Chinese Medicine for Major Depressive Disorder: Clinical Evidence, Patients’ Experience and Expectations, and Doctors’ Perceptions

A thesis submitted in fulfilment of the requirement for the degree of

Doctor of Philosophy

Lingling Yang

BMed, MMed (Beijing University of Chinese Medicine)

School of Health and Biomedical Sciences

College of Science, Engineering and Health

RMIT University

December 2019

Declaration

I certify that except where due acknowledgement has been made, the work is that of the author alone; the work has not been submitted previously, in whole or in part, to qualify for any other academic award; the content of the thesis is the result of work which has been carried out since the official commencement date of the approved research program; and any editorial work, paid or unpaid, carried out by a third party is acknowledged; and, ethics procedures and guidelines have been followed. I acknowledge the support I have received for my research through the provision of an Australian Government Research Training Program Scholarship.

Lingling Yang

05 December 2019

Acknowledgements

Firstly, I would like to express my sincere gratitude to my supervisors, Professor Charlie

Changli Xue, Associate Professor Anthony Lin Zhang, Dr Johannah Linda Shergis and

Professor Yan Li, for the invaluable supervision of my PhD study and related research, for their patience, motivation and immense knowledge. My sincere thanks go to Professor Chuanjian

Lu, Professor Yubo Lv, Professor Xinfeng Guo and Professor Zehuai Wen for their continuous support of my PhD study. I am grateful to Dr Yuan Di, who has provided me moral and emotional support during my study. Special thanks go to Dr Meaghan Coyle for always giving me valuable advice. I also thank Dr Jingjie Yu for his assistance in this research.

I would like to thank the candidature milestone panels for their insightful comments and encouragement, also for their challenging questions which encouraged me to refine and consider my research from various perspectives.

A very special thanks goes to the China–Australia International Research Centre for Chinese

Medicine (CAIRCCM), a joint initiative of RMIT University, Australia, and the Guangdong

Provincial Academy of Chinese Medical Sciences, China, which provided me this learning opportunity and scholarship. I am also grateful to all research fellows in the CAIRCCM and staff at the Department of Psychology and Sleep Medicine of the Guangdong Provincial

Hospital of Chinese Medicine for their unfailing support and assistance.

Professional accredited editor Mary-Jo O’Rourke AE provided copyediting and proofreading services according to the national university-endorsed ‘Guidelines for editing research theses’

(IPEd 2019).

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Finally, I would like to thank my family: my parents, my grandparents, my aunty and uncle, and my cousin, for supporting me spiritually throughout writing this thesis and my life in general. I would also like to thank my friends for all their encouragement.

Table of Contents

Declaration ...... ii

Acknowledgements ...... iii

Table of Contents ...... v

List of Figures ...... ix

List of Tables ...... xii

Publications ...... xvi

Abbreviations ...... xvii

Summary ...... 1

Background ...... 1

Objectives ...... 1

Conclusion ...... 4

Chapter 1 Introduction ...... 6

Background ...... 6

Rationale and components of the research ...... 8

Aims ...... 11

Significance...... 11

Research questions ...... 12

Organisation of the thesis ...... 12

Chapter 2 Overview of Evidence-Based Medicine ...... 14

Introduction ...... 14

Evidence-based medicine ...... 14

Evidence-based medicine in mental health ...... 21

Evidence-based medicine in Chinese medicine ...... 23

Knowledge gap and knowledge translation ...... 24

Limitations, challenges and strengths ...... 26

Conclusion ...... 27

Chapter 3 Literature Review of Major Depressive Disorder ...... 28

Introduction ...... 28

Epidemiology ...... 29

Burden ...... 29

Risk factors ...... 31

Pathological processes ...... 32

Course of illness ...... 34

Diagnosis...... 35

Assessment of risk ...... 38

Treatment ...... 38

Conclusion ...... 44

Chapter 4 Contemporary and Classical Chinese Medicine Therapies for Major Depressive Disorder...... 45

Foreword ...... 45

Introduction ...... 46

CM theory of depression ...... 47

Contemporary CM treatments...... 48

Search and analysis of the classical Chinese medicine literature ...... 58

Conclusion ...... 75

Chapter 5 Chinese Herbal Medicine for Major Depressive Disorder: A Systematic Review and Meta-analysis of Randomised Controlled Trials...... 76

Introduction ...... 76

Methods...... 81

Results ...... 86

Discussion ...... 117

Conclusion ...... 122

Chapter 6 Acupuncture for Major Depressive Disorder: Systematic Reviews and Meta-analyses of Randomised Controlled Trials ...... 123

Introduction ...... 123

Methods...... 125

Results ...... 130

Discussion ...... 166

Conclusion ...... 172

Chapter 7 Patients’ Experience and Expectations of Using Chinese Medicine for Major Depressive Disorder: A Survey ...... 173

Foreword ...... 173

Introduction ...... 174

Methods...... 176

Pilot survey ...... 180

Survey results ...... 181

Discussion ...... 216

Conclusion ...... 223

Chapter 8 Doctors’ Perception of Using Chinese Medicine for Major Depressive Disorder: A Qualitative Study ...... 225

Foreword ...... 225

Introduction ...... 226

Methods...... 228

Results ...... 237

Discussion ...... 272

Conclusion ...... 283

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Chapter 9 General Discussion and Conclusion ...... 284

Introduction ...... 284

Summary of findings...... 285

Limitations of this project ...... 290

Implications for clinical practice ...... 293

Implications for future research ...... 296

Conclusion ...... 299

References ...... 300

Appendices ...... 347

Appendix A Publications...... 347

Appendix B Chinese herbal medicine for major depressive disorder: full electronic search strategy of PubMed ...... 350

Appendix C Acupuncture for major depressive disorder: full electronic search strategy of PubMed ...... 351

Appendix D Pilot questionnaire ...... 352

Appendix E Questionnaire ...... 360

Appendix F Ethics approval for survey granted by the ethics committee of the Guangdong Provincial Hospital of Chinese Medicine, China ...... 369

Appendix G Ethics approval for survey registered with the RMIT University Science Engeneering and Health College Human Ethics Advisory Network, Australia ...... 370

Appendix H Pilot survey results ...... 371

Appendix I Interview guide ...... 376

Appendix J Ethics approval for qualitative study granted by the ethics committee of the Guangdong Provincial Hospital of Chinese Medicine, China ...... 388

Appendix K Ethics approval for qualitative study registered with the RMIT University Science Engeneering and Health College Human Ethics Advisory Network, Australia ... 389

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List of Figures

Figure 1-1 Rationale and components of the research ...... 11

Figure 2-1 Practice of evidence-based medicine ...... 15

Figure 2-2 Hierarchy of evidence: A) EBM and B) GRADE ...... 17

Figure 2-3 The third model of clinical expertise in EBM ...... 21

Figure 2-4 A model for closing the evidence-to-practice gap ...... 25

Figure 4-1 Dynastic distribution of treatment citations ...... 67

Figure 5-1 Flow chart of study selection ...... 88

Figure 5-2 Risk of bias: CHM for MDD ...... 98

Figure 5-3: Funnel plot of CHM for Depression ...... 100

Figure 5-4 Forest plot comparing Chinese herbal medicine to SSRIs alone in terms of Hamilton

Rating Scale for MDD ...... 102

Figure 5-5 Forest plot comparing CHM to SSRIs alone in terms of Hamilton Rating Scale for

MDD (removing studies with baseline imbalance) ...... 105

Figure 5-6 Mean change from baseline to end of treatment on Hamilton Rating Scale for MDD within Chinese herbal medicine groups and within selective serotonin reuptake inhibitor

(SSRI) groups at different time points ...... 107

Figure 5-7 Forest plot comparing Chinese herbal medicine plus selective serotonin reuptake inhibitors (SSRIs) to SSRIs alone in terms of Hamilton Rating Scale for MDD ...... 111

Figure 5-8 Mean change from baseline to end of treatment on the Hamilton Rating Scale for

MDD, within Chinese herbal medicine plus selective serotonin reuptake inhibitor (SSRI) groups and within SSRI groups at different time points ...... 114

Figure 6-1 Flow chart of study selection ...... 131

Figure 6-2 Risk of bias: acupuncture for MDD ...... 145

Figure 6-3 Funnel plot: acupuncture for MDD ...... 146

Figure 6-4 Forest plot comparing acupuncture to SSRIs alone in terms of Hamilton Rating

Scale for MDD ...... 148

Figure 6-5 Forest plot comparing acupuncture to SSRIs alone in terms of Hamilton Rating

Scale for MDD (removing studies with baseline imbalance) ...... 152

Figure 6-6 Mean change from baseline to end of treatment on Hamilton Rating Scale for MDD, within acupuncture and selective serotonin reuptake inhibitor (SSRI) groups at different time points ...... 153

Figure 6-7 Forest plot comparing acupuncture plus selective serotonin reuptake inhibitors

(SSRIs) to SSRIs alone in terms of Hamilton Rating Scale for MDD ...... 157

Figure 6-8 Forest plot comparing acupuncture plus SSRIs to SSRIs alone in terms of Hamilton

Rating Scale for MDD (removing studies with baseline imbalance) ...... 160

Figure 6-9 Mean change from baseline to end of treatment on Hamilton Rating Scale for MDD within acupuncture plus selective serotonin reuptake inhibitor (SSRIs) and SSRI groups at different time points ...... 162

Figure 7-1 Flow chart of participants recruitment and data collection ...... 182

List of Tables

Table 3.1 DSM-5 diagnostic criteria for a major depressive episode ...... 36

Table 3.2 Treatment phases of MDD ...... 40

Table 3.3 Pharmacological treatments for MDD ...... 41

Table 4.1 Summary of Chinese herbal medicines for MDD ...... 56

Table 4.2 Summary of acupuncture for MDD ...... 58

Table 4.3 Search terms related to depression ...... 60

Table 4.4 Hit frequency by search term ...... 65

Table 4.5 Most frequently cited herbal formulae ...... 68

Table 4.6 Most frequently cited herbs ...... 70

Table 5.1 Characteristics of included studies ...... 89

Table 5.2 Summary of findings of Chinese herbal medicine vs. selective serotonin reuptake inhibitors ...... 103

Table 5.3 Adverse events: CHM vs. SSRIs ...... 109

Table 5.4 Summary of findings of Chinese herbal medicine plus selective serotonin reuptake inhibitors (SSRIs) vs. SSRIs ...... 112

Table 5.5 Adverse events: CHM plus SSRIs vs. SSRIs ...... 117

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Table 6.1 Characteristics of included studies ...... 133

Table 6.2 Summary of findings of acupuncture vs. selective serotonin reuptake inhibitors . 149

Table 6.3 Adverse events: acupuncture vs. SSRIs ...... 156

Table 6.4 Summary of findings of acupuncture plus selective serotonin reuptake inhibitors

(SSRIs) vs. SSRIs ...... 158

Table 6.5 Adverse events: acupuncture plus SSRIs vs. SSRIs ...... 165

Table 7.1 Demographic characteristics of the survey participants ...... 184

Table 7.2 Communication with doctors ...... 191

Table 7.3 Distribution of using CM for MDD among demographic variables ...... 193

Table 7.4 Use of CM for MDD among diagnostic information variables ...... 195

Table 7.5 Coefficients of logistic regression model of the use of CM for MDD ...... 196

Table 7.6 Distribution of treatment preferences among demographic variables ...... 197

Table 7.7 Distribution of treatment preferences among diagnostic information variables .... 199

Table 7.8 Coefficients of multinomial logistic regression model of treatment preferences .. 200

Table 7.9 Distribution of continuing use of conventional medicine for MDD among demographic variables in participants using conventional medicine only ...... 201

Table 7.10 Distribution of continuing use of conventional medicine for MDD among diagnostic information variables in participants using conventional medicine only ...... 203

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Table 7.11 Distribution of continuing use of CM for MDD among demographic variables in participants using CM only ...... 204

Table 7.12 Distribution of continuing use of CM for depression among diagnostic information variables in participants using CM only ...... 206

Table 7.13 Distribution of continuing use of conventional medicine for MDD among demographic variables in participants using integrative medicine ...... 207

Table 7.14 Distribution of continuing use of conventional medicine for MDD among diagnostic information variables in participants using integrative medicine ...... 209

Table 7.15 Distribution of continuing use of CM for MDD among demographic variables in participants using integrative medicine ...... 210

Table 7.16 Distribution of continuing use of CM for MDD among diagnostic information variables in participants using integrative medicine ...... 211

Table 7.17 Comparison of treatment types among demographic variables ...... 212

Table 7.18 Comparison of treatment types among diagnostic information variables ...... 214

Table 7.19 Comparison between use of conventional medicine and CM in terms of self- reported treatment experience ...... 215

Table 7.20 Comparison of treatment types in terms of treatment preference ...... 216

Table 8.1 Researcher characteristics ...... 228

Table 8.2 Demographic information of participants ...... 239

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Table 8.3 Overview of themes and sub-themes ...... 242

Publications

Arising from the thesis:

1. Yang L, Shergis JL, Di YM, Zhang AL, Lu C, Guo X, et al. Managing depression with

Bupleurum Chinese herbal formula: a systematic review and meta-analysis of randomized controlled trials. Journal of Alternative and Complementary Medicine. 2020;26(1):8-24.

(Journal article)

2. Yang L, Di YM, Shergis JL, Li Y, Zhang AL, Lu C, et al. A systematic review of acupuncture and Chinese herbal medicine for postpartum depression. Complementary

Therapies in Clinical Practice. 2018;33:85-92. (Journal article)

3. Di YM, Yang L, Shergis JL, Zhang AL, Li Y, Guo X, et al. Clinical evidence of

Chinese medicine therapies for depression in women during perimenopause and menopause.

Complementary Therapies in Medicine. 2019;47:102071. (Journal article)

4. Di YM, Yang L. Evidence-based Clinical Chinese Medicine. Volume 14: Unipolar

Depression. Xue CC, Lu C, editors. Singapore: World Scientific Publishing Co Pte Ltd; 2020.

(Monograph)

Conference abstracts:

1. Yang L, Di YM, Shergis JL, Zhang AL, Lu C, Guo X, Li Y, Xue C. A systematic review of Chinese herbal medicine for postpartum depression. Presented at International

Congress on Complementary Medicine Research (ICCMR). Brisbane, Australia, May 2019.

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Abbreviations

AE Adverse event

AMED Allied and Complementary Medicine Database

ANZCTR Australian New Zealand Clinical Trial Registry

BDI Beck Depression Inventory

BDNF Brain-derived neurotrophic factor

CAM Complementary and alternative medicine

CBM Chinese Biomedical Literature Database

CCT Controlled clinical trials

CENTRAL Cochrane Central Register of Controlled Trials

ChiCTR Chinese Clinical Trial Registry

CHM Chinese Herbal Medicine

CINAHL Cumulative Index of Nursing and Allied Health Literature

CITES Convention on International Trade in Endangered Species of Wild Fauna and Flora

CM Chinese Medicine

CNKI China National Knowledge Infrastructure

CQVIP Chongqing VIP Information Company

CRH Corticotropin-releasing hormone

DALY Disability adjusted life years

DSM Diagnostic and Statistical Manual of Mental Disorders

EBM Evidence-based medicine

EBP Evidence-based practice

Embase Excerpta Medica database

xvii

EPDS Edinburgh Postnatal Depression Scale

EU-CTR EU Clinical Trials Register

GPHCM Guangdong Provincial Hospital of Chinese Medicine

GRADE Grading of Recommendations Assessment, Development and Evaluation

HRSD Hamilton Rating Scale for Depression

ICD-10 International Classification of Diseases-10th Revision

MADRS Montgomery–Asberg Depression Rating Scale

MD Mean difference

MDD Major depressive disorder

NaSSA Noradrenergic and specific serotonergic antidepressants

NICE National Institute for Health and Clinical Excellence

PICF Patient Informed Consent Form

PubMed PubMed

RCT Randomised controlled trial

RR Risk ratio

SD Standard deviation

SDS Zung’s Self-Rating Depression Scale

SERS Rating Scale for Side Effects –Asberg

SMD Standardised mean difference

SNRI Serotonin norepinephrine reuptake inhibitors

SSRIs Selective serotonin reuptake inhibitors

TCA Tricyclic antidepressants

TESS Treatment Emergent Symptom Scale

Wanfang Wangfang database

WHO World Health Organization

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WHOQOL- World Health Organization Quality of Life Scale-Brief Version BREF

YLD Years lived with disability

ZHYD Zhong Hua Yi Dian 中华医典

xix

Summary

Background

Major depressive disorder (MDD), also known as unipolar depression or simply referred to as depression, is characterised by a mood disorder that causes a persistent feeling of sadness and worthlessness and loss of interest in activities. Second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are perceived as first-line pharmacological treatment. Non-pharmacological therapies such as psychotherapy are also commonly used.

There are differing results of using these treatments and some with reported adverse events.

The practice of Chinese medicine (CM) including Chinese herbal medicine (CHM) and acupuncture for depression is common. Such practice should be developed in parallel with the adoption of evidence-based medicine (EBM) considering the best available evidence, patients’ values and clinical expertise. These elements have been systematically investigated in this project, to identify the gaps between evidence and practice, and to improve knowledge translation during clinical decision-making.

Objectives

The objectives of this study were to:

1. evaluate the evidence of CM for depression in the historical CM literature;

2. evaluate the current clinical trial evidence of CM for depression;

3. understand patients’ experience and expectations of using CM for depression; and

4. understand doctors’ perceptions of using CM for depression.

Chinese herbal medicine and acupuncture in historical Chinese medicine literature

The Encyclopedia of Chinese Medicine, a collection of over 1,000 historical CM books, was researched. The findings indicated that the most frequently used formulae and herb ingredients identified in the classical literature are still commonly used today and recommended in the contemporary CM clinical guidelines for depression, including the formulae Gan mai da zao tang and Gui pi tang and the herbs, fu ling, ren shen, bai zhu and dang gui. Acupuncture is commonly used in contemporary clinical practice for depression but was found to be only mentioned in a few classical citations. Acupuncture points used in this setting included PC7

Da ling，PC5 Jian shi, PC6 Nei guan, KI3 Zhao hai, and BL15 Xin shu.

Chinese herbal medicine and acupuncture in clinical trials

Modern clinical evidence was evaluated and synthesised through systematic reviews and meta- analyses of RCTs following the Cochrane Systematic Reviews of Interventions methods. The reviews were registered in PROSPERO. Quality of the evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE).

Chinese herbal medicine

Forty-six studies were identified that compared CHM to SSRIs and 32 studies that compared

CHM plus SSRIs to SSRIs alone. CHM alone or given as integrative medicine with SSRIs reduced depression severity. The number of adverse events in the CHM groups was less than the SSRIs groups. However, the certainty of evidence is low, limited by bias in the included studies and heterogeneity.

Acupuncture

Forty-five RCTs including 30 studies were identified that compared acupuncture to SSRIs and

15 studies that compared acupuncture plus SSRIs to SSRIs alone. Meta-analysis results indicated that acupuncture treatment alone or in combination with SSRIs produced statistically significant reductions in depression severity with considerable heterogeneity. Fewer adverse events were observed among people treated with acupuncture compared to the SSRI groups.

The certainty of evidence is very low to low. Results should be interpreted with caution due to the trials’ risk of bias and heterogeneity.

Acupuncture plus Chinese herbal medicine

Six RCTs were identified that compared the effect of acupuncture plus CHM to SSRIs.

Acupuncture plus CHM indicated positive effects on improving HRSD scores and appeared to be well-tolerated for patients with depression. However, there is insufficient evidence due to the small number of studies and sample sizes in these studies.

Patients’ experience and expectations of using Chinese medicine

An anonymous, self-administered survey was conducted among 139 participants with depression to investigate their experience and expectations of using CM for depression. Thirty- four participants (50.0% of 68 responses) preferred to use integrative treatments. The majority of participants who used CM (31, 83.8% of 37 responses) rarely experienced adverse events and continued using CM (36, 97.3% of 37 responses). Patients expressed a desire/preference for their doctor to communicate with them regarding treatment types and options. About half of participants (80, 57.6% of 139 responses) were given adequate information about CM for depression. Participants also expressed an interest in knowing information on research

evidence for CM, CM classical literature and case studies, but most of all were concerned to know the doctors’ experience of using CM for depression.

Doctors’ perceptions of using Chinese medicine

Based on thematic analysis driven by grounded theory, two rounds of semi-structured interviews involving 26 and 24 doctors were conducted. Doctors indicated that they treated patients with depression based on clinical training and experience, new knowledge and patient preferences. Participants acknowledged the potential benefits and safety of CM for mild to moderate depression but not severe depression. Gaps were identified in the evidence and limitations in applying research into practice. Participants attempted to integrate clinical expertise, evidence and patient preferences during clinical decision-making, but this was yet to be fully optimised or standardised in the practice.

Conclusion

Chinese medicine including CHM and acupuncture has been consistently used from premodern times to contemporary clinical practice. The systematic reviews conducted herein provided evidence showing benefits of CM for reducing depressive symptoms and severity, and that CM use was safe for people with depression. These results provide the scientific basis and guidance for using CHM and acupuncture for depression in clinical practice. However, due to risk of bias and methodological shortfalls, caution should be taken when interpreting and translating these findings into clinical practice or when forming clinical decisions.

The survey of patients with depression revealed that they perceived CM to be beneficial and they chose to continue using CM mainly because of fewer side effects associated with its use.

Overall, patients with depression preferred to use integrative medicine for their condition. They

expected to communicate with doctors about the use of CM as well as knowing about doctors’ experience. Understanding patients’ experience and expectations can help doctors have better collaboration with patients when formulating treatment plans. Findings from the interviews understood doctors’ perception of using CM for depression. Doctors acknowledged the potential benefits and safety of CM for depression based on evidence from classical and modern literature and summary information from patients’ value. They acknowledged the benefit of integrative medicine for depression, which was also preferred by some patients.

Doctors intended to update their practice and translate knowledge based on EBM. They perceived CM may be beneficial for patients with mild to moderate depression. This is helpful for implementing EBM into CM clinical practice for depression and contributes to future research.

Chapter 1 Introduction

Background

Major depressive disorder (MDD), commonly known as depression, unipolar depression or clinical depression, is one of the most common mood disorders that impacts individuals and societies worldwide.(1, 2) Herein, MDD is simply referred to as depression. This condition is linked to disability and mortality, and accounts for over 40% of all mental disorders and substance abuse disorders.(3) It is characterised by depressed mood, diminished interest or pleasure, significant weight or appetite change, insomnia or hypersomnia, psychomotor agitation or retardation, loss of energy or fatigue, inappropriate guilt or feelings of worthlessness, diminished ability to concentrate or make decisions, or thoughts of death or suicide.(1)

Depression is increasing in prevalence and is a major public health problem.(4) It ranks as the second most common burden of disease in 2020.(5) The Global Burden of Disease Study reported that the disability-adjusted life years for MDD ranked 15th in 1990 and 11th in 2010.(6)

Estimated lifetime prevalence was estimated as high as 12% in developed and developing countries.(7)

For this condition, treatments mainly include pharmacological agents including antidepressants, and non-pharmacological treatments including psychotherapy, electroconvulsive therapy, light therapy, and complementary and alternative medicine (CAM), etc.(8) Practitioners of conventional medicine often prescribe antidepressants for people with MDD in primary health care settings to provide rapid relief of depressive symptoms.(9, 10) Among antidepressants, selective serotonin reuptake inhibitors (SSRIs) are first-line agents for depression although

many adverse events are associated with their use, including dizziness, sweating, gastrointestinal upset, sexual dysfunction, sedation and weight gain.(11-13)

It was suggested that patients should follow up with medication treatment for at least six months after remission.(14-16) However, about 25% of patients were not compliant with their treatment program when taking medications.(17) The reasons for discontinuation included increased risk of recurrence, high medical costs and adverse events.(18-20) Patients may seek

CAM when conventional treatments do not meet their expectations.

Chinese medicine (CM), as a type of CAM, has been used for depression in Asia for thousands of years and is increasingly used in Western countries.(21) Contemporary clinical evidence concerning the efficacy of CM, including Chinese herbal medicine (CHM) and acupuncture, for depression increased and is being updated.(22, 23) Pre-clinical studies showed that CHM may employ antidepressant effects relating to antioxidant and neurotransmitter properties.(24-

27) Acupuncture relieved depression symptoms by promoting neurogenesis, protecting the hippocampal neurons, modulating mood and regulating neurotransmitters and hormones.(28-

31) However, there is a lack of evidence about how patients feel or what doctors’ perceptions are about using CM for this condition.

Although MDD is a modern condition defined through conventional medicine theory, similar descriptions could be found in CM classical literature. Over a long history, classical CM literature recorded an abundance of knowledge on CM for conditions that are associated with depression, although conventional medicine and CM recognise diseases from different perspectives using different medical theories.(32, 33) Many types of the treatments described in contemporary guidelines or textbooks have their origins as recorded in CM classical literature. However, many of these works were not investigated by using a systematic method.

As synthesis of evidence from contemporary research and classical literature was lacking, a

‘whole evidence’ method was used in this project to clarify evidence-based medicine (EBM) of CM for MDD, including systematic reviews and analyses of modern literature and classical literature, investigation of patients’ values and exploration of doctors’ perceptions. This comprehensive approach could supply and provide the best available evidence of CM for MDD and improve clinical decision-making. This project was dedicated to understanding the current evidence of using CM for depression and how patients and doctors experience the treatment of depression in the clinical setting.

Rationale and components of the research

This project addressed gaps in the understanding of using CM for MDD, including integration of evidence from modern clinical trials, classical literature, patients’ value and doctors’ perceptions.

Part 1. Classical evidence on Chinese medicine for MDD

Classical CM literature dated from the Spring and Autumn periods (770–476 BC), including evidence of CM theory and CM practice.(34) The classical literature recorded and comprised definitions, concepts, discussion and clinical cases of CM in many CM books. Words related to ‘depression’, such as ‘sad’ and ‘worry’, could be found in texts at least as old as the Huang

Di Nei Jing (605–616 AD). Information on CM conditions that are related to depression increased in volume and detail over time. The classical literature provided a large body of data that could be searched and analysed. The classical literature is considered foundational and supplementary evidence for contemporary CM practice. The Zhong Hua Yi Dian (ZHYD) is a collection of more than 1,000 CM books which has been digitalised and hence is readily

searchable. This project searched and analysed data from the ZHYD and summarised the classical evidence of CM for depression.

Part 2. Modern evidence on Chinese medicine for MDD

Systematic reviews and meta-analyses of clinical trials provided the best evidence of efficacy and safety of CM for depression. Recent systematic reviews of randomised controlled trials

(RCTs) focused on various types of depression including dysthymia, bipolar depression and secondary depression such as post-stroke depression, and compared single herbs, formulae or all types of acupuncture (including manual acupuncture, electroacupuncture, auricular acupuncture and laser acupuncture) to pharmacotherapy or psychotherapy.(22, 23, 35-42)

Given the frequent use of CHM and acupuncture for MDD, this project specifically focused on systematically evaluating the efficacy of CHM or acupuncture (manual acupuncture and electroacupuncture) alone and combined with SSRIs, compared to SSRIs alone, and evaluated adverse events related to CHM and acupuncture compared to SSRIs for individuals with depression.

Part 3. Experience and expectations of using Chinese Medicine among patients with MDD

Most research focused on the efficacy and safety of CM for MDD. However, little attention was paid to patients’ values. There was an information gap in evidence of patients’ values in using CM for this condition, including their experience and expectations. To address this gap, this project included a survey to investigate the use of CM for MDD among patients with depression. This survey highlighted patients’ experience and expectations of using CM to manage their condition. The study was undertaken in order to improve the understanding of

patient values in using CM for MDD, promote communication between patients and doctors, and inform CM clinical practice during clinical decision-making.

Part 4. Perceptions of Chinese medicine for MDD among doctors

Although the number of CM clinical trials increased and there was a rich source of information in classical literature, the extent to which doctors used these findings in their practice was unclear. There was a lack of information on doctors’ perceptions of using CM for MDD. The application of research results to patients remained challenging in evidence-based practice

(EBP).(43) Whether patients’ values have any impact on clinical decision-making was also unknown. Thus, knowledge gaps between available evidence and clinical decision-making occurred at all levels of health care among researchers, patients and doctors. Knowledge translation refers to using high-quality evidence in decision-making.(44) To improve the knowledge translation of using CM for MDD, this project integrated the evidence from modern clinical trials, classical literature and patients’ values into a qualitative study to understand doctors’ perceptions of using CM for this condition.

Finally, this project integrated modern clinical evidence, classical literature evidence, patients’ values and clinical expertise to explicate EBM in CM for MDD (Figure 1-1).

Figure 1-1 Rationale and components of the research

Abbreviations: CHM: Chinese herbal medicine; CM: Chinese medicine; MDD: major depressive disorder.

Aims

This project aimed to evaluate the contemporary evidence and classical evidence of CM for

MDD; understand patients’ values of using CM for the condition; and understand doctors’ perceptions of using CM for this condition.

Significance

The findings of this project could provide the best available evidence of CM for depression

(modern clinical trials and classical literature), improve the understanding of patients’ values and doctors’ perceptions of using CM for depression, and promote knowledge translation during clinical decision-making of CM for depression.

Research questions

1. Are CHM and acupuncture effective and safe for MDD?

2. What is the historical evidence from classical literature of CHM and acupuncture for MDD?

3. What are patients’ experience and expectations of using CHM and acupuncture for MDD?

4. What are doctors’ perspectives and perceptions of using CHM and acupuncture for MDD?

Organisation of the thesis

This thesis included nine chapters:

Chapter 1 introduced the background of this project. The rationale, components, aims and significance of this project were highlighted. The research questions were also presented. An overview of the thesis was included.

Chapter 2 described the understanding of EBM, including best available evidence, patients’ values and clinical expertise. The current status of EBM in CM was introduced, highlighting the issues and challenges in applying EBM to CM.

Chapter 3 described the understanding of MDD based on conventional medicine perspectives, including the definition, epidemiology, burden, risk of factors, pathophysiology, prognosis, diagnosis and management.

Chapter 4 described the understanding of MDD based on the CM perspective by reviewing contemporary clinical guidelines and textbooks. This chapter included CM terminology of depression, traditional CM theory of the condition, treatment principles, CHM treatment and

acupuncture therapy. Furthermore, the classical evidence of CM for the condition was evaluated using the ZHYD. Citations related to depression were identified. The frequently used herbs, formulae and acupoints were descriptively analysed.

Chapter 5 referred to systematic reviews and meta-analysis of CHM for depression. This chapter evaluated the efficacy and safety of CHM alone or combined with SSRIs for MDD, compared with SSRIs alone.

Chapter 6 systematically evaluated the clinical evidence of acupuncture alone or combined with SSRIs when compared to SSRIs, and its safety. This chapter also evaluated the efficacy and safety of acupuncture combined with CHM.

The methodology used to evaluate the efficacy and safety of CHM and acupuncture in Chapters

5 and 6 followed the procedure recommended by the Cochrane handbook for systematic reviews of interventions.(45)

Chapter 7 presented the results of a survey conducted among 139 participants with MDD at

Guangdong Provincial Hospital of Chinese Medicine. The survey investigated the patients’ values in using CM for MDD, including their experience and expectations. The methodology and findings were comprehensively presented in this chapter.

Chapter 8 presented the results of interviews of doctors to understand their perceptions of using

CM for MDD. Research findings from Chapter 4 to 7 were used as a part of interview materials in this study. Detailed information and findings were presented in this chapter.

Chapter 9 discusseed and summarised the overall research findings across chapters. Limitations of this project were included, as were implications for clinical practice and future research.

Chapter 2 Overview of Evidence-Based Medicine

Introduction

In the early 1990s evidence-based medicine (EBM) began to gather momentum as a way to make decisions in clinical medicine.(46) EBM integrates clinical experience and patient values with the best available research information and has received a great deal of interest from health professionals over the last few decades.(47) EBM initially aimed to optimise clinical practice based on education including understanding and using the published literature, such as the science of systematic reviews.(48) As it progessed, EBM recognised the limitations of using evidence alone, and began to incorporate patients’ preferences into critical appraisal of evidence during shared clinical decision-making. Furthermore, EBM combined with clinical expertise to improve and develop clinical practice guidelines.(48) In the future, it is likely to improve again by incorporating computer-based clinical decision support systems.(48, 49)

EBM developed and spread three major principles, including an increasingly sophisticated hierarchy of evidence, the requirement for taking patient values or preferences into consideration during clinical decisions, and the need for systematic summaries of the best evidence to guide health care.(48)

EBM contributes to improved clinical practice by utilising a solid scientific basis, including development of hierarchies of evidence combined with patient values and clinical expertise, and development of the methodology for producing trustworthy recommendations for clinical practice.(48)

Evidence-based medicine

EBM defines the practice of integrating clinical expertise and patient values with the best available clinical evidence from systematic research (Figure 2-1).(50, 51) In clinical practice, good doctors use both individual clinical expertise and the best available external evidence, combined with consideration of patient values and preferences in clinical decision-making , to make clinical decisions for a patient’s condition.(50) Based on EBM, “patients’ values and preferences” was defined as a broad term, including patient perceptions, beliefs, expectations, and goals for quality of health and life, as well as the process that patients think of the potential benefits, harms, costs, and burdens from management or treatments.(52)

The practice of EBM includes four steps: 1) proposing an answerable clinical question; 2) finding the best available evidence; 3) critical appraisal of the evidence; and 4) applying the evidence to patients’ health care.(53, 54)

Figure 2-1 Practice of evidence-based medicine

Best available clinical evidence

Since the 1970s, many researchers have highlighted the need for strengthening the empirical practice of medicine and advocated evidence to guide clinical decision-making with evidentiary rules.(55-57) EBM proposes a particular relationship between evidence and practice. Clinical practice should be based on the best available evidence that is necessary for effective decision-making.(48) EBP requires clinicians be guided by best available evidence.(58) In response, EBM developed schemas to assess the quality (hierarchy) of the evidence. The higher the hierarchy of evidence, the closer to the true clinical setting, including estimation of diagnosis, prognosis, and the effects of interventions.(48) The hierarchy of evidence helps to identify the best available evidence. CM has been widely practiced over thousands of years(59), but it lacks robust evidence from a EBM perspective. Whether EBM could be applied to CM generating high quality evidence has long been a topic of debate where much effort needs to be focused.(60) For example, acupuncture treatment could not be fully double-blinded in clinical trials, hampering generation of reliable evidence.(61)

Hierarchy of evidence

The quality of evidence is associated with the extent of confidence in estimates of effects that is adequate to support a specific recommendation.(62) From the inception of EBM, schemas have been developed for assessing the quality of evidence.(63) An initial hierarchy of evidence focusing on the design of clinical studies has been proposed for EBM (Figure 2-2 A).(64) The

Oxford Centre published an extended hierarchy of evidence for EBM including diagnosis, prognosis, benefits and harms of treatment, and screening studies.(65) A new approach to rating the quality of evidence and grading the strength of recommendations was firstly established in 2004 and is known as the Grading of Recommendations, Assessment,

Development and Evaluations (GRADE) system.(66) Since then, GRADE has been utilised widely in all fields among over 100 organisations, including the World Health Organization

(WHO), the Cochrane Collaboration and the National Institute for Health, etc (Figure 2-2

B).(66) The hierarchy of evidence is ranked according to the probability of bias in studies.

RCT

Cohort Study Case control study

Case Series Case reports

Animal research In-vitro research

Expert experience

B Quality of evidence Study design Low quality if: Higher quality if: High Randomised trial • Study limitations • Large effect Moderate • Inconsistency • Dose response Low Observational study • Indirectness • Plausible Very Low • Imprecision residual • Publication Bias confounding

Figure 2-2 Hierarchy of evidence: A) EBM and B) GRADE

Note: Figure 2.2 adapted from Djulbegovic et al. in The Lancet 2017, 390(10092):415–23.(48)

EBM and GRADE both consider randomised controlled trials (RCTs) as the highest level in the hierarchy of evidence, with observational studies and expert experience at a low level.

RCTs are presented as the highest-level evidence due to unbiased research design and less risk of systematic bias. For instance, RCTs control for confounding factors that may bias results by appropriate allocation concealment or blinding. (67) Observational studies and expert opinion cannot be free of bias in personal experience and have no control of confounding factors.(63)

Systematic reviews and meta-analysis

EBM proposes that health medicine claims need to be based on systematic reviews that can summarise the best available evidence, including evidence from RCTs, cohort studies or case studies.(48, 68)

The greatest development in systematic review methodology was produced by the Cochrane

Collaboration.(69) Its concepts and principles are that critical summaries of all relevant RCTs should be organised and adapted periodically by speciality or subspecialty.(57) Systematic reviews of RCTs remain a primary focus addressing effects of interventions in the Cochrane

Collaboration, while reviews of observational studies are also included as well as prognostic and diagnostic tests.(70) The necessity for systematic summary has been acknowledged to inform new findings for medicine and designs for new research, which should combine existing and updated evidence by referencing existing systematic reviews or meta-analysis.(71)

Currently, the integration of systematic reviews into summary of evidence tables to facilitate shared decision-making is still being developed.(72) Systematic reviews and meta-analysis can provide the best quality of evidence for clinical decision-making and play a key role in the procedure for clinical decision-making.(73)

Systematic reviews and meta-analyses collect eligible studies that are related to clinical questions and study design, and reviews and analyses their results, summarising and combining existing evidence.(74) During this process, the quality of studies is evaluated and statistical meta-analysis, a valid and scientific method, is conducted to analyse and combine different results from all eligible studies.(75) In terms of obtaining more reliable results, systemic reviews and meta-analyses are mainly conducted with RCTs that represent high quality of evidence in the evidence hierarchy.(76)

Patient values

EBM accommodates basic principles of science, subtleties of doctors’ clinical judgement and patient idiosyncrasies.(46) Evidence-based research may play a key role in the complex process of making accurate clinical decisions, without necessarily dictating the decision.(77) EBM incorporates patients’ values, such as experience or expectations, into clinical decision-making, and this was a crucial movement in the development of EBM.(51) This means that making clinical decisions should not be solely based on external evidence but also the needs and wishes of patients,(77) and has partly overcome earlier criticism of EBM.(78) Some research has shown how patient values and evidence can be integrated into the process of shared decision- making.(79-81) For example, clinical practitioners need to ascertain patients’ values and understand their preferences in conjunction with evidence during clinical consultation.(81)

Comprehensive health care and empathetic listening to patients views are always valued.(82)

Patients require better evidence, better presented and better explained in a more personalised manner to achieve individual treatment goals.(83) Management for some conditions has focused on patient values and presented good models for clinical practice. For instance, the importance of combining evidence and patient-centred strategies for patients with arthritis has been emphasised for more than 30 years, and also has influenced the choice of outcome measures used in studies of comparative effectiveness.(84) Also, the guidelines of the National

Institute for Health and Clinical Excellence focused on the input and experience of patients with psoriasis.(85) Thus, studies on patients’ values for different conditions are needed to validate good practice of EBM.

Clinical expertise

The practice of EBM combines clinical expertise, as shown in Figure 2-1 and considers it to be just as important as the other elements, because external evidence alone or patient preferences do not replace clinical judgement.(49) Clinical expertise includes skills in clinical practice and experience of individual practitioners.(86) Ultimately decisions about care are made by the health care practitioner and the patient in light of the circumstances and evidence available.(86)

Substantial clinical expertise is fundamental to optimal clinical decision-making, including the skills of appropriate clinical assessment and accurate diagnosis, the ability to approach the best available evidence, the skill of communicating the risks and benefits of treatments with patients, and the insight into patients’ values.(49) Doctors are required to effectively integrate clinical expertise, the best available evidence and patients’ values during clinical decision-making.(87,

88)

In EBM, there are three main models of clinical expertise.(89) In the first model (Figure 2-2

A), clinical expertise is considered as the bottom of the traditional hierarchy of evidence.(46,

90) In the case of GRADE, clinical expertise is kept in the traditional hierarchy of evidence and placed as external evidence with low quality (Figure 2-2 B).(66) The first model of clinical expertise means that expertise can be regarded as a kind of evidence although with low standing.

The second model comes out of the work on EBM by Sackett et al. in 1996.(51) This newer model defines the role of clinical expertise external to the best available evidence. Clinical expertise refers to the skills for diagnosis and proper application of evidence to patient values.(50) Figure 2-1 features a structure of three overlapping circles including the best available evidence, clinical expertise and patient values, of which the intersection is known as

‘EBM’. This new model suggests that these three elements of EBM should be given equal consideration.(89) The third and most recent model of clinical expertise was defined by Haynes

et al. and retains the structure of three overlapping circles shown in Figure 2-1, but modifies the content and influence of clinical expertise by adding clinical state and circumstances.(86)

The clinical state and clinical circumstances of patients are key factors in clinical decisions when seeking medical care.(86) For the third model of clinical expertise, a fourth circle component is included, ‘clinical expertise’, encircling portions of the other three circular parts including: research evidence, clinical state and circumstances, and a patient’s preferences and action (Figure 2-3).(89) This third model indicates that clinical expertise needs to balance and encompass evidence, patient preferences and clinical state and circumstances. The changes in models of clinical expertise indicate that EBM highlights the role of expertise and is open to further improvement.

Figure 2-3 The third model of clinical expertise in EBM

Note: Figure 2.3 adapted from Wieten et al. in Philosophy, Ethics, and Humanities in Medicine

2018 13(1):2.(89)

Evidence-based medicine in mental health

Since the very first conception of applied psychology, EBP has been implemented over the past quarter of a century in line with EBM development. This has informed and improved clinical practice with relevant research for patients with mental health.(91, 92) For example, the first evidence-based treatment review of depression dates back to 1998.(93) The aims of applying

EBM in clinical practice for mental health is to enhance public health by the uptake of empirically supported principles of psychological assessment and management as well as improve effective psychological practice.(92)

Recent intergovernmental initiatives that aim to reduce gaps in treatments for mental health are all based on systematic appraisals of existing evidence.(94) For example, the WHO launched the Mental Health Gap Action Programme to enhance the capacity of member states to respond to the increasing burden of mental disorders and implement evidence-based guidelines for mental disorders and related conditions, particularly in low- and middle-income countries.(95-

97) In 2013, the WHO's Comprehensive Mental Health Action Plan 2013–2020 was adopted by the 66th World Health Assembly, which indicates that strategies and interventions for mental health need to be based on best scientific evidence or practice regarding treatment, prevention, etc.(98) Furthermore, in 2017 Cochrane Global Mental Health was established based on five Cochrane Review Groups that cover conditions of mental health and the WHO

Collaborating Centre for Research and Training in the area of mental health.(94) The aims and scope of Cochrane Global Mental Health include supporting the generation and use of systematic reviews for mental health and providing training and knowledge exchange on evidence synthesis for mental health.(94) Complementary and alternative medicine (CAM) approaches that have an established evidence base are also under serious consideration by

Cochrane Global Mental Health.(94)

Although these initiatives based on EBM have been successful in placing mental health into the development of public health, the task of EBP in mental health is far from complete regarding optimising promotion, prevention and interventions.

Evidence-based medicine in Chinese medicine

For over 2,500 years clinical practice of Chinese medicine (CM) has been based on unique CM theories such as yin and yang and has made a great contribution to health care for Asian populations and more recently worldwide.(60) However, the traditional influences on CM including the use of traditional knowledge as a source of evidence is not acknowledged in EBM frameworks. Theories of CM are rooted in ancient knowledge that continue to influence and pervade understanding of health and disease. The evidence base has not progressed as quickly as conventional medicine and there is a paucity of high-quality research on CM, hindering its acceptance and integration into mainstream health care.(60)

The combination of CM and EBM has become a point of discussion worldwide.(99) Thus, for

CM to be rationally used for patients who benefit from it, there is a great need to evaluate its efficacy and safety in a more scientific and systematic way.(60, 100)

In terms of applying EBM in clinical practice of CM, the first step is to produce the best available clinical evidence of CM. A screening of all systematic reviews related to CM published in the Cochrane library found that almost all of these reviews commented on the limited high-quality evidence from clinical trials and therefore a conclusion on the efficacy of

Chinese herbal medicine or acupuncture could not be established.(60) Criticisms include methodological shortfalls, lack of clinical trials, limited sample sizes, high risk of bias and poor reporting. For instance, it is difficult to create an appropriate placebo for herbal decoctions and

acupcunture that compromises the effectiveness of blinding.(60) Thus to get the best available clinical evidence on CM, well-designed studies are needed to validate the evidence of CM.

Despite the limitations in the existing evidence, CM is known to be a rich source of treatments for various diseases (59) For example, the compound artemisinin is derived from a traditional

CM herb called Qing hao (Artemisia annua), and was discovered after classical CM books were searched for possible natural product leading for drug development.(101, 102)

Techniques of evaluating historical herbal texts for new leads are not unique to CM and many traditional medicine systems from around the world are used to find new drug compounds.(103)

Thus, information in historical CM literature presents significant evidence of the benefits and use of CM. The framework of EBM does not comprehensively include the framework of CM practice that incorporates historical literature as a source of evidence and this has led to misunderstanding.(100) Records of classical CM literature can present a special kind of evidence as an important supplement to the evidence system of CM.(100) Based on the hierarchy of evidence published by the Oxford Centre, the extensive body of information derived from classical CM literature can be considered as evidence at levels 4 or 5.(65)

Knowledge gap and knowledge translation

Different performances in health care are caused by the gap between production of knowledge and its implications.(104) To eliminate this gap, EBP was proposed to improve health care quality, and is defined as the integration of clinical experience with patient values and clinical expertise.(105, 106) Although EBP plays a positive role in improving the quality of health care(107), there are still many barriers to its successful implementation.(104, 108) The knowledge gap in practice of EBM exists between the publication of clinical research evidence and the implementation of these findings by clinicians.(49) Also, practice should ideally

establish a strong interpersonal relationship between doctors and patients to achieve shared

goals.(77) To address this problem, knowledge translation was introduced into practice as a

new discipline of EBM research.(109)

Knowledge translation is defined as the exchange, synthesis and application of knowledge

within a complicated system of interactions among researchers and users such as doctors and

policymakers.(44) The aims of knowledge translation include supplying continued medical

education for doctors regarding new clinical evidence that is relevant to their clinical practice,

adapting clinical practice behaviour and improving clinical application of proven

interventions.(109, 110)

The process of knowledge translation to action is an iterative, compound and dynamic process

concerning the formation and application of knowledge.(44, 111) To understand knowledge

translation in the practice of EBM, a model to close the evidence–practice gap was

introduced.(109) This model involves two main categories, ‘getting the evidence straight’ and

‘getting the evidence used’, including four stages as shown in Figure 2-4.(109)

1. Research synthesis guidelines, 3. Clinical Evidence-based continuous medicine quality journals improvement

Evidence Practice

2. Beside 4. Decision Evidence-based aids, patient medicine education and compliance aids Figure 2-4 A model for closing the evidence-to-practice gap

Note: Figure 2.4 adapted from Lang et al. in Ann Emerg Med. 2007; 49(3):355–63.(109)

Limitations, challenges and strengths

There are some limitations and challenges to apply EBM in CM to generate best available evidence(60): a fundamental limitation is the comparison of research findings among similar studies. CM studies are often inconsistent making it difficult to draw conclusions and leading to lack of reproducibility of clinical trials and the validity of generalising clinical use. For example, there are variations of the active constituents contained in herbal formulations due to product-to-product variation from different brands, manufacturers or formulations of herbal decoctions. It is also challenging to incorporate CM principles and theories into RCTs as CM practice is individualised, while RCTs require a standardised treatment approach. The conventional standards of ‘quality evidence’ for CM are limited.(100) However, this does not necessarily mean that EBM cannot be applied. Precise reporting of clinical trials has to be implemented to ensure the validity of CM trials. Standard of interventions and controls among studies should also be required. Accommodating CM principles under the rigorous framework of EBM should be used. For example, a systematic process can be applied which assesses the diagnosis using quantification of CM syndrome differentiation and gives the corresponding patients an individualised treatment.(112)

Meanwhile, there is significant anecdotal evidence that CM incorporates patient values, including cultural values in clinical decision-making; however, at present there are limited studies that focus on patient values using a conventional framework.(100) Based on this, further investigation and integration of clinical evidence, patient values and clinical expertise can help

to build a more comprehensive and optimised system of evidence-based CM, better translating the evidence into clinical practice.

The integration all elements of EBM (clinical expertise, patient values alongside the best available clinical evidence from systematic research) will be used to underpin this project to comprehensively understand the use of CM for depression. Furthermore, the understanding of knowledge gaps and knowledge translation in applying EBM in CM could best be preserved as a bridge that combines the best available evidence, patient values and clinical expertise in the hope of addressing the gap between scientific research and clinical practice.

Conclusion

To improve clinical practice of CM for depression, the elements of EBM presented above will be incorporated together in the proceeding chapters to identify the gaps and better translate knowledge into practice. Specifically, the best available clinical evidence from systematic reviews of RCTs and historical CM literature will be evaluated (Chapters 4–6). Patient values will be collected and evaluated though a survey delivered to patients of an outpatient mental health clinic in an integrative medicine hospital (Chapter 7). Furthermore, the results from the clinical evidence analysis along with the results from the patient survey will be shown to doctors who deliver mental health services (Chapter 8). This whole EBM approach will provide a comprehensive understanding of current evidence and how practice reflects (or does not reflect) evidence, values and expertise. Overall, applying the EBM approach will help to identify gaps and determine if doctors incorporate clinical evidence and patient values into treatments for patients with depression and how doctors can better their clinical practice in the future.

Chapter 3 Literature Review of Major Depressive Disorder

Introduction

Major depressive disorder (MDD), also called major depression, unipolar depression or clinical depression(2), is the most commonly reported mental disorder worldwide and its impact is increasing due to population growth and ageing.(113) MDD is often simply referred to as depression. In this thesis depression is used interchangeably with MDD.

As a distinct mental disorder, MDD indicates one or more major depressive episodes including a heterogeneous set of clinical symptoms and disorders that relate to an individuals’ low mood, declining interest in day-to-day activites and work, psychomotor disturbance and impaired concentration. The depressive episodes are not caused by psychosis or substance abuse or general medical conditions, and they are not better explained by specified or unspecified schizophrenia spectrum and psychotic disorders. Also, there is no history of manic, mixed or hypomanic episodes as seen in bipolar disorder.(114, 115) According to the Diagnostic and

Statistical Manual of Mental Health Disorders (DSM-5), published by the American

Psychiatric Association in 2013(1), MDD occurs for 2-week periods or more, with five or more of the following symptoms: depressed mood, loss of interest or pleasure, change in appetite or weight, sleep disturbance, fatigue or lack of energy, psychomotor agitation or retardation, feelings of worthlessness or excessive guilt, suicidal ideation and behaviour; and at least one of the symptoms of depressed mood or loss of interest or pleasure. These symptoms lead to significant clinical distress or impaired social, occupational or daily life activites.

The clinical presentation of depression is heterogeneous and characterised by depressed mood, markedly diminished interest and a range of disturbances of emotion, cognition and behaviour.

People with depression may have an isolated episode or suffer from recurrent episodes.(116,

117) However, for most people MDD is a life-long disorder.(1)

Epidemiology

The rate of MDD rose significantly during the latter half of the twentieth century. The WHO reported that 151.1 million people were affected by this condition.(113) The lifetime prevalence of depression and dysthymia was estimated to be about 12% in developed and developing contries.(7) Comparing data from 1992 with 2002, the prevalence of depression in the United States appeared to have more than doubled from 3% to 7%.(118) Due to cultural differences, genetic factors, sample selection bias and the cross-cultural portability of diagnostic criteria, there are differences in prevalence between regions, sex and age.(119, 120)

The prevalence of MDD in developed settings such as the United States and Europe was almost

18%, while in China and Mexico as in other developing countries it was 9.4%.(7) A face-to- face household survey conducted in 15 countries by the WHO on the lifetime prevalence rate of MDD showed approximately a two times greater rates in females compared with males.(121)

The lifetime prevalence of MDD in females and males was 17% and 9%, respectively.(122)

MDD is more common in younger people compared to older adults.(123) In the United States, a survey of more than 9000 people indicated that the lifetime prevalence rate of MDD in young adults and adults over 65 years was up to 23% and 10%, respectively.(124) However, older people who suffer from a wide range of medical conditions have a greater prevalence rate of depression compared with older people without health concerns.(125, 126)

Burden

Depression is ranked as the 11th most common cause of disability and mortality.(6)

Furthermore, the Global Burden of Disease Study predicted that depression would be the second most common worldwide disease burden by 2020.(5) Trends show that this burden continues to rise, causing functional impairement, reduced quality of life, lost social connections and econonomic costs.

Depressive disorder is ranked as one of the top causes of global years lived with disability

(YLD), accounting for 8.2% of global YLDs.(127) In high-income countries, it accounts for

55.3 million and 10.4% of total YLDs.(113) For males the yearly YLD is 24.3 million and 8.3% of total YLD, while for females it is 41.0 million and 13.4% of total YLD.(113) In terms of age, depressive disorders account for 9.6% of global YLDs as the second leading cause of

YLDs, occurring at working ages between 15 to 64 years with 60.4 million YLDs, followed by the 0–14 year age group with 7.8 million YLDs and the 65 and over age group with 6.1 million

YLDs.(127)

Depressive disorders are also reported as a leading cause of global disability adjusted life years

(DALYs), accounting for 3% of global DALYs.(127) It is predicted to become the second leading cause of DALYs by 2030, surpassing previously top-ranked diseases such as lower respiratory tract infections and perinatal conditions.(128) In Europe, it is the third highest burden of disease and accounts for 3.8% of all DALYs.(129)

A national survey conducted in 48 contiguous states of the United States revealed that approximately 60% of patients with depression have severely or very severely impaired psychosocial functioning including imbalances in work, social life and relationships.(130) The

WHO World Health Survey reported that depressive disorder causes the greatest reduction in quality of health compared with chronic diseases including angina, asthma and diabetes. The

comorbid state of depression worsens health scores compared with depression alone, or with any chronic disease alone, or with any combination of chronic diseases without depression.(131)

The Collaborative Research on Ageing in Europe (COURAGE) and the WHO’s Global Ageing and Adult Health (SAGE) study showed that the biggest impact from depression was on life, work and interpersonal activities.(132) In addition, it has been shown that quality of life may remain impaired despite resolution of the depressive syndrome.(133)

People with depression may be more likely to intentionally injure themselves or commit suicide.(134) As an example, a prospective study illustrated that the suicide rate was 27 times higher than that in the general population.(135) Patients with suicidal ideation are more likely to subsequently develop major depression, compared to patients with minor depression.(136)

Many risk factors for suicide have been identified, including more severe depression, prior history of suicide attempt, male sex, family history of psychiatric disorders, hopelessness, and comorbidities.(137)

On average, depression leads to five weeks of lost work productivity and the annualised human capital loss to employers is estimated to be more than US$36 billion.(117) In Europe, €136.3 billion is lost due to the economic costs associated with depression, including reduced productivity (€99.3 billion) and health care system costs (€37.0 billion).(138, 139) In China, the yearly loss in work days, medical expenses and funeral expenses amounts to US$7.8 billion.(140)

Risk factors

The risk factors for depression include internal and external factors, adversity, social factors and psychological factors in term of biological and family history, and environmental factors.

The heritability of this condition is estimated that up to 42%.(141) The biological children of depressed parents have a two-fold increased risk of depression compared with those who have non-depressed parents; biological offspring with two previous generations with depression are at even higher risk of depression.(142) Non-genetic factors that contribute to about 70% of susceptibility to depression include childhood or recent interpersonal adversities, childhood sexual abuse, lifetime trauma, low levels of social support and marital problems or divorce.(143-145) Depression is twice as common among females as males,(146) and women are more likely to have recurrence.(116) Biological events including menopause, dementia and chronic diseases and environmental factors including childhood maltreatment and childbirth are associated with depression.(1, 147)

Pathological processes

Depression has behavioural signs and clinical symptoms rather than clearly specific pathophysiology. Signs and symptoms include depressed mood, reduced interest in daily activities, weight or appetite changes, diminished concentration, insomnia and fatigue.(148,

149) There is a lack of knowledge of the aetiology and pathophysiology of this condition.(148-

150)

In terms of neurobiological studies of depression, the most common research is on monoaminergic neurotransmitter systems.(150) The monoaminergic systems are associated with the network of limbic, striatal and prefrontal cortical neuronal circuits.(149) These regions, and interconnected circuits, potentially show the pathophysiology of depression.(151) These systems regulate emotions, contextual memory and learning processes, executive function and reward, and are the basis of pharmacological agents for depression.(148)

Abnormalities of neurotransmitter and neuropeptide systems, including the GABAergic system, noradrenergic system, serotonergic system, dopaminergic system, corticotropin-releasing factor, cholinergic system, hypothalamic–pituitary–adrenal axis and glutamatergic system, were reported to be involved in depression.(150) Depression is associated with levels of neurotransmitters and functional interactions among monoamine neurotransmitters, including serotonin, norepinephrine and dopamine.(152) Serotonin is associated with obsession and anxiety, while norepinephrine is related to interest, attention, energy, alertness and anxiety, and dopamine is thought to be related to concentration, motivation, interest and reward.(153)

Existing drug therapy with antidepressants mediates these monoamine neurotransmitters to improve symptoms of depression.(154) For example, some antidepressants act selectively on only one monoamine, such as selective inhibitors of serotonin reuptake.(155) Among these, the hypothesis of serotonin is considered as the most supported model of pathophysiology. The majority of antidepressants can quickly enhance the synaptic serotonin level, which usually takes a few weeks to discern treatment effect for depression.(156)

Brain-derived neurotrophic factor (BDNF) is widely accepted as being a critical neurotrophin in key brain circuits to maintain, grow and survive neurons, involved in cognitive and emotional function.(157) Convergent evidence showed that the neuroplastic mechanism of

BDNF is deleteriously changed in depression.(157) Preclinical and clinical evidence provided that stress-induced depressive pathology leads to altered function and levels of BDNF among patients with depression.(157) Effective treatments for depression, such as antidepressants, could optimise BDNF in key brain regions, promoting neuronal function and health.(157)

Recent evidence indicated that BDNF in the mesolimbic dopamine circuit plays a crucial role in development of depressive behaviours.(158)

Brain regions are associated with depressive symptoms, referring to dysregulation of cognitive processing, circadian rhythms, functioning and high levels of episode-related impairment.(115)

Different regions are involved in different stages of depression and refer to varying pathophysiologies in different individuals.(148) For example, the hippocampus and frontal regions of the cortex regulate and mediate cognitive aspects of depression including a sense of low mood, hopelessness, guilt and memory impairment.(148) The involvement of the striatum and amygdala in depression is considered to mediate aversive and rewarding responses that could further mediate reduced motivation and anxiety symptoms among people with depression.(148) The hypothalamus can regulate metabolic and autonomic systems, mediating symptoms associated with depression such as disrupted sleep, altered appetite, low levels of interest in sex and energy, etc.(148)

Hormones are also involved in depression. Corticotropin-releasing hormone (CRH) is released during psychological stress.(143) CRH causes physiological and behavioural changes including poor sleep, significant appetite change and psychomotor alterations. It may also be involved in the initiation or perpetuation of depression.(159)

Many studies have reported whether genetic factors may play a role in depression in terms of onset and progression since the first related study published in the last quarter-century.(160)

More than 100 candidate genes were examined to identify protential relationships with the risk of depressive symptoms and depression occurrence. However, these studies on the pathogenesis of this condition have reported conflicting results and different genetic factors may make a limited contribution to depression.(161, 162)

Course of illness

Depression is a lifetime and recurrent condition affecting people at any age.(116) It is a heterogeneous condition with some people experiencing remission while others suffer over many years between discrete episodes.(1) Recovery begins within three months of onset for two in five people and within one year in others.(1) The risk of recurrence is 50% or more after recovery from the first depressive episode.(16) Strategies and management to prevent recurrence of one depressive episode can be highly effective.(163)

Diagnosis

Diagnosis of MDD is based on symptomatic criteria including the DSM-V (16) and the

International Classification of Diseases-10th Revision (ICD-10).(164)

A major depressive episode is diagnosed based on a single episode, but symptoms should be newly present or clearly worse compared with the status of the individual pre-episode. The following diagnostic criteria for MDD are adapted from the DSM-V (1) (Table 3.1):

Table 3.1 DSM-5 diagnostic criteria for a major depressive episode

A. Five (or more) of the following symptoms have been present during the same two-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

NOTE: Do not include symptoms that are clearly attributable to another medical condition.

• Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad, empty, hopeless) or observations made by others (eg, appears tearful). (NOTE: In children and adolescents, can be irritable mood). • Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). • Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of body weight in a month) or decrease or increase in appetite nearly every day. (NOTE: In children, consider failure to make expected weight gain). • Insomnia or hypersomnia nearly every day. • Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). • Fatigue or loss of energy nearly every day. • Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). • Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by their subjective account or as observed by others). • 9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

C. The episode is not attributable to the direct physiological effects of a substance or to another medical condition.

NOTE: Criteria A through C represent a major depressive episode.

NOTE: Responses to a significant loss (eg, bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability) may include the feelings of intense sadness, rumination about the loss, insomnia, poor appetite, and weight loss noted in Criterion A, which may resemble a depressive episode. Although such symptoms may be understandable or considered appropriate to the loss, the presence of a major depressive episode in addition to the normal response to a significant loss should also be carefully considered. This decision inevitably requires the exercise of clinical judgement based on the individual's history and the cultural norms for the expression of distress in the context of loss.

D. The occurence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders.

E. There has never been a manic or hypomanic episode.

NOTE: This exclusion does not apply if all of the manic-like or hypomanic-like epsidoes are substance-induced or are attributable to the physiological effects of another medical condition.

MDD can be classified as mild, moderate or severe based on depressive symptoms and functional impairment.(164) Mild depression presents with depressive symptoms, but symptoms can be manageable and social or occupational functioning shows only minor impairment. Moderate depression includes symptoms and functional impairment between mild and severe depression. People with mild depression may have withdrawal from social and work activities, decreased socialisation and vague or occasional suicidal thoughts. Severe depression includes withdrawal from social activites and relationships, severe functional impairment, recent suicide attempt or specific suicide plans or clear intent, or psychotic symptoms. The number of symptoms may be substantially more than those required criteria for diagnosis, the

severity of symptoms may be intensively distressed or unmanageable, and the symptoms markedly interfere with social functioning.(1)

Assessment of risk

Before treatment, assessment of suicide risk is essential. The following assessment factors are adapted from the Practice Guideline for the Treatment of Patients with Major Depressive

Disorder 2010(16):

• presence of suicidal or homicidal ideation, intent or plans

• history and seriousness of previous attempts

• access to means for suicide and the lethality of those means

• presence of severe anxiety, panic attacks, agitation and/or impulsivity

• presence of psychotic symptoms, such as command hallucinations

• poor reality testing

• presence of alcohol or other substance use

• family history of or recent exposure to suicide

• absence of protective factors

These factors do not predict attempted or complete suicide. Close monitoring is required of patients with depression and presenting signs of suicide or homicide intention or clear planning.

Psychiatric management and/or hospitalisation should be provided if the risk is significant.(16)

The severity and duration of depression should be routinely examined and determined.(165)

Treatment

The clinical management for depression focuses on treatment phases and treatment types. The goal in initial treatment is to achieve symptom remission and restore baseline functioning.(166)

In terms of minor depression, the primary treatment goal includes reducing depressive symptoms and improving functioning; additional goal is to alleviate other related symptoms, such as somatic or anxious symptoms, as well as prevent minor depression from progressing to major depression.(167) As for major depression (resistant depression), the standard management includes evaluating patients to confirm the diagnosis of unipolar depression, assessing adherence to current and past treatment, and determining if comorbidity presents and requires treatment.(168)

Treatment phases

Treatment of depression consists of three phases: acute (6 to 12 weeks), continuation (4 to 9 months) and maintenance (≥1 year) (Table 3.2)(169): each phase of treatment has different goals: 1) acute phase aims to achieve remission and return functioning; 2) continuation phase is to reduce the high risk of relapse and continue treatment; 3) maintenance phase aims to determine if the patient needs maintenance treatment.

Table 3.2 Treatment phases of MDD

Phase Pre-treatment Assessment Treatment Goals

Acute (6-12 weeks) Suicide risk • Induce remission • Achieve full return of patients’ level of functioning prior to the depressive episode Continuation (4-9 Monitor for signs of relapse • Reduce the high risk of relapse months) • Continue treatment

Maintenance Monitor for signs of • Determine if the patient needs (≥1year) recurrence maintenance treatment

Discontinuation For stable patients, consider discontinuation of treatment.

Monitoring Systematic assessment • Monitor for potential relapse • Schedule follow-up visit

Treatment types

Treatments include pharmacotherapy and non-pharmacotherapy. Selection of treatments for depression generally aims to help each patient receive the appropriate treatment among available treatment options which is most likely to contribute to positive outcomes.(170)

Lifestyle management should be considered for treatment of depression, including evidence- based therapies, such as dietary modification, physical exercise or activity, adequate relaxation, mindfulness-based meditation, social interaction, and the reduction of using substances (e.g. nicotine, drugs, and alcohol).(8, 171)

Pharmacological treatments

The use of antidepressants is determined by the severity and duration of depression.

Antidepressants are considered the first-line treatment for moderate and severe depression, but are not recommended for mild depression, especially in children or adolescents.(165) First- generation antidepressants include tricyclic antidepressants (TCAs) and monoamine oxidase

inhibitors (MAOIs), while second-generation antidepressants include SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs) and bupropion (Table 3.3).(16) Currently, in terms of efficacy and safety, the second-generation antidepressants are widely used for patients with depression, compared with the first-generation antidepressants that are rarely used today.(16,

172)

Table 3.3 Pharmacological treatments for MDD

Drug Class (mechanism of action) Drugs Usual Dose (mg/day)

Selective serotonin reuptake Citalopram 20–60 inhibitors (selectively inhibits the reuptake of serotonin) Escitalopram 10–20

Fluoxetine 20-60

Paroxetine 20-60

Paroxetine, extended release 25-75

Sertraline 50-200

Fluoxetine 20-60

Tricyclic antidepressants (non- Amitriptyline 25–50 100–300 100-300 selectively inhibits the reuptake of monoamines, including serotonin, Doxepin 100-300 dopamine, and norepinephrine) Imipramine 100-300

Desipramine 100-300

Nortriptyline 50-200

Trimipramine 75-300

Protriptyline 20-60

Maprotiline 100-225

Drug Class (mechanism of action) Drugs Usual Dose (mg/day)

Norepinephrine-dopamine reuptake Bupropion, immediate release 300–450 inhibitor (inhibits the reuptake of norepinephrine and dopamine) Bupropion, sustained release 300–400

Bupropion, extended release 300–450

Serotonin modulator (primarily Nefazodone 150-300 antagonises 5-HT2 receptors) Trazodone 150-600

Serotonin-norepinephrine reuptake Venlafaxine, immediate release 75-375 inhibitors (inhibits the reuptake of serotonin and norepinephrine) Venlafaxine, extended release 75-375

Desvenlafaxine 50

Duloxetine 60-120

Noradrenergic and specific Mirtazapine 15-45 serotonergic modulator (primarily antagonises α-2 and 5-HT2C receptors) MAO inhibitors (non-selectively Phenelzine 45-90 inhibits enzymes (MAO-A and MAO-B) involved in the Tranylcypromine 30-60 breakdown of monoamines, including serotonin, dopamine, and Isocarboxazid 30-60 norepinephrine MAO-B selective inhibitor) Selegiline transdermal 6-12

Moclobemide 300-600

Serotonin reuptake inhibitor and 5- Vilazodone 20-40 HT1A-receptor partial agonist (potently and selectively inhibits serotonin reuptake and acts as a partial agonist at the 5-HT1A receptor)

Note: Drug classes and dose information adapted from American Psychiatric Association 2010 and Kupfer 2012.(16, 146)

Non-pharmacological treatments

Non-pharmacological treatments for depression can alleviate depression symptoms and should be considered along with antidepressant therapy, especially for patients with mild-to-severe depression.(173) Non-pharmacological treatments include psychological and cognitive behavioural therapies, electroconvulsive therapy (ECT), light therapy and complementary and alternative treatments.

Psychotherapy and cognitive behavioural therapy (174) can be undertaken in the acute phase of mild to moderate depression.(165, 175) A study illustrated that the benefits of either pharmacotherapy alone or psychotherapy alone were comparable for patients with depression.(176) In terms of severe depression, psychological or behavioural treatment is routinely used as an add-on therapy to pharmacological therapy.(165)

ECT is recommended as a first-line treatment for severe depression.(177) It can be used in an emergency situation including not eating or drinking, extreme distress, depressive stupor, suicidality or depression accompanied with melancholia and psychotic features.(165, 178)

Light therapy combined with antidepressants is considered as a first-line treatment for the acute treatment of seasonal depression and as effective prophylaxis against relapse.(16)

Complementary and alternative treatments for depression commonly include St John’s wort, omega-3 fatty acids and acupuncture.(179) Chinese medicine (CM) is one of the common types of treatments including Chinese herbal medicine (CHM) and acupuncture. In CM theory, depression can be identified by symptoms and clinical features.(180) Currently, CM is commonly used to treat depression in China and emerging research indicates it may be an effective treatment.(23, 30, 179, 181-183)

Conclusion

MDD is extremely prevalent and disabling. The burden of this condition remains high, whether from individual distress, functional impairment, reduced quality of life, family and relationship problems, or societal economic cost.(184) The core principles of health care for depression should be applied, including precise diagnosis, comprehensive assessment, therapeutic alliance, evidence-based treatments, support of self-management, and measurement-based monitoring.

Chapter 4 Contemporary and Classical Chinese Medicine Therapies for

Major Depressive Disorder

Foreword

Chinese medicine (CM) understanding of disease is rooted in ancient knowledge including observation of patterns and symptoms rather than biomedical knowledge of the body and disease. A key element of CM theory is the unique conceptualisation of aetiology which encompasses yin/yang theory and five elements. These theories are not rooted in biomedicine or scientific understanding of the human body, rather they encompass elements of spiritual belief systems.(185)

Theories and treatments in CM have been widely preserved and used for over two thousand years.(59) Written records of the professional practice of CM are derived from records over

2,500 years, dating as far back as the Spring and Autumn periods (770–476 BC) and the

Warring states period (474–221 BC). Although there is an increasing amount of contemporary clinical evidence for the effectiveness of CM,(186) particularly Chinese herbal medicine (CHM) and acupuncture for depression,(21) the historical records continue to offer an abundance of knowledge and guide contemporary clinical practice.

The term ‘classical’ refers to ancient and traditional works written and/or published in dynastic

China rather than modern China. However, the shift from classical to modern literature styles cannot be identified exactly. The end of the Qing Dynasty (1644–1911) and the beginning of the Republic of China (the Year 1911) are considered to mark the political end of the traditional period, while China’s modernisation started since the establishment of the People’s Republic

of China (the Year 1949). Therefore, classical literature in this research is defined as any record published from the dynastic period up until 1949.

Search and analysis of the classical literature are a method to select potential herbs and formulae that may have positive effect on specific conditions.(187, 188) Furthermore, classical literature citations of CM may contribute to new drug exploration, exemplified by the discovery of artemisinin for malaria based on a historical passage from a CM book.(101)

Currently, there is no universally acknowledged methodology for systematic assessment of historical evidence from classical CM literature. The methodology presented in this chapter is based on the principles and standard operating procedures developed by the China–Australia

International Research Centre for Chinese Medicine between RMIT University and the

Guangdong Provincial Hospital of Chinese Medicine (GPHCM, Guangzhou, China).(189, 190)

This method involved a text-mining approach for systematic analysis of large collections of premodern CM literature. Based on this methodology, researchers can investigate changes in conceptions and names of a condition in different eras, identify particular threrapies that were more or less frequently used over time, and to assist in the selection of natural products for development of new drugs.(190)

Introduction

Major depressive disorder (MDD) is a modern disease term but depression symptoms can be traced back thousands of years. Traditional CM classical literature does not cite MDD as it is a modern conception of depression which has more specific features, based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V).(1) Therefore, the term

‘major depressive disorder’ cannot be found in classical CM literature texts. However, related

terms such as ‘sad’ (Bei 悲) and ‘worry’ (You 忧) can be found in medical books as old as the

Huang Di Nei Jing written before 618 AD. The negative effects of these emotions on an individuals’ wellbeing were also described in the Huang Di Nei Jing. Information on diagnosis and treatment for depression and related symptoms increased in volume and detail from the past to the present. The peak period was during the Ming dynasty (1368–1644) and Qing dynasty (1644–1911) when depression was presented in a similar way compared with the modern description of this condition. The terms used in traditional CM are more general compared with those used in modern medicine, but descriptions of depression in classical literature citations are broadly consistent with how it is understood today.

CM theory of depression

Based on traditional CM theory, depression is caused by the seven emotions and emotional frustration, which results in an imbalance of internal organs, yin and yang, and qi and Blood, leading to malnourishment of the shen (mind). The emotions are aligned with organ systems.

Depression is located in the Liver and related to the Heart, Spleen and Kidney. Note that these theories do not parallel conventional understanding of the organ functions. It may cause diseases when the seven emotions are in excess or deficient; for example, excessive anger injures the Liver which leads to Liver qi stagnation, while excessive thinking injures the Spleen and causes stagnation of Spleen qi, resulting in stagnant qi transforming into phlegm. If Liver qi is stagnant it may overact and impair the Spleen, resulting in a disharmony of the Liver and

Spleen. Stagnant Liver qi can transform into Fire leading to hyperactive Heart Fire. In addition,

Liver Fire can impair the yin, causing malnourishment of the Heart and drawing excessively from the Kidney, causing yin deficient Fire or Heart and Kidney yin deficiency. Stagnant

Spleen qi may result in phlegm-dampness and stagnant Liver qi may transform into fire. When

Liver fire is combined with dampness, turning into damp-heat, it may accumulate in the Liver and Gallbladder. Long-term stagnation of qi will affect the Blood, leading to Blood stasis. Also, when the Spleen is deficient, there is insufficient generation of qi and Blood, and when qi and

Blood are deficient, the Heart and mind are not nourished, resulting in melancholy disturbing the mind or deficiency of both the Heart and Spleen. The early stages of pathogenesis of depression is excess with stagnation of qi, Blood, dampness, phlegm, fire and food. In a long- term, there is deficiency or a complex syndrome of deficiency and excess.(180, 191) There is a paucity of research on CM theories and difficulty gathering evidence to prove the theories of

CM concepts such as “Blood stasis” or “stagnant Liver qi”.

Contemporary CM treatments

CM treatment principles

Currently, several references are used to guide clinical practice for depression based on CM syndrome differentiation. The Internal Medicine Branch of the China Association of Chinese

Medicine developed standards for diagnosis, syndrome differentiation and evaluation of the clinical effects of depression.(180) The China Academy of Chinese Medical Sciences developed an evidence-based clinical practice guideline of CM for depression based on findings from clinical trials using CM to treat depression as well as practitioners' consensus.

Although this guideline is not the standard for CM treatment for depression, it includes important suggestions and evaluation of the efficacy of CM based on current research evidence.(192) On the basis of existing standards and expert consensus, the Guidelines for

Depression Prevention and Treatment in China has been composed.(193) These guidelines are the main reference for practitioners in China in terms of treatments for depression.

The basic treatment principles of CM for depression are to regulate qi and soothe qi movement, treating with both elimination and reinforcement. When treating excess, it is important to regulate qi and activate Blood, purge fire, resolve phlegm, dispel dampness and promote digestion according to the underlying cause of stagnation, such as qi, Blood, dampness, phlegm, fire or food. In addition, attention should be paid to regulating qi rather than consuming qi, activating Blood rather than impairing Blood, clearing fire rather than injuring the Spleen and

Stomach, and dispelling phlegm rather than damaging healthy qi. As for deficiency syndrome, tonification should be based on the affected internal Zang fu organs, qi, Blood, yin and yang, using various treatment methods including nourishing the Heart and calming the mind, tonifying the Spleen and Stomach, and enriching and nourishing the Liver and Kidney. In terms of combined deficiency-excess syndrome, both deficiency and excess should be taken into consideration and treated according to the severity of the deficiency and excess.(180, 191)

Chinese herbal medicine

Traditional Chinese herbal medicine (CHM) for depression is based on syndrome differentiation. The following syndromes and herbal medicine formulae for depression are commonly used and based on the Guidelines for Diagnosis and Treatment of Common Internal

Diseases in Chinese Medicine-Symptoms of Modern Medicine,(180) the Evidence-based

Clinical Practice Guidelines of Chinese Medicine(192) and the Chinese Internal Medicine

Textbook.(191) A summary of syndromes and CHM treatments is presented in Table 4.1.

Liver qi stagnation

Clinical manifestations of Liver qi stagnation include depressed mood, emotional instability, irritability, chest distension and tightness, hypochondriac distension and pain, abdominal

distension, belching, loss of appetite, irregular bowel motions, thin and greasy tongue coating and string-like pulse. CM treatment principles should soothe the Liver and regulate qi. Herbal formulae that can be prescribed are modified Chai hu shu gan san (180, 191) and Xiao yao wan or Yue ju wan(192):

• Herbs that can be used include Chai hu, xiang fu, zhi ke, chen pi, yu jin, qing pi, zi su

gen, he huan pi, chuan xiong, shao yao and gan cao.

• Chai hu, xiang fu and zhi ke soothe the Liver, regulate qi and soothe the middle jiao

(Spleen and Stomach). Yu jin, qing pi, zi su gen and he huan pi regulate qi. Chuan xiong

regulates qi and activates Blood. Shao yao and gan cao soothe the Liver and release

tension. Gan cao harmonises all herbs.

Liver qi stagnation and phlegm stagnation

Clinical manifestations of this CM syndrome include depressed mood, chest tightness, hypochondriac distension, globus hystericus, white and greasy tongue coating and string-like and slippery pulse. Phlegm-heat manifestations include vomiting and nausea, bitter taste in the mouth, yellow and greasy tongue coating and string-like and slippery pulse. Treatment principles should regulate qi and resolve phlegm. Clear heat if it presents. CM herbal formulae can include modified Ban xia hou po tang(191, 192) or if combined with phlegm-heat, modified Wan dan tang can be used(192):

• The commonly used herbs for this syndrome include Ban xia, hou po, zi su, fu ling,

sheng jiang, zhu ru, zhi shi, chen pi and gan cao.

• The main actions of Hou po and zi su are regulating qi, soothing the chest and soothing

the Spleen and Stomach. Bai xia and sheng jiang resolve phlegm, dissipate stagnation

and harmonise the Stomach and direct qi downward. The combined use of bai xia and

zhu ru, which are warm and cool, stops vomiting and relieves irritability. Chen pi

regulates qi, moves stagnation, dries dampness and resolves phlegm. Zhi shi directs qi

downward, removes stagnation and relieves phlegm and fullness. The combination of

chen pi and zhi shi, which are warm and cool, regulates qi and resolves phlegm. Fu ling

tonifies the Spleen and drains dampness to cut off the source of phlegm.

Liver qi stagnation and Spleen qi deficiency

Clinical manifestations include low mood, chest tightness, hypochondriac distension, abdominal distension and belching, excessive thinking, feelings of uncertainty, worry, sighing, loss of appetite, weight loss, fatigue (especially after activities), menstrual irregularity, irregular bowel motions, thin and greasy tongue coating and fine and string-like pulse or string- like and slippery pulse. Soothing the Liver, tonifying the Spleen, resolving phlegm and dissipating stagnation are the treatment principles. Modified Xiao yao san combined with Ban xia hou po tang can be used for this syndrome(180):

• Chai hu, dang gui, bai shao, bai zhu, gan cao, bai xia, hou po, fu ling, sheng jiang and

zi su can be used.

• Chai hu soothes the Liver and regulates qi. Dang gui nourishes and harmonises Blood.

Bai shao nourishes Blood, replenishes yin, soothes the Liver and releases tension. Bai

zhu and fu ling tonify the Spleen and dispel dampness. Gan cao tonifies qi and the

middle, soothes the Liver and releases tension. Sheng jiang warms the Stomach and

harmonises the middle. Hou po and zi su regulate qi and soothe the middle. Bai xia, fu

ling and sheng jiang resolve phlegm, dissipate stagnation, harmonise the Stomach and

direct qi downward.

Qi stagnation transforming into fire

Clinical manifestations include emotional irritability, impatience and being easily angered, chest and hypochondriac fullness, dry bitter taste in the mouth or headache, red eyes and tinnitus; or epigastric distress, acid regurgitation, constipation, red tongue and yellow tongue coating, string-like and rapid pulse. Treatment principles include soothing the Liver, regulation of qi and purging fire. Modified Dan zhi xiao yao san can be used for this syndrome(191, 192):

• Herbs can be used including Chai hu, bo he, yu jin, xiang fu, dang gui, bai shao, bai

zhu, fu ling, mu dan pi and zhi zi.

• Chai hu, bo he, yu jin and xiang fu soothe the Liver and regulate qi. Dang gui and bai

shao can tonify Blood and soothe the Liver. Bai zhu and fu ling tonify the Spleen and

dispel dampness. Mu dan pi and zhi zi regulate the Liver qi and purge heat.

Qi stagnation with blood stasis

Clinical manifestations include depressed mood, irritability, headache, insomnia, forgetfulness, hypochondriac distension and pain, feelings of heat or cold in certain parts of the body, purple tongue with petechia and ecchymosis (red or purple spots or patches) and string-like or rough pulse. Regulating qi, activating Blood and resolving stasis are the treatment principles. CM formulae for this syndrome include modified Tong qiao huo xue tang combined with Si ni san or modified Xue fu zhu yu tang(192):

• Herbs for this syndrome include Tao ren, hong huo, dang gui, sheng di huang, niu xi,

chuan xiong, chi shao, chai hu, zhi ke, jie geng and gan cao.

• Tao ren breaks up Blood stagnation and moistens dryness. Hong hua activates Blood

and dispels stasis to relieve pain. Chi shao, chuan xiong and niu xi activate Blood,

unblock the meridians and dispel stasis to relieve pain. Sheng di huang and dang gui

tonify Blood, replenish yin, clear heat and activate Blood. Chai hu soothes the Liver

and regulates qi. Jie geng soothes the chest and regulates qi. The combined use of chai

hu, jie geng and zhi ke regulates qi and moves stagnation to promote the movement of

qi and Blood. Gan cao harmonises all herbs.

Liver-gallbladder damp-heat

Clinical manifestations include depressed mood or emotional irritability, insomnia with dream- disturbed sleep, hypochondriac distension, bitter taste in the mouth and loss of appetite, vomiting and nausea, fullness in the epigastrium, irregular bowel motions, reddish-yellow urine, red tongue and yellow greasy tongue coating and string-like, slippery, and rapid pulse.

Treatment for this syndrome should clear the Liver and drain the Gallbladder, clear damp-heat and nourish the Heart to calm the mind. Formulae that can be used include modified Long dan xie gan tang(180):

• Long dan cao, zhi zi, huang qin, mu tong, ze xie, che qian zi, chai hu, dang gui, sheng

di huang and gan cao can be used.

• Long dan cao clears the Liver, drains the Gallbladder and clears damp-heat in the Liver

meridian. Huang qin and zhi zi dry dampness and clear heat. Ze xie, mu tong and che

qian zi drain dampness, purge heat and conduct fire back to its origin. Dang gui and

sheng di huang nourish Blood and enrich yin, which leads to the removal of unhealthy

qi without impairing yin and Blood. Chai hu soothes the Liver and regulates qi. Gan

cao harmonises all herbs.

Yin deficiency with fire

Clinical manifestations of this syndrome refer to emotional depression, irritability, sadness, loss of interest, loss of willpower, being easily frightened, trance-like state, slow response and slow movements, hypochondriac distension and pain, abdominal distension and belching, loss of appetite, aching and cold lower back and knees, red complexion, night sweating, heat on the palms and soles, dry mouth and throat, red tongue with little coating and string-like, thin and rapid pulse. Treatment should clear heat and soothe the Liver, enrich the Kidney and nourish yin. Modified Zi shui qin gan yin can be used(180, 192):

• Herbs for this condition include Shu di huang, dang gui, bai shao, suan zao ren, shan

zhu yu, fu ling, shan yao, chai hu, zhi zi, mu dan pi and ze xie.

• Shu di huang, shan yao and shan zhu yu enrich the Kidney and nourish yin. Dang gui

tonifies qi and Blood. Bai shao nourishes Blood, replenishes yin, soothes the Liver and

releases tension. Fu ling and suan zao ren tonify the Heart to calm the mind. Chai hu

soothes the Liver and regulates qi. Mu dan pi and zhi zi cool Blood and clear heat. Ze

xie drains dampness and purges heat.

Deficiency of the Heart and Spleen

Clinical manifestations include worry, paranoia, dizziness, lassitude, palpitations, timidity, insomnia, forgetfulness, loss of appetite, dull complexion, pale tongue with white and thin coating and fine, weak pulse. Tonification of the Spleen and Heart and tonification of qi and

Blood can be as treatment principles. Modified Gui pi tang can be used(191, 192):

• Herbs include Ren shen, bai zhu, huang qi, dang gui, fu ling, yuan zhi, suan zao ren,

mu xiang, long yan rou, sheng jiang, da zao and gan cao.

• Ren shen, bai zhu and huang qi tonify qi and the Spleen to generate Blood. Dang gui

and long yan rou tonify qi and nourish the Heart. Fu ling, suan zao ren and yuan zhi

tonify the Heart to calm the mind. Mu xiang regulates qi and nourishes the Spleen. Gan

cao, sheng jiang and da zao harmonise the Spleen and the Stomach.

Heart and Kidney yin deficiency

Clinical manifestations include emotional instability, palpitations, forgetfulness, insomnia, dream-disturbed sleep, vexing heat in the chest, palms and soles, night sweats, thirst and dry throat, red tongue with little moisture and fine pulse. Tonification of the Heart and Kidney yin should be used. Formulae for this syndrome include modified Tian wang bu xin dan combined with Liu wei di huang wan(191):

• Herbs include Di huang, shan yao, shan zhu yu, tian dong, mai dong, xuan shen, ren

shen, fu ling, wu wei zi, dang gui, bai zi ren, suan zao ren, yuan zhi, dan shen and mu

dan pi.

• Di huang, shan yao, shan zhu yu, tian dong, mai dong and xuan shen tonify the Heart

and Kidney. Ren shen, fu ling, wu wei zi and dang gui tonify qi and Blood. Bai zi ren,

suan zao ren, yuan zhi and dan shen tonify the Heart to calm the mind. Mu dan pi cools

the Blood and clears heat.

Melancholy disturbing the mind

Clinical manifestations include mental confusion, paranoia, being easily frightened, sadness with crying, irritability, fatigue, overactive body movements, mania or delirium, pale tongue and string-like pulse. Treatment should nourish the Heart to calm the mind, moisten and release tension using herbs with sweet properties. Modified Gan mai da zao tang can be used for this syndrome(180, 191, 192):

• Herbs mainly include Gan cao, xiao mai and da zao.

• Gan cao moistens and releases tension with its sweet property. Xiao mai tonifies the

Heart qi. Da zao tonifies Blood and replenishes the Spleen.

Table 4.1 Summary of Chinese herbal medicines for MDD

Syndrome Treatment Principle Formula(e) Differentiation Liver qi stagnation Soothe the Liver, Modified Chai hu shu gan san, Xiao regulate qi, and soothe yao wan, or Yue ju wan the Spleen and Stomach

Liver qi stagnation and Move qi, resolve phlegm, Modified Ban xia hou po tang, or if phlegm stagnation and clear heat. combined with phlegm-heat, use modified Wan dan tang

Liver qi stagnation and Soothe the Liver and Modified Xiao yao san combined Spleen qi deficiency tonify the Spleen, resolve with Ban xia hou po tang phlegm and dissipate stagnation.

Qi stagnation Soothe the Liver and Modified Dan zhi xiao yao san transforming into fire regulate qi, clear the Liver and purge fire.

Qi stagnation with Blood Regulate qi, activate Modified Tong qiao huo xue tang stasis Blood, and resolve stasis. combined with Si ni san or modified Xue fu zhu yu tang

Liver-Gallbladder damp- Clear the Liver and drain Modified Long dan xie gan tang heat the Gallbladder.

Syndrome Treatment Principle Formula(e) Differentiation Yin deficiency with fire Clear heat and soothe the Liver, enrich the Kidney Modified Zi shui qin gan yin and nourish yin.

Deficiency of the Heart Tonify the Spleen and Modified Gui pi tang and Spleen nourish the Heart, tonify qi and Blood. Heart and Kidney yin Tonify the Heart and Modified Tian wang bu xin dan deficiency Kidney yin combined with Liu wei di huang wan

Melancholy disturbing Nourish the Heart to Modified Gan mai da zao tang the mind calm the mind, moisten and release tension with sweet herbs.

Acupuncture

Acupuncture has been documented since the publication of the Huang Di Nei Jing (written before 618 AD). Acupuncture may reduce depressive symptoms and physical symptoms.

Excess syndromes should be treated with purging methods, while deficiency syndromes should be treated with tonifying methods. Acupuncture points that are commonly used for this condition are summarised below(180):

• HT7 Shen men can calm the spirit, regulate and tonify the Heart;

• PC6 Nei guan unbinds the chest and regulates qi, regulates the Heart, calms the spirit,

harmonises the Stomach and alleviates nausea and vomiting, clears heat and opens the

yin linking vessels;

• PC7 Da ling clears heat from the Heart and calms the spirit, harmonises the Stomach

and intestines, unbinds the chest and cools Blood;

• LR14 Qi men can spread the Liver and regulate qi, invigorate Blood and disperse

masses, and harmonise the Liver and Stomach;

• BL15 Xin shu tonifies and nourishes the Heart, regulates Heart qi, calms the spirit,

unbinds the chest, resolves Blood stasis and clears Heart fire;

• LI4 He gu activates the channels, alleviates pain and restores the yang;

• LR3 Tai chong can nourish Liver Blood and Liver yin and clear the head and eyes.

Specific acupuncture points should be added based on syndrome differentiation, as shown in

Table 4.2.

Table 4.2 Summary of acupuncture for MDD

Syndrome Treatment Principle Acupuncture Points Differentiation Soothe the Liver, Add LR2 Xing jian and BL18 Gan Liver qi stagnation regulate qi, and soothe shu the Middle Jiao (Spleen and Stomach).

Liver qi stagnation and Soothe the Liver and Add BL18 Gan shu, BL20 Pi shu, Spleen qi deficiency tonify the Spleen, and ST36 Zu san li resolve phlegm and dissipate stagnation.

Liver-Gallbladder damp- Clear the Liver and Add LR14 Qi men, GB24 Ri yue, heat drain the Gallbladder. KI3 Tai xi, and SP6 San yin jiao

Yin deficiency with fire Clear heat and soothe Add BL23 Shenshu, BL18 Gan shu, the Liver, enrich the and KI3 Tai xi Kidney and nourish yin. Melancholy disturbing Nourish the Heart to Add GV20 Bai hui, HT5 Tong li, the mind calm the mind, moisten and GB24 Ri yue and release tension with sweet herbs.

Search and analysis of the classical Chinese medicine literature

To better understand the use of traditional CM therapies for depression and potentially guide future clinical practice or rediscover ancient practices, this study searched and analysed the

classical CM literature. The aim of the study was to identify CM treatments that had been referenced and used for conditions similar to depression. In addition, this study aimed to reveal the most frequently used individual herbs, CHM formulae and acupuncture points for depression cited in historical literature.

Methods

Search strategy

Depression is a modern disease name and cannot be used to search for classical literature citations. However, CM disease terminologies include various traditional disease names and symptoms that are relevant to depression. To identify CM disease names or symptoms related to depression, textbooks, official CM clinical practice guidelines and CM dictionaries as well as consultation with experts were used.(180, 191, 192, 194-197) The selected search terms most relevant to depression can be categorised into four groups (Table 4.3):

• Yu (depression) and its synonyms

• depressive symptomatic terms such as ‘sadness’ and its synonyms

• CM disease terms that present with depressive disorder symptoms, for example, zang

zao, a CM disease that presents with sadness, tendency to cry, inability to concentrate,

unstable mood and restlessness

• ‘suicide’ and its synonyms

Table 4.3 Search terms related to depression

Pinyin Chinese Characters English Translation Yu 郁 Depression with other diseases or symptoms Yu Bin 郁病 Depression with other diseases or symptoms Yu Zheng 郁证 Depression with other diseases or symptoms Yu Zheng 郁症 Depression with other diseases or symptoms You 忧 Sadness/worry or with other symptoms You Si 忧思 Sadness/worry or with other symptoms You lv 忧虑 Sadness/worry or with other symptoms Bei 悲 Sadness Bei Shang 悲伤 Sadness Bei Die 卑惵 Sadness or with fear Shen Tui 神颓 Sadness with fatigue Zang Zao 脏躁 CM disease with depressive disorder symptoms Mei He Qi 梅核气 CM disease with depressive disorder symptoms: feels like something stuck in throat Shi Zhi 失志 CM disease with depressive disorder symptoms: loss of ambition and confidence or feel the lack of something Bai He Bing 百合病 CM disease with depressive disorder symptoms Ben Tun Qi 奔豚气 CM disease with depressive disorder symptoms: feels like something rush to the chest from the abdomen Zi Sha 自杀 Suicide Zi Jin 自尽 Suicide Zi Yi 自缢 Suicide Zi Wen 自刎 Suicide

After confirming the search terms, an electronic search was conducted in the Zhong Hua Yi

Dian (ZHYD)(198) to obtain a vast sample of the classical and pre-modern medical literature

on depression. The ZHYD, is a CD-ROM with 1,156 books of traditional CM included, and is the largest currently available collection and representative of other collections and pre-modern

CM literature.(188, 199) These books cover CM publications from 200 BC to the period of the

Republic of China (1911–1948).

Pilot search

A pilot search was implemented to test search terms. Search terms were confirmed based on the results of the pilot search to ensure approporiate citations were selected in the full search.

Eligibility

The inclusion of citations was judged by whether their description included at least one main symptom of depression (depressed mood or diminished interest), or plus two or more of the following associated symptoms: changed appetite, poor sleep, fatigue, feeling of worthlessness, agitation or retardation, diminished ability to concentrate, thoughts of death, etc. Citations that most closely corresponded to the modern conception of depression were included. Citations irrelevant to depression were coded and removed from the data set.

• Inclusion criteria

a. relevant to depression

b. including treatment information

• Exclusion criteria

a. relevant to other types of mood disorders, such as bipolar disorder or anxiety

disorder

b. relevant to psychiatric disorders such as mania, hypomania, bipolar disorder

or schizophrenia

c. attributable to physical diseases or another medical condition

d. attributable to the effects of substances

e. relevant to children

f. written after 1949

Data collection and extraction

Citations were exported into a Microsoft® Excel spreadsheet. Citation source, book dynasty, authors, symptoms/signs, formulae names and ingredients were extracted after removing duplicates.

Rating and coding

At this step, all citations were reviewed and rated to identify the best descriptions of depression.

The final data set included citations considered to be potentially associated with depression.

Rating categories accorded to a predefined coding system including the following items:

• book dynasty

• core content (whether the citation was relevant to depression or not)

• main complaint

• accompanying conditions

• symptoms

• treatment type (herbal formula, acupuncture or combined herbal formula and

acupuncture)

• CHM formula names

• herbal ingredients

• acupuncture points

• differential diagnosis

• type of patients (such as male/female, chilren/elderly)

• citation type (whether the citation referred to a case study or not)

When a citation referred to multiple treatments, each treatment was treated as a separate citation for further data analysis. Citations from pharmacopeia entries that only described names of CM diseases or symptoms without detailed information on these conditions were excluded.

Contrarily, citations in pharmacopeia entries which included detailed description of the condition, with or without reference to other herbs, were included. Acupuncture points were reviewed in a similar approach. Overall judgements were made by two researchers (LY and

YMD) independently. Any disagreement was discussed with a third researcher (JS).

Data synthesis and analysis

The data was transferred to SPSS (IBM® SPSS® Statistics Version 22) for statistical analysis:

• basic characteristics: present basic characteristics of all citations, including search

terms, number of citations, book title, authors, book dynasty, CHM formulas, herbs or

acupoints

• frequency analysis: assess the frequency of CHM formula, herbs and acupoints

Results

Twenty terms were searched, and 4,806 citations were identified (Table 4.4). Identified citations were from 649 classical books. The earliest book that mentioned conditions similar to depression was the Huang Di Nei Jing (AD 618), while the most recent classical book was the

Ben cao jian yao fang (1938). The highest number of citations was from the Ben cao gang mu with 22 citations (6.5%). The majority of citations were from the Qing dynasty (1645–1911) with 2,216 citations (46.1%), followed by the Ming dynasty (1369–1644) with 1,291 citations

(26.9%).

The search term You si (‘sadness with overthinking’) found the largest proportion of citations

(925, 19.3%). The term You lv (‘sadness with excessive worry’) found the second largest number of citations (825, 17.2%). Search terms that directly related to depression symptoms also produced high numbers of citations, such as Shi zhi (447, 9.3%), Bai he bing (416, 8.7%) and Bei shang (374, 7.8%). The term Shen tui found the smallest number of citations (5, 0.1%).

The number and proportion of citations from each search term are presented in Hit frequency by search term.

A total of 319 citations related to depression with treatment information were included for data analysis. 290 citations described depressed mood and 103 citations specified loss of interest.

Other citations did not clearly state or describe depressive symptoms. For those citations that did not clearly mention depressed mood or loss of interest, the citation had a CM diagnosis

such as Yu zheng, Yu bing, Bei die or Zang zao. More than one-third (36.0%) of citations were specifically related to females. Yu (146, 45.8%), Bei (78, 24.5%), and Yu bing (37, 11.6%) located the most relevant citations for depression. The total percentage may exceed one hundred precent because some citations were identified by more than one search term.

Table 4.4 Hit frequency by search term

Pinyin Chinese Characters Hit Frequency (n, %) Relevant Citation Frequency (n, %)

You si 忧思 925 (19.3) 1 (0.3)

You lv 忧虑 825 (17.2) 1 (0.3)

Shi zhi 失志 447 (9.3) 8 (2.5)

Bai he bing 百合病 416 (8.7) 1 (0.3)

Bei shang 悲伤 374 (7.8) 0 (0.0)

Yu 郁 321 (6.7) 146 (45.8)

Zi yi 自缢 254 (5.3) 5 (1.6)

Mei he qi 梅核气 246 (5.1) 6 (1.9)

Bei 悲 195 (4.1) 78 (24.5)

Yu zheng 郁证 180 (3.8) 3 (0.9)

Yu zheng 郁症 144 (3.0) 24 (7.5)

Zi jin 自尽 103 (2.1) 1 (0.3)

Yu bing 郁病 80 (1.7) 37 (11.6)

Ben tun qi 奔豚气 72 (1.5) 0 (0.0)

Zang zao 脏躁 66 (1.4) 6 (1.9)

You 忧 47 (1.0) 0 (0.0)

Pinyin Chinese Characters Hit Frequency (n, %) Relevant Citation Frequency (n, %)

Zi sha 自杀 45 (0.9) 0 (0.0)

Zi wen 自刎 38 (0.8) 0 (0.0)

Bei die 卑惵 23 (0.5) 2 (0.6)

Shen tui 神颓 5 (0.1) 0 (0.0)

Total 4806 319

Frequency of treatment citations by dynasty

The largest proportion of citations from classical books was from the Ming and Qing dynasties, accounting for 84.6%. The result showed that knowledge on this condition was at its peak during these periods. Dynastic distribution of treatment citations outlines the distribution of citations with treatment information sorted by dynasty (Figure 4-1).

350 319

300

250

200

148 150 122

100

2 1 5 4 7 8 0

Figure 4-1 Dynastic distribution of treatment citations

Chinese herbal medicine results

CHM formulae were the most frequently used therapies with 297 citations for depression and conditions analogous to depression, which accounted for 93.1% among included citations.

Most CHM formulae were named, but some formulae just included the herbal ingredients without providing a formula name. Eight citations combined oral formula with external wash therapy.

Frequently cited herbal formulae

The three most frequently used formulae were modified Gan mai da zao tang (63 citations),

Gui pi tang (29) and Qi fu yin (8). There were 20 citations that did not have a formula name, but 5 citations provided the same herb ingredients as Gan mai da zao tang. The first historical record of Gan mai da zao tang was from the book Jin Gui Yao Lue (206 AD), which is specially used for the CM disease Zang zao. The formula, which nourishes the Heart and calms the mind, only included three herb ingredients (gan cao, xiao mai and da zao). It stated that ‘woman with

Zang zao feel sad and tend to cry with no apparent cause, frequent yawning, and should be treated with Gan mai da zao tang’. This formula is still widely used in contemporary CM practice for females and postpartum. The most common formulae found in citations are presented in Table 4.5.

Table 4.5 Most frequently cited herbal formulae

Formula Name Herb Ingredients No. of Citations (n)

Gan mai da zao tang gan cao, xiao mai, da zao 63

Gui pi tang/ wan bai zhu, dang gui, fu ling, huang qi, long dan 29 rou, yuan zhi, suan zao ren, mu xiang, gan cao, and ren shen

Qi fu yin ren shen, shu di huang, dang gui, bai zhu, gan 8 cao, suan zao ren, yuan zhi

Qi qi tang ren shen, gan cao, rou gui, ban xia 7

Ren shen yang rong ren shen, bai zhu, huang qi, gan cao, chen pi, 7 tang rou gui, dang gui, shu di huang, wu wei zi, fu ling, yuan zhi, bai shao

Zi su zi tang zi su zi, da fu pi, cao guo, ban xia, hou po, mu 7 xiang, chen pi, mu tong, bai zhu, zhi shi, ren shen, gan cao

Formula Name Herb Ingredients No. of Citations (n)

Xiao yan san chai hu, dang gui, bai shao, bai zhu, fu ling, 6 sheng jiang, bo he, gan cao

Dan zhu ru tang mai dong, xiao mai, ban xia, ren shen, fu ling, 6 gan cao, sheng jiang, da zao, dan zhu ru

dan zhu ru, mai dong, gan cao, xiao mai, sheng 5 jiang, da zao

Sheng chai jun zi tang ren shen, bai zhu, fu ling, gan cao, chai hu, zhi 5 zi, sheng ma

Wen dan tang bai xia, dan zhu ru, zhi shi, chen pi, gan cao, fu 5 ling

Chen xiang jiang qi xiang fu, chen xiang, sha ren, gan cao 4 tang

Bai he di huang tang bai he, sheng di huang 4

Er chen tang chen pi, ban xia, fu ling, bai zhu, cang zhu, sha 4 ren, shan yao, che qian zi, mu tong, hou po, gan cao

ban xia, ju hong, fu ling, gan cao, shao yao, 1 dang gui, wu yao, qin pi, zhi qiao, xiang fu, hou po, zi su ye

Bu zhong yi qi tang huang qi, gan cao, ren shen, dang gui, chen pi, 3 sheng ma, chai hu, bai zhu

The use of some herbs such as mu xiang may be restricted in some countries.

Frequently cited herbs

A total of 151 herbs were used in the herbal formulae. The most frequent herb was Gan cao

(238 citations), which is the key herbal ingredient in Gan mai da zao tang and also used as a harmonising herb. Ren shen (123 citations), Fu ling/fu shen (119 citations) and Bai zhu (98

citations) were also commonly used herbs. The most frequent herbs found in depression citations are included in Table 4.6.

Table 4.6 Most frequently cited herbs

Herb Name Scientific Name No. of Citations (n) Gan cao/zhi gan cao Glycyrrhiza spp. 238 (232/6) Ren shen Panax ginseng C.A. Mey 123 Fu ling/ fu shen Porias cocos (Schw.) Wolf 119 (99/20) Bai zhu Atractylodes macrocephala Koidz 98 Dang gui Angelica sinensis (Oliv.) Diels 93 Da zao Ziziphus jujube Mill. 92 Xiao mai Triticum aestivum L. 79 Yuan zhi Polygala tenuifolia Willd. var. sibirica 68 L. Mu xiang Aucklandia lappa Decne. 62 Suan zao ren Ziziphus jujuba Mill. var. spinosa 58 (Bunge) Hu ex H. F. Chou Jiang/sheng jiang/gan jiang Zingiber officinale Rosc. 51 (8/34/9) Chen pi Citrus reticulata Blanco 50 Di huang Rehmannia glutinosa Libosch. 47 Shao yao Paeonia lactiflora Pall. 40 Ban xia Pinellia ternata (Thunb.) Breit. 36 Long yan rou Dimocarpus longan Lour. 36 Rou gui/gui zhi Cinnamomum cassia Presl 37 (33/4) Chai hu Bupleurum chinense DC. var. 33 scorzonerifolium Willd. Zhi shi Citrus aurantium L. var. sinensis 28 Osbeck Mai dong Ophiopogon japonicus (L.f) Ker- 27 Gawl. Zhi zi Gardenia jasminoides Ellis 23 The use of some herbs may be restricted in some countries.

Acupuncture results

There were very few citations that described acupuncture or moxibustion for depression. This was only found in eight citations including five acupuncture and three moxibustion citations.

Acupuncture points included PC7 Da ling, PC5 Jian shi, PC6 Nei guan, KI6 Zhao hai and

BL15 Xin shu. For example: one citation from the Huang Di Nei Jing Tai Su stated that ‘Those who are sad can be treated from the Jueyin meridian, tonify or reduce depending on the disease condition’. The Zhen Jiu Jia Yi Jing stated: ‘heartache, feeling sorrow, qi upsurge, emptiness in the Heart, feeling no interest and edgy, use PC7 Da ling and PC5 Jian shi; feeling no interest and frightened, feeling sad, use PC6 Nei guan.’ Another citation stated, ‘Feeling edgy, unhappy and depressed, feeling down, no sweating, dark complexion, no appetite, use KI6 Zhao hai.’

Acupuncture combined with CHM results

In terms of combining herbal formulae and moxibustion for depressive symptoms, the Bian

Que Xin Shu stated that ‘when patient reaches middle-age, his constitution will weaken, Heart-

Blood may be consumed by overthinking, melancholy, or greed, until Jing qi is depleted and results in death. Treat with moxibustion on CV4 Guan yuan plus CHM formula Yan shou dan.’

Discussion

Summary of evidence

MDD, unipolar depression and depression are modern disease terms. These terms cannot be used to search and identify information in classical literature. However, CM disease terms related to depression have appeared in classical literature texts as early as the Huang Di Nei

Jing. In the dynastic period of China, CM doctors treated depression based on traditional CM

theory, which refers to CM theory on aetiology and syndromes. For example, qi and phlegm stagnation primarily contributed to depression.

The search results showed classical literature citations for conditions that are consistent with depression. The inclusion criteria were effective in including specific citations and the search terms were accurate in locating relevant herbs and formulae, while the exclusion criteria were effective in removing non-specific citations. Yu (146, 45.8%), Bei (78, 24.5%) and Yu bing (37,

11.6%) successfully located a considerable number of citations that were relevant to depression, followed by Zang zao, Yu zhen, Bei, Bai he bing, You lv, Bei die, Zi yi, Yu bing, Yu zheng and

Mei he qi. Yu bing is considered the modern term for depression which is commonly used in contemporary guidelines or textbooks of CM for depression.(180, 191, 192) The results also revealed that depression is correlated to the CM disease diagnoses of Zang zao, Mei he qi, Bai he bing, Ben tun qi and Bei die, which are consistent with the understanding of modern CM of depression.(195) The majority of classical literature citations are relevant to depression and related symptoms.

Although citations did not describe depression according to diagnosed symptoms like the modern guidelines for disease classification, all citations were reviewed and judged to be most likely about depression based on main and associated symptoms. Main symptoms included depressed mood and loss of interest, while associated symptoms included change in appetite or sleep, psychomotor agitation, fatigue, feeling of worthlessness, excessive or inappropriate guilt, diminished ability to think or concentrate, thoughts of death and irritability, tension or anxiety. The most common main symptom was depressed mood and the most common associated symptoms were tension and anxiety. This finding is consistent with contemporary understanding of depression.(1) The modern conception of this condition often refers to tension

or anxiety as highly relevant to depression.(1) Particularly, depression in females and postpartum, which was commonly found in citations. This is also in line with modern understanding of depression.(200)

The largest proportion of depression citations cited in classical literature were from the Ming and Qing dynasties. This indicates that knowledge of the condition and its treatments was at a peak during these periods. The majority of included citations described oral CHM formulae, while there were few acupuncture and moxibustion citations. The reason could not be clearly identified but is likely because acupuncture and moxibustion may not have been popular for conditions similar to depression in ancient periods, or CHM may have showed superior effects compared with other CM therapies.

The most frequently used formulae and their herb ingredients identified in the classical literature are still commonly used today(201, 202) such as Gan mai da zao tang and Gui pi tang. These formulae are also recommended in the contemporary CM clinical guidelines for depression.(180, 192) Commonly cited herbs included fu ling, ren shen, bai zhu and dang gui.

The analysis of herb frequencies informs researchers what treatments were used for conditions broadly consistent with depression.

Although contemporary treatments for depression often include acupuncture and it is recommended in clinical practice guidelines,(179) acupuncture was only found in a few classical literature citations. Included citations that described acupuncture showed points: PC7

Da ling, PC5 Jian shi, PC6 Nei guan, KI3 Zhao hai and BL15 Xin shu were common.

Limitations of this study

The classical literature is abundant, but the scope of this search was limited to 20 search terms.

All these terms were based on textbooks, official CM clinical practice guidelines and CM dictionaries as well as practitioners’ consensus but are not all-inclusive and there may be missed terms that are likely to be related to depression.

The search was only performed using one published collection, the ZHYD. This CD-ROM is comprehensive and representative of a wide range of classical works across the span of eras; however, it is still not comprehensive, and the results do not represent all possible books available.

Defining search terms related to depression is an issue since classical terms change over time, contributing incorrectly included citations. Although the search terms used in this study were most likely matched to and aligned with depression, citations may have been missed due to the vast extent of classical literature. Two experienced researchers manually extracted the data, but misinterpretation or mistakes still may have occurred. However, these limitations should be few and not alter or affect the overall data.

Implications for clinical practice

A summary of clinical guidelines and textbooks provides important guidance for CM practice in people with depression. Depression is a condition that arises from emotional upset, overthinking or excess worry. In terms of CM theory, the main organs involved are the Liver,

Heart, Spleen and Kidney. Liver qi stagnation has been described across contemporary and classical evidence, and it should be considered the main syndrome of depression.

Implications for future research

Some clinical trials have evaluated the efficacy and safety of Gan mai da zao tang and Gui pi tang for depression. These formulae are the two most frequently used formulae in this study.(38,

203) Encouraging evidence is available for CHM but there is still a lack of high-quality evidence. Further research on formulae identified in this study should increase and improve the quality of evidence. Despite the common use of several herbs in clinical studies, preclinical studies relevant to depression are limited. Future experimental studies will improve the understanding of the mechanisms of actions of herbal formula and may lead to new therapeutic agents.

Conclusion

Contemporary CM treatments are mainly based on resources of textbooks and clinical guidelines. The search and analysis of classical literature found a considerable number of citations that were broadly consistent with depression. The method used in this study was rational and systematic. The search terms were successful in locating relevant conditions for depression. The relevant citations were also able to identify individual herbs and formulae that can be potentially used in practice, while the herbs and formulae used in the classical literature were broadly similar to what is used in the contemporary setting. The findings can guide further clinical studies and experimental research.

Chapter 5 Chinese Herbal Medicine for Major Depressive Disorder: A

Systematic Review and Meta-analysis of Randomised Controlled Trials

Introduction

Based on conventional medicine, major depressive disorder (MDD) is characterised by depressed mood, diminished interest or pleasure, significant weight or appetite change, insomnia or hypersomnia, psychomotor agitation or retardation, loss of energy or fatigue, inappropriate guilt or feelings of worthlessness, diminished ability to concentrate or make decisions, or thoughts of death or suicide.(1) According to Chinese medicine (CM), depression is caused by an imbalance within internal organ systems with various CM pathological mechanisms among different individual patients, likely caused by stagnation of qi, Blood stasis or damp-heat.(204) In primary care practice for patients with MDD, antidepressants are commonly prescribed, such as selective serotonin reuptake inhibitors (SSRI).(9, 10) American and British treatment guidelines recommend that people with depression take medication for at least six months after remission to make sure their symptoms remain stable.(14-16) However, about one-quarter of patients become non-compliant when using antidepressants.(17) This non- compliance is sometimes due to adverse events such as dry mouth, dizziness, gastrointestinal effects, sexual dysfunction, sedation and weight gain.(11, 13, 19, 205) Discontinuing medication and non-compliance have been reported to be associated with increased risk of recurrence of depression and high medical costs.(18, 20)

People with depression often use herbal medicine to treat their symptoms to avoid adverse events caused by antidepressants and because they believe complementary and alternative medicine (CAM) is safe.(206, 207) Research also indicates depression is an indicator and predictor of CAM use.(208, 209) However, more research into CAM for psychological disorders is needed to make sure it is safe and effective due to its widespread use.(210, 211)

As one common types of CAM, CM mainly includes Chinese herbal medicine (CHM) and acupuncture.(59, 212) CHM and acupuncture have been used to treat depression in Asia for thousands of years and are being increasingly used in Western countries.(21, 213)

Research has revealed a variety of chemicals, pharmacological agents and clinical benefits of herbs for depression.(214, 215) The mechanisms underlying CHM’s antidepressant effects include reduced activation of the hypothalamic–pituitary–adrenal axis, enhancement of monoamine and neuroimmune response, and neurotrophic factors.(216) The full extent of

CHM’s effects is not fully understood; however, it is likely they produce antidepressant effects through multiple pathways or targets which interact with each other.(183)

A systematic review answers a defined research question by collecting and summarising all empirical evidence that fits pre-specified eligibility criteria.(45) The process of systematic reviews is to systematically search and critically appraise all RCTs on particular topic.(217)

Meta-analysis, described as “the analysis of the analyses”(218), is a key technique that uses statistical methods to combine and summarise the results of studies with different sample sizes.(45) The Cochrane Collaboration developed many methodological advances in designing,

performing and reporting of systematic reviews and meta-analyses, and the Cochrane

Handbook(45) is the key textbook to guide the conduct of systematic reviews and meta- analyses.(219) A meta-analysis should only be conducted when participants, study design, interventions and controls, and outcomes in studies are sufficiently similar, of which data could be justifiedly synthesised. However, inevitably, included studies that are synthesised in systematic reviews differ in some aspects.(217, 219) Assessment for the consistency of the findings across included studies is important in the meta-analysis.(220) The generalisability of the results of meta-analysis cannot be concluded if the data is inconsistent.(219) Undertaking systematic review and meta-analysis has pros and cons.(219) Although existing available data is thoroughly searched for a particular topic, it may have limitations on what aggregate data can be used in a systematic review, incluing not all trails identified(221), not all trials used the same comparison(222), not all outcomes available(223), etc. Nevertheless, systematic reviews and meta-analyses can minimise bias and to maximise available evidence, informing decision- makers.(45, 219) Assessing the effectiveness of interventions, systematic reviews and meta- analyses are at the top of the hierarchy of evidence.(217) A screening of CM systematic reviews published in the Cochrane library database showed that almost all of the reviews commented on the limited quality of clinical trials, and negating any definitive conclusion on the effectiveness of CHM, due to diversity of participants, different herbs used and control groups, difficulty blinding and the placebo effect.(60) Recent systematic reviews of CHM for depression have some of the limitations identified above. However, these issues cannot be rectified until new evidence from RCTs becomes available.

Yeung et al. reported the efficacy and safety of CHM for dysthymia, depression, mood disorders, etc.(39) This systematic review included 296 studies and involved 24,867 participants. The meta-analysis showed that CHM was superior to placebo, but there were no significant differences between CHM and antidepressants. The quality of all studies was assessed by a modified Jadad scale and Cochrane's assessment tool. However, most included studies had poor methodological quality, such as unclear or high risk of bias on blinding and allocation concealment.

Yeung et al. also reviewed the efficacy and safety of Gan mai da zhao tang used alone or as an add-on therapy for depression and concurrent conditions such as diabetes and post-stroke depression.(38) Ten RCTs involving 968 participants were included. Results showed that Gan mai da zao tang combined with antidepressants could reduce depressive symptoms and risk of adverse events. Nevertheless, the number of included studies was limited by lack of quality.

Yeung et al. also published a systematic review of CHM for depression based on CM syndromes.(224) This review was part of two of the previous systematic review above. A total of 61 studies including 2,504 participants were included. The results showed that there was not adquate evidence that certain formulae had greater effects for specific syndromes of depression.

Thus, evidence for syndrome differentiation of depression was insufficient.

Jun et al. evaluated the efficacy and safety of Gan mai da zhao tang for depression.(35) This review included 13 trials and evaluated a wide range of depression types including: major depression, melancholia, post-stroke depression, postpartum depression, involutional

depression and senile depression. Results showed Gan mai da zhao tang was not superior to antidepressants for any of the depression types except post-stroke depression. Limited studies and poor methodologies reduced the reliability of the evidence.

Peng et al. included 16 studies (n=1,378) that reviewed Wuling capsules for post-stroke depression.(36) The pooled results indicated Wuling capsules were effective for depression when used alone or combined with antidepressants, but included studies were not free from bias and had methodological shortfalls.

Ren et al. reviewed CHM for primary depression, post-stroke depression and other secondary depression compared with fluoxetine.(225) This review included 26 studies including 3,294 participants. The pooled result showed CHM, for both primary and secondary depression, was as effective as 20 mg of fluoxetine per day in terms of reducing scores on the Hamilton Rating

Scale for Depression (HRSD). CHM had fewer adverse events compared with fluoxetine.

Although comparisons in this study was clearly defined, caution should be taken when interpreting the findings as the included studies were low quality.

Wang et al. evaluated CHM for different types of depression including major depression, unipolar depression, bipolar depression, treatment-resistant depression, first-episode depression and senile depression.(22) 40 studies involving 3,549 participants were included.

Meta-analyses showed that CHM was better than placebo and as effective as conventional medications, however, the level of evidence was low.

Previous reviews were limited by poor quality of studies and focused on specific CHM for different types of depression compared to placebo or various types of antidepressants. The review presented in this chapter focusing on providing updated evidence on CHM for MDD, systematically evaluating CHM efficacy alone and in combination with SSRIs, compared to

SSRIs alone, and evaluating adverse events related to CHM compared to SSRIs for individuals with MDD. Comprehensive systematic reviews and meta-analyses of RCTs are presented to summarise current clinical evidence from RCTs of CHM for MDD.

Methods

Methods followed the Cochrane handbook of systematic reviews(45) and the review is registered with PROSPERO (ID No. CRD42018091770). English and Chinese databases were searched from their inception to February 2018. English databases included PubMed, Excerpta

Medica Database (Embase), Cumulative Index of Nursing and Allied Health Literature

(CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL) and Allied and

Complementary Medicine Database (AMED). Chinese databases included China BioMedical

Literature (CBM), China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP) and Wanfang.

Search terms were mapped to controlled vocabulary in three groups: (1) condition (depression, depressive disorder, unipolar depression, major depression, major depressive disorder and related terms); (2) intervention type (CM, CHM, herbal medicine and related terms); and (3) study design (RCTs and related terms) (Appendix B).

In addition to electronic databases, we searched the reference lists of previous systematic reviews and their included studies. To identify ongoing clinical trials, we also searched clinical trial registries, including the US National Institutes of Health register (ClinicalTrials.gov),

Chinese Clinical Trial Registry (ChiCTR), European Union Clinical Trials Register (EU-CTR) and Australian New Zealand Clinical Trial Registry (ANZCTR).

Data extraction

Search results from the English and Chinese databases were merged and duplicates were removed. Three reviewers (Lingling Yang [LY], Johannah Shergis [JS] and Yuan Ming Di

[YMD]) screened titles and abstracts, and disagreements were resolved by discussion with a fourth reviewer (Anthony Lin Zhang [ALZ]). Full texts were obtained and screened against the inclusion criteria. Two reviewers (LY and YMD) independently extracted data from relevant studies in EpiData software (EpiData Association, Odense, Denmark). Data checking and disagreements were resolved by discussion with a third reviewer, JS. Data included author names, publication year, title, journal, location, study design, diagnostic criteria, age, gender, intervention, comparator, outcome measures, treatment duration, sample size, dropouts and adverse events.

Risk of bias

Two reviewers (LY and YMD) independently used the risk of bias assessment tool from the

Cochrane handbook to assess risk of bias for each publication.(45) A third reviewer (JS) resolved any disagreement about risk of bias. In risk of bias assessment, other bias was defined

as baseline imbalance on outcome measures. Potential publication bias was assessed using

Funnel plots and Egger's test.

Inclusion and exclusion criteria

Included studies were prospective, parallel RCTs with participants aged 18–65 years and diagnosed with depression based on established clinical guidelines.(1, 164, 226) Studies that involved participants with other types of depression were excluded, such as bipolar disorder, dysthymia, depressive symptoms caused by other mental or physical disorders, and depression caused by another medical condition or a substance.

Studies that used oral CHM as the intervention were included. St John’s wort was excluded if the study used an extract instead of the whole plant because St John’s wort extract is not a

CHM therapy, but it is used in Western herbal medicine.(227) Purified, plant-derived single compounds such as oligosaccharides and herbs administered using non-CM theory such as naturopathy or Western herbal medicine were excluded.

SSRIs were chosen as the control in this review due to clinical guidelines recommending them for depression.(11, 179, 228) We excluded studies that did not specify the type of antidepressant used as the control.

Pre-specified outcomes included clinician-rated scales such as the HRSD(229) and the

Montgomery–Asberg Depression Rating Scale (MADRS)(230), and self-rated scales such as

Zung’s Self-Rating Depression Scale (SDS).(231) These scales are the most commonly used instruments to measure depression severity and related symptoms, which also are reliabile,

valid, sensitive and specific measures for assessing treatment effects in patients with depression.(232, 233) Other outcomes included number of participants who relapsed or achieved remission, quality of life, functional capacity (e.g. social adjustment scales), suicidality and adverse events.

Data analysis

CHM effects were synthesised using meta-analysis. Continuous outcome data was analysed using mean difference (MD) and 95% confidence interval (CI). When different versions of outcome measures were used, standardised mean difference (SMD) was used for data analysis.(45)

In terms of dichotomous outcome data, risk ratios (RR) and 95% CI were used. Statistical heterogeneity was assessed using the I2 statistic. An I2 over 50% was considered to be an indicator of substantial heterogeneity.(45)

The GRADE approach was used to produce summary of findings tables.(234) The GRADE approach summarises and rates the strength and quality (‘certainty’) of evidence in systematic reviews using a structured process for presenting evidence summaries. The results are presented in summary of findings tables.

A panel of experts was established to evaluate the quality (certainty) of evidence. The panel included the systematic review team, CM practitioners, integrative medicine experts, research methodologists and conventional medicine physicians. The experts were asked to rate the clinical importance of key interventions from CHM as well as comparators and outcomes.

Results were collated and, based on the rating scores and subsequent discussion, a consensus on the content for the summary of findings tables was achieved.

The GRADE levels of evidence are grouped into four categories:

• High certainty evidence: We are very confident that the true effect lies close to that of

the estimate of the effect.

• Moderate certainty evidence: We are moderately confident in the effect estimate. The

true effect is likely to be close to the estimate of the effect, but there is a possibility that

it is substantially different.

• Low certainty evidence: Our confidence in the effect estimate is limited. The true effect

may be substantially different from the estimate of the effect.

• Very low certainty evidence: We have very little confidence in the effect estimate. The

true effect is likely to be substantially different from the estimate of effect.

Subgroup analysis

Subgroup analysis refers to splitting all participant data into subgroups and making comparisons between them. Subgroup analyses are conducted to investigate heterogeneity, or to answer particular research questions about specific patient groups, types of interventions or types of study design.(45) In this review, subgroup analyses were planned based on participant characteristics and study design such as treatment duration, low risk of bias for sequence generation and different versions of outcome measures.

Sensitivity analysis

A sensitivity analysis aims to address a question if the findings are robust to make decisions in the process of obtaining evidence.(45) A posteriori sensitivity analysis was performed to examine the possible contribution of excluding trials with baseline imbalances between groups on different outcome measures.

Results

This section presents the efficacy and safety of CHM used alone or in combination with SSRIs.

Characteristics of the included studies

Database searches identified 30,733 citations. After removing duplicates and excluding ineligible studies, a total of 78 RCTs were included (Figure 5-1).(24, 26, 235-308) Forty-six of these RCTs compared CHM to SSRIs and 32 RCTs compared CHM plus SSRIs to SSRIs alone

(Table 5.1). All clinical studies were conducted in China and published over 2006–2017.

Studies enrolled 7,407 participants (sample size range: 20–480). Participants' ages ranged over

18–65 years. The duration of depression ranged from two weeks to 15 years, including single and recurrent episodes. Treatment duration ranged from one to 12 weeks (Table 5.1).

All CHM treatments were orally administered via the following herbal preparations: decoctions, oral solutions, capsules, granules, pills or tablets. The studies used 72 distinct herbal formulae and 135 different herbs. Frequently used formulae were Chai hu shu gan san (three studies),

Xiao yao san/wan (three studies), Bu shen shu gan hua yu tang (two studies) and Jia wei xiao yao capsules (two studies) (Table 5.1). The most commonly used herbs were Bupleurum

chinense (Chinese name: Chai hu, 57 studies), Glycyrrhiza spp. (Chinese name: Gan cao, 46 studies) and Paeonia lactiflora (Chinese name: Shao yao, 40 studies).

The studies included the following SSRIs: fluoxetine (47 studies), paroxetine (19 studies), sertraline (8 studies), citalopram (2 studies) and escitalopram (2 studies). All controls were fixed dose and recommended by current clinical guidelines.(11, 309, 310)

In terms of outcome measures, depression symptoms were commonly assessed using the HRSD

(73 studies) and SDS (8 studies). Quality of life was assessed using the Short Form 36-Item

Health Survey (SF-36) in one study. Relapse and remission of depression, functional capacity and suicidality were not assessed in the included studies. Adverse events were reported in 34 studies.

Identification

Screening

Eligibility

Randomised controlled trials Included included in meta-analysis (n=78)

Figure 5-1 Flow chart of study selection

Table 5.1 Characteristics of included studies

Author, Year No. of Intervention Control Outcomes Treatment Risk of Bias (SG, Participants Duration AC, BPt, BPn, (I: C) BOA, IOD, SG, Other) a, b

Cao AQ 2010 60 (30:30) Chai hu jie yu tang Paroxetine HRSD 5 weeks U, U, H, H, H, L, U, L Chang YJ 2013 60 (30:30) Modified Xiao yao Fluoxetine AEs 4 weeks U, U, H, H, H, L, san; Modified U, L Zhen jing an shen long dan xie gan tang; Modified Gui pi tang; Modified Zhi shui qing gan yin; Modified An shen ding zhi pills + Fluoxetine Chen L 2014 65 (34:31) Jia wei xiao yao Sertraline + HRSD, AEs 8 weeks L, L, L, L, L, L, U, capsule + placebo placebo of Jia wei L of Sertraline xiao yao capsule Chen LP 2009 65 (32:33) Shu gan san Fluoxetine HRSD, AEs 6 weeks U, U, H, H, L, L, U, L Chen NH 2010 70 (35:35) Huan shao capsule Fluoxetine HRSD 8 weeks H, U, H, H, H, L, U, L Chen SM 2009 63 (36:27) Wang you fang Fluoxetine HRSD 6 weeks L, U, H, H, H, L, (formula) U, L Chen W 2013 68 (34:34) Gui pi tang + Escitalopram HRSD 8 weeks U, U, H, H, H, L, Escitalopram U, L

Author, Year No. of Intervention Control Outcomes Treatment Risk of Bias (SG, Participants Duration AC, BPt, BPn, (I: C) BOA, IOD, SG, Other) a, b

Chen Z 2012 80 (40:40) Modified Chai hu Fluoxetine AEs 8 weeks U, U, H, H, H, L, long gu mu li tang U, L combined with Bai he zhi mu tang Chen ZL 2016 60 (30:30) Modified Xiao yao Fluoxetine HRSD 8 weeks U, U, H, H, H, L, san U, L Cheng K 2008 72 (36:36) Unnamed formula Paroxetine SDS 6 weeks U, U, H, H, H, L, (Chen pi, Chao bai U, L zhu, Dang shen, Zhi Gan cao, Qin ban xia, Fu ling, Mu xiang, Sha ren, Huo xiang, Hong po, Zi su, Pei lan, Bai dou kou, Chai hu, Zhi ke, He huan pi) + Paroxetine Ding ZJ 2006 70 (35:35) Tong luo jie yu Sertraline HRSD, TESS, 8 weeks L, U, H, H, H, L, tang + Sertraline AEs U, L Dong T 2016 142(71:71) Modified Zhi zi Fluoxetine HRSD, SDS, AEs 12 weeks U, U, H, H, H, L, chi tang + U, L Fluoxetine Gao N 2010 62 (31:31) Le xin tang Paroxetine HRSD 12 weeks U, U, H, H, H, L, U, L Guo JH 2011 72 (38:34) Chai hu shu gan Fluoxetine HRSD, AEs 4 weeks L, U, H, H, H, L, san combined with U, L Gan mai da zao tang

Author, Year No. of Intervention Control Outcomes Treatment Risk of Bias (SG, Participants Duration AC, BPt, BPn, (I: C) BOA, IOD, SG, Other) a, b

Guo YQ 2010 60 (30:30) Chai hu shu gan Fluoxetine HRSD 6 weeks U, U, H, H, H, L, san + Fluoxetine U, L He H 2008 100 (50:50) Modified Xiao yao Fluoxetine HRSD 4 weeks U, U, H, H, H, U, san + Fluoxetine U, L Huang NN 2014 60 (30:30) Wen yang jie yu Fluoxetine HRSD, AEs 12 weeks L, U, H, H, H, L, tang U, L Huo L 2010 60 (30:30) Meng shi gun tan Fluoxetine AEs 6 weeks L, L, H, H, H, L, pills + Fluoxetine U, L Jiang RQ 2016 90 (45:45) Modified Chai hu Paroxetine HRSD, TESS, SF- 8 weeks L, U, H, H, H, L, tang + Paroxetine 36 U, L Li GY 2014 60 (30:30) Modified Er xian Fluoxetine HRSD, AEs 6 weeks U, U, H, H, H, L, tang U, L Li SH 2013 150 (75:75) Tang he chen qi Fluoxetine HRSD, AEs 6 weeks U, U, H, H, H, L, tang combined U, L with Xiao chai hu tang Li YC 2014 58 (30:28) Yue ju sheng jiang Fluoxetine HRSD, AEs 12 weeks U, U, H, H, H, L, tang U, L Lian Z 2013 80 (40:40) Dan zhi xiao yao Sertraline HRSD 6 weeks U, U, H, H, H, L, san + Sertraline U, L Liang WH 2012 60 (30:30) Jian pi shu gan Fluoxetine HRSD 6 weeks L, U, H, H, H, L, fang (fomula) U, L Liang Y 2010 76 (38:38) Modified Xiao yao Paroxetine HRSD, AEs 6 weeks H, U, H, H, H, L, san + Paroxetine U, L Lin B 2011 60 (30:30) Jia wei chai hu shu Fluoxetine HRSD, SDS 2-3 weeks (20 U, U, H, H, H, L, gan san days) U, L Lin JS 2011 60 (30:30) Jie yu xing shen Fluoxetine HRSD 6 weeks U, U, H, H, H, L, fang (formula) U, L

Author, Year No. of Intervention Control Outcomes Treatment Risk of Bias (SG, Participants Duration AC, BPt, BPn, (I: C) BOA, IOD, SG, Other) a, b

Lin Y 2013 480 (240:240) Bu shen jie yu Fluoxetine HRSD, AEs 12 weeks U, U, H, H, L, L, fang (formula) U, L Liu B 2011 80 (42:38) Shu gan jie yu an Citalopram HRSD, AEs 8 weeks L, U, H, H, H, L, shen fang U, L (formula) + Citalopram Liu GL 2015 82 (43:39) Hu li shu oral Sertraline HRSD, AEs 8 weeks L, U, H, H, H, L, liquid + Sertraline U, L Liu J 2013 70 (35:35) Jie yu granule + Paroxetine + HRSD, AEs 8 weeks L, U, L, L, L, L, placebo of placbo of Jie yu U, L Paroxetine granule Liu K 2015 70 (30:30) Wan mei pills Paroxetine HRSD 4 weeks U, U, H, H, H, L, U, L Liu SS 2011 455 (341:114) Ke xin shu pian + Fluoxetine + HRSD, AEs 6 weeks U, U, L, L, L, L, placebo of placebo of Ke xin U, L Fluoxetine shu pian Lv XR 2014 80 (40:40) Jie yu ning shen Fluoxetine HRSD, AEs 6 weeks U, U, H, H, H, L, tang U, L LV ZG 2011 48 (24:24) Xiao yao san Fluoxetine HRSD 6 weeks U, U, H, H, H, L, U, L Ma QQ 2011 78 (40:38) Xiao yao san Fluoxetine HRSD 6 weeks U, U, H, H, H, L, U, L Mai JY 2017 120 (76:44) Bu zhong yi qi Sertraline HRSD 4 weeks U, U, H, H, H, L, pills combined U, L with Ban xia xie xin tang; Xiao chai hu tang; Dang gui si ni tang; Wen shi ben tun tang

Author, Year No. of Intervention Control Outcomes Treatment Risk of Bias (SG, Participants Duration AC, BPt, BPn, (I: C) BOA, IOD, SG, Other) a, b

Mao ZX 2012 60 (30:30) Jie yu tang + Fluoxetine HRSD 6 weeks U, U, H, H, H, L, Fluoxetine U, L Pan HF 2008 24 (13:11) Yue ju bao he pills Fluoxetine HRSD, SDS 4 weeks U, U, H, H, H, L, U, L Ren SH 2017 48 (24:24) Jie yu pills Fluoxetine HRSD, AEs 4 weeks U, U, H, H, H, L, U, L Song YM 2011 60 (30:30) Chai hu shu gan Fluoxetine HRSD 4 weeks U, U, H, H, H, U, san U, L Sun L 2013 128 (60:58) * Wu ling capsule Fluoxetine HRSD 6 weeks U, U, H, H, H, L, U, L Tang JH 2013 60 (30:30) Modified Wen dan Fluoxetine HRSD, AEs 6 weeks L, U, H, H, U, L, tang U, L Tong ZS 2016 60 (30:30) Modified Xiao yao Paroxetine + HRSD, AEs 8 weeks L, U, L, L, L, L, san + Paroxetine placbo of U, L Modified xiao yao san Wang HY 2016 433 (108:109) Jie yu casule (high Fluoxetine HRSD, AEs 6 weeks U, U, L, L, L, L, dosage) or Jie yu U, L casule (low dosage) Wang JF 2013 78 (39:39) Yang yin qin gan Paroxetine HRSD 8 weeks U, U, H, H, H, L, tang + Paroxetine U, L Wang T 2016 70 (35:35) Shu gan fang Escitalopram HRSD, SDS 4 weeks U, U, H, H, H, L, (formula) + U, L Escitalopram Wu R,2015 20 (10:10) Yueju pills + Fluoxetine + AEs 1 weeks L, U, L, L, L, L, Fluoxetine placbo of Yueju U, L pills

Author, Year No. of Intervention Control Outcomes Treatment Risk of Bias (SG, Participants Duration AC, BPt, BPn, (I: C) BOA, IOD, SG, Other) a, b

Xu EP 2007 60 (30:30) Modified Dan zhi Fluoxetine HRSD, SDS 8 weeks U, U, H, H, H, L, xiao yao san U, L Xu FQ 2013 164 (82:82) Bu shen shu gan Fluoxetine HRSD 8 weeks U, U, H, H, H, L, hua yu tang U, L Yang HN 2010 60 (30:30) Bao shen tang + Fluoxetine HRSD, AEs 6 weeks U, U, H, H, H, L, Fluoxetine U, L

Yang S 2012 100 (50:50) Er he xiao yao Fluoxetine HRSD, AEs 8 weeks U, U, H, H, H, L, tang U, L Yao LJ 2014 78 (40:38) Zhong yao yu xiao Paroxetine HRSD, TESS 6 weeks L, U, H, H, H, L, No.1 + Paroxetine U, L Ye Q 2015 80 (40:40) Zhen jing ding zhi Fluoxetine HRSD 8 weeks U, U, H, H, H, L, he ji U, L Yi ZH 2010 190 (92:98) Chai hu xiao yao Paroxetine + HRSD, AEs 8 weeks L, U, L, L, L, L, he ji + Paroxetine placbo of Chai hu U, L xiao yao he ji Yin YR 2011 46 (23:23) Xiao yao pills + Fluoxetine HRSD, TESS 4 weeks U, U, H, H, H, L, Fluoxetine U, L Yu M 2011 80 (40:40) An shen ding zhi Sertraline HRSD, TESS 6 weeks U, U, H, H, H, L, tang + Sertraline U, L Yu XP 2013 60 (30:30) Unnamed formula Fluoxetine HRSD 6 weeks U, U, H, H, H, L, (Chai hu, Bai shao U, L yao, Ban xia, Shi cang pu, Chen pi, He huan hua) Zang HL 2008 30 (18:12) Shu yu fang Fluoxetine HRSD, AEs 12 weeks L, U, H, H, H, L, (formula) U, L Zhang GQ 2009 72 (38:34) Zhao ren bu xie Fluoxetine HRSD, AEs 4 weeks L, U, H, H, H, L, tang + Fluoxetine U, L

Author, Year No. of Intervention Control Outcomes Treatment Risk of Bias (SG, Participants Duration AC, BPt, BPn, (I: C) BOA, IOD, SG, Other) a, b

Zhang GR 2009 200 (100:100) Jie yu he huan Paroxetine HRSD 12 weeks U, U, H, H, H, L, tang + Paroxetine U, L Zhang HD 2009 62 (31:31) Xiao yao pills + Paroxetine HRSD, TESS, 6 weeks U, U, H, H, H, L, Paroxetine AEs U, L Zhang J 2014 60 (30:30) Unnamed formula Sertraline HRSD, TESS, 8 weeks H, U, H, H, L, L, (Chai hu, Yu jin, AEs U, L Chuan xiong, Mu dan pi, Ban xia, Tian nan xin, Tu fu ling, Chen pi, Sheng di huang, Bai shao yao, Suan zao ren, Bai zi ren, Yuan zhi, Cao wu, Gou teng, Gan cao) + Sertraline Zhang LS 2010 63 (32:31) Modified Chai hu Paroxetine HRSD, SDS 6 weeks U, U, H, H, H, L, long gu mu li tang U, L Zhang PZ 2014 455 (341:114) Jin xiang shu gan Fluoxetine HRSD 6 weeks L, U, L, L, L, L, pian U, L Zhang Y 2013 64 (32:32) Bu shen shu gan Paroxetine HRSD 8 weeks U, U, H, H, H, L, hua yu tang U, L Zhang ZM 2009 72 (36:36) Chang pu yu jin Fluoxetine HRSD 8 weeks U, U, H, H, H, L, tang + Fluoxetine U, L Zhang ZQ 2009 60 (30:30) Yu le shu he ji Paroxetine HRSD 6 weeks L, L, H, H, H, L, U, L Zhao HM 2016 76 (38:38) Chai gui kai yu Paroxetine HRSD, AEs 12 weeks U, U, H, H, H, L, tang U, L

Author, Year No. of Intervention Control Outcomes Treatment Risk of Bias (SG, Participants Duration AC, BPt, BPn, (I: C) BOA, IOD, SG, Other) a, b

Zhao XP 2006 87 (45:42) Chai hu shu gan Fluoxetine HRSD 4 weeks L, U, H, H, H, L, san + Fluoxetine U, L Zhong L 2013 51 (26:25) Unnamed formula Fluoxetine HRSD, AEs 6 weeks U, U, H, H, H, L, (Chai hu, Xiang U, L fu, Yu jin, Zhi zi, Dan shen, Chi shi, Suan zao ren, Chen pi, Huang lian, Bai shao yao, Sheng di huang, Sha ren, Da zao, Gan cao) Zhong XY 2012 100 (50:50) Chai hu long gu Paroxetine HRSD, SDS 8-9 weeks (60 U, U, H, H, H, L, mu li tang days) U, L Zhou B 2012 60 (30:30) Fu fang kuai wei Fluoxetine HRSD, TESS 4 weeks U, U, H, H, H, L, shu gan pills + U, L Fluoxetine Zhou J 2013 127 (65:62) Modified Xiao yao Sertraline HRSD 8 weeks L, U, L, L, L, L, capsule U, L Zhou MY 2012 80 (40:40) Unnamed formula Citalopram HRSD 5-6 weeks (40 L, U, H, H, H, L, (Chai hu, Xiang days) U, L fu, Yu jin, Bai zhu, Fu ling, Shi cang pu, Bo he, Zhen zhu mu) + Citalopram Zhu CJ 2014 60 (30:30) Gui pi tang Fluoxetine HRSD 6 weeks L, U, H, H, H, L, U, L

Author, Year No. of Intervention Control Outcomes Treatment Risk of Bias (SG, Participants Duration AC, BPt, BPn, (I: C) BOA, IOD, SG, Other) a, b

Zhu JP 2014 63 (32:31) Suan zao ren tang Paroxetine HRSD, AEs 4 weeks U, U, H, H, H, L, U, L Zong CC 2014 60 (30:30) Yi shen qing xin Fluoxetine HRSD 6 weeks U, U, H, H, H, L, fang U, L a Risk of bias abbreviations: SG: Sequence Generation, AC: Allocation Concealment, BPt: Blinding of Participants, BPn: Blinding of Personnel, BOA: Blinding of Outcome Assessment, IOD: Incomplete Outcome Data, SOR: Selective Outcome Reporting, Other: defined as baseline balance for the HRSD scores and the SDS scores. b Risk of bias judgements: L: low risk, U: Unclear risk or no information provided, H: High risk.

Abbreviations: AEs, adverse events; C, control groups; CHM, Chinese herbal medicine; HRSD, Hamilton Rating Scale for Depression; I, intervention groups; RCT, randomised controlled trial; SDS, Zung Self-Rating Depression Scale; SF-36, 36-Item Short Form Health Survey; SSRIs, selective serotonin reuptake inhibitors; TESS, Toxic Exposure Surveillance System

Risk of bias

All studies were described as randomised; however, only 24 (30.8%) described an appropriate method of random sequence generation and were judged at low risk of bias. Three (3.8%) described an appropriate method of allocation concealment, while 75 (96.2%) did not describe the details of allocation concealment so were judged as having unclear risk of bias. Blinding of participants and personnel was reported in nine studies (11.5%) so these were judged to be at low risk of bias, while the remaining 69 studies (88.5%) were judged at high risk of bias.

The method of blinding of outcome assessors was judged at low risk of bias in 12 studies

(15.4%). Outcome data was available for most studies, with 76 (97.4%) judged at low risk of bias. Selective outcome reporting was judged at unclear risk in all the studies because protocols were not available. Five studies (6.4%) were judged at high risk of bias for other bias due baseline imbalance on the HRSD scores. Risk of bias assessement for each study is included in Table 5.1 and Figure 5-2.

Other bias 93.6 6.40

Selective reporting 0 100

incomplete outcome data 97.4 2.60

Blinding of assessors 15.4 83.3 1.3

Blinding of personnel 11.5 88.5 0

Blinding of participants 11.5 88.5 0

Allocation concealment 3.80 96.2 Sequence generation 30.8 3.8 65.4

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Low (%) High (%) Unclear (%)

Figure 5-2 Risk of bias: CHM for MDD

Publication bias

Publication bias was assessed using Funnel plots and Egger's tests.(45) For CHM vs. SSRIs for

HRSD, the funnel plot was asymmetrical and publication bias was not detected (Egger’s test t=−1.84, 95% CI −3.6 to 0.16, p=0.072). Also, for CHM plus SSRIs vs. SSRIs for HRSD, the funnel plot was symmetrical and publication bias was not detected (Egger’s test t=−1.48, 95%

CI −14.49 to 2.38, p=0.15). The number of studies reporting other outcomes was less than ten and funnel plot evaluation was not appropriate. Figure 5-3 presents the funnel plots, Image A includes studies that compare CHM to SSRIs for the HRSD outcome, while Image B includes studies that compare CHM plus SSRIs to SSRIs for HRSD (Figure 5-3).

studies that compare CHM to SSRIs for the HRSD

outcome Funnel plot with pseudo 95% confidence limits

.2 _seES

-1.5 -1 -.5 0 .5 _ES

studies that compare CHM plus SSRIs to SSRIs for the HRSD

outcome Funnel plot with pseudo 95% confidence limits

_seES

.3 .4

-4 -3 -2 -1 0 1 _ES

Figure 5-3: Funnel plot of CHM for Depression

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CHM vs SSRIs

Outcome measures for CHM compared with SSRIs included HRSD, SDS and adverse events.

Other prespecified outcomes such as the MADRS and quality of life were not assessed in the included studies.

Hamilton Rating Scale for Depression (HRSD)

Forty-five out of 78 studies (4,782 participants) used the HRSD to assess severity of depression

(Table 5.1).(26, 235, 237-240, 243, 247, 248, 251, 254-256, 258, 260-262, 265-270, 272-276,

280, 281, 283, 285, 289, 290, 295-299, 301, 302, 304, 306-308) Several versions of the HRSD, including HRSD-17 and HRSD-24, were used across these studies. Therefore, SMD was used to pool studies.

End of treatment between groups

After 2–12 weeks of treatment, significant reductions in HRSD scores were seen in CHM groups compared to SSRI groups (SMD –0.30 [–0.44, –0.16]; I2=80.9%), although heterogeneity was substantial (Figure 5-4). The quality of the evidence was low (Table 5.2).

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Study % ID SMD (95% CI) Weight

Cao AQ 2010 -0.07 (-0.57, 0.44) 2.10 Chen L 2014 -0.53 (-1.04, -0.02) 2.10 Chen LP 2009 0.04 (-0.45, 0.52) 2.15 Chen NH 2010 -1.23 (-1.74, -0.72) 2.09 Chen SM 2009 0.14 (-0.36, 0.64) 2.12 Chen ZL 2016 -1.20 (-1.75, -0.65) 2.00 Gao N 2010 0.24 (-0.28, 0.76) 2.08 Guo JH 2011 -1.45 (-1.98, -0.93) 2.07 Huang NN 2014 0.61 (0.09, 1.13) 2.08 Li YC 2014 -1.71 (-2.32, -1.11) 1.89 Li GY 2014 -0.79 (-1.32, -0.27) 2.06 Li SH 2013 -0.65 (-0.98, -0.32) 2.49 Liang WH 2012 0.09 (-0.42, 0.59) 2.10 Lin Y 2013 0.28 (0.10, 0.46) 2.74 Lin B 2011 -0.24 (-0.74, 0.27) 2.10 Lin JS 2011 -0.03 (-0.54, 0.48) 2.09 Liu K 2015 -1.33 (-1.89, -0.77) 1.98 Liu SS 2011 -0.12 (-0.33, 0.10) 2.69 Lv XR 2014 -0.89 (-1.35, -0.43) 2.20 Lv ZG 2011 -0.35 (-0.92, 0.22) 1.96 Ma QQ 2011 -0.24 (-0.69, 0.21) 2.24 Mai JY 2017 -0.63 (-1.01, -0.25) 2.38 Pan HF 2008 -0.18 (-0.98, 0.63) 1.49 Ren SH 2017 0.07 (-0.49, 0.64) 1.97 Song YM 2013 -0.91 (-1.45, -0.38) 2.04 Sun L 2013 -0.02 (-0.38, 0.34) 2.42 Tang JH 2013 0.13 (-0.38, 0.64) 2.10 Wang HY 2016 (a) -0.33 (-0.60, -0.06) 2.60 Wang HY 2016 (b) -0.22 (-0.49, 0.04) 2.60 Xu EP 2007 -1.06 (-1.60, -0.52) 2.02 Xu FQ 2013 -1.09 (-1.42, -0.76) 2.49 Yang S 2012 -0.73 (-1.13, -0.32) 2.32 Ye Q 2015 0.17 (-0.27, 0.61) 2.25 Yu XZ 2013 0.23 (-0.28, 0.74) 2.10 Zang HL 2008 0.44 (-0.30, 1.18) 1.61 Zhang LS 2010 0.23 (-0.26, 0.73) 2.12 Zhang PZ 2014 -0.12 (-0.33, 0.09) 2.69 Zhang Y 2013 -0.02 (-0.53, 0.49) 2.10 Zhang ZQ 2009 -0.27 (-0.80, 0.25) 2.07 Zhao HM 2016 0.24 (-0.21, 0.69) 2.22 Zhong L 2013 -0.08 (-0.63, 0.47) 2.01 Zhong XY 2012 -0.22 (-0.62, 0.17) 2.35 Zhou J 2013 0.09 (-0.28, 0.46) 2.40 Zhu CJ 2014 -0.04 (-0.55, 0.47) 2.10 Zhu JP 2014 -0.06 (-0.55, 0.44) 2.13 Zong CC 2014 -0.22 (-0.73, 0.29) 2.10 Overall (I-squared = 80.9%, p = 0.000) -0.30 (-0.44, -0.16) 100.00

NOTE: Weights are from random effects analysis

-2.32 0 2.32 Favours CHM Favours SSRIs

Figure 5-4 Forest plot comparing Chinese herbal medicine to SSRIs alone in terms of Hamilton Rating Scale for MDD

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Table 5.2 Summary of findings of Chinese herbal medicine vs. selective serotonin

reuptake inhibitors

Outcomes No. of Certainty of Anticipated Absolute Effects Participants the Assumed Risk (Studies) Evidence SSRIs Risk Difference with CHM (GRADE) Depressive symptoms 4,782 ⨁⨁◯◯ - SMD 0.30 SD lower (clinician-rated) (45 RCTs) LOW 1,2 (0.44 lower to 0.16 lower) Hamilton Rating Scale for Depression Treatment duration: mean 6.9 weeks Depressive symptoms 307 ⨁⨁◯◯ The mean Self- MD 1.63 points lower (patient‐reported) (5 RCTs) LOW 1,3 rating (2.68 lower to 0.57 lower) Self-rating Depression Depression Scale Scale was 39.40 points Treatment duration: mean 6.0 weeks Quality of life Not reported Adverse events Not reported *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

Abbreviations: CHM: Chinese herbal medicine; MD: Mean difference; RCT: randomized controlled trial; SD: standard deviation; SMD: standardised mean difference; SSRI: selective serotonin reuptake inhibitors GRADE Working Group grades of evidence. High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

1. Downgraded one level for unclear sequence generation and allocation concealment, lack of blinding of participants and personnel. 2. Downgrade one level for considerable statistical heterogeneity. 3. Downgrade one level for small sample size.

Subgroup analysis

In terms of studies judged at low risk of bias for sequence generation, there were no significant

differences between CHM and SSRIs after subgroup analysis. Treatment for 6 weeks or less in

29 studies favoured CHM (SMD –0.27 [–0.41, –0.14]; I2 = 66.0%), as did treatment equal to

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or greater than 6 weeks in 16 studies (SMD –0.35 [–0.69, –0.02]; I2 = 90.0%). CHM reduced depression severity more than fluoxetine did in 35 studies (SMD –0.34 [–0.50, –0.17]

I2=83.0%), but there was no statistical difference when CHM treatment was compared to paroxetine and sertraline treatment. Subgrouping the HRSD version (Version 17) showed that

CHM was superior to SSRIs (SMD –0.21 [–0.37, –0.04]; I2=67.3%, 20 studies) although it was not superior in the HRSD-24 subgroup (SMD –0.23 [–0.49, –0.03]; I2=83.1%, 17 studies).

Heterogeneity remained substantial after subgrouping and the reasons were not identifiable.

Sensitivity analysis

At baseline, the CHM group was balanced in all except five studies.(237, 248, 255, 268, 270)

Removing these studies from the end-of-treatment analysis showed similar effects (SMD –0.25

[–0.40, –0.10], I2= 80.0%) (Figure 5-5).

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Study % ID SMD (95% CI) Weight

Cao AQ 2010 -0.07 (-0.57, 0.44) 2.36 Chen LP 2009 0.04 (-0.45, 0.52) 2.41 Chen NH 2010 -1.23 (-1.74, -0.72) 2.34 Chen SM 2009 0.14 (-0.36, 0.64) 2.37 Chen ZL 2016 -1.20 (-1.75, -0.65) 2.24 Gao N 2010 0.24 (-0.28, 0.76) 2.33 Huang NN 2014 0.61 (0.09, 1.13) 2.32 Li YC 2014 -1.71 (-2.32, -1.11) 2.10 Li GY 2014 -0.79 (-1.32, -0.27) 2.30 Liang WH 2012 0.09 (-0.42, 0.59) 2.36 Lin Y 2013 0.28 (0.10, 0.46) 3.12 Lin B 2011 -0.24 (-0.74, 0.27) 2.35 Lin JS 2011 -0.03 (-0.54, 0.48) 2.34 Liu K 2015 -1.33 (-1.89, -0.77) 2.21 Liu SS 2011 -0.12 (-0.33, 0.10) 3.06 Lv XR 2014 -0.89 (-1.35, -0.43) 2.48 Ma QQ 2011 -0.24 (-0.69, 0.21) 2.51 Pan HF 2008 -0.18 (-0.98, 0.63) 1.65 Ren SH 2017 0.07 (-0.49, 0.64) 2.20 Song YM 2013 -0.91 (-1.45, -0.38) 2.29 Sun L 2013 -0.02 (-0.38, 0.34) 2.73 Tang JH 2013 0.13 (-0.38, 0.64) 2.35 Wang HY 2016 (a) -0.33 (-0.60, -0.06) 2.95 Wang HY 2016 (b) -0.22 (-0.49, 0.04) 2.95 Xu EP 2007 -1.06 (-1.60, -0.52) 2.26 Xu FQ 2013 -1.09 (-1.42, -0.76) 2.81 Yang S 2012 -0.73 (-1.13, -0.32) 2.62 Ye Q 2015 0.17 (-0.27, 0.61) 2.53 Yu XZ 2013 0.23 (-0.28, 0.74) 2.35 Zang HL 2008 0.44 (-0.30, 1.18) 1.79 Zhang LS 2010 0.23 (-0.26, 0.73) 2.38 Zhang PZ 2014 -0.12 (-0.33, 0.09) 3.06 Zhang Y 2013 -0.02 (-0.53, 0.49) 2.35 Zhang ZQ 2009 -0.27 (-0.80, 0.25) 2.31 Zhao HM 2016 0.24 (-0.21, 0.69) 2.50 Zhong L 2013 -0.08 (-0.63, 0.47) 2.24 Zhong XY 2012 -0.22 (-0.62, 0.17) 2.65 Zhou J 2013 0.09 (-0.28, 0.46) 2.70 Zhu CJ 2014 -0.04 (-0.55, 0.47) 2.36 Zhu JP 2014 -0.06 (-0.55, 0.44) 2.39 Zong CC 2014 -0.22 (-0.73, 0.29) 2.35 Overall (I-squared = 80.0%, p = 0.000) -0.25 (-0.40, -0.10) 100.00

NOTE: Weights are from random effects analysis

-2.32 0 2.32 Favours CHM Favours SSRIs

Figure 5-5 Forest plot comparing CHM to SSRIs alone in terms of Hamilton Rating Scale for MDD (removing studies with baseline imbalance)

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Before and after treatment within groups

Within the CHM groups, there were significant improvements in HRSD at all points compared to baseline. Potential improvement occurred at 2 weeks but not at 6–8 weeks and then increased after 8 to 12 weeks (Figure 5-6). Similarly, for HRSD there were improvements at all measured points within SSRIs groups that started as early as 2-week treatment and was particularly noticeable at 8 weeks, and after 12 week improvements increased again, which is consistent with previous literature.(311) A small reduction in improvement occurred after 2 weeks of

SSRI intake (Figure 5-6). The current guidelines recommend minimum treatment duration of at least 2 weeks until unsatisfactory response occurs and then a change of the treatment strategy should be considered.(228) In terms of trajectories over time, improvements within CHM groups increased and declined more steadily compared SSRIs groups (Figure 5-6).

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0 2-3 (n=1) 4 (n=7) 5 (n=1) 6 (n=20) 8 (n=9) 8-9 (n=1) 12 (n=6)

-1

-2

-3

-4 Change in HRSDScores Changein

-5

-6

Time (weeks) Mean change from baseline in CHM groups (SMD, 95%CI) Mean change from baseline in SSRIs groups (SMD, 95%CI)

Figure 5-6 Mean change from baseline to end of treatment on Hamilton Rating Scale for MDD within Chinese herbal medicine groups and within selective serotonin reuptake inhibitor (SSRI) groups at different time points

Abbreviations: CHM: Chinese herbal medicine; CI: confidence interval; n, number of studies;

HRSD: Hamilton Rating Scale for Depression; SMD: standardised mean difference.

Zung’s Self-Rating Depression Scale (SDS)

The SDS was assessed in five studies comparing CHM to SSRIs (307 participants).(260, 272,

280, 295, 302) Treatment duration ranged from 3 to 9 weeks. Three studies used fluoxetine as control and two studies used paroxetine as control. Baseline for SDS scores was balanced between CHM group and SSRIs groups.

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End of treatment between groups

After treatment, CHM was found to be superior to SSRIs (MD –1.63 [–2.68, –0.57]; I²=10.0%); low quality evidence (Table 5.2).

Before and after treatment within groups

Within the CHM group, CHM showed significant improvement in SDS scores, comparing baseline and end of treatment (MD –27.07 [–43.06, –11.08], I2=98.6%), while SSRI also showed significant improvement (MD –25.60 [–40.65, –10.55], I2=98.8%).

Adverse events

Nineteen (41.3%) of the studies comparing CHM with SSRIs reported adverse events. These adverse events were mild. People allocated CHM interventions reported 152 adverse events and people allocated SSRIs reported 354 adverse events. Sixteen studies reported details about

95 adverse events. Dry mouth (19 cases) was the most common adverse event, followed by loss of appetite (17 cases) and nausea (12 cases). In the SSRI groups, 250 detailed adverse events were reported, including dry mouth (64 cases), loss of appetite (31 cases), constipation

(18 cases) and dizziness (18 cases). One study reported the number of adverse events in each group without giving detailed information about the type of event.(290) One study reported the nature of the event, but did not specify the number of adverse events in the SSRI group (Table

5.3).(262)able

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Table 5.3 Adverse events: CHM vs. SSRIs

Comparisons No. of Intervention Group Adverse Control Group Adverse Studies Events Events

Chinese herbal 19 Most common events (number of Most common events (number medicine cases) of cases) (CHM) vs selective • Dry month (19) • Dry mouth (64) serotonin • Loss of appetite (17) • Loss of appetite (31) reuptake • Nausea (12) • Constipation (18) inhibitors • Headache (8) • Dizziness (18) (SSRI) • Restlessness (5) • Nausea (15) • Dizziness (4) • Sweating (8) • Hypersomnia (4) • Insomnia (7) • Sweating (3) • Nausea and loss of • Nasal congestion (3) appetite (7) • Hypersomnia (7) • Dizziness and headache (7)

Total adverse events = 152 Total adverse events = 354

CHM plus SSRIs vs SSRIs alone

Outcome measures for CHM plus SSRIs compared with SSRIs alone included HRSD, SDS,

Short Form SF-36 health survey and adverse events. Other pre-specified outcomes were not assessed in the included studies.

HRSD

Twenty-eight studies including 2,333 participants used the HRSD to compare the effects of

CHM plus SSRIs with the same SSRIs alone.(24, 241, 245, 246, 249, 250, 253, 257, 259, 263,

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264, 271, 277, 278, 282, 284, 286-288, 291-294, 300, 303, 305). Baseline HRSD scores were balanced between CHM plus SSRIs and SSRIs alone.

End of treatment between groups

After 4–12 weeks of treatment, CHM plus SSRIs reduced the severity of depression more than

SSRIs alone (SMD –0.97 [–1.32, –0.62]; I2=93.4%) (Figure 5-7). The quality of evidence was low (Table 5.4). The studies listed in the figure that reported significant results, much greater than the overall pool are likely due to a larger sample size and a stronger effect.

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Study % ID SMD (95% CI) Weight

Chen W 2013 -0.65 (-1.14, -0.17) 3.59 Ding ZJ 2006 -0.59 (-1.07, -0.12) 3.60 Dong T 2016 -3.54 (-4.07, -3.01) 3.54 Guo YQ 2010 -0.63 (-1.15, -0.11) 3.55 He H 2008 -0.66 (-1.08, -0.23) 3.65 Jiang RQ 2016 -3.56 (-4.23, -2.90) 3.38 Lian Z 2013 -1.52 (-2.02, -1.02) 3.58 Liang Y 2010 -0.61 (-1.07, -0.15) 3.61 Liu Bin 2014 -0.98 (-1.45, -0.52) 3.61 Liu GL 2015 -1.30 (-1.78, -0.82) 3.60 Liu J 2013 -0.53 (-1.03, -0.04) 3.58 Mao ZX 2009 -0.47 (-0.98, 0.04) 3.56 Tong ZS 2016 -0.67 (-1.19, -0.15) 3.55 Wang JF 2013 -1.08 (-1.55, -0.60) 3.60 Wang T 2016 -0.57 (-1.05, -0.08) 3.59 Yang HN 2010 -3.83 (-4.69, -2.97) 3.13 Yao LJ 2014 -0.91 (-1.38, -0.45) 3.61 Yi ZH 2010 -0.43 (-0.73, -0.14) 3.75 Yin YR 2011 -0.04 (-0.62, 0.54) 3.49 Yu M 2011 -0.38 (-0.82, 0.06) 3.63 Zhang GQ 2009 -0.46 (-0.93, 0.01) 3.61 Zhang GR 2009 -2.70 (-3.08, -2.32) 3.68 Zhang HD 2009 -0.42 (-0.92, 0.09) 3.57 Zhang J 2014 -1.18 (-1.73, -0.63) 3.52 Zhang ZM 2009 -0.19 (-0.66, 0.27) 3.61 Zhao XP 2006 -0.38 (-0.81, 0.04) 3.65 Zhou B 2012 1.04 (0.50, 1.58) 3.53 Zhou MY 2012 -0.46 (-0.90, -0.02) 3.63 Overall (I-squared = 93.4%, p = 0.000) -0.97 (-1.32, -0.62) 100.00 NOTE: Weights are from random effects analysis

-4.69 0 4.69 Favours CHM plus SSRIs Favours SSRIs

Figure 5-7 Forest plot comparing Chinese herbal medicine plus selective serotonin reuptake inhibitors (SSRIs) to SSRIs alone in terms of Hamilton Rating Scale for MDD

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Table 5.4 Summary of findings of Chinese herbal medicine plus selective serotonin reuptake inhibitors (SSRIs) vs. SSRIs

Outcomes No. of Certainty of Anticipated Absolute Effects Participants the (Studies) Evidence Assumed Risk (GRADE) SSRIs Risk Difference with CHM plus SSRIs Depressive symptoms 2,333 ⨁⨁◯◯ - SMD 0.97 SD lower (clinician-rated) (28 RCTs) LOW 1,2 (1.32 lower to 0.62 lower) Hamilton Rating Scale for Depression Treatment duration: mean 6.8 weeks Depressive symptoms 284 ⨁⨁◯◯ The mean Self- MD 7.19 points lower (patient‐reported) (3 RCTs) LOW 1,3 rating (8.39 lower to 5.99 lower) Self-rating Depression Depression Scale Scale was 44.90 points Treatment duration: mean 7.3 weeks Quality of life 90 ⨁⨁◯◯ The SF-36 was MD 13.53 points higher Short Form SF-36 Health (1 RCT) LOW 1,3 60.68 points (9.82 higher to 17.24 Survey higher) Treatment duration: 8 weeks Adverse events 546 ⨁⨁◯◯ The mean TESS MD 1.12 lower (1.69 Toxic Exposure (8 RCTs) LOW 1,2 was 4.51 points lower to 0.55 lower) Surveillance System (TESS) Treatment duration: 6.25 weeks *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

Abbreviations: CHM: Chinese herbal medicine, MD: Mean difference, RCT: randomized controlled trial; SD: standard deviation; SMD: standardised mean difference; SSRI: selective serotonin reuptake inhibitors

GRADE Working Group grades of evidence. High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

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Subgroup analysis

In 11 studies at low risk of bias for sequence generation, subgrouping also showed that CHM plus SSRIs was superior to SSRIs alone (SMD –0.90 [–1.31, -0.50]; I2=88.4%). Treatment with

CHM for less than 6 weeks produced lower HRSD scores between groups (SMD –0.66 [–1.05,

–0.28]; I2=88.3%, 14 studies). Treatment for equal to or greater than 6 weeks had similar results

(SMD –1.27 [–1.82, –0.72]; I2=95.0%, 14 studies). Subgrouping the HRSD version (Version

17) showed that CHM plus SSRIs was superior to SSRIs alone in 15 studies (SMD −0.66

[−0.83, −0.48], I2=52.9%).

Before and after treatment within groups

The mean changes on the HRSD within CHM groups and SSRIs groups followed similar trajectories from 4 weeks to 12 weeks (Figure 5-8). However, the change scores on the HRSD of CHM plus SSRIs was superior to that of SSRIs at the measured points. Improvements were more obvious after treatment for 6 weeks and 12 weeks. Research indicates that a minimum of

8 to 10 weeks of treatment are needed for optimal symptom reduction.(179, 228)

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0 4 (n=6) 6 (n=9) 8 (n=11) 12 (n=2) -1

-2

-3

-4

-5

-6

Change in HRSDScores Changein -7

-8

-9 Time (weeks) Mean change from baseline in CHM plus SSRIs groups (SMD, 95%CI) Mean change from baseline in SSRIs groups (SMD, 95%CI)

Figure 5.7 1

Figure 5-8 Mean change from baseline to end of treatment on the Hamilton Rating Scale for MDD, within Chinese herbal medicine plus selective serotonin reuptake inhibitor (SSRI) groups and within SSRI groups at different time points

Abbreviations: CHM: Chinese herbal medicine; CI: confidence interval; n, number of studies;

HRSD: Hamilton Rating Scale for Depression; SMD: standardised mean difference.

SDS

Three studies including 289 participants used the SDS to compare CHM plus SSRIs with SSRIs

alone.(244, 246, 277) All these studies were baseline balanced for SDS scores.

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End of treatment between groups

After 4–12 weeks of treatment, SDS scores in the CHM plus SSRIs groups were significantly lower than those in the SSRIs alone groups (MD –7.19 points [–8.39, –5.99]; I2 =0.0%); low quality evidence (Table 5.4).

Before and after treatment within groups

CHM plus SSRIs showed significant improvement in SDS scores, comparing baseline and end of treatment (MD –25.45 [–34.17, –16.73], I2=96.0%). SSRIs only also showed significant improvement (MD –18.34 [–27.33, –9.35], I2=95.3%).

Short Form SF-36 Health Survey

One RCT evaluated 90 participants using the SF-36 to measure quality of life.(253) Individual health domains were not reported, but an aggregate score was given.

End of treatment between groups

CHM plus paroxetine was superior to paroxetine alone after 8 weeks of treatment (MD 13.53

[9.82, 17.24]). The quality of evidence was low (Table 5.4).

Before and after treatment within groups

With CHM plus paroxetine, there was significant improvement, comparing end of treatment to the baseline of scores of SF-36 (MD 28.94 [25.35, 32.53]). A similar improvement was also found in the paroxetine group (MD 16.87 [13.67, 20.07]).

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Adverse events

Fifteen studies mentioned adverse events. These adverse events were mild. In the CHM plus

SSRIs groups 153 events were reported, while in the SSRI groups 222 events were reported.

Thirteen studies provided adverse event information. Nausea and vomiting were the most common adverse events in the CHM plus SSRIs and control groups (21 and 28 cases, respectively). Other adverse events included nausea, diarrhea and constipation (Table 5.5).

Eight of the studies reported adverse events on the Toxic Exposure Surveillance System (TESS); after treatment TESS was lower, indicating less severe and fewer adverse events in the integrative medicine group compared to SSRIs alone (low quality; MD −1.12 [−1.69, −0.55]

I2= 93.2%) (Table 5.4).

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Table 5.5 Adverse events: CHM plus SSRIs vs. SSRIs

Comparisons No. of Intervention Group Adverse Control Group Adverse Events Studies Events

CHM plus 15 Most common events (number Most common events (number of SSRIs vs of cases) cases) SSRIs • Nausea and vomiting • Constipation (28) (21) • Nausea and vomiting (28) • Diarrhea (20) • Hypersomnia (27) • Nausea (18) • Nausea (22) • Constipation (15) • Dry mouth (18) • Dry mouth (11) • Diarrhea (14) • Dizziness (11) • Sweating (11) • Hypersomnia (11) • Insomnia (11) • Blurred vision (9) • Blurred vision (11) • Sweating (7) • Loss of appetite (10) • Headache (7)

Total adverse events = 153 Total adverse events = 222

Discussion

Summary of evidence

This study is an updated systematic review of the effecacy and safety of CHM, used alone or as add-on therapy for depression. Seventy-eight studies with 7,407 participants were included.

However, the methodological quality of included RCTs was not free from risk of bias.

CHM vs. SSRIs

CHM appears to be more effective than SSRIs for improving clinical symptoms and alleviating depression severity. It also seems to be safer, with the number of adverse events in the CHM groups half that of the SSRI groups. In addition, meta-analyses for depression severity

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measured on the HRSD and SDS scales consistently indicated that CHM is superior to SSRIs for reducing depression (certainty of evidence: low). Our meta-analysis showed that at the end of treatment there was a significant difference in the HRSD (SMD –0.30) and SDS (MD –1.63 points) between CHM and SSRI groups, indicating a moderate to large effect.(45) This result was consistent with previous systematic reviews of CHM for depression.(22, 35, 39, 40, 225)

Our review indicates that CHM for depression is more effective in the short term, similar to acute-phase treatment with antidepressants.(312, 313)

CHM plus SSRIs vs. SSRIs

When CHM was used as integrative medicine, the pooled results showed it produced better outcomes than SSRIs alone, in terms of reducing depression severity based on the HRSD and

SDS scores. It is hard to conclude if the majority of change in the SSRI with CHM group is accounted for by SSRIs or CHM. The total number of adverse events in the CHM or CHM and

SSRI groups was also less than that in SSRI groups (quality of evidence: low). All events in

CHM groups were considered mild. Despite these positive results, there was considerable heterogeneity and subgrouping did not substantially reduce heterogeneity. These findings are consistent with previous reviews of CHM for depression.(181)

Common herbal medicines

Of the 135 herbs used in the included RCTs, Chai hu, Gan cao and Shao yao were the most common. Preclinical studies have shown these herbs’ antidepressant effects are related to their antioxidant and neurotransmitter properties.(24-27, 314) Chai hu shu gan san was the most

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frequently used herbal formula and experimental studies have shown its effects are comparable to the antidepressant drug fluoxetine.(182, 315) More research into key herbal compounds in animal models and neuronal cells is needed to further elucidate the possible mechanisms of action of these herbs, and this may lead to new therapeutic agents.

Chai hu (bupleurum chinense DC [radix bupleuri; family: apiaceae; Chinese name: Chai hu]) was the most commonly reported herb in this review. 55 RCTs (70.5%) of included studies used Chai hu. Approximately 74 compounds have been isolated from it including essential oils, triterpenoid saponins, polyacetylenes, flavonoids, lignans, fatty acids and sterols.(316) Chai hu is commonly combined with other herbal ingredients to make a formula (for example, it is combined with Citrus reticulata, Ligusticum chuanxiong, Citrus aurantium, Paeonia lactiflora,

Glycyrrhiza spp. and Cyperus rotundus to make Chai hu shu gan san; or with Angelica sinensis,

Paeonia lactiflora, Atractylodes macrocephala, Poria cocos, Glycyrrhiza spp., Mentha haplocalyx and Zingiber officinale to make Xiao yao san).

Limitations of this study

Most included studies did not conduct formal pretrial sample size calculation and the majority of these studies involved small sample sizes. The risk of overestimating therapeutic efficacy with insufficient statistical power may have occured.(317) All the studies reported the duration of treatment ranged from one to 12 weeks. It is difficult to assess the long-term effect and safety of CHM for depression.

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Methodological limitations exist in the included studies. Only one-third reported adequate information about random sequence generation. Almost all the studies had inadequate or unclear concealment of allocation. Blinding is an essential method to avoid performance bias and detection bias.(318) However, only nine studies reported double blinding of participants and personnel, likely because interventions were unable to be blinded due to different preparation and special colour, smell and taste of CHM or SSRIs. In addition, only 12 studies described the blinding of outcome assessors.

In terms of database searches, we only searched papers published in Chinese or English, so eligible studies published in other languages may have been left out, limiting the possibility of generating comprehensive findings. Publishing positive results, especially in Chinese is an issue that has previously been identified.(319) This may lead to overstating results when synthesising data included in this research. In addition, the results were limited to what outcome measures the included studies used, because not all the validated outcome measures were included.

Considerable heterogeneity was noted in this review. Although key methods for heterogeneity mitigation included using a random effects model in pooled results and exploring heterogeneity through subgroup analysis and sensitivity analysis, it was still difficult to overcome as the included studies had differences in terms of variable aetiologies, severity of depression, disease history, study protocols, outcome measurements and interventions in terms of treatment duration, ingredients, dosage or medication compliance etc.

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Implications for clinical practice

This systematic review revealed that applying CHM as monotherapy or adjuvant therapy may be beneficial and safe for individuals with MDD. Chai hu and related CHM formulae were most commonly used, and these formulae should be considered key treatments in clinical practice.

Implications for future research

Future clinical studies of CHM for MDD need rigorous methodology, including clearly stated methods of sequence generation and allocation concealment. Future studies should also publish their protocols and be registered with a clinical trial registry to minimise reporting bias and increase transparency in the reporting of results.

Cause of depression, severity and disease history should be taken into consideration when designing trials and selecting participants. Selecting similar participants, in terms of aetiology, age range and severity, may help to achieve more comparable and reliable results. Assessing clinically important outcomes, such as relapse and remission of depression, quality of life, functional capacity and suicidality, would provide a comprehensive understanding of the effect of CHM.

Treatment duration in the current clinical trials ranged from one to 12 weeks (acute phase of depression treatment). Depression is a lifelong disease and should be monitored every two weeks during treatments. Follow-up assessment would provide long-term data around CHM

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therapies and further strengthen the evidence regarding treatment phase continuation (4 to 9 months) and maintenance (≥1 year).

Future clinical studies should follow the items required by the Consolidated Standards of

Reporting Trials (CONSORT) (320) and its extensions for herbal medicine.(321, 322)

Informative reporting of trial participants, reason for intervention selection, control and results of validated outcome measures will provide high-level clinical evidence and will benefit practitioners, researchers, patients and knowledge translation.

Conclusion

CHM alone or given as integrative medicine with SSRIs may produce statistically significant improvement in depressive symptoms. The current evidence should be interpreted with caution due to bias and methodological shortfalls in the included studies, and the substantial heterogeneity identified in meta-analysis. CHM does not appear to increase the risk of adverse events. New studies with rigorous methodologies in well-defined populations, and that include follow-up regarding treatment phases of continuation and maintenance, could validate the promising evidence identified in this review.

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Chapter 6 Acupuncture for Major Depressive Disorder: Systematic Reviews and Meta-analyses of Randomised Controlled Trials

Introduction

Acupuncture is frequently used for major depressive disorder (MDD).(130, 213, 323)

Acupuncture treatment may improve depression in several ways and its mechanisms of action have been evaluated. Acupuncture may inhibit the neurotransmitter gamma-aminobutyric acid, which then reduces neural excitability and suppresses the central nervous system.(28) It also reduces hippocampal neurochemical levels in animal models of depression.(29, 30).

Acupuncture can also increase serotonin levels in the hippocampus and decrease the stress hormone cortisol.(31) In these ways, acupuncture may relieve depression symptoms by protecting the hippocampal neurons, regulating neurotransmitters and hormones, and modulating mood. Recent pragmatic randomised controlled trial showed that either manual acupuncture or electroacupuncture combined with SSRIs could reduce depressive symptoms and improve quality of life in patients with moderate to severe depression.(324) Clinical and preclinical evidence showed acupuncture treatments have benefits for improving depression.

Previous systematic reviews evaluated the efficacy of acupuncture and related therapies either alone or in combination with conventional therapies for MDD. Shen Hui et al. (2014) investigated the efficacy of acupuncture for depression compared to pharmacotherapy.(325)

The review included 13 randomised controlled trials (RCTs) involving 884 participants. Meta- analysis showed that acupuncture was more effective than pharmacotherapy in terms of improving effective rate (i.e reducing depressive symptoms). Chan et al. (2015) included 13 studies (1,046 participants) to evaluate the effect of all types of acupuncture (including manual acupuncture, electroacupuncture, auricular acupuncture and laser acupuncture) plus

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antidepressants compared with antidepressants alone.(41) Meta-analysis showed significant differences in Hamilton Rating Scale for Depression (HRSD) scores and effective rates in favour of the combined treatment group. Zhang et al. (2016) analysed 6 studies (431 participants) to investigate the efficacy and safety of electroacupuncture plus SSRIs.(42) Meta- analysis revealed that electroacupuncture as an add-on therapy was superior to SSRIs alone in terms of HRSD, Zung’s Self-rating Depression Scale (SDS) and the Side Effect Rating Scale of Asberg (SERS). Smith et al. (2018) investigated the efficacy of acupuncture for depressive disorder, compared to no treatment, sham acupuncture, pharmacotherapy and psychological therapy. This review included 64 studies that involved 7,104 participants.(23) Meta-analysis showed insufficient evidence of a consistent beneficial effect from acupuncture compared with pharmacotherapy or psychotherapy.Randomised, double-blind, placebo-controlled clinical trials are recommended to evaluate the cost effectiveness of a treatment, which is the most rigorous method of determining if a cause-effect relationship exists between treatment and outcome.(326) However, previous systematic reviews included data of RCTs, but the majority of studies did not successfully conduct a double-blind placebo trial. Evaluating the risk of bias

(RoB) of 4,715 acupuncture RCTs over the last five decades, has identified major issues in terms of allocation concealment and blinding.(327) Although some studies used control measures such as sham acupuncture, developing appropriate placebo for blinding in acupuncture clinical trials is still a challenge.(328) Some evidence has indicated that sham acupuncture can recall a physiological response to alleviatie disease symptoms, thus placebo effects cannot be excluded.(329)

In addition, previous systematic reviews evaluated acupuncture for depression, but most were outdated or did not include a comprehensive search of Chinese literature.

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Therefore, the systematic review and meta-analysis in this chapter aims to include a comprehensive search and analysis of all major English and Chinese databases as well as rigorously evaluate the bias within the included studies. In-depth meta-analyses are conducted with a focus on acupuncture used alone or as add-on therapy with SSRIs. It also includes a detailed analysis of the safety of acupuncture for MDD.

Methods

The methods used in this review are based on the Cochrane handbook for systematic reviews of interventions 6.0.(45) The review was registered in PROSPERO (ID No. CRD42018091774).

Search strategy

Nine English and Chinese databases were searched from their inception to February 2018.

Databases included the Allied and Complementary Medicine Database (AMED), Cochrane

Central Register of Controlled Trials (CENTRAL) on the Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Excerpta Medica Database (EMBASE),

PubMed, China BioMedical Literature (CBM), China National Knowledge Infrastructure

(CNKI), Chongqiong VIP (CQVIP) and Wanfang.

Search terms were grouped into three blocks: 1) intervention (including acupuncture and synonyms); 2) clinical condition (including depression, depressive disorder, unipolar depression, major depression, major depressive disorder and synonyms); and 3) trial design

(including clinical trial, random, control and synonyms). Complete lists of search terms are available in Appendix C.

In addition to electronic databases, reference lists of previous systematic reviews and included studies were searched. The clinical trial registries were explored to identify completed studies,

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including the Australian New Zealand Clinical Trial Registry (ANZCTR), Chinese Clinical

Trial Registry (ChiCTR), European Union Clinical Trials Register (EU-CTR) and US National

Institutes of Health register (ClinicalTrials.gov).

Data extraction

Titles and abstracts were screened by three independent reviewers (Lingling Yang [LY],

Johannah Shergis [JS] and Yuan Ming Di [YMD]) for potentially relevant citations.

Disagreements were resolved by discussion with a fourth reviewer (Anthony Lin Zhang [ALZ]).

Full texts were obtained, screened and extracted against the inclusion criteria by two reviewers

(LY and YMD). Data checking and disagreements were resolved by discussing with a third reviewer (JS).

Risk of bias

ROB was assessed using the Cochrane handbook risk of bias assessment tool for each publication.(45) Risk of bias is categorised using the following six domains:

• Sequence generation: the method used to generate the allocation sequence is given in

sufficient detail to allow an assessment of whether it should produce comparable groups.

Low risk of bias refers to a random number from a table or computer random generator.

High risk of bias includes studies that describe a non-random sequence generation such

as odd or even date of birth or date of admission.

• Allocation concealment: the method used to conceal the allocation sequence is given in

enough detail to determine whether intervention allocations could have been foreseen

before or during enrolment. Low risk of bias includes central randomisation or sealed

envelopes and high risk of bias includes open random sequence etc.

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• Blinding of participants and personnel: measures used to describe if the study

participants and personnel are blind to the intervention received. In addition,

information relating to whether the blinding was effective is also assessed. Studies that

ensure blinding of participants and personnel are at low risk of bias. If a study is not

blind or incompletely blind, it is at high risk of bias.

• Blinding of outcome assessors: measures used to describe if the outcome assessors are

blind to knowledge of which intervention a participant received. In addition,

information relating to whether the blinding was effective is also assessed. Studies that

ensure blinding of outcome assessors are at low risk of bias. If a study is not blind or

incompletely blind, it is at high risk of bias.

• Incomplete outcome data: completeness of outcome data for each main outcome,

including dropouts, exclusions from the analysis with numbers missing in each group

and reasons for dropouts and exclusions. Studies with low risk of bias include all

outcome data or if there is missing data it is unlikely to relate to the true outcome or is

balanced between groups. Studies at high risk of bias have unexplained missing data.

• Selective reporting: the study protocol is available. The pre-specified outcomes are

included in the report. Studies with a published protocol and which include all pre-

specified outcomes in their report are at low risk of bias. Studies at high risk of bias do

not include all pre-specified outcomes or the outcome data is reported incompletely.

• Other sources of bias were defined as baseline imbalance. Two reviewers made

independent judgements of risk of bias and a third reviewer resolved any disagreement.

Potential publication bias was assessed using Funnel plots and Egger's test.

Inclusion and exclusion criteria

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Included studies were RCTs of any duration published in English or Chinese. Participants were diagnosed with MDD based on the Diagnostic and Statistical Manual of Mental Disorders

(DSM),(1) International Classification of Disease (ICD)(164) or Chinese Classification of

Mental Disorders (CCMD).(226) Participants were aged 18 to 65 years. Participants with other types of depression were excluded, such as dysthymia, bipolar depression and depression caused by other mental disorders, physical disorders, medical conditions or substances.

Included studies used acupuncture (manual acupuncture or electroacupuncture) as interventions and SSRIs as controls. Studies that did not specify the type of antidepressant were excluded.

Pre-specified outcome measures included clinician-rated and self-rating depression severity scales that werereliabile, valide, sensitive and specificfor assessing treatment effects in patients with depression(232, 233), the number of participants who relapsed or achieved remission, quality of life, functional capacity, suicidality and adverse events.

The groupings included the following comparators:

1) acupuncture versus SSRIs

2) acupuncture plus SSRIs versus SSRIs; and

3) acupuncture plus Chinese herbal medicine (CHM) versus SSRIs.

Data analysis

Continuous outcome data was analysed using mean difference (MD) with 95% confidence interval (CI). When different versions of outcome measures were used, standardised mean difference (SMD) was used for data analysis. For dichotomous outcome data, risk ratios (RR) with 95% CI were used. Heterogeneity was assessed using I2. An I2 score greater than 50% was

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considered to indicate substantial heterogeneity. Between-group differences were assessed using the random effects model due to expected heterogeneity.

Subgroup analysis

Predefined subgroup analyses were planned to explore heterogeneity, including treatment duration, type of SSRI, low risk of bias for sequence generation and different versions of outcome measures.

Sensitivity analysis

A posteriori sensitivity analysis was performed to examine the possible contribution of excluding trials with baseline imbalances between groups.

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Results

This section presents the effectiveness and safety of acupuncture (alone or as add-on therapy) or acupuncture combined with CHM compared to SSRIs.

Effect and safety of acupuncture

Data search identified 30,733 potentially relevant citations. Of these, 45 RCTs were included in the final analysis (Figure 6-1).

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Identification

Screening

Eligibility

Included

Randomised controlled trials included in meta-analysis (n=45)

Figure 6-1 Flow chart of study selection

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Characteristics of included studies

Thirty RCTs compared manual acupuncture or electroacupuncture alone with SSRIs and 15

RCTs compared acupuncture or electroacupuncture with SSRIs. All studies were conducted in

China, except one that was conducted in the USA.(330) These studies were published from

2003 to 2017. The included studies enrolled 3,771 participants (sample size range: 20–240).

Participants’ ages ranged over 22–65 years. The duration of depression ranged from 2 weeks to 7 years. Treatment duration ranged between 4 and 12 weeks. Four studies had a followup period, ranging from 4 to 6 weeks(331-334) (Table 6.1).

The included studies used 274 acupoints. The most commonly used acupoints were GV20 Bai hui (32 studies), EX-HN3 Yin tang (23 studies), PC6 Nei guan (20 studies), LR3 Tai chong (17 studies), SP6 San yin jiao (17 studies), BL18 Gan shu (12 studies), HT7 Shen men (11 studies),

LI4 He gu (10 studies) and BL23 Shen shu (9 studies). SSRIs used in the studies included fluoxetine (29 studies), paroxetine (11 studies), sertraline (2 studies), escitalopram (2 studies) and citalopram (1 study) (Table 6.1).

Outcome measures used in included studies were the Hamilton Rating Scale for Depression

(HRSD) (42 studies), Zung’s Self-Rating Depression Scale (SDS) (4 studies) and

Montgomery-Asberg Depression Rating Scale (MADRS) (one study). Quality of life was assessed using the WHO Quality of Life questionnaire in one study. Relapse and remission of depression, functional capacity and suicidality were not assessed in the included studies.

Adverse events were reported in 17 studies. SERS and Treatment-Emergent Signs and

Symptoms (TESS) were used to evaluate the severity of adverse events (1 and 5 studies, respectively) (Table 6.1).

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Table 6.1 Characteristics of included studies

Author, Year No. of Participants Intervention Control Treatment Outcomes Risk of Bias (SG, (I:C) Duration AC, BPt, BPn, BOA, IOD, SG, Other) Chen HD 2014 73 (40:33) MA+ Paroxetine Paroxetine 6 weeks HRSD, SERS, AEs L, U, H, H, H, L, U, GV20 Bai hui, EX- H HN3 Yin tang, GV16 Feng fu, GV14 Da zhui, GB20 Feng chi, PC6 Nei guan, SP6 San yin jiao Chen J 2010 52 (26:26) MA Fluoxetine 6 weeks HRSD, AEs L, U, H, H, H, L, U, GV 20 Bai hui, EX- L HN1 Si shen cong, PC6 Nei guan, LI4 He gu, LR3 Tai chong, SP6 San yin jiao, ST 36 Zu san li Chen XL 2012 60 (30:30) EA Paroxetine 4 weeks HRSD, AEs L, U, H, H, H, L, U, EX-HN1 Si shen L cong Chen XY 2015 20 (10:10) MA Escitalopram 8 weeks HRSD, TESS L, L, H, H, L, L, U, GV24 Shen ting, +follow up L CV 12 Zhong wan, CV4 Guan yuan, PC6 Nei guan, LI4 He gu, LR3 Tai chong, ST36 Zu san li, GV20 Bai hui,

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Author, Year No. of Participants Intervention Control Treatment Outcomes Risk of Bias (SG, (I:C) Duration AC, BPt, BPn, BOA, IOD, SG, Other) BL13 Fei shu, BL15 Xin shu, BL18 Gan shu, BL20 Pi shu BL23 Shen shu, HT7 She nmen Chi H 2011 60 (30:30) MA Fluoxetine 4 weeks HRSD, AEs U, U, H, H, L, L, U, GV 20 Bai hui, EX- L HN3 Yin tang, EX- HN1 Si shen cong, LR14 Qi men, ST- 36 Zu san li, SP6 San yin jiao, LR3 Tai chong, KI3 Tai xi Ding L 2007 78 (39:39) MA Fluoxetine 4 weeks HRSD U, U, H, H, H, L, U, BL23 Shen shu, L BL18 Gan shu, BL21 Pi shu, BL15 Xin shu, GV20 Bai hui, HT7 Shen men, SP6 San yin jiao, LR3 Tai chong Duan DM 2009 95 (48:47) EA+ Fluoxetine Fluoxetine 6 weeks HRSD U, U, H, H, H, L, U, GV 20 Bai hui, EX- L HN3 Yin tang Gao H 2008 115 (65:50) MA Fluoxetine 8 weeks HRSD U, U, H, H, H, L, U, BL13 Fei shu, L BL15 Xin shu, BL18 Gan shu,

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Author, Year No. of Participants Intervention Control Treatment Outcomes Risk of Bias (SG, (I:C) Duration AC, BPt, BPn, BOA, IOD, SG, Other) BL21 Pi shu, BL23 Shen shu, BL17 Ge shu, GV20 Bai hui, GV24 Shen ting Gao P 2016 80 (40:40) MA+Fluoxetine Fluoxetine 5 weeks HRSD U, U, H, H, H, L, U, LI4 He gu, LI11Qu L chi, EX-HN3 Yin tang, GB20 Feng fu, DU15 Ya men, CV17 Tan zhong, LR3 Tai chong, BL18 Gan shu, LR14 Qi men Li HB 2015 64 (34:32) MA Fluoxetine 12 weeks HRSD, AEs U, U, H, H, H, L, U, BL23 Shen shu, L BL18 Gan shu, BL21 Pi shu, GV20 Bai hui, EX-HN3 Yin tang, EX-HN1 Si shen cong, GV24 Shen ting, PC6 Nei guan Li XN 2017 60 (30:30) MA Paroxetine 8 weeks HRSD U, U, H, H, H, L, U, GV20 Bai hui, L GV24 Shen ting, EX-HN3 Yin tang, LI4 He gu, LR3 Tai chong, BL18 Gan shu, LR14 Qi men,

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Author, Year No. of Participants Intervention Control Treatment Outcomes Risk of Bias (SG, (I:C) Duration AC, BPt, BPn, BOA, IOD, SG, Other) SJ6 Zhi gou GB34 Yang ling quan Li ZF 2015 90 (30:30:30) EA Escitalopram 12 weeks HRSD, KMI, AEs L, L, L, L, L, L, U, CV4 Guan yuan, L EX-8 Zi gong, ST25 Tian shu, SP6 San yin jiao, LI4 He gu, LR3 Tai chong, GV20 Bai hui, EX- HN3 Yin tang Lin YQ 2014 60 (30:30) MA+Fluoxetine Fluoxetine 6 weeks HRSD L, U, H, H, H, L, U GV20 Bai hui, L GV24 Shen ting, PC6 Nei guan, LR3 Tai chong, HT7 Shen men Liu SX 2010 160 (118:42) MA Fluoxetine 6 weeks HRSD U, U, H, H, H, L, U, GV20 Bai hui, EX- L HN3 Yin tang, EX- HN1 Si shen cong Lu T 2017 60 (30:30) MA Fluoxetine 4 weeks HRSD, SDS, TESS H, U, H, H, H, L, U, GV20 Bai hui, LR3 L Tai chong, HT7 Shen men Luo HC 2003 95 (31:32:32) EA+placebo Fluoxetine 6 weeks HRSD U, U, L, L, L, L, U, electro Vs sham Vs GV20 Bai hui, EX- L drug HN3 Yin tang Luo RH 2009 60 (30:30) MA Fluoxetine 4 weeks HRSD L, U, H, H, H, L, U, LR3 Tai chong, LI4 L He gu, HT7 Shen

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Author, Year No. of Participants Intervention Control Treatment Outcomes Risk of Bias (SG, (I:C) Duration AC, BPt, BPn, BOA, IOD, SG, Other) men, GV20 Bai hui, EX-HN3 Yin tang Ma 2012 157 (53 acu: 56 MA Paroxetine 6 weeks WHO quality of life L, U, H, H, L, L, U, elctro: 48) DU16 Feng fu, scale L GV14 Da zhui, GV20 Bai hui, EX- HN3 Yin tang, GB20 Feng chi, PC6 Nei guan, SP6 San yin jiao Ma X 2012 52 (26:26) MA+Setraline Setraline 6 weeks HRSD U, U, H, H, H, L, GV20 Bai hui, EX- U,L HN3 Yin tang, EX- HN1 Si shen cong, PC6 Nei guan, HT7 Shen men, SP6 San yin jiao, LR3 Tai chong, Ma XH 2011 88 (28 elctro: 25 EA+ Paroxetine Paroxetine 6 weeks HRSD, AEs L, L, H, H, L, L, U, acup: drug 28) GV20 Bai hui, EX- +follow up L HN3 Yin tang, DU16 Feng fu, GV14 Da zhui, GB20 Feng chi, GV14 Da zhui, PC6 Nei guan, SP6 San yin jiao Miao MM 2015 67 (33:34) MA Fluoxetine 8 weeks HRSD, AEs L, U, H, H, H, L, U, GV24 Shen ting, H CV12 Zhong wan,

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Author, Year No. of Participants Intervention Control Treatment Outcomes Risk of Bias (SG, (I:C) Duration AC, BPt, BPn, BOA, IOD, SG, Other) CV4 Guan yuan, PC6 Nei guan, LI4 He gu, LR3 Tai chong, ST36 Zu san li Niu XS 2017 82 (41: 41) MA Fluoxetine 6 weeks HRSD, AEs L, U, H, H, H, L, U, BL11 Fei shu, L BL19 Ge shu, BL23 Shen shu, BL18 Gan shu, BL21 Pi shu, BL15 Xin shu Pan YY 2014 90 (45:45) MA+Citalopram Citalopram 4 weeks HRSD, TESS U, U, H, H, H, L, U, GV20 Bai hui, PC6 H Nei guan, SP6 San yin jiao Pei Y 2006 120 (62:58) MA Fluoxetine 6 weeks HRSD, AEs L, U, H, H, H, L, U, BL13 Fei shu, L BL15 Xin shu, BL18 Gan shu, BL21 Pi shu, BL23 Shen shu, BL17 Ge shu Qian J 2007 66 (33:33) MA Fluoxetine 6 weeks HRSD, AEs L, U, H, H, H, L, U, BL13 Fei shu, L BL17 Ge shu, BL23 Shen shu, BL18 Gan shu, BL21 Pi shu, BL15 Xin shu Qu 2013 160 (54 par: 58 MA+ Paroxetine Paroxetine 6 weeks AES L, L, H, H, L, L, U, elctro: 48) +follow up L

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Author, Year No. of Participants Intervention Control Treatment Outcomes Risk of Bias (SG, (I:C) Duration AC, BPt, BPn, BOA, IOD, SG, Other) GV20 Bai hui, EX- HN3 Yin tang, Feng fu, GV14 Da zhui, GB20 Feng chi, PC6 Nei guan, SP6 San yin jiao Qu SS 2015 195 (65:65:65) or EA Paroxetine 6 weeks HRSD, AEs L, U, U, U, L, L, U, 64:62:65 GV20 Bai hui, EX- H HN3 Yin tang, DU16 Feng fu, GV14 Da zhui, GB20 Feng chi, PC6 Nei guan, SP6 San yin jiao Shi Y 2015 MA Fluoxetine 8 weeks HRSD L, L, U, U, H, L, U, LU9 Tai yuan, LR3 L Tai chong Song SC 2013 80 (40:40) MA Fluoxetine 6 weeks HRSD L, U, H, H, L, L, U, EX-HN3 Yin tang, L GV20 Bai hui Song YQ 2007 90 (60:30) EA Fluoxetine 6 weeks HRSD U, U, H, H, L, L, U, EX-HN3 Yin tang, L GV20 Bai hui Tian Y 2017 36 (18: 18) EA+paroxetine Paroxetine 5 weeks HRSD, AEs U, U, H, H, H, L, U, GV20 Bai hui, EX- L HN3 Yin tang, DU26 Shui gou, PC6 Nei guan, HT7 Shen men, LI4 He gu, LR3 Tai chong,

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Author, Year No. of Participants Intervention Control Treatment Outcomes Risk of Bias (SG, (I:C) Duration AC, BPt, BPn, BOA, IOD, SG, Other) ST36 Zu san li, ST40 Feng long, SP6 San yin jiao, LU9 Tai yuan Wang CQ 2010 65 (33:32) EA Paroxetine 4 weeks HRSD L, U, H, H, L, L, U, GV20 Bai hui, EX- +follow up L HN3 Yin tang, DU16 Feng fu, GB20 Feng chi, GV14 Da zhui, PC6 Nei guan, SP6 San yin jiao Xing K 2011 240 (120:120) MA Fluoxetine 6 weeks HRSD L, U, H, H, H, L, U, GV26 Ren zhong, H PC5 Jian shi Xu FM 2009 41 (21:20) MA Fluoxetine 6 weeks HRSD U, U, H, H, H, L, U, GV20 Bai hui, PC6 L Nei guan Xu WT 2017 61 (30: 30) EA Fluoxetine 6 weeks HRSD, SDS L, U, H, H, H, L, U, GV20 Bai hui, EX- L HN3 Yin tang, GB34 Yang ling quan, SP6 San yin jiao, PC6 Nei guan, KI3 Tai xi Ye GX 2015 36 (18:18) MA+Fluoxetine Fluoxetine 12 weeks SDS, MADRs L, U, L, H, H, L, U, CV12 Zhong wan, L CV10 Xia wan, CV6 Qi hai, CV4 Guan yuan

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Author, Year No. of Participants Intervention Control Treatment Outcomes Risk of Bias (SG, (I:C) Duration AC, BPt, BPn, BOA, IOD, SG, Other) Yi Y 2011 42 (14:14:14) MA, Fluoxetine 4 weeks HRSD L, U, H, H, H, L, U, MA+Fluoxetine L LR3 Tai chong Yu SJ 2015 60 (30:30) MA Fluoxetine 4 weeks HRSD U, U, H, H, H, L, U, GV26 Ren zhong, L DU23 Shang xing, DU16 Feng fu, CV24 Cheng jiang, PC8 Lao gong, PC7 Da ling, GV1 Hui yin, BL62 Sheng mai, LI1 Shao shang, GV20 Bai hui, GV24 Shen ting Yu YS 2012 64 (32:31) MA Fluoxetine 6 weeks HRSD H, U, H, H, H, L, U, GV20 Bai hui, EX- L HN3 Yin tang, HT7 Shen men, PC6 Nei guan, BL18 Gan shu, GB20 Feng chi, LI4 He gu, LR3 Tai chong Zhang GJ 2007 42 (22: 20) EA+Paroxetine Paroxetine 6 weeks HRSD, TESS, AEs U, U, H, H, H, L, U, GV 20 Bai hui, EX- L HN3 Yin tang, PC6 Nei guan, SJ5 Wai guan, HT7 Shen men, LI4 He gu, LR3 Tai chong,

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Author, Year No. of Participants Intervention Control Treatment Outcomes Risk of Bias (SG, (I:C) Duration AC, BPt, BPn, BOA, IOD, SG, Other) ST36 Zu san li, ST40 Feng long, LU9 Tai yuan Zhang XX 2017 90 (30: 30) MA Paroxetine 8 weeks HRSD, Aes U, U, H, H, H, L, U, BL15 Xin shu, L BL18 Gan shu, BL21 Pi shu, BL13 Fei shu, BL23 Shen shu Zheng YH 2016 120 (60:60) MA+Fluxetine Fluoxetine 4 weeks HRSD, AEs U, U, H, H, U, L, U, PC6 Nei guan, HT7 H Shen men, GV20 Bai hui, SP6 San yin jiao, GV26 Ren zhong, LU5 Chi ze, ST40 Wei zhong, HT1 Ji quan Zhou JP 2013 164 (84:80) MA Fluoxetine 5 weeks HRSD, TESS U, U, H, H, H, L, U, GV20 Bai hui, PC6 L Nei guan, EX-HN5 Tai yang, EX-HN3 Yin tang, HT7 Shen men, ST36 Zu san li, SP6 San yin jiao, KI3 Tai xi, KI6 Zhao hai Zhou L 2011 58 (28:30) EA Setraline 6 weeks HRSD, SDS L, U, H, H, H, L, U, GB20 Feng chi L

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Author, Year No. of Participants Intervention Control Treatment Outcomes Risk of Bias (SG, (I:C) Duration AC, BPt, BPn, BOA, IOD, SG, Other) Zhou SH 2007 60 (30:30) MA Fluoxetine 6 weeks HRSD L, U, H, H, H, L, U, BL23 Shen shu, L BL18 Gan shu, BL15 Xin shu, ST36 Zu san li SP6 San yin jiao, GV24 Shen ting, GB13 Ben shen, EX-HN1 Si shen cong Abbreviations: AEs, adverse events; AC, Allocation Concealment; BPt, Blinding of Participants; BPn, Blinding of Practitioner; BOA, Blinding of Assessors; C, control groups; EA, electro-acupuncture; H, High risk of bias; HRSD, Hamilton Rating Scale for Depression; I, intervention groups; IOD, Incomplete Outcome Data; KMI, Kuppermans Index for menopause; L, Low risk of bias; MA, manual acupuncture; SDS, Self-rating depression scale; MADRS, Montgomery and Asberg Depression Rating Scale; SERS, Side-Effect Rating Scale; SG, Sequence Generation; SR, Selective Reporting; TESS, Treatment- emergent signs and symptoms; U, Unclear risk of bias.

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Risk of bias

All studies were described as randomised; however, only 24 (53.3%) described an appropriate method of random sequence generation, judged to be at low risk of bias. Five (11.1%) described an appropriate method of allocation concealment; the remaining studies (n=40, 88.9%) did not describe the details of allocation concealment and were judged as unclear risk of bias. Blinding of participants was adequately reported in three studies (6.7%) and were judged as low risk of bias, while 40 studies (89.9%) were judged at high risk. Blinding of personnel was adequately described in 2 studies (4.4%) that were judged as low risk, while 41 studies (91.1%) were at high risk of bias. Blinding of outcome assessors was judged to be at low risk in 11 studies

(24.4%). Outcome data was available for all included studies. Selective outcome reporting was judged at unclear risk of bias because of no available protocols. Other bias was judged as high risk of bias due to baseline imbalance in 6 studies (13.3%). Risk of bias assessment for each study is presented in Table 6.1 and Figure 6-2.

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Other bias 86.7 13.3 0

Selective reporting 0 100

incomplete outcome data 100 0

Blinding of assessors 24.4 73.3 2.2

Blinding of personnel 4.4 91.1 4.4

Blinding of participants 6.7 88.9 4.4

Allocation concealment 11.1 0 88.9

Sequence generation 53.3 4.4 42.2

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Low (%) High (%) Unclear (%)

Figure 6-2 Risk of bias: acupuncture for MDD

Publication bias

Funnel plots and Egger's tests were reviewed for two comparisons. For acupuncture vs. SSRIs for HRSD, the funnel plot was symmetrical and publication bias was not detected (Egger’s test t=−1.14, 95% CI −5.06 to 1.44, p=0.26). For acupuncture plus SSRIs vs. SSRIs for HRSD, the funnel plot was asymmetrical and publication bias was not detected (Egger’s test t=−0.49, 95%

CI −8.15 to 5.16, p=0.64). For other outcomes, the number of studies reporting them was less than ten and funnel plot evaluation was not appropriate. Figure 6-3 presents the funnels plots,

Image A includes studies that compare acupuncture to SSRIs for the HRSD outcome, while

Image B includes studies that compare acupuncture plus SSRIs to SSRIs for the HRSD outcome (Figure 6-3).

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studies that compare acupuncture to SSRIs for the HRSD

outcome Funnel plot with pseudo 95% confidence limits 0

_seES .3

-2 -1 0 1 _ES

studies that compare acupuncture plus SSRIs to SSRIs for the HRSD

outcome

Funnel plot with pseudo 95% confidence limits 0

.2 _seES

-1.5 -1 -.5 0 .5 1 _ES

Figure 6-3 Funnel plot: acupuncture for MDD

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Acupuncture vs SSRIs

Thirty studies (n=2,654) compared acupuncture or electroacupuncture to SSRIs using HRSD,

SDS, quality of life and adverse events and their severity.(330, 331, 333, 335-361) The number of participants who relapsed or achieved remission, functional capacity and suicidality were not assessed among these included studies.

Hamilton Depression Rating Scale (HRSD)

HRSD scores were assessed in 29 studies (n=2,356).(330, 331, 333, 335-358, 360, 361)

End of treatment between groups

At end of treatment, acupuncture showed significant improvement in HRSD scores compared to SSRIs (SMD –0.25 [–0.44, –0.06], I2= 78.9%) (Figure 6-4). The quality of evidence was low (Table 6.2). One study had a followup of 12 weeks, but no significant difference was observed between groups at the end of followup.(341)

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Study % ID SMD (95% CI) Weight

Chen J 2010 -0.01 (-0.56, 0.53) 3.29 Chen XL 2012 -0.55 (-1.06, -0.03) 3.38 Chen XY 2015 -0.67 (-1.68, 0.34) 1.96 Chi H 2011 -0.95 (-1.48, -0.41) 3.32 Ding L 2007 -0.25 (-0.70, 0.19) 3.62 Gao H 2008 -0.31 (-0.69, 0.06) 3.86 Li HB 2015 -0.77 (-1.28, -0.27) 3.41 Li ZF 2015 0.67 (0.22, 1.12) 3.61 Liu SX 2010a -0.92 (-1.29, -0.55) 3.88 Luo HC 2003a -0.18 (-0.69, 0.32) 3.43 Luo RH 2009 -1.73 (-2.33, -1.14) 3.11 Miao MM 2015 -0.21 (-0.71, 0.28) 3.45 Niu XS 2018 -0.57 (-1.02, -0.13) 3.63 Pei Y 2006 0.07 (-0.29, 0.43) 3.90 Qian J 2007 -0.16 (-0.65, 0.34) 3.45 Qu SS 2015a 0.25 (-0.09, 0.60) 3.94 Shi Y 2015 -0.52 (-0.96, -0.07) 3.62 Song SC 2013 -0.67 (-1.12, -0.22) 3.60 Song YQ 2007 -0.06 (-0.56, 0.45) 3.42 Xing K 2011 0.16 (-0.09, 0.42) 4.20 Xu FM 2009 0.18 (-0.44, 0.79) 3.06 Xu WT 2017 0.07 (-0.46, 0.60) 3.32 Yi Y 2011b -0.10 (-0.84, 0.64) 2.66 Yu SJ 2015 -0.70 (-1.22, -0.17) 3.36 Yu YS 2012 -0.21 (-0.71, 0.29) 3.45 Zhang XX 2017 0.87 (0.34, 1.40) 3.33 Zhou JP 2013 -0.27 (-0.58, 0.03) 4.05 Zhou L 2011 -0.70 (-1.23, -0.17) 3.33 Zhou SH 2007 0.69 (0.17, 1.21) 3.36 Overall (I-squared = 78.9%, p = 0.000) -0.25 (-0.44, -0.06) 100.00 NOTE: Weights are from random effects analysis

-2.33 0 2.33 Favours acupuncture Favours SSRIs

Figure 6-4 Forest plot comparing acupuncture to SSRIs alone in terms of Hamilton Rating Scale for MDD

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Table 6.2 Summary of findings of acupuncture vs. selective serotonin reuptake inhibitors

Outcomes No. of Certainty of Anticipated Absolute Effects Participants the Evidence (Studies) (GRADE) Assumed Risk SSRIs Risk Difference with Acupuncture Depressive symptoms 2,356 ⨁⨁◯◯ - SMD 0.25 SD lower (clinician-rated) (29 RCTs) LOW 1,2 (0.44 lower to 0.06 Hamilton Rating Scale lower) for Depression Treatment duration: mean 6.3 weeks

Depressive symptoms 312 ⨁◯◯◯ The mean Self- MD 3.59 points lower (patient‐reported) (4 RCTs) VERY LOW rating Depression (12.79 lower to 5.61 Self-rating Depression 1,2,3 Scale was 48.35 lower) Scale points Treatment duration: mean 6.0 weeks

Quality of life 157 ⨁⨁◯◯ The mean Quality MD 2.34 points higher WHO Quality of Life (1 RCT) LOW 1,3 of Life was 53.1 (0.35 higher to 4.33 Treatment duration: mean higher) 6.0 weeks

Adverse events 184 ⨁⨁◯◯ The mean TESS MD 3.33 lower (3.72 Toxic Exposure (2 RCTs) LOW 1,3 was 6.72 points lower to 2.95 lower) Surveillance System (TESS) Treatment duration:

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*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

Abbreviations: MD: Mean difference; RCT: randomized controlled trial; SD: standard deviation; SMD: standardised mean difference; SSRI: selective serotonin reuptake inhibitors

Subgroup analysis

In terms of studies judged at low risk of bias for sequence generation, there were no significant differences between acupuncture and SSRIs after subgroup analysis.

Subgroup analysis of treatment duration did not reduce heterogeneity. Twenty-two studies

(n=1847) that involved acupuncture treatment for 6 weeks or less showed the acupuncture group showed significantly improve HRSD scores compared to the SSRI group (SMD –0.29

[–0.50, –0.09], I2= 77.7%).(330, 333, 335-338, 342, 343, 345-347, 349-354, 356-358, 360, 361)

In treatment duration longer than 6 weeks, the acupuncture group did not show improvement in HRSD scores when compared with the SSRI group (SMD –0.11 [–0.58, 0.36], I2= 83.8%) among 7 studies.(331, 339-341, 344, 348, 355)

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Acupuncture reduced HRSD scores more than fluoxetine in 23 studies (n=1,938, SMD –0.32

[–0.51, –0.13]; I2=74.8%)(330, 335, 337-340, 342-354, 356, 358, 360, 361) but there was no statistical difference when comparing acupuncture to paroxetine and escitalopram.

The acupuncture group produced significant improvement in scores of HRSD-24 in 13 studies

(SMD –0.41 [–0.68, –0.14] I2=80.3%)(335-338, 342, 344, 346, 350, 354, 356, 357, 360, 361), but not HRSD-17.

Sensitivity analysis

At baseline, the acupuncture group was balanced in all studies except three.(333, 344, 350)

Removing these three studies from the end-of-treatment analysis showed similar effects (SMD

–0.29 [–0.50, –0.09], I2= 78.2%) (Figure 6-5).

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Study % ID SMD (95% CI) Weight

Chen J 2010 -0.01 (-0.56, 0.53) 3.73 Chen XL 2012 -0.55 (-1.06, -0.03) 3.83 Chen XY 2015 -0.67 (-1.68, 0.34) 2.26 Chi H 2011 -0.95 (-1.48, -0.41) 3.76 Ding L 2007 -0.25 (-0.70, 0.19) 4.08 Gao H 2008 -0.31 (-0.69, 0.06) 4.34 Li HB 2015 -0.77 (-1.28, -0.27) 3.86 Li ZF 2015 0.67 (0.22, 1.12) 4.07 Liu SX 2010a -0.92 (-1.29, -0.55) 4.36 Luo HC 2003a -0.18 (-0.69, 0.32) 3.88 Luo RH 2009 -1.73 (-2.33, -1.14) 3.54 Niu XS 2018 -0.57 (-1.02, -0.13) 4.10 Pei Y 2006 0.07 (-0.29, 0.43) 4.39 Qian J 2007 -0.16 (-0.65, 0.34) 3.90 Shi Y 2015 -0.52 (-0.96, -0.07) 4.09 Song SC 2013 -0.67 (-1.12, -0.22) 4.07 Song YQ 2007 -0.06 (-0.56, 0.45) 3.86 Xu FM 2009 0.18 (-0.44, 0.79) 3.48 Xu WT 2017 0.07 (-0.46, 0.60) 3.76 Yi Y 2011b -0.10 (-0.84, 0.64) 3.04 Yu SJ 2015 -0.70 (-1.22, -0.17) 3.81 Yu YS 2012 -0.21 (-0.71, 0.29) 3.90 Zhang XX 2017 0.87 (0.34, 1.40) 3.78 Zhou JP 2013 -0.27 (-0.58, 0.03) 4.55 Zhou L 2011 -0.70 (-1.23, -0.17) 3.77 Zhou SH 2007 0.69 (0.17, 1.21) 3.81 Overall (I-squared = 78.2%, p = 0.000) -0.29 (-0.50, -0.09) 100.00 NOTE: Weights are from random effects analysis

-2.33 0 2.33 Favours acupuncture Favours SSRIs

Figure 6-5 Forest plot comparing acupuncture to SSRIs alone in terms of Hamilton Rating Scale for MDD (removing studies with baseline imbalance)

Before and after treatment within groups

When compared with baseline HRSD scores, within-group analysis showed significant improvement in the acupuncture (SMD –3.21 [–3.64, –2.78], I2= 92.1%) and SSRI groups

(SMD –2.87 [–3.30, –2.45], I2= 91.7%). The mean changes on the HRSD within acupuncture and SSRIs groups followed similar trajectories. Significantly potential improvement occurred at 5 weeks and then was stable over 6–12 weeks (Figure 6-6).

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0 4 (n=6) 5 (n=1) 6 (n=15) 8 (n=5) 12 (n=2)

-1

-2

-3

-4 Change in HRSDScores Changein -5

-6

-7 Time (weeks) Mean change from baseline in acupuncture groups (SMD, 95%CI) Mean change from baseline in SSRIs groups (SMD, 95%CI)

Figure 6-6 Mean change from baseline to end of treatment on Hamilton Rating Scale for MDD, within acupuncture and selective serotonin reuptake inhibitor (SSRI) groups at different time points

Abbreviations: CI: confidence interval; n, number of studies; HRSD: Hamilton Rating Scale for Depression; SMD: standardised mean difference.

Zung Self-rating Depression Scale (SDS)

Four studies (n=312) compared acupuncture to SSRIs for SDS after 6-week treatments.(330,

333, 343, 357, 362)

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End of treatment between groups

At the end of the treatment, acupuncture did not improve SDS scores when compared to SSRIs alone (MD –3.59 [–12.79, 5.61], I2=96.9%); very low quality of evidence (Table 6.2).

Sensitivity analysis

Baseline data of SDS scores was balanced between groups except for one study.(333)

Removing this study from the end of treatment, the result did not produce significant results between groups (MD –5.55 [–14.93, 3.83], I2= 94.7%).

Before and after treatment within groups

Acupuncture showed significant improvement in SDS scores, comparing baseline and end of treatment (MD –23.86 [–37.12, –10.59], I2=98.1%), while SSRIs also showed significant improvement (MD –19.66 [–31.71, –7.61], I2=97%).

Quality of life

One study (n=157)(363) evaluated the effect of acupuncture on quality of life among patients with depression using the WHO Quality of Life questionnaire. Baseline data was balanced in both acupuncture and SSRI groups.

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End of treatment between groups

At the end of treatment, acupuncture significantly improved quality of life in patients with depression compared to SSRIs (MD 2.34 [0.35, 4.33]). The quality of evidence was low (Table

6.2).

Before and after treatment within groups

Comparing baseline and end of treatment scores, within-group analysis produced significant improvement in the acupuncture group (MD 6.42 [4.78, 8.06]), but not in the SSRI group (MD

2.3 [0.02, 4.58]).

Adverse events

No severe adverse events were reported in both acupuncture and SSRIs groups. Eleven studies reported on adverse events (Table 6.3). (333, 335-337, 340, 341, 344-347, 355) Six studies that reported no adverse events were in the acupuncture group.(335, 336, 340, 346, 355) Five studies reported 14 adverse events in the acupuncture group(333, 341, 344, 345, 347) including dizziness (4 cases), nausea (3 cases), local bruising (2 cases), palpitations (one case) and dry mouth (one case). All studies reported adverse events in the antidepressant group (183 cases).

The most frequent adverse events included dry mouth, fatigue, nausea, dizziness and loss of appetite (Table 6.3). Two studies(331, 356) reported acupuncture significantly improved the severity of adverse events in terms of TESS scores (low quality of evidence; MD: –3.33 [–3.72,

−2.95], I2=0%) when compared with SSRIs (Table 6.2). However, these two studies did not specify the adverse events.

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Table 6.3 Adverse events: acupuncture vs. SSRIs

Comparisons No. of Intervention Group Control Group Adverse Studies Adverse Events Events

Acupuncture vs. 11 Most common events Most common events (number SSRIs (number of cases) of cases)

• dizziness (4) • dry mouth (32) • nausea (3) • fatigue (17) • local bruising (2) • dizziness (16) • palpitations (1) • nausea (14) • dry mouth (1) • sweating (11) • loss of appetite (8) • constipation (8) • palpitations (7) • insomnia (7) • sleepiness (4) • headache (3) • indigestion (2)

Total adverse events =14 Total adverse events= 183

Acupuncture plus SSRIs vs. SSRIs alone

Fifteen studies (n=1,090) compared acupuncture plus SSRIs to SSRIs alone by evaluating

HRSD, SDS, MADRS, adverse events and their adverse events.(332-334, 352, 359, 362, 364-

372) Other outcome measures were not identified.

HRSD

All 15 studies (n=1090) assessed HRSD scores.(332-334, 352, 359, 362, 364-372)

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End of treatment between groups

At the end of treatment, the add-on therapy studies with acupuncture plus SSRIs significantly improved HRSD scores compared to SSRIs alone (low quality of evidence; SMD –0.66, [–

0.96, –0.35, I2=82.3%) (Figure 6-7) (Table 6.4). Two studies had a followup period.(332, 334)

At the end of followup, a significant difference in HRSD scores was found between acupuncture and SSRIs groups in two studies (MD –2.63 [–4.02, –1.23], I2=0%).

Study %

ID SMD (95% (95% CI) CI) Weight

Chen HD 2014 -0.64 (-1.12, (-1.12, -0.17) -0.17) 6.92

Duan DM 2009 -0.49 (-0.91, (-0.91, -0.07) -0.07) 7.18

Gao P 2016 -1.46 (-1.96, (-1.96, -0.97) -0.97) 6.82

Li XN 2017 -0.73 (-1.27, (-1.27, -0.19) -0.19) 6.61

Lin YQ 2014 -0.66 (-1.18, (-1.18, -0.14) -0.14) 6.69

Lu T 2017 -1.58 (-2.16, (-2.16, -1.00) -1.00) 6.38

Ma X 2012 -0.07 (-0.62, (-0.62, 0.47) 0.47) 6.57

Ma XH 2011 -1.16 (-1.64, (-1.64, -0.69) -0.69) 6.91

Pan YY 2014 -0.45 (-0.86, (-0.86, -0.03) -0.03) 7.18

Qu SS 2015b 0.11 (-0.24, (-0.24, 0.46) 0.46) 7.49

Tian Y 2017 0.93 (0.24, (0.24, 1.62) 1.62) 5.83

Wang CQ 2010 -0.59 (-1.10, (-1.10, -0.09) -0.09) 6.77

Yi Y 2011a -1.43 (-2.27, (-2.27, -0.59) -0.59) 5.12

Zhang GJ 2007 -0.49 (-1.11, (-1.11, 0.12) 0.12) 6.21

Zheng YH 2016 -1.16 (-1.55, (-1.55, -0.77) -0.77) 7.32

Overall (I-squared = 82.3%, p = 0.000) -0.66 (-0.96, (-0.96, -0.35) -0.35) 100.00

NOTE: Weights are from random effects analysis

-2.27 0 2.27 Favours acupuncture plus SSRIs Favours SSRIs

Figure 6-7 Forest plot comparing acupuncture plus selective serotonin reuptake inhibitors (SSRIs) to SSRIs alone in terms of Hamilton Rating Scale for MDD

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Table 6.4 Summary of findings of acupuncture plus selective serotonin reuptake inhibitors (SSRIs) vs. SSRIs

Outcomes No. of Certainty of Anticipated Absolute Effects Participants the Assumed Risk (Studies) Evidence SSRIs Risk Difference (GRADE) with Acupuncture plus SSRIs Depressive symptoms 1,090 ⨁⨁◯◯ - SMD 0.66 SD lower (clinician-rated) (15 RCTs) LOW 1,2 (0.96 lower to 0.35 Hamilton Rating Scale lower) for Depression Treatment duration: mean 5.3 weeks Depressive symptoms 226 ⨁◯◯◯ The mean Self- MD 5.57 points (patient‐reported) (3 RCTs) VERY LOW rating lower Self-rating Depression 1,2,3 Depression Scale (11.95 lower to 0.81 Scale was 48.12 points higher) Treatment duration: mean 7.3 weeks Depressive symptoms 36 ⨁⨁◯◯ The MADRS MD 8.62 points (patient‐reported) (1 RCT) LOW 1,3 was 14.06 points lower Montgomery–Asberg (9.38 lower to 7.87 Depression Rating Scale lower) (MADRS) Treatment duration: 12 weeks Adverse events 323 ⨁⨁◯◯ The mean TESS MD 2.17 lower Toxic Exposure (5 RCTs) LOW 1,2 was 4.96 points (4.27 lower to 0.07 Surveillance System lower) (TESS) Treatment duration: 5.0 weeks Adverse events 288 ⨁◯◯◯ The mean SERS MD 2.61 lower Side-Effect Rating Scale (3 RCTs) VERY LOW was 8.04 points (4.42 lower to 0.81 scores (SERS) 1,2,3 lower) Treatment duration: 6.0 weeks *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

Abbreviations: MD: Mean difference; RCT: randomized controlled trial; SD: standard deviation; SMD: standardised mean difference; SSRI: selective serotonin reuptake inhibitors.

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different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Subgroup analysis

Subgroup analysis for studies that had low risk of bias in sequence generation showed acupuncture was better than SSRIs in terms of improving HRSD scores, but there was considerable heterogeneity in 6 studies (n=455, SMD –0.68 [–1.13, –0.23], I2= 79.8%).(332-

334, 352, 364, 367)

Fourteen studies (n=1030) that involved acupuncture combined with SSRIs for 6 weeks or less showed a better improvement in HRSD scores when compared to SSRIs alone (SMD –0.65 [–

0.98, –0.32], I2= 83.6%).(332-334, 352, 359, 362, 364, 365, 367-372) In one study (n=60) with a treatment period of more than 6 weeks, acupuncture plus SSRIs also improved HRSD scores

(SMD –0.73 [–1.27, –0.20]).(366)

Acupuncture reduced HRSD scores more than fluoxetine (6 studies, 457 participants) and citalopram (1 study, 90 participants) (SMD –1.10 [–1.47, –0.72]; I2=68.7% and SMD –0.45 [–

0.86, –0.03]; I2=0.0%, respectively), but there was no statistical difference when comparing acupuncture with other SSRIs.

When HRSD versions were looked at separately, acupuncture plus SSRI was more effective at improving HRSD scores than SSRI alone: in HRSD-17 (10 studies) (SMD –0.57 [–0.85, –0.29],

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I2=67.8%)(332-334, 352, 359, 364, 366, 367, 369, 371) and HRSD version unknown (5 studies)

(SMD –0.78 [–1.50, –0.05, I2=90.6%).(362, 365, 368, 370, 372)

Sensitivity analysis

At baseline, the HRSD scores were not balanced in three studies(364, 369, 372) (Figure 6-8).

Removing these studies from the end-of-treatment meta-analysis did not change the results

(SMD –0.63 [–1.01, –0.25], I2= 84.5%).

Study %

ID SMD (95% (95% CI) CI) Weight

Duan DM 2009 -0.49 (-0.91, (-0.91, -0.07) -0.07) 8.99

Gao P 2016 -1.46 (-1.96, (-1.96, -0.97) -0.97) 8.62

Li XN 2017 -0.73 (-1.27, (-1.27, -0.19) -0.19) 8.41

Lin YQ 2014 -0.66 (-1.18, (-1.18, -0.14) -0.14) 8.49

Lu T 2017 -1.58 (-2.16, (-2.16, -1.00) -1.00) 8.17

Ma X 2012 -0.07 (-0.62, (-0.62, 0.47) 0.47) 8.37

Ma XH 2011 -1.16 (-1.64, (-1.64, -0.69) -0.69) 8.72

Qu SS 2015b 0.11 (-0.24, (-0.24, 0.46) 0.46) 9.30

Tian Y 2017 0.93 (0.24, (0.24, 1.62) 1.62) 7.58

Wang CQ 2010 -0.59 (-1.10, (-1.10, -0.09) -0.09) 8.57

Yi Y 2011a -1.43 (-2.27, (-2.27, -0.59) -0.59) 6.79

Zhang GJ 2007 -0.49 (-1.11, (-1.11, 0.12) 0.12) 7.99

Overall (I-squared = 84.5%, p = 0.000) -0.63 (-1.01, (-1.01, -0.25) -0.25) 100.00

NOTE: Weights are from random effects analysis

-2.27 0 2.27 Favours acupuncture plus SSRIs Favours SSRIs

Figure 6-8 Forest plot comparing acupuncture plus SSRIs to SSRIs alone in terms of Hamilton Rating Scale for MDD (removing studies with baseline imbalance)

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Before and after treatment within groups

Overall, within-group analysis comparing before and after treatment showed significant improvement in HRSD scores in the intervention (SMD –3.62 [–3.96, –3.27], I2=68%) and

SSRI groups (SMD –2.66 [–2.89, –2.42], I2=47.1%). Significant improvements in the acupuncture plus SSRI group occurred at 4 weeks, while in the SSRI group improvements occurred at 5 weeks (Figure 6-9).

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0 4 (n=5) 5 (n=2) 6 (n=7) 8 (n=1)

-1

-2

-3

-4 Change in HRSDscores Changein

-5

-6 Time (weeks) Mean change from baseline in acupuncture plus SSRIs groups (SMD, 95%CI) Mean change from baseline in SSRIs groups (SMD, 95%CI)

Abbreviations: CI: confidence interval; n, number of studies; HRSD: Hamilton Rating Scale for Depression; SMD: standardised mean difference.

SDS

Three studies (n=226) evaluated the effect of acupuncture plus SSRI to SSRI for SDS.(333,

368, 373)

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End of treatment between groups

At the end of treatment, there was no significant difference between the two groups (MD –5.57,

[–11.95, 0.81], I2=95.1%); very low quality of evidence (Table 6.4).

Sensitivity analysis

Removing one study(333) due to baseline imbalance reduced the heterogeneity, but did not produce significant results between groups (MD 0.00, [–1.04, 1.04], I2=0.0%).

Before and after treatment within groups

The acupuncture plus SSRI group produced significant improvement in SDS scores, comparing before and after treatment (MD –19.07 [–25.24, –12.89], I2=95.6%), as did the SSRI alone group (MD –12.22 [–15.10, –9.34], I2=78.1%).

Montgomery–Asberg Depression Rating Scale (MADRS)

One study with 36 participants reported MADRS.(373) At end of treatment, a significant improvement was found in acupuncture plus SSRIs when compared to SSRIs (low quality of evidence; MD –8.62 [–9.38, –7.87]) (Table 6.4). Within the acupuncture plus SSRI group and

SSRI alone group, significant differences were also observed before and after treatment.

Adverse events

Seven studies reported on adverse events.(332, 333, 364, 370-372, 374) The acupuncture plus

SSRI group reported 192 events, while the SSRI group reported 141 events. Two studies(332,

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374) had three arms including manual acupuncture, electroacupuncture and SSRIs. In the acupuncture group, adverse events for manual acupuncture and electroacupuncture were counted together (Table 6.5).

The most frequently reported adverse event for two groups were physical tiredness (55 cases and 19 cases, respectively). Other common adverse events included sleep disturbance, headache and dry mouth (Table 6.5).

Five studies (n=323)(365, 368-371) assessed TESS scores and showed significant improvement in the acupuncture group (MD –2.17 [–4.27, –0.07], I2=98%). The quality of this evidence was low (Table 6.4). However, the studies did not specify the type of adverse event.

Three studies involving 288 participants(332, 333, 364) showed that acupuncture as add-on therapy significantly improved SERS scores compared to SSRIs alone (low quality of evidence;

MD –2.61 [–4.42, –0.81], I2=80.9%) (Table 6.4).

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Table 6.5 Adverse events: acupuncture plus SSRIs vs. SSRIs

Comparisons No. of Intervention Group Adverse Control Group Adverse Events Studies Events

Acupuncture plus 7 Most common events (number Most common events (number of SSRIs vs. SSRIs of cases) cases)

• physical tiredness (55) • physical tiredness (19) • sleep disturbance (49) • sleep disturbance (18) • headache (16) • dry mouth (15) • sexual problem (10) • headache (11) • constipation (8) • constipation (9) • gastrointestinal • insomnia (8) discomfort (7) • gastrointestinal discomfort (7) • vertigo (7) • difficulty with urination (6) • palpitations (6) • palpitations (6) • anxiety (5) • anxiety (5)

Total adverse events =192 Total adverse events =141

Efficacy and safety of acupuncture combined with CHM

Six RCTs (442 participants) assessed the efficacy of acupuncture plus CHM compared to

SSRIs.(355, 375-379)

HRSD

Baseline scores on HRSD were balanced in all studies between the two intervention groups. At the end of treatment, the combination therapy of acupuncture and CHM was superior to SSRIs alone (SMD -0.78 [-1.43, -0.13], I2=89.9%). Within-group analysis found improvement in the

SSRI group (SMD -4.27 [-5.94, -2.61], I2=96.8%) or the intervention group (SMD -2.99 [−4.43,

-1.55], I2=96.7%).

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SDS

One study (70 participants) assessed SDS scores.(377) Acupuncture in combination with CHM did not significantly improve SDS scores in 70 patients after 8 weeks of treatment (MD −0.79

[−2.64, 1.06]). Significant improvement was observed within the intervention group (MD

−5.63 [−7.37, −3.89]) and within the control group (MD −5.39 [−7.04, −3.74]).

Adverse events

Three studies reported on adverse events.(355, 375, 376) The intervention group reported 4 adverse events including dizziness (2 cases), disturbed sleep (1 case) and diarrhoea (1 case).

The control group reported a total of 36 adverse events. The most common adverse events included dry mouth (8 cases), sleepiness (6 cases) and sweating (5 cases).

Discussion

Summary of evidence

Effect-size estimations are based on comparisons between acupuncture and SSRIs, acupuncture plus SSRIs and SSRIs, and acupuncture plus CHM and SSRIs.

Acupuncture vs. SSRIs

Acupuncture alone compared with SSRIs alone reduced depression at the end of treatment or before and after treatment (very low to low quality of evidence), which may indicate that acupuncture cannot be routinely recommended as a treatment for depression based on the

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results. A larger number of adverse events from SSRIs was reported compared to acupuncture.

However, the outcome of adverse events was not reported in every study as an assessment of safety.

Acupuncture plus SSRIs vs. SSRIs

Acupuncture plus SSRIs compared to SSRIs also reduced depression at the end of treatment or before and after treatment. The quality of evidence was very low to low. More adverse events were reported in the combination of acupuncture plus SSRI group than that in the SSRI group.

However, this outcome was not widely reported. The end of treatment comparisons showed the 12 weeks follow up group had no effect, but the shorter duration did. This may indicate a placebo effect in these participants, or the time course of effect is short and/or the time of effect is short.

Acupuncture plus CHM vs. SSRIs

Acupuncture plus CHM showed significant improvement on reducing the HRSD scorces when compared to SSRIs used alone, although only a small number of studies contributed to the results.

Outcome measures

HRSD results showed there were statistically significant improvements in acupuncture groups compared to SSRIs groups at the end of treatment. Findings are consistent with previous systematic reviews.(23, 40, 380) Within the acupuncture group, there were significant

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improvements in HRSD scores before and after treatments. The findings are consistent with the clinical significance of a mean difference of three HRSD points.(381)

When assessing acupuncture alone, studies with treatment durations of 6 weeks and less produced the most statistically significant differences. Significant improvements occurred at 5 weeks. This may suggest that acupuncture alone is more beneficial for improving depression in the short term. When acupuncture was combined with SSRIs, treatment was effective regardless of whether it occurred for more or less than 6 weeks.

In terms of SDS, there were limited studies that reported this outcome. Only acupuncture combined with SSRIs showed statistical differences between groups. When acupuncture alone was compared to SSRIs alone, no statistically significant difference was found. The effect of electroacupuncture alone or in combination with SSRIs on SDS is inconclusive and needs further investigation. Statistical significance and statistical power depend on effect size and sample size. If the effect size of the intervention is large, it is possible to detect such an effect in a smaller sample size, while a small effect size requires a larger sample.(382) In this study, there were only four included studies (312 participants) comparing acupuncture to SSRIs, and three studies (226 participants) comparing acupuncture plus SSRIs to SSRIs alone, using SDS as the outcome measure. At the end of treatment, the effect size was, mean difference (MD)

3.59 points lower (12.79 lower to 5.61 higher) and MD 5.57 points lower (11.95 lower to 0.81 higher), respectively. A non-significant effect is likely due to a small effect size and a sample size.

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Only one study assessed acupuncture’s effect on quality of life in participants with depression.(359) When compared to SSRIs, acupuncture showed benefit in improving quality of life. Due to the small number of studies, evidence for acupuncture’s effect on quality of life in people with depression is inconclusive.

In terms of adverse events, using acupuncture alone produced fewer adverse events than SSRIs.

In combination with SSRIs, acupuncture had more adverse events than using SSRIs alone; however, some studies did not specify clearly the number or type of adverse events. This suggests that acupuncture does not increase the risk of adverse events and can be used safely along with SSRIs.

These results may suggest that acupuncture is beneficial for improving depression in the short term and in managing depression symptoms alone or in combination with SSRIs, with no increased risk of adverse events when used alone.

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Limitations of this study

Most of the included studies had small sample sizes and were not large enough to detect a difference between groups. Included studies had methodological flaws and provided low- quality and inconclusive evidence. These studies are mainly from China, so the results do not necessarily represent other populations. In research. the placebo effect may be observed. This also has been reported in studies of people with depression taking anti-depressants.(383)

Acupuncture studies that include a sham or placebo control arm can help to understand specific effects of the treatment and non-specific effect and/or placebo effects, but creating an apprariate placebo for acupuncture remains the challengage.(384) Techniques to design high quality acupuncture trials, minimising the placebo effect and optimising acupuncture administration are important for future clinical trials.(385)

High heterogeneity was observed across all comparisons. We performed explorative analysis but could not identify the source of heterogeneity. It may have arisen from several causes, including the different acupuncture points used, treatment duration or the cause and severity of depression. Baselines were not balanced in some studies. Sensitivity analysis for removing these studies did not change the overall results or reduce the substantial heterogeneity.

Implications for clinical practice

This review suggests acupuncture is beneficial when used alone in the short term to improve depression severity and that it poses no additional risk when used in combination with SSRIs.

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Therefore, in clinical practice acupuncture may be considered as an additional treatment for people with depression.

Common acupuncture points identified in this review, such as PC6 Nei guan, HT7 Shen men,

LI4 He gu and LR3 Tai chong, are consistent with clinical practice and recommendations by

CM guidelines.(180) Their main functions are to calm the spirit, regulate and tonify the Heart, and activate the channels.(386)

This review identified two acupoints commonly used in the included trials: GV20 Bai hui and

EX-HN3 Ying tang. In CM theory, GV20 benefits the brain and calms the spirit. It is used for signs and symptoms of agitation and oppression, fright, palpitations, poor memory, lack of mental vigour, crying, sadness and crying with suicidality.(386) EX-HN3 Yin tang calms the mind and is used for insomnia, anxiety and agitation.(386) Based on this, coupled with available clinical evidence, practitioners should consider adding these points to their selection of acupoints for treating depression.

Implications for future research

Future trials on acupuncture for depression should follow the rigorous clinical practice guidelines(387) and protocols should be published prior to the conduct of trials to ensure the reporting of all planned outcomes.

One out of 50 included studies assessed the quality of life outcome, while most studies assessed depression scores. Depression is a debilitating condition and has significant impact on the person’s quality of life, so future trials should assess the effect of acupuncture on quality of life

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for depression patients. Only 3 included studies had a followup period and the long-term effect of acupuncture alone or in combination with SSRIs should be assessed in the future.

Future trials should also consider severity of depression when recruiting participants, as this may have impacts on SDS scores because it is a self-rating scale. Depression is a life-long disease and remission often occurs, so this is an important outcome when assessing the efficacy of a treatment. None of the included studies assessed the remission rate of depression and this should be assessed in future trials.

Conclusion

Acupuncture produces statistically significant improvements in depression symptoms, when used alone or combined with SSRIs. Acupuncture alone or in combination with CHM does not increase the risk of adverse events. However, current evidence should be interpreted with caution due to their not being free of risk of bias, methodological shortfalls and substantial heterogeneity in the meta-analysis, and acupuncture cannot be routinely recommended as a treatment for depression based on the findings. Future studies with rigorous methodologies, including consideration of depression severity, short-term and long-term followup and clinically important outcome measures, would validate the encouraging evidence identified in this review.

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Chapter 7 Patients’ Experience and Expectations of Using Chinese Medicine for Major Depressive Disorder: A Survey

Foreword

Patients with major depressive disorder (MDD) are increasingly using complementary and alternative medicine (CAM).(388) A study showed that about 40% of patients used CAM therapies but most of them did not tell their family doctors.(389) With this in mind, it is vital that doctors ask their patients about CAM use and gain basic knowledge of the commonly used therapies.(390)

As stated above, in China, CAM mainly refers to Chinese medicine (CM) and primarily includes herbal medicine and acupuncture therapies. CM is officially state-supported and institutionalised in Chinese hospitals. Statistics collected at the end of 2015 show that there were 446 hospitals of integrative medicine in China.(391) Furthermore, about 95% of hospitals have a CM department and the majority of these hospitals conduct integrative medicine.(392)

Herein, integrative medicine refers to both Western conventional medicine plus CM. The

Chinese government has positively supported this integration over the last 60 years.(393) There were 452,000 practitioners and assistant practitioners of CM, including practitioners of integrative medicine and ethnic minority medicine.(391) There are about 910 million visits to

CM medical and health services across the country per year.(391) The use of integrative medicine is high among Chinese people.(394) Integrative medicine is widely used in clinical practice for various health conditions including depression.(395, 396)

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Introduction

CM is formally recognised as an important part of the Chinese health care system along with conventional medicine.(212) The Chinese government has listed CM as a required service in community health centres(397) and the majority of hospitals conduct integrative medicine

(integration of CM and conventional medicine).(398, 399) A national survey covering urban and rural areas in China showed that 14% of Chinese households considered CM their typical source of health care.(400) Improving CM use in the nation’s basic health care system has been identified as a goal in the national 13th Five-Year Plan.(401) CM is popular in the Guangdong province of China, especially services of Chinese herbal medicine (CHM).(394)

Evidence-based decision-making in CM for depression is a complex problem. Many clinical trials have investigated the use of CM for depression in various patient types and study settings.(204, 402, 403) Most of these studies report on the treatments, effectiveness and safety of using CM for depression, with relatively few studies exploring patient experience and expectations of using CM. However, patient experience and expectations, as a part of patient values, play an important role in health care.(404) Patients have impact on the decision-making process.(405) It is important for a doctor to obtain feedback from patients which may influence their compliance with treatment and ultimately impact on the efficacy of treatment. Results from a previous study suggested that the impact of preference among patients with depression is complicated including depression severity, establishment of therapeutic alliance, and initiation, engagement, adherence, and persistence for treatment; further, taking patient

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preferences for depression treatments into consideration may contribute to increasing treatment initiation and improving therapeutic alliance.(406) The majority of the studies on treatment preference focused on psychotherapy, pharmacotherapy and comparisons between them.(407-

409) Recently, patients’ experience and preference of using CM was investigated on some specific topics(410, 411). However, experience and expectations of using CM among Chinese patients with MDD is unknown. There is an information gap in terms of who uses it and why.

Therefore, the aims of this study and research questions were:

1) Aim 1: Explore experience of using CM among Chinese patients with depression in an integrative medicine hospital.

Research question 1: What is patients’ treatment experience of using CM/conventional medicine and their preference?

• What is patients’ treatment experience of using CM for MDD (in relation to self-

reported effecacy and safety, reasons for use or no use)?

• What is patients’ treatment experience of using conventional medicine for MDD (in

relation to self-reported effecacy and safety, reasons for use or no use)?

• What is patients’ treatment preference for MDD?

2) Aim 2: Understand these patients’ expectations when using CM for MDD.

Research question 2: What are treatment expectations among patients with MDD when using

CM?

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• What are patients’ expectations when communicating with doctors?

• What are patients’ expectations when raising treatment goals of using CM for MDD?

• What are patients’ preferred information about CM for MDD?

3) Aim 3 Preliminarily explore the prediction of using CM for MDD.

Research question 3: What are possible predictive factors of treatment use for MDD?

There are no existing questionnaires that focus on investigating experience and expectations of using CM among patients with depression. To specifically answer research questions, a new survey was designed and conducted at the Guangdong Provincial Hospital of Chinese Medicine

(GPHCM, Guangzhou, China). The GPHCM was established in 1933 and is one of the largest and leading hospitals in China,(412) providing integrated health services of conventional medicine and CM. In 2018, the number of outpatients reached 7.02 million, while the inpatient numbers were more than 140,000.(413) With the above considerations, we performed the survey in the GPHCM as explorative research. This study provides important evidence of CM use in clinical practice and may inform clinical decision-making and guide future research of

CM use for depression.

Methods

Survey design

This survey was designed to collect information on patients’ experience and expectations when treating depression. The implementation followed the guidance recommendations on

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conducting and reporting a survey.(414) The survey used a new format that had not been implemented previously. It was anonymous, self-administered and in the Chinese language

(Mandarin), and participants were allowed to freely answer the questions. This survey included three sections consisting of 26 questions (Appendix D and Appendix E).

The first section was comprised of 9 questions and collected demographic information such as age, gender, marital status and education, and diagnostic information such as the place where they were diagnosed with depression and its diagnosis year. The second section included 8 questions and focused on the patients’ experience of using conventional medicine or CM. This section collected information on the patients’ treatment experience referring to self-reported efficacy and safety, reasons for using or not using conventional treatments or CM and treatment preference. The third section consisted of 9 questions regarding patient expectations when seeking treatment including communication with doctors, treatment goals and treatment information that the patient wanted to know.

All patients completed the sections concerning demographics (Section 1) and treatment expectations (Section 3) sections. Only patients who had used treatments for depression at the time of the survey or before the survey completed Section 2. Patients who were first-time users of treatment for their depression jumped to Section 3 after answering Section 1.

The survey was developed by a bilingual Chinese researcher (LY), a bilingual Australian researcher (ALZ) and an Australian researcher (JLS). The questionnaire was developed in

English, translated into Chinese (Mandarin) and then was back-translated into English for

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verification. The Chinese version that was used in the pilot survey and the full survey was checked by three CM physicians, while its English version was checked by a bilingual translator (AQ) and a bilingual Australian researcher (YMD). During instrument development, several items were changed based on cultural appropriateness of item wording.

Participant recruitment

Eligible participants were adults aged 18 to 65 years, diagnosed with depression and who had consulted a medical practitioner, including CM doctors, conventional medicine doctors and integrative medicine doctors, from the Department of Psychology and Sleep Medicine

(Department of PSM) at the GPHCM. First-time visitors or patients who visited the clinic in the 12 months prior to the time of the survey were eligible to participate in the study. People using CM therapy other than CHM or acupuncture were excluded. Potential participants were identified via practitioners, psychologists and psychiatrists at the Department of PSM of

GPHCM. Potentially eligible participants were approached directly when they visited the department or contacted by telephone as recorded in the electronic health record database of the hospital. Research personnel explained details of the study to potentially eligible participants and invited them to participate.

Sample size

This study aimed to gain explorative information from patients with depression; therefore, convenience sampling was used to collect the data.(415, 416) The Department of PSM has about 40,000 outpatient appointments annually and about 10,000 quarterly. In one quarter,

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approximately one-tenth to one-seventh of patients, about 1000 to 1500, that present to the department are diagnosed with depression. Aiming to get a 10% response rate, predetermined sample size was around 100–150 participants.

Data collection

Participants were required to read a brief letter that provided details of the study. Those who agreed and consented to participate were requested to complete the paper-based survey and place the completed form in a collection box at the survey site. It took participants around 15 minutes to complete the survey. Data was entered and checked by using the EpiData software and then transferred to SPSS for analysis. All survey forms were kept in a locked cabinet and data will be stored for a minimum of seven years after the publication date as per the Australian code for the responsible conduct of research. (417)

Data analysis

Statistical analyses were performed in IBM SPSS Statistics, Version 25.(418)

• Descriptive analyses were mainly performed to answer research questions one and two

as well as identify patients’ demographic characteristics and diagnostic information.

• Bivariate analyses, as the supplementary and exploratory analysis for addressing

research question three, were conducted to further understand the relationship between

demographic characteristics/diagnostic information and treatment experience/

treatment expectations. Data collected in this study for analysis was categorical data

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using chi-square tests. According to the characteristics of data, parametric statistics

were not used, such as t-tests. Chi-square tests and the Fishers exact tests were

performed to reveal latent details of the sample, and to get more clues for further study.

• Binary logistic regression models were used as exploratory analyses to answer research

question three, looking for predictive factors of treatment use for depression among

demographic variables and diagnostic information variables. An association was

considered statistically significant at an alpha of 0.05.

Ethics

Ethics approval was granted by the Ethics Committee of the GPHCM (Approval number:

Y2017-120-01), China and registered with the RMIT University Science Engeneering and

Health College Human Ethics Advisory Network (Approval number: SEHAPP 90-17)

(Appendix F and Appendix G).

Pilot survey

A pilot study was conducted aiming to test the feasibility of the survey including readability of the questions, time of completing the survey and acceptance of participants, etc. A paper-based pilot survey was conducted in the Department of PSM. The pilot questionnaire version was in the Chinese language (Mandarin) as presented in Appendix D (Edition No: 001/20170607).

The pilot survey was conducted from October to November 2017.

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The questionnaire appeared to be well accepted by the participants and took on average 10 minutes to complete. Section 1 on demographics was acceptable and some minor updates were made to one question and four questions removed. Section 2 on treatment history and information was reformatted to improve readability; however, the questions remained largely unchanged. Section 3 on treatment expectation was reformatted to improve readability; however, the questions remained largely unchanged. After updates, the final questionnaire

(Appendix E, Edition No: 002/20180123) was implemented for the full survey. Ethics approval did not need to be updated. Twenty participants consented to the pilot survey and 17 completed the questionnaire. The results are presented in Appendix H.

Survey results

The survey was conducted from February 2018 to April 2018 at the Department of PSM of

GDHTCM and there were 139 respondents (Figure 7-1).

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Participants approached (n=170)

Eligible participants (n=155) Participants excluded (n=16): Reasons for exclusion: Participants enrolled in the survey Refused to consent (n=7) (n=139) Discontinue the survey (n=9)

Participants completed the questionnaire (n=139) (n=155)

Included in the final analysis (n=139)

Figure 7-1 Flow chart of participants recruitment and data collection

Demographic characteristics

Of the 139 participants, 137 responded to the questions about age. Age range was between 18 to 61 years (mean 34.3 and standard deviation [SD] 12.0). The largest proportion of respondents were aged 21 to 30 years (n=56, 40.9%). 138 participants responded to the questions on gender, marital status and education, of whom 88 (63.8%) were female and 50

(36.2%) were male, 73 (52.9%) were married and 72 (52.2%) had education lower than a bachelor’s degree. A total of 78 (56.5%) were employed. 123 participants responded to the

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question on monthly income, of whom 45 (36.6%) reported no income, 37 (30.1%) less than

5000 Chinese Yuan (CNY; 1 Chinese Yuan is approximately AU$0.20), 29 (23.6%) reported an income of 5001 to 10,000 CNY and 12 (9.8%) responded more than 10,000 CNY. Most participants had medical insurance (113, 82.5%) and 103 (74.6%) were diagnosed with depression in an integrative medicine hospital (Table 7.1). Sixty-three participants had been diagnosed with depression for the first time at the time of completing the survey, while 76 had a diagnosis of depression prior to undertaking the survey.

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Table 7.1 Demographic characteristics of the survey participants

Characteristics Total (n=138); n (%)

Age, mean (standard deviation) 34.3 (12.0) 18-20 years 11 (8.0) 21-30 years 56 (40.9) 31-40 years 29 (21.2) 41-50 years 22 (16.1) 51-65 years 19 (13.9) Not stated 2 Gender Female 88 (63.8) Male 50 (36.2) Not sated 1 Marital status Married 73 (52.9) Not married 65 (47.1) Not stated 1 Education Diploma or under 72 (52.2) Bachelor 56 (40.6) Master or Doctorate 10 (7.2) Not stated 1 Occupation Student 26 (18.8) Employed 78 (56.5) Unemployed 20 (14.5) Retired or other 14 (10.1) Not stated 1 Monthly income 0 Chinese Yuan (CNY) 45 (36.6) <5000 CNY 37 (30.1) 5001-10000 CNY 29 (23.6) >10000 Yuan 12 (9.8) Not stated 16 Medical insurance Insured 113 (82.5) Not insured 24 (17.5) Not stated 2 Place where participants were diagnosed Psychological and psychiatric hospital 16 (11.6) Conventional medicine hospital 19 (13.8) Integrative medicine hospital 103 (74.6) Not stated 1

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Patients’ treatment experience

The 76 participants who had had a previous diagnosis of depression were asked questions related to treatment experience. The other 63 participants did not complete this section of the survey (Section 2) but moved to Section 3. Treatment experience referred to the use of conventional medicine treatments and/or CM treatments, and treatment preferences. The use of conventional medicine and/or CM treatments included patients’ self-reported types of treatments, effects, adverse events and their reasons for continuing or discontinuing using these treatments. Patients could select one or more reasons for continuing or discontinuing treatment.

Use of conventional medicine for MDD

The conventional medicine treatments included: 1) treatments that participants were using at the time of the survey; and 2) treatments that had been used before but were not being used at the time of the survey.

Conventional treatments used at the time of the survey

Forty-five participants used conventional medicine, including 22 participants who used convention medicine only and 23 participants who used conventional medicine and CM at the same time. As for the use of conventional medicine, 32 (71.1%) of 45 participants reported that they were taking antidepressants only, 2 (4.4%) used psychotherapy only and 11 (24.4%) used both antidepressants and psychotherapy. Medications used at the time of the survey were

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reported by 37 participants; the most common pharmacotherapies were escitalopram (13 participants), sertraline (10) and venlafaxine (5).

Two (4.4%) of 45 patients thought they went into remission after conventional treatments, 39

(86.7%) had relief or some help (patients with depression feel the relief of symptoms and the treatment is helpful), while 4 (8.9%) reported conventional medicine treatments had no effect and did not help them. Seventeen participants (37.8%) reported that conventional medicine had adverse effects and 16 reported specific adverse effects. The common adverse effects included sleepiness (6, 37.5%), vomiting (4, 25.0%) and fatigue (4, 25.0%).

Forty-three (95.6%) participants were willing to use conventional medicine continuously. The most common reason to continue using conventional medicine was because their doctors told them to do so (35, 81.4%). There were two participants who decided not to take antidepressants.

One reported it was intolerable, with adverse effects, and the other preferred to use CM.

Conventional treatments used before the survey

The term “Conventional treatments used before the survey” means that patients did not use conventional medicine at the time of the survey but rather had used conventional medicine for the condition before. Twenty participants had used conventional medicine before the survey was undertaken and 17 gave details about the treatments. Eleven (55.0%) participants reported that they had once taken antidepressants, 2 (10.0%) had used psychotherapy, 3 (15.0%) had used antidepressants and psychotherapy simultaneously, and 1 (5.0%) had been treated with

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transcranial magnetic stimulation. Nine participants reported specific antidepressants they had used. The most common were escitalopram (3 participants), sertraline (3) and paroxetine (2).

Sixteen participants (80.0%) specified reasons for discontinuing their treatments. The main reasons included adverse effects (4, 25.0%), not being effective (3, 18.8%) and being inconvenient to take (3, 18.8%).

Use of Chinese medicine for MDD

The CM treatments included: 1) treatments that participants were using at the time of the survey; and 2) treatments that had been used before but were not being used at the time of the survey.

Chinese medicine treatments used at the time of the survey

Thirty-seven participants used CM, including 14 participants who used CM only and 23 participants who used CM combined with conventional medicine. Of the 37 patients, 30 (81.1%) reported they took CHM only, 1 (2.7%) was undertaking acupuncture treatments and 6 (16.2%) used both CHM and acupuncture.

In terms of efficacy, one participant reported remission, 35 (94.6%) had relief or some help

(patients with depression feel the relief of symptoms and the treatment is helpful), and 1 reported not benefit from taking the CM treatment. Most participants (31, 83.8%) had not experienced any adverse effects. Adverse effects were reported by 6 participants (16.2%).

Adverse effects were diarrhea (2 participants), fatigue (2), vomiting (1) and poor appetite (1).

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A high number of participants (97.3%) were willing to use CM continuously, mainly because of fewer adverse effects (25, 69.4%), effectiveness (16, 44.4%) and doctor’s advice (16, 44.4%).

There was only one participant who decided not to take CM because they found it inconvenient to cook the CHM formula.

Chinese medicine treatments used before the survey

The term “Chinese medicine treatments used before the survey” means that patients did not use

CM at the time of the survey but rather had used CM for the condition before. Of the 26 participants who had taken CM treatment before the survey, 22 reported that they had taken

CHM only, 3 had taken CHM and acupuncture treatments at the same time, and 1 had taken

CHM and acupuncture treatments but not at the same time. The main reasons they discontinued their treatment included inconvenience in taking the treatments (6, 23.1%), lack of effectiveness (5, 19.2%), slower relief of symptoms (5, 19.2%), remission (4, 15.4%) and doctors’ advice (4, 15.4%).

Treatment preference for MDD

Sixty-eight of the 76 (89.5%) participants responded to the question on treatment preference for depression. Eighteen (26.5%) preferred conventional medicine treatments (10 antidepressants; 5 psychotherapy; 3 antidepressants and psychotherapy), 16 (23.5%) preferred

CM (6 CHM; 9 CHM and acupuncture), while 34 (50.0%) preferred the combination of CM and conventional medicine. In terms of integrated CM and conventional medicine, except for one participant who did not respond, CHM (30, 90.9%) and antidepressants (26, 78.8%)

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accounted for the largest proportion among conventional treatments and CM treatments, respectively.

Patients’ treatment expectations

Treatment expectation refers to: 1) expectation of communication with doctors; 2) treatment goals if using CM; and 3) preferred information on CM.

Communication with doctors

All 139 participants responded to questions referring to expectation of communication with doctors (Table 7.2).

A total of 125 (89.9%) wanted their doctor to communicate with them about possible treatment types and options. If participants used conventional medicine, 111 (80.4%) reported they would like their doctors to communicate with them about conventional medicine treatments when visiting the CM clinic and 115 (82.7%) were willing to tell their doctors about their use of conventional medicine treatments. If patients used CM, 110 (79.1%) reported they would like doctors to communicate with them about CM treatments when visiting the conventional medicine clinic and 112 (80.6%) were willing to tell their doctors about using CM.

If participants visited a conventional medicine clinic, around two thirds (91, 65.5%) wanted to gain CM information from their conventional medicine doctor, such as modern research evidence, classical literature research evidence, case studies or doctors' experience. If

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participants visited a CM clinic, 115 (82.7%) wanted to gain this information from their CM doctors.

However, only half of the participants (80, 57.6%) felt that they had been given adequate information about CM for depression from their CM doctors, while 55 (39.6%) felt that they had gained adequate information about CM for depression from conventional medicine doctors.

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Table 7.2 Communication with doctors

Questions Yes No Not sure Not Applicable (n (%)) (n (%)) (n (%)) (n (%))

16. Would you like your doctor to communicate 125 (89.9) 5 (3.6) 5 (3.6) 4 (2.9) with you about treatment types and options of depression?

17. If you use conventional medicine for your 111 (80.4) 2 (1.4) 4 (2.9) 21 (15.2) condition, would you like the doctor that you visit at the Chinese medicine clinic to ask you about conventional medicine treatments?

18. If you use conventional medicine for your 115 (82.7) 2 (1.4) 3 (2.2) 19 (13.7) condition, do you want to tell the doctor that you visit the Chinese medicine clinic about your conventional medicine treatment?

19. If you use Chinese medicine for your condition, 110 (79.1) 3 (2.2) 9 (6.5) 17 (12.2) would you like the doctor that you visit at the conventional medicine clinic to ask you about Chinese medicine treatments?

20. If you use Chinese medicine for your condition, 112 (80.6) 2 (1.4) 8 (5.8) 17 (12.2) do you want to tell the doctor that you visit at the conventional medicine clinic about your Chinese medicine treatment?

21. If you visit at conventional medicine clinic, 91 (65.5) 15 (10.8) 14 (10.1) 19 (13.7) would you like to gain medical information (e.g. modern research evidence, classical literature research evidence, case studies, or doctors' experience, etc.) on Chinese medicine for your condition from your doctor with conventional medicine background?

22. If you visit at Chinese medicine clinic, would 115 (82.7) 3 (2.2) 9 (6.5) 12 (8.6) you like to gain medical information (e.g. modern research evidence, classical literature research evidence, case studies, or doctors' experience, etc.) on Chinese medicine for your condition from your doctor with Chinese medicine background?

23. Currently, do you think you have gained 55 (39.6) 29 (20.9) 46 (33.1) 9 (6.5) adequate medical information (e.g. modern research evidence, classical literature research evidence, case studies, or doctors' experience, etc.) on Chinese medicine for your condition from your doctor with conventional medicine background?

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Questions Yes No Not sure Not Applicable (n (%)) (n (%)) (n (%)) (n (%))

24. Currently, do you think you have gained 80 (57.6) 15 (10.8) 38 (27.3) 6 (4.3) adequate medical information (e.g. modern research evidence, classical literature research evidence, case studies, or doctors' experience, etc.) on Chinese medicine for your condition from your doctor with Chinese medicine background?

Treatment goals of using Chinese medicine for MDD

One hundred and thirty-four (134) participants responded to the question regarding treatment goals. The survey allowed them to give multiple answers and most participants, 101 (75.4%), wanted to reduce physical symptoms such as poor sleep, abdominal distension and constipation,

97 (72.4%) wanted to reduce depressive symptoms and 30 (22.4%) wanted to reduce adverse effects of antidepressant medications.

Preferred information about Chinese medicine

One hundred and thirty-seven (137) participants responded to this question regarding treatment information. The most common response was their desire to know about their doctors’ clinical experience (110, 80.3%). More than two thirds (95, 69.3%) indicated they would like to know about contemporary research evidence and about half wanted to know about case studies and classical literature evidence (64, 46.7% and 53, 38.7% respectively).

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Predictors of the use of Chinese medicine

To assess whether CM use differed according to demographic variables and diagnostic information variables, bivariate analyses were performed. To determine predictors of CM use, variables that met significance were entered for binary logistic regression models.

Demographic characteristics of CM users

Participants with undergraduate qualifications (χ2=5.97, P=0.05) were more likely to use CM for depression compared to people with lower levels of education or no tertiary education

(Table 7.3).

Table 7.3 Distribution of using CM for MDD among demographic variables

Using CM for MDD Characteristics Total (n=138) Yes No χ2 P n (%)

Gender

Male 50 (36.2) 19 (38.0) 31 (62.0) 1.85 0.17

Female 88 (63.8) 44 (50.0) 44 (50.0)

Age

18-20 years 11 (8.0) 7 (63.6) 4 (36.4) 6.91 0.14

21-30 years 56 (40.9) 20 (35.7) 36 (64.3)

31-40 years 29 (21.2) 12 (41.4) 17 (58.6)

41-50 years 22 (16.1) 12 (54.5) 10 (45.5)

51-65 years 19 (13.9) 12 (63.2) 7 (36.8)

Marital status

Married 73 (52.9) 36 (49.3) 37 (50.7) 0.84 0.36

Not married 65 (47.1) 27 (41.5) 38 (58.5)

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Using CM for MDD Characteristics Total (n=138) Yes No χ2 P n (%)

Education

Diploma or under 72 (52.2) 33(45.8) 39 (54.2) 5.97 0.05

Bachelor 56 (40.6) 29(51.8) 27 (48.2)

Master or Doctorate 10 (7.2) 1 (10.0) 9 (90.0)

Occupation

Student 26 (18.8) 10 (38.5) 16 (61.5) 4.83 0.18

Employed 78 (56.5) 32 (41.0) 46 (59.0)

Unemployed 20 (14.5) 12 (60.0) 8 (40.0)

Retired or other 14 (10.1) 9 (64.3) 5 (35.7)

Monthly income

0 Chinese Yuan 45 (36.6) 24 (53.3) 21 (46.7) 5.66 0.13 (CNY)

<5000 CNY 37 (30.1) 16 (43.2) 21 (56.8)

5001-10000 CNY 29 (23.6) 11 (37.9) 18 (62.1)

>10000 CNY 12 (9.8) 2 (16.7) 10 (83.3)

Not stated 15

Medical insurance

Insured 113 (82.5) 50 (44.2) 63 (55.8) 0.78 0.38

Not insured 24 (17.5) 13 (54.2) 11 (45.8)

Not stated 1

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Diagnostic information of CM users

The use of CM for depression was correlated with place where diagnosed. Participants who were diagnosed in a conventional medicine hospital were more likely to use CM for depression

(χ2=7.73, p=0.02) (Table 7.4).

Table 7.4 Use of CM for MDD among diagnostic information variables

Using CM for MDD Characteristics Total (n=138) Yes No χ2 P n (%)

Place of diagnosis

Psychological and 16 (11.6) 10 (62.5) 6 (37.5) 7.73 0.02 Psychiatric hospital

Conventional 19 (13.8) 13 (68.4) 6 (31.6) medicine hospital

Integrative medicine 103 (74.6) 40 (38.8) 63 (61.2) hospital

Predictors of the use of CM

The logistic regression model suggested that education level and place of diagnosis were the best predictors of the use of CM for depression (Table 7.5). The probability of using CM for depression among participants who had a diploma or under was 9.59 times that of participants who had a master’s or doctoral degree (95% CI, 1.09, 84.5, p=0.04). The probability of using

CM among those who had a bachelor’s degree was 11.0 times than that of people who had a master’s or doctoral degree (95% CI, 1.24, 97.8, p=0.03) (Table 7.5).

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Participants diagnosed in a conventional medicine hospital were more likely to choose CM as treatment for depression. In terms of using CM for depression, the probability of participants diagnosed in the conventional medicine hospital was 3.45 times that of participants diagnosed in an integrative medicine hospital (95% CI, 1.17, 10.2, p=0.03) (Table 7.5).

Table 7.5 Coefficients of logistic regression model of the use of CM for MDD

Variables Beta Standard Wald χ2 P Odds Ratio (95% Error Confidence Interval) (SE)

Education level (reference group= ‘Master or 4.62 0.10 Doctorate’)

Diploma or under 2.26 1.11 4.15 0.04 9.59 (1.09, 84.5)

Bachelor 2.40 1.12 4.62 0.032 11.0 (1.24, 97.8)

Place of diagnosis (reference group= ‘Integrative 7.67 0.02 medicine hospital’)

Psychological and 1.14 0.59 3.68 0.06 3.13 (0.98, 10.0) psychiatric hospital

Conventional medicine 1.24 0.55 5.04 0.03 3.45 (1.17, 10.2) hospital

Constant -2.67 1.10 5.94 0.02

Predictors of treatment preferences

To assess whether treatment preference differed according to demographic variables and diagnostic information variables, bivariate analyses were performed using chi-square tests for categorical data. To determine predictors of treatment preference, variables that met significance were entered for multinomial logistic regression models.

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Demographic characteristics of treatment preferences

Distribution of treatment preferences on depression was correlated with participants with

medical insurance. Details are shown in Table 7.6. Participants who were medically insured

were more likely to choose CM for depression.

Table 7.6 Distribution of treatment preferences among demographic variables

Treatment Preferences Characteristics Total Conventional Chinese Integrative χ2 P (n=67) Medicine Medicine Medicine n (%)

Gender

Male 23 (34.3) 7 (30.4) 4 (17.4) 12 (52.2) 0.99 0.61

Female 44 (65.7) 10 (22.7) 12 (27.3) 22 (50.0)

Age

18-20 years 7 (10.4) 3 (42.9) 0 (0.0) 4 (57.1) — 0.28#

21-30 years 21 (31.3) 8 (38.1) 5 (23.8) 8 (38.1)

31-40 years 14 (20.9) 3 (21.4) 2 (14.3) 9 (64.3)

41-50 years 12 (17.9) 2 (16.7) 5 (41.7) 5 (41.7)

51-65 years 13 (19.4) 1 (7.7) 4 (30.8) 8 (61.5)

Marital status

Married 39 (58.2) 7 (17.9) 13 (33.3) 19 (48.7) 5.60 0.06

Not married 28 (41.8) 10 (35.7) 3 (10.7) 15 (53.6)

Education

Diploma or 35(52.2) 8 (22.9) 11 (31.4) 16 (45.7) — 0.41# under

Bachelor 29 (43.3) 8 (27.6) 4 (13.8) 17 (58.6)

Master or 3 (4.5) 1 (33.3) 1 (33.3) 1 (33.3) Doctorate

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Treatment Preferences Characteristics Total Conventional Chinese Integrative χ2 P (n=67) Medicine Medicine Medicine n (%)

Occupation

Student 11 (16.4) 5 (45.5) 0 (0.0) 6 (54.5) — 0.24#

Employed 34 (50.7) 9 (26.5) 10 (29.4) 15 (44.1)

Unemployed 11 (16.4) 2 (18.2) 2 (18.2) 7 (63.6)

Retired or other 11 (16.4) 1 (9.1) 4 (36.4) 6 (54.5)

Monthly income

0 Chinese Yuan 25 (44.6) 8 (32.0) 5 (20.0) 12 (48.0) — 0.89# (CNY)

<5000 CNY 18 (32.1) 3 (16.7) 5 (27.8) 10 (55.6)

5001~10000 CNY 11 (19.6) 3 (27.3) 3 (27.3) 5 (45.5)

>10000 Yuan 2 (3.6) 0 (0.0) 1 (50.0) 1 (50.0)

Not stated 1

Medical insurance

Insured 53 (79.1) 8 (15.1) 15 (28.3) 30 (56.6) — 0.00#

Not insured 14 (20.9) 9 (64.3) 1 (7.1) 4 (28.6)

Note: #Fisher's exact test was used to assess the correlation.

Diagnostic information on treatment preferences

Distribution of treatment preferences did not correlate with depression diagnostic information

variables (Table 7.7).

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Table 7.7 Distribution of treatment preferences among diagnostic information variables

Treatment Preferences Characteristics Total Conventional Chinese Integrative χ2 P# (n=67) Medicine Medicine Medicine n (%)

Place where patients were diagnosed

Psychological 12 (17.9) 3 (25.0) 1 (8.3) 8 (66.7) — 0.72 and Psychiatric hospital

Conventional 17 (25.4) 4 (23.5) 5 (29.4) 8 (47.1) medicine hospital

Integrative 38 (56.7) 10 (26.3) 10 (26.3) 18 (47.4) medicine hospital

Note: #Fisher's exact test was used to assess the correlation.

Predictors of treatment preferences

The logistic regression model suggested that medical insurance was not a predictor of

depression treatment preference (Table 7.8). Participants who were insured were more likely

to use CM for their depression. The probability of using CM for depression among participants

who had medical insurance was 16.9 times that of participants who had no medical insurance.

(95% CI 1.80, 158.1), p=0.01) (Table 7.8). Participants who were insured were more likely to

choose both conventional and CM for depression. The probability of choosing both

conventional and CM was 8.44 times that of participants who were not insured (95% CI, 2.06,

34.7, p=0.01) (Table 7.8).

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Table 7.8 Coefficients of multinomial logistic regression model of treatment preferences

Model Beta Standard Wald χ2 P Odds Ratio (95% Error Confidence interval) (SE)

Chinese medicine

Intercept -2.20 1.05 4.35 0.04

Insured 2.83 1.14 6.13 0.01 16.9 (1.80, 158.1)

Not insured 0

Integrative medicine

Intercept -0.81 0.60 1.82 0.18

Insured 2.13 0.72 8.76 0.00 8.44 (2.06, 34.7)

Not insured 0

Note: Conventional medicine was used as the reference group for Chinese medicine and

Integrative medicine.

Predictors of continuing use of conventional medicine for MDD in participants using conventional medicine only

Bivariate analyses were used to assess whether continuing the use of conventional treatments differed according to demographic variables and diagnostic information variables. Predictors of continuing to use conventional medicine were determined by logistic regression models based on variables that were significant in bivariate analyses.

Demographic characteristics of continuing use of conventional medicine

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The distribution of continuing to use conventional medicine for depression did not significantly correlate with any demographic variables in participants using conventional medicine only

(Table 7.9).

Table 7.9 Distribution of continuing use of conventional medicine for MDD among demographic variables in participants using conventional medicine only

Continuing Using Conventional Medicine for MDD Characteristics Total (n=21) Yes No χ2 P# n (%)

Gender

Male 9 (42.9) 9 (100.0) 0 (0.0) — 1.00

Female 12 (57.1) 11 (91.7) 1 (8.3)

Age

18-20 years 4 (19) 4 (100.0) 0 (0.0) — 0.71

21-30 years 6 (28.6) 6 (100.0) 0 (0.0)

31-40 years 3 (14.3) 3 (100.0) 0 (0.0)

41-50 years 4 (19) 4 (100.0) 0 (0.0)

51-65 years 4 (19) 3 (75) 1 (25)

Marital status

Married 12 (57.1) 11 (91.7) 1 (8.3) — 1.00

Not married 9 (42.9) 9 (100.0) 0 (0.0)

Education

Diploma or under 12 (57.1) 11 (91.7) 1 (8.3) — 1.00

Bachelor 9 (42.9) 9 (100.0) 0 (0.0)

Occupation

Student 5 (23.8) 5 (100.0) 0 (0.0) — 0.29

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Continuing Using Conventional Medicine for MDD Characteristics Total (n=21) Yes No χ2 P# n (%)

Employed 10 (47.6) 10 (100.0) 0 (0.0)

Unemployed 3 (14.3) 3 (100.0) 0 (0.0)

Retired or other 3 (14.3) 2 (66.7) 1 (33.3)

Monthly income

0 Chinese Yuan (CNY) 8 (44.4) 8 (100.0) 0 (0.0) — 0.56

<5000 CNY 7 (38.9) 6 (85.7) 1 (14.3)

5001~10000 CNY 3 (16.7) 3 (100.0) 0 (0.0)

Medical insurance

Insured 16 (76.2) 15 (93.8) 1 (6.3) — 1.00

Not insured 5 (23.8) 5 (100.0) 0 (0.0)

Note: #Fisher's exact test was used to assess correlation.

Diagnostic information on continuing use of conventional medicine

The distribution of continuing to use conventional medicine for depression did not significantly correlate with diagnostic information in participants using conventional medicine only (Table

7.10).

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Table 7.10 Distribution of continuing use of conventional medicine for MDD among diagnostic information variables in participants using conventional medicine only

Continuing Using Conventional Medicine for MDD Characteristics Total (n=21) Yes No χ2 P# n (%)

Place of diagnosis

Psychological and 4 (19) 4 (100.0) 0 (0.0) — 1.00 Psychiatric hospital

Conventional 7 (33.3) 7 (100.0) 0 (0.0) medicine hospital

Integrative medicine 10 (47.6) 9 (90.0) 1 (10.0) hospital

Note: #Fisher's exact test was used to assess the correlation.

Predictors of continuing use of CM for MDD in participants using CM only

Bivariate analyses were used to assess whether continuing the use of CM treatments differed according to demographic variables and diagnostic information variables. However, there were no significant difference.

Demographic characteristics of continuing use of CM

The distribution of continuing to use CM for depression did not correlate with any demographic variables (Table 7.11).

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Table 7.11 Distribution of continuing use of CM for MDD among demographic variables in participants using CM only

Continuing Using Chinese Medicine for MDD Characteristics Total (n=14) Yes No χ2 P# n (%)

Gender

Male 2 (14.3) 2 (100.0) 0 (0.0) — —

Female 12 (85.7) 12 (100.0) 0 (0.0)

Age

18-20 years 3 (21.4) 3 (100.0) 0 (0.0) — —

21-30 years 2 (14.3) 2 (100.0) 0 (0.0)

31-40 years 2 (14.3) 2 (100.0) 0 (0.0)

41-50 years 3 (21.6) 3 (100.0) 0 (0.0)

51-65 years 4 (28.6) 4 (100.0) 0 (0.0)

Marital status

Married 9 (64.3) 9 (100.0) 0 (0.0) — —

Not married 5 (35.7) 5 (100.0) 0 (0.0)

Education

Diploma or under 8 (57.1) 8 (100.0) 0 (0.0) — —

Bachelor 6 (42.9) 6 (100.0) 0 (0.0)

Occupation

Students 3 (21.4) 3 (100.0) 0 (0.0) — —

Employed 5 (35.7) 5 (100.0) 0 (0.0)

Unemployed 3 (21.4) 3 (100.0) 0 (0.0)

Retired or other 3 (21.4) 3 (100.0) 0 (0.0)

Monthly income

0 Chinese Yuan (CNY) 9 (69.2) 9 (100.0) 0 (0.0) — —

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Continuing Using Chinese Medicine for MDD Characteristics Total (n=14) Yes No χ2 P# n (%)

<5000 CNY 2 (15.4) 2 (100.0) 0 (0.0)

5001-10000 CNY 1 (7.7) 1 (100.0) 0 (0.0)

>10000 CNY 1 (7.7) 1(100.0) 0 (0.0)

Medical insurance

Insured 11 (78.6) 11 (100.0) 0 (0.0) — —

Not insured 3 (21.4) 3 (100.0) 0 (0.0)

Note: #Fisher's exact test and chi-square test could not be used to assess the correlation.

Diagnostic information on continuing use of CM

The distribution of continuing to use CM for MDD did not significantly correlate with diagnostic information variables in patients using CM only (Table 7.12).

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Table 7.12 Distribution of continuing use of CM for depression among diagnostic information variables in participants using CM only

Continuing Using Chinese Medicine for MDD Characteristics Total (n=14) Yes No χ2 P# n (%)

Place where patients were diagnosed

Psychological 1 (7.1) 1 (100.0) 0 (0.0) — — and Psychiatric hospital

Conventional 3 (21.4) 3 (100.0) 0 (0.0) medicine hospital

Integrative 10 (71.4) 10 (100.0) 0 (0.0) medicine hospital

Note: #Fisher's exact test and chi-square test could not be used to assess the correlation.

Predictors of continuing use of conventional medicine for MDD in participants using integrative medicine

There was no significant difference between continuing the use of conventional treatments among demographic variables and diagnostic information variables.

Demographic characteristics of continuing use of conventional medicine

The distribution of continuing to use conventional medicine for depression did not significantly correlate with any demographic variables in participants using conventional treatment combined with CM treatments (Table 7.13).

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Table 7.13 Distribution of continuing use of conventional medicine for MDD among demographic variables in participants using integrative medicine

Continuing Using Conventional Medicine for MDD Characteristics Total (n=23) Yes No χ2 P# n (%)

Gender

Male 8 (34.8) 8 (100.0) 0 (0.0) — 1.00

Female 15 (65.2) 14 (93.3) 1 (6.7)

Age

18-20 years 1 (4.3) 1 (100.0) 0 (0.0) — 0.65

21-30 years 8 (34.8) 8 (100.0) 0 (0.0)

31-40 years 7 (30.4) 6 (85.7) 1 (14.3)

41-50 years 4 (17.4) 4 (100.0) 0 (0.0)

51-65 years 3 (13) 3 (100.0) 0 (0.0)

Marital status

Married 13 (56.5) 12 (92.3) 1 (7.7) — 1.00

Not married 10 (43.5) 10 (100.0) 0 (0.0)

Education

Diploma or under 11 (47.8) 10 (90.9) 1 (9.1) — 1.00

Bachelor 11 (47.8) 11 (100.0) 0 (0.0)

Master or Doctorate 1 (4.3) 1 (100.0) 0 (0.0)

Occupation

Student 3 (13) 3 (100.0) 0 (0.0) — 1.00

Employed 13 (56.5) 12 (92.3) 1 (7.7)

Unemployed 4 (17.4) 4 (100.0) 0 (0.0)

Retired or other 3 (13) 3 (100.0) 0 (0.0)

Monthly income

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Continuing Using Conventional Medicine for MDD Characteristics Total (n=23) Yes No χ2 P# n (%)

0 Chinese Yuan (CNY) 5 (26.3) 5 (100.0) 0 (0.0) — 1.00

<5000 CNY 6 (31.6) 6 (100.0) 0 (0.0)

5001~10000 CNY 7 (36.8) 6 (85.7) 1 (14.3)

>10000 CNY 1 (5.3) 1 (100.0) 0 (0.0)

Medical insurance

Insured 21 (91.3) 20 (95.2) 1 (4.8) — 1.00

Not insured 2 (8.7) 2 (100.0) 0 (0.0)

Note: #Fisher's exact test was used to assess the correlation.

Diagnostic information on continuing use of conventional medicine

The distribution of continuing to use conventional medicine for depression did not significantly correlate with the place where participants were diagnosed (Table 7.14).

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Table 7.14 Distribution of continuing use of conventional medicine for MDD among diagnostic information variables in participants using integrative medicine

Continuing Using Conventional Medicine for MDD Characteristics Total (n=23) Yes No χ2 P# n (%)

Place where patients were diagnosed

Psychological and 6 (26.1) 6 (100.0) 0 (0.0) — 1.00 Psychiatric hospital

Conventional 4 (17.4) 4 (100.0) 0 (0.0) medicine hospital

Integrative medicine 13 (56.5) 12 (92.3) 1 (7.7) hospital

Note: #Fisher's exact test was used to assess the correlation.

Predictors of continuing use of CM for MDD in participants using integrative medicine

Bivariate analyses were used to assess whether there were differences between continuing the use of CM treatments and demographic variables or diagnostic information variables among participants who used conventional medicine plus CM. However, no significant difference was found.

Demographic characteristics of continuing use of CM

The distribution of continuing to use CM for depression did not significantly correlate with any demographic variables among participants using conventional medicine treatments and CM treatments (Table 7.15).

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Table 7.15 Distribution of continuing use of CM for MDD among demographic variables in participants using integrative medicine

Continuing Using Chinese Medicine for MDD Characteristics Total (n=23) Yes No χ2 P# n (%)

Gender

Male 8 (34.8) 7 (87.5) 1 (12.5) — 0.35

Female 15 (65.2) 15 (100.0) 0 (0.0)

Age

18-20 years 1 (4.3) 1 (100.0) 0 (0.0) — 1.00

21-30 years 8 (34.8) 7 (87.5) 1 (12.5)

31-40 years 7 (30.4) 7 (100.0) 0 (0.0)

41-50 years 4 (17.4) 4 (100.0) 0 (0.0)

51-65 years 3 (13) 3 (100.0) 0 (0.0)

Marital status

Married 13 (56.5) 13 (100.0) 0 (0.0) — 0.44

Not married 10 (43.5) 9 (90.0) 1 (10.0)

Education

Diploma or under 11 (47.8) 11 (100.0) 0 (0.0) — 1.00

Bachelor 11 (47.8) 10 (90.9) 1 (9.1)

Master or Doctorate 1 (4.3) 1 (100.0) 0 (0.0)

Occupation

Students 3 (13) 2 (66.7) 1 (33.3) — 0.26

Employed 13 (56.5) 13 (100.0) 0 (0.0)

Unemployed 4 (17.4) 4 (100.0) 0 (0.0)

Retired or other 3 (13) 3 (100.0) 0 (0.0)

Monthly income

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Continuing Using Chinese Medicine for MDD Characteristics Total (n=23) Yes No χ2 P# n (%)

0 Chinese Yuan (CNY) 5 (26.3) 4 (80.0) 1 (20.0) — 0.36

<5000 CNY 6 (31.6) 6 (100.0) 0 (0.0)

5001-10000 CNY 7 (36.8) 7 (100.0) 0 (0.0)

>10000 CNY 1 (5.3) 1 (100.0) 0 (0.0)

Medical insurance

Insured 21 (91.3) 20 (95.2) 1 (4.8) — 1.00

Not insured 2 (8.7) 2 (100.0) 0 (0.0)

Note: #Fisher's exact test was used to assess the correlation.

Diagnostic information on continuing use of CM

Among participants who used integrative medicine, the distribution of continuing to use CM for depression did not significantly correlate with the place where participants were diagnosed (Table 7.16).

Table 7.16 Distribution of continuing use of CM for MDD among diagnostic information variables in participants using integrative medicine

Continuing Using Chinese Medicine for MDD Characteristics Total (n=23) Yes No χ2 P# n (%)

Place where patients were diagnosed

Psychological and 6 (26.1) 5 (83.3) 1 (16.7) — 0.44 Psychiatric hospital

Conventional 4 (17.4) 4 (100.0) 0 (0.0) medicine hospital

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Continuing Using Chinese Medicine for MDD Characteristics Total (n=23) Yes No χ2 P# n (%)

Integrative medicine 13 (56.5) 13 (100.0) 0 (0.0) hospital

Note: #Fisher's exact test was used to assess the correlation.

Comparison of treatment types

Comparison of treatment types refers to comparing the use of conventional medicine only, CM

only and integrative medicine across demographic characteristics, diagnostic information and

treatment experience. Treatment experience refers to patients’ self-reported information and

treatment preference.

Comparison of treatment types in terms of demographic characteristics and diagnostic

information

Participants who used CM only, conventional medicine only or integrative medicine for

depression showed no difference across demographic variables (Table 7.17) or diagnostic

information variables (Table 7.18).

Table 7.17 Comparison of treatment types among demographic variables

Treatment Types for MDD Characteristics Total Conventional Chinese Integrative χ2 P (n=58) Medicine Medicine Medicine n (%)

Gender

Male 19 (32.8) 9 (47.4) 2 (10.5) 8 (42.1) 3.18 0.20

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Treatment Types for MDD Characteristics Total Conventional Chinese Integrative χ2 P (n=58) Medicine Medicine Medicine n (%)

Female 39 (67.2) 12 (30.8) 12 (30.8) 15 (38.5)

Age

18-20 years 8 (13.8) 4 (50.0) 3 (37.5) 1 (12.5) — 0.56#

21-30 years 16 (27.6) 6 (37.5) 2 (12.5) 8 (50.0)

31-40 years 12 (20.7) 3 (25.0) 2 (16.7) 7 (58.3)

41-50 years 11 (19.0) 4 (36.4) 3 (27.3) 4 (36.4)

51-65 years 11 (19.0) 4 (36.4) 4 (36.4) 3 (27.3)

Marital status

Married 34 (58.6) 12 (35.3) 9 (26.5) 13 (38.2) 0.25 0.88

Not married 24 (41.4) 9 (37.5) 5 (20.8) 10 (41.7)

Education

Diploma or under 31 (53.4) 12 (38.7) 8 (25.8) 11 (35.5) — 0.96#

Bachelor 26 (44.8) 9 (34.6) 6 (23.1) 11 (42.3)

Master or Doctorate 1 (1.7) 0 (0.0) 0 (0.0) 1 (100.0)

Occupation

Student 11 (19.0) 5 (45.5) 3 (27.3) 3 (27.3) — 0.89#

Employed 28 (48.3) 10 (35.7) 5 (17.9) 13 (46.4)

Unemployed 10 (17.2) 3 (30.0) 3 (30.0) 4 (40.0)

Retired or other 9 (15.5) 3 (33.3) 3 (33.3) 3 (33.3)

Monthly income

0 Chinese Yuan 22 (44.0) 8 (36.4) 9 (40.9) 5 (22.7) — 0.13# (CNY)

<5000 CNY 15 (30.0) 7 (46.7) 2 (13.3) 6 (40.0)

5001-10000 CNY 11 (22.0) 3 (27.3) 1 (9.1) 7 (63.6)

>10000 CNY 2 (4.0) 0 (0.0) 1 (50.0) 1 (50.0)

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Treatment Types for MDD Characteristics Total Conventional Chinese Integrative χ2 P (n=58) Medicine Medicine Medicine n (%)

Medical insurance

Insured 48 (82.8) 16 (33.3) 11 (22.9) 21 (43.8) — 0.34#

Not insured 10 (17.2) 5 (50.0) 3 (30.0) 2 (20.0)

Note: #Fisher's exact test was used to assess the difference.

Table 7.18 Comparison of treatment types among diagnostic information variables

Treatment Types for MDD Characteristics Total Conventional Chinese Integrative χ2 P# (n=58) Medicine Medicine Medicine n (%)

Place where participants were diagnosed

Psychological 11 (19.0) 4 (36.4) 1 (9.1) 6 (54.5) — 0.49 and Psychiatric hospital

Conventional 14 (24.1) 7 (50.0) 3 (21.4) 4 (28.6) medicine hospital

Integrative 33 (56.9) 10 (30.3) 10 (30.3) 13 (39.4) medicine hospital

Note: #Fisher's exact test was used to assess the difference.

Comparison between use of conventional medicine and CM

There were no significant differences between conventional medicine and CM in terms of self-

reported effect, the number of adverse events and whether participants continued using

treatments (Table 7.19). In integrative medicine, a complicated treatment setting, it was hard

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to identify where the effect and adverse events came from based on patients’ self-reported information, so the related quantitative analysis of comparison was not performed.

Table 7.19 Comparison between use of conventional medicine and CM in terms of self- reported treatment experience

Treatment Types for MDD Characteristics Total Conventional Chinese χ2 P# n (%) Medicine Medicine

Effect

Remission 2 (5.6) 2 (9.1) 0 (0.0) — 0.26

Relief 31 (86.1) 17 (77.3) 14 (100.0)

Ineffective 3 (8.3) 3 (13.6) 0 (0.0)

Adverse effect

Yes 9 (25.0) 8 (36.4) 1 (7.1) — 0.06

No 27 (75.0) 14 (63.6) 13 (92.9)

Use continually

Yes 35 (97.2) 21 (95.5) 14 (100.0) — 1.00

No 1 (2.8) 1 (4.5) 0 (0.0)

Note: #Fisher's exact test was used to assess the difference.

Comparison of treatment types in terms of treatment preference

Treatment types relates to patients’ treatment preference. Participants with depression who used integrative medicine also preferred this type of treatment (Table 7.20).

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Table 7.20 Comparison of treatment types in terms of treatment preference

Treatment Types for MDD Characteristics Total Conventional Chinese Integrative χ2 P# (n=54) Medicine Medicine Medicine n (%)

Treatment preference

Conventional 15 (27.8) 13 (59.1) 1 (8.3) 1 (5.0) — <0.001 medicine

Chinese 11 (20.4) 2 (9.1) 6 (50.0) 3 (15.0) medicine

Conventional 28 (51.9) 7 (31.8) 5 (41.7) 16 (80.0) and Chinese medicine

Note: #Fisher's exact test was used to assess the difference.

Discussion

This study of 139 participants at an integrative medicine hospital in China is the first to explore patient experience and expectations of using CM for depression. The importance of these results is to highlight a unique medical system of using CM for depression and demonstrate patients experience and expectations of using CM for depression, which could inform evidence-based research and improve practitioners’ care of patients in clinical practice.

Summary of findings

This survey is explorative research on patient values in using CM for depression. It reflects the status of treatments for depression in a hospital of integrative medicine. In 76 patients with depression who had experience of treatments, 22 used conventional medicine only at the time

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of the survey, while 14 used CM only and 23 used integrated conventional medicine and CM medicine. Patients used different treatments including monotherapy or integrative therapy, which is consistent with the current status of holistic integrative medicine.(419, 420)

In this survey, participants were from an integrative medicine hospital in Guangzhou, China.

Participants, aged from 21 to 30, accounted for a larger proportion compared to other age groups, showing an example of a much broader phenomenon of the global trends of depression in young people In a previous European study, young adults reported the highest levels of psychological distress compared to older age groups.(421) This indicates that mental health issues among young adults are a significant matter worldwide.(422) In this study more females completed the survey than males and this might reflect the proportion of genders with the condition. WHO reported depression is more common among females than males.(423)

Similar results were also found in an Australian national survey of mental health and wellbeing.(424)

The majority of participants (74.6%) were diagnosed at an integrative medicine hospital.

Integrative medicine hospitals are common types of hospitals in China that provide CM treatments, conventional medicine treatments or integrative treatments. Patients in this type of hospital can choose and receive different types of treatments according to their condition, treatment preference, or doctors’ advice, etc.(425) Though, it cannot identify reasons that 74% of respondents came from integrative medicine hospital, it presents a status of patients more likely to visit integrative medicine hospitals for health care.(398, 399)

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In terms of using CM, the use of CHM was the largest proportion among 63 participants who used or had used CM. This result is consistent with the findings in the prevous chapters of the systematic reviews and meta-analysis (Chapters 5–6), where the largest proportions of studies evaluate CHM. Consistent results were also found in the classical literature chapter (Chapter

4), where CHM citations among included classical literature accounted for 93.1% of all citations. CHM is a particularly common therapy in the Guangdong region.(394) CHM is increasingly considered a cost-effective and lower risk treatment for depression and its comorbidities.(426)

Although a small number of participants used acupuncture in this survey, acupuncture is recommended as an alternative treatment in clinical guidelines of CM.(179). Some studies have shown acupuncture to be a useful adjunct treatment for reducing depressive symptoms.(23, 427,

428) Despite these positive findings, the quality of evidence was of low quality (Chapter 6).

In this survey, 6 participants (16.2%) were using both CHM and acupuncture therapies among

37 people who used CM at the time of the survey. There was paucity of studies that evaluated acupuncture combined with CHM for depression (Chapter 6). In the classical literature chapter

(Chapter 4), there were no included citations referring to a combination of CHM and acupuncture therapy. Some CM or integrative medicine practitioners recommend combined

CHM and acupuncture in practice. It seems this stems from a belief that a combination of treatments could increase benefits, but it is is still unknown and limited by practical application and research evidence.(429)

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As for the effect and safety of CM for depression, the patient’s self-reported results are similar to results found in previous evidence-based studies that CHM or acupuncture can reduce depressive symptoms and CHM or acupuncture has fewer adverse effects compared to antidepressants.(22, 23) Half of the participants in the survey indicated that they preferred the combined treatment of CM and conventional medicine, mainly including antidepressants and

CHM. Compared to the commonly recommended integrative complementary medicine treatment model, that is, the ‘antidepressant-lifestyle-psychological-social depression treatment model’ in Western countries,(430) the utilisation of CM reflects Chinese history, culture and politics.(59, 431) On the other hand, although there is a growing body of studies that have investigated the effect of psychotherapy like cognitive behavioural therapy, the overall efficacy for Chinese individuals remains unclear.(432) Therefore, the integrative model of pharmacotherapy and CM seems to be one of the key components of combination treatments in Chinese clinical setting.

In this survey, the regression models, as an exploration analysis, suggested that participants who were diagnosed in conventional medicine hospitals were more likely to use CM. It was also found that participants wanted to communicate with their doctors about treatment types and options, and also wanted to communicate with conventional medicine doctors about this treatment if they used it. However, not many participants felt that they received adequate information concerning CM for depression from conventional medicine doctors. These results provide another perspective in understanding the previous study that suggested CAM therapies are commonly used among patients with depression and it is appropriate for doctors with a

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conventional medicine background to have greater knowledge of the use of CAM, supporting and informing patients.(206) This is also important for doctors with CM or an integrative medicine background, as only half of the participants involved in this survey thought they received adequate CM information.

The results also indicated that people with medical insurance were more likely to prefer CM.

However, a previous study indicated that CHM is cheaper than Western medicines, and was popular among patients who were uninsured.(394)

Participants indicated that they wanted to use integrative medicine. It has been suggested that national support for integrative medicine plays an essential role in individuals’ health care.(398,

399)

Limitations of this study

This survey aimed to explore patient values (experience and expectations) in using CM for depression in an integrative medicine hospital. It used a convenience sampling method to enrol participants.(416) All participants were from the GPHCM; therefore there is a lack of representation for other areas of China. Also unknown are the conditions of patients with depression who seek health care at conventional medicine hospitals or psychiatric and psychological hospitals. Future studies need to include wider groups of participants.(433)

Before the survey, eligible participants were diagnosed by doctors using the DSM-5 or ICD-

10. Participants could not report the level of severity of depression by themselves because they

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should be differentiated and diagnosed by trained professionals. This survey was anonymous, self-administered. Patients with depression, voluntarily participating in this study, were allowed to respond freely according to their feeling or thoughts. Information other than this cannot be identified, particularly the information that participants cannot report by themselves.

This may result in bias when patients reporting their experience and expecations becaure major depression patients may have more severe congnitive impairment compared to patients with minor depression.(434)

A power calculation requires specification of the null hypothesis, the alternative hypothesis, type of outcome measure and statistical test.(435) This study explored experience and expectations of using CM among patients with depression instead of testing specified statistical hypotheses or evaluating specified outcomes. Thus, sample size and a power calculation were not performed statistically via mathematical equations in this study to get exact numbers, but rather using the number of outpatient services to estimate the sample size. It is suggested to use random sampling that can remove bias from the selection procedure and contribute to representative sampling.(436) A pilot study should be designed to calculate sample sizes for future studies.(437) Sample size calculation requires consideration of the primary outcome variables, statistical analysis method, statistical power, benefits, risks and costs of a study.(437,

438)

Due to the distribution of the sample in this study, the robust confidence intervals were not obtained in this study, and the significance of the predictive results were limited. Based on the

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preliminary results, using logistic regression for investigation may need to expand the sample size of the distribution in future studies to get a more robust result.This survey was conducted based on quantitative methods. The findings are valuable in providing an overview of patient experience and expectations, but the reasons for these findings were not addressed in this survey. For example, why patients prefer to use integrative medicine for depression is unknown and needs to be further explored. Thus, a qualitative study should be performed to investigate detailed information among the same patients.

Implications for clinical practice

This study has produced validated and available information on patient values regarding experience and expectations. This information provides practitioners with information that can help them to communicate with patients on choosing appropriate treatments, making treatment plans and putting forward treatment proposals. As most participants indicated the preference to use integrative medicine combining conventional medicine and CM, this may provide conventional medicine doctors with a broad consideration of treatments when communicating with patients who would not like to use conventional medicine alone. It could give integrative medicine doctors a positive signal and support in using integrative medicine for patients with this condition. Meanwhile, CM doctors can provide a more reasonable choice, integrative medicine, for patients who would like to use only CM but where this is not appropriate for their condition.

Implications for future research

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It has long been suggested to include patient values and preferences in clinical practice guidelines.(439, 440) The National Institute for Health and Clinical Excellence (NICE) considers the impacts of patient values in recommendations for practice, referring to accessing patient reports of experience as well as reviewing surveys and qualitative research evidence.(441) Recently, guidelines have been published that consider the impact of patient values in the process of developing clinical recommendations.(442) There has been a systematic review of preferences among patients with depression,(443) but these are rarely used in guidelines, especially guidelines for CM. In a previous study, researchers suggested an empirical strategy to incorporate patient values into guidelines by conducting systematic reviews and eliciting information from patient representatives and panel members of guidelines using the Evidence-to-Decision framework established based on the GRADE work group.(444)

Therefore, future research should start with increasing studies on patient values, including relevant systematic reviews, surveys and qualitative studies, and summarising these research findings. This could be further used for incorporating patient values into guidelines.

There are a small number of studies that evaluate CM users in other integrative medicine hospitals in the Guangzhou region of China. Further study would explore how the sample of participants in this study compares to CM users in other hospitals with integrative medicine services.

Conclusion

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This study has explored patient experience and expectations of using CM for depression. It also investigated the communication between doctors and patients regarding their treatment preferences, treatment goals and sources of medical information related to depression.

Most participants prefer to use integrative treatment. Antidepressants and CHM are the most common treatments. Participants who used CM reported relatively fewer adverse events compared to those who used conventional medicine. The main reason for stopping conventional medicine was mainly because of adverse events. Patients wanted their doctors to communicate with them about treatment types and options. They were interested in knowing about doctors’ experience and they also wanted to communicate with doctors about the use of

CM. However, the majority of them were not given adequate information about CM for depression, neither from CM doctors nor conventional medicine doctors. Patient experience and expectations suggest there is room for improvement in clinical practice to better reflect patients’ needs. A systems approach is needed to involve patient experience and expectations to modify outcome measures of conditions and improve practitioners’ clinical conduct regarding communication with participants during clinical decision-making.

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Chapter 8 Doctors’ Perception of Using Chinese Medicine for Major

Depressive Disorder: A Qualitative Study

Foreword

Clinical decision-making is a contextual, continuous and evolving process which requires an evidence-based clinical action using information gathered, interpreted and evaluated by doctors.(88) Theprocess of clinical decision-making is varied and complicated, and there is not always a linear connection between the research evidence, patient preferences and the final clinical decision.(445)

Doctors inform patients about their conditions and explore the values of using the interveniotns, which can help patients to understand what happens and make appropriate decisions about how they recognise or feel about possible outcomes of their health conditions. When proposing a treatment plan, practitioners need to combine their clinical expertise with reference to the available evidence, as well as patient values. Thus, it is important that doctors are conscious of all these elements of evidence-based medicine (EBM), and work with their patients to realise shareddecision-making.(446, 447)

The use of research evidence among doctors during clinical decision-making varies. Specific barriers to doctors applying EBM may be caused by different characteristics of practitioners and clinical settings. Awareness of these barriers can provide insight into evidence-based practice (EBP) and facilitate it.(448) There is an increasing number of studies that have reported on how to target these barriers and promote EBM.(448-450) Yet, incorporating EBM into clinical EBP while respecting clinical expertise remains problematic, especially as the fundamental concept of EBM downgrades the value of expertise.(89)

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Introduction

The first step in EBP for doctors is to determine whether the research evidence fits with the clinical presentation of the patient and if it is feasible to apply in the situation. Choosing treatments for the condition should also be compatible with the patient’s values. Optimal clinical decision-making should include treatments that are applicable and where the benefits outweigh potential harms.(451)

However, doctors implementing the process of EBM into clinical practice have barriers. A recent review indicated that many doctors have poor EBM knowledge and skills, but the majority of them had a positive attitude toward the implementation of EBM in the clinical setting.(452) Compared to developed countries, the implementation and practice of EBM in developing countries encounters more challenges and difficulties.(453) Focusing on physicians in China, a study showed that Chinese doctors had positive attitudes towards EBM but had a moderate level of clinical evidence competency.(454) Although an increasing number of empirical studies on doctors’ knowledge, opinion, attitude, competency, and practice of applying EBM in conventional medicine for specific clinical topics have been witnessed(455,

456), perception of using EBM in CM has not been fully explored. Only one recent study indicated that Chinese doctors showed positive attitudes to EBM and acknowledged the necessity of applying EBM in the field of CM for insomnia, but the major barriers included inadequate knowledge and skills of EBM as well as insufficient high-quality evidence.(457)

In previous chapters, it showed that CM has been used for depressive symptoms for thousands of years (Chapter 4). More recently, CM clinical trials have been undertaken to explore its efficacy and safety for treating major depressive disorder (MDD) (Chapters 5 and 6). In

Chapter 7, a survey of Chinese patients with depression indicated that they chose CM for their

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condition but were seldom informed as to why doctors recommended certain treatments. If

Chinese doctors translate these CM reseach evidence into clinical practice for patients with

MDD based on the EBM, little is known.To address this knowdedge gap between researchers, patients and doctors to improve clinical decision making in CM practice for depression in

China, EBM perceptions and use among Chinese doctors should be explored. Three aims and three corresponding research questions of this study were raised:

1) Aim 1: Understand doctors’ in-depth perceptions of using CM for depression.

Research question 1: How do doctors report treating patients with depression and what perceptions do doctors’ have about using CM for depression? (in relation to clinical practice, perceptions of patient preferences and knowledge access)?

2) Aim 2: Improve understanding of doctors’ intended knowledge translation based on the research results.

Research question 2: Do doctor’s translate research knowledge into practice and how?

3) Aim 3: Facilitate evidence-based CM in clinical decision-making.

Research question 3: Do doctor’s use evidence in their decision-making and how?

Based on the theory of knowledge translation (regarding the process of facilitating uptake of knowledge into clinical practice or decision-making)(44) using a qualitative method, this study probed Chinese doctors’s experience of treating depression, perceptions of using CM, thoughts of patients’ preference in clinical setting; observed their knowledge access and reactions to the research findings; and discerned their intended use of research results in clinical practice and

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clinical decision making, better understanding applying EBM CM for depression in Chinese clinical setting.

Methods

This is a qualitative study using established methodologies.(458-462) Data collection and analysis thoroughly explored via qualitative interviews. Semi-structed in-depth interviews(458) that obtain detailed understanding of doctors’ perceptions on EBM and clinical practice were undertaken. The implementation and reporting was based on the Consolidated Criteria for

Reporting Qualitative Research (COREQ).(463)

Research team

This study was conducted by Lingling Yang (LY) with the assistance of three research personnel, Johannah Shergis (JS), Anthony Lin Zhang (ALZ) and Jingjie Yu (JY). The characteristics of the researchers are presented in Table 8.1. All researchers have experience and training in qualitative studies. LY and JY are bilingual (Chinese and English) researchers and they conducted the data analysis, data checking and translation of the coded data. ALZ

(also bilingual Chinese and English) checked data and translation. JS checked the themes that were generated during the data analysis.

LY conceptualised the interview guide and conducted all interviews. As well as being the PhD student, she is also a psychotherapist at the Department of Psychology and Sleep Medicine of the GPHCM.

Table 8.1 Researcher characteristics

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Name Gender Highest Position Role in the Academic Study Award Lingling Female MD PhD student at RMIT Interviewer, Yang University; Practitioner of data (LY) CM and psychotherapist at analysis, the GPHCM and translation Johannah Female PhD Research fellow at RMIT Theme Shergis University and student checking (JS) supervisor Anthony Male PhD Associated professor at Data Lin RMIT University and checking Zhang student supervisor and (ALZ) translation checking Jinjie Yu Male PhD Research fellow at GPHCM Data (JY) checking and translation

Abbreviations: CM: Chinese medicine; GPHCM: Guangdong Provincial Hospital of Chinese Medicine; MD: Medical doctor; PhD: Doctor of Philosophy.

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Theoretical framework

Theoretical framework used was based on thematic analysis driven by grounded theory.

Previous research has often used thematic analysis driven by grounded theory (464-467).

Grounded theory was first proposed in the Discovery of Grounded Theory.(468) This methodology is commonly used to provide fresh insights based on existing knowledge or to generate a theory that is little known.(469) Grounded theory generates theory or insights that is grounded in systematically gathered and analysed data, from the views of participants, focusing on the problems that the participant faces, how they resolve such problems and studying a process, action, or interaction involving many individuals.(470, 471) There is little knowledge of doctors’ perceptions of using CM for depression, their intended knowledge translation from CM research evidence to clinical practice or clinical decision making. This knowledge gap that needs to be filled in the EBM of CM for depression can be explored via grounded theory.

Thematic analysis is a process alongside grounded theory helping researchers to take a well- structured approach to handle large amounts of data and produce a clear and organised report.(472) Thematic analysis in the context of grounded theory can offer a systematic approach to data analysis for qualitative interviews in healthcare settings.(470)

In this study, the process of data analysis followed with the step of thematic analysis, which is guided by grounded theory.

Participant selection

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In line with the research questions mentioned above, the interviewer recruited doctors with conventional medicine, CM or integrative medicine backgrounds who had experience treating depression.

Sampling

Purposive sampling was used to include participants with appropriate qualifications and experience. Eligibility included qualifications in conventional medicine, CM or integrative medicine and commonly treating depression, and willingness to participate in the interview.

Selection was open to include a broad range of doctors from different specialities related to mental health. No restrictions were applied for number of years in practice, gender or age.

Recruitment

Participants were recruited in the Departments of Psychology and Psychiatry at hospitals in

Guangzhou, China, who are members of the Guangdong Association of Chinese Integrative

Medicine. Directors from the hospitals were contacted via face-to-face conversation, telephone, email or mail. They were introduced to this project and given recruitment invitations to be forwarded to their staff. Doctors who were interested in this study could contact researchers to seek further information.

Eligible participants were dotors who have clinical experience of using CM, conventional medicine, or integrative medicince for depression. They were provided with detailed information about this study. Any queries or concerns were answered by researchers. After written informed consent was obtained, the participants were contacted via phone, mail or email (depending on the participant’s preference) to set up an appointment for the interview.

There is no restriction on age, gender, or professional title.

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Sample size

It was anticipated that approximately 20 doctors would participate in the interviews, including at least 5 doctors with CM backgrounds, 5 doctors with conventional medicine backgrounds and 5 doctors with integrative medicine backgrounds. The sample size was not fixed. The final number was determined by theoretical saturation, sample specificity and quality of dialogue.

In qualitative research, information is extracted from information sources and interpreted into codes. Theoretical saturation refers to a point when each code in the population has been observed at least one time.(473)

Setting

This study was set among hospitals with departments of psychology or psychiatry in

Guangzhou, China, including Guangdong Provincial People’s Hospital, Nanfang Hospital,

Guangzhou Huiai Hospital and GPHCM. Guangdong Provincial People’s Hospital, Nanfang

Hospital and GPHCM are holistic hospitals, while Guangzhou Huiai Hospital is a specialised hospital providing psychology or psychiatry services. Interviews were conducted at participants’ workplaces at a time chosen by participants during or after office hours.

Data collection

Data collection was performed through qualitative, semi-structured interviews with an interview guide of open-ended questions. The interview guide was designed based on the research questions and semi-structured, and participants introduced relevant topics during the interview and discussed topics freely. The interview guide was developed in English and translated into Chinese (Mandarin) (Appendix I).

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The interview questions referred to doctors’ clinical experience, individual thoughts, and reaction to previous research findings of this project (from the three systematic reviews (CHM, acupuncture and combination of CHM and acupuncture for depression), the study of CM classical literature and the survey of patients’ experience and expectations in using CM for depression (Chapters 4–7)).

The interview questions were pilot tested to ensure the validity of the interview guide

(Appendix I) and developed an interview technique. All interviews were conducted individually face-to-face in Chinese.

Based on grounded theory, updates of the interview guide and interview questions were prompted by new data from the sequence of interviews, which could be modified with concurrent analysis of the interview data, subsequent questions modified and new questions added.(474)

Interview schedule

Each participant had two interviews. Interview one lasted about 10 to 15 minutes and the main purpose was to gather information: on the participants demographics, how they reported treating patients with depression regarding experience of clinical practice, communication with patients, perceptions of patient preferences and updating related knowledge, and how they generally perceived the use of CM for depression. After the first interview, the doctors were introduced to the new research results (i.e. the systematic reviews, classical literature review and survey results (descriptive results regarding patients’ treatment experience and expectations)) using pre-prepared materials. The evidence presented to doctors was included in a previous publication as part of a larger research project(475) and peer-reviewed by a

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Content Expert Advisor Panel of three experts in the field. They were asked to read over the results and told that the topic of the second interview would partly focus on their perceptions of the new research.

Interview two took place two weeks after the first interview, to allow enough time for them to familiarise themselves with the new research results. The second interview lasted about 30 minutes and was conducted two weeks after the first interview to gather the following information: their perceptions of the new research results, their intended updated treatment practices, knowledge transfer with colleagues and communication with patients, and their perceptions of clinical decision-making in using CM for depression.

Field notes were made during the interviews. All interviews were audio-recorded on two devices and transcribed verbatim. Data that required further explanation or clarification was checked against the notes via telephone or email. Participants’ identifiable information was replaced by code numbers. Data saturation was discussed amongst the researchers.

Data analysis

Thematic analysis driven by ground theory was used to perform data analysis, commencing with open coding.(470, 476)

The process of thematic analysis included(476): 1) read and re-read transcripts and field notes to become familiar with the data; 2) generate initial coding; 3) identify tentative themes; 4) review the themes; 5) define and name the themes; and (6) produce the report. Following this process based on grounded theory, a series of themes and sub-themes were generated.

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All the interviews were transcribed in full and verbatim by using the original language

(Chinese). Transcripts were de-identified and coded and uploaded to NVivo 12 software (QSR

International Version 12, 2018) for data management and data coding. Transcripts were coded line by line to label themes.

Preliminary data analysis was conducted to determine if the interview guide needed to be revised after every interview. Preliminary data analysis was carried out by using the original language (Chinese) of the interview. There was no revision of the interview guide during data collection. Themes and sub-themes were created derived from the translation of coded data into English.

Data coding was completed by LY and checked by JY. New code generation and discrepancies were discussed by a third researcher (JLS). Translation of data coding was checked by ALZ.

Researchers met for discussion every two weeks throughout data analysis to ensure consistency of data analysis and data saturation, as well as to guide the next stage of the study.

Ethics

Ethics approval was obtained from the Ethics Committee of the GPHCM (Approval number:

Y2017-119-01). The protocol was registered with the RMIT University Human Ethics

Advisory Network (Approval number: SEHAPP 91-17) (Appendix J and Appendix K).

Participants were informed about the purpose and background of the study. Participants could ask questions about the study before deciding to participate. After participants were satisfied that they understood what was involved, they were provided with the Patient Informed Consent

Form (PICF) to sign. Both the researcher and participant signed the PICF and the participant was given a copy for their records. Participants were informed that they could decline to

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respond to any question that they would not like to answer throughout the interview. It was not anticipated that questions would cause concern, but the interviewer was observant of verbal and nonverbal responses during the interviews. If participants were concerned or uncomfortable with a question or the questioning direction, they were given the option to answer the question or continue with the interview. Participants could also discuss issues with the interviewer if they had further concerns. Participants could withdraw from the study at any stage.

Pilot interview

A pilot interview was conducted using participants from the Department of Psychology and

Sleep Medicine of the GPHCM. The pilot interview aimed to further refine the interview procedure and test the clarity of the interview guide, including participants’ understanding or responses to the interview questions, as well as developing the interviewer’s technique. No change was made to the interview guide based on the pilot. Data from the pilot interview was not used in data analysis.

Data security

The audio recordings of interviews were transferred to a password-protected computer for storage. Labels of the recording file were code numbers without identifiable information.

Transcriptions of the recording were completed by LY and JY using a document which was also stored on a password-protected computer. Transcriptions were de-identified by using the same code numbers consistent with the recording stored on the computer. Demographic information of participants was retained on a password-protected computer by researchers. The password for the computer was known only among the researchers in this study. Hard copies

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of field notes and related interview files were kept in a locked filing cabinet at the GPHCM.

As per the Australian code for the responsible conduct of research(477) all data will be stored for a minimum of seven years from the publication date.

Results

Interviews commenced in December 2018 and were completed in February 2019. A total of 33 people enquired about participating. 5 of them did not participate in this study. Reasons for non-participation included lack of time for taking two interviews (two people), no experience of treating depression (one is psychometrician, and one is nurse), no further interest (one person). 26 participants wanted to be interviewed who were eligible. Two participants were from Guangdong Provincial People’s Hospital, three were from Guangzhou Huiai Hospital, seven were from Nanfang Hospital, and 14 were doctors of GPHCM. They completed the first interview. Two of the 26 participants dropped out after the first interview. Therefore, data from

24 participants was available for both interviews. In terms of reasons for dropping out, one participant stated that she was going on an overseas vacation for two months and would not be available for the second interview. The other participant resigned from her job and moved to another city.

Demographic information

Twenty-six participants in Guangzhou, China were included in the study (Table 8.2). Eleven

(42.3%) were doctors with conventional medicine backgrounds, 7 (26.9%) were doctors with

CM backgrounds, while 8 were doctors (30.8%) of integrative medicine. Ages ranged from 24 to 46 years (mean ± standard deviation (SD): 34.15 years old ± 5.77). There were 18 (69.2%) females and 8 (30.8%) males. Five (19.2%) doctors had doctoral degrees, 16 (61.5%) had

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master’s degrees and 5 (19.2%) bachelor’s degrees. The maximum clinical experience was 26 years and the minimum were one year (mean ± SD: 8.96 years ± 6.59). In terms of professional titles, 3 (11.5%) were chief physicians, 2 (7.7%) were associate chief physicians, 9 (34.6%) were attending physicians and 12 (46.2%) were resident physicians. Ten (38.5%) participants worked in an outpatient setting, 6 (23.1%) worked in an inpatient setting, 6 (23.1%) worked in both inpatient and outpatient settings, while 4 (15.4%) worked neither in an inpatient nor an outpatient setting. These four doctors provided patients with psychotherapy. Of the 26 participants, 17 (65.4%) provided psychotherapy for patients with depression (Table 8.2).

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Table 8.2 Demographic information of participants

No. Medical Age Gen Highest Level Clinical Professional Specialty Outpatien Inpatien Psycho Attended Attended Training der of Education Experien Title t Service t Service therap Interview Interview Background ce (years) (Y/N) (Y/N) y (Y/N) 1 (Y/N) 2 (Y/N) 01 Conventional 24 F Master’s degree 1 Resident Psychiatry N Y N Y Y medicine physician 02 Conventional 27 F Master’s degree 2 Resident Psychiatry N Y N Y Y medicine physician 03 Conventional 38 F Master’s degree 15 Associate Psychiatry Y Y N Y Y medicine chief physician 04 Conventional 29 F Master’s degree 4 Resident Psychology N N Y Y Y medicine physician and psychiatry 05 Conventional 36 F Master’s degree 10 Attending Psychiatry N Y N Y N medicine physician 06 Conventional 40 F Bachelor’s 17 Resident Psychology N Y Y Y Y medicine degree physician and psychiatry 07 Conventional 31 M Bachelor’s 7 Attending Psychiatry Y Y N Y Y medicine degree physician 08 Chinese 34 F Master’s degree 7 Attending Psychology Y N Y Y Y medicine physician and psychiatry 09 Chinese 29 F Master’s degree 3 Resident Psychology Y N Y Y Y medicine physician 10 Conventional 32 F Master’s degree 6 Resident Psychology N N Y Y Y medicine physician

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No. Medical Age Gen Highest Level Clinical Professional Specialty Outpatien Inpatien Psycho Attended Attended Training der of Education Experien Title t Service t Service therap Interview Interview Background ce (years) (Y/N) (Y/N) y (Y/N) 1 (Y/N) 2 (Y/N) 11 Conventional 37 F Master’s degree 12 Attending Neuropsycho N Y Y Y N medicine physician logy 12 Integrative 31 F Bachelor’s 5 Resident Psychology N N Y Y Y medicine degree physician 13 Chinese 30 F Master’s degree 4 Attending Psychology Y N Y Y Y medicine physician 14 Chinese 28 M Master’s degree 1 Resident Psychology Y N Y Y Y medicine physician 15 Chinese 28 F Master’s degree 1 Resident Psychology N Y N Y Y medicine physician 16 Integrative 43 M Doctor's degree 21 Chief Psychiatry Y Y Y Y Y medicine physician 17 Integrative 34 F Master’s degree 10 Attending Psychology Y N Y Y Y medicine physician and psychiatry 18 Integrative 46 M Bachelor’s 26 Chief Psychology Y N Y Y Y medicine degree physician and psychiatry 19 Integrative 38 M Master’s degree 12 Attending Psychology Y N Y Y Y medicine physician and psychiatry 20 Integrative 34 F Doctor's degree 10 Resident Psychology Y N N Y Y medicine physician and psychiatry 21 Conventional 45 M Doctor's degree 17 Chief Psychiatry Y Y Y Y Y medicine physician

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Themes and sub-theme

Themes emerged from data analysis and coding (Table 8.3). Representative quotes are included in the theme descriptions as illustrated by examples from the participants. Identifying personal information has been removed and a code given to the participants (i.e. Participant 01–26) followed by their medical training background (e.g. Participant 03 Conventional medicine doctor).

Table 8.3 Overview of themes and sub-themes

Interview Theme Sub-theme

Experience of Requiring a detailed process for formulating a diagnosis of clinical practice for MDD MDD Individualised treatments depending on the patient’s condition Perceptions of using CM having advantages for MDD, its scope of use depends CM for depression on many factors Uncertain mechanism of antidepressant action

High recognition of using CM in China

Communication with Affirmation of CM is only communicated to certain patients patients Interview 1 Recommending CM relying on expertise

Respecting patients’ preferences

Perceptions of Patient preferences impact outcomes patient preferences Limits to patient preferences

Clinical decision-making balances expertise and patients’ preferences

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Interview Theme Sub-theme

Accessing and Importance of formal learning and wisdom of famous CM approaching new scholars knowledge of MDD Accessing new knowledge based on individualised preference Using new knowledge in clinical practice

Perceived benefits of Systematic reviews and meta-analysis improving clinical new knowledge of practice CM for MDD Directly using classical evidence in clinical practice

Understanding importance of patients’ experience

Knowledge Flexibly using new evidence in clinical practice translation No universal support for improving communication with patients Transferring new evidence to patients can be difficult Interview 2 Transferring new knowledge to colleagues on certain occasions Clinical decision- Importantly attending to the patient's condition making on CM for MDD Doctors communicate by making recommendations

Individually personalised treatment or recommendation

Tension between No sub-theme research and clinical practice

Themes of interview one

Themes from interview one related to experience of clinical practice for depression, perceptions of using CM, communication with patients who were interested in CM, perceptions of patients’ treatment preferences and accessing new knowledge.

Theme 1: Experience of clinical practice for MDD

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Participants recalled how they diagnosed and treated patients with depression by considering patients’ symptoms, risk of condition, diagnostic criteria, psychological scales, treatment types, etc. As detailed below, there were two sub-themes.

Sub-theme 1A: Requiring a detailed process for formulating a diagnosis of MDD

Participants described the detailed process of formulating a diagnosis for MDD. ‘First, patients may give me some information about themselves, like their medical history, and family members may also add some information about them.’ Medical history was considered to be an important part of diagnosis but also to understand the impact of disease; ‘we see if the course, time and severity of the condition have a significant impact on their work, study and life, and assess the risk of severity.’ (Participant 03 Conventional medicine doctor)

Finally, a formalised diagnosis using validated diagnostic criteria is essential; ‘Then, using the diagnostic criteria of ICD-10 or DSM-5 to see if [the patient] meets those core diagnostic items or other additional items.’ (Participant 03 Conventional medicine doctor)

Sub-theme 1B: Individualised treatments depending on the patient’s condition

Most participants believed that, ‘In terms of treatment, it should be according to the patient’s individual condition.’ Based on the participants’ training, they recommended treatments, illustrated by a conventional medicine doctor using pharmacotherapy and psychotherapy: ‘I normally start with medications. At the same time, psychotherapy depends on the situation; normally, depression is treated by combining medications with psychotherapy … patients with

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this condition should use antidepressants first, and then use psychotherapy according to circumstance.’ (Participant 02 Conventional medicine doctor)

Conventional medicine doctors acknowledged the use of herbal medicine for associated symptoms such as sleep: ‘Chinese [herbal] patent medicine may occasionally be given … for example, those Chinese patent medicines can help sleep, such as An shen capsules, Wu ling capsules, etc.’ (Participant 02 Conventional medicine doctor)

Doctors who had backgrounds in integrative medicine used both Chinese medicine and pharmacotherapy based on the patient’s individual condition: ‘if the depression is relatively mild, like mild or moderate depression, perhaps the first choice is Chinese herbal medicine

(CHM). If they suffer from severe depression, accompanied by some self-injury or risks of suicide, they will be treated with integrated CM and conventional medicine.’ (Participant 24

Integrative medicine doctor). One integrative medicine doctor stated, ‘I will implement these things [CM treatments] throughout the whole treatment process.’ (Participant 18 Integrative medicine doctor)

The CM doctors also thought that different CM treatments could be used according to a patients’ individual situations, including syndrome differentiation of CM, severity of the condition and a patient’s preference. ‘CM has its own distinguishing features for the treatment of depression.

I would like to choose Chinese herbal medicine, acupuncture, cupping and moxibustion according to patients’ individual condition. According to his/her choice. It is not necessary to

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use them all.’ They also believed that CM can be used alongside conventional medicine. ‘When adding on CM, the effect of treatments will be better.’ (Participant 26 Chinese medicine doctor)

Theme 2: Perceptions of using CM for depression

Theme two emerged from the data coding and revealed participants’ perceptions of using CM for MDD. As shown below, there were three sub-themes.

Sub-theme 2A: CM having advantages for MDD, its scope of use depends on many factors

Doctors acknowledged CM was effective and safe for this condition. For example: ‘I used to think CM has additional therapeutic effect. It has effects on adverse events that were caused by medications. I think that CM has some advantages in this kind of respect.’ (Participant 03

Conventional medicine doctor) and ‘According to patients that I met, some patients’ feedback is relatively good … And among patients who only used CM, many of them can improve.’

(Participant 12 Conventional medicine doctor)

They also illustrated other benefits according to their individual experiences: ‘CHM can improve symptoms, including mood and sleep. Secondly, it can reduce the frequency of using medication or reduce the time of using medication. Thirdly, it reduces the occurrence of side effects of medication.’ (Participant 14 Chinese medicine doctor) ‘In addition, in terms of patient's daily quality of life, it is better than conventional medicine.’ (Participant 16 Integrative medicine doctor)

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However, doctors expressed that CM had a particular scope of use for the condition. For example, they believed that CM was suitable for people with mild to moderate depression, while for patients with severe depression they thought the efficacy of using CM was unsatisfactory. An integrative medicine doctor explained, ‘I think the method of only using

Chinese herbal medicine is very effective for patients with mild to moderate depression, especially for those who are mild. It may be enough to only use Chinese herbal medicine’.

(Participant 18 Integrative medicine doctor) A Chinese medicine doctor had a similar opinion:

‘Depends on the severity of patients' condition, if it is moderate to severe depression, I feel that the effect of using CM only is not particularly ideal.’ (Participant 09 Chinese medicine doctor)

Doctors suggested that integrative medicine combining CM and conventional medicine could be used for patients who had severe depression. For example: ‘If the depression is relatively mild, like mild or moderate depression, perhaps the first choice is Chinese herbal medicine

(CHM). If they suffer from severe depression, accompanied by some self-injury or risks of suicide, they will be treated with integrated CM and conventional medicine.’ (Participant 24

Integrative medicine doctor)

Sub-theme 2B: Uncertain mechanism of antidepressant action

Despite some advantages, doctors thought using CM for depression ‘may be a very long process’ indicating that the ‘onset may not be as fast as conventional medicine’. (Participant

22 Conventional medicine doctor)

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Some doctors thought that the antidepressive mechanism of CM was unclear: ‘Some of its [CM] mechanisms may not be clear… One Chinese herbal formula may not be able to apply to all patients.’ (Participant 23 Chinese medicine doctor)

Furthermore, ‘CHM is difficult to boil, inconvenient to take along with and troublesome to drink. It's not as simple as medications. This is a limitation.’ (Participant 23 Integrative medicine doctor)

Sub-theme 2C: High recognition of using CM in China

Doctors indicated that the use of CM was culturally ingrained in China, thus many patients with depression were willing to accept CM treatment for depression. They thought that Chinese patients easily understood when doctors prescribed CM treatments: ‘In fact, because of the national situation in our country, especially in provinces like Guangdong, everyone's recognition and identity of CM is very high … They may consider that CM has no side effects, so many patients are willing to accept CM treatment.’ (Participant 21 Conventional medicine doctor)

Theme 3: Communication with patients

When patients were interested in using CM for depression, doctors stated their different perspectives on communicating with patients. They stated this kind of communication was based on consideration of patients’ condition and preference. Theme three emerged from the

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data coding and revealed interviewee perceptions of communication with patients who were interested in CM. As detailed below, there were three sub-themes.

Sub-theme 3A: Affirmation of CM is only communicated to certain patients

Doctors thought the severity of the condition should be considered when devising the treatment plan. A conventional medicine doctor stated, ‘If the patient is interested [in CM], I think it depends on the situation. If it's mild depression, or mild to moderate, they can seek an expert in the field of CM. If it's severe depression, it's definitely not suggested.’ (Participant 07

Conventional medicine doctor). CM doctors also endorsed the use of CM and conventional medicine depending on the severity of the condition. ‘If depression is severe or patients are diagnosed with taking medications, firstly, I will tell them to take medication regularly. Even if the symptoms are improved by using CM, it is not allowed to reduce and stop using medication without doctors’ permission.’ (Participant 26 Chinese medicine doctor)

Sub-theme 3B: Recommending CM relying on expertise

Many conventional medicine doctors indicated that they would not give detailed advice on using or not using CM because they did not know about CM. Some of them thought they would transfer the patient to CM doctors when patients were interested in using CM. One doctor stated:

‘It's hard for me to give them some advice. If they want to use CM, I would suggest them to seek a CM doctor who is senior for treatments.’ (Participant 01 Conventional medicine doctor)

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Some CM doctors emphasised that it was necessary to let patients know about using CM first.

They felt that comprehensive communication with patients about CM could reduce patients’ unreasonable anticipation of benefits and improve compliance. For example: ‘I will introduce to them about CM according to their physical condition. Let them understand depression from

CM perspectives clearly … The best situation is that we get their consent. In this way, there will be better compliance in the future.’ (Participant 26 Chinese medicine doctor)

Sub-theme 3C: Respecting patients’ preferences

Doctors stated that they were willing to respect patient preferences. They thought that patients had the right to choose the treatment that they preferred. In addition, they thought that respect for patients’ preferences should be based on their having a stable condition and providing informed consent. For example: ‘I think it depends on patients’ needs. If the patient wants to use it [CM], we can let them try.’ (Participant 03 Conventional medicine doctor) ‘Based on patients’ stable condition, I also support you [the patient] in seeking for other treatments.’

(Participant 06 Conventional medicine doctor) ‘After informing various situations [of using

CM] to patients, let patients choose treatments by themselves, CM or conventional medicine.’

(Participant 24 Integrative medicine doctor)

Theme 4: Perceptions of patient preferences

Theme four emerged from the data coding and revealed participants’ perceptions of patients’ preferences. As detailed below, there were three sub-themes.

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Sub-theme 4A: Patient preferences impact outcomes

Doctors recognised that patients’ preferences were a widespread issue in the process of clinical decision-making. They perceived that patient preferences played a crucial role in the system of health care. Many doctors thought patient preferences had various impacts on their condition.

They sated that it was related to the prognosis of the condition: ‘The patients’ treatment preference plays an important role in the effects and the development of the condition.’

(Participant 14 Chinese medicine doctor)

They also considered it was associated with patients’ motivation, compliance and effects of treatment. For example: ‘If the patient has greater preference, his/her compliance for medication will be higher and it is faster to access the effect.’ (Participant 22 Conventional medicine doctor)

Sub-theme 4B: Limits to patient preferences

Although doctors all acknowledged the importance of patient preferences, they stated that a doctor’s advice should comply with the Mental Health Law of the People's Republic of

China.(478) One doctor indicated that an official document with legal effects would be used to protect both doctors and patient benefits: ‘It is certain that we carry out treatments under the framework of the mental health law … If the patient has risks, like involuntary hospitalisation, only after their guardian signs relevant legal documents, the patient can be treated.’

(Participant 21 Conventional medicine doctor)

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Sub-theme 4C: Clinical decision-making balances expertise and patients’ preferences

Many doctors stated that in providing treatment programs to patients they needed to think how to combine and balance clinical expertise and patient preferences. Doctors thought all situations should be considered based on the severity and risk of the condition as well as the actual needs of patients. They thought they would systematically consider and assess the patients’ symptoms, cognitive ability and risks based on clinical expertise. They also believed that patient preferences should be respected if it is reasonable. Doctors also thought comprehensive discussions were needed regarding recognition, treatment types and prognosis of the condition.

They thought they should communicate widely with patients, their guardians and family members to reach a consensus on the treatment program. Two doctors gave detailed examples as shown below:

Generally, I conduct a psychiatric and psychological assessment, not necessarily according to the patient’ ideas… For instance, the patient likes CM and I think the patient’s depression may be associated with his physical condition. I will follow up with this aspect and think about this way, but if I don’t think the patient’ situation is like this, because there are some patients who have their own understanding which I think it has bias. So maybe I will tell them that some of these treatments cannot completely solve the condition, or even be ineffective. I may tell them that there might be other ways which are better. (Participant 08 Chinese medicine doctor)

Maybe it depends on if patients’ preference is reasonable and if it is roughly the same as my treatment plan. For example, a patient with severe depression, and the patient does not prefer

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to choose conventional medicine and only just want to use some other psychological treatments or CM treatments. This risk of condition is relatively great, so I would like to communicate with their family members to confirm if there is the risk of self-injury, suicide or more serious.

I communicate with family members to see if there is any need of compulsory treatments. If the patient is admitted receiving hospital care, there may be two situations: one is involuntary and the other is voluntary. In fact, the patient [and their family] has the right to choose. (Participant

25 Integrative medicine doctor)

Theme 5: Accessing and approaching new knowledge of MDD

Theme five emerged from the data coding and revealed interviewees’ accessing and approaching new knowledge of depression. As detailed below, there were three sub-themes.

Sub-theme 5A: Importance of formal learning and wisdom of famous CM scholars

Doctors indicated various ways to update knowledge associated with depression, including publications, guidelines, textbooks, workshops, seminars, training salons, professional training, learning meetings, lectures, academic annual meetings, continuing education, online learning groups, medical websites, online learning courses, online learning research papers and regular professional learning for staff at workplaces. In addition, some integrative medicine doctors and CM doctors indicated that they updated knowledge by learning from experts who had rich clinical experience; as one doctor indicated: ‘For example, some famous old Chinese doctors and doctors.’ (Participant 08 Chinese medicine doctor)

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Sub-theme 5B: Accessing new knowledge based on individualised preference

Doctors indicated various types of knowledge they normally accessed including clinical trials, experimental studies, case studies and reviews. Doctors with a background in integrative medicine or CM also updated knowledge from summaries of classical CM literature. As for frequency of updating knowledge, doctors expressed that they updated knowledge on a different frequent basis, such as per week or when need to figure out clinical questions. They indicated that they preferred new knowledge that was associated with clinical practice. One doctor indicated: ‘I pay more attention to diagnosis and treatment which is closely related to the clinic.’ (Participant 17 Integrative medicine doctor)

Sub-theme 5C: Using new knowledge in clinical practice

Doctors with different backgrounds all indicated that they would translate new knowledge into clinical practice to explore better treatment and improve a treatment program. For example:

‘Using this knowledge means using it in my own clinical practice.’ (Participant 10

Conventional medicine doctor) ‘I may more use [the new knowledge] in clinical practice.’

(Participant 23 Chinese medicine doctor) and ‘I will try it [new knowledge] on my clinical patients to see how it works.’ (Participant 24 Integrative medicine doctor)

In addition, doctors stated that they would like to communicate the new knowledge to patients.

They thought that it enabled patients to improve compliance with treatment and reduce their concerns or misunderstanding of the condition and treatments, as well as unreasonable expectations of treatments and prognosis. For example: ‘You can use [new evidence] but words

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are simple and easily understood to explain for the patient … so that can improve compliance.’

(Participant 05 Conventional medicine doctor) ‘Especially for some patients who have more concerns of medications and CHM, or sometimes they are not very clear about psychotherapy.

We will tell them what benefits the treatments will bring to them, what adverse events they will have, how to avoid them and we establish the compliance with them via this way.’ (Participant

19 Integrative medicine doctor)

Themes of interview two

Themes of interview two included perceived benefits of new knowledge of CM for MDD, knowledge translation, clinical decision-making on CM for MDD, and tension between research and clinical practice.

Theme 1: Perceived benefits of new knowledge of CM for MDD

Participants generally acknowledged the benefits of new knowledge especially from systematic reviews and meta-analyses. Classical CM literature was also perceived to be beneficial because it can be directly used in clinical practices of integrative medicine doctors and CM doctors.

Participants acknowledged the benefits of this new knowledge for communicating with their patients. In terms of the survey, the participants believed that they had a good idea of their patients’ experience and expectations; however, the results from the survey made it clearer.

There were three sub-themes.

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Sub-theme 1A: Systematic reviews and meta-analysis improving clinical practice

Participants stated that they were interested in the systematic reviews and meta-analysis of the efficacy and safety of CM for depression. They believed this information would give them further understanding of the use of CM for this condition. Furthermore, some integrative medicine doctors and CM doctors stated that this information would improve their confidence in using CM for the condition in clinical practice. Generally, they believed CM had fewer adverse events when compared to antidepressants, but they were concerned about the low- quality evidence. For example: ‘According to this systematic review and meta-analysis, CM presents it has effects and has fewer adverse events … Because the analysis definitely needs to assess its quality … the quality of the evidence is not good enough.’ (Participant 02

Conventional medicine doctor) ‘I think it seems to improve my confidence in the treatment of depression with traditional CM. Before this, I think CHM is effective for depression … after learning, I think we can use more CHM and integrative medicine to help patients to relieve the depressive symptoms … Side effects of either CHM or acupuncture are obviously less than that of conventional medicine.’ (Participant 25 Integrative medicine doctor) and ‘It's true that CHM has certain improvement on depression, but its certainty of evidence is low or low to medium …

Through this research, I think it has a certain corroborative effect based on our clinical observation. And then I looked at that the quality of the evidence of acupuncture for depression, which is low or very low.’ (Participant 26 Chinese medicine doctor)

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Some doctors stated that the new information, as supporting evidence for using CM, could help them to communicate with patients and improve patient compliance: ‘It can be used in clinical practice to increase patients’ compliance when communicating with them about treatment plans.’ (Participant 26 Chinese medicine doctor)

Sub-theme 1B: Directly using classical evidence in clinical practice

Participants had divergent views on the classical evidence. Most integrative medicine doctors and CM doctors thought it expanded their knowledge of using CM and could directly use it in the clinical setting. For example: ‘It can be directly used in clinical practice, verifying the efficacy and increasing our clinical experience.’ (Participant 14 Chinese medicine doctor)

One doctor indicated: ‘Some herbal formulae that were used by the ancients in the past ... can broaden the horizons of my clinical practice.’ (Participant 19 Integrative medicine doctor)

There were doctors indicating it to be beneficial for communicating with patients. For example, one doctor stated: ‘This may be useful when introduce it to people or propagate it to patients.’

(Participant 07 Conventional medicine doctor)

However, some doctors found it was useless because the information contatined in classical

CM literature was different to that their clinical experience. They did not believe it could be used in clinical practice. For example: ‘Many of the information is quite different from what we currently use in clinical practice ... I don't know if it can be applied to our present clinical practice.’ (Participant 09 Chinese medicine doctor)

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Many conventional medicine doctors stated that they did not understand classical CM literature and found it hard to gain knowledge from this source. For example, one doctor indicated:

‘Because I don't really know [about classical CM literature], I may get less information.’

(Participant 01 Conventional medicine doctor)

Sub-theme 1C: Understanding importance of patients’ experience

Many doctors indicated that they had a concept of their patients’ experience before knowing about the new information. However, they thought that the survey results gave them more detailed information about patient experience and expectations of using CM for depression.

For example: ‘I didn't have this kind of intuitive data before. Now I found that patients' expectations and acceptability of traditional CM are much higher than I thought.’ (Participant

15 Chinese medicine doctor) ‘First, I didn't expect that patients would have such an idea. I think they may pay more attention to the effects and the use of medications that can get effects immediately. Patients would like to look at the integrative medicine, which gives me a great guidance for treating depression.’ (Participant 22 Conventional medicine doctor)

Many perceived that the patient information would play a positive role in their future clinical practice. For example, two doctors indicated: ‘There are many patients who want to be treated with traditional Chinese medicine, and many patients want to be treated with traditional

Chinese and Western medicine. This is a very good thing for us.’ (Participant 16 Integrative medicine doctor) ‘I think, in the future, I will be more confident in CM to treat patients with depression.’ (Participant 23 Chinese medicine doctor)

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Some doctors indicated that the information inspired them to explore reasons for patients’ choices and think more deeply about the deficiency in their clinical practice. For example: ‘We also hope to understand some of the reasons behind this [patients’ preference].’ (Participant

09 Chinese medicine doctor) ‘I don't think our doctors have explained some information and experience about using to treat depression from patients’ perspectives.’ (Participant 22

Conventional medicine doctor)

Some doctors indicated that they realised the importance of knowing about patients’ preference and expectations that could improve their compliance. They indicated that they were willing to do better in this regard. For example, one participant stated, ‘As for patients' expectations, in fact, communicate more, patients know more, and their compliance will be better, so I think it may be necessary to further strengthen this aspect in the future work.’ (Participant 15 Chinese medicine doctor)

Theme 2: Knowledge translation

Theme two emerged from the data coding and revealed participants’ knowledge translation. As detailed below, there were four sub-themes:

Sub-theme 2A: Flexibly using new evidence in clinical practice

This sub-theme emerged from the coding data of participants with integrative medicine backgrounds and CM backgrounds, regarding updating clinical practice based on the information from systematic reviews and meta-analysis and classical CM literature.

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Many doctors stated that they would like to use the evidence from both classical CM literature and systematic reviews and meta-analysis in clinical practice. For example: ‘I will try to use the evidence [the classical CM literature].’ (Participant 14 Chinese medicine doctor) ‘Yes, I will refer to this [the systematic reviews and meta-analysis].’ (Participant 20 Integrative medicine doctor)

However, doctors indicated that some evidence was easy to start to use, while some was difficult. They had different views on this. They stated they considered the use of new knowledge based on their practice. For example: ‘such as Chai hu shu gan san and Xiao yao san, those which are frequently used in the treatment of depression, and the evidence-based research results showed that they are effective, so I think I will try to use them in clinical practice … I think if I use acupuncture only to treat depression, I feel it is too difficult to apply.’

(Participant 09 Chinese medicine doctor) ‘[The knowledge that is easy to start to use] is these herbal formulae from classical CM literature ... All these are not too difficult [to be used in clinical practice].’ (Participant 18 Integrative medicine doctor)

For either systematic reviews and meta-analysis or classical CM literature, many doctors thought that the evidence of CHM was easier to use in clinical practice compared to acupuncture. For example, one doctor indicated: ‘[The use of] acupoints are a little more difficult for me, because I cannot reflect to use what acupoints for patients in mind immediately by only provided acupoints, which are the same as mentioned herbal formulae.’ (Participant

26 Chinese medicine doctor)

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When doctors imagined updating their clinical practice based on the evidence from the systematic reviews and meta-analysis as well as classical CM literature, most thought they were willing to update their clinical practice based on a patients’ condition and clinical setting, and the chance was generally more than 50%. They indicated varying degrees of concern when using the new evidence in clinical practice. Some of them stated that they felt concerned about how effective the evidence is shown to be in real clinical practice. For example: ‘Some herbal formulae [in classical literature] I haven't used before. I may go to explore which people it may be suitable for according to its composition ... The chance should be 50% ... Not much concern.’ (Participant 08 Chinese medicine doctor) ‘I may use CM more for patients with depression [based on the evidence of systematic review and SR] ... I think at least 70% – 80% ...

For example, if the depression is first episode and is mild to moderate based on my evaluation,

I will first recommend some CHM decoctions or CM treatments, and I will also tell the patient about the antidepressive effect of CM as well as its advantages … I consider the issue of efficacy and the time of onset. I believe that CHM and acupuncture will definitely help patients, but the time of onset may be needed.’ (Participant 25 Integrative medicine doctor)

Some doctors would like to update practice, but they thought that the chance of change was not high or was even hard to identify because of concerns about the low certainty of the evidence.

They thought if they used the evidence it should be considered in actual circumstances with self-judgement. For example, one doctor stated: ‘It's hard to predict the possibility. It gives me a good new idea and a hint … Once I meet a suitable situation in clinical practice, I will still formulate a diagnosis and conduct treatments according to my own experience, and it will also

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give me such a hint or choice ... I feel that the quality of the evidence is slightly low.’

(Participant 09 Chinese medicine doctor)

Some doctors did not want to change their practice because they thought they use what the evidence shows in practice and they did not need to change. For example, one doctor stated:

‘My clinical practice has always used CM in this way, so it [the evidence] is quite consistent with my clinical practice.’ (Participant 19 Integrative medicine doctor)

Sub-theme 2B: No universal support for improving communication with patients

Doctors had opposing views on whether they would update the way they communicated with patients based on the information they gained from the survey. Some doctors intended to communicate more about treatment options and treatment plans with their patients after knowing about patient preferences. They believed that comprehensive communication with patients could improve patient compliance with their treatment. For example: ‘Yes, because there are patients who often ask: “what will happen if I take CHM and what are your suggestions and so on?” ... If I talk to them about more information about this aspect, and the information about the treatment plan, it may also be able to better promote patient to take medication in later treatment.’ (Participant 01 Conventional medicine doctor)

Doctors who wanted to update their communication with patients, generally indicated a high percentage of likelihood to update. Most of them felt unconcerned about the updates, but conventional medicine doctors were afraid that they could not explain clearly about CM because of their limited relevant experience in the field, some CM doctors were concerned that

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there was not enough time to communicate with patients in clinical practice, while integrative medicine doctors thought it was hard to balance the patients’ preference and condition even when it is communicated. For example: ‘I have concerns because I don't think I have enough time [in clinical practice].’ (Participant 08 Chinese medicine doctor) ‘The greatest concern is that I don't have a professional background in this [CM] field.’ (Participant 10 Conventional medicine doctor) ‘There will be a few [concerns], which is the assurance of circumstance. It cannot be completely according to the patient's ideas, and it should always be combined with their condition.’ (Participant 17 Integrative medicine doctor)

On the other hand, three doctors had no intention to update their communication with patients.

Two thought they had already made efforts in improving their communication with patients, while the other thought patients’ compliance was good enough without any need for updating the way of communicating with their patients.

Sub-theme 2C: Transferring new evidence to patients can be difficult

Doctors were asked to consider communicating the evidence regarding exsistence of clinical evidence (Chapter 4 to 6) to patients as well as the survey results (Chapter 7). With respect to the systematic reviews and meta-analyses, the majority of doctors stated that they would like to inform their patients about this new evidence. They thought mentioning the evidence could make patients establish compliance and give confidence for using CM for depression. They also thought that sharing the evidence and what kind of evidence was shared depended on a patients’ preferences for gaining information as well as a patients’ level of education and

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understanding. For example: ‘Some patients may have some concerns about the use of CM.

When we use such evidence to communicate with patients, the convincing may be greater.’

(Participant 09 Chinese medicine doctor) ‘In fact, after the first interview, when I went to clinic, there were patients asked me about [CM], I really communicated with them some information

I had gained from the presentation. I also hope that there will be at least one more way to help patients solve the problem.’ (Participant 22 Conventional medicine doctor) and ‘It depends on the patients’ level of education and acceptance.’ (Participant 25 Integrative medicine doctor)

In term of the evidence from classical CM literature, a few doctors thought they would like to inform their patients of it, while many doctors thought it would be hard for patients to understand the information from classical CM literature and it might waste time during practice.

One doctor indicated: ‘I may be afraid of wasting time, and then talk this [classical CM literature] for a long time, he/she is not interested, it is difficult for the patient to understand and accept.’ (Participant 25 Integrative medicine doctor)

Sub-theme 2D: Transferring new knowledge to colleagues on certain occasions

With respect to the evidence from classical CM literature and systematic reviews as well as of patient information obtained from the survey, many doctors indicated that they would like to discuss this with their colleagues as well as sharing the summary report with them. For example:

‘I'm interested in including the CHM and acupuncture that I just mentioned. I would like to communicate these with my colleagues.’ (Participant 12 Conventional medicine doctor)

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However, when thinking about recommending information to colleagues to read, doctors had divergent ideas. Most doctors thought they would highly recommend the evidence to their colleagues without any concerns. For example: ‘I may also [recommend to colleagues] in appropriate occasions.’ (Participant 12 Conventional medicine doctor) ‘I think maybe I'll use the evidence for a week, and then add on my feeling as well as my feedback of clinical practice

[to recommend to colleagues].’ (Participant 26 Chinese medicine doctor) Some doctors stated that they would not like to recommend the evidence from the classical CM literature because of their limited understanding of this evidence. For example, one doctor indicated: ‘No, because I don’t understand it.’ (Participant 06 Conventional medicine doctor).

Doctors thought it was worth recommending the evidence to their colleagues. They indicated there were a lot of reasons. For example: ‘First, CM is very supported by our country now. It is possible that medical insurance will be reimbursed in an all-round way. Second, antidepressants have many side effects, some of which can't be tolerated by patients. Patients can try many ways.’ (Participant 06 Conventional medicine doctor)

In terms of information about patients’ experience and expectations, the majority of doctors stated that they would like to recommend this to their colleagues to read it. They indicated a high chance of recommendation. Some of them thought doctors should know a patients’ preferences. They perceived that transferring this information could help their colleagues to improve the effects of treatment. For example: ‘Let these colleagues know more about the ideas of these patients, become more familiar with them, and let them find more ways to improve

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quality of treatments.’ (Participant 16 Integrative medicine doctor) ‘Let doctors and colleagues know what the patients’ expectations of treatments, and then we can try to match some of patients’ expectations of treatments from our own perspective. ‘(Participant 22 Conventional medicine doctor)

However, one doctor stated that their colleagues did not need a recommendation of knowing the survey results: ‘I don't think we need to recommend this [to colleagues], because our understanding is like this, because the information of patients we are exposed to is like this.’

(Participant 22 Conventional medicine doctor)

Theme 3: Clinical decision-making on CM for MDD

Theme three emerged from the data coding and revealed clinical decision-making on CM for depression was based on doctors combining their clinical experience and the new knowledge.

As detailed below, there were three sub-themes.

Sub-theme 3A: Importantly attending to the patient's condition

When considering the use of CM for MDD, doctors drew their perceptions from various perspectives. Doctors thought about this based on the condition, treatment and patient regarding the suitability of CM given the patients’ condition, the efficacy and safety of CM, patient preferences, acceptance or compliance, and a patients’ economic condition. For example, conventional medicine doctors indicated: ‘Doctors should consider the patients' liver and kidney function, and then the patients' economic ability and compliance.’ (Participant 01

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Conventional medicine doctor) ‘The first is to consider the patient's acceptance. Second, recommend some methods with better efficacy and safety in the acceptable range of patients.’

(Participant 21 Conventional medicine doctor)

Despite this information, integrative medicine doctors also indicated that one should consider the convenience of using CM for patients as well as how to change treatment plan when the effect was not good. For example:

The patient has some physical diseases, some of whom are unable to receive acupuncture, some of whom are inconvenient to take CHM. These may need to be considered as well as patients’ treatment preference. (Participant 20 Integrative medicine doctor)

Doctors should pay close attention to the patient's condition. If the effect of the CM treatment is not good, it may be necessary to combine some conventional medicine treatments.

(Participant 24 Integrative medicine doctor)

In addition, CM doctors indicated similar ideas on considering the use of CM for this condition, as some doctors stated below:

I think the first thing is whether the patient is suitable, whether the [treatment] plan is suitable for him/her ... And the cost. (Participant 08 Chinese medicine doctor)

I think it is necessary to consider the compliance of patients, and there are still some inconvenient factors in the use of it [CM]. I insist on looking at whether it is suitable for the

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patient … For example, if the patient is a student who lives at school, it may not be convenient for the patient to cook CHM. (Participant 23 Chinese medicine doctor)

Among considerations for using CM for the condition above, doctors thought it is important to consider including the risk and severity of the condition, the efficacy and safety of CM, and patients’ preference and acceptance. For example: ‘The most important aspect is efficacy and safety.’ (Participant 03 Conventional medicine doctor) ‘It’s the condition itself, and if [the treatment] has any risk to the patient’s condition.’ (Participant 20 Integrative medicine doctor)

‘It is whether the patient is willing to accept it, patient's preference!’ (Participant 23 Chinese medicine doctor)

Sub-theme 3B: Doctors communicate by making recommendations

When doctors considered a patient who preferred to use CM alone for depression and how to communicate with this kind of patient, they generally thought that they would communicate with their patients depending on their risk and severity of the condition combined with a respect for the patients’ preferences. They indicated that the main preferred form of communication was based on providing recommendations. For example: ‘I will tell the patient that I may need to make a relevant assessment first, to assess whether the condition is suitable for using CM only. If it is suitable, I will help to achieve it.’ (Participant 12 Conventional medicine doctor)

Doctors stated different ways to communicate with their patients. Some doctors thought they should explain clearly about the condition to patients: For example, one doctor stated:

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I will tell the patient that if they choose CM only, if the condition is suitable, we can have a try, but the condition may have changes ... If I don't think the patient is suitable [for using CM only], I will say that if they only use CM, I think the disadvantages of the treatment outweigh the advantages for the current condition, and I may positively recommend some medications for them. If I think it's necessary, but the patient still insists [on using CM only], I may ask them to sign the informed consent. (Participant 08 Chinese medicine doctor)

Some doctors suggested using integrative medicine for patients. They also indicated adjusting the treatment plan in a timely way based on observation of the condition. One doctor stated: ‘I will suggest that the patient can maintain conventional medicine treatment for a while. I will also treat them by using CM. After observing for a period, I gradually reduce the amount of medications when the patient’s symptoms gradually stabilise.’ (Participant 19 Integrative medicine doctor)

Some doctors stated they would use the new knowledge and provide more information about depression for patients to consider and make choices if the patients’ condition was mild to moderate. For example: ‘I may tell the patient about the study of classical CM literature. In addition, I may mention to them studies on the efficacy of acupuncture and CHM for depression, compared to conventional medicine, and the patient can make a choice. Furthermore, we will also provide some health education, especially for the patients with depression who have suicidal behaviour such as self-mutilation and so on. We may provide some related education, so that they can better understand depression.’ (Participant 22 Conventional medicine doctor)

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Sub-theme 3C: Individually personalised treatment or recommendation

Doctors proposed several pieces of advice that patients with depression needed to pay attention to during treatment. Doctors thought their advice for patients should closely associated with the effects of treatment and development of the condition. Some doctors thought compliance with the treatment should be raised with patients. Some doctors also acknowledged that compliance was one of the most important aspects of treatment they would advise their patients.

For example: ‘Take medicine regularly.’ (Participant 01 Conventional medicine doctor)

‘Regularity and timeliness of taking CHM as well as the adjustment of the treatment.’

(Participant 08 Chinese medicine doctor) and ‘Cooperate with the doctor's treatment plan.’

(Participant 19 Integrative medicine doctor)

Some doctors stated that directions on the use of treatment were another significant point for patients. For example, one doctor indicated: ‘The directions including both CHM and medications.’ (Participant 17 Integrative medicine doctor)

Some doctors perceived that adverse events were part of the most important pieces of advice to inform patients about. They thought both CM and conventional medicine had adverse events.

For example: ‘If conventional medicine, I may tell the patient some possible adverse events. As for CM, I would tell the patient that CHM has some physical reactions … which also has some adverse events.’ (Participant 15 Chinese medicine doctor)

Some doctors indicated that the risk of control of the condition played a crucial role in doctors’ advice. For example: ‘As for MDD, the most worried problem is that the rate of suicide will

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increase when the patient is just getting better. We need to tell the family members to achieve prevention.’ (Participant 01 Conventional medicine doctor) ‘At first, it should be risk prevention and control ... If some severe patients get better, I will particularly pay attention to risk control in the second stage, because when the patient is better, in the second stage the patient may have the motivation to implement suicidal behaviour.’ (Participant 08 Chinese medicine doctor)

Some doctor advised patients to focus on the development and change of their condition. For example: ‘If the condition changes and the mood changes, patients should have a followup visit as soon as possible.’ (Participant 24 Integrative medicine doctor)

Some doctors indicated that they would advise patients to properly manage their daily life well.

For example: ‘When there is progress [in treatment], it may focus on regulating the patient’s daily life and diet.’ (Participant 08 Chinese medicine doctor) ‘In terms of daily diet, it should be based on the patient’s physical condition. There is some food are warnings. I would explain to the patient. And [ask them] sleep well.’ (Participant 16 Integrative medicine doctor)

Theme 4: Tension between research and clinical practice

Doctors generally perceived that studies on CM for MDD were not well established. Many doctors thought that these studies normally had shortfalls in study design and methodology.

They were concerned about the certainty of the evidence that may indicate the validity and feasibility of using CM in clinical practice. For example, one doctor stated the research finding showed differences with clinical practice based on clinical experience: ‘This literature is all

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nationwide, and there are still some differences between regions in [clinical practice]. For example, bupleurum may be used more in the north, but in Guangdong bupleurum may be used more in the acute phase for patients with depression.’ (Participant 16 Integrative medicine doctor)

They stated their ideas on the research questions about which they were interested in. They thought these research question could be further explored. For example:

First, CM may indeed have advantages. Second, we need to see how to convert the dose- response relationship between the herbal formula, including its active ingredients, and compared to medications. For example, fluoxetine is a kind of antidepressant with good effects which has been widely accepted. But in different doses, such as 10 mg, 20 mg and 30 mg, the effect is definitely different in different dose groups. So, I'm not sure if you compare this formula with fluoxetine, how to convert such a dose-effect relationship … What are the strategies of

CM in the management of consolidation, maintenance and even rehabilitation for depression?’

(Participant 01 Conventional medicine doctor)

I will think that CHM is effective, so how to use it, I think we still need to study syndrome differentiation, which is the essence of CM. (Participant 23 Chinese medicine doctor)

Discussion

To understand CM for depression and itsrelated knowledge translation based on the EBM concept in the Chinese clinical settingas well as improving clinical decision-making on CM for

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depression, this study explored Chinese doctors’ in-depth perceptions. Chinese doctors with three types of backgrounds, conventional medicine, integrative medicine and CM, who regularly treated patients with depression were interviewed to probe their experience of treating depression, perceptions of using CM, thoughts of patients’ preference, knowledge access, reactions to the research findings, and intended use of research results in clinical practice and clinical decision making.

The analysis of the interviews generated 9 themes and 24 sub-themes to illustrate doctors’ perceptions, experiences, beliefs, intentions and considerations in using CM for depression, regarding clinical practice, knowledge translation and clinical decision-making.

Summary of findings

Diagnosing and treating depression

In terms of treating depression, doctors with different backgrounds indicated that they used the same process of formulating a diagnosis of depression, which should be standardised and confirmed using validated screening examinations and diagnostic criteria.(479) As for treatments, they indicated their experiences of using pharmacological and nonpharmacological therapies. Their choice of treatment types was generally consistent with clinical guidelines.(16, 180)

Some doctors highlighted that patients’ individual medical history is an important part when formulating a diagonosis, and treatments are individualised depending on the patients’

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condition. Doctors would systematically consider and assess the patients’ symptoms, cognitive ability and risks based on clinical expertise. Furthermore, affirmation of CM is only communicated or recommended to certain patients, whose depression is mild to moderate.

From interview one to interview two, doctors mentioned that personalised diagnostics and treatment for depression and patients may derive medical benefit from this clinical pattern.

Current evidence also supports the view that the efficacy of treatment for depression can be dramatically improved if the diagnosis is precise and treatments aresuited to the individual.(480)

Doctors all generally acknowledged CM could be used for depression. Conventional medicine doctors showed positive attitudes towards CM for depression. They believed that CM had beneficial effects and fewer side effects compared to antidepressants. Doctors with backgrounds of integrative medicine and CM indicated that they used CM to treat depression.

However, all doctors perceived the use of CM to have a specific scope. They generally thought the use of CM was suitable for patients with mild to moderate depression, but not severe depression or suicidality. This perception is consistent with the results of previous clinical research.(481, 482) As for severe depression, some integrative medicine doctors and CM doctors perceived that integrated CM and conventional medicine could be used, but currently there is a lack of research evidence to support this view.

Patients’ preference and clinical expertise

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Doctors indicated that they normally would consider the severity of a patients’ condition and evaluate the risks in formulating their professional advice when patients had a preference for using CM for depression. In addition, they presented the necessity and importance of a comprehensive informed consent for patients. They highlighted that they respected a patients’ preferences. They thought patient preferences were associated with the development of the condition, patient compliance and the effects of treatments. A previous study on patient preferences showed that patients could provide particular insight into their condition, treatment and needs.(483) Increasingly, patient preferences are being perceived as an important part of health care decision-making and there is a growing need to incorporate their perspectives into the process, rather than doctors making decisions on patients’ behalf.(484)

Doctors indicated that treating depression and communicating with patients with depression should follow the Mental Health Law of the People's Republic of China. This law was adopted at the 29th session of the Eleventh National People's Congress Standing Committee in

2012.(478) This law builds a legal framework for people with mental disorders in China.(485)

The law includes how to respond to patients' need for therapy and how to protect their interests, liberties and autonomy, as well as specifying detailed processes that health facilities must undergo regarding diagnosis, treatment and involuntary admission of patients.(486) Those who are involuntary have obvious presence of suicide. This patient may not have a good self- awareness of his/her condition or understanding of treatments. They are likely to be sent to hospital by their family members and receive mandatory treatments. Prior studies highlighted that the family plays a significant role in depression management with a potential to strengthen

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or impede care, particularly in the elderly.(487, 488) Families play treatment-promoting roles for patients with depression, including providing a supportive home environment, promoting patients’ self-management, understanding risks of the condition and facilitating communication with doctors during primary care visits.(488)

The interview one and interview two revealed that doctors evaluated patients’ condition and provided them with the best available treatment choices and advice based on their experience and knowledge. They not only respected patients’ needs and preferences but also understood the importance of patients’ preference. However, doctors have no concensus on updating their communication with patients. There is still room for improvement and a balance between expertise and patient preferences during clinical decision-making is yet to be fully realised.

These have been highlighted in the study of clinical expertise. Researchers have recognised clinical expertise should encompass and balance clinical circumstances and conditions of patients, patient preferences and research evidence to achieve a satisfying and successful outcome.(86, 89) These results showed that a doctors’ main form of communication with patients was to make recommendations and then patients made their decisions based on advice and options provided by the doctors. Previous research has also indicated that patients choose

CAM according to the health care provided by practitioners; thus, there is room for improvement in communication with patients regarding listening to patients’ needs and providing the opportunity for shared decision-making.(489, 490) One review indicated that doctors should avoid decision bias in making their decisions, such as selectively including and

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excluding certain research evidence, pushing patients too fast or hard during treatment programs and failing to verify information from their patients’ family members.(491)

Knowledge translation

One previous study reported that the time between knowledge becoming available and its integration into clinical psychiatric practice was long, and that research results needed to be further implemented to strengthen EBP in the field of clinical psychiatry. (492) This study explored how doctors treated depression in their daily practice, how they normally accessed and approached relevant knowledge, and their intention of updating their conduct in the clinical setting regarding practice and flow of information between colleagues and patients.

In the results presented above from the first interview, doctors indicated that they accessed new knowledge via various resources as well as based on their preference. Ordinarily, they applied the new knowledge to their clinical practice to address related clinical questions and improve clinical practice. After interview one, new clinical evidence and information on patients’ experience and expectations of using CM for depression (the results from Chapters 4 to 7) was introduced to doctors before commencing interview two. In the second interview, doctors demonstrated their intention of updating clinical practice, transferring knowledge to colleagues and updating communication with patients based on the new evidence presented to them.

Although doctors acknowledged the benefit of the new knowledge from the systematic reviews and meta-analyses, they were concerned that the certainty of the evidence was low. Previous studies found that the mean Jadad score (a measure of methodological quality of clinical trials

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on a scale from 0 to 5) of CM randomised control trials (RCTs) was 1.03 from 1990 to 2004

(7422 RCTs), 1.25 from 2005 to 2009 (4133 RCTs) and 1.22 from 2011 to 2012 (2861

RCTs).(493, 494) This research result highlights the huge gap between the quality and the quantity of CM RCTs. It needs much more work to improve this aspect to provide high levels of evidence for health practitioners. The CONSORT standard and its extension for CM elaborate the requirements for reporting clinical trials in CM.(320, 322)

Interviews revealed that doctors use new evidence in practice but there is flexibility.

Participants who had backgrounds in integrative medicine and CM updated their CM knowledge via learning from experienced practitioners and reading classical CM literature.

They acknowledged the evidence related to depression in classical CM literature because of direct integration into practice. Currently, there is an increasing number of studies that explore the mechanisms of CM for many conditions.(495, 496) However, only limited studies have evaluated the antidepressant action of CM, so future experimental studies are needed to critically investigate the mechanism of CM for depression to scientifically support its use.

When participants thought of the use of CM for depression, the majority generally focused on integrative medicine, using CM as an add-on therapy for conventional medicine. Increasingly, a large body of evidence supports the use of integrative medicine for a wide range of conditions including depression.(497) Although the use of integrative medicine is promising, there remains a lack of methodologically rigorous research to confirm its efficacy, safety and mechanisms.(498) For example, during the interviews some participants stated that they were

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interested in the integrative use of CM and psychotherapy for patients with depression.

However, there is limited available evidence to support this. Previous research indicated that the efficacy of antidepressants is generally comparable to psychotherapy at the end of treatment.(499, 500) Thus, the integrative use of psychotherapy and CM is worthy of further exploration, which may provide doctors with new insights into the treatment of depression.

Doctors acknowledged knowledge translation between peers, but only on certain occasions.

Although doctors respected patients’ preference and understood its importance, there was no universal concensus on updating communiation with patients. To go one step further, they thought it is difficult in reality to transfer knowledge to patients. However, they would like to transfer the new knowledge to colleagues and communicate the new evidence with patients because they believed that this process of knowledge translation had benefits for clinical practice. In fact, knowledge translation is perceived to improve health care and outcomes.(501,

502) A previous study on knowledge translation in clinical practice indicated that the basic unit of knowledge translation should be up-to-date systematic reviews and syntheses of research findings.(503)

Clinical decision-making on CM for depression

The process of clinical decision-making is perceived as shared decision-making and has been recognised as an important tool in the field of mental health.(504) This study explored the perspectives of doctors with different backgrounds regarding clinical decision-making on the use of CM among patients with depression. Participants perceived that clinical decision-

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making on CM for this condition should integrate clinical expertise, research evidence and patients’ preference, which is the practice of EBM. They considered the severity and risks of this condition, focused on the efficacy and safety of CM, and thought of patients’ preference and acceptance. There have been studies on shared decision-making on antidepressants in primary care of depression(505, 506) but this kind of research on the use of CM is limited, indicating much further work is needed in the future.

Limitations of this study

Participants were all from Guangzhou, Guangdong, which could not be representative of the whole status of China or other countries. For example, in terms of perceptions of using CM for depression, some participants indicated that their patients were influenced by regional culture in Guangdong and easily accepted CM treatment. Furthermore, doctors’ perceptions of using acupuncture for depression remain unclear in this study likely because participants talked less about acupuncture compared to CHM or few acupuncturists were included in this study. As known, CHM is particularly popular in the region of Guangdong.(394) Thus, future studies should include participants from other regions or countries and include more acupuncturists.

Ensuring trustworthiness of research findings is based on a rigorous method,(507) including credibility, transferability, dependability and confirmability.(508) Although member checking referring to the review of transcripts by participants for accuracy has been highlighted to ensure credibility as a gold standard,(508) member checking was not used in this study because it also may cause confusion if participants change information.(509) Transferability depends on

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potential users comparing the similarity between the qualitative study and potential settings.

Thus, further research to confirm the qualitative research finding is required, such as validating doctors’ perceptions by other types of research. Furthermore, for the purposes of the thesis and publication the Chinese transcripts were translated into English, which may have introduced errors, although considerable efforts were made by the researchers to minimise this source of error.

Implications for clinical practice

This study provides further understanding of using CM for depression. Before introducing the new research results (Chapters 4 to 7) to them, participants recognised that CM is beneficial and safe for mild to moderate depression. Participants acknowledged the findings of systematic reviews and meta-analyses but had concerns that the evidence was low certainty. Integrative medicine doctors and CM doctors perceived classical CM literature as beneficial because it can be directly used in clinical practice. Participants acknowledged the benefits of these source of new knowledge for providing promising evidence and communicating with their patients.

Participants were interested in the evidence of integrative medicine for the condition.

Participants also got clear information in the survey about patients’ preference of using integrative medicine for their condition. Thus, the integrative use of CM and conventional medicine could be further applied and verified in clinical practice but should be practiced with caution and a clear understanding of the evidence of using of CM for MDD remains low. High‐

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quality RCTs are urgently needed to examine the clinical efficacy and acceptability of integrative medicine.

The process of clinical decision-making on CM for depression based on EBM has become clearer regarding integration of doctors’ clinical expertise, utilisation of research evidence and consideration of patients’ preferences. This process should be implemented in the future clinical practice of CM for depression, which needs much more work to achieve.

Implications for future research

Participants with backgrounds of conventional medicine, integrative medicine and CM were all shared the concern about the lack of certainty of the evidence on CM for depression. Well- designed studies with high-quality methodology and clinical significance are needed to validate the evidence for practitioners. For example, participants focused on integrative medicine for this condition. Further studies need to further investigate the mechanisms of integrative medicine and the comparative effectiveness of different types of integrative medicine, as well as its various combinations for treating this condition. Future clinical trials should include larger sample sizes and standardised study protocols.

During the interviews, participants were introduced to the new research results to explore their perceptions of the new knowledge and intentions of updating clinical practice. Follow up studies on the use of new knowledge in clinical practice are recommended, which could use a series of qualitative or quantitative methods.

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Conclusion

This study explored doctors’ perceptions of using CM for depression and the translation of research findings into clinical practice, as well as clinical decision-making based on EBM.

Doctors with backgrounds in conventional medicine, integrative medicine and CM formulated their diagnosis of depression in the same way. They treated patients based on their training and clinical experience, accessing and approaching new knowledge, and understanding their patients’ preferences. Doctors generally acknowledged the benefits and safety of CM for mild and moderate depression, and they believed in the benefit of integrative medicine based on the new research results. They intended to use the new knowledge to update clinical practice, transfer it to colleagues and communicate with patients. To improve the clinical decision- making on CM for depression, doctors integrated clinical expertise, the best available evidence and patient preferences into their practice.

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Chapter 9 General Discussion and Conclusion

Introduction

Major depressive disorder (MDD), simply referred to as depression in this thesis, is the most common mental health disorder worldwide.(6) MDD is characterised by depressed mood, diminished interest or pleasure, significant weight or appetite change, insomnia or hypersomnia, psychomotor agitation or retardation, loss of energy or fatigue, inappropriate guilt or feelings of worthlessness, diminished ability to concentrate or make decisions, or thoughts of death or suicide.(1) Clinical presentation of this condition is heterogeneous.(1) Patients with depression may suffer from an isolated episode or recurrent episodes,(116, 117) but for most it is a lifetime mental disorder(1), which means patients may experience several episodes of depression across their lifetime. There is a high prevalence and frequent relapse and recurrence.(510)

In primary care, most patients with depression are prescribed second-generation antidepressants(511) such as selective serotonin reuptake inhibitors (SSRIs) that are superior in terms of efficacy and safety and an important treatment for depression.(512, 513) However, various adverse events have been highlighted across different antidepressants.(514) Non- pharmacological therapies, such as psychological and behavioral treatments and electroconvulsive therapy, are also recommended as they have positive effects, but benefits vary across individuals.(511) Complementary and alternative therapies are available for the

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management of depression, such as Chinese medicine (CM) including Chinese herbal medicine

(CHM) and acupuncture.(179, 183, 515)

To improve clinical practice of CM for depression, the elements of evidence-based medicine

(EBM) regarding the best available evidence, patients’ values and clinical expertise have been incorporated together in this study to identify the gaps between evidence and practice and improve knowledge translation. This thesis includes a ‘whole-evidence’ analysis(516) of CM for the management of depression, including the best available clinical evidence from systematic reviews of randomised controlled trials and historical evidence from classical CM literature (Chapters 4–6); a survey of patients that evaluated their experience and expectations of using CM for depression (Chapter 7); and interviews with doctors to explore and understand their clinical decision-making when treating patients with depression (Chapter 8). This whole

EBM approach provides a comprehensive understanding of the best available evidence, patient values and clinical perspectives, and how these can be better integrated into clinical practice of

CM for depression.

Summary of findings

This study gained an overview of the contemporary evidence and traditional knowledge, patients’ experience and expectations, and Chinese practitioners’ perceptions related to the use

CM for MDD, based on the implementation of EBM in clinical decision-making. The research

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findings of CM for MDD comprise four parts including classical evidence, modern evidence, patients’ experience and expectations and doctors’ perceptions.

Part 1 Classical clinical evidence of CM for MDD

Chapter 4 provides classical evidence of CM for depression via a search and analysis of historical CM literature. The search was conducted using an electronic database called the

Zhong Hua Yi Dian (Encyclopaedia of Traditional Chinese Medicine), which is the largest searchable resource of historical CM books. The methods were based on the principles and standard operating procedures developed by the China–Australia International Research Centre for Chinese Medicine.(189) A total of 4806 citations were identified using 20 search terms.

After reviewing, 319 citations were included in the data analysis. The most frequently used

CM treatments identified in the classical literature are still commonly used today, such the herbal formulae Gan mai da zao tang and Gui pi tang. These formulae are also recommended in the contemporary CM clinical guidelines for depression. Commonly cited herbs included fu ling, ren shen, bai zhu and dang gui. Acupuncture is also commonly used in contemporary clinical practice for depression. However, it was only mentioned in a few classical citations.

Acupuncture points included PC7 Da ling, PC5 Jian shi, PC6 Nei guan, KI3 Zhao hai and

BL15 Xin shu.

Part 2 Modern clinical evidence of CM for MDD

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Chapters 5 to 7 provide modern clinical evidence of using CM for depression via systematic reviews and meta-analyses of randomised controlled trials (RCTs) that compared CHM and/or acupuncture to SSRIs. The methods were based on the Cochrane handbook for systematic reviews of interventions.(45) The reviews were registered in PROSPERO (ID No.

CRD42018091770 and ID No. CRD42018091774). RCTs were retrieved from English and

Chinese databases from their inception to February 2018. Databases included PubMed,

EMBASE, CINAHL, CENTRAL, CBM, CNKI, CQVIP and Wanfang. The search was unrestrained, and terms included depression, CHM, RCTs and their synonyms. Two reviewers screened titles and abstracts. Relevant RCTs were obtained and data extracted by the reviewers in predefined EpiData files. Data included participant details, interventions, controls and outcomes. Primary outcome measures included clinician-rated and self-reported depression severity scales. Methodological quality was assessed using the Cochrane risk of bias tool.

Meta-analysis was conducted in STATA software. Sensitivity analysis and subgroup analysis were also performed.

Chinese herbal medicine results

Chapter 5 provides an up-to-date and comprehensive systematic review and meta-analysis of

CHM for MDD. Seventy-eight RCTs compared CHM with SSRIs or compared CHM plus

SSRIs (i.e. integrative medicine) to SSRIs alone. Studies included people with MDD aged 18–

65 years. People with other types of depression such as bipolar disorder and mental or physical

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disorders were excluded. Forty-six studies compared CHM to SSRIs and 32 studies compared

CHM plus SSRIs to SSRIs alone. CHM alone or given as integrative medicine with SSRIs reduced depression severity. However, the heterogeneity of the included RCTs was high. The total number of adverse events in the CHM groups was less than in the SSRI groups. Overall, thequality of evidence was low and limited by bias in the included studies and heterogeneity.

Well-designed studies are required to validate the evidence identified in this review.

Acupuncture results

Chapter 6 provides an up-to-date and comprehensive systematic review and meta-analysis of acupuncture for MDD. A total of 45 studies with 4570 participants were identified. Thirty studies compared acupuncture to SSRIs and 15 studies compared acupuncture plus SSRIs to

SSRIs alone. Meta-analysis results indicated that acupuncture was more effective than SSRIs in terms of reducing depression symptoms as measured on the Hamilton Rating Scale of

Depression (HRSD). However, the heterogeneity of the included studies was high, and the quality was very low to low. Fewer adverse events were observed among people treated with acupuncture compared to the SSRI groups. Acupuncture treatment alone or in combination with SSRIs produced statistically significant reductions in depression severity. However, this should be interpreted with caution due to the trials’ methodological shortfalls and heterogeneity in meta-analysis.

Acupuncture plus Chinese herbal medicine results

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Chapter 6 provides a systematic review and meta-analysis of acupuncture plus CHM for MDD.

Six RCTs (442 participants) compared the effect of acupuncture plus CHM to that of SSRIs.

Acupuncture in combination with CHM showed positive effects on improving HRSD scores and had fewer adverse events compared to SSRIs. The number of studies and sample sizes were limited. Overall, there was insufficient evidence for the efficacy and safety of the combination of acupuncture and CHM for the treatment of depression.

Part 3 Experience and expectations of using CM among patients with MDD

Chapter 7 provides the results of a survey that investigated the experience and expectations of using CM among patients with depression. The survey was conducted at the Department of

Psychology and Sleep Medicine of the GPHCM. The study included 139 respondents. Results indicated that most participants preferred integrative treatments. Antidepressants and CHM were the most common treatments. Most respondents who had taken antidepressants had experienced side effects and that was also the main reason for cessation of use. Those who used

CM had rarely experienced side effects and insisted on using it due to fewer side effects. As for communication between doctors and patients on treatment options, patients wanted their doctor to communicate about treatment types and options such as conventional or complementary therapies. Generally, they were given inadequate information about CM for depression. Patients were also interested in knowing information on research evidence for CM,

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they wanted to know about CM classical literature and case studies, but most of all they wanted to know about doctors’ experience of using CM for their condition.

Part 4 Perceptions on CM for MDD among doctors

Chapter 8 provides the results from interviews with doctors to gather their perceptions of using

CM for depression. Doctors with backgrounds in conventional medicine, integrative medicine and CM formulated a diagnosis of depression using validated criteria and similar processes of evaluation. They treated patients with depression based on clinical experience, new knowledge and patient preferences. Participants acknowledged the general efficacy and safety of using

CM for this condition. Many of them focused on treatment using integrative medicine for depression based on the new research results. Doctors had an intention to update their clinical practice, transfer new knowledge to colleagues and communicate new knowledge to patients.

However, there is room for improvement on the forms of communication between doctors and patients. Doctors were likely to integrate clinical expertise, evidence and patient preferences during clinical decision-making to some extent, but this is far from consistent or standardised.

Limitations of this project

Significant efforts were made to collect and analyse data from a range of sources, yet there may have been omissions from each of the data sets. Chapter 4 presents an overview of current clinical practice of CM for depression. It is mainly based on CM textbooks and authoritative

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clinical practice guidelines, but this is not a comprehensive list. Some CM differentiation syndromes and related therapies included in Chapter 4 are not frequently used in clinical practice, while some others are commonly used but not listed. Chapter 4 also refers to classical literature clinical evidence and provides a comprehensive summary of treatments for conditions related to depression in ancient times. However, the historical literature was sourced only taken from the ZHYD using 20 search terms. Therefore, it did not include all possible terms for depression or all possible sources of CM literature, and some may have been omitted. In addition, the search results showed that there were not many citations related to acupuncture.

It is unknown and hard to identify whether acupuncture was seldom used for the condition in ancient times or this lack of citations was due to other reasons.

Chapters 5 and 6 provide modern clinical evidence including literature from a comprehensive search of English and Chinese databases. These studies were mainly from China and results may not be generalisable to other populations. Studies included in the meta-analyses varied across depression aetiology, severity of depression, disease history, study protocols, outcome measurements and interventions. Consequently, considerable heterogeneity was highlighted across all comparisons and this could not be explained by subgroup analysis. As for outcome measures, the HRSD has multiple versions with poor consistency among included studies.

Adverse events were insufficiently reported. Included studies were not free of bias, with methodological shortfalls such as unclear sequence generation and allocation concealment, and

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a lack of blinding of participants and personnel. The methodological flaws and insufficient reporting details of studies led to downgrading of certainty of the evidence and inconclusive evidence.

Chapter 7 provides information on experience and expectations of using CM among patients with MDD. All participants in this survey were from the GPHCM, so there is a lack of representativeness for other people with depression seeking CM treatments. This survey used a convenience sampling method to recruit participants. Future studies are needed to include a wider group of people, such as patients who visit conventional medicine hospitals or psychological and psychiatric hospitals also seeking CM. Random sampling can be used to remove bias from the selection procedure and contributes to representative samples.(433)

Sample size also needs to be accurately calculated by using a well-designed pilot study.

Chapter 8 includes participants with different medical backgrounds in the interviews, but all participants were from the Guangdong province, which may not be representative of doctors from the whole of China. It remains uncertain whether there are similarities or differences in doctors’ perceptions between Guangdong province and other areas. Furthermore, a limitation is associated with cultural factors because of the common use in Guangdong of CM, especially

CHM. Participants in this study talked less about acupuncture so doctors’ perceptions of using this treatment for depression remain unclear. Although many efforts were made to ensure a

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trustworthy qualitative study, member checking was not used in this study. The transferability of this study also needs further research to be validated.

The limitations discussed above should be taken into consideration when interpreting and translating the findings in this project.

Implications for clinical practice

In Chapter 4, a summary of evidence from CM textbooks and clinical guidelines provides important guidance for clinical practice on CM for depression. In terms of recognition of depression based on CM theory, Liver qi stagnation should be considered the main syndrome of depression as it was described across classical and contemporary evidence. The systematic reviews and meta-analysis (Chapters 5 and 6) reveal that CHM or acupuncture alone, or combined with SSRI, may improve depression severity. CHM and acupuncture as monotherapy or adjuvant therapy were perceived to be safe for individuals with MDD. Chai hu and related CHM formulae were most commonly used and should be considered the key treatments in clinical practice. Practitioners should consider adding the common acupuncture points identified in the review, such as PC6 Nei guan, HT7 Shen men, LI4 He gu, LR3 Tai chong, GV20 Bai hui and EX-HN3 Ying tang, to their selection of acupoints for treating depression. The review suggests CHM or acupuncture is beneficial when used alone for the short term to improve depression severity. Taken together, these findings indicate CHM and acupuncture could be considered in treatment of depression.

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The survey has produced evidence of patient experience and expectations of using CM for depression. Patient experience and expectations should be considered when formulating CM treatments for depression. Patient involvement in care could improve their compliance with treatments and help achieve satisfactory outcomes. Understanding the patients’ expectations and experience could improve communication between doctors and patients regarding choosing appropriate treatments, making treatment plans and putting forward treatment proposals. An optimal treatment program requires better collaboration between doctors and patients.

After showing the new research results (from Chapters 4 to 7) to doctors, they reflected on their understanding, perceptions and intentions of using CM for depression and the results are presented in Chapter 8. Participants thought CM was suitable for mild to moderate depression, which could be further validated in health practice. Participants acknowledged the evidence on integrative medicine and patient preferences of using it for their condition. The integrative use of CM and conventional medicine could be further applied in clinical practice. The results of the interviews make understanding of the process of clinical decision-making clearer. Doctors integrated their clinical expertise with the available evidence and patient preferences during clinical decision-making. They acknowledged that patient involvement could improve compliance and treatment success. However, the results from the survey and the interviews

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show that there are still some gaps that need to be addressed to fully realise evidence-based practice of CM for depression.

It is necessary to incorporate the best available clinical evidence, patient values and clinical expertise into clinical decision-making of CM for depression. However, a method to unify the methods of conventional efficacy evaluation and traditional CM practice is yet to be established hampering wider acknowledgment of CM.(517) To gain wider acceptance international CM guidelines for clinical practice are needed to transform evidence into practice. In addition, a greater understanding of doctor-patient relationships is required to communicate evidence while acknowledging the cultural conceptions of healthcare. Particularly, in the clinical practice of CM for MDD, the following aspects are essential to consider:

• First, high-quality systematic reviews are perceived as the basis for the critical appraisal

and evaluation of effectiveness and safety in CM practice in the treatment of depression.

A comprehensive summary of this evidence combined with expert consensus in CM

clinical guidelines can provide the most applicable reference for clinical practice for

mental health practitioners in the area of integrative medicine and CM, as well as

reliable information for conventional medicine practitioners.

• Second, despite advances in pharmacological and psychological therapies for

depression, treatment outcomes for this condition need to be improved.(518) Although

depressed patients have remission after appropriate treatments, the majority continue to

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have residual symptoms that lead to functional impairment.(519) Consequently, new

avenues of optimised treatments need to be explored to achieve residual symptom

reduction, minimisation of adverse events and individualised treatment optimisation. In

this project, CM is identified to follow similar trajectories with antidepressants in term

of reducing depressive severity, but CM has fewer side effects Doctors acknowledged

that CM is suitable for mild to moderate depression and is well tolerated among patients

with the condition. Well-structured treatment plans, drawing on existing guidelines,

should be used in clinical practice to apply CM for depression, including applicable

conditions, standards, and procedures.

• Third, in terms of early optimised treatments, customising treatment to the individual

patient may achieve the best possible outcomes.(520) Successful management for

depression needs to develop a personalised treatment plan.(521) This project reveals

patients have preference on using integrative medicine for depression and there is room

for improvement of communication between doctors and patients. A collaborative

approach between patients and doctors is necessary to develop and follow the treatment

plan to achieve treatment goals, referring to discussing and deciding together how to

best improve symptoms and recover function.(520)

Implications for future research

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Despite the common use of several herbs in classical literature and clinical studies (see

Chapters 4 to 5), relevant preclinical studies were limited. Future experimental studies are needed to further explore the mechanisms of the antidepressant actions of the herbal medicines, which would lead to optimised treatment and possibly new therapeutic agents. Combining the modern molecular medicine with CHM, it not only provides an opportunity to scientifically explore the benefits and risks of the use of CHM, but also promotes the development of novel antidepressant agents.(204)

Limited high-quality clinical evidence is a major issue that exists in the field of CM research.(60, 522) To achieve high certainty of evidence on CM for depression, rigorous methodology is required for future clinical studies, including clearly stated methods of sequence generation and allocation concealment. Future clinical trials should be registered and publish relevant protocols, which could minimise bias in reporting research findings as well as improving transparency. When designing clinical trials, cause, severity and medical history of the condition should be taken into consideration. Including participants with similar features, in terms of etiology, age range and severity, may help to achieve more reliable and comparable results. Assessing more clinically relevant outcomes would provide a comprehensive understanding of the efficacy and safety of CM, such as relapse and remission of depression, quality of life, functional capacity and suicidality. Future studies should follow the items

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required by the CONSORT,(320) providing high-level clinical evidence and benefiting clinical practice.

A long-term treatment plan is beneficial for patients with depression to reduce relapse or recurrence and ensure they return to pre-illness founctioning.(520) However, long-term evidence of CM for depression needs to be further evaluated in future, which may further identify precise CM treatments for depression in the long-term management.

Importantly, future clinical trials need to answer clinical questions that incorporate CM theory whereby the results can be translated into clinical practice. Furthermore, there is no evidence of patient values being used in CM clinical guidelines. Future studies should also consider patient values as outcome measures in CM clinical trials, guideline development, combining quantitative and qualitative research methods, and assessing the quality of evidence on patient values.

The interviewed doctors were introduced to the new research results to explore their perceptions of the new knowledge and intentions of updating their clinical practice. Further studies could explore the results of using this new knowledge by a series of qualitative or quantitative research studies. Also, participants acknowledged the treatment of integrative medicine for depression, thus further relevant research should be conducted to confirm its efficacy and safety.

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Conclusion

This project provided a complete evaluation of EBM elements including evidence from historical CM literature, contemporary clinical literature, patient experience and expectations of using CM for depression, and clinical expertise from doctors on CM for depression. There is a vast array of evidence from clinical trials and historical books (a key resource for CM) but it does not fully address clinical questions and cannot be directly used during clinical decision- making.

Findings from the survey reveal that patients with depression believed CM was effective and they experienced relatively fewer adverse effects. Based on beliefs and experience, they chose to continue using CM and preferred to use integrative medicine for their condition. They also expected to communicate with doctors about the use of CM as well as learning about doctors’ experience. Understanding patient experience and expectations can help doctors formulate optimal treatments and communicate with their patients. Findings from the interviews show that doctors acknowledged the potential benefits and safety of CM for depression based on the evidence presented to them, but still acknowledged gaps in terms of their ability to directly implement changes in clinical practice. There was mutual acknowledgment from doctors and patients that communication is important during the decision-making process, but it is currently not optimal. Addressing these issues will improve clinical decision-making and health practice of CM for depression.

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References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-V). 5th ed. Arlington, VA: American Psychiatric Association; 2013.

2. Shahrokh NC, Hales RE, Phillips KA, Yudofsky SC. The Language of Mental health: A Glossary of Psychiatric Terms. Washington, DC: American Psychiatric Publishing; 2011.

3. Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382(9904):1575-86.

4. Andrade L, Caraveo-Anduaga JJ, Berglund P, Bijl RV, De Graaf R, Vollebergh W, et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric Epidemiology (ICPE) Surveys. International journal of methods in psychiatric research. 2003;12(1):3-21.

5. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;349(9064):1498-504.

6. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability- adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2197-223.

7. Kessler RC, Ormel J, Petukhova M, McLaughlin KA, Green JG, Russo LJ, et al. Development of lifetime comorbidity in the World Health Organization world mental health surveys. Archives of general psychiatry. 2011;68(1):90-100.

8. Berk M, Sarris J, Coulson CE, Jacka FN. Lifestyle management of unipolar depression. Acta psychiatrica Scandinavica Supplementum. 2013(443):38-54.

9. Arroll B, Elley CR, Fishman T, Goodyear-Smith FA, Kenealy T, Blashki G, et al. Antidepressants versus placebo for depression in primary care. The Cochrane database of systematic reviews. 2009(3):Cd007954.

10. Simon GE. Evidence review: efficacy and effectiveness of antidepressant treatment in primary care. General hospital psychiatry. 2002;24(4):213-24.

300

11. Cleare A, Pariante CM, Young AH, Anderson IM, Christmas D, Cowen PJ, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines. Journal of psychopharmacology (Oxford, England). 2015;29(5):459-525.

12. Jakobsen JC, Katakam KK, Schou A, Hellmuth SG, Stallknecht SE, Leth-Møller K, et al. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC psychiatry. 2017;17(1):58.

13. Uher R, Farmer A, Henigsberg N, Rietschel M, Mors O, Maier W, et al. Adverse reactions to antidepressants. Br J Psychiatry. 2018;195(3):202-10.

14. Anderson IM, Nutt DJ, Deakin JF. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. British Association for Psychopharmacology. Journal of psychopharmacology (Oxford, England). 2000;14(1):3-20.

15. National Collaborating Centre for Mental Health (UK). National Institute for Health and Clinical Excellence: Guidance: Depression in Adults with a Chronic Physical Health Problem: Treatment and Management. Leicester, UK: British Psychological Society; 2010.

16. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. Washington, DC: American Psychiatric Association; 2010.

17. Serna MC, Real J, Cruz I, Galvan L, Martin E. Monitoring patients on chronic treatment with antidepressants between 2003 and 2011: analysis of factors associated with compliance. BMC public health. 2015;15:1184.

18. Cantrell CR, Eaddy MT, Shah MB, Regan TS, Sokol MC. Methods for evaluating patient adherence to antidepressant therapy: a real-world comparison of adherence and economic outcomes. Medical care. 2006;44(4):300-3.

19. Demyttenaere K. Risk factors and predictors of compliance in depression. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2003;13 Suppl 3:S69-75.

20. Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet. 2003;361(9358):653-61.

301

21. Qureshi NA, Al-Bedah AM. Mood disorders and complementary and alternative medicine: a literature review. Neuropsychiatric disease and treatment. 2013;9:639-58.

22. Wang Y, Shi YH, Xu Z, Fu H, Zeng H, Zheng GQ. Efficacy and safety of Chinese herbal medicine for depression: A systematic review and meta-analysis of randomized controlled trials. Journal of psychiatric research. 2019;117:74-91.

23. Smith CA, Armour M, Lee MS, Wang LQ, Hay PJ. Acupuncture for depression. The Cochrane database of systematic reviews. 2018;3:Cd004046.

24. Liu J, Fang Y, Yang L, Qin X, Du G, Gao X. A qualitative, and quantitative determination and pharmacokinetic study of four polyacetylenes from Radix Bupleuri by UPLC-PDA-MS. Journal of pharmaceutical and biomedical analysis. 2015;111:257-65.

25. Parker S, May B, Zhang C, Zhang AL, Lu C, Xue CC. A Pharmacological Review of Bioactive Constituents of Paeonia lactiflora Pallas and Paeonia veitchii Lynch. Phytotherapy research : PTR. 2016;30(9):1445-73.

26. Wang Y, Gao SM, Li R, Zhang M, Gao S, Yu CQ. Antidepressant-like effects of the Radix Bupleuri and Radix Paeoniae Alba drug pair. Neuroscience letters. 2016;633:14-20.

27. Wang YL, Wang JX, Hu XX, Chen L, Qiu ZK, Zhao N, et al. Antidepressant-like effects of albiflorin extracted from Radix paeoniae Alba. Journal of ethnopharmacology. 2016;179:9-15.

28. Lee BH, Ku JY, Zhao RJ, Kim HY, Yang CH, Gwak YS, et al. Acupuncture at HT7 suppresses morphine self-administration at high dose through GABA system. Neuroscience letters. 2014;576:34-9.

29. Shao RH, Jin SY, Lu J, Hu L, Tu Y. [Effect of Acupuncture Intervention on Expression of NF-kappaB Signal Pathway in the Hippocampus of Chronic Stress-induced Depression Rats]. Zhen ci yan jiu = Acupuncture research. 2015;40(5):368-72.

30. Xu MM, Zhang DM, Shi RX, Zhang XH, Wang Y, Yu M, et al. [Effect of Electroacupuncture Intervention on Behavior Changes and Levels of Hippocampal Transforming Growth Factor beta 3 and Basic Fibroblast Growth Factor Proteins in Depression Rats]. Zhen ci yan jiu = Acupuncture research. 2016;41(2):138-43.

31. Shi RX, Ding HT, Li H, Yu ZG, Wu JM, Tang XZ. [Effect of Acupuncture Stimulation of Different Acupoint Groups on Levels of Stress Hormones and Serum Brain- derived Neurotrophic Factor in Depression Rats]. Zhen ci yan jiu = Acupuncture research. 2015;40(6):444-8.

302

32. Lam TP. Strengths and weaknesses of traditional Chinese medicine and Western medicine in the eyes of some Hong Kong Chinese. Journal of Epidemiology and Community Health. 2001;55(10):762.

33. Dong J. The Relationship between Traditional Chinese Medicine and Modern Medicine. Evidence-Based Complementary and Alternative Medicine. 2013;2013:10.

34. Needham J, Yates RDS. Science and Civilisation in China: Volume 5, Chemistry and Chemical Technology, Part 6, Military Technology: Missiles and Sieges. Cambridge: Cambridge University Press; 1995.

35. Jun JH, Choi TY, Lee JA, Yun KJ, Lee MS. Herbal medicine (Gan Mai Da Zao decoction) for depression: a systematic review and meta-analysis of randomized controlled trials. Maturitas. 2014;79(4):370-80.

36. Peng L, Zhang X, Kang DY, Liu XT, Hong Q. Effectiveness and safety of Wuling capsule for post stroke depression: a systematic review. Complementary therapies in medicine. 2014;22(3):549-66.

37. Sun Y, Xu X, Zhang J, Chen Y. Treatment of depression with Chai Hu Shu Gan San: a systematic review and meta-analysis of 42 randomized controlled trials. BMC complementary and alternative medicine. 2018;18(1):66.

38. Yeung WF, Chung KF, Ng KY, Yu YM, Ziea ET, Ng BF. A meta-analysis of the efficacy and safety of traditional Chinese medicine formula Ganmai Dazao decoction for depression. Journal of ethnopharmacology. 2014;153(2):309-17.

39. Yeung WF, Chung KF, Ng KY, Yu YM, Ziea ET, Ng BF. A systematic review on the efficacy, safety and types of Chinese herbal medicine for depression. Journal of psychiatric research. 2014;57:165-75.

40. Zhao H, Wan X, Chen JX. A mini review of traditional Chinese medicine for the treatment of depression in China. The American journal of Chinese medicine. 2009;37(2):207-13.

41. Chan YYL, W. Y.Yang, S. N.Chen, Y. H.Lin, J. G. The benefit of combined acupuncture and antidepressant medication for depression: A systematic review and meta- analysis. Journal of affective disorders. 2015;176:106-17.

42. Zhang Y, Qu SS, Zhang JP, Sun YL, Liu WL, Xie L, et al. Rapid Onset of the Effects of Combined Selective Serotonin Reuptake Inhibitors and Electroacupuncture on Primary

303

Depression: A Meta-Analysis. Journal of alternative and complementary medicine (New York, NY). 2016;22(1):1-8.

43. Veziari Y, Leach MJ, Kumar S. Barriers to the conduct and application of research in complementary and alternative medicine: a systematic review. BMC Complement Altern Med. 2017;17(1):166.

44. Straus SE, Tetroe J, Graham I. Defining knowledge translation. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2009;181(3- 4):165-8.

45. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019): Cochrane; 2019. Available from: www.training.cochrane.org/handbook.

46. Guyatt G, Cairns J, Churchill D, Cook D, Haynes B, Hirsh J, et al. Evidence-Based Medicine: A New Approach to Teaching the Practice of Medicine. Jama. 1992;268(17):2420- 5.

47. Masic I, Miokovic M, Muhamedagic B. Evidence based medicine - new approaches and challenges. Acta Inform Med. 2008;16(4):219-25.

48. Djulbegovic B, Guyatt GH. Progress in evidence-based medicine: a quarter century on. Lancet. 2017;390(10092):415-23.

49. Mellis C. Evidence-based medicine: what has happened in the past 50 years? Journal of paediatrics and child health. 2015;51(1):65-8.

50. Sackett DL. Evidence-based medicine. Seminars in Perinatology. 1997;21(1):3-5.

51. Sackett DL, Rosenberg WMC, Gray JAM, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn't. BMJ (Clinical research ed). 1996;312(7023):71.

52. Montori V, Devereaux P, Straus S, et al. Advanced topics in moving from evidence to action: decision making and the patient. In: Gordon H. Guyatt, Drummond Rennie, Maureen O. Meade, Deborah J. Cook, editors. Users’ Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice. New York, NY: American Medical Association; 2008.

53. Szajewska H. Evidence-Based Medicine and Clinical Research: Both Are Needed, Neither Is Perfect. Annals of nutrition & metabolism. 2018;72 Suppl 3:13-23.

304

54. Chene G, Wittkop L, Saves M. Evidence-based medicine: basic principles. La Revue du praticien. 2017;67(8):903-7.

55. Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest. 1989;95 (2 Suppl ):2s-4s.

56. Eddy DM, Billings J. The quality of medical evidence: implications for quality of care. Health affairs (Project Hope). 1988;7(1):19-32.

57. Archie Cochrane. Effectiveness and efficiency: random reflections on health services. London: Nuffield Provincial Hospitals Trust; 1972.

58. Lee CM, Hunsley J. Evidence-Based Practice: Separating Science From Pseudoscience. Canadian journal of psychiatry Revue canadienne de psychiatrie. 2015;60(12):534-40.

59. National Center for Complementary and Integrative Health. Traditional Chinese Medicine: What You Need To Know [Internet]. 2019 [updated 2013 Oct; cited 2019 Nov 16]. Available from: https://nccih.nih.gov/health/whatiscam/chinesemed.htm.

60. Fung FY, Linn YC. Developing traditional chinese medicine in the era of evidence- based medicine: current evidences and challenges. Evidence-based complementary and alternative medicine : eCAM. 2015;2015:425037.

61. Vase L, Baram S, Takakura N, Takayama M, Yajima H, Kawase A, et al. Can acupuncture treatment be double-blinded? An evaluation of double-blind acupuncture treatment of postoperative pain. PloS one. 2015;10(3):e0119612.

62. Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schunemann HJ. What is "quality of evidence" and why is it important to clinicians? BMJ (Clinical research ed). 2008;336(7651):995-8.

63. Burns PB, Rohrich RJ, Chung KC. The levels of evidence and their role in evidence- based medicine. Plastic and reconstructive surgery. 2011;128(1):305-10.

64. Guyatt GH, Sackett DL, Sinclair JC, Hayward R, Cook DJ, Cook RJ. Users' guides to the medical literature. IX. A method for grading health care recommendations. Evidence- Based Medicine Working Group. Jama. 1995;274(22):1800-4.

65. OCEBM Levels of Evidence Working Group. The Oxford 2011 Levels of Evidence [Internet]. Oxford Centre for Evidence-Based Medicine; [cited 2019 Nov 16]. Available from: http://www.cebm.net/index.aspx?o=5653.

305

66. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. Grading quality of evidence and strength of recommendations. BMJ (Clinical research ed). 2004;328(7454):1490.

67. Akobeng AK. Understanding randomised controlled trials. Archives of Disease in Childhood. 2005;90(8):840.

68. Chalmers I. Addressing uncertainties about the effects of treatments offered to NHS patients: whose responsibility? J R Soc Med. 2007;100(10):440-1.

69. Chalmers I. The Cochrane collaboration: preparing, maintaining, and disseminating systematic reviews of the effects of health care. Annals of the New York Academy of Sciences. 1993;703:156-63; discussion 63-5.

70. Cochrane Collaboration. About Us [Internet]. 2016 [cited 2019 Oct 11]. Available from: http://www.cochrane.org/about-us

71. Young C, Horton R. Putting clinical trials into context. Lancet. 2005;366(9480):107- 8.

72. Agoritsas T, Heen AF, Brandt L, Alonso-Coello P, Kristiansen A, Akl EA, et al. Decision aids that really promote shared decision making: the pace quickens. BMJ : British Medical Journal. 2015;350:g7624.

73. Haines T, McKnight L, Duku E, Perry L, Thoma A. The role of systematic reviews in clinical research and practice. Clinics in plastic surgery. 2008;35(2):207-14.

74. Kalra R, Arora P, Morgan C, Hage FG, Iskandrian AE, Bajaj NS. Conducting and interpreting high-quality systematic reviews and meta-analyses. Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 2017;24(2):471-81.

75. McKenzie JE, Beller EM, Forbes AB. Introduction to systematic reviews and meta- analysis. Respirology (Carlton, Vic). 2016;21(4):626-37.

76. Uetani K, Nakayama T, Ikai H, Yonemoto N, Moher D. Quality of reports on randomized controlled trials conducted in Japan: evaluation of adherence to the CONSORT statement. Internal medicine (Tokyo, Japan). 2009;48(5):307-13.

77. Greenhalgh T, Howick J, Maskrey N, Evidence Based Medicine Renaissance G. Evidence based medicine: a movement in crisis? BMJ (Clinical research ed). 2014;348:g3725-g.

306

78. Straus SE, McAlister FA. Evidence-based medicine: a commentary on common criticisms. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2000;163(7):837-41.

79. Rawlins M. De Testimonio: on the evidence for decisions about the use of therapeutic interventions. Clinical medicine (London, England). 2008;8(6):579-88.

80. K W M Fulford, Heidi Carroll, Ed Peile. Essential values-based practice: clinical stories linking science with people. Cambridge Cambridge University Press; 2012.

81. Peile E. Evidence-based medicine and values-based medicine: partners in clinical education as well as in clinical practice. BMC medicine. 2013;11:40.

82. Arthur W F. Just Listening: Narrative and Deep Illness. Families, Systems & Health. 1998;16(3):197-212.

83. TF. R, VM. M, VF M, F. G, FF G, PF. L, et al. Let the patient revolution begin. BMJ (Clinical research ed). 2013(346):f2614.

84. Gierisch JM, Myers ER, Schmit KM, McCrory DC, Coeytaux RR, Crowley MJ, et al. Prioritization of patient-centered comparative effectiveness research for osteoarthritis. Annals of internal medicine. 2014;160(12):836-41.

85. National Clinical Guideline Centre (UK). National Institute for Health and Clinical Excellence: Guidance: Psoriasis: Assessment and Management of Psoriasis. London, UK: Royal College of Physicians (UK); 2012.

86. Haynes RB, Devereaux PJ, Guyatt GH. Clinical expertise in the era of evidence-based medicine and patient choice. ACP journal club. 2002;136(2):A11-4.

87. De Alencastro L, Clair C, Locatelli I, Ebell MH, Senn N. Clinical decision making : from theory to practice... and backward. Revue medicale suisse. 2017;13(562):986-9.

88. Tiffen J, Corbridge SJ, Slimmer L. Enhancing Clinical Decision Making: Development of a Contiguous Definition and Conceptual Framework. Journal of Professional Nursing. 2014;30(5):399-405.

89. Wieten S. Expertise in evidence-based medicine: a tale of three models. Philosophy, Ethics, and Humanities in Medicine. 2018;13(1):2.

90. Jones K. Evidence Based Medicine—How to Practice and Teach EBM. BMJ (Clinical research ed). 1996;313(7069):1410.

307

91. Woolf SH, Atkins D. The evolving role of prevention in health care: contributions of the U.S. Preventive Services Task Force. American journal of preventive medicine. 2001;20(3 Suppl):13-20.

92. APA Presidential Task Force on Evidence-Based Practice. Evidence-based practice in psychology. The American psychologist. 2006;61(4):271-85.

93. Weersing VR, Jeffreys M, Do MT, Schwartz KT, Bolano C. Evidence Base Update of Psychosocial Treatments for Child and Adolescent Depression. Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53. 2017;46(1):11-43.

94. Barbui C, Purgato M, Churchill R, Adams CE, Amato L, Macdonald G, et al. Evidence‐based interventions for global mental health: role and mission of a new Cochrane initiative. Cochrane Database of Systematic Reviews. 2017(4):ED000120.

95. Dua T, Barbui C, Clark N, Fleischmann A, Poznyak V, van Ommeren M, et al. Evidence-based guidelines for mental, neurological, and substance use disorders in low- and middle-income countries: summary of WHO recommendations. PLoS medicine. 2011;8(11):e1001122.

96. Barbui C, Dua T, Harper M, Tablante EC, Thornicroft G, Saxena S. Using GRADE to update WHO recommendations for MNS. The lancet Psychiatry. 2015;2(12):1054-6.

97. Dua T, Barbui C, Patel AA, Tablante EC, Thornicroft G, Saxena S. Discussion of the updated WHO recommendations for mental, neurological, and substance use disorders. The lancet Psychiatry. 2016;3(11):1008-12.

98. Saxena S, Funk MK, Chisholm D. Comprehensive mental health action plan 2013- 2020. Eastern Mediterranean health journal = La revue de sante de la Mediterranee orientale = al-Majallah al-sihhiyah li-sharq al-mutawassit. 2015;21(7):461-3.

99. Li Y, Wu T, Shang H, Yang K. Strategies for promoting the development of evidence-based medicine in China. Journal of evidence-based medicine. 2009;2(1):47-52.

100. Chen H, Wang Y, Jiang WB, Kwong JSW, Gu YH. The evidence system of traditional Chinese medicine based on the Grades of Recommendations Assessment, Development and Evaluation framework. Annals of translational medicine. 2017;5(21):435.

101. Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nature medicine. 2011;17(10):1217-20.

308

102. Tu Y. Artemisinin-A Gift from Traditional Chinese Medicine to the World (Nobel Lecture). Angewandte Chemie (International ed in English). 2016;55(35):10210-26.

103. Buenz EJ, Schnepple DJ, Bauer BA, Elkin PL, Riddle JM, Motley TJ. Techniques: Bioprospecting historical herbal texts by hunting for new leads in old tomes. Trends in pharmacological sciences. 2004;25(9):494-8.

104. Sadeghi-Bazargani H, Tabrizi JS, Azami-Aghdash S. Barriers to evidence-based medicine: a systematic review. Journal of evaluation in clinical practice. 2014;20(6):793-802.

105. Windle PE. Moving beyond the barriers for evidence-based practice implementation. Journal of perianesthesia nursing : official journal of the American Society of PeriAnesthesia Nurses. 2006;21(3):208-11.

106. Pagoto SL, Spring B, Coups EJ, Mulvaney S, Coutu MF, Ozakinci G. Barriers and facilitators of evidence-based practice perceived by behavioral science health professionals. Journal of clinical psychology. 2007;63(7):695-705.

107. Pereira F, Salvi M, Verloo H. Beliefs, Knowledge, Implementation, and Integration of Evidence-Based Practice Among Primary Health Care Providers: Protocol for a Scoping Review. JMIR research protocols. 2017;6(8):e148.

108. Weiss CH. Why do we fail to deliver evidence-based practice in critical care medicine? Current opinion in critical care. 2017;23(5):400-5.

109. Lang ES, Wyer PC, Haynes RB. Knowledge translation: closing the evidence-to- practice gap. Annals of emergency medicine. 2007;49(3):355-63.

110. Nutbeam D, Milat AJ. Knowledge translation: evidence into action. Public health research & practice. 2017;27(1):e2711700.

111. Graham ID, Logan J, Harrison MB, Straus SE, Tetroe J, Caswell W, et al. Lost in knowledge translation: time for a map? The Journal of continuing education in the health professions. 2006;26(1):13-24.

112. Berle C, Cobbin D, Smith N, Zaslawski C. An innovative method to accommodate Chinese medicine pattern diagnosis within the framework of evidence-based medical research. Chinese journal of integrative medicine. 2011;17(11):824-33.

113. World Health Organization. The global burden of disease: 2004 update. Part 3: Disease incidence, prevalence and disability. Geneva, Switzerland: World Health Organization; 2004.

309

114. Belmaker RH, Agam G. Major depressive disorder. The New England journal of medicine. 2008;358(1):55-68.

115. Fava M, Kendler KS. Major depressive disorder. Neuron. 2000;28(2):335-41.

116. Mueller TI, Leon AC, Keller MB, Solomon DA, Endicott J, Coryell W, et al. Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. The American journal of psychiatry. 1999;156(7):1000-6.

117. Kessler RC, Akiskal HS, Ames M, Birnbaum H, Greenberg P, Hirschfeld RM, et al. Prevalence and effects of mood disorders on work performance in a nationally representative sample of U.S. workers. The American journal of psychiatry. 2006;163(9):1561-8.

118. Compton WM, Conway KP, Stinson FS, Grant BF. Changes in the prevalence of major depression and comorbid substance use disorders in the United States between 1991- 1992 and 2001-2002. The American journal of psychiatry. 2006;163(12):2141-7.

119. Gureje O, Kola L, Afolabi E. Epidemiology of major depressive disorder in elderly Nigerians in the Ibadan Study of Ageing: a community-based survey. Lancet. 2007;370(9591):957-64.

120. Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG, et al. Cross-national epidemiology of major depression and bipolar disorder. Jama. 1996;276(4):293-9.

121. Pedersen CB, Mors O, Bertelsen A, Waltoft BL, Agerbo E, McGrath JJ, et al. A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders. JAMA psychiatry. 2014;71(5):573-81.

122. Hasin DS, Goodwin RD, Stinson FS, Grant BF. Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Archives of general psychiatry. 2005;62(10):1097-106.

123. Williams DR, Gonzalez HM, Neighbors H, Nesse R, Abelson JM, Sweetman J, et al. Prevalence and distribution of major depressive disorder in African Americans, Caribbean blacks, and non-Hispanic whites: results from the National Survey of American Life. Archives of general psychiatry. 2007;64(3):305-15.

124. Kessler RC, Birnbaum H, Bromet E, Hwang I, Sampson N, Shahly V. Age differences in major depression: results from the National Comorbidity Survey Replication (NCS-R). Psychological medicine. 2010;40(2):225-37.

310

125. Charney DS, Reynolds CF, 3rd, Lewis L, Lebowitz BD, Sunderland T, Alexopoulos GS, et al. Depression and Bipolar Support Alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life. Archives of general psychiatry. 2003;60(7):664-72.

126. Lyness JM, Niculescu A, Tu X, Reynolds CF, 3rd, Caine ED. The relationship of medical comorbidity and depression in older, primary care patients. Psychosomatics. 2006;47(5):435-9.

127. Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJ, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS medicine. 2013;10(11):e1001547.

128. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS medicine. 2006;3(11):e442.

129. World Health Organisation. Global Health Estimates 2014 Summary Tables: DALY by cause, age and sex, by WHO Region, 2000-2012. Geneva, Switzerland: World Health Organisation; 2014.

130. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). Jama. 2003;289(23):3095-105.

131. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. 2007;370(9590):851-8.

132. Kamenov K, Caballero FF, Miret M, Leonardi M, Sainio P, Tobiasz-Adamczyk B, et al. Which Are the Most Burdensome Functioning Areas in Depression? A Cross-National Study. Frontiers in Psychology. 2016;7:1342.

133. IsHak WW, Mirocha J, James D, Tobia G, Vilhauer J, Fakhry H, et al. Quality of life in major depressive disorder before/after multiple steps of treatment and one-year follow-up. Acta psychiatrica Scandinavica. 2015;131(1):51-60.

134. Hawton K, van Heeringen K. Suicide. Lancet. 2009;373(9672):1372-81.

135. Angst F, Stassen HH, Clayton PJ, Angst J. Mortality of patients with mood disorders: follow-up over 34-38 years. Journal of affective disorders. 2002;68(2-3):167-81.

311

136. Fogel J, Eaton WW, Ford DE. Minor depression as a predictor of the first onset of major depressive disorder over a 15-year follow-up. Acta psychiatrica Scandinavica. 2006;113(1):36-43.

137. Hawton K, Casañas ICC, Haw C, Saunders K. Risk factors for suicide in individuals with depression: a systematic review. Journal of affective disorders. 2013;147(1-3):17-28.

138. Andlin-Sobocki P, Jonsson B, Wittchen HU, Olesen J. Cost of disorders of the brain in Europe. European journal of neurology. 2005;12 Suppl 1:1-27.

139. Smit F, Shields L, Petrea I. Preventing Depression In the WHO European Region. Denmark: WHO Regional Office for Europe; 2016.

140. World Health Organisation. WHO China Office Fact Sheet: Depression. Geneva, Switzerland: World Health Organisation; 2017.

141. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: review and meta-analysis. The American journal of psychiatry. 2000;157(10):1552-62.

142. Weissman MM, Berry OO, Warner V, Gameroff MJ, Skipper J, Talati A, et al. A 30- Year Study of 3 Generations at High Risk and Low Risk for Depression. JAMA psychiatry. 2016;73(9):970-7.

143. Hasler G. Pathophysiology of depression: do we have any solid evidence of interest to clinicians? World psychiatry : official journal of the World Psychiatric Association (WPA). 2010;9(3):155-61.

144. Kendler KS, Gardner CO, Prescott CA. Toward a comprehensive developmental model for major depression in men. The American journal of psychiatry. 2006;163(1):115- 24.

145. Kendler KS, Sheth K, Gardner CO, Prescott CA. Childhood parental loss and risk for first-onset of major depression and alcohol dependence: the time-decay of risk and sex differences. Psychological medicine. 2002;32(7):1187-94.

146. Kupfer DJ, Frank E, Phillips ML. Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet. 2012;379(9820):1045-55.

147. Power RA, Tansey KE, Buttenschon HN, Cohen-Woods S, Bigdeli T, Hall LS, et al. Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Biological psychiatry. 2017;81(4):325-35.

312

148. Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science (New York, NY). 2006;311(5762):864-8.

149. Drevets WC. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Current opinion in neurobiology. 2001;11(2):240-9.

150. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nature medicine. 2001;7(5):541-7.

151. Chirita AL, Gheorman V, Bondari D, Rogoveanu I. Current understanding of the neurobiology of major depressive disorder. Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie. 2015;56(2 Suppl):651-8.

152. Hamon M, Blier P. Monoamine neurocircuitry in depression and strategies for new treatments. Progress in neuro-psychopharmacology & biological psychiatry. 2013;45:54-63.

153. Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. The Journal of clinical psychiatry. 2008;69 Suppl E1:4-7.

154. aan het Rot M, Mathew SJ, Charney DS. Neurobiological mechanisms in major depressive disorder. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2009;180(3):305-13.

155. Kraus C, Castrén E, Kasper S, Lanzenberger R. Serotonin and neuroplasticity - Links between molecular, functional and structural pathophysiology in depression. Neurosci Biobehav Rev. 2017;77:317-26.

156. Tiger M, Varnäs K, Okubo Y, Lundberg J. The 5-HT(1B) receptor - a potential target for antidepressant treatment. Psychopharmacology (Berl). 2018;235(5):1317-34.

157. Phillips C. Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection. Neural Plast. 2017;2017:7260130.

158. Koo JW, Chaudhury D, Han MH, Nestler EJ. Role of Mesolimbic Brain-Derived Neurotrophic Factor in Depression. Biological psychiatry. 2019;86(10):738-48.

159. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. Journal of psychosomatic research. 2002;53(4):865-71.

313

160. Beckman G, Beckman L, Cedergren B, Perris C, Strandman E. Serum protein and red cell enzyme polymorphisms in affective disorders. Human heredity. 1978;28(1):41-7.

161. Ebmeier KP, Donaghey C, Steele JD. Recent developments and current controversies in depression. Lancet. 2006;367(9505):153-67.

162. Shadrina M, Bondarenko EA, Slominsky PA. Genetics Factors in Major Depression Disease. Frontiers in psychiatry. 2018;9:334.

163. Hardeveld F, Spijker J, De Graaf R, Hendriks SM, Licht CM, Nolen WA, et al. Recurrence of major depressive disorder across different treatment settings: results from the NESDA study. Journal of affective disorders. 2013;147(1-3):225-31.

164. World Health Organization. International Statistical Classification of Diseases and Related Health Problems (ICD-10). Geneva, Switzerland: World Health Organization; 1992.

165. Anderson IM, Ferrier IN, Baldwin RC, Cowen PJ, Howard L, Lewis G, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. Journal of psychopharmacology (Oxford, England). 2008;22(4):343-96.

166. Simon G. Unipolar major depression in adults: Choosing initial treatment: Uptodate; 2019 [updated Nov 13, 2019; cited 2020 July 22].

167. Lyness JM. Unipolar minor depression in adults: Management: Uptodate; 2020 [updated Apr 26, 2020; cited 2020 July 22]. Available from: https://www.uptodate.com/contents/unipolar-minor-depression-in-adults- management?search=depression%20management&source=search_result&selectedTitle=4~15 0&usage_type=default&display_rank=4.

168. McLachlan G. Treatment resistant depression: what are the options? BMJ (Clinical research ed). 2018;363:k5354.

169. Gartlehner G, Gaynes B, Amick H, Asher G, Morgan LC, Coker-Schwimmer M, et al. Nonpharmacological Versus Pharmacological Treatments for Adult Patients With Major Depressive Disorder: RTI International-University of North Carolina Evidence-based Practice Cener; 2015.

170. Cohen ZD, DeRubeis RJ. Treatment Selection in Depression. Annu Rev Clin Psychol. 2018;14:209-36.

314

171. Sarris J, O'Neil A, Coulson CE, Schweitzer I, Berk M. Lifestyle medicine for depression. BMC psychiatry. 2014;14:107.

172. Lumsden MA. The NICE Guideline - Menopause: diagnosis and management. Climacteric : the journal of the International Menopause Society. 2016;19(5):426-9.

173. Farah WH, Alsawas M, Mainou M, Alahdab F, Farah MH, Ahmed AT, et al. Non- pharmacological treatment of depression: a systematic review and evidence map. Evid Based Med. 2016;21(6):214-21.

174. Lampe L, Coulston CM, Berk L. Psychological management of unipolar depression. Acta psychiatrica Scandinavica Supplementum. 2013(443):24-37.

175. National Collaborating Centre for Mental Health (UK). National Institute for Health and Clinical Excellence: Guidance: Depression: The Treatment and Management of Depression in Adults (Updated Edition). Leicester, UK: British Psychological Society; 2010.

176. Cuijpers P, Reynolds CF, 3rd, Donker T, Li J, Andersson G, Beekman A. Personalized treatment of adult depression: medication, psychotherapy, or both? A systematic review. Depression and anxiety. 2012;29(10):855-64.

177. Weiner RD, Reti IM. Key updates in the clinical application of electroconvulsive therapy. Int Rev Psychiatry. 2017;29(2):54-62.

178. Ellis P. Australian and New Zealand clinical practice guidelines for the treatment of depression. The Australian and New Zealand journal of psychiatry. 2004;38(6):389-407.

179. Qaseem A, Barry MJ, Kansagara D. Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of Physicians. Annals of internal medicine. 2016;164(5):350-9.

180. China Association of Chinese Medicine. [Guidelines for Diagnosis and Treatment of Common Internal Diseases in Chinese Medicine Symptoms in Chinese Medicine]. Beijing, China: China Press of Traditional Chinese Medicine; 2008.

181. Butler L, Pilkington K. Chinese herbal medicine and depression: the research evidence. Evidence-based complementary and alternative medicine : eCAM. 2013;2013:739716.

182. Li YH, Zhang CH, Qiu J, Wang SE, Hu SY, Huang X, et al. Antidepressant-like effects of Chaihu-Shugan-San via SAPK/JNK signal transduction in rat models of depression. Pharmacognosy magazine. 2014;10(39):271-7.

315

183. Wang Y, Li M, Liang Y, Yang Y, Liu Z, Yao K, et al. Chinese Herbal Medicine for the Treatment of Depression: Applications, Efficacies and Mechanisms. Current pharmaceutical design. 2017;23(34):5180-90.

184. Lam RW, McIntosh D, Wang J, Enns MW, Kolivakis T, Michalak EE, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 1. Disease Burden and Principles of Care. Canadian journal of psychiatry Revue canadienne de psychiatrie. 2016;61(9):510-23.

185. Lu AP, Jia HW, Xiao C, Lu QP. Theory of traditional Chinese medicine and therapeutic method of diseases. World J Gastroenterol. 2004;10(13):1854-6.

186. Hu J, Zhang J, Zhao W, Zhang Y, Zhang L, Shang H. Cochrane systematic reviews of Chinese herbal medicines: an overview. PloS one. 2011;6(12):e28696.

187. Kong DX, Li XJ, Zhang HY. Where is the hope for drug discovery? Let history tell the future. Drug discovery today. 2009;14(3-4):115-9.

188. May BH, Lu C, Bennett L, Hugel HM, Xue CC. Evaluating the traditional Chinese literature for herbal formulae and individual herbs used for age-related dementia and memory impairment. Biogerontology. 2012;13(3):299-312.

189. May BH, Lu C, Xue CC. Collections of traditional Chinese medical literature as resources for systematic searches. Journal of alternative and complementary medicine (New York, NY). 2012;18(12):1101-7.

190. May BH, Zhang A, Lu Y, Lu C, Xue CC. The systematic assessment of traditional evidence from the premodern Chinese medical literature: a text-mining approach. Journal of alternative and complementary medicine (New York, NY). 2014;20(12):937-42.

191. Zhou Z. [Internal Medicine of Traditional Chinese Medicine]. Beijing, China: China Press of Traditional Chinese Medicine; 2007.

192. China Academy of Chinese Medical Sciences. [Evidence-based Guidelines of Clinical Practice in Chinese Medicine: Internal Medicine]. Beijing, China: China Press of Traditional Chinese Medicine 2011.

193. Chinese Society of Psychiatry. [Interpretation of drug therapy of Chinese Guidelines for Prevention and Treatment of Depression]. 2nd ed. Beijing, China: Chinese Medical Multimedia Press; 2015.

316

194. Dong X. [Psychology of Traditional Chinese Medicine]. Beijing, China: People's Medical Publishing House; 2007.

195. Zhao Y, Cai D. [Psychopathology of traditional Chinese Medicine]. Shanghai, China: Shanghai pujiang education press; 2009.

196. Tang Q. [Depression Fundamental and Clinical Research of Chinese and Western Medicine]. Beijing, China: People's Medical Publishing House; 2009.

197. Huang P, Huang Y. [Clinical diagnosis and treatment of Neurological Diseases in Traditional Chinese Medicine]. 3rd ed. Beijing, China: People's Medical Publishing House; 2013.

198. China Association of Chinese Medicine. [Zhong Hua Yi Dian ‘Encyclopaedia of Traditional Chinese Medicine’]. 4 ed ed. Changsha, China: Hunan Electronic and Audio- Visual Publishing House; 2000.

199. May BH, Lu Y, Lu C, Zhang AL, Chang S, Xue CC. Systematic assessment of the representativeness of published collections of the traditional literature on Chinese medicine. Journal of alternative and complementary medicine (New York, NY). 2013;19(5):403-9.

200. Viguera AC, Tondo L, Koukopoulos AE, Reginaldi D, Lepri B, Baldessarini RJ. Episodes of mood disorders in 2,252 pregnancies and postpartum periods. The American journal of psychiatry. 2011;168(11):1179-85.

201. Bensky D, Clavey S, Stoger E. Chinese herbal medicine: Materia medica. 3rd ed. Seattle: Eastland Press; 2004.

202. Scheid V, Bensky D, Ellis A, R. B. Chinese Herbal Medicine: Formulas & Strategies. 2nd ed. Seattle: Eastland Press; 2009.

203. Sheng CX, Chen ZQ, Cui HJ, Yang AL, Wang C, Wang Z, et al. Is the Chinese medicinal formula Guipi Decoction effective as an adjunctive treatment for depression? A meta-analysis of randomized controlled trials. Chinese journal of integrative medicine. 2017;23(5):386-95.

204. Zhang YW, Cheng YC. Challenge and Prospect of Traditional Chinese Medicine in Depression Treatment. Frontiers in neuroscience. 2019;13:190.

205. Jakobsen JC, Katakam KK, Schou A, Hellmuth SG, Stallknecht SE, Leth-Moller K, et al. Selective serotonin reuptake inhibitors versus placebo in patients with major depressive

317

disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC psychiatry. 2017;17(1):58.

206. Badger F, Nolan P. Use of self-chosen therapies by depressed people in primary care. Journal of clinical nursing. 2007;16(7):1343-52.

207. Wu P, Fuller C, Liu X, Lee HC, Fan B, Hoven CW, et al. Use of complementary and alternative medicine among women with depression: results of a national survey. Psychiatric services (Washington, DC). 2007;58(3):349-56.

208. Kessler RC, Soukup J, Davis RB, Foster DF, Wilkey SA, Van Rompay MI, et al. The use of complementary and alternative therapies to treat anxiety and depression in the United States. The American journal of psychiatry. 2001;158(2):289-94.

209. de Jonge P, Wardenaar KJ, Hoenders HR, Evans-Lacko S, Kovess-Masfety V, Aguilar-Gaxiola S, et al. Complementary and alternative medicine contacts by persons with mental disorders in 25 countries: results from the World Mental Health Surveys. Epidemiology and psychiatric sciences. 2017;27(6):552-67.

210. Freeman MP, Fava M, Lake J, Trivedi MH, Wisner KL, Mischoulon D. Complementary and alternative medicine in major depressive disorder: the American Psychiatric Association Task Force report. The Journal of clinical psychiatry. 2010;71(6):669-81.

211. Fischer FH, Lewith G, Witt CM, Linde K, von Ammon K, Cardini F, et al. High prevalence but limited evidence in complementary and alternative medicine: guidelines for future research. BMC complementary and alternative medicine. 2014;14:46.

212. Tang J-L, Liu B-Y, Ma K-W. Traditional Chinese medicine. Lancet. 2008;372(9654):1938-40.

213. MacPherson H, Sinclair-Lian N, Thomas K. Patients seeking care from acupuncture practitioners in the UK: a national survey. Complementary therapies in medicine. 2006;14(1):20-30.

214. El-Alfy AT, Abourashed EA, Matsumoto RR. Nature against depression. Current medicinal chemistry. 2012;19(14):2229-41.

215. Iovieno N, Dalton ED, Fava M, Mischoulon D. Second-tier natural antidepressants: review and critique. Journal of affective disorders. 2011;130(3):343-57.

318

216. Chen G, Guo X. Neurobiology of Chinese Herbal Medicine on Major Depressive Disorder. International review of neurobiology. 2017;135:77-95.

217. Paul M, Leibovici L. Systematic review or meta-analysis? Their place in the evidence hierarchy. Clin Microbiol Infect. 2014;20(2):97-100.

218. Chalmers I, Dickersin K, Chalmers TC. Getting to grips with Archie Cochrane's agenda. BMJ (Clinical research ed). 1992;305(6857):786-8.

219. Askie L, Offringa M. Systematic reviews and meta-analysis. Semin Fetal Neonatal Med. 2015;20(6):403-9.

220. Delgado-Rodríguez M, Sillero-Arenas M. Systematic review and meta-analysis. Med Intensiva. 2018;42(7):444-53.

221. Ghersi D, Pang T. From Mexico to Mali: four years in the history of clinical trial registration. Journal of evidence-based medicine. 2009;2(1):1-7.

222. Salanti G. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. Research synthesis methods. 2012;3(2):80-97.

223. Page MJ, McKenzie JE, Kirkham J, Dwan K, Kramer S, Green S, et al. Bias due to selective inclusion and reporting of outcomes and analyses in systematic reviews of randomised trials of healthcare interventions. The Cochrane database of systematic reviews. 2014(10):Mr000035.

224. Yeung WF, Chung KF, Ng KY, Yu YM, Zhang SP, Ng BF, et al. Prescription of Chinese Herbal Medicine in Pattern-Based Traditional Chinese Medicine Treatment for Depression: A Systematic Review. Evidence-based complementary and alternative medicine : eCAM. 2015;2015:160189.

225. Ren Y, Zhu C, Wu J, Zheng R, Cao H. Comparison between herbal medicine and fluoxetine for depression: a systematic review of randomized controlled trials. Complementary therapies in medicine. 2015;23(5):674-84.

226. Chinese Psychiatric Association. [Chinese Classification of Mental Disorders (CCMD-3)]. 3rd ed. Jinan, People’s Republic of China: Shandong Science Technology Press; 2011.

227. National Center for Complementary and Integrative Health. St. John's Wort [Internet]. 2016 [cited 2019 Nov 16]. Available from: https://nccih.nih.gov/health/stjohnswort.

319

228. Bauer M, Severus E, Moller HJ, Young AH. Pharmacological treatment of unipolar depressive disorders: summary of WFSBP guidelines. International journal of psychiatry in clinical practice. 2017;21(3):166-76.

229. Hamilton M. A rating scale for depression. Journal of neurology, neurosurgery, and psychiatry. 1960;23:56-62.

230. Montgomery SA, Smeyatsky N, de Ruiter M, Montgomery DB. Profiles of antidepressant activity with the Montgomery-Asberg Depression Rating Scale. Acta psychiatrica Scandinavica Supplementum. 1985;320:38-42.

231. Zung WW. A Self-rating Depression Scale. Archives of general psychiatry. 1965;12:63-70.

232. American Psychiatric Association. Handbook of Psychiatric Measures. 2 ed. Washington, DC: American Psychiatric Publishing, Inc.; 2008.

233. Nelson CJ, Cho C, Berk AR, Holland J, Roth AJ. Are gold standard depression measures appropriate for use in geriatric cancer patients? A systematic evaluation of self- report depression instruments used with geriatric, cancer, and geriatric cancer samples. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(2):348-56.

234. Schünemann H BJ, Guyatt G, Oxman A, (eds.). GRADE handbook for grading quality of evidence and strength of recommendations: The GRADE Working Group; 2013 [updated 2013 Oct; cited 2019 Nov 16]. Available from: http://www.guidelinedevelopment.org/handbook/.

235. Cao AQ, Guo YL, Zhang XQ. [Treatment of Liver Stagnation and Blood Deficiency Type Depression with Chai Hu Jie Yu Tang-30 cases]. Chinese Medicine Modern Distance Education of China. 2010;8(2):23.

236. Chang YJ. [A Controlled Study of Fluoxetine plus Chinese Medicine for Depression]. Nei Mongol Journal of Traditional Chinese Medicine 2013;32(14):25-6.

237. Chen L. [The effect of Jia Wei Xiao Yao Capsules on the treatment of mild to moderate depression of the stagnation turned to fire syndrome, 62 cases]. Beijing, China: Beijing University of Chinese Medicine; 2014.

238. Chen LP, Wu ZJ, Wang FW, Duan DM. [Clinical study of Shu Yu San for depression]. Journal of Emergency in Traditional Chinese Medicine 2009;18(10):1583-4.

320

239. Chen NH, Wang SL, Wang Y. [Clinial Study of Huan Shao capsules for depression]. Journal of Nanjing University of Chinese Medicine 2010;26(06):471-2.

240. Chen SM, Zhang XL, Lin AJ, Feng GZ. [The effect of Wang You Fang for the treatment of depression patients aged 30-50]. Journal of Liaoning University of Chinese Medicine. 2009;8(11):92-4.

241. Chen W, Liu L, Yang XS, Wang NN, Liu ZT. [Clinical observation of Gui Pi Tang combined with Escitalopram for the treatment of depression]. World Journal of Integrated Traditional and Western Medicine. 2013;8(08):829-31.

242. Chen Z, Ding LW. [Chai Hu plus Long Gu Mu Li Tang and Bai He Zhi Mu Tang for depression, an observation of 40 clinical cases]. Clinical Journal of Chinese Medicine 2012;4(3):38-9.

243. Chen ZL, Wu ZG. [The effect of Modified Xiao Yao san for depression of Liver Qi stagnation with Spleen deficiency syndrome]. Journal of Integreated Research of Chinese Medicine and Western Medicine. 2016;6(8):298-300.

244. Cheng K, Yan H, Duan KJ. [An Observation of the Effects of a Self-compiled Chinese Medicine Formula for Depression]. Clinical Journal of Chinese Medicine. 2008;4:375-6.

245. Ding ZJ. A controlled study of Tong Luo Kai Yu Tang combined with Setraline for the treatment of depression. Health Vocational Education 2006;22:147-8.

246. Dong T. [A Clinical study of Jia Wei Zhi Zi Tang for the treatment of depression]. Henan Traditional Chinese Medicine 2016;36(05):867-8.

247. Gao N. [Clinical observation on the effect of Le Xin Tang for depression during perimenopause]. Heilongjiang, China: Heilongjiang University of Chinese Medicine; 2010.

248. Guo JH, Wang SS, Fan R. [Clinical observation on the effect of Chai Hu Shu Gan San combined with Modified Gan Mai Da Zao Tang for the treatment of postpartum depression]. Journal of North Pharmcy. 2011;8(2):18-20.

249. Guo YQ, Su YM. [30 cases of treating Liver Qi stagnation type depression using an integration of Chinese medicine and western medicine]. Traditional Chinese Medicinal Research 2010;23(7):46-7.

321

250. He H, Ren Lr. [Clinical observation of Modified Xiao Yao San combined with fluoxetine for the treatment of postpartum depression] Hubei Journal of Traditional Chinese Medicine 2008;30(12):37-8.

251. Huang NN, Pu X, He XJ, Ye MR. [Wen Yang Jie Yu Tang for depression of the Spleen and Kidney Yang defiency syndrome, 30 cases]. Traditional Chinese Medicinal Research. 2014;27(8):25-7.

252. Huo L. [The effect of modified Meng Shi Gun Tan Wan on the treatment of depression and quality of life for patients with phlegm-heat syndrome]. Shandong, China: Shandong University of Chinese Medicine; 2010.

253. Jiang RQ, Wu MJ, He GJ. [The effect of modified Chai hu tang on serum inflammatory factors and quality of life in patients with depression]. Chinese Archives of Traditional Chinese Medicine. 2016;5(34):1250-2.

254. Li GY. [Clinical study of modified Er Xian Tang for depression during menopause]. Shangdong, China: Shangdong University of Chinese Medicine; 2014.

255. Li SH, Li JQ, Li WQ, Ma QQ, Liao WS, Xuan SM, et al. The effect of Chinese medicine and management measures for postpartum depression. Chinese Journal of Ethnomedicine and Ethnopharmacy 2013;22(14):161-3.

256. Li YC. [The effect of Yue Ju Sheng Jiang Tang on the improvements of physical symptoms in mild to moderate depression patients]. Hebei Chinese Medicine. 2014;36(11):1641-3.

257. Lian Z, Wu Q, Zhao SN. [A Controlled study of Setraline combined with Dan Zhi Xiao Yao San for depression]. Journal of Clinical Psychosomatic Diseases. 2013;19(3):237- 8.

258. Liang WH, Zhang DF. [The effect of Jian Pi Shu Yu formula on 5-HT levels in patients with depression]. China's Naturopathy. 2012;20(9):27-8.

259. Liang Y. [38 cases of Xiao Yao San combined with Paroxetine for the treatment of depression]. Shanxi Chinese Medicine. 2010;31(6):677-8.

260. Lin B, Xia J. [Clinical Study of Modified Chai Hu Shu Gan San for the treatment of depression]. Journal of New Chinese Medicine 2011;43(8):36-7.

322

261. Lin JS, Guo XL, Chen JX, Guo ML. [Clinical observation of Jie Yu Xing Pi Fang for the treatment of deprssion with Liver Qi Stagnation syndrome]. China Journal of Traditional Chinese Medicine and Pharmacy. 2011;26(2):338-40.

262. Lin Y, Yang LQ, Yang XM, Qiu CR, Zhang Y. [The effect of tonify the Kidneys and remove stagnation methods for depression patients with Liver Qi stagnation and Kidney defiencey syndrome]. China Journal of Traditional Chinese Medicine and Pharmacy 2013;31(10):2143-415.

263. Liu B. [Clinical study of Shu Gan Jie Yu An Shen formula for the treatment of moderate depression]. Henan, China: Henan University of Chinese Medicine; 2011.

264. Liu GL. [Huo Li Su combined with Setraline for the treatment of postpartum depression patients with Qi and Blood deficiency]. International Journal of Traditional Chinese Medicine. 2015(3):228-31.

265. Liu K. [The clinical application of Wu Mei Wan for depression patients with the Liver Yang deficient syndrome]. Shandong, China: Shandong University of Chinese medicine; 2015.

266. Liu SS, Chen WY, Liu FY, Xue J, Liu YX, Zhao YL, et al. [Stage III clincal study of Ke Xin Shu for the treatment of mild to moderate depression in patients with Liver Qi stagnation and Spleen deficiency syndrome]. Chinese Journal of New Drugs and Clinical Remedies 2011;30(2):107-10.

267. Lv XR, Li FH. [40 cases of Jie Yu Ning Shen Tang for the treatment of depression]. Nei Mongol Journal of Traditional Chinese Medicine 2014;33(10):11-2.

268. Lv ZG. [Clinical study of regulate Liver, remove stagnation and tonify Spleen method for treating depression of Liver Qi stagnation and Spleen defiency syndrome]. Changchun, China: Changchun University of Chinese medicine; 2011.

269. Ma QQ, Lin H. [Xiao Yao San plus modified Suan Zao Ren Tang for the treatment of mild depression-40 cases]. Henan Traditional Chinese Medicine. 2011;31(9):1063-4.

270. Mai JY, Wai LSQ, Gong D, Zhang YY, Li Y, Zhang ZM, et al. [Clinical observation of treating depression using the Spleen-Stomach theory and syndrome differentiation using the six-meridian theory]. Journal of Liaoning University of Traditional Chinese Medicine. 2017;10(19):150-3.

323

271. Mao ZX, Li GQ, Yang Y, Guo XY, Cheng J, Zhang JH. [30 clinical cases of Jie Yu Tang plus fluoxetine for the treatment of depression with the Liver Qi stagnation and Spleen Deficiency syndrome]. Hebei Chinese Medicine. 2012;34(2):223-6.

272. Pan HF, Dong XY, Liu Y, Xu JY, Zeng Q, Liang J. [Clinical oberservation of Yue Ju Bao He Wan for the treatment of mild to moderate depression]. Lishizhen Medicine and Materia Medica Research 2008(4):887-9.

273. Ren SH, Yang CX. [The clincal effects of Jie Yu Wan for the treatment of mild to moderate postpartum depression] Journal of Guang Ming Chinese Medicine. 2017;2(32):225- 6.

274. Song YM. [30 cases of Shu Gan Jie Yu Li Qi method for the treatment of depression]. Chinese Medicine Modern Distance Education of China 2011;9(16):7.

275. Sun L, Gu CH, Ren JX, Tian Y, Yang LB, Zhang XF. [A randomised controlled trial of Wu Ling capsules for the treatment of mild to moderate depression]. Chinese Journal of Basic Medicine in Traditional Chinese Medicine 2013;19(3):290-1.

276. Tang JH, Zhang LP, Wu PR, Yan H. [Controlled study of Modified Wen Dan Tang plus Fluoxetine for the treatment of depression]. Global Chinese Medicine 2013;6(4):253-7.

277. Wang T, Wang X, Fan HF, Sun CX, Wang ZR, Li DH. [Clinical observation of modified Shu Gan Fang combined with Escitalopram for the treatment of depression]. Hebei Chinese Medicine. 2016;8(38):1184-6.

278. Wang JF. [The effect of Yang Yin Qing Gan Tang combined with paroxetine on the physical symptoms of depression]. Medical Journal of Chinese People's Health 2013;25(20):64.

279. Wu R, Zhu D, Xia Y, Wang H, Tao W, Xue W, et al. A role of Yueju in fast-onset antidepressant action on major depressive disorder and serum BDNF expression: a randomly double-blind, fluoxetine-adjunct, placebo-controlled, pilot clinical study. Neuropsychiatric disease and treatment. 2015;11:2013-21.

280. Xu EP. [Modified Dan Zhi Xiao Yao capsules for the treatment of depression, a clinical and mechanistic study]. Nanjing, China: Nanjing University of Chinese Medicine; 2007.

281. Xu FQ, Zhang Y, Zhang LY. [Clinical study of Bu Shen Shu Gan Hua Yu Tang for depression during perimenopause-82 cases]. Hebei Chinese Medicine. 2013;35(3):333-4.

324

282. Yang HN, Wang Q, Jiang L, Qiao J. [Clinical study of Bao Shen Tang combined with fluoxetine for the treatment of depression]. Journal of Chinese medicine Pharmacology. 2010;38(5):108-10.

283. Yang S, Liu DY. [Clinical observation of Er He Xiao Yao Tang plus Fluoxetine for the treatment of depression]. Journal of Sichuan of Traditional Chinese Medicine. 2012;30(5):77-8.

284. Yao LJ, Gu ZZ, Ji B, Ai ZY, Shen XH, Liu JB. [Clinical observation of Yu Xiao Formula 1 for the treatment of Liver Qi stagnation syndrome depression]. Chinese Journal of Traditional Medical Science and Technology. 2014;21(5):546-7.

285. Ye Q, Cai DF, Zhou J, Gu C, Yuan SX. [Clinical study of Zhen Jing Ding Zhi formula fo the treatment of mild to moderate depression]. Liaoning Journal of Traditional Chinese Medicine. 2015;42(9):1686-8.

286. Yi ZH, Zhu LP, Long B, Yao PF, Zhao GX, Shen AZ, et al. [Clinical observation of paroxetine plus Chai Hu Xiao Yao San for the treatment of depression]. Chinese Journal of Integrated Traditional and Western Medicine. 2010;30(12):1257-60.

287. Yin YR, Wu LN, Zhang M. [A study of fluoxetine plus Chinese Herbal Medicine for the treatment of postpartum depression due to labor induction]. Journal of Clinical and Experimental Medicine. 2011;10(19):1513-5.

288. Yu M, Yu X, Li N, You H, Liu CM, Li YD, et al. [Controlled study of An Shen Ding Zhi Tang plus Setraline for depression]. Hebei Medical Journal. 2011;33(13):2054-5.

289. Yu XP, Zhang X, Liu XY. [Clinical observation of regulating Qi and resolve phlegm treatment method for depression]. Liaoning Journal of Traditional Chinese Medicine. 2013;40(11):2292-3.

290. Zang HL. [A clinical study of Shu Yu Formula for the treatment of depression during menopause]. Nanjing, China: Nanjing University of Chinese Medicine; 2008.

291. Zhang GQ, Zhang GP, Ai CM, Xie YQ, Zhao WX, Yue CZ. [Clinical observations of 38 cases of Zao Ren Bu Xue Tang plus Fluoxetine for the treatment of depression during menopause]. Beijing Journal of Traditional Chinese Medicine. 2009;28(11):873-4.

292. Zhang GR, Sun Q, Wang JC, Gong S, Wang ZH, Li YH. [Clinical observation of Jie Yu He Huan Tang for the treatment of depression]. Qinghai Medical Journal. 2009;39(08):84-5.

325

293. Zhang HD, Su H. [Controlled study of paroxetine plus Xiao Yao Wan for the treatment of depression]. Modern Journal of Integrated Traditional Chinese and Western Medicine. 2009;18(33):4060-3.

294. Zhang J, Tang QP, Xu WJ. [Observation on the effect of Chinese Herbal medicine combined with Setraline for the treatment of depression]. Chinese Archives of Traditional Chinese Medicine. 2014;32(11):2800-2.

295. Zhang LS. [Clinical observation of Modified Chai Hu Long Gu Mu Li Formula for the treatment of depression]. Hebei Medical Journal. 2010;32(22):3185-6.

296. Zhang PZ. [Jin Xiang Shu Gan pills for the treatment of depression (Liver Qi stagnation and Spleen deficiency syndrome): a randomised double-blind, multi-center parallel study]. World Clinical Drugs. 2014;35(7):399-403.

297. Zhang Y. Clinical study of Bu Shen Shu Gan Hua Yu formula for the treatment of depression during menopause Beijing, China: Beijing University of Chinese Medicine; 2013.

298. Zhang ZQ. [A randomised controlled study of Yu Le Shu Formula for depression with the Liver stagnation transforming into fire syndrome]. Chengdu, China: Chengdu University of Chinese Medicine; 2009.

299. Zhao HM, Jiang H, Pang TL. [Chai Gui Kai Yu Tang for the treatment of depression patients with the Liver stagnation and phlegm stagnation syndrome-38 cases]. Hebei Chinese Medicine. 2016;38(2):209-11.

300. Zhao XP, Lin H. [Fluoxetine combined with Chai Hu Shu Gan San modified for the treatment of postpartum depression]. Liaoning Journal of Traditional Chinese Medicine. 2006(5):586-7.

301. Zhong L. [Clinical observation of Kai Yu Ning Shen Tang for the treatment of depression]. Guang Ming Chinese Medicine. 2013;28(5):931-2.

302. Zhong XY, Li QQ, Liao XN. [50 cases of Chai Hu combined with Modified Long Gu Mu Li Tang for depression]. China Health Care Nutrition. 2012(11):4746-7.

303. Zhou B, Yan H. [Integration of Chinese medicine and western medicine for the treatment of deprssion-30 cases]. Tianjin Journal of Traditional Chinese Medicine. 2012;29(4):329-31.

304. Zhou J. [Modified Xiao Yao capsules for the treatment of mild to moderate depression with the Liver Qi stagnation transformed to fire syndrome: a multi-center

326

randomised controlled trial]. Beijing, China: China Academy of Chinese Medical Sciences; 2013.

305. Zhou MY. [Shu Gan Jie Yu Tang combined with Citalopram for the treatment of depression-40 cases]. Traditional Chinese Medicinal Research. 2012;25(3):33-4.

306. Zhu CJ, Li X, Qu M. [Gui Pi Tang for the treatment of depression of the Heart and Spleen deficiency-30 cases]. Chinese Journal of Experimental Traditional Medical Formulae. 2014;20(16):209-13.

307. Zhu JP. [Observation on the effect of modified Suan Zao Ren Tang for the treatment of postpartum depression]. Journal of New Chinese Medicine. 2014;46(7):105-6.

308. Zong CC. [Clinical study of Yi Shen Qing Xin Tang on the treatment of depression]. Shandong, China: Shandong University of Chinese Medicine; 2014.

309. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J, Moller HJ. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. 2013;14(5):334-85.

310. Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments. Canadian journal of psychiatry Revue canadienne de psychiatrie. 2016;61(9):540-60.

311. Olgiati P, Serretti A, Souery D, Dold M, Kasper S, Montgomery S, et al. Early improvement and response to antidepressant medications in adults with major depressive disorder. Meta-analysis and study of a sample with treatment-resistant depression. Journal of affective disorders. 2018;227:777-86.

312. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-66.

313. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple- treatments meta-analysis. Lancet. 2009;373(9665):746-58.

327

314. Chen Y, Liu J, Wu X, Nice EC. Xiangshao Granule Exerts Antidepressive Effects in a Depression Mouse Model by Ameliorating Deficits in Hippocampal BDNF and TrkB. Evidence-based complementary and alternative medicine : eCAM. 2013;2013:309262.

315. Qiu J, Hu SY, Zhang CH, Shi GQ, Wang SE, Xiang T. The effect of Chaihu-Shugan- San and its components on the expression of ERK5 in the hippocampus of depressed rats. Journal of ethnopharmacology. 2014;152(2):320-6.

316. Yang F, Dong X, Yin X, Wang W, You L, Ni J. Radix Bupleuri: A Review of Traditional Uses, Botany, Phytochemistry, Pharmacology, and Toxicology. BioMed research international. 2017;2017:7597596.

317. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Annals of internal medicine. 2001;135(11):982-9.

318. Abdulraheem S, Bondemark L. The reporting of blinding in orthodontic randomized controlled trials: where do we stand? European journal of orthodontics. 2019;41(1):54-8.

319. Vickers A, Goyal N, Harland R, Rees R. Do certain countries produce only positive results? A systematic review of controlled trials. Control Clin Trials. 1998;19(2):159-66.

320. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ (Clinical research ed). 2010;340:c332.

321. Gagnier JJ, Boon H, Rochon P, Moher D, Barnes J, Bombardier C. Reporting randomized, controlled trials of herbal interventions: an elaborated CONSORT statement. Annals of internal medicine. 2006;144(5):364-7.

322. Bian Z, Liu B, Moher D, Wu T, Li Y, Shang H, et al. Consolidated standards of reporting trials (CONSORT) for traditional Chinese medicine: current situation and future development. Frontiers of medicine. 2011;5(2):171-7.

323. Elkins G, Rajab MH, Marcus J. Complementary and alternative medicine use by psychiatric inpatients. Psychological reports. 2005;96(1):163-6.

324. Zhao B, Li Z, Wang Y, Ma X, Wang X, Wang X, et al. Can acupuncture combined with SSRIs improve clinical symptoms and quality of life in patients with depression? Secondary outcomes of a pragmatic randomized controlled trial. Complementary therapies in medicine. 2019;45:295-302.

328

325. Hui S. [A systematic review of randomized controlled trials of acupuncture for depression]. New Chinese Medicine 2014;46(6):220-2.

326. Nichol AD, Bailey M, Cooper DJ. Challenging issues in randomised controlled trials. Injury. 2010;41 Suppl 1:S20-3.

327. Long Y, Chen R, Guo Q, Luo S, Huang J, Du L. Do acupuncture trials have lower risk of bias over the last five decades? A methodological study of 4 715 randomized controlled trials. PloS one. 2020;15(6):e0234491.

328. Shea JL. Applying evidence-based medicine to traditional chinese medicine: debate and strategy. Journal of alternative and complementary medicine (New York, NY). 2006;12(3):255-63.

329. Lundeberg T, Lund I, Sing A, Näslund J. Is placebo acupuncture what it is intended to be? Evidence-based complementary and alternative medicine : eCAM. 2011;2011:932407-.

330. Xu WT. [Investigation of the clinical effect and mechanism of electro-acupuncture for depression]. Guangzhou, China: Guangzhou University of Chinese Medicine; 2017.

331. Chen XY. [The effect of acupuncture on emotionally effected brain regions in patients with depression]. Chengdu, China: Chengdu University of Traditional Chinese Medicine; 2015.

332. Ma XH. [Clinical research of acupuncture for depression]. Beijing, China: Beijing University of Chinese Medicine; 2011.

333. Qu SS. [Clinical observation of electroacupuncture on Baihui and Yintang for the treatment of mild to moderate depression and Rs-fMRI]. Guangzhou, China: Southen Medical University, China; 2015.

334. Wang CQ. [The clinical research on the combination of electroacupuncture and Xerorat in treating depression]. Nanjing, China: Nanjing Medical University; 2007.

335. Chen J, Zhang J, Pei Y. [The effect of acupuncture for the treatment of post-partum depression]. Chinese Journal of Infomration on Traditional Chinese Medicine. 2010;17(7):77-8.

336. Chen XL, Xu K, Luo RH, Lin MJ. [Observation of the clinical effect of electroacupuncture on Sishencong for depression]. Shanghai Journal of Acupuncture and Moxa. 2012;31(1):26-8.

329

337. Chi H, Jiu W. [Tonify Kidney and regulating Liver method of acupuncture for depression during perimenopause-30 cases]. Journal of Clinical Acupuncture and Moxibustion. 2011;27(7):4-7.

338. Ding L, Liu B. [Clinical observation of tonify the Spleen and calm the Heart method of acupuncture for the treatment of depression during perimenopause]. Chinese Archives of Traditional Chinese Medicine 2007(5):1066-7.

339. Gao H. [The effect of acupuncture for depression]. Chinese Journal of Misdiagnostics. 2008;8(34):8348-9.

340. Li HB. [Clinical observation of acupuncture for depression during perimenopause]. Heilongjiang, China: Heilongjiang University of Chinese Medicine; 2015.

341. Li ZF. [Clinical study of electroacupuncture for the treatment of mild to moderate depression during perimenopause]. Guangzhou, China: Guangzhou University of Chinese Medicine; 2015.

342. Liu SX, Wang XH, Liu XL, Zhang XH, Zhang L. [Electroacupuncture for the treatment of depression-118 cases]. Traditional Chinese Medicine Research. 2010;23(9):76-7.

343. Luo HC, Ureil H, Shen YT, Meng FQ, Zhao XY, Liang W, et al. [Clinical research on the effect of electroacupuncture and fluoxetine for the treatment of depression]. Chinese Journal of Psychiatry. 2003;36(4):215-9.

344. Miao MM, Wu JM. [Clinical observation of "Shugan Jianpi, Tongdu Tiaoxin" acupuncture therapy in the treatment of depression with Liver Qi stagnation]. Clinical Journal of Traditional Chinese Medicine. 2015;27(8).

345. Niu XS, Wang P. [Clinical study of Wang method acupuncture for the treatment of Liver Qi stagnation depression in females during menopause]. International Journal of Traditional Chinese Medicine. 2017;39(11):999-1002.

346. Pei Y, Zhang J, Chen J, Qian J. [Clinical observation of Wang style acupuncture for the treatment of depression]. Chinese Journal of Information on Traditional Chinese Medicine. 2006;13(6):62-3.

347. Qian J, Zhang J, Pei Y, Chen J. [Wang Shi Wu Zang Shu method plus Ge Shu method for the treatmet of depression during menopause, a clinical observation]. Beijing Journal of Traditional Chinese Medicine. 2007(8):491-2.

330

348. Shi Y, Wang ZX, Zhou ZY, Lu CJ. [Clinical research of Reducing Liver and Tonifying Lung method for the treatment of depression]. Journal of Nanjing Unversity of Traditional Chinese Medicine. 2015;31(2).

349. Song SC, Lu Z, Chen H, Wang LC, Zhang QW. [Combined Physique-Spirit acupuncture therapy for treating 40 patients with depression]. Journal of Clinical Acupuncture and Moxa. 2013;29(9):27-9.

350. Xing K. [Clinical observation of Xing Shen Jie Yu method for the treatment of depression during menopause in females-120 cases]. Maternal and Child Health Care of China 2011(26):34.

351. Xu FM, Wang Q, Liu XL. [Clinical observation of acupuncture for depression]. Journal of Clinical Acupuncture and Moxa. 2009;25(9):27.

352. Yi Y. [Correlation between the Liver meridian and the frontal lobe in depression by needling at Taichong]. Journal of Integrative Medicine. 2011;31(8):1044-50.

353. Yu SJ. [The clinical effect of needling the Thirteen Ghost acupoints for post-partum depression]. Journal of Sichuan Traditional Chinese Medicine. 2015;33(3):163-5.

354. Yu YS. [Clinical effect of acupuncture for the treatment of depression with Liver Qi stagnation]. Guangzhou, China: Guangzhou University of Chinese Medicine; 2012.

355. Zhang XX, Lu HH, Sun LL, Wang XX. [Clinical observation of Back Shu acupuncture combined with Bailemian for depression]. Journal of Shanxi Chinese Medicine. 2017;38(11):1592-4.

356. Zhou JP. [The clinical efficacy and safety of acupuncture for depression]. Chinese Journal of Medicine. 2013;48(2):90-1.

357. Zhou L. [Clinical research of electroacupuncture for depression]. Heilongjiang, China: Heilongjiang University of Chinese Medicine; 2011.

358. Zhou SH. [60 cases of acupuncture for the treatment of depression during menopause in females]. Chinese Journal of Tissue Engineering Research. 2007(39):7817-9.

359. Ma X. [Observation on the effect of acupuncture in combination with Setraline for the treatment of depression]. Journal of Sichuan Traditional Chinese Medicine. 2012;30(8):140- 1.

331

360. Song Y, Zhou D, Fan J, Luo H, Halbreich U. Effects of electroacupuncture and fluoxetine on the density of GTP-binding-proteins in platelet membrane in patients with major depressive disorder. Journal of affective disorders. 2007;98(3):253-7.

361. Luo RH. [Clinical observation of the effect of acupuncture for depression]. Shanghai Journal of Acupuncture and Moxa. 2009;28(2):69-71.

362. Gao P. [Observation on the clinical effect of acupuncture in combination with fluoxetine for depression]. Guide of China Medicine. 2016;14(7):29.

363. Ma S, Qu S, Huang Y, Chen J, Lin R, Wang C, et al. Improvement in quality of life in depressed patients following verum acupuncture or electroacupuncture plus paroxetine: A randomized controlled study of 157 cases. Neural regeneration research. 2012;7(27):2123-9.

364. Chen HD. [Clinical observation of acpuncture combined with paroxetine for mild to moderate depression]. Chinese Journal of Information on Traditional Chinese Medicine. 2014;21(8):35-7.

365. Duan DM, Tu Y, Chen LP, Wu ZJ. Efficacy evaluation for depression with somatic symptoms treated by electroacupuncture combined with Fluoxetine. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan. 2009;29(3):167-73.

366. Li XN, Gao S, Wu L, Mei JL, Li N. [Observation of the clinical effect of acupuncture in combination with paroxetine for the treatment of depression with Liver Qi stagnation] Shanghai Journal of Acupuncture and Moxa. 2017;36(2):138-41.

367. Lin YQ. [The clinical investigation of acupuncture in combination with fluoxetine for the treatment of depression patients with Liver Qi stagnation syndrome]. Fu Jian, China: Fu Jian Chinese Medicine University; 2014.

368. Lu T, Yan P, Jin XF. [Clinical observation of acupuncturing "Jieyu Prescription" with fluoxetine on depression]. Journal Shanxi University of Chinese Medicine 2017;18(2):52-3.

369. Pan YY. [Study of acupuncture combined with citalopram in the treatment of recurrent depression]. Journal of Psychiatry. 2014;27(1):24-6.

370. Tian Y. [The clinical observation of electroacupuncture and paroxetine for the treatment of depression]. Journal of Baotou Medicine. 2017;41(2):99-100.

371. Zhang GJ, Shi ZY, Liu S, Gong SH, Liu JQ, Liu JS. Clinical observation on treatment of depression by electro-acupuncture combined with Paroxetine. Chinese journal of integrative medicine. 2007;13(3):228-30.

332

372. Zheng YH, Hou L. [Clinical effect of Xing nao kai qiao therapy combined with fluoxetine for the tratment of depression]. Modern Diagnosis and Treatment. 2016;27(2):220- 2.

373. Ye GX. [Investigation on the effect of acupuncture combined with medication in MRI study of brain functional connectivity in depression]. Guangzhou, China: Guangzhou University of Chinese Medicine; 2015.

374. Qu SS, Huang Y, Zhang ZJ, Chen JQ, Lin RY, Wang CQ, et al. A 6-week randomized controlled trial with 4-week follow-up of acupuncture combined with paroxetine in patients with major depressive disorder. Journal of psychiatric research. 2013;47(6):726- 32.

375. Lv PW. [Clinical observation of Shu Gan Jie Yu therapy using herbal medicine plus acupuncture for the treatment of depression]. Chinese Journal of Basic Medicine in Traditional Chinese Medicine. 2011;17(9):1010-1.

376. Shao Y, Wang J. [Clinical observation of Chinese herbal medicine combined with acupuncture for the treatment of depression-42 cases]. China Journal of Traditional Medicine and Pharmacy. 2007;5(10):40-3.

377. Zhang YL, Sui LP. [The effect of Gui Long Yi combined with acupuncture on 5-HT levels in patients with depression]. Integrated Journal of Traditional Chinese Medicine. 2013;35(4):303-5.

378. Zhou XF, Hu J, Zhang YM, Chen HY. [Clinical observation of Fu Zi Xiao Yao San combined with acupuncture for the treatment of depression]. China Pharmacy. 2016;27(11):1515-7.

379. Zhu HL. [Clinical observation of acupuncture combined with Chinese medicine for the treatment of depression during perimenopause]: Heilongjiang University of Chinese Medicine; 2013.

380. Smith CA, Hay PP, Macpherson H. Acupuncture for depression. The Cochrane database of systematic reviews. 2010(1):Cd004046.

381. Jakobsen JC, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC medical research methodology. 2014;14:120.

382. Sullivan GM, Feinn R. Using Effect Size-or Why the P Value Is Not Enough. J Grad Med Educ. 2012;4(3):279-82.

333

383. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5(2):e45-e.

384. Zheng C, Wan X, Xu X, Zhang M, Huang G, Wang W. General Issues in Clinical Research of Acupuncture and In Vitro Fertilization. Evidence-based complementary and alternative medicine : eCAM. 2020;2020:3460641.

385. Deng S, Zhao X, Du R, He SI, Wen Y, Huang L, et al. Is acupuncture no more than a placebo? Extensive discussion required about possible bias. Exp Ther Med. 2015;10(4):1247- 52.

386. Deadman P, Al-Khafaji M, Baker K. A Manual of Acupuncture. East Sussex, England: Journal of Chinese Medicine Publications; 2000.

387. International Organisation for Standardization. Clinical investigation of medical devices for human subjects-Good clinical practice. 2003.

388. Haller H, Anheyer D, Cramer H, Dobos G. Complementary therapies for clinical depression: an overview of systematic reviews. BMJ Open. 2019;9(8):e028527.

389. Freeman MP. Complementary and Alternative Medicine (CAM): considerations for the treatment of major depressive disorder. The Journal of clinical psychiatry. 2009;70 Suppl 5:4-6.

390. Nahas R, Sheikh O. Complementary and alternative medicine for the treatment of major depressive disorder. Can Fam Physician. 2011;57(6):659-63.

391. The State Council Information Office of the People’s Republic of China. Traditional Chinese Medicine in China [Internet]. Xinhua News Agency; 2016 [cited 2019 Nov 16]. Available from: http://english.www.gov.cn/archive/white_paper/2016/12/06/content_281475509333700.htm.

392. M. Chen. [Year Book of Health in the People’s Republic of China]. Beijing, China: People's Medical Publishing House 1997.

393. Volker Scheid. Chinese Medicine in Contemporary China: Plurality and Synthesis Durham, North Carolina: Duke University Press Books; 2002.

394. Chung VCH, Ma PHX, Wang HHX, Wang JJ, Hong LC, Wei X, et al. Integrating traditional chinese medicine services in community health centers: insights into utilization

334

patterns in the pearl river region of china. Evidence-based complementary and alternative medicine : eCAM. 2013;2013:426360-.

395. Horrigan B, Lewis S, Abrams DI, Pechura C. Integrative Medicine in America—How Integrative Medicine Is Being Practiced in Clinical Centers Across the United States. Glob Adv Health Med. 2012;1(3):18-94.

396. Steinhorn DM, Din J, Johnson A. Healing, spirituality and integrative medicine. Annals of palliative medicine. 2017;6(3):237-47.

397. The China State Council. The instructional opinion of the development of community health service2006.

398. The China State Council. [Outline of National Medical and Health Service System Planning]. China: The China State Council; 2015.

399. Wang L, Suo S, Li J, Hu Y, Li P, Wang Y, et al. An investigation Into Traditional Chinese Medicine Hospitals in China: Development Trend and Medical Service Innovation. Int J Health Policy Manag. 2016;6(1):19-25.

400. Jin L. From mainstream to marginal? Trends in the use of Chinese medicine in China from 1991 to 2004. Social science & medicine (1982). 2010;71(6):1063-7.

401. China GotPsRo. The 13th Five-year Plan for Economic and Social Development of The People’s Republic fo China (2016–2020). Beijing, China: Compilation and Translation Bureau,

Central Committee of the Communist Party of China,; 2015.

402. Li HH, Livneh H, Yeh CC, Guo HR, Lai NS, Lu MC, et al. Association between use of Chinese herbal medicine and depression risk in patients with rheumatoid arthritis: A nationwide retrospective cohort study. International journal of rheumatic diseases. 2019.

403. Zhang XY, Li YX, Liu DL, Zhang BY, Chen DM. The effectiveness of acupuncture therapy in patients with post-stroke depression: An updated meta-analysis of randomized controlled trials. Medicine. 2019;98(22):e15894.

404. Bowling A, Rowe G, McKee M. Patients' experiences of their healthcare in relation to their expectations and satisfaction: a population survey. J R Soc Med. 2013;106(4):143-9.

335

405. Florin J, Ehrenberg A, Ehnfors M. Patient participation in clinical decision-making in nursing: A comparative study of nurses' and patients' perceptions. Journal of clinical nursing. 2006;15(12):1498-508.

406. Gelhorn HL, Sexton CC, Classi PM. Patient preferences for treatment of major depressive disorder and the impact on health outcomes: a systematic review. The primary care companion for CNS disorders. 2011;13(5):PCC.11r01161.

407. Raue PJ, Schulberg HC, Heo M, Klimstra S, Bruce ML. Patients' depression treatment preferences and initiation, adherence, and outcome: a randomized primary care study. Psychiatric services (Washington, DC). 2009;60(3):337-43.

408. Iacoviello BM, McCarthy KS, Barrett MS, Rynn M, Gallop R, Barber JP. Treatment preferences affect the therapeutic alliance: implications for randomized controlled trials. J Consult Clin Psychol. 2007;75(1):194-8.

409. Holst A, Nejati S, Björkelund C, Eriksson MC, Hange D, Kivi M, et al. Patients' experiences of a computerised self-help program for treating depression - a qualitative study of Internet mediated cognitive behavioural therapy in primary care. Scand J Prim Health Care. 2017;35(1):46-53.

410. Coyle ME, Yu JJ, Zhang AL, Jones L, Xue CC, Lu C. Patient experiences of using Chinese herbal medicine for psoriasis vulgaris and chronic urticaria: a qualitative study. The Journal of dermatological treatment. 2020;31(4):352-8.

411. Hu G, Chen Y, Liu Q, Wu S, Guo J, Liu S, et al. Patient experience of hospital care in China: major findings from the Chinese Patient Experience Questionnaire Survey (2016- 2018). BMJ open. 2019;9(9):e031615-e.

412. Institute of Asclepius Hospital Management. Bule book of hospitals Beijing, China: Social sciences academic press (China); 2018.

413. Medicine GPHoTC. Introduction of Guangdong Provincial Hospital of Traditional Chinese Medicine [Internet]. 2018 [cited 2019 7th November]. Available from: http://www.gdhtcm.com/sitecn/yyjs/index.html.

414. Bordens. KS, Abbott. BB. Research design and methods: a process approach. 8th. ed. New York, NY, US: McGraw-Hill Education - Europe; 2010.

415. Lisa M. Given. The Sage encyclopedia of qualitative research methods. Thousand Oaks, California: Sage Publications; 2008.

336

416. Johnson. RB, Christensen. LB. Educational research : quantitative, qualitative, and mixed approaches. 5th ed. Thousand Oaks, California: SAGE Publications; 2014.

417. Australian Research Council, Universities Australia. Australian Code for the Responsible Conduct of Research: National Health and Medical Research Council; 2018.

418. IBM Corp. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp; 2017.

419. Leung TH, Wong W. Development of integrative medicine in Hong Kong, China. Chin J Integr Med. 2017;23(7):486-9.

420. Fan D. Holistic integrative medicine: toward a new era of medical advancement. Front Med. 2017;11(1):152-9.

421. Public Health Agency of Sweden. Mental Health 2018 [Available from: https://www.folkhalsomyndigheten.se/the-public-health-agency-of-sweden/living-conditions- and-lifestyle/mental-health/

422. Winzer R, Sorjonen K, Lindberg L. What Predicts Stable Mental Health in the 18(-)29 Age Group Compared to Older Age Groups? Results from the Stockholm Public Health Cohort 2002(-)2014. International journal of environmental research and public health. 2018;15(12).

423. World health Organization. Depression and Other Common Mental Disorders: Global Health Estimates. Geneva, Switzerland: World health Organization; 2017.

424. Australian Bureau of Statistics. National Health Survey: Mental and behavioural conditions [Internet]. Australia: Australian Bureau of Statistics; 2018 [cited 2019 Nov 16]. Available from: https://www.abs.gov.au/ausstats/[email protected]/Lookup/by%20Subject/4364.0.55.001~2017- 18~Main%20Features~Mental%20and%20behavioural%20conditions~70.

425. Xu H, Chen K. Integrative medicine: the experience from China. (1075-5535 (Print)).

426. Li M, Chen Z, Liu Z, Zhang N, Liu J, Wang H, et al. Twelve Chinese herbal preparations for the treatment of depression or depressive symptoms in cancer patients: a systematic review and meta-analysis of randomized controlled trials. BMC Complement Altern Med. 2019;19(1):28-.

337

427. Tu C-H, MacDonald I, Chen Y-H. The Effects of Acupuncture on Glutamatergic Neurotransmission in Depression, Anxiety, Schizophrenia, and Alzheimer's Disease: A Review of the Literature. Frontiers in psychiatry. 2019;10:14-.

428. Kou R-Z, Chen H, Yu M-L, Xu T-C, Fu S-P, Lu S-F. Acupuncture for behavioral changes of experimental depressive disorder: a systematic review and meta-analysis. Sci Rep. 2017;7(1):9669-.

429. Chen Y, Zhang W, Wu H, Lao L, Xu J, Xu S. Combination of acupuncture and Chinese herbal formula for elderly adults with mild cognitive impairment: protocol for a randomized controlled trial. Trials. 2019;20(1):117-.

430. Sarris J. Clinical depression: an evidence-based integrative complementary medicine treatment model. Alternative therapies in health and medicine. 2011;17(4):26-37.

431. McQuade JL, Meng Z, Chen Z, Wei Q, Zhang Y, Bei W, et al. Utilization of and Attitudes towards Traditional Chinese Medicine Therapies in a Chinese Cancer Hospital: A Survey of Patients and Physicians. Evidence-based complementary and alternative medicine : eCAM. 2012;2012:504507.

432. Ng TK, Wong DFK. The efficacy of cognitive behavioral therapy for Chinese people: A meta-analysis. The Australian and New Zealand journal of psychiatry. 2018;52(7):620-37.

433. Setia MS. Methodology Series Module 5: Sampling Strategies. Indian journal of dermatology. 2016;61(5):505-9.

434. Roca M, Vives M, López-Navarro E, García-Campayo J, Gili M. Cognitive impairments and depression: a critical review. Actas Esp Psiquiatr. 2015;43(5):187-93.

435. Schmidt SAJ, Lo S, Hollestein LM. Research Techniques Made Simple: Sample Size Estimation and Power Calculation. J Invest Dermatol. 2018;138(8):1678-82.

436. Frederick J Gravetter , Lori-Ann B. Forzano. Research Methods for the Behavioral Sciences. 6th ed. US: Cengage Learning; 2018.

437. In J. Introduction of a pilot study. Korean journal of anesthesiology. 2017;70(6):601- 5.

438. Moore CG, Carter RE, Nietert PJ, Stewart PW. Recommendations for planning pilot studies in clinical and translational research. Clinical and translational science. 2011;4(5):332-7.

338

439. Chong C, Chen I, Naglie G, Krahn M. Do clinical practice guidelines incorporate evidence on patient preferences. Med Decis Making. 2007;27:E63-E4 ST.

440. Chong CA, Chen IJ, Naglie G, Krahn MD. How well do guidelines incorporate evidence on patient preferences? Journal of general internal medicine. 2009;24(8):977-82.

441. National Institute for Health and Clinical Excellence. The guidelines manual. London: National Institute for Health and Clinical Excellence; 2012.

442. Goodman SM, Miller AS, Turgunbaev M, Guyatt G, Yates A, Springer B, et al. Clinical Practice Guidelines: Incorporating Input From a Patient Panel. Arthritis care & research. 2017;69(8):1125-30.

443. Mohiuddin S, Payne K. Utility Values for Adults with Unipolar Depression: Systematic Review and Meta-Analysis. Medical decision making : an international journal of the Society for Medical Decision Making. 2014;34(5):666-85.

444. Zhang Y, Coello PA, Brozek J, Wiercioch W, Etxeandia-Ikobaltzeta I, Akl EA, et al. Using patient values and preferences to inform the importance of health outcomes in practice guideline development following the GRADE approach. Health and quality of life outcomes. 2017;15(1):52.

445. Falzer PR. Cognitive schema and naturalistic decision making in evidence-based practices. Journal of Biomedical Informatics. 2004;37(2):86-98.

446. Epstein RM. Whole mind and shared mind in clinical decision-making. Patient Education and Counseling. 2013;90(2):200-6.

447. Hoffmann TC, Montori VM, Del Mar C. The Connection Between Evidence-Based Medicine and Shared Decision Making. Jama. 2014;312(13):1295-6.

448. Swennen MHJ, van der Heijden GJMG, Boeije HR, van Rheenen N, Verheul FJM, van der Graaf Y, et al. Doctors’ Perceptions and Use of Evidence-Based Medicine: A Systematic Review and Thematic Synthesis of Qualitative Studies. Academic Medicine. 2013;88(9).

449. Thomas RE, Kreptul D. Systematic review of evidence-based medicine tests for family physician residents. Family medicine. 2015;47(2):101-17.

450. van Dijk N, Hooft L, Wieringa-de Waard M. What are the barriers to residents' practicing evidence-based medicine? A systematic review. Academic medicine : journal of the Association of American Medical Colleges. 2010;85(7):1163-70.

339

451. Groff MW. How to incorporate clinical experience into evidence-based medicine. Clinical neurosurgery. 2009;56:54-6.

452. Barzkar F, Baradaran HR, Koohpayehzadeh J. Knowledge, attitudes and practice of physicians toward evidence-based medicine: A systematic review. Journal of evidence-based medicine. 2018;11(4):246-51.

453. Lam WW, Fielding R, Johnston JM, Tin KY, Leung GM. Identifying barriers to the adoption of evidence-based medicine practice in clinical clerks: a longitudinal focus group study. Med Educ. 2004;38(9):987-97.

454. Hong J, Chen J. Clinical Physicians' Attitudes towards Evidence-Based Medicine (EBM) and Their Evidence-Based Practice (EBP) in Wuhan, China. Int J Environ Res Public Health. 2019;16(19):3758.

455. Jeve YB, Doshani A, Singhal T, Konje J. Knowledge, skills and attitude of evidence- based medicine among obstetrics and gynaecology trainees: a questionnaire survey. JRSM short reports. 2013;4(12):2042533313498719.

456. Mittal R, Perakath B. Evidence-Based Surgery: Knowledge, Attitudes, and Perceived Barriers among Surgical Trainees. J Surg Educ. 2010;67(5):278-82.

457. Ni X. Chinese herbal medicine for insomnia: evidence, practice and opinions. Melbourne, Australia: RMIT University; 2018.

458. Liamputtong P. Qualitative research methods 4th ed. Australia: Oxford University Press Australia; 2012.

459. Smith JA. Qualitative psychology: A practical guide to research methods. 3rd ed. London: Sage Publications Ltd; 2015.

460. Sofaer S. Qualitative research methods. International Journal for Quality in Health Care. 2002;14(4):329-36.

461. Willig C. Introducing qualitative research in psychology. 3rd ed. Milton Keynes, United Kingdom: Open University Press; 2013.

462. McBride DM. The Process of Research and Statistical Analysis in Psychology. 1st ed. US: SAGE Publications Inc; 2019.

340

463. Tong A, Sainsbury P, Craig J. Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups. International Journal for Quality in Health Care. 2007;19(6):349-57.

464. Nagraj S, Hinton L, Praveen D, Kennedy S, Norton R, Hirst J. Women's and healthcare providers' perceptions of long-term complications associated with hypertension and diabetes in pregnancy: a qualitative study. BJOG. 2019;126 Suppl 4(Suppl Suppl 4):34- 42.

465. Gaasterland CMW, van der Weide MCJ, du Prie-Olthof MJ, Donk M, Kaatee MM, Kaczmarek R, et al. The patient's view on rare disease trial design - a qualitative study. Orphanet J Rare Dis. 2019;14(1):31.

466. Epstein A, Whitehouse A, Williams K, Murphy N, Leonard H, Davis E, et al. Parent- observed thematic data on quality of life in children with autism spectrum disorder. Autism. 2019;23(1):71-80.

467. Fix GM, VanDeusen Lukas C, Bolton RE, Hill JN, Mueller N, LaVela SL, et al. Patient-centred care is a way of doing things: How healthcare employees conceptualize patient-centred care. Health expectations : an international journal of public participation in health care and health policy. 2018;21(1):300-7.

468. Goulding C. Grounded theory: evolutionary developments and fundamental processes. 2002. In: Grounded theory [Internet]. London: SAGE Publications Ltd; [38-54]. Available from: https://methods.sagepub.com/book/grounded-theory.

469. Walker D, Myrick F. Grounded theory: an exploration of process and procedure. Qual Health Res. 2006;16(4):547-59.

470. Chapman AL, Hadfield M, Chapman CJ. Qualitative research in healthcare: an introduction to grounded theory using thematic analysis. J R Coll Physicians Edinb. 2015;45(3):201-5.

471. Noble H, Mitchell G. What is grounded theory? Evid Based Nurs. 2016;19(2):34-5.

472. Nowell L, Norris J, White D, Moules N. Thematic Analysis: Striving to Meet the Trustworthiness Criteria. International Journal of Qualitative. 2017;16.

473. van Rijnsoever FJ. (I Can't Get No) Saturation: A simulation and guidelines for sample sizes in qualitative research. PloS one. 2017;12(7):e0181689.

341

474. Evans J. The semi-structured interview as part of grounded theory. 2007. In: Your psychology project: The essential guide [Internet]. London: SAGE Publications Ltd [186-92].

475. Di YM, Yang L. Evidence-based Clinical Chinese Medicine. Volume 14: Unipolar Depression. Xue CC, Lu C, editors. Singapore: World Scientific Publishing Co Pte Ltd; 2020.

476. Braun V., Clarke V., Hayfield N., Terry G. Handbook of Research Methods in Health Social Sciences. Singapore: Springer; 2019.

477. National Health and Medical Research Council, Australian Research Council, Universities Australia. Australian code for the responsible conduct of research Australia: National Health and Medical Research Council; 2018.

478. Standing Committee of the National People's Congress. [Mental Health Law of the People's Republic of China]. China: Standing Committee of the National People's Congress; 2012.

479. Maurer DM, Raymond TJ, Davis BN. Depression: Screening and Diagnosis. American family physician. 2018;98(8):508-15.

480. Beekman ATF, Spijker J. [Personalised diagnosis and treatment of depression]. Tijdschrift voor psychiatrie. 2018;60(3):156-60.

481. Feng DD, Tang T, Lin XP, Yang ZY, Yang S, Xia ZA, et al. Nine traditional Chinese herbal formulas for the treatment of depression: an ethnopharmacology, phytochemistry, and pharmacology review. Neuropsychiatric disease and treatment. 2016;12:2387-402.

482. Wu J, Yeung AS, Schnyer R, Wang Y, Mischoulon D. Acupuncture for Depression: A Review of Clinical Applications. The Canadian Journal of Psychiatry. 2012;57(7):397-405.

483. Irony T, Ho M, Christopher S, Levitan B. Incorporating Patient Preferences into Medical Device Benefit-Risk Assessments. Statistics in Biopharmaceutical Research. 2016;8(3):230-6.

484. Jackson Y, Janssen E, Fischer R, Beaverson K, Loftus J, Betteridge K, et al. The evolving role of patient preference studies in health-care decision-making, from clinical drug development to clinical care management. Expert Review of Pharmacoeconomics & Outcomes Research. 2019;19(4):383-96.

485. Diesfeld K, Mellsop G. Mental Health Law of the People's Republic of China: inviting dialogue. Shanghai archives of psychiatry. 2012;24(6):360-1.

342

486. Chen H, Phillips M, Cheng H, Chen Q, Chen X, Fralick D, et al. Mental Health Law of the People's Republic of China (English translation with annotations): Translated and annotated version of China's new Mental Health Law. Shanghai archives of psychiatry. 2012;24(6):305-21.

487. Apesoa-Varano EC, Hinton L, Barker JC, Unützer J. Clinician approaches and strategies for engaging older men in depression care. Am J Geriatr Psychiatry. 2010;18(7):586-95.

488. Hinton L, Apesoa-Varano EC, Unützer J, Dwight-Johnson M, Park M, Barker JC. A descriptive qualitative study of the roles of family members in older men's depression treatment from the perspectives of older men and primary care providers. Int J Geriatr Psychiatry. 2015;30(5):514-22.

489. Lin V, Canaway R, Carter B, Manderson L. Room for improvement: complementary therapy users and the Australian health system. Health expectations : an international journal of public participation in health care and health policy. 2015;18(5):1451-62.

490. McCaffrey AM, Pugh GF, O'Connor BB. Understanding patient preference for integrative medical care: results from patient focus groups. Journal of general internal medicine. 2007;22(11):1500-5.

491. Magnavita JJ, Lilienfeld SO. Clinical expertise and decision making: An overview of bias in clinical practice. Clinical decision making in mental health practice. Washington, DC, US: American Psychological Association; 2016. p. 23-60.

492. Munk-Jorgensen P, Blanner Kristiansen C, Uwawke R, Larsen JI, Okkels N, Christiansen B, et al. The gap between available knowledge and its use in clinical psychiatry. Acta psychiatrica Scandinavica. 2015;132(6):441-50.

493. Wang G, Mao B, Xiong ZY, Fan T, Chen XD, Wang L, et al. The quality of reporting of randomized controlled trials of traditional Chinese medicine: a survey of 13 randomly selected journals from mainland China. Clinical therapeutics. 2007;29(7):1456-67.

494. Li J, Liu Z, Chen R, Hu D, Li W, Li X, et al. The quality of reports of randomized clinical trials on traditional Chinese medicine treatments: a systematic review of articles indexed in the China National Knowledge Infrastructure database from 2005 to 2012. BMC complementary and alternative medicine. 2014;14:362.

495. Li X, Zhang Y, Wang Y, Xu J, Xin P, Meng Y, et al. The Mechanisms of Traditional Chinese Medicine Underlying the Prevention and Treatment of Parkinson's Disease. Frontiers in pharmacology. 2017;8:634.

343

496. Lu Z, Zhong Y, Liu W, Xiang L, Deng Y. The Efficacy and Mechanism of Chinese Herbal Medicine on Diabetic Kidney Disease. Journal of Diabetes Research. 2019;2019:14.

497. Rakel D. Integrative medicine. 3rd ed ed. Philadelphia: Elsevier Saunders; 2012.

498. Luberto CM, White C, Sears RW, Cotton S. Integrative Medicine for Treating Depression: An Update on the Latest Evidence. Current Psychiatry Reports. 2013;15(9):391.

499. Amick HR, Gartlehner G, Gaynes BN, Forneris C, Asher GN, Morgan LC, et al. Comparative benefits and harms of second generation antidepressants and cognitive behavioral therapies in initial treatment of major depressive disorder: systematic review and meta-analysis. BMJ (Clinical research ed). 2015;351:h6019.

500. Cuijpers P, Sijbrandij M, Koole SL, Andersson G, Beekman AT, Reynolds CF, 3rd. The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: a meta-analysis of direct comparisons. World psychiatry : official journal of the World Psychiatric Association (WPA). 2013;12(2):137-48.

501. Kitson AL, Harvey G. Methods to Succeed in Effective Knowledge Translation in Clinical Practice. Journal of Nursing Scholarship. 2016;48(3):294-302.

502. Soguel L, Vaucher C, Bengough T, Burnand B, Desroches S. Knowledge Translation and Evidence-Based Practice: A Qualitative Study on Clinical Dietitians’ Perceptions and Practices in Switzerland. Journal of the Academy of Nutrition and Dietetics. 2019;119(11):1882-9.

503. Grimshaw JM, Eccles MP, Lavis JN, Hill SJ, Squires JE. Knowledge translation of research findings. Implementation science : IS. 2012;7:50.

504. Grim K, Rosenberg D, Svedberg P, Schon UK. Shared decision-making in mental health care-A user perspective on decisional needs in community-based services. International journal of qualitative studies on health and well-being. 2016;11:30563.

505. LeBlanc A, Herrin J, Williams MD, Inselman JW, Branda ME, Shah ND, et al. Shared Decision Making for Antidepressants in Primary Care: A Cluster Randomized Trial. JAMA internal medicine. 2015;175(11):1761-70.

506. Zaini S, Manivanna Bharathy HA, Sulaiman AH, Singh Gill J, Ong Hui K, Zaman Huri H, et al. Development of a Strategic Tool for Shared Decision-Making in the Use of Antidepressants among Patients with Major Depressive Disorder: A Focus Group Study. International journal of environmental research and public health. 2018;15(7).

344

507. Shenton AK. Strategies for ensuring trustworthiness in qualitative research projects. Education for information. 2004;22(2):63-75.

508. Guba EG. Criteria for assessing the trustworthiness of naturalistic inquiries. ECTJ. 1981;29(2):75.

509. Sandelowski M. The SAGE Encyclopedia of Qualitative Research Methods. In: Given LM, editor. Thousand Oaks, California2008.

510. Malhi GS, Mann JJ. Depression. Lancet. 2018;392(10161):2299-312.

511. Association AP. Practice guideline for the treatment of patients with major depressive disorder (revision). American Psychiatric Association. The American journal of psychiatry. 2000;157(4 Suppl):1-45.

512. Lochmann D, Richardson T. Selective Serotonin Reuptake Inhibitors. Handbook of experimental pharmacology. 2019;250:135-44.

513. Ferguson JM. SSRI Antidepressant Medications: Adverse Effects and Tolerability. Primary care companion to the Journal of clinical psychiatry. 2001;3(1):22-7.

514. Barth M, Kriston L, Klostermann S, Barbui C, Cipriani A, Linde K. Efficacy of selective serotonin reuptake inhibitors and adverse events: meta-regression and mediation analysis of placebo-controlled trials. Br J Psychiatry. 2016;208(2):114-9.

515. Ravindran AV, Balneaves LG, Faulkner G, Ortiz A, McIntosh D, Morehouse RL, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Complementary and Alternative Medicine Treatments. Canadian journal of psychiatry Revue canadienne de psychiatrie. 2016;61(9):576-87.

516. Xue CC, Lyu Y. Accelerating the comprehensive and systematic evaluation of clinical evidence for Chinese medicine using a whole-evidence approach. Global Health Journal. 2019;3(2):33-6.

517. Li B. Critical appraisal and evidence-based Chinese medicine. Annals of translational medicine. 2019;7(6):111-.

518. Kraus C, Kadriu B, Lanzenberger R, Zarate Jr CA, Kasper S. Prognosis and improved outcomes in major depression: a review. Transl Psychiatry. 2019;9(1):127.

345

519. Culpepper L, Muskin PR, Stahl SM. Major Depressive Disorder: Understanding the Significance of Residual Symptoms and Balancing Efficacy with Tolerability. Am J Med. 2015;128(9 Suppl):S1-s15.

520. Oluboka OJ, Katzman MA, Habert J, McIntosh D, MacQueen GM, Milev RV, et al. Functional Recovery in Major Depressive Disorder: Providing Early Optimal Treatment for the Individual Patient. Int J Neuropsychopharmacol. 2018;21(2):128-44.

521. McIntyre RS, Lee Y, Mansur RB. Treating to target in major depressive disorder: response to remission to functional recovery. CNS spectrums. 2015;20 Suppl 1:20-30; quiz 1.

522. Wang JY, Jin XJ. Evidence-based medicine in China. Chronic diseases and translational medicine. 2019;5(1):1-5.

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Appendices

Appendix A Publications

1. Yang L, Shergis JL, Di YM, Zhang AL, Lu C, Guo X, et al. Managing Depression with

Bupleurum chinense Herbal Formula: A Systematic Review and Meta-Analysis of

Randomized Controlled Trials. Journal of Alternative and Complementary Medicine.

2020;26(1):8-24. (Journal article)

2. Yang L, Di YM, Shergis JL, Li Y, Zhang AL, Lu C, et al. A systematic review of acupuncture and Chinese herbal medicine for postpartum depression. Complementary

Therapies in Clinical Practice. 2018; 33:85-92. (Journal article)

3. Di YM, Yang L, Shergis JL, Zhang AL, Li Y, Guo X, et al. Clinical evidence of Chinese medicine therapies for depression in women during perimenopause and menopause.

Complementary Therapies in Medicine. 2019; 47:102071. (Journal article)

4. Di YM, Yang L. Evidence-based Clinical Chinese Medicine. Volume 14: Unipolar

Depression. Xue CC, Lu C, editors. Singapore: World Scientific Publishing Co Pte Ltd; 2020.

(Monograph)

347

Appendix A Publications (continued)

348

Appendix A Publications (continued)

349

Appendix B Chinese herbal medicine for major depressive disorder: full electronic search strategy of PubMed

Search Block Search terms

Condition depressive disorder OR major depressive disorder OR major depression OR

depression

Intervention Traditional Chinese Medicine OR Chinese Traditional Medicine OR

Chinese Herbal Drugs OR Chinese Drugs, Plant OR Medicine, Traditional

OR Ethnopharmacology OR Ethnomedicine OR Ethnobotany OR

Medicine, Kampo OR Kanpo OR TCM OR OR Medicine, Ayurvedic OR

Phytotherapy OR Herbology OR Plants, Medicinal OR Plant Preparation

OR Plant Extract OR Plants, Medicine OR Materia Medica OR Single

Prescription OR Herbs OR Chinese Medicine Herb OR Herbal Medicine

Study design randomized controlled trial OR controlled clinical trial OR randomized OR

placebo OR drug therapy OR randomly OR trial OR groups

350

Appendix C Acupuncture for major depressive disorder: full electronic search strategy of PubMed

Search Block Search terms

Condition depressive disorder OR major depressive disorder OR major depression OR

depression

Intervention acupuncture OR acupuncture therapy OR electroacupuncture OR

moxibustion OR moxa OR ear acupuncture OR meridians OR plum

blossom OR acupressure OR ear acupressure OR acupuncture, ear OR

auriculotherapy OR laser acupuncture OR seven star needle OR

acupuncture analgesia OR acupuncture points OR electro-acupuncture OR

electro acupuncture OR TENS OR transcutaneous nerve stimulation OR

transcutaneous electric nerve stimulation OR transcutaneous electrical

nerve stimulation OR electro-stimulation OR electro stimulation OR

pharmacopuncture OR point injection OR catgut embedding

Study design randomized controlled trial OR controlled clinical trial OR randomized OR

placebo OR drug therapy OR randomly OR trial OR groups

351

Appendix D Pilot questionnaire

Section 1: Demographics

[Please fill in or tick the appropriate box indicating your response.]

1. What is your age? ______

2. What is your gender? 1 Male 2 Female

3. What is your marital status? 1 Married 2 Unmarried

4. What is your highest level of education?

1 Diploma 2 Bachelor 3 Master 4 Doctorate 5 Other. Please specify: ______

5. What is your occupation?

1 Student 2 Employed 3 Retirement 4 Demission 5 Other. Please specify: _____

6. What is your average monthly income (CNY)?

1 5000 or less 2 5001-10,000 3 10,001-15,000

4 15,001-20,000 5 20,001-25,000 6 25,001-30,000

7 30,001-35,000 8 More than 35,000 9 No income

7. Do you have medical insurance? 1Yes 2 No（Please go to Question 8）

1 Public health care system 2 Labour insurance system

3 Rural cooperative medical system 4 Other. Please specify: ______

8. Which year did you diagnose depression? ______

9. Where were you diagnosed with depression?

1 Psychological and psychiatric hospital

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2 Conventional medicine Hospital

3 Integrative medicine hospital

4 Other. Please specify: ______

10. Did you smoke before being diagnosed with depression? 1Yes 2 No

11. Do you smoke after being diagnosed with depression? 1Yes 2 No

12. Did you drink alcohol before being diagnosed with depression? 1Yes 2 No

13. Do you drink alcohol after being diagnosed with depression? 1Yes 2 No

Section 2: Treatment experience

14.1 Treatment history [Please tick the appropriate box indicating your response.]

1 First occurrence and first visit -- Please go to Section 3 (Last page)

2 First occurrence and subsequent visit -- Please go to Question 14.2

3 Reoccurrence and first visit -- Please go to Question 14.2

4 Reoccurrence and subsequent visit -- Please go to Question 14.2

14.2 Are you using Conventional medicine? 1Yes 2 No

14.3 Have you ever used Conventional medicine? 1Yes 2 No

14.4 Are you using Chinese medicine? 1Yes 2 No

14.5 Have you ever used Conventional medicine? 1Yes 2 No

15. Treatment type. [Please fill in or tick the appropriate box indicating your response.]

15.1 Are you taking, or have you ever taken antidepressants for unipolar depression? 1 Yes. Please specify: ______(Please go to Question 15.1a-15.1f)

2 No (Please go to Question 15.2)

15.1a. What do you think of the treatment efficacy of antidepressants?

1 Remission 2 Relief 3 Some help 4 Without any help

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15.1b. Are there any adverse/side effect?

1Yes. Please specify: ______2 No

15.1c. Would you like to continue using antidepressants?

1 Yes (Please go to Question 15.1d) 2 No (Please go to Question 15.1f)

15.1d. What are the reasons that you continue using antidepressants? (Multiple choices)

1 Effective 2 Combined with less medicine 3 Less adverse/side effect

4 Reasonable medical cost 5 Others. Please specify: ______

15.1f. What are/were the reasons that you stop using antidepressants? (Multiple choices)

1Not effective 2 Combined with much medicine 3 Much adverse/side effect

4 Unreasonable medical cost 5 Others. Please specify: ______

15.2 Are you using, or have you ever used psychotherapy for unipolar depression?

1 Yes. (Please go to Question 15.2a-15.2f) 2 No (Please go to Question 15.3)

15.2a. What do you think of the treatment efficacy of psychotherapy?

1 Remission 2 Relief 3 Some help 4 Without any help

15.2b. Are there any adverse/side effect?

1Yes. Please specify: ______2 No

15.2c. Would you like to continue using psychotherapy?

1 Yes (Please go to Question 15.2d) 2 No (Please go to Question 15.2f)

15.2d. What are the reasons that you continue using psychotherapy? (Multiple choices)

1 Effective 2 Combined with less medicine 3 Less adverse/side effect

4 Reasonable medical cost 5 Others. Please specify: ______

15.2f. What are/were the reasons that you stop using psychotherapy? (Multiple choices)

1Not effective 2 Combined with much medicine 3 Much adverse/side effect

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4 Unreasonable medical cost 5 Others. Please specify: ______

15.3 Are you using, or have you ever used combination of Chinese herbal medicine and acupuncture for unipolar depression?

1 Yes. (Please go to Question 15.3a-15.3f) 2 No (Please go to Question 15.4)

15.3a. What do you think of the treatment efficacy of combination of Chinese herbal medicine and acupuncture?

1 Remission 2 Relief 3 Some help 4 Without any help

15.3b. Are there any adverse/side effect?

1Yes. Please specify: ______2 No

15.3c. Would you like to continue using combination of Chinese herbal medicine and acupuncture?

1 Yes (Please go to Question 15.3d) 2 No (Please go to Question 15.3f)

15.3d. What are the reasons that you continue using combination of Chinese herbal medicine and acupuncture? (Multiple choices)

1 Effective 2 Combined with less medicine 3 Less adverse/side effect

4 Reasonable medical cost 5 Others. Please specify: ______

15.3f. What are/were the reasons that you stop using combination of Chinese herbal medicine and acupuncture? (Multiple choices. Please go to Question 15.6 after answering this question.)

1Not effective 2 Combined with much medicine 3 Much adverse/side effect

4 Unreasonable medical cost 5 Others. Please specify: ______

15.4 Are you using, or have you ever used Chinese herbal medicine for major depressive disorderas the only Chinese medicine treatment?

1 Yes. (Please go to Question 15.4a-15.4f) 2 No (Please go to Question 15.5)

15.4a. What do you think of the treatment efficacy of Chinese herbal medicine?

1 Remission 2 Relief 3 Some help 4 Without any help

15.4b. Are there any adverse/side effect?

355

1Yes. Please specify: ______2 No

15.4c. Would you like to continue using Chinese herbal medicine?

1 Yes (Please go to Question 15.4d) 2 No (Please go to Question 15.4f)

15.4d. What are the reasons that you continue using Chinese herbal medicine? (Multiple choices)

1 Effective 2 Combined with less medicine 3 Less adverse/side effect

4 Reasonable medical cost 5 Others. Please specify: ______

15.4f. What are/were the reasons that you stop using Chinese herbal medicine? (Multiple choices. Please go to Question 15.6 after answering this question.)

1 Not effective 2 Combined with much medicine 3 Much adverse/side effect

4 Unreasonable medical cost 5 Others. Please specify: ______

15.5 Are you using, or have you ever used acupuncture for major depressive disorderas the only Chinese medicine treatment?

1 Yes. (Please go to Question 15.5a-15.5f) 2 No (Please go to Question 15.6)

15.5a. What do you think of the treatment efficacy of acupuncture?

1 Remission 2 Relief 3 Some help 4 Without any help

15.5b. Are there any adverse/side effect?

1Yes. Please specify: ______2 No

15.5c. Would you like to continue using acupuncture?

1 Yes (Please go to Question 15.5d) 2 No (Please go to Question 15.5f)

15.5d. What are the reasons that you continue using Acupuncture? (Multiple choices)

1 Effective 2 Combined with less medicine 3 Less adverse/side effect

4 Reasonable medical cost 5 Others, please specify: ______

15.5f. What are/were the reasons that you stop using Acupuncture? (Multiple choices. Please go to Question 15.6 after answering this question.)

356

1 Not effective 2 Combined with much medicine 3 Much adverse/side effect

4 Unreasonable medical cost 5 Others, please specify: ______

15.6 Are you using, or have you ever used other therapy for unipolar depression? 1 Yes. Please specify: ______(Please go to Question 15.6a-15.6f)

2 No (Please go to Question 16)

15.6a. What do you think of the treatment efficacy of the treatment?

1 Remission 2 Relief 3 Some help 4 Without any help

15.6b. Are there any adverse/side effect?

1Yes. Please specify: ______2 No

15.6c. Would you like to continue using the treatment?

1 Yes (Please go to Question 15.56d) 2 No (Please go to Question 15.6f)

15.6d. What are the reasons that you continue using the treatment? (Multiple choices)

1 Effective 2 Combined with less medicine 3 Less adverse/side effect

4 Reasonable medical cost 5 Others. Please specify: ______

15.6f. What are/were the reasons that you stop using the treatment? (Multiple choices)

1 Not effective 2 Combined with much medicine 3 Much adverse/side effect

4 Unreasonable medical cost 5 Others. Please specify: ______

16. Treatment preferences. [Please fill in or tick the appropriate box indicating your response.]

16.1What type of treatments would you like to use? (Single choice)

1Conventional medicine 2Chinese medicine 3 Integrative medicine

16.2 What sort of treatments would you like to use? (Multiple choices)

1 Antidepressants 2 Psychotherapy 3 Chinese herbal medicine (CHM)

4 Acupuncture 5 Acupuncture plus CHM 6 Others. Please specify: ______

16.3 What kind of treatments would you like to recommend? (Multiple choices)

357

1 Antidepressants 2 Psychotherapy 3 Chinese herbal medicine (CHM)

4 Acupuncture 5 Acupuncture plus CHM 6 Others. Please specify: ______

Section 3: Treatment expectation

Please tick the appropriate box indicating your response: Yes No Not applicable

17. Would you like your doctor to communicate with you on treatment types? 1 2 3

18. Would you like doctors with Conventional medicine background to know 1 2 3 Chinese medicine treatments?

19. Would you like doctors with Chinese medicine background to know 1 2 3 Conventional medicine treatments?

20. If you use Chinese medicine for your condition, would you like the doctor 1 2 3 that you visit at Conventional medicine clinic to communicate with you on Chinese medicine treatments?

21. If you use Conventional medicine for your condition, would you like the 1 2 3 doctor that you visit at Chinese medicine clinic to communicate with you on Conventional medicine treatments?

22. Would you like to gain information on Chinese medicine for your condition 1 2 3 from your doctors with Conventional medicine background?

23. Would you like to gain information on Chinese medicine for your condition 1 2 3 from your doctors with Chinese medicine background?

24. Currently, do you think you have gained adequate information on Chinese 1 2 3 medicine for your condition from your doctors with Conventional medicine background?

358

25. Currently, do you think you have gained adequate information on Chinese 1 2 3 medicine for your condition from your doctors with Chinese medicine background?

26. Would you like to know about Chinese herbal medicine, or acupuncture, or combined Chinese herbal medicine and acupuncture for your condition from your doctors? (Multiple choices); what sort of information would you like to know? [Please fill in or tick the appropriate box indicating your response.]

1Chinese herbal medicine (CHM) 2 Acupuncture 3 Acupuncture plus CHM

4 Others. Please specify the information you would like to know: ______

______

27. If you would like to use Chinese medicine for unipolar depression, what is your treatment goal? [Please tick the appropriate box or fill in indicating your response.] (Multiple choices)

1 Improve depressive symptoms 2 Improve physical symptoms

3 Reduce adverse events due to antidepressants

4 Others, please specify: ______

359

Appendix E Questionnaire

Section 1: Demographics

1. What is your age? ______

2. What is your gender? 1 Male 2 Female

3. What is your marital status? 1 Married 2 Single

4. What is your highest level of education?

1 Diploma or under 2 Bachelor 3 Master 4 Doctorate

5. What is your employment status?

1 Student 2 Employed 3 Unemployed 4 Retired

5 Others. Please specify: ______

6. What is your average monthly income (CNY)?

1 5000 or less 2 5001-10,000 3 10,001-15,000

4 15,001-20,000 5 20,001-25,000 6 25,001-30,000

7 30,001-35,000 8 More than 35,000 9 No income

7. Do you have medical insurance?

1Yes (Please go to Question 7.1) 2 No (Please go to Question 8)

7.1 What type of medical insurance do you have?

1 Public health care system 2 Labour insurance system 3 Rural cooperative medical system 4 Others. Please specify: ______5 Not sure

8. When were you diagnosed with depression? ______

9. Where were you diagnosed with depression?

360

1 Psychiatric and psychology hospital 2 Conventional medicine hospital

3 Integrative medicine hospital 4 Others. Please specify: ______

Section 2: Treatment experience

10. Is this your first diagnosis of depression or previous diagnosis?

1 First diagnosis of depression with no experience of treatments (Please go to Section 3）

2 Previous diagnosis of depression

Conventional medicine

11. Are you using Conventional medicine for your depression?

1Yes 2 No (Please go to Question 12)

11.1 If yes, what type of Conventional medicine are you receiving? (Single choice)

1 Antidepressants only, the name of antidepressants: ______

2 Psychotherapy only

3 Antidepressants and Psychotherapy, the name of antidepressants: ______

4 Others. Please specify: ______

11.2 If yes, do you think the Conventional medicine treatment is effective?

1 Remission 2 Relief or have some help 3 No effect without any help

11.3 If yes, have you experienced any adverse effects from the Conventional medicine treatment?

1Yes. Please specify: ______2 No

11.4 If yes, do you continue on using the Conventional medicine treatment?

1Yes (Please go to Question 11.4a) 2 No (Please go to Question 11.4b)

11.4a If you answer ‘Yes’ for Question 11.4, what is the reason? (Multiple choices)

361

1 Effective

2 Faster relief of symptoms

3 Easy to take

4 Fewer adverse events

5 Tolerable with the adverse events

6 Reasonable medical costs

7 Doctor told me to take it, and I agree

8 Others. Please specify: ______

11.4b If you answer ‘No’ for Question 15.4, what is the reason? (Multiple choices)

1 Not effective

2 Slower relief of symptoms

3 Inconvenient to take

4 Many adverse events

5 Intolerable with the adverse events

6 Unreasonable medical costs

7 Doctor told me to stop, and I agree

8 Others. Please specify: ______

12. Have you ever used Conventional medicine for your depression and stopped?

1Yes 2 No (Please go to Question 13)

12.1 If yes, what type of Conventional medicine did you used? (Single choice)

1 Antidepressants only, the name of antidepressants: ______

2 Psychotherapy only

3 Antidepressants and Psychotherapy (used simultaneously), the name of antidepressants: ______

362

4 Antidepressants and Psychotherapy (not used simultaneously), the name of antidepressants: ______

5 Others. Please specify: ______

12.2 If yes, what is the reason you stopped using the Conventional medicine? (Multiple choices)

1 Remission 2 Not effective

3 Slower relief of symptoms 4 Inconvenient to take

5 Many adverse events 6 Intolerable with the adverse events

7 Unreasonable medical costs 8 The doctor changed the treatment

9 Others. Please specify: ______

Chinese medicine

13. Are you using Chinese medicine for your depression?

1Yes 2 No (Please go to Question 14)

13.1 If yes, what type of Chinese medicine are you receiving? (Single choice)

1 Chinese herbal medicine (CHM) only 2 Acupuncture only

3 CHM and acupuncture 4 Others. Please specify: ______

13.2 If yes, do you think the Chinese medicine treatment is effective?

1 Recovery 2 Relief or have some help 3 No effect without any help

13.3 If yes, have you experienced any adverse events from the Chinese medicine?

1Yes. Please specify: ______2 No

13.4 If yes, do you continue on using Chinese medicine?

1Yes (Please go to Question 13.4a) 2 No (Please go to Question 13.4b)

363

13.4a If you answer ‘Yes’ for Question 13.4, what is the reason? (Multiple choices)

1 Effective

2 Faster relief of symptoms

3 Easy to take

4 Fewer adverse events

5 Tolerable with the adverse events

6 Reasonable medical costs

7 Doctor told me to take it, and I agree

8 Others. Please specify: ______

13.4b If you answer ‘No’ for Question 13.4, what is the reason? (Multiple choices)

1 Not effective

2 Slower relief of symptoms

3 Inconvenient to take

4 Many adverse events

5 Intolerable with the adverse events

6 Unreasonable medical costs

7 Doctor told me to stop, and I agree

8 Others. Please specify: ______

14. Have you ever used Chinese medicine for your depression and stopped?

1Yes 2 No (Please go to Question 15)

14.1 If yes, what type of Chinese medicine did you used? (Single choice)

1 Chinese herbal medicine (CHM) only

2 Acupuncture only

3 CHM and acupuncture (used simultaneously)

364

4 CHM and acupuncture (not used simultaneously)

5 Others. Please specify: ______

14.2 If yes, what is the reason you stopped using Chinese medicine? (Multiple choices)

1 Remission 2 Not effective

3 Slower relief of symptoms 4 Inconvenient to take

5 Many adverse events 6 Intolerable with the adverse events

7 Unreasonable medical costs 8 The doctor changed the treatment

9 Others. Please specify: ______

15. What type of treatment would you like to use for your depression? (Single choice)

1 Conventional medicine only (Please go to Question 15.1)

2 Chinese medicine only (Please go to Question 15.2)

3 Integrated medicine (Please go to Question 15.3)

15.1 What sort of Conventional medicine treatment would you like to use for your depression? (Single choice)

1 Antidepressants only

2 Psychotherapy only

3 Combination of antidepressants and psychotherapy

4 Others. Please specify: ______

15.2 What sort of Chinese medicine treatment would you like to use for your depression? (Single choice)

1 Chinese herbal medicine (CHM)

2 Acupuncture

3 Acupuncture plus CHM

4 Others. Please specify: ______

365

15.3 What sort of Integrative medicine treatment would you like to use for your depression? (Multiple choices)

1 Antidepressants

2 Psychotherapy

3 Chinese herbal medicine

4 Acupuncture

5 Others. Please specify: ______

Section 3: Treatment expectation

Please tick the appropriate box indicating your response Yes No Not Not sure applicable

16. Would you like your doctor to communicate with you 1 2 3 3 about treatment types and options of depression?

17. If you use Conventional medicine for your condition, 1 2 3 3 would you like the doctor that you visit at Chinese medicine clinic to ask you about Conventional medicine treatments?

18. If you use Conventional medicine for your condition, do 1 2 3 3 you want to tell the doctor that you visit at Chinese medicine clinic about your Conventional medicine treatment?

19. If you use Chinese medicine for your condition, would 1 2 3 3 you like the doctor that you visit at Conventional medicine clinic to ask you about Chinese medicine treatments?

20. If you use Chinese medicine for your condition, do you 1 2 3 3 want to tell the doctor that you visit at Conventional medicine clinic about your Chinese medicine treatment?

21. If you visit at Conventional medicine clinic, would you 1 2 3 3 like to gain medical information (e.g. modern research

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Please tick the appropriate box indicating your response Yes No Not Not sure applicable evidence, classical literature research evidence, case studies, or doctors' experience, etc.) on Chinese medicine for your condition from your doctor with Conventional medicine background?

22. If you visit at Chinese medicine clinic, would you like to 1 2 3 3 gain medical information (e.g. modern research evidence, classical literature research evidence, case studies, or doctors' experience, etc.) on Chinese medicine for your condition from your doctor with Chinese medicine background?

23. Currently, do you think you have gained adequate 1 2 3 3 medical information (e.g. modern research evidence, classical literature research evidence, case studies, or doctors' experience, etc.) on Chinese medicine for your condition from your doctor with Conventional medicine background?

24. Currently, do you think you have gained adequate 1 2 3 3 medical information (e.g. modern research evidence, classical literature research evidence, case studies, or doctors' experience, etc.) on Chinese medicine for your condition from your doctor with Chinese medicine background?

25. If you would like to use Chinese medicine, what is your main goal for Chinese medicine treatment for your depression? (Multiple choices)

1 Improve depressive symptoms

2 Improve physical symptoms

3 Reduce adverse events due to antidepressants

4 Others. Please specify: ______

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26. If you would like to know Chinese medicine, what sort of medical information would you like to know? (Multiple choices)

1 Modern research evidence 2 Classical literature research evidence

3 Chinese medicine case studies 4 Doctors' experience

5 Others. Please specify: ______

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Appendix F Ethics approval for survey granted by the ethics committee of the Guangdong

Provincial Hospital of Chinese Medicine, China

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Appendix G Ethics approval for survey registered with the RMIT University Science

Engeneering and Health College Human Ethics Advisory Network, Australia

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Appendix H Pilot survey results

The following presents the key findings of the pilot survey. Twenty participants consented to the pilot survey and 17 completed the questionnaire. The results from the three participants that did not complete the survey were not included in this data analysis. Participant demographic information is presented in Table 1 below:

Table 1 Demographic characteristics of pilot survey:

Characteristics Total N (%) Age, mean (standard deviation) 36.41 (13.05) 18-20 years 2 (11.8) 21-30 years 4 (23.5) 31-40 years 6 (35.3) 41-50 years 2 (11.8) 51-65 years 3 (17.6) Gender Female 14 (82.4) Male 3 (17.6) Marital status Married 10 (58.8) Single 7 (41.2) Education Diploma or under 10 (58.8) Bachelor 3 (17.6) Master or Doctorate 4 (23.5) Employment status Student 2 (11.8) Employed 10 (58.8) Unemployed 2 (11.8) Retired or other 3 (17.6) Monthly income 0 Chinese Yuan (CNY) 2 (11.8) < 5000 CNY 5 (29.4) 5001-10000 CNY 4 (23.6) >10000 CNY 6 (35.3) Medical insurance

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Characteristics Total N (%) Insured 12 (70.6) Not insured 5 (29.4) Place where participants were diagnosed Psychological and psychiatric hospital 4 (23.5) Conventional medicine hospital 3 (17.6) Integrative medicine hospital 10 (58.8)

Treatment experience

Use of conventional medicine

In term of conventional medicine utilisation, 12 out of the 17 participants (70.6%) used it at the time of the pilot survey, while 9 participants (52.9%) had ever used conventional medicine.

Eleven participants had used antidepressant pharmacotherapy (11, 64.7%), and 10 participants specified the type of antidepressants used including sertraline (4 participants), escitalopram (3 participants), citalopram (2 participants), mirtazapine (1 participant), and venlafaxine extended-release (1 participant). One participant did not mention the name of antidepressants.

After taking antidepressants, 7 (63.6%) felt relief and 4 (36.4%) felt that it had some positive effects. Eight participants (72.7%) experienced adverse events, including nausea (2 cases), headache (1 case), poor memory (1 case), hypersomnia and fatigue (1 case), weight loss (1 case), bloating (1 case), and loss of appetite (1 case). Six participants (54.5%) would like to continue using antidepressants. The reasons for continuing using was because antidepressants were effective (3 participants, 50.0%), with less adverse events (2 participants, 33.3%), combined with less medication (1 participant, 16.7%).

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Use of Chinese medicine

As for the use of CM, 7 of the 17 participants (41.2%) used CM at the time of the pilot survey and 7 (41.2%) had used CM before.

Six participants (35.3%) used CHM and one (5.9%) used acupuncture at the time of the pilot survey. Three people felt relief or got some help from taking the CHM. No one experienced adverse events. All six people would like to continue using CM. The reason for continuing CM was because of its effectiveness (4 participants, 66.7%). Other reasons included having less adverse events (3 participants, 50.0%), combined with less medications (2 participants, 33.3%), and reasonable medical cost (1 participant, 16.7%).

Treatment preference

Integrated CM and conventional medicine accounted for 76.5% (13 participants), as the largest number of treatment preference. Among 17 participants, 11 (64.7%) would like to use psychotherapy as the largest proportion among conventional medicine treatments, while 7 participants (41.2%) prefer to use combination of CHM and acupuncture as the largest proportion among CM treatments.

Treatment expectations

Expectations of communicating with doctors

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Fifteen participants (88.2%) would like their doctors to communicate with them on treatment types. 16 participants (94.1%) would like their doctors with conventional medicine background to know about CM, and 15 participants (88.2%) would like this kind of doctors communicate with them on CM if use they used CM. Also, 16 participants (94.1%) would like their doctors with CM background to know about conventional medicine and communicate with them on this type of treatment if they use it. 15 participants (88.2%) would like to gain information of

CM for their condition from doctors with conventional medicine background but only 7 participants (41.2%) thought they gained adequate information. 16 participants (94.1%) would like to get information on CM for depression of from their CM doctors but more than half participants (9, 52.9%) thought they did not get adequate information.

Treatment goal of using Chinese medicine for depression

Among 17 participants, if they use CM, 16 (91.4%) of them aimed to reduce depressive symptoms, 11 (64.7%) aimed to reduce physical symptoms, and 7 (41.2%) would like to reduce adverse events caused by antidepressants. There were four participants specified other treatment goals including long-term efficacy, stable effect and good sleep.

Summary

The pilot survey invited 20 participants, of which, 17 completed the questionnaire. The questionnaire appeared to be well accepted by the participants and took on average 10 minutes to complete. Section 1 demographics was acceptable, and some minor updates were made to

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one question and removed four question. Section 2 personal treatment history has been reformatted to improve readability; however, the questions remain largely unchanged. Section

3 Treatment information has been reformatted to improve readability however, the questions remain largely unchanged.

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Appendix I Interview guide

Demographics

1. What is your age? ______

2. What is your gender? Male  Female 

3. Where did you receive your education/ training on treating unipolar depression? (Multiple choices)

University  Short-term course  Continuing Education  Other  Specify:

______

4. What is your highest level of education?

Diploma  Bachelor  Master  Doctorate  Other  Specify:

______

5. In what division of medicine are you licensed?

Chinese medicine  Conventional Integrative Other 

medicine  medicine  Specify: _____

6. How many years have you been a licenced as a practitioner? ______

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7. What is your professional title?

Resident  Attending  Vice-chief  Chief 

8. Where do you implement clinic practice? (Multiple choice)

Public Hospital  Private Hospital  Community  Other 

Specify: ______

9. What is your clinical specialty? (Multiple choice)

Psychology  Psychiatry  Neurology  Others 

Specify: ______

10. How many patients with depression do you see on average per day when you practice?

10.1 How many patients with depression do you see on average per day when you practice?

______

11. Do you practice at ward of hospital? Yes (go to Q 11.1)  No (go to Q 12) 

11.1 How many patients with depression do you receive on average per week when you practice?

______

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12. Do you work on psychotherapy? Yes (go to Q 12.1)  No 

12.1 How many patients with depression do you treat on average per half a year when you practice?

______

Interview 1

Treatment process

• How long have you practiced Chinese medicine (CM)/Conventional medicine/Integrative

medicine for depression?

• [For doctors with a background of conventional medicine] Have you heard about CM for

depression? What do you think of CM for depression?

• What do you think of CM for depression?

• [Scenario simulation] If a patient has symptoms that are consistent with the diagnosis of

depression and visit the clinic for treatments, could you please describe the process of

clinical practice?

 If this patient is interested in CM for his condition and seek your advice, what would

you tell the patient?

Knowledge access

• How do you update knowledge on depression? How often do you update?

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• What sort of knowledge on depression do you focus on? How do you use the knowledge

that you acquire?

• Have you heard about systematic reviews and meta-anslyses?

 [If yes], what do you know about this kind of study?

 [If no], go to the next question.

• Have you heard about the study on classical CM literature? (classical CM literature refers

to CM books published before the People’s Republic of China (1949))

 [If yes], what do you know about this kind of study?

 [If no], go to the next question.

• Have you heard of the survey study?

 [If yes], what do you know about this kind of study?

 [If no], go to the next question.

Patient preference

• How do you address patients who have a preference for a specific type of treatments

for depression?

• What do you think of patient preferences on treatments?

New Research Results Presentation

• A research group has conducted three studies on CM for depression including three

systematic reviews and meta-analyses of Chinese herbal medicine (CHM), acupuncture,

and combination of acupuncture and CHM, a review of CM classical literature, and a

survey for patients’ experience and expectations of using CM for depression. Now I

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will present the key findings by a presentation and provide you with the detailed

materials for the further reading. (Presentation…)

• Interview 2 will be conducted, partly based on these research findings of CM for

depression. Please make sure you have read the provided materials and understand the

research findings.

• If you have any questions, please feel free to contact me before Interview 2.

Interview 2

Thank you very much for participating Interview 2. This interview includes four sections. As for Section 1 to 3, please answer questions according to your understanding of the research findings, while in terms of section 4, please answer questions according to your clinical experience plus the research findings that you acquired. If you have no further questions, now we will start with the interview from Section 1.

Section 1 Perceptions on the research findings from systematic reviews and meta-analyses of CM for depression

Please answer the following questions referring to the research findings that you acquired.

1. What is the new knowledge that you acquired from the systematic reviews and meta-analyses of CHM, acupuncture and combination of acupuncture and CHM for depression?

• What are you most interested in? And for what reason?

• What are you less interested in? And for what reason?

• What do you think is the most important? And for what reason?

• What do you think is less important? And for what reason?

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2. [For doctors with a background of CM or integrative medicine], can you imagine that you may use the new knowledge that you acquired in your future practice?

• [If yes], what would be easy for you to start using? What would be the most difficult?

Could you please give some examples？

• [If yes], what sort of knowledge may change your practice? Could you please give some

examples (regarding therapies, treatment procedure, situations, or patient conditions)?

 What is the likelihood of changing your practice based on the research findings?

 Do you have any concerns about changing your practice based on the research

findings?

• [If yes], what are your concerns?

 Do you ever change you practice for treating depression based on other

systematic reviews and meta-analyses?

• [If no], do you ever use knowledge from systematic reviews and meta-analyses in your

practice for treating depression?

3. Can you imagine that you discuss the research findings with colleagues?

• [If yes], who, when and where?

• [If yes], would you share the research findings with that person (those people)?

 [If yes], would you recommend? What is the likelihood?

• [If yes], for what reason? What sort of research findings would you

recommend?

• [If yes], do you have any concerns about recommending the research

findings? [If yes], what are your concerns?

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• [If no], do you ever recommend other research findings of systematic

reviews and meta-analyses of depression treatments to your colleagues?

 [If no], do you ever share reports of systematic reviews and meta-analyses of

depression treatments with your colleagues?

• [If no], do you ever discuss other systematic reviews and meta-analysis of depression

treatment with colleagues?

Section 2 Perceptions on the research findings from classical CM literature of Depression

Please answer the following questions referring to the research findings that you acquired.

1. What is the new knowledge that you acquired from the study on classical CM literature of depression?

• What are you most interested in? And for what reason?

• What are you less interested in? And for what reason?

• What do you think is the most important? And for what reason?

• What do you think is less important? And for what reason?

2. [For doctors with a background of CM or integrative medicine], can you imagine that you may use the new knowledge that you acquired in your future practice?

• [If yes], what would be easy for you to start using? What would be the most difficult?

Could you please give some examples？

• [If yes] What sort of knowledge may change your practice? Could you please give some

examples (regarding therapies, treatment procedure, situations, or patient conditions)?

 What is the likelihood of changing your practice based on the research findings?

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 Do you have any concerns about changing your practice based on the research

findings?

• [If yes], what are your concerns?

 Do you ever change you practice for treating depression based on other research

findings from classical CM literature?

• [If no], do you ever use knowledge from classical CM literature in your practice for

treating depression?

3. Can you imagine that you would discuss the research findings with colleagues?

• [If yes], who, when and where?

• [If yes], would you share the research findings with that person (those people)?

 [If yes], would you recommend? What is the likelihood?

• [If yes], for what reason? What sort of research findings would you

recommend?

• [If yes], do you have any concerns about recommending the research

finding? [If yes], what are your concerns?

• [If no], do you ever recommend knowledge from classical CM

literature of depression to colleagues?

 [If no], do you ever share materials of classical CM literature of depression with

colleagues?

• [If no], [for doctors with CM or integrative medicine background] do you ever discuss

classical CM literature of depression with colleagues? [for doctors with conventional

medicine background] do you ever discuss CM classical literature with colleagues?

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Section 3 Perceptions of patients’ experience and expectations of using CM for depression

Please answer the following questions referring to the research findings that you acquired.

1. What is the information that you acquired from the survey findings of patients’ experience and expectations of using CM for depression?

• What are you most interested in? And for what reason?

• What are you less interested in? And for what reason?

• What do you think is the most important? And for what reason?

• What part do you think is less important? And for what reason?

2. In your future practice, can you image you may change your way to communicate with your patients based on the survey results?

• [If yes], what sort of survey findings may change your way to communicate with your

patients? Could you please give some examples (regarding treatments, situations, or

patients)?

• [If yes], what is the likelihood of changing your way?

• [If yes], do you have any concerns about changing your way?

 [If yes] What are your concerns about the changes?

• [If no], do you ever change your way to communicate with your patients? For what

reason?

3. Can you imagine that you would discuss this survey with colleagues?

• [If yes], who, when and where?

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• [If yes], would you share the research findings with that person (those people)?

 [If yes], would you recommend? What is the likelihood to recommend?

• [If yes], for what reason? What sort of research findings would you

recommend?

• [If yes], do you have any concerns about recommending the research

findings? [If yes], what are your concerns?

• [If no], do you ever recommend colleagues to learn about patients’

experience and expectation?

 [If no], do you ever share other materials of survey on patient to colleagues?

What is it about?

• [If no], do you ever discuss patients’ experience and expectation with colleagues?

Section 4 Communications and shared decision making between doctors and patients

Please answer the following questions referring to your clinical experience and the research findings that you acquired.

1. Please imagine that some of your patients would like to use CHM, acupuncture or combination of acupuncture and CHM for depression. What considerations do you make

(regarding the patient symptoms, social support, contact with the patient, economy, other probes, etc.)? Would you recommend CM treatments? What is the likelihood?

• [If yes], for what reason? what sort of CM treatments would you recommend?

• [If yes], Do you have any concerns about recommending these treatments? What are

your concerns?

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• [If yes], when you recommend the treatments, would you mention the research findings

from systematic reviews and meta-analyses to patients?

 [If yes], what do you think of mentioning the research findings from

systematic reviews and meta-analyses to patients? what sort of evidence

would you mention to your patients?

 [If yes], do you have any concerns about mentioning the evidence? [If yes],

what are your concerns?

 [If no], what do think of not mentioning the research findings from

systematic reviews and meta-analysis to your patients?

• [If yes], when you recommend the treatments would you mention the research findings

from classical CM literature to your patients?

 [If yes], what do think of mentioning the research findings from classical

literature CM to your patients? What sort of evidence would you mention

to your patients?

 [If yes], do you have any concerns about mentioning the evidence? [If yes],

what are your concerns?

 [If no], what do think of not mentioning the research findings from

classical CM literature to your patients?

• [If no], what do you think of not recommending CM treatments?

2. What should a doctor consider when using CM for depression?

• What is the most important thing that the doctor needs to consider when using CM for

depression? And for what reason?

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3. If your patients prefer to use CM for depression, what are your opinions? How would you talk to your patients and could you please describe it?

4. What issues would you raise your patients regarding to the treatment plan for depression?

• What is the most important thing that you would like to raise with your patients? And

for what reason?

Closing Remarks

Do you have any questions?

• [If yes], please feel free to ask me?

• [If no], our interview is finished. Thank you again for participating this interview.

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Appendix J Ethics approval for qualitative study granted by the ethics committee of the

Guangdong Provincial Hospital of Chinese Medicine, China

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Appendix K Ethics approval for qualitative study registered with the RMIT University

Science Engeneering and Health College Human Ethics Advisory Network, Australia

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