interventions will be delivered over a 6-week period (EA: 3 times a week for 6 weeks; 30 min a session. Counseling: once a week for 6 weeks; 50–60 min a session). The primary outcome measure will be the HAMD-17; BDI-II. The secondary outcome measures will be: Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS), and Pittsburgh Sleep Quality Index (PSQI). The assessments will occur at baseline, 2, 4, and 6 weeks and a follow-up period. Recruitment will commence in March 2020 and is anticipated to occur over a 2-year period.
This study intends to conduct a multicenter randomized controlled trial to compare the effectiveness among EA, counseling and the combined therapy in the treatment of patients with sub-threshold depression, and to further study the mechanisms of effect.
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Sub-threshold depression is commonly referred to as “subsyndromal depression” or “minor depression,” and it is mainly characterized by depressive symptoms for at least 2 weeks that fall short of full diagnostic criteria for major depressive disorder (MDD) or dysthymia (
Intervening at an early stage could help relieve symptoms and reduce the risk of major depression as well as prevent progression to other undesirable outcomes (
Therefore, this study intends to conduct a multicenter randomized controlled trial to compare the effectiveness among EA, counseling and the combined therapy in the treatment of patients with sub-threshold depression, and to further study the mechanism of EA and counseling in the treatment of sub-threshold depression, which will provide more options for the treatment of sub-threshold depression, and provide possible solutions for better efficacy.
This protocol was designed according to the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) 2010 checklist (
We suspect that EA could alleviate the clinical symptoms of patients with sub-threshold depression as well as counseling. If EA is not only the placebo, the combination therapy will have a better effect, and may reduce the risk of conversion from mild to severe, as well as help determine whether patients with sub-threshold depression will need multiple therapies in the future. If acupuncture does no effect, the combination group will have the same clinical effect as the counseling group. Therefore, the objective of this trial is to evaluate the effectiveness of sub-threshold depression treatment by comparing the effects among EA, counseling, and combination therapy, as well as to further study the mechanism of EA and counseling.
This study will be a multicenter, randomized, single blind clinical trial with three treatment groups (EA, counseling, and combination therapy). The flow chart in
Flow chart of study design.
Investigators will conduct the trial in four hospitals in Guangzhou, China. These four hospitals are: The First Affiliated Hospital of Guangzhou University of Chinese Medicine; Affiliated Brain Hospital of Guangzhou Medical University; Guangdong Provincial Hospital of Chinese Medicine; and Guangdong Sanjiu Brain Hospital.
As a single-blinded trial, only outcome evaluators and statistical analysts will be blinded to treatment group. Evaluators and statistical analysts will not be allowed to participate in the treatment process of subjects and will be forbidden from knowing the grouping of subjects. Trial grouping information will be open to subjects, physicians, and data collectors. The analysts will generate a randomized sequence, only known by him or her, to allocate subjects accordingly to ensure the randomization of the grouping. The analyst will be responsible for the preservation and confidentiality of information and data and will prepare a backup of both electronic devices and paperwork. Special personnel will be in charge of those data and documentation. In addition, to ensure strict implementation of the blinded method in the test and reduce the bias of conclusions, physicians (psychologists and acupuncturists), outcome evaluators, data collectors, and statisticians will all be independent of each other and will have no communication during the test.
Independent statisticians will use the block randomization method with SAS version 9.4 (SAS Institute. Inc., Cary, NC) to create a randomization table for each hospital. Randomization numbers will be sealed in opaque, sequentially numbered envelopes, and sent to each participating hospital (
Participants will be recruited by advertisement and doctor referrals from psychology department clinics. Interested individuals can contact research assistants by email or phone. A series of criteria and prerequisites will be sent to the prospective volunteers for filtering the most eligible subjects. First, registration information and pre-selection query forms with Self-rating Depression Scale (SDS), Pittsburgh Sleep Quality Index (PSQI), and Self-rating Anxiety Scale (SAS) will be sent to registered volunteers. Volunteers will be required to complete the form as a first-round selection prior to scheduling a first visit. This visit will further screen and evaluate a volunteer's eligibility according to inclusion criteria (
Inclusion criteria.
| No | Item | Answer |
|---|---|---|
| 1 | 18<age<55 | □Yes |
| □No | ||
| 2 | Presence of ≥ 1 but < 5 symptoms required for the diagnosis of major depression as detailed in the Diagnostic Statistical Manual of mental disorders (DSM-V), including loss of enjoyment/interest, marked tiredness or reduction of energy, agitation or psychomotor retardation, feelings of worthlessness or guilt, sleep disorders, reduced concentration, loss of appetite and body weight, loss of libido, recurrent suicidal thoughts; | □Yes |
| □No | ||
| 3 | symptoms lasting at least 2 weeks | □Yes |
| □No | ||
| 4 | BDI-II score≥14 points ( |
□Yes |
| □No | ||
| 5 | HAMD-17 score: 7 points ≤ HAMD total score < 17 points ( |
□Yes |
| □No |
Exclusion criteria.
| No | Item | Answer |
|---|---|---|
| 1 | Patients diagnosed with depression, previous mental illness, or organic mental disorders | □Yes |
| □No | ||
| 2 | Patients suffering from serious diseases such as heart, brain, liver, kidney, or hematopoietic system disease | □Yes |
| □No | ||
| 3 | Women during pregnancy and lactation or women of childbearing age who have fertility intentions | □Yes |
| □No | ||
| 4 | Patients with depressive episodes caused by psychoactive substances and non-addictive substances | □Yes |
| □No | ||
| 5 | Patients prescribed other drugs or therapies for treating depression during the trial | □Yes |
| □No | ||
| 6 | Individuals addicted to alcohol or other drugs | □Yes |
| □No | ||
| 7 | Patients with strong suicidal ideation | □Yes |
| □No | ||
| 8 | Patients who are participating in other clinical trials at the same time | □Yes |
| □No | ||
| 9 | Patients who have undergone antidepressant treatment within 1 week before the test | □Yes |
| □No | ||
| 10 | Skull defects in the acupuncture site, or a surgical scar or skin infection that affects the treatment | □Yes |
| □No | ||
| 11 | Patients who are allergic to acupuncture or faint when they are stuck with needles | □Yes |
| □No | ||
| 12 | Age older than 55 years or younger than 18 years. | □Yes |
| □No |
Misdiagnosis;
Those who fail to follow the prescribed treatment or for whom there is incomplete data that would affect the efficacy evaluation and safety evaluation;
Subjects with poor compliance, or who use self-administered antidepressants and sleeping pills during the course of treatment, or change the treatment method on their own.
Fail to adhere to the treatment requirement;
Cases with serious adverse events that are not suitable for continued treatment;
Serious clinical complications that occur in other clinical trials;
The progression of disease during treatment.
Sample size estimation uses a completely random design to compare multiple sample means. Target sample size was estimated using the PASS11 version, 1-β = 0.9, α = 0.05. According to a previous study (
According to the diagnostic criteria, inclusion criteria, and exclusion criteria, a total of 138 patients with sub-threshold depression will be randomly divided into three groups: EA group, counseling group, and combined therapy group.
Participants will receive 24 sessions of acupuncture treatment (three times a week for 6 weeks; 30 min a session;
Procedure of EA and operation parameters.
Sub-threshold depressed participants will receive individual counseling (once a week for 6 weeks; 50–60 min a session). Counseling will be performed by licensed psychologists with more than 3 years' experience and will be conducted in the psychiatric department of the hospital. Before the trial, the psychologists will receive brief training in counseling and conduct counseling activities based on a treatment manual designed by
Participants will receive 24 sessions of EA treatment (three times a week for 6 weeks; 30 min a session) combined with individual counseling (once a week for 6 weeks; 50–60 min a session). Treatment details are the same as the EA and the counseling mentioned above.
Patients will be discouraged from any extra treatment beyond this trial requirement. If this trial does not show an obvious effect after 2 weeks of treatment (HAMD 17 scale score maintained at 7–17 points), or a patient's symptoms have worsened (HAMD 17 scale score > 17 points), we will then consider drug intervention to ensure the safety of the patients. At this point, participants will be forced to stop the trial, and relevant data will be analyzed for intention-to-treat (ITT). Prescription drugs will be assessed under the guidance of a psychiatrist. Such assessment will need to fully consider the physiological characteristics of patients, including age, physical condition, drug tolerance, presence or absence of comorbidities, and prescribing based on guidelines for depression or relevant clinical consensus.
The progress and safety data of the clinical trial will be monitored and managed by an independent Data and Safety Monitoring Committee. The committee will remind participants to report any undesirable and unexpected experiences, whether related to the intervention or not, to the research team at any time during the trial. In addition, the time of occurrence, severity, management, and outcome of these adverse events will need to be recorded on the case report forms. Common adverse events related to EA are fainting during acupuncture, local hematoma, local infection, stucking of needle, broken needle, or bending of needle. The main causes of these adverse events include poor disinfection, improper operation, improper use of needles, and unexpected reactions from patients themselves. The research team will need to explain the work to the patient before starting acupuncture. To achieve proficiency, we will conduct training about acupuncture therapy for acupuncturists. In the case of an adverse event, the researcher, in addition to providing an immediate positive treatment to the patient, will be required to complete an adverse event report and escalate the case to the staff in charge of the research center and the responsible unit for clinical research. All adverse events will be followed up from the reported date until the incident is resolved. According to the WHO Uppsala Monitoring Centre System for Standardized Case Causality Assessment, the research team will evaluate the causality between adverse events and interventions (
The primary outcome measure is the HAMD-17 and BDI-II. Evaluation timelines are set as: before treatment, and the second, fourth, and sixth weeks of the treatment. HAMD-17 and BDI-II are widely used in the diagnosis and outcome evaluation of depression. The range of the HAMD-17 score is 0 to 52, with 25 scores or more indicating severe major depressive disorder, 18–24 scores indicating moderate, 7–17 scores indicating patients may have mild depression, and 0–6 scores indicating normal (
Statistical analysis will be performed by qualified statisticians in a blinded manner using Statistical Product and Service Solutions (SPSS) software (IBM Corporation, Version 21.0). An ITT analysis will be performed. The baseline comparability of the three groups will be assessed on demographic and clinical characteristics, as well as baseline data. Analysis of variance will be used to compare the mean changes between groups from baseline to each time point. The withdrawal of any subjects from clinical trials will be statistically described one by one. The missing data of a withdrawn patient will be randomly filled with the filling method based on the principle of multiple imputations (
All types of instruments, equipment, and reagents used for various inspection items in clinical trials will have strict quality standards, to ensure a smooth workflow. Prior to recruitment, every member of the research team, including psychologists, research nurses, and acupuncturists, as well as research assistants in all centers will be required to take part in a training workshop. This requires all personnel to adhere to the research protocol and be familiar with the clinical trial management process. Acupuncturists who perform the treatment will be required to have a certificate as a certified physician issued by the Ministry of Health of the People's Republic of China and have more than 3 years of practical clinical experience. All observation results and abnormal findings in the clinical trial will be carefully verified and recorded on time to ensure the reliability of the data. Research assistants will oversee data collection and constantly check data quality. The various conclusions of the clinical trial must be derived from raw data. To reduce the withdrawal of patients, it will be necessary to streamline the trial procedure, follow-up on time, have good communication with patients, and issue subsidies in a timely manner. As for the dropout rate, whether it occurs during the treatment phase or the follow-up period, the reason should be stated, and the dropout rates should be statistically analyzed.
Depression results in a heavy burden on medical care, severe consequences for society, and huge psychological and health burdens on patients (
EA has been widely used to treat different psychiatric conditions, including depressive disorder (
In terms of clinical outcome assessment, we selected HAMD-17, BDI-II as the primary indicator, and SDS, SAS, and PSQI as the secondary indicators. HAMD-17 was developed by Max Hamilton in 1960 to assess the severity of depressive symptoms (
Some of the key technical issues that need to be addressed in this trial are: (1) in view of the current problems in the treatment of subthreshold depression, this study will explore whether acupuncture could be used as a new non-drug therapy to avoid the deterioration of subthreshold depression and promote the effect of counseling. (2) Determining the value and advantages of acupuncture treatment (effectiveness, onset time, duration of maintenance, side effects, patient compliance, and economic burden). (3) We will establish a biological sample bank before and after acupuncture treatment for patients with subthreshold depression for use in future research.
Our study has some limitations. First of all, in terms of grouping, we cannot achieve double blindness, because acupuncture and counseling belong to different fields, so it is difficult to implement blindness for patients. Second, as all research centers are located in China, it may not be possible to recruit participants from other regions or countries, so the validity of different races needs to be further verified. Thirdly, since the follow-up period is only 12 months, information about long-term prognostic assessment cannot be provided.
This study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Affiliated Brain Hospital of Guangzhou Medical University, Guangdong Provincial Hospital of Chinese Medicine, and Guangdong Sanjiu Brain Hospital (NO. ZYYECK YJ [2019] 068). Written informed consent to participate in this study will be provided by the participants.
This protocol was first conceived by YC, JH, DL, and LY with critical contributions from the other authors. XW and HL drafted the protocol, designed the picture, and submitted the registration on Chinese Clinical Trial Registry. MM, DS, CF, SW, XJ, and YS revised the manuscript and provide advice. All authors contributed constructive comments on the paper and approved the final protocol.
This work was supported, in part, by Science and Technology Program of Guangdong (2018B030334001); National Natural Science Fund of China (81973948); Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme [2016]; Innovation Team Program of Guangdong Provincial Department of education [grant number 2018KCXTD006]; Grant of Guangdong Province Key Laboratory of Psychiatric Disorders [grant number N201801] and Excellent Doctoral Dissertation Incubation Grant of Guangzhou University of Chinese Medicine (No. GZYXB[2020]18).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All authors thank Junjie Feng, a master of Chinese medicine from the First School of Clinical Medicine of Guangzhou University of Chinese Medicine, for his help in drawing
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