Introduction Sleep disorders including insomnia occur frequently in depressive patients. Acupuncture is a widely recognised therapy to treat depression and sleep disorders in clinical practice. This multicentre randomised controlled trial (RCT) is aimed to investigate the efficacy and safety of electroacupuncture (EA) in the treatment of depression patients with insomnia.
Methods and analysis We describe a protocol for a multicentre RCT. A total of 270 eligible patients in three different healthcare centres in Shanghai will be randomly assigned to one of these three groups: treatment group (EA + standard care), control A group (sham electroacupuncture + standard care) and control B group (standard care). Treatment will be given three times per week for 8 consecutive weeks. The primary outcome is the Pittsburgh Sleep Quality Index. The secondary outcomes are sleep parameters recorded in the actigraphy, Hamilton Rating Scale for Depression score and Self-rating Anxiety Scale score. Daily dose of patients’ antidepressant and sedative-hypnotic medication will be recorded in the dairy. All adverse effects will be assessed by the Treatment Emergent Symptom Scale. Outcomes will be evaluated at baseline, 4 weeks post-treatment and 8 weeks post-treatment, as well as at 1-month, 3-month and 6-month follow-up.
Ethics and dissemination The trial has been approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine (2017SHL-KY-04). Written informed consent will be obtained from all participants. The results of this study will be published in peer-reviewed journals or presented at academic conferences.
Trial registration number NCT03122080; Pre-results.
- complementary medicine
- randomized controlled trial
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Strengths and limitations of this study
This is a strictly designed, single-blinded, randomised controlled trial with long intervention and follow-up period.
Sleep indicators in the actigraphy will be used as objective outcomes of patients’ sleep quality.
We will do comprehensive evaluation about the efficacy of acupuncture treatment.
Rigorous central randomisation and allocation concealment methods will be applied.
This cannot be designed as a double-blinded trial because acupuncturists cannot be blinded to the group assignment.
Depression and its related sleep disorders are becoming serious public health problems worldwide. The global point prevalence of major depressive disorder (MDD) is 4.7%,1 and the estimation of a 12-month cumulative incidence of depression in China is 5.23%,2 causing an urgent need to improve depressive patients’ health. Insomnia may occur in 60%–80% of patients with MDDs3; it is one of the most frequent residual symptoms of depression,4 and may persist even after depressive mood symptoms have been relieved.5
Insomnia is characterised by persistent dissatisfaction with sleep quantity or quality for at least 4 weeks, with specific complaints of difficulty falling asleep, frequent nighttime awakenings and/or awakening earlier in the morning than desired.6It may be triggered by different factors including psychiatric disorders, organic diseases and the intake of drugs or alcohol.7 In fact, depressive symptoms are the largest and most consistent risk factors for insomnia because it affects the normal sleep–wake cycle.8 9 Previous meta-analysis indicated moderate to large effect size (ES) improvement in depression as measured with the Hamilton Depression Rating Scale (ES=−1.29, 95% CI [−2.11 to –0.47]), supporting that treating insomnia by Cognitive Behavioural Therapy for Insomnia (CBTI) in patients with depression is effective and also have a positive effect on mood.10 11 With regard to the current medical conditions in China, the need for CBTI for patients with depression cannot be met. Although selective serotonin reuptake inhibitors (SSRIs) and barbiturates have considerably improved the efficacy and prognosis in the treatment of comorbid depression with insomnia, their side effects such as nausea, vomiting, tolerance, addiction, excessive sedation and neurological toxicity cannot be ignored.12–14 What makes the pharmacotherapy more difficult is that some antidepressant drugs may worsen insomnia or cause daytime sleepiness,15 and high hypnotic dosages for insomnia is closely associated with worsened depressive outcomes.16 In these cases, a drug-free alternative intervention is urgently needed as an effective and safe therapeutic approach for treating insomnia and depression.
Our previous study demonstrated that acupuncture is an effective treatment to improve patients’ sleep efficacy, prolong total sleep time (TST) and relieve patients’ depressive mood.17 The preliminary result of our pilot study18 about the effect of electroacupuncture (EA) for depression-related insomnia showed that the Pittsburgh Sleep Quality Index (PSQI) score in depression patients with EA treatment obviously decreased (from 16.47±1.89 to 9.83±3.11), and there was significant difference between EA and sham electroacupuncture (SA) (p<0.01). Meta-analysis also suggested that acupuncture combined with SSRIs is an effective and well-tolerated therapy for depression and adverse effects of antidepressants.19 However, other studies showed that acupuncture is not significantly effective in relieving residual insomnia associated with depression.20 21 As a result, randomised clinical trials in high quality are needed to evaluate the clinical effects and long-term effectiveness of acupuncture in the treatment of depression-related insomnia.
We planned this patient-blinded, multicentre, randomised and controlled trial with a sufficient observation period in three healthcare centres in Shanghai, China. We aim to observe the effects of EA treatment on sleep status, and eliminate the possible placebo effect by setting reasonable sham methods. All interventions will be administrated by licensed acupuncturists and psychiatrists under the supervision of an independent Data and Safety Monitoring Board (DSMB). The results will help to demonstrate if EA is an effective and safe therapy for improving sleep quality in patients with depression.
Methods and analysis
We hope to provide conclusive evidence to test the hypothesis that acupuncture plus standard care is superior than sham acupuncture plus standard care or standard care alone in treating depression-related insomnia.
This is a multicentre, patient–assessor-blinded, randomised and controlled trial, aimed at evaluating the efficacy and safety of EA for insomnia in depression patients and comparing the effects between EA plus standard care, sham acupuncture plus standard care and simple standard care.
The trial will be performed in three healthcare centres in Shanghai: the acupuncture department in Shanghai Municipal Hospital of Traditional Chinese Medicine, the acupuncture department in Changhai Hospital of Shanghai and the therapeutic department in Shanghai Mental Health Center. We will recruit 270 patients who meet the inclusion criteria and randomly assign them to one of three groups, receiving EA, sham acupuncture and/or standard medical care. After a week baseline, participants will enter an 8-month observation period in this trial. All treatments will be given three times a week (every other day) for 8 weeks. Participants will be assessed at the following time points: the baseline (1 week before treatment), the middle of the treatment (4 weeks after treatment starts), the end of the treatment (8 weeks after treatment starts) and follow-up (1 month, 3 months and 6 months after treatment finishes). All participants will complete the assessments by the PSQI, actigraphy, Hamilton Rating Scale for Depression (HAMD), Self-rating Anxiety Scale (SAS) and Treatment Emergent Symptom Scale (TESS) (detailed trial process seen in figure 1 and table 1). We will follow the Standards for Reporting Interventions in Clinical Trials of Acupuncture22 throughout the trial.
The study will include 270 depression patients with insomnia. To ensure the precision of the results, we developed the following eligibility criteria.
Participants meeting the following criteria will be included:
Male or female participants aged 18–70 years.
Participants who meet the diagnostic criteria of depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.23
Participants whose HAMD score is 20–35 (mild-to-moderate depression).
Participants who have taken the same antidepressants for >4 weeks or have not taken antidepressants.
Participants who complained about insomnia during first screening.
Participants whose PSQI score is >7.
Participants who have not received acupuncture treatment for at least 1 year.
Participants who voluntarily agree with the investigation and sign a written informed consent form for the clinical trial.
Participants who report any of the following conditions will be excluded:
Participants with secondary depressive disorders caused by organic diseases, medicine or psychotic disorders.
Participants who are in the depressive episode of bipolar disorder, or suffering from dysthymia, reactive depression and depressive syndrome caused by other diseases.
Participants who had severe diseases of the cardiovascular or hematopoietic systems, or had severe hepatic or renal insufficiency.
Participants with a history of alcohol abuse or drug dependence.
Participants who refuse to wear the actigraphy during the trial.
Pregnant or lactating women.
The participants will be recruited through hospital-based advertisements from outpatient clinics and from official websites of all three healthcare centres. If depression patients have interest in participating in the trial, they can take the phone screening first and then will be asked for face-to-face screening in any of the three healthcare centres where they need to fill in some forms with guidance from psychologists or doctors with professional training. Participants then will be asked to wear a wrist actigraphy to monitor their sleep quality for 3 days. Once the participants meet the inclusion criteria, they will be asked to sign the written informed consent form before intervention begins. Before intervention, we will incorporate the expectation questionnaire which is modified from Vincent’s four questions24 to value patients’ anticipation of acupuncture treatment. Patients will be asked to rate their expectations of the treatment from very pessimistic to very optimistic, in on a 5-point Likert scale.
Sample size calculation
The sample calculation is based on changes in the primary outcome of this trial, the PSQI score. In our previous trial, we also used PSQI score as the primary outcome to evaluate and compare the effects between acupuncture, superficial acupuncture at sham points and sham acupuncture on treating depression related insomnia.18 According to the preliminary results, the PSQI score of the acupuncture group at the end of the 8 weeks’ intervention was 9.83 ± 3.11 and that of the sham acupuncture group was 13.93 ± 3.22. We assumed 0.2 of the PSQI difference is the superior effect.
H0: A-B<= but H1: A-B>
We used the following formula to calculate the sample size in this trial:
where δ is the difference between group, Δ is the assumed superior effect threshold and N is the estimated sample size of each group. σ is the
According to the previous study,25 the minimal clinically important differenceof PSQI is about 1.14–1.75. Since there will be a comparison between the treatment group and the control A group as well as a comparison between the treatment group and the control B group, a sample size of 27 in each group will have a power of 90% to detect the superior effect of 1.5 of PSQI at an α-value of 0.025 and a β-value of 0.1. Assuming a 10% dropout rate, a sample size of 30 for each group is needed. For a better power and quality control among centres, we decided the recruiting sample size to 30 for each group in each healthcare centre. As a result, the total number of participants needed to be randomised is 270.
Randomisation and blinding
An online random allocation system will be designed by the central randomisation system with a 1:1:1 ratio, using the Pocock and Simon minimisation method.26 Staff of Shanghai BioGuider Medicinal Technology Co. (Pudong New District, Shanghai) established the data analysis system for the Electronic Data Capture V.5.0 system and prepared the randomisation database. They offered technical support for the central randomisation service and are not connected with the study. The system is based on the Internet Information Server V.5.0 as the Web Server, the SQL Server 2000 as the Database server and the Active Server Page as the scripting language.27 Central randomisation has strict limits of authority; only researchers and the specialists from the DSMB in this trial have access to the system. If the participant meets the inclusion criteria and agrees to join in the trial, a researcher who is not involved in the intervention in each healthcare centre will login in to the central randomisation system with his own username and password, enter the participant’s personal information and then get the randomised number and the group assignment. The patients’ personal information will be protected and keep confidential to the acupuncturists and the assessors before, during and after the trial.
We will conduct a patient–assessor-blinded trial where participants are not aware of their group assignments and acupuncturists will not be involved in the outcome assessment or data analysis. Participants will be informed that they have an equal chance of allocation to the three groups. Participants who are assigned to the EA or SA will be treated in a closed unit to avoid communication. Furthermore, they will be asked to wear eye masks before and during the trial. Since there are inserted needles around participants’ wrist joints, they will not be able to move their hands easily and cannot take off the eye masks. With these methods, participants will not be aware of the difference between EA and SA. To test the success of blinding, all participants in three centres will be asked by their acupuncturists whether they received EA or SA treatment at the end of treatment. Except the acupuncturists, other researchers including the statisticians, outcome assessors and data analysts are all blinded to the group assignments. All researchers will receive training on the specifications of this research method before the trial and strictly adhere to the task separation principle.
Participants in treatment group and control A group will receive EA or SA treatment. Participants in these two groups will receive 24 sessions of different treatments, three times a week for 8 weeks. EA or SA treatment will be performed after skin cleansing, with patients wearing eye masks and lying supine. Each treatment will last for 30 min. The temperature of the treatment room cannot be lower than 25°C.
Considering the participants’ psychological state, participants in all three groups can continue regular administration of antidepressants, sedatives, hypnotics or anxiolytics during the trial. They must record the dose, especially when they reduce the amount; and dose escalation will not be allowed unless the patient has consulted the psychiatrist. The patients will not be withdrawn the trial by changing the dose of the drug.
Participants in the treatment group will receive EA treatment. The acupuncture method of each acupoint is shown in table 2. The regular acupuncture method will be applied at Baihui (GV20), Shenting (GV24), Yintang (GV29), bilateral Anmian (EX-HN22), Shenmen (HT7), Neiguan (PC6) and SanYinjiao (SP6). The acupuncture needles are produced by asia-med GmbH & Co. KG (seen figure 2), with the same appearance as those used in sham acupuncture treatment. After needle insertion, rotating manipulation or lifting-thrusting manipulation will be applied for ‘Deqi’ sensation. Two electrodes of the electro-stimulator (CMNS6-1, Wuxi Jiajian Medical Device CO., China) will be connected to the needles at Baihui (GV20) and Yintang (GV29) for 30 min, delivering a continuous wave. The frequency will be set to 30 Hz with a current intensity of 0.1–1 mA during the treatment, based on the tolerance of each patient.
Control A group
Participants in the control A group will receive SA treatment at the same acupoints as the treatment group. Sham acupuncture will be applied with the placebo needles (Streitberger Placebo needle, asia-med GmbH & Co. KG, seen in figure 2)28 29 that have been successfully used in our previous study.17 18 When the tip of the blunt needles touches to the skin, the patient will get a pricking sensation but there is no real needle inserted into the skin. The electro-stimulator will be set beside the patients and two electrodes will be connected to the needles at Baihui (GV20) and Yintang (GV29). Acupuncturists will turn on the electro-stimulator, but all indicators will be set to ‘0’. Participants will be informed when removing the needles after 30 min. Acupuncturists will use dry cotton balls to press the acupoints so that patients can feel the withdrawal of the ‘needles’.
We are aware that some of the published trials show that non-needle insertion Streitberger sham device may also have non-specific effect which may lead to ‘negative’ results. However, this is the most appropriate control for a randomised patient-blinded controlled trial at present. Our previous study on acupuncture for primary insomnia show that acupuncture was superior to the non-insertion sham control.17 Therefore, we are confident that the non-specific effect of Streitberger sham device will be minimised.
Control B group
Standard care (also known as treatment-as-usual or routine care) in randomised controlled trials (RCTs) is frequently employed as the control condition to establish if the intervention is a significant improvement over existing practice.30 In this trial, we set control B group as the standard care group to investigate the differences between EA treatment group and the blank control group so that the effects of EA for insomnia and depression will be observed more clearly. All 90 participants in three healthcare centres in control B group will continue taking in their routine antidepressants and/or sedative-hypnotics as before from baseline to 8 weeks. After finishing all the required scales and actigraphy records, they will get 10 sessions of free acupuncture treatment for insomnia.
The PSQI is a widely used questionnaire with 19 items to assess sleep quality and disturbances over a 1-month interval.31 Four open-ended questions are followed by closed-ended questions that are rated on a 4-point Likert scale. The scores include the following indicators: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency (SE), sleep disturbances, use of medication and daytime dysfunction. The accumulated scores of the seven indicators constitute the total score (ranging from 0 to 21). A higher score indicates worse sleep quality and more severe sleep disorders.
The actigraphy (wActiSleep-BT. LLC, Pensacola, Florida, USA) worn on the patient’s wrist can monitor the sleep quality, such as sleep onset, sleep latency, duration, awakenings during the night, etc. The software ActiLife6 V.6.8.1 (ActiGraph, LLC) will be used to analyse every participant’s sleep condition recorded in the actigraphy. The indicators used in our trial will be SE, sleep awakenings and TST.
The HAMD is an observer-rating questionnaire with 17 items used to assess the symptoms of patients diagnosed as suffering from depressive states.32 Each item is rated in 3-point or 5-point scales. A higher total score indicates a higher depression level.
The SAS is primarily used as a measure of somatic symptoms associated with anxiety.33 In using the scale, the participant will be asked to rate each item from 0 to 3 points according to how it applies to him or her within the past week. The standard score is the sum of the integer part of 1.25 times the raw score of the 20 items. A standard score of >50 points means the subject has anxious symptoms. A higher score indicates a more serious case of anxiety.
The dose dairy is a notebook where participants will be required to record their daily dose of antidepressants or sedative-hypnotics from baseline to 6-month follow-up, as well as the dosage time.
Any adverse events (described as unfavourable or unintended signs, symptoms or diseases occurring during the trial) related to the administration of antidepressant and sedative-hypnotics must be reported by patients and practitioners. These adverse events will be recorded in the TESS.34
For the adverse events related to the acupuncture treatment, the most common ones include bleeding, faint, bruising ecchymoma and serious pain. These AE data will be assessed in terms of severity and causality, and the incidence will also be determined. The 3-point grading categories will be applied: grade 1, mild, grade 2, moderate, grade 3, severe or medically significant. The causality categories used will be certain, probable/likely, possible, unlikely, conditional/unclassified and unassessable/unclassifiable. The incidence of AEs was presented as the number of AEs per number of acupuncture sessions (%).
The statistical analyst will be blinded to the participants’ personal information and their group assignment during the trial. The primary analysis will be a comparison of the changes of patients' PSQI score among three groups at 8 weeks after inclusion (comparison of the primary endpoint). The secondary analysis will be performed to assess the changes of the SE, TST and sleep awakenings recorded in the actigraphy, as well as the HAMD scores and SAS scores from baseline to 8 weeks after inclusion. We will also count the number of patients who increase or decrease the drug dose, and then analyse the differences among three groups. All analyses will be performed on the intention-to-treat population of participants who have at least one treatment. Missing data will be handled using the multiple imputation method, on the assumption that values at each time point follow a specific distribution calculated by the computer software R V.3.5. We will also perform a complete-case analysis without imputation of missing data, to find out if the results are consistent. Data analyses will be performed with the use of the statistical software SPSS V.20.0. The t-test will be used to compare the measurement data between either two groups from the baseline to 6-month follow-up; the rank sum test will be used for ranked data while the χ2 test will be used to analyse categorical data. The significance level that will be used for statistical analysis with two-tailed testing will be 2.5%. Data values will mainly be presented as mean ± SD.
Patient and public involvement
Depression patients with insomnia in the clinical department were consulted by the main researcher prior to the trial design. The treatment frequency and duration of this study were summarised from clinical experience and patients’ feedback. We will recruit all participants from the outpatient clinics in three healthcare centres. Patients who were involved in the consultation about the trial design before will not be recruited as participants. A journal article manuscript will be written to present the results after the trial completed, and a brief summary of results with plain language will be sent to all participants. The burden of intervention will not be assessed by participants themselves.
Ethics and dissemination
All acupuncturists are licensed doctors with 3–5 years of experience in acupuncture treatment; and they will join in the clinical training before the intervention to ensure the standard real and sham acupuncture operation in three centres.
To guarantee the quality of the study, this trial will be carried out under the supervision of an independent DSMB. The DSMB consists of three experts from different fields: Professor Bingshun Wang in medical statistics from the School of medicine at Shanghai Jiaotong University, Dr Lin Sun in psychology from the Department of Geriatrics at Shanghai Mental Health Center and Professor Xueyong Shen in acupuncture from the Acupuncture College at Shanghai University of Traditional Chinese Medicine. The DSMB works to identify problems in the project, examine collected data and control bias. Researchers in each healthcare centre will promptly input data on the website (https://ecdm2.drugchina.net/crct2/) so that members in the DSMB can supervise the process at any time. Once they find problems or serious adverse events during the intervention, they can raise objections directly and even stop the trial until the problem has been resolved. Meanwhile, a qualified clinical trial expert (Lixing Lao) will be invited to monitor this study.
The results of this study will be published in peer-reviewed journals or presented at academic conferences.
Acupuncture has been used to treat insomnia and some mental disorders since antiquity in China. According to the theory of traditional Chinese medicine, acupuncture provides balance to the body by stimulating specific acupoints, helping the body to achieve a state of relative equilibrium (the harmony of ‘yin-yang’), thereby restoring the normal sleep–wake cycle.
Previous RCTs always focus on either the acupuncture treatment for insomnia or that for depression, ignoring the relationship between these two diseases. Insomnia has been identified as the most common sleep disorder comorbid to depressive disorders35; so a reasonable acupuncture treatment programme should be developed to normalise sleep disturbance and to relieve depressive mood as well. At the time of this writing, there are no similar RCTs about acupuncture for insomnia in depression patients that included a large sample size and were conducted in multiple healthcare centres. Our trial intends to present a strictly designed trial to study the effects of EA on insomnia in depression patients and to overcome some existing limitations, including illogical design, imperfect blinding method and practical difficulties in previous acupuncture clinical researches. With a long follow-up period, we will be able to explore the persistent effects of acupuncture for insomnia and determine for how long the therapeutic effect will last.
For patients in the EA group, we decided to use EA at Baihui (GV20) and Yintang (GV29), with the frequency set to 30 Hz during the treatment. According to the traditional Chinese medicine (TCM) theory, GV20 is the convergent point of six yang meridians as well as the foot Jueyin meridian; it is located on the top of the head, governs yang qi of the body and is the key point of calming mind. GV29 promotes the circulation of qi and blood in the head and restores the function of brain. EA at GV20 and GV29 enhances the effect of soothing nerves. In addition, a functional connectivity MRI (fcMRI) study suggested that EA at GV20 and GV29 may have effect on mental disorders.36 Using fcMRI to identify the key cerebral functional region affected by EA at GV20 and GV29 found that the centre of the cerebral network changed from the caudate nucleus to the parahippocampal gyrus and hypothalamus. The network centred on the parahippocampal gyrus and hypothalamus primarily functioned in somatic movement, sensation, vision, hearing and language. This finding may indicate a mechanism for treating depression using EA at GV20 and GV29.
A frequency-specific neurochemical response in the central nervous system may be related to differential response of the body to low-frequency and high-frequency EA stimulation and different peripheral and central pathways.37 Previous research found that low-frequency EA could be useful in clinical settings to manage pain38 while high-frequency stimulation has more potent effects on 5-hydroxytryptamine (5-HT) activity.39 Thirty hertz separates the continuous wave of the electro-stimulator from disperse wave to dense wave and we chose 30 Hz based on an acupuncture textbook.40
Considering the complicated mental state of depression patients with insomnia, we will apply standard medication instead of unified antidepressants or sedative-hypnotics in this trial. Participants in all groups will continue taking in their individual routine dosage from baseline to 6-month follow-up. If their conditions obviously change during the study, they will be free to consult our psychologists from Shanghai Mental Health Center to adjust the dose. The use of standard care control groups has been the subject of much debate, with some pointing out that what constitutes standard care is unclear.41 42 For better implementation of the standard care, researchers in our trial will try to carry out proper health education for all patients and supervise them in recording their daily medication dosage.
As a multi-centre RCT conducted in a first-tier city, our study can provide more representative results about the role and value of acupuncture as a complementary and alternative therapy for insomnia and depressive moods than other single-centre RCTs.
Considering the high prevalence of insomnia and depression in rural areas in China,43 44 the correlated heavy economic burden and serious public health problems cannot be underestimated. In future studies, the focus might be on the acupuncture treatment for insomnia in nationwide healthcare centres.
This clinical trial is now recruiting participants.
The authors would like to thank Dr Andrew Zeng, from the International Education College, Shanghai University of Traditional Chinese Medicine, for his editorial support. The authors are also grateful to Bojuan Feng as a patient representative, for providing her experience as an insomnia patient with depression to the design and detail of this study, and to other patient advisers.
Contributors SX is the main researcher who provided conception, design of the study and contributed to the final approval of the manuscript. LL is the coresearcher who contributed to the design of the study and critical revision of the manuscript. XY contributed to the design of the protocol, writing and review of the manuscript. BD, TL and XLin contributed to the manuscript draft. PY and XQ contributed to the statistical design. XLi and SZ are the project managers for the design of the randomisation. All authors read and approved the final manuscript.
Funding This work was supported by Shanghai Hospital Development Center, grant number (SHDC12016124) and by Shanghai Municipal Commission of Health and Family Planning, grant number (201640026).
Competing interests None declared.
Ethics approval The trial has been approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, China (2017SHL-KY-04).
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Obtained.
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