https://orcid.org/0009-0007-5158-7568
Abstract
Objective
Increasing number of depression cases, drug tolerability and compliance issues have triggered researchers to actively seek potential alternative treatment modalities. Integrating traditional Chinese medicine (TCM) and Western medicine (integrative medicine) has demonstrated favourable treatment outcomes for depression. However, most studies have focused on single-modality of TCM therapy, and its sustainability has rarely been evaluated. This protocol aims to describe a trial investigating the multi-modality integrative medicine effectiveness while measuring the post-intervention effect sustainability in treating liver stagnation and spleen deficiency in major depressive disorder (MDD).
Methods/design
A total of 318 eligible patients meeting the International Statistical Classification of Disease 10th Edition criteria for MDD and diagnosed with liver stagnation and spleen deficiency will be randomly allocated to receive Western medicine (Group A), Western medicine plus single-modality non-invasive TCM (Group B) or Western medicine plus comprehensive TCM (Group C). Each patient will receive a 6-week treatment; primary outcomes measured will be the overall response rate, changes in both Hamilton Depression Rating Scale 24 and Treatment Emergent Symptom Scale scores 18 weeks after randomisation. The secondary outcomes will include scores on the Pittsburgh Sleep Quality Index, Beck Depression Inventory-II, Health-related Quality of Life scale and Family Burden Scale 0, 3, 6, 10 and 18 weeks post-randomisation. Intention-to-treat analysis will be conducted using repeated-measures analysis of variance and covariance.
Discussion
Because there are various manifestations of MDD from the perspective of TCM, this trial may recommend a customised evidence-based regimen with longer potency for treating liver stagnation and spleen deficiency in MDD.
reviewing editor:
Introduction
Depression is a common mental health disorder associated with high rates of disability, elevated suicide risk, and substantial economic and social burdens (Fanaja et al., Citation2023; Kessler & Bromet, Citation2013; Miret et al., Citation2013). According to the Global Burden of Disease Study, depression accounted for 21.3% of the worldwide disease burden in 2017. Due to the COVID-19 pandemic, this rate has increased to 27.6% due to the pandemic. Moreover, China, which accounts for 18.4% of the global population, is one of the ten leading contributors to this global burden (Amuda et al., Citation2021; Ren et al., Citation2020; Sankova et al., Citation2021; Santomauro et al., Citation2021).
Depression is a mood disorder in which individuals experience persistent sadness and disinterest (Hou et al., Citation2016). Although it is a state of low mood, not all low moods are recognized as major depressive disorder (MDD) (Chand, Citation2022). This study focuses only on MDD, which is a common and prominent psychological disease (Jeong et al., Citation2023). The patient group will be selected according to the diagnostic criteria of the International Statistical Classification of Disease 10th Edition (ICD-10), Code F32 (Vujovic et al., Citation2005). Depression negatively impacts multiple aspects of life, including personal productivity, finances, and socio-occupational functioning (König et al., Citation2019). Hence, the Chinese government has proposed the following goal for the near future – ‘The level of prevention and treatment of common mental disorders and identification and intervention of psychological and behavioral problems will be significantly improved by 2030’ (Zhao, Citation2017). Given the high prevalence of MDD and associated disability rates, research into treatments for MDD is ongoing to contribute to the vision of a healthy China (Askelund et al., Citation2019).
The most frequently employed clinical treatments for MDD in China include antidepressant drugs, psychotherapy, novel device-based therapies, and traditional Chinese medicine (TCM) (Hou et al., Citation2016), but the traditional Chinese medical effective rate is approximately 70% (Madsen et al., Citation2015,Yang et al., Citation2020). Pharmacologically, depression in China is usually treated with drugs such as fluoxetine, sertraline, doxepin, duloxetine, and Rolipram (a PDE4 inhibitor) (Hou et al., Citation2016,Montgomery et al., Citation2014 ,Blum et al., Citation2015). For instance, a previous study compared the results of randomized controlled trials on nine antidepressants for poststroke depression (PSD). Despite the efficacy of these antidepressants, the results revealed that six out of nine antidepressants (escitalopram, mirtazapine, sertraline, citalopram, venlafaxine, and paroxetine) reduced patients’ depression levels (Li & Zhang, Citation2020). Similarly, a meta-analysis of 28,552 studies also demonstrated that 21 antidepressants were more effective than placebo in adults with MDD (Cipriani et al., Citation2018). However, studies have reported side effects associated with antidepressant treatment, including dry lips, constipation, poor appetite, kidney damage, restlessness, and lethargy (Künzel et al., Citation2003,Kronenberg et al., Citation2007). In addition, as most of these studies were conducted in other countries, there is still a lack of evidence for the effectiveness of many antidepressant drugs in the Chinese population (Hou et al., Citation2016).
In TCM, depression is referred to as Yu Zheng (郁证) or stagnation syndrome, which is caused by emotional distress and Qi stagnation (气). Similar to current international descriptions of MDD, the manifestations of Yu Zheng include low mood, insomnia, labile emotions, and somatic symptoms such as restlessness, chest tightness, and chest pain. It is believed that Yu Zheng is caused by anger, liver Qi stagnation, worry and contemplation, spleen dysfunction, and excessive emotions (Hongsheng et al., Citation2011). Liver stagnation and spleen deficiency are the most common features of Yu Zheng and are diagnosed according to The Clinical Diagnosis and Treatment Terminology of Traditional Chinese Medicine (GB/T16751.2-1997) issued by the National Technical Supervision Bureau in 1997 (Rongjuan et al., Citation2015). Liver stagnation and spleen deficiency are usually characterized by distension pain in the subcostal region, emotional depression, poor appetite, low food intake, abdominal distension, and loose stools.
Several TCM modalities are used to treat depression, including acupuncture, moxibustion, and herbal formulas () (Li et al., Citation2021; Liu, Citation2019; Liu et al., Citation2021; Yuan et al., Citation2022; Zhou et al., Citation2021). Apart from the aforementioned single-modality treatment, there is mixed evidence on the comparative efficacy of antidepressant and TCM approaches. In two separate studies, TCM and antidepressants were found to be effective because they increased the proliferation in the hippocampus (Borgsted et al., Citation2022; Malberg, Citation2004; Wang et al., Citation2022). Conversely, some studies have suggested that the Xiaoyao Recipe treatment for PSD is safer and more effective than antidepressants (Wang et al., Citation2022). Similarly, another TCM modality, i.e. acupuncture, was shown to be beneficial because of its fast onset and long-term effectiveness compared with antidepressants.
Table 1. Literature showing recent trials conducted among depressive patients in China.
Given the challenges of using a single TCM modality for treating MDD, exploring an alternative treatment option such as integrative medicine could be beneficial. Therefore, we designed a new treatment method that integrates multi-modality TCM therapies (Chinese herbal medicine, acupuncture, and auricular acupressure) and Western medicine. This study protocol describes a randomized controlled trial to evaluate the effectiveness of this multimodal integrative medicine regimen for treating liver stagnation and spleen deficiency in MDD.
Materials and methods
Study design
A single-center, randomized controlled trial will be adopted in this study. A total of 318 patients are expected to be recruited from Wushan County Hospital of TCM. This is a national second-class, first-class traditional Chinese medicine hospital with 370 employees (including 130 doctors and 232 nurses), 350 beds, and 20 clinical departments in Chongqing. illustrates the flow diagram of this three-arm parallel trial with an allocation ratio of 1:1:1 (McCullough et al., Citation2022). This study has obtained ethical review approval from the hospital and will follow the Declaration of Helsinki (Li et al., Citation2021). This trial has also been registered with the China Clinical Trials Registry at Current Controlled Trials (ChiCTR2200059857).
Figure 1. Flow diagram of the trial.
A flow chart of a randomised controlled trial recruiting three groups of study subjects
Patient recruitment
Patients will be recruited mainly through advertisements on the hospital’s social networking media (WeChat), outpatient clinics, and outreach at community service centers. Patients will be required to meet the diagnostic criteria of ICD-10 F-32 (Vujovic et al., Citation2005). Diagnostic criteria of liver-stagnation and spleen-deficiency type of depression follows the Clinical Diagnosis and Treatment Terminology of Traditional Chinese Medicine (Rongjuan et al., Citation2015). All patients will be required to provide written informed consent before randomization.
Sample size
The required sample size is estimated to be 318 people. The sample size calculation was determined based on the primary outcome, applying the two-mean formula using Power and Sample Size Software. To obtain a power of 0.9, a level of significance of 0.05, a standard deviation of the Hamilton Depression Scale 24 (HAMD-24) score reduction of four units (in accordance with the previous studies (Chen et al., Citation2003,Zhang, Citation2012),, a clinically detectable difference of two-unit scores, and a ratio of one, the minimum sample size required was 85 patients. Considering a 20% attrition rate, 106 patients will be required for each group; hence, the total number of patients recruited will be 318.
Inclusion criteria
Age of subjects: 18–60 years old.
Meet the criteria for the diagnosis of liver stagnation and spleen deficiency in major depressive disorder (MDD) (Rongjuan et al., Citation2015,Castro Gonçalves et al., Citation2022 ,Belica-Pacha et al., Citation2021).
Patients take sertraline hydrochloride (treatment-as-usual at the study site) (Butler et al., Citation2021).
Obtain a score of 8–35 points on the HAMD-24.
Provided consent.
Exclusion criteria
Diagnosed with other severe organic diseases.
Terminally ill patients, including those with severe organ function injury, unstable vital signs, and coma.
Concomitant with other psychotic disorders or long-term multiple medication of psychotropic drugs.
Acute suicidal ideation/attempts.
Substance dependence.
Pregnant or lactating women.
Randomization and allocation concealment
A block randomization design will be implemented. The psychiatrist will use the HAMD-24 score sheet to divide the subjects into three categories of depression: mild, moderate, and severe depression. The recruited subjects who meet the inclusion criteria will be classified according to different degrees of depression. The specific grouping method will be as follows. A block randomization design will be implemented. Each type of subject will be encoded in order. Each patient will be assigned a random number according to a random number table (Rajpurkar et al., Citation2020). For example: if there are 9 patients, it will be that No. 1, No. 7, and No. 9 have mild depression; No. 2, No. 3, and No. 6 have moderate depression; and No. 4, No. 5, and No. 8 have severe depression. Patients with the same degree of depression, ordered according to the size of the random number, will be categorized into groups A, B, and C.
Masking
Due to the therapeutic nature of the interventions (acupuncture, consumption of Chinese herbal drinks, and auricular acupressure), complete masking will be challenging to achieve. Study subjects will not be informed of the grouping treatment plan.
Interventions
As shown in , group A will receive Western medicine (treatment-as-usual), group B will receive Western medicine and noninvasive traditional Chinese medicine (Chinese herbal medicine in liquid form and auricular acupressure), and Group C will receive Western medicine and comprehensive traditional Chinese medicine (Chinese herbal medicine in liquid form, auricular acupressure, and acupuncture).
All study participants will continue taking Western medicine (which is the treatment prescribed at the study site) – sertraline hydrochloride – orally at a dosage of 50 mg once a day. Food has no significant effect on the bioavailability of sertraline hydrochloride (Belica-Pacha et al., Citation2021). The composition of Chinese herbal medicines will include Chai Hu (15 g), Angelica sinensis (15 g), white peony (15 g), Atractylodes macrocephala (15 g), Poria (15 g), ginger (15 g), peppermint (6 g), and roasted licorice (6 g) (Wang et al., Citation2022). These ingredients are certified by the state government and are made into liquid form by Chinese medicine machinery that meets national standards and packaged into small packets (). Chinese herbal medicine will be taken in one pack thrice daily after a meal for six weeks. The liquid sachet must be placed into a bowl of hot water and soaked for 3 minutes before consumption.
Figure 2. Chinese herbal medicines.
Chinese herbal medicines produced by the Wushan County Hospital of Traditional Chinese Medicine in liquid form using sealed vacuumed packaging.
Auricular acupressure, which is applied to the hepatic region of the ear, will be taught to the subjects (Kong et al., Citation2022). Subjects will need to apply pressure for 3 minutes daily for six weeks ()
Figure 3. Auricular acupressure.
Auricular acupressure corresponding to the point of the liver at the ear is located in the middle of the outside of the ear fossa, close to the helix.
outlines the acupuncture points that will be introduced to subjects and practiced for six weeks, five times daily for weeks 1 and 2 and subsequently two times a day for week three until week 6 using selected Yunlong brand needles GB/T4240-2009 (registration number: 20142200226).
Table 2. Acupoints locations.
Outcomes
Primary outcomes
The Hamilton Depression Rating Scale 24 (HAMD-24) will be evaluated by certified medical practitioners. A total of 24 items are included, and the level of depression is evaluated as a total score, with higher scores indicating more severe depression. The total score is used to assess the degree of depression, with higher scores indicating more significant depression. A score of <7 indicates no depression; a score of 7–17 indicates mild depression; a score of >17–24 indicates moderate depression; and a score of >24 indicates severe depression. Analysis of the change in patient scores before and after treatment will be used as one of the criteria for observing efficacy. A study reported that the Chinese version of the HAMD-24 scale to have a reliability of 0.985, implying good reliability in the assessment of depression (Bech et al., Citation1975; Citation2010; Li et al., Citation2006).
The Treatment Emergent Symptom Scale (TESS) will be used to assess the incidence of adverse events related to the treatment. The scale consists of 34 symptoms (the last item is the last symptom that can be included in the above items and its severity rating, i.e. the complementary phase) grouped into six groups of symptoms: adverse behavioral reactions, laboratory tests, neurological reactions, autonomic nervous system symptoms, cardiovascular system reactions, and others. The scale is scored according to two major components, severity, and management. Therefore, scores can be calculated for the severity, management components, and total scale. Higher scores indicate more severe side effects. This scale will be used to assess the safety of the medication. After treatment, a score ≥ 2 points for any item (defined as mild or above) will be considered to indicate an adverse reaction. The reliability of the Chinese version of the TESS scale’s was 0.88 (Licht et al., Citation2005).
Secondary outcomes
The Pittsburgh Sleep Quality Index (PSQI) will assess subjects’ sleep quality in the past month. It consists of 19 self-rated and five other rated items. The total score ranges from 0 to 2l, with higher scores indicating poorer sleep quality. The reliability of the Chinese version of the scale for the study surface PSQI was 0.994 (Chang et al., Citation2020).
Self-reported depression will be assessed using the Beck Depression Inventory-II (BDI-II) (Lu et al., Citation2014). The Cronbach’s α coefficient for the Chinese version of the BDI-II is 0.94, demonstrating its good reliability in self-assessment of the severity of depressive symptoms (Wang et al., Citation2011).
Health-related Quality of Life (HRQoL) will be assessed by the SF-36 questionnaire, which includes 11 items and 36 questions. The reliability of the Chinese version of the SF-36 was 0.90 (Jiang, Citation2019). The questionnaire is self-reported by the patient. As each health concept includes different questions, the raw data must be restored so that the score visually reflects good or bad health, with a high score indicating good health. This questionnaire is used to assess the health status of the patient. This experiment was used to evaluate the impact of different treatment regimens on the quality of life of families.
The Family Burden Scale (FBS) is divided into six dimensions and has 24 items. The scale is a semiquantitative scale that measures the impact of illness on the family in six dimensions: family financial burden, daily family activities, family recreational activities, family relationships, family members’ physical health, and family members’ mental health. The scale is scored on a 3-point scale: 0 indicates no impact, 1 indicates a moderate burden, and 2 indicates a severe burden. The Family Burden Scale has good construct validity for evaluating the family burden of patients. The Chinese version of the FBS has been shown to have high internal consistency with Cronbach’s α coefficient above 0.7 (Guyatt et al., Citation1993,Chen et al., Citation2003). This experiment is used to evaluate the extent to which different treatment options are a burden on families.
Adverse events
Throughout the trial, patients, participating physicians, and outcome assessors will monitor and record any adverse events using a preset form. Depending on their potential association with the intervention, the participating physicians and relevant experts classify adverse events as treatment-related or not within 24 hours (Zhang, Citation2012). Everyday treatment-related adverse events include allergic reactions, dizziness, nausea and vomiting, itchy skin, and pain after needling.
Data management
All study staff, including doctors and statisticians involved in treatment, will be trained in data management. The data collected will be entered into a case report form for each patient. The Clinical Research Assistant is responsible for maintaining these data, keeping them up to date, and ensuring that they are not altered. All paper and electronic study documents will be kept for at least five years after publication. Patients’ personal information, including names, telephone numbers, and identity card numbers, will not be made available to others on a confidential basis.
Statistical analysis
An intention-to-treat (ITT) analysis will be employed. To ensure the reliability and accuracy of this study, all patients will be considered included in the analysis, and the analysis of subjects lost to follow-up will use the most recent data.
Data entry and analysis will be conducted using SPSS 26.0 software. Each follow-up’s measurement data (scores) in different treatment groups will be statistically described by means and standard deviations. The differences between groups will be compared via repeated-measures analysis of variance (RM-ANOVA) and repeated-measures analysis of covariance (RM-ANCOVA).
Discussion
Integrated traditional Chinese and Western medicine treatment can improve the therapeutic effect and reduce adverse reactions more than Western medicine alone (Blum et al., Citation2015; Cipriani et al., Citation2018; Li & Zhang, Citation2020; Montgomery et al., Citation2014). This experiment will prove that the integration of traditional Chinese medicine and Western medicine (integrative medicine) for treating major depressive disorder (MDD) is more effective than a single approach for the treatment of depression.
The trial fulfilled the CONSORT requirements regarding the methodological requirements for adequate randomization and allocation concealment, outcome assessors, and statisticians. All treatment protocols were developed based on data from the literature about Chinese clinical practice. In addition, Chinese herbal medicine, acupuncture, and auricular acupressure were proposed according to current Chinese clinical practice (Zhang et al., Citation2015). The trial protocol will be reviewed and revised by experts, including acupuncturists, psychiatrists, and statisticians. The study’s predetermined intervention protocol, including Chinese herbal medicine, acupuncture, auricular acupressure, outcome assessment, and data management, will be briefed to the staff. Health education will also be provided to patients before, during, and after the intervention to improve adherence. An attempt will also be made to evaluate the outcomes of patients who have dropped out of the study protocol.
There are several anticipated challenges to conducting this trial, including the hurdles for data collection, in which the fluctuating phenomenon attributed to the COVID-19 pandemic might affect subject recruitment, compliance with treatment, and follow-up. In addition, this trial is not a funded research; hence, financial commitment (such as the expenses for medications, traveling, and time off work) might decrease recruitment and increase the dropout rate. Researchers will try to minimize the practical implications while not interfering with the individual autonomy to opt-out or withdraw from the trial.
Examining the effectiveness of multi-modality integrative medicine in treating liver stagnation and spleen deficiency in MDD may allow us to recommend a customised evidence-based regimen with long-lasting effect after completion of the TCM therapies. The framework or outcome of the research may also be extended and contextualized to encapsulate other manifestations of MDD from the TCM perspective. Hence, in line with the country’s focus on treating depression, such treatment approach will reduce the negative impact of depression on society (Guo et al., Citation2020,Zeng & Liu, Citation2016).
Disclosure statement
The authors report there are no competing interests to declare.
Data availability statement
No data has been collected for present protocol paper.
Additional information
Notes on contributors
Yao Song Han
Yao Song Han, is a doctoral student in the medical faculty, Universiti Teknologi MARA. He is a practicing Chinese physician in Wushan County Hospital of Traditional Chinese Medicine with vast clinical experiences. His areas of research interests include application of traditional Chinese Medicine in diseases, particularly in psychiatric illness.
Jo Anne Saw
Dr Jo Anne Saw, is a clinical psychology and senior lecturer with a strong commitment in creating mental health awareness. She excels in clinical practice, research, and teaching in the field of psychology with special interest in adolescence well-being, complementary therapies and medicine, and Cognitive Behavioural Therapy (CBT).
JiangWei Yu
JiangWei Yu, PhD, is the deputy director of the library of Guizhou University of Traditional Chinese Medicine. He is mainly engaged in the informatization and intellectualization of traditional Chinese Medicine diagnosis and the research of traditional Chinese medicine culture.
Xin Wee Chen
Dr Xin Wee Chen, DrPH, is an epidemiologist at the medical faculty, Universiti Teknologi MARA, Malaysia. She is an expert in research methodology and health education on mental health issues. Her research has been on seeking innovative approaches to promote mental health and exploring the role of traditional Chinese medicine in mental disorders.
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