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For peer review only
Herbal medicine (Ganmai Dazao Decoction) for depression:
a systematic review protocol
Journal: BMJ Open
Manuscript ID: bmjopen-2013-003690
Article Type: Protocol
Date Submitted by the Author: 30-Jul-2013
Complete List of Authors: Jun, Ji Hee; Korea Institute of Oriental Medicine, Choi, Tae-Young; Korea Institute of Oriental Medicine, Yun, Kyung-Jin; Korea Institute of Oriental Medicine, Lee, Myeong Soo; Korea Institute of Oriental Medicine,
<b>Primary Subject Heading</b>:
Complementary medicine
Secondary Subject Heading: Complementary medicine, Mental health
Keywords: COMPLEMENTARY MEDICINE, MENTAL HEALTH, Depression & mood
disorders < PSYCHIATRY
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Herbal medicine (Ganmai Dazao Decoction) for depression:
a systematic review protocol
Ji Hee Jun, Tae-Young Choi, Kyung-Jin Yun, Myeong Soo Lee*
Medical Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
*Correspondence to:
Myeong Soo Lee, PhD
Medical Research Division,
Korea Institute of Oriental Medicine,
Daejeon, 305-811, South Korea
Tel: 82-(0)42-868-9266
Fax: 82-(0)42-868-9622
E-mail: [email protected]
Jun JH: [email protected]
Choi T-Y: [email protected]
Yun K-J: [email protected]
Lee MS: [email protected]
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License statement
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behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a
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Article focus
� The aim of systematic review is to analyse trial data on the effectiveness of herbal
medicine (Ganmai Dazao Decoction) in treating depression.
Key messages
� This systematic review will be performed using a comprehensive search strategy and
will determine the current status of evidence with unbiased methods.
Strengths and limitations of this study
� The strength of this systematic review is its extensive, unbiased search of various
databases without language restriction.
� Our review will give readers the opportunity to access studies originally published in
East Asian languages that they would otherwise be unable to read.
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Abstract
Introduction: The aim of this systematic review is to analyse trial data on the effectiveness
of a herbal medicine (Ganmai Dazao Decoction (GDD)) in treating depression.
Methods and analysis: Twelve databases will be searched from their inception: PubMed,
EMBASE, AMED, the Cochrane Library, five Korean medical databases (KoreaMed, DBpia,
OASIS, the Research Information Service System (RISS), and the Korean Studies
Information Service System (KISS)), and three Chinese medical databases (China National
Knowledge Infrastructure (CNKI), the Wanfang Database, and the Chinese Scientific
Journals Database (VIP)). Randomised clinical trials (RCTs) or quasi-RCTs using GDD
therapy for any type of depression will be considered. The selection of the studies, data
abstraction, and validations will be performed independently by two researchers.
Dissemination: The findings will be disseminated to appropriate audiences via peer-
reviewed publication and conference presentations.
Trial registration number: PROSPERO 2013:CRD42013005100.
Keywords: Depression, complementary and alternative medicine, herbal decoction, Ganmai
Dazao Decoction, randomised clinical trials, systematic review
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Introduction
Description of the condition
The prevalence of depression is up to 10% of the population, with half of affected people
having recurrent symptoms.1 Depression is the most common clinical mental disorder and is
characterised by emotional depression, a loss of interest or pleasure, insomnia, more
dreaming, a loss of appetite, feelings of worthlessness or excessive guilt, and recurrent
thoughts of death or suicide.2 3
This disorder is a common and debilitating condition with a
pervasive impact on the quality of life of both patients and their families.4 Additionally,
depression is a serious mental illness, with a high morbidity rate, a high relapse rate, a high
disability rate, a high suicide rate, and strong negative effects on people’s health. According
to the World Health Organization, depression is the leading cause of disability for all ages and
both sexes worldwide, with an estimated 350 million people affected,5 and in 2020,
depression will become the second largest burden of disease after heart attack.3 Therefore, we
must find effective treatment methods for patients and society.
Description of the intervention
Ganmai Dazao Decoction (GDD) is a classic formula used by Zhang Zongjing to treat
Zangzao syndrome.6 Physicians use this formula for the same condition and for emotional
obstacles, such as mental disease of the heart, liver, and spleen-based prescription, certificate
application addition and subtraction. GDD is a well-known Chinese herbal formula that has
long been used for the treatment of depression. The composition of GDD includes the
following three herbs: Glycyrrhiza, Triticum, and Zizyphi fructus.
How the intervention might work
The key functions of GDD are nourishing the heart and quieting the spirit, invigorating the
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spleen, and replenishing qi from the point of view of traditional Chinese medicine.7 In
addition, GDD tranquilises the mind by means of sweet and moistened herbs that ameliorate
the symptoms.8 Most of studies have shown that the disturbed release of neurotransmitters
(norepinephrine (NE) and 5-hydroxytryptamine (5-HT)) might be associated with an
increased susceptibility to depression.9 10
In animal studies, GDD had certain beneficial
effects on behaviour and brain monoamine neurotransmitters (NE and 5-HT) in a depression
model.8 11
Thus, this herbal medicine may be useful in the treatment of depression.
Why it is important to do this review
Currently, GDD alone or combined with antidepressant drugs is widely used as an effective
alternative method for depression treatment in China. However, there is no critically
appraised evidence, such as a systematic review or meta-analyses, of the potential benefits
and harm of GDD in depression. Therefore, this systematic review aims to summarise and
critically evaluate the evidence from clinical trials that have tested the effectiveness of GDD
as a treatment for depression, either alone or in combination with other antidepressant drugs,
compared with antidepressant drugs alone.
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Methods
Criteria for considering studies for this review
Types of studies
All prospective randomised clinical trials (RCTs) and quasi-RCTs will be included in this
systematic review. Evaluations of the use of GDD for the treatment of depression will be
included in this review. Case studies, case series, qualitative studies, and uncontrolled trials
will be excluded. Trials that failed to provide detailed results will also be excluded.
Dissertations and abstracts will be included if these documents contained sufficient detail for
critical evaluation. No language restrictions will be imposed.
Types of participants
Patients of any age and sex with depression (comorbidity), diagnosed based on the Diagnostic
and Statistical Manual (DSM-IV),12
the International Classification of Mental and Behavioral
Disorders (ICD-10),13 or the Criteria for Classification and Diagnosis of Mental Diseases
(CCMD-3-R) 14 will be included.
Types of interventions
Studies that used a GDD or modified GDD will be included. GDD includes the following
thee herbs: Glycyrrhiza, Triticum, and Zizyphi fructus. Trials of combined interventions with
other types of herbal medicine (e.g., extracts, tablets, capsules, pills, powders, or injections)
or with other decoction treatments will be excluded. Trials in which GDD was used as an
adjunct to conventional treatment, usual care, or standard care will also be included if the
control group received the same concomitant treatments as the GDD group.
The control groups will include antidepressant drug use, placebo use, or no treatment. Herbal
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medicines (e.g., extracts, tablets, capsules, pills, powders, or injections) and other types of
complementary medicine will be excluded.
Types of outcome measures
For inclusion, data on at least one primary outcome need to be reported:
Primary outcomes
1. Treatment efficacy: the number of patients who responded to treatment.
2. Severity of depression (self-reported scale) with the Beck Depression Inventory (BDI) 15
and Hamilton Rating Scale for Depression (HAMD) 16
Secondary outcomes
1. Quality of life
2. Adverse events
Search methods for the identification of studies
Electronic searches
The following databases will be searched from their inception: PubMed, EMBASE, AMED,
the Cochrane Library, five Korean medical databases (KoreaMed, DBpia, OASIS, the
Research Information Service System (RISS), and the Korean Studies Information Service
System (KISS)), and three Chinese medical databases (China National Knowledge
Infrastructure (CNKI), the Wanfang Database, and the Chinese Scientific Journals Database
(VIP)).
Other sources
Studies will also be obtained from the following sources:
- The reference lists of all relevant articles
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- Hand searching of department files
- Unpublished conference proceedings relevant to depression will be reviewed, if available.
Search strategy
The search will be conducted in Korea, Chinese, and English using the following terms:
(depression OR major depression) and (Ganmai Dazao Decoction OR Ganmai Dazao OR
Ganmai Dazao soup OR Ganmai Dazao powder). Only data available in full-text papers will
be reviewed.
Data collection and analysis
Selection of studies
All of the titles and abstracts of studies retrieved with the electronic searches will be
reviewed by two authors (Jun JH and Choi T-Y), and will select relevant articles by title and
abstract. Hard copies of each publication will be reviewed by two independent authors to
determine their inclusion based on the inclusion criteria (Jun JH and Choi T-Y). Any
disagreements will be resolved through discussion by three authors (Jun JH,Choi T-Y and
Yun K-J) and an arbiter (Lee MS). We will contact the authors of the included studies for
clarification if necessary.
Data extraction and management
Two authors (Jun JH and Choi T-Y) will extract data from the selected reports or studies and
independently complete a data collection form. We will use the GRADEpro software in
Cochrane systematic reviews to create a Summary of Findings table. In addition, information
such as the participants, interventions, outcomes and results will be obtained from each report.
Any disagreement between two authors will be resolved by discussion. Another author (Lee
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MS) will act as an arbiter for unresolved disagreements.
Assessment of risk of bias in included studies
According to the guidelines of the Cochrane Handbook of Systematic Reviews of
Interventions, the risk of bias will be assessed to evaluate the methodological quality of the
included studies.17 18 The following domains will be evaluated for methodological quality
based on the following: sequence generation, allocation concealment, blinding of participants
and outcome assessors, incomplete outcome data and selective outcome reporting. The
evaluated domains will be judged as "Low", "High" or "Uncertain" according to the criteria
of the Cochrane guidelines.
Measures of treatment effect
Dichotomous data will be presented as a risk ratio (RR) with 95% confidence intervals (CIs).
For continuous data, the mean difference (MD) will be used with 95% CIs. In cases of
outcome variables with different scales, the standard mean difference (SMD) will be used
instead of weighted MD (WMD).
Unit of analysis issues
Principal data from the parallel-group studies will be included in the meta-analysis. If there
are cross-over trials, the first phase of the data will be adopted for analysis. Data from
multiple time-point observations will be classified as either short-term (within 4 weeks) or
long-term (over 4 weeks) follow-up, and analysis will be conducted.
Dealing with missing data
If there are missing data for statistical analysis, we will make an effort to contact the original
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authors of the study to obtain any missing or incomplete information.
Assessment of heterogeneity
The fixed-effects model and the random-effects model will be simultaneously used for the
meta-analysis. Heterogeneity will be tested with the Higgins I2 test. We will conduct the I
2
statistic, which will provide the quantity of inconsistencies among the included studies. We
will use a 50% cut-off point for meaningful heterogeneity among the included studies. If
heterogeneity is observed, subgroup analysis will be conducted.19
Assessment of reporting biases
Funnel plots will be used to detect reporting biases and small-study effects. If more than 10
studies are included in the meta-analysis, the test for funnel plot asymmetry will be
conducted using Egger's method. 20 21
Data synthesis
If a significant number of studies are identified, a meta-analysis will be conducted according
to simultaneous use of the fixed-effect and random-effect models. All statistical analysis
performed using RevMan 5.1 (the Cochrane Collaboration) software. To summarize the
effects of a ganmai dazao decoction on outcomes (response rate), we abstracted the risk
estimates (relative risk, RR), and a 95% confidence interval (CI) was calculated using
Review Manager Version 5.0 for Windows (Cochrane Collaboration’s software). For studies
with insufficient information, we contacted the primary authors to acquire and verify data
where possible. If appropriate, we then pooled the data across studies using random effect
models.
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Subgroup analysis and investigation of heterogeneity
To explore differences in effect sizes, subgroup analyses will be conducted on the following
topics: the severity of depression, sex, the type of GDD, the design of the trial (e.g., crossover
group or and parallel group), and the dose of GDD and treatment frequency.
Sensitivity analysis
Sensitivity analysis will be principally conducted according to the following criteria:
1. Methodological qualities (sequence generation, allocation concealment, or blinding)
2. Sample size (small sample studies, e.g., less than 40 subjects in each group, or large
sample studies, e.g., more than 40 subjects in each group)
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Ethics and dissemination
Ethical approval is not required, given that this protocol is for a systematic review. The
findings of this review will be disseminated widely through peer-reviewed publication and
conference presentation.
Discussion
This systematic review will provide a detailed summary of the current status of evidence of
the effectiveness of the herbal medicine GDD in treating the symptoms of patients with
depression. The review will benefit patients and practitioners in the field of traditional and
complementary medicine.
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Contribution of authors
The protocol was drafted by Jun JH, Choi T-Y, Yun K-J, and Lee MS. The search strategy
was developed and will be run by Jun JH and Choi T-Y. Copies of studies will be obtained by
Jun JH and Choi T-Y. Selection of the studies to include will be done by Jun JH and Choi T-
Y. Lee MS will act as an arbiter in the study selection stage. Extraction of data from studies
will be conducted by Jun JH and Choi T-Y. Entering data into RevMan will be conducted by
Jun JH and Yun K-J. Carrying out the analysis will be done by Jun JH and Lee MS.
Interpretation of the analysis will be done by Jun JH, Choi T-Y, Yun K-J, and Lee MS. The
final review will be drafted Jun JH, Choi T-Y, Yun K-J, and Lee MS. The review will be
updated by Jun JH and Lee MS.
Competing interests
None declared
Funding
No external funding was received. The authors were supported by Korea Institute of Oriental
Medicine (K13400, K13130, K13281).
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References
1. Cipriani A, Barbui C, Butler R, Hatcher S, Geddes J. Depression in adults: drug and
physical treatments. Clin Evid (Online) 2011;2011(05):1003.
2. Organization WH. Depression: definition. Available at http://www.euro.who.int/en/what-
we-do/health-topics/noncommunicable-diseases/sections/news/2012/10/depression-
in-europe/depression-definition.
3. World Health Organization. Mental health: depression in Europe. Avaible at
http://www.euro.who.int/en/what-we-do/health-topics/noncommunicable-
diseases/mental-health/news/news/2012/10/depression-in-europe, 2012.
4. Wray NR, Pergadia ML, Blackwood DH, Penninx BW, Gordon SD, Nyholt DR, et al.
Genome-wide association study of major depressive disorder: new results, meta-
analysis, and lessons learned. Mol Psychiat 2012;17(1):36-48.
5. World Health Organization. Depression. Available at
http://www.who.int/topics/depression/en/, 2012.
6. Li CX, Cao S, Zhang Y, Yang XN. Discussion on the selection of "weat" in Ganmai Dazao
Decoction J Chin Med 2012(08):993-94.
7. Zhou ZY. Internal Medicine of Traditional Chinese Medicine. Beijing: Chinese TCM
Publishing House, 2007.
8. Zhang X, L., Dai WW, Jin GQ, Xia HY, Yao LA, Gong ZB, et al. Depression model rats
hippocampal receptor ion channel gene expression profile changes and modified
ganmai dazao decoction. Pharmacol Clin Chin Mater Med 2011(06):6-10.
9. Kiyohara C, Yoshimasu K. Association between major depressive disorder and a functional
polymorphism of the 5-hydroxytryptamine (serotonin) transporter gene: a meta-
analysis. Psychiatr Genet 2010;20(2):49-58.
10. Li XR, Sun N, Wang YF, Li SP, Du QR, Peng JY, et al. The norepinephrine transporter
Page 15 of 17
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BMJ Open
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rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2013-003690 on 6 January 2014. D
ownloaded from
For peer review only
gene is associated with the retardation symptoms of major depressive disorder in the
Han Chinese population. Neural Regen Res 2012;7(25):1985-91.
11. Zhang Q, Yang J, Liu YX, Liu YP, Zhou QZ. Influence on neurotransmitter in brain of
depressed model rat treated by Bai-di-gan-zao Decoction. J Chengdu Univ TCM
2006(02):21-23.
12. American Psychiatric Association. Diagnostic and statistical manual of mental disorders.
4th ed. Washington, DC: American Psychiatric Association, 1994.
13. World Health Organisation. The ICD-10 Classification o mental and Behavioural
Disorders. Diagnostic Criteria for Research. Geneva: World Health Organisation,
1993.
14. Chinese Psychiatric Society. The Chinese classification of mental disorders [CCMD-3].
Shandong, China: Shandong Publishing House of Science and Technology, 2001.
15. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring
depression. Arch Gen Psychiatry 1961;4:561-71.
16. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.
17. Higgins J, Green SP. Cochrane handbook for systematic reviews of interventions. Oxford:
Wiley-Blackwell, 2008.
18. Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included
studies. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0 (updated March 2011). : The Cochrane
Collaboration. Available from www.cochrane-handbook.org, 2011.
19. Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing data and undertaking meta-
analyses. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0 (updated March 2011). : The Cochrane
Collaboration. Available from www.cochrane-handbook.org, 2011.
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jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2013-003690 on 6 January 2014. D
ownloaded from
For peer review only
20. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a
simple, graphical test. BMJ 1997;315(7109):629-34.
21. Sterne JAC, Egger M, Moher D. Chapter 10: Addressing reporting biases. In: Higgins JPT,
Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions
Version 5.1.0 (updated March 2011). : The Cochrane Collaboration. Available from
www.cochrane-handbook.org, 2011.
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Herbal medicine (Gan Mai Da Zao Decoction) for depression:
a systematic review protocol
Journal: BMJ Open
Manuscript ID: bmjopen-2013-003690.R1
Article Type: Protocol
Date Submitted by the Author: 20-Nov-2013
Complete List of Authors: Jun, Ji Hee; Korea Institute of Oriental Medicine, Lee, Ju Ah; Korea Institute of Oriental Medicine, Choi, Tae-Young; Korea Institute of Oriental Medicine, Yun, Kyung-Jin; Korea Institute of Oriental Medicine, Lim, Hyun-Ja; Chodang University, Lee, Myeong Soo; Korea Institute of Oriental Medicine,
<b>Primary Subject Heading</b>:
Complementary medicine
Secondary Subject Heading: Complementary medicine, Mental health, Pharmacology and therapeutics
Keywords: COMPLEMENTARY MEDICINE, MENTAL HEALTH, Depression & mood disorders < PSYCHIATRY
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Herbal medicine (Gan Mai Da Zao Decoction) for depression:
a systematic review protocol
Ji Hee Jun,1 Ju Ah Lee,
1 Tae-Young Choi,
1 Kyung-Jin Yun,
1 Hyun-Ja Lim,
2
Myeong Soo Lee1,*
1Medical Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
2 Department of Nursing, Chodang University, Muan, South Korea
*Correspondence to:
Myeong Soo Lee, PhD
Medical Research Division,
Korea Institute of Oriental Medicine,
Daejeon, 305-811, South Korea
Tel: 82-(0)42-868-9266
Fax: 82-(0)42-868-9622
E-mail: [email protected]
Jun JH: [email protected]
Lee JA: [email protected]
Choi T-Y: [email protected]
Yun K-J: [email protected]
Lim HJ: [email protected]
Lee MS: [email protected]
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Article focus
� The aim of this systematic review is to analyse trial data on the effectiveness of an
herbal medicine (Gan Mai Da Zao decoction) in treating depression.
Key messages
� This systematic review will be performed using a comprehensive search strategy and
will determine the current state of evidence using unbiased methods.
Strengths and limitations of this study
� The strength of this systematic review is its extensive, unbiased search of various
databases without language restrictions.
� Our review will give readers the opportunity to access studies originally published in
East Asian languages that they would otherwise be unable to read.
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Abstract
Introduction: The aim of this systematic review is to analyse trial data on the effectiveness
of an herbal medicine (Gan Mai Da Zao (GMDZ) decoction) in treating depression.
Methods and analysis: Twelve databases will be searched from their inception: PubMed,
EMBASE, AMED, the Cochrane Library, five Korean medical databases (KoreaMed, DBpia,
OASIS, the Research Information Service System (RISS), and the Korean Studies
Information Service System (KISS)), and three Chinese medical databases (China National
Knowledge Infrastructure (CNKI), the Wanfang Database, and the Chinese Scientific
Journals Database (VIP)). Randomised clinical trials (RCTs) or quasi-RCTs using a GMDZ
decoction for any type of depression will be considered. The selection of the studies, data
abstraction, and validations will be performed independently by two researchers.
Dissemination: The findings will be disseminated to appropriate audiences via peer-
reviewed publication and conference presentations.
Trial registration number: PROSPERO 2013:CRD42013005100.
Keywords: Depression, complementary and alternative medicine, herbal decoction, Gan Mai
Da Zao decoction, randomised clinical trials, systematic review
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Introduction
Description of the condition
The prevalence of depression is as high as 10% of the population, with half of affected people
having recurrent symptoms.1 Depression is the most common clinical mental disorder and is
characterised by emotional depression, a loss of interest or pleasure, insomnia, increased
dreaming, a loss of appetite, feelings of worthlessness or excessive guilt, and recurrent
thoughts of death or suicide.2 3 This disorder is a common and debilitating condition with a
pervasive impact on the quality of life of both patients and their families. 4 Additionally,
depression is a serious mental illness, with a high morbidity rate, a high relapse rate, a high
disability rate, a high suicide rate, and strong negative effects on people’s health. According
to the World Health Organisation, depression is the leading cause of disability for all ages and
both sexes worldwide, with an estimated 350 million people affected,5 and in 2020,
depression will become the second largest burden of disease after heart attack.3 Therefore, we
must find effective treatment methods for patients and society.
Description of the intervention
The Gan Mai Da Zao (GMDZ) decoction is one of most well-known herbal prescriptions for
depression, and its use was first documented in the Jin Gui Yao Lue (Synopsis of
Prescriptions of the Golden Chamber), a classical Chinese medical book by Dr. Zongjing
Zhang (AD 152-219). 6 The composition of GMDZ decoction includes the three herbs
Glycyrrhiza, Triticum, and Zizyphi fructus. Many pharmaceutical companies around the
world manufacture GMDZ to manage depression and emotional disturbances. They are
regulated as pharmaceutical drugs in China, Japan, Korea and Taiwan and as dietary
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supplements in North America. Several forms of GMDZ are available, such as extracts,
tablets, capsules, pills, powders, or injections. The composition of commercial GMDZ per
100 g is generally 16.1 g Glycyrrhiza, 64.5 g Triticum, and 19.4 g Zizyphi fructus and the
dosage is 2.00-3.25 g/day for adults. Physicians have used this formula for depression and
for emotional problems. Several studies have demonstrated the antidepressant effects of the
GMDZ decoction. 7 8
How the intervention might work
GMDZ may improve depression symptoms by reducing glutamate levels and increasing the
N-methyl-D-aspartate receptor (NR) subunits NR2A and NR2B in the frontal cortex and
hippocampus. 9 The GMDZ decoction had beneficial effects on behaviour and brain
monoamine neurotransmitter levels (NE and 5-HT) in a depression model.10 11
However,
further studies are required to identify the exact mechanisms of action.
Why it is important to this review
Currently, the GMDZ decoction alone or combined with antidepressant drugs is widely used
as an effective alternative method for depression treatment in China. However, there is no
critically appraised evidence, such as a systematic review or meta-analyses, of the potential
benefits and harm of the GMDZ decoction in depression. Therefore, this systematic review
aims to summarise and critically evaluate the evidence from clinical trials that have tested the
effectiveness of the GMDZ decoction as a treatment for depression, either alone or in
combination with other antidepressant drugs, compared with antidepressant drugs alone.
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Methods
Criteria for considering studies for this review
Types of studies
All prospective randomised clinical trials (RCTs) and quasi-RCTs (RCTs in which the
allocation to treatment was obtained by alternation, the use of alternate medical records, date
of birth or other predictable methods) will be included in this systematic review. All
evaluations of the use of the GMDZ decoction for the treatment of depression will be
included in this review. Case studies, case series, qualitative studies, and uncontrolled trials
will be excluded. Trials that failed to provide detailed results will also be excluded.
Dissertations and abstracts will be included if these documents contain sufficient detail for
critical evaluation. No language restrictions will be imposed. If we encounter languages other
than English, Korean and Chinese, we will either contact the original authors or translate the
manuscript using a professional service.
Types of participants
Patients of any age and sex with depression (comorbidity), diagnosed based on the Diagnostic
and Statistical Manual (DSM-IV),12 the International Classification of Mental and
Behavioural Disorders (ICD-10),13 or the Criteria for Classification and Diagnosis of Mental
Diseases (CCMD-3-R) 14 will be included.
Types of interventions
Studies that used a GMDZ decoction or a modified GMDZ decoction will be included. A
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GMDZ decoction includes the following three herbs: Glycyrrhiza, Triticum, and Zizyphi
fructus. We will include all forms of this medication, such as extracts, tablets, capsules, pills,
powders, or injections. The modified GMDZ decoction formula is defined by practitioners as
a decoction with no more than one herb of the three original herbs, but which has almost the
same actions as the original GMDZ decoction formula. Trials of combined interventions with
other decoction treatments will be excluded. Trials in which the GMDZ decoction was used
as an adjunct to conventional treatment (treatments that are widely accepted and used by the
mainstream medical community, including antidepressants), usual care (which can include
routine care received by patients for prevention or treatment of disease), or standard care (the
ordinary level of skill and care that any health care practitioner would be expected to observe
in caring for patients) will also be included if the control group received the same
concomitant treatments as the GMDZ decoction group. The control groups will include
antidepressant drug use, placebo use, no treatment and usual care or standard care.
Types of outcome measures
For inclusion, data on at least one primary outcome needs to be reported:
Primary outcomes
1. Treatment efficacy: the number of patients whose depression symptoms improved
2. Severity of depression (self-reported scale) with the Beck Depression Inventory (BDI) 15
and the Hamilton Rating Scale for Depression (HAMD) 16
Secondary outcomes
1. Quality of life
2. Adverse events
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Search methods for the identification of studies
Electronic searches
The following databases will be searched from their inception: PubMed, EMBASE, AMED,
the Cochrane Library, five Korean medical databases (KoreaMed, DBpia, OASIS, the
Research Information Service System (RISS), and the Korean Studies Information Service
System (KISS)), and three Chinese medical databases (China National Knowledge
Infrastructure (CNKI), the Wanfang Database, and the Chinese Scientific Journals Database
(VIP)).
Other sources
Studies will also be obtained from the following sources:
- The reference lists of all relevant articles
- Hand searching of department files
- Unpublished conference proceedings relevant to depression will be reviewed, if available.
Search strategy
The search will be conducted in Korean, Chinese, and English using the following terms:
(depression OR Melancholia OR major depression OR post stroke depression OR postpartum
depression OR involutional depression OR climacteric depression OR senile depression)
AND (gan mai da zao OR gan mai da zao tang OR ganmai dazao OR ganmai dazao tang OR
gan mai da zao* OR modified gan mai da zao OR modified ganmai dazao OR
kambakutaisoto OR kam baku tai soto). These strategies will be modified for use with other
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databases.
Data collection and analysis
Selection of studies
All of the titles and abstracts of studies retrieved with the electronic searches will be
reviewed by three authors (Jun JH, Lee JA and Choi T-Y), who will select relevant articles by
title and abstract. Hard copies of each publication will be reviewed by three independent
authors to determine their inclusion based on the inclusion criteria (Jun JH, Lee JA and Choi
T-Y). Any disagreements will be resolved through discussion by three authors (Jun JH, Choi
T-Y and Yun K-J) and an arbiter (Lee MS). We will contact the authors of the included
studies for clarification if necessary. The details of the study selection are shown in a
PRISMA flow chart (Figure 1).
Data extraction and management
Two authors (Jun JH and Choi T-Y) will extract data from the selected reports or studies and
independently complete a data collection form. We will use GRADEpro software in the
Cochrane Systematic Reviews to create a Summary of Findings table. In addition,
information such as the participants, interventions, outcomes and results will be obtained
from each report. Any disagreement between the two authors will be resolved by discussion.
Another author (Lee MS) will act as an arbiter for unresolved disagreements.
Assessment of risk of bias in included studies
According to the guidelines of the Cochrane Handbook of Systematic Reviews of
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Interventions, the risk of bias will be assessed to evaluate the methodological quality of the
included studies. 17 The following domains will be evaluated for methodological quality:
sequence generation, allocation concealment, blinding of participants and outcome assessors,
incomplete outcome data and selective outcome reporting. The evaluated domains will be
judged as "Low", "High" or "Uncertain" according to the criteria of the Cochrane guidelines.
Measures of treatment effect
Dichotomous data will be presented as a risk ratio (RR) with 95% confidence intervals (CIs).
For continuous data, the mean difference (MD) will be used with 95% CIs. In cases of
outcome variables with different scales, the standard mean difference (SMD) will be used
instead of the weighted MD (WMD).
Unit of analysis issues
The meta-analysis will include data from parallel-group design studies. In the case of cross-
over trials, we will use the first phase of the data. If there are multiple time-point observations,
the data will be analysed as either short-term (within 4 weeks) or long-term (over 4 weeks)
follow-up.
Dealing with missing data
If missing data are detected, we will request any missing or incomplete information from the
original study investigators.
Assessment of heterogeneity
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A fixed-effects model and a random-effects model will be simultaneously used for the meta-
analysis. Heterogeneity will be tested with the Higgins I2 test. We will calculate the I
2
statistic, which will provide a measure of the inconsistencies among the included studies. We
will use a 50% cut-off point for meaningful heterogeneity among the included studies. If
heterogeneity is observed, subgroup analysis will be conducted.18
Assessment of reporting biases
Funnel plots will be used to detect reporting biases and small-study effects. If more than 10
studies are included in the meta-analysis, the test for funnel plot asymmetry will be
conducted using Egger's method. 19 20
Data synthesis
If a significant number of studies are identified, a meta-analysis will be conducted with
simultaneous use of fixed-effect and random-effect models. All statistical analyses will be
performed using RevMan 5.1 (the Cochrane Collaboration) software. To summarise the
effects of a Gan Mai Da Zao decoction on outcomes (response rate), we will abstract the risk
estimates (relative risk, RR), and 95% confidence intervals (CI) using Review Manager
Version 5.0 for Windows (Cochrane Collaboration’s software). For studies with insufficient
information, we will contact the primary authors to acquire and verify data where possible. If
appropriate, we will then pool the data across studies using random effect models.
Subgroup analysis and investigation of heterogeneity
To explore differences in effect sizes, subgroup analyses will be conducted on the following
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topics: the severity of depression, sex, the type of GMDZ decoction, the design of the trial
(e.g., crossover group or parallel group), the dose of GMDZ decoction, and treatment
frequency. We will also summarise the standardisation and characteristics of GMDZ
decoctions from all included studies.
Sensitivity analysis
Sensitivity analysis will be conducted according to the following criteria:
1. Methodological qualities (sequence generation, allocation concealment, or blinding)
2. Sample size (small sample studies, e.g., less than 40 subjects in each group, or large
sample studies, e.g., more than 40 subjects in each group)
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Ethics and dissemination
Ethical approval is not required, given that this protocol is for a systematic review. The
findings of this review will be disseminated widely through peer-reviewed publications and
conference presentations.
Discussion
This systematic review will provide a detailed summary of the current state of evidence on
the effectiveness of the herbal medicine GMDZ decoction in treating the symptoms of
patients with depression. The review will benefit patients and practitioners in the field of
traditional and complementary medicine.
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Contribution of authors
The protocol was drafted by Jun JH, Lee JA, Choi T-Y, Yun K-J, Lim HJ and Lee MS. The
search strategy was developed and will be run by Jun JH and Lee JA. Copies of studies will
be obtained by Jun JH, Lee JA and Choi T-Y. Selection of the studies to include will be done
by Jun JH, Lee JA and Choi T-Y. Lee MS will act as an arbiter in the study selection stage.
Extraction of data from studies will be conducted by Jun JH, Lee JA and Choi T-Y. Entering
data into RevMan will be conducted by Lee JA and Yun K-J. Carrying out the analysis will
be done by Jun JH, Lee JA and Lee MS. Interpretation of the analysis will be done by Jun JH,
Choi T-Y, Yun K-J, and Lee MS. The final review will be drafted Jun JH, Lee JA, Choi T-Y,
Yun K-J, Lim HJ, and Lee MS. The review will be updated by Jun JH and Lee MS.
Competing interests
None declared
Funding
No external funding was received. The authors were supported by Korea Institute of Oriental
Medicine (K13400, K13130, K13281).
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References
1. Cipriani A, Barbui C, Butler R, et al. Depression in adults: drug and physical treatments.
Clin Evid 2011;2011(05):1003.
2. World Health Organization. Depression: definition. Available at
http://www.euro.who.int/en/what-we-do/health-topics/noncommunicable-
diseases/sections/news/2012/10/depression-in-europe/depression-definition. Accessed
Nov, 20, 2013.3. World Health Organization. Mental health: depression in Europe.
Avaible at
http://www.euro.who.int/en/what-we-do/health-topics/noncommunicable-
diseases/mental-health/news/news/2012/10/depression-in-europe. Accessed Nov, 20,
2013.
4. Wray NR, Pergadia ML, Blackwood DH, et al. Genome-wide association study of major
depressive disorder: new results, meta-analysis, and lessons learned. Mol Psychiat
2012;17(1):36-48.
5. World Health Organization. Depression. Available at
http://www.who.int/topics/depression/en/. Accessed Nov, 20, 2013.
6. Ruan J. Chinese-english Synopsis of Prescription of the Golden Chamber. Shanghai,
China: Shanghai Science and Technology Publishing Company, 2003.
7. Wu J. Antidepressant effect of gan-mai-da-zao tang on depression compared with
fluoxetine. J Chin Physician 2002;30:18-19.
8. Yang FE, Qiao QF, Gong YP. Antidepressant effect of gan-mai-da-zao tang on 30 women
with postpartum depression. Shanxi J TCM 2009;30:851-52.
Page 16 of 39
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rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2013-003690 on 6 January 2014. D
ownloaded from
For peer review only
17
9. Lou JS, Li CY, Yang XC, et al. Protective effect of gan mai da zao decoction in
unpredictable chronic mild stress-induced behavioral and biochemical alterations.
Pharm Biol 2010;48(12):1328-36.
10. Zhang Q, Yang J, Liu YX, et al. Influence on neurotransmitter in brain of depressed
model rat treated by Bai-di-gan-zao Decoction. J Chengdu Univ TCM 2006(02):21-23.
11. Zhang X, L., Dai WW, Jin GQ, et al. Depression model rats hippocampal receptor ion
channel gene expression profile changes and modified ganmai dazao decoction.
Pharmacol Clin Chin Mater Med 2011(06):6-10.
12. American Psychiatric Association. Diagnostic and statistical manual of mental disorders.
4th ed. Washington, DC: American Psychiatric Association, 1994.
13. World Health Organisation. The ICD-10 Classification o mental and Behavioural
Disorders. Diagnostic Criteria for Research. Geneva: World Health Organisation,
1993.
14. Chinese Psychiatric Society. The Chinese classification of mental disorders [CCMD-3].
Shandong, China: Shandong Publishing House of Science and Technology, 2001.
15. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch
Gen Psychiatry 1961;4:561-71.
16. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.
17. Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included
studies. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0 (updated March 2011). : The Cochrane
Collaboration. Available from www.cochrane-handbook.org, 2011.
18. Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing data and undertaking meta-
Page 17 of 39
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jopen.bmj.com
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MJ O
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For peer review only
18
analyses. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0 (updated March 2011). : The Cochrane
Collaboration. Available from www.cochrane-handbook.org, 2011.
19. Egger M, Davey Smith G, et al. Bias in meta-analysis detected by a simple, graphical test.
BMJ 1997;315(7109):629-34.
20. Sterne JAC, Egger M, Moher D. Chapter 10: Addressing reporting biases. In: Higgins JPT,
Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version
5.1.0 (updated March 2011). : The Cochrane Collaboration. Available from
www.cochrane-handbook.org, 2011.
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Figure legends
Figure 1. Flow diagram of the trial selection process. NRS: non randomised studies.
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Herbal medicine (Gan Mai Da Zao Decoction) for depression:
a systematic review protocol
Ji Hee Jun,1 Ju Ah Lee,
1 Tae-Young Choi,
1 Kyung-Jin Yun,
1 Hyun-Ja Lim,
2
Myeong Soo Lee1,*
1Medical Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea
2 Department of Nursing, Chodang University, Muan, South Korea
*Correspondence to:
Myeong Soo Lee, PhD
Medical Research Division,
Korea Institute of Oriental Medicine,
Daejeon, 305-811, South Korea
Tel: 82-(0)42-868-9266
Fax: 82-(0)42-868-9622
E-mail: [email protected]
Jun JH: [email protected]
Lee JA: [email protected]
Choi T-Y: [email protected]
Yun K-J: [email protected]
Lim HJ: [email protected]
Lee MS: [email protected]
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License statement
The Corresponding Author has the right to grant on behalf of all authors and does grant on
behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a
worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if
accepted) to be published in BMJ Open and any other BMJPGL products to exploit all
subsidiary rights, as set out in our licence (http://group.bmj.com/products/journals/
instructions-for-authors/licence-forms).
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Article focus
� The aim of this systematic review is to analyse trial data on the effectiveness of an
herbal medicine (Gan Mai Da Zao decoction) in treating depression.
Key messages
� This systematic review will be performed using a comprehensive search strategy and
will determine the current state of evidence using unbiased methods.
Strengths and limitations of this study
� The strength of this systematic review is its extensive, unbiased search of various
databases without language restrictions.
� Our review will give readers the opportunity to access studies originally published in
East Asian languages that they would otherwise be unable to read.
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Abstract
Introduction: The aim of this systematic review is to analyse trial data on the effectiveness
of an herbal medicine (Gan Mai Da Zao (GMDZ) decoction) in treating depression.
Methods and analysis: Twelve databases will be searched from their inception: PubMed,
EMBASE, AMED, the Cochrane Library, five Korean medical databases (KoreaMed, DBpia,
OASIS, the Research Information Service System (RISS), and the Korean Studies
Information Service System (KISS)), and three Chinese medical databases (China National
Knowledge Infrastructure (CNKI), the Wanfang Database, and the Chinese Scientific
Journals Database (VIP)). Randomised clinical trials (RCTs) or quasi-RCTs using a GMDZ
decoction for any type of depression will be considered. The selection of the studies, data
abstraction, and validations will be performed independently by two researchers.
Dissemination: The findings will be disseminated to appropriate audiences via peer-
reviewed publication and conference presentations.
Trial registration number: PROSPERO 2013:CRD42013005100.
Keywords: Depression, complementary and alternative medicine, herbal decoction, Gan Mai
Da Zao decoction, randomised clinical trials, systematic review
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Introduction
Description of the condition
The prevalence of depression is as high as 10% of the population, with half of affected people
having recurrent symptoms.1 Depression is the most common clinical mental disorder and is
characterised by emotional depression, a loss of interest or pleasure, insomnia, increased
dreaming, a loss of appetite, feelings of worthlessness or excessive guilt, and recurrent
thoughts of death or suicide.2 3 This disorder is a common and debilitating condition with a
pervasive impact on the quality of life of both patients and their families. 4 Additionally,
depression is a serious mental illness, with a high morbidity rate, a high relapse rate, a high
disability rate, a high suicide rate, and strong negative effects on people’s health. According
to the World Health Organisation, depression is the leading cause of disability for all ages and
both sexes worldwide, with an estimated 350 million people affected,5 and in 2020,
depression will become the second largest burden of disease after heart attack.3 Therefore, we
must find effective treatment methods for patients and society.
Description of the intervention
The Gan Mai Da Zao (GMDZ) decoction is one of most well-known herbal prescriptions for
depression, and its use was first documented in the Jin Gui Yao Lue (Synopsis of
Prescriptions of the Golden Chamber), a classical Chinese medical book by Dr. Zongjing
Zhang (AD 152-219). 6 The composition of GMDZ decoction includes the three herbs
Glycyrrhiza, Triticum, and Zizyphi fructus. Many pharmaceutical companies around the
world manufacture GMDZ to manage depression and emotional disturbances. They are
regulated as pharmaceutical drugs in China, Japan, Korea and Taiwan and as dietary
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supplements in North America. Several forms of GMDZ are available, such as extracts,
tablets, capsules, pills, powders, or injections. The composition of commercial GMDZ per
100 g is generally 16.1 g Glycyrrhiza, 64.5 g Triticum, and 19.4 g Zizyphi fructus and the
dosage is 2.00-3.25 g/day for adults. Physicians have used this formula for depression and
for emotional problems. Several studies have demonstrated the antidepressant effects of the
GMDZ decoction. 7 8
How the intervention might work
GMDZ may improve depression symptoms by reducing glutamate levels and increasing the
N-methyl-D-aspartate receptor (NR) subunits NR2A and NR2B in the frontal cortex and
hippocampus. 9 The GMDZ decoction had beneficial effects on behaviour and brain
monoamine neurotransmitter levels (NE and 5-HT) in a depression model.10 11
However,
further studies are required to identify the exact mechanisms of action.
Why it is important to this review
Currently, the GMDZ decoction alone or combined with antidepressant drugs is widely used
as an effective alternative method for depression treatment in China. However, there is no
critically appraised evidence, such as a systematic review or meta-analyses, of the potential
benefits and harm of the GMDZ decoction in depression. Therefore, this systematic review
aims to summarise and critically evaluate the evidence from clinical trials that have tested the
effectiveness of the GMDZ decoction as a treatment for depression, either alone or in
combination with other antidepressant drugs, compared with antidepressant drugs alone.
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Methods
Criteria for considering studies for this review
Types of studies
All prospective randomised clinical trials (RCTs) and quasi-RCTs (RCTs in which the
allocation to treatment was obtained by alternation, the use of alternate medical records, date
of birth or other predictable methods) will be included in this systematic review. All
evaluations of the use of the GMDZ decoction for the treatment of depression will be
included in this review. Case studies, case series, qualitative studies, and uncontrolled trials
will be excluded. Trials that failed to provide detailed results will also be excluded.
Dissertations and abstracts will be included if these documents contain sufficient detail for
critical evaluation. No language restrictions will be imposed. If we encounter languages other
than English, Korean and Chinese, we will either contact the original authors or translate the
manuscript using a professional service.
Types of participants
Patients of any age and sex with depression (comorbidity), diagnosed based on the Diagnostic
and Statistical Manual (DSM-IV),12 the International Classification of Mental and
Behavioural Disorders (ICD-10),13 or the Criteria for Classification and Diagnosis of Mental
Diseases (CCMD-3-R) 14 will be included.
Types of interventions
Studies that used a GMDZ decoction or a modified GMDZ decoction will be included. A
GMDZ decoction includes the following three herbs: Glycyrrhiza, Triticum, and Zizyphi
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fructus. We will include all forms of this medication, such as extracts, tablets, capsules, pills,
powders, or injections. The modified GMDZ decoction formula is defined by practitioners as
a decoction with no more than one herb of the three original herbs, but which has almost the
same actions as the original GMDZ decoction formula. Trials of combined interventions with
other decoction treatments will be excluded. Trials in which the GMDZ decoction was used
as an adjunct to conventional treatment (treatments that are widely accepted and used by the
mainstream medical community, including antidepressants), usual care (which can include
routine care received by patients for prevention or treatment of disease), or standard care (the
ordinary level of skill and care that any health care practitioner would be expected to observe
in caring for patients) will also be included if the control group received the same
concomitant treatments as the GMDZ decoction group. The control groups will include
antidepressant drug use, placebo use, no treatment and usual care or standard care.
Types of outcome measures
For inclusion, data on at least one primary outcome needs to be reported:
Primary outcomes
1. Treatment efficacy: the number of patients whose depression symptoms improved
2. Severity of depression (self-reported scale) with the Beck Depression Inventory (BDI) 15
and the Hamilton Rating Scale for Depression (HAMD) 16
Secondary outcomes
1. Quality of life
2. Adverse events
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Search methods for the identification of studies
Electronic searches
The following databases will be searched from their inception: PubMed, EMBASE, AMED,
the Cochrane Library, five Korean medical databases (KoreaMed, DBpia, OASIS, the
Research Information Service System (RISS), and the Korean Studies Information Service
System (KISS)), and three Chinese medical databases (China National Knowledge
Infrastructure (CNKI), the Wanfang Database, and the Chinese Scientific Journals Database
(VIP)).
Other sources
Studies will also be obtained from the following sources:
- The reference lists of all relevant articles
- Hand searching of department files
- Unpublished conference proceedings relevant to depression will be reviewed, if available.
Search strategy
The search will be conducted in Korean, Chinese, and English using the following terms:
(depression OR Melancholia OR major depression OR post stroke depression OR postpartum
depression OR involutional depression OR climacteric depression OR senile depression)
AND (gan mai da zao OR gan mai da zao tang OR ganmai dazao OR ganmai dazao tang OR
gan mai da zao* OR modified gan mai da zao OR modified ganmai dazao OR
kambakutaisoto OR kam baku tai soto). These strategies will be modified for use with other
databases.
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Data collection and analysis
Selection of studies
All of the titles and abstracts of studies retrieved with the electronic searches will be
reviewed by three authors (Jun JH, Lee JA and Choi T-Y), who will select relevant articles by
title and abstract. Hard copies of each publication will be reviewed by three independent
authors to determine their inclusion based on the inclusion criteria (Jun JH, Lee JA and Choi
T-Y). Any disagreements will be resolved through discussion by three authors (Jun JH, Choi
T-Y and Yun K-J) and an arbiter (Lee MS). We will contact the authors of the included
studies for clarification if necessary. The details of the study selection are shown in a
PRISMA flow chart (Figure 1).
Data extraction and management
Two authors (Jun JH and Choi T-Y) will extract data from the selected reports or studies and
independently complete a data collection form. We will use GRADEpro software in the
Cochrane Systematic Reviews to create a Summary of Findings table. In addition,
information such as the participants, interventions, outcomes and results will be obtained
from each report. Any disagreement between the two authors will be resolved by discussion.
Another author (Lee MS) will act as an arbiter for unresolved disagreements.
Assessment of risk of bias in included studies
According to the guidelines of the Cochrane Handbook of Systematic Reviews of
Interventions, the risk of bias will be assessed to evaluate the methodological quality of the
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included studies. 17 The following domains will be evaluated for methodological quality:
sequence generation, allocation concealment, blinding of participants and outcome assessors,
incomplete outcome data and selective outcome reporting. The evaluated domains will be
judged as "Low", "High" or "Uncertain" according to the criteria of the Cochrane guidelines.
Measures of treatment effect
Dichotomous data will be presented as a risk ratio (RR) with 95% confidence intervals (CIs).
For continuous data, the mean difference (MD) will be used with 95% CIs. In cases of
outcome variables with different scales, the standard mean difference (SMD) will be used
instead of the weighted MD (WMD).
Unit of analysis issues
The meta-analysis will include data from parallel-group design studies. In the case of cross-
over trials, we will use the first phase of the data. If there are multiple time-point observations,
the data will be analysed as either short-term (within 4 weeks) or long-term (over 4 weeks)
follow-up.
Dealing with missing data
If missing data are detected, we will request any missing or incomplete information from the
original study investigators.
Assessment of heterogeneity
A fixed-effects model and a random-effects model will be simultaneously used for the meta-
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analysis. Heterogeneity will be tested with the Higgins I2 test. We will calculate the I
2
statistic, which will provide a measure of the inconsistencies among the included studies. We
will use a 50% cut-off point for meaningful heterogeneity among the included studies. If
heterogeneity is observed, subgroup analysis will be conducted.18
Assessment of reporting biases
Funnel plots will be used to detect reporting biases and small-study effects. If more than 10
studies are included in the meta-analysis, the test for funnel plot asymmetry will be
conducted using Egger's method. 19 20
Data synthesis
If a significant number of studies are identified, a meta-analysis will be conducted with
simultaneous use of fixed-effect and random-effect models. All statistical analyses will be
performed using RevMan 5.1 (the Cochrane Collaboration) software. To summarise the
effects of a Gan Mai Da Zao decoction on outcomes (response rate), we will abstract the risk
estimates (relative risk, RR), and 95% confidence intervals (CI) using Review Manager
Version 5.0 for Windows (Cochrane Collaboration’s software). For studies with insufficient
information, we will contact the primary authors to acquire and verify data where possible. If
appropriate, we will then pool the data across studies using random effect models.
Subgroup analysis and investigation of heterogeneity
To explore differences in effect sizes, subgroup analyses will be conducted on the following
topics: the severity of depression, sex, the type of GMDZ decoction, the design of the trial
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(e.g., crossover group or parallel group), the dose of GMDZ decoction, and treatment
frequency. We will also summarise the standardisation and characteristics of GMDZ
decoctions from all included studies.
Sensitivity analysis
Sensitivity analysis will be conducted according to the following criteria:
1. Methodological qualities (sequence generation, allocation concealment, or blinding)
2. Sample size (small sample studies, e.g., less than 40 subjects in each group, or large
sample studies, e.g., more than 40 subjects in each group)
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Ethics and dissemination
Ethical approval is not required, given that this protocol is for a systematic review. The
findings of this review will be disseminated widely through peer-reviewed publications and
conference presentations.
Discussion
This systematic review will provide a detailed summary of the current state of evidence on
the effectiveness of the herbal medicine GMDZ decoction in treating the symptoms of
patients with depression. The review will benefit patients and practitioners in the field of
traditional and complementary medicine.
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Contribution of authors
The protocol was drafted by Jun JH, Lee JA, Choi T-Y, Yun K-J, Lim HJ and Lee MS. The
search strategy was developed and will be run by Jun JH and Lee JA. Copies of studies will
be obtained by Jun JH, Lee JA and Choi T-Y. Selection of the studies to include will be done
by Jun JH, Lee JA and Choi T-Y. Lee MS will act as an arbiter in the study selection stage.
Extraction of data from studies will be conducted by Jun JH, Lee JA and Choi T-Y. Entering
data into RevMan will be conducted by Lee JA and Yun K-J. Carrying out the analysis will
be done by Jun JH, Lee JA and Lee MS. Interpretation of the analysis will be done by Jun JH,
Choi T-Y, Yun K-J, and Lee MS. The final review will be drafted Jun JH, Lee JA, Choi T-Y,
Yun K-J, Lim HJ, and Lee MS. The review will be updated by Jun JH and Lee MS.
Competing interests
None declared
Funding
No external funding was received. The authors were supported by Korea Institute of Oriental
Medicine (K13400, K13130, K13281).
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References
1. Cipriani A, Barbui C, Butler R, Hatcher S, Geddes J. Depression in adults: drug and
physical treatments. Clin Evid 2011;2011(05):1003.
2. World Health Organization. Depression: definition. Available at
http://www.euro.who.int/en/what-we-do/health-topics/noncommunicable-
diseases/sections/news/2012/10/depression-in-europe/depression-definition. Accessed
Nov, 20, 2013.3. World Health Organization. Mental health: depression in Europe.
Avaible at
http://www.euro.who.int/en/what-we-do/health-topics/noncommunicable-
diseases/mental-health/news/news/2012/10/depression-in-europe. Accessed Nov, 20,
2013.
4. Wray NR, Pergadia ML, Blackwood DH, Penninx BW, Gordon SD, Nyholt DR, et al.
Genome-wide association study of major depressive disorder: new results, meta-
analysis, and lessons learned. Mol Psychiat 2012;17(1):36-48.
5. World Health Organization. Depression. Available at
http://www.who.int/topics/depression/en/. Accessed Nov, 20, 2013.
6. Ruan J. Chinese-english Synopsis of Prescription of the Golden Chamber. Shanghai, China:
Shanghai Science and Technology Publishing Company, 2003.
7. Wu J. Antidepressant effect of gan-mai-da-zao tang on depression compared with
fluoxetine. J Chin Physician 2002;30:18-19.
8. Yang FE, Qiao QF, Gong YP. Antidepressant effect of gan-mai-da-zao tang on 30 women
with postpartum depression. Shanxi J TCM 2009;30:851-52.
9. Lou JS, Li CY, Yang XC, Fang J, Yang YX, Guo JY. Protective effect of gan mai da zao
Page 36 of 39
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rotected by copyright.http://bm
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pen: first published as 10.1136/bmjopen-2013-003690 on 6 January 2014. D
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For peer review only
17
decoction in unpredictable chronic mild stress-induced behavioral and biochemical
alterations. Pharm Biol 2010;48(12):1328-36.
10. Zhang Q, Yang J, Liu YX, Liu YP, Zhou QZ. Influence on neurotransmitter in brain of
depressed model rat treated by Bai-di-gan-zao Decoction. J Chengdu Univ TCM
2006(02):21-23.
11. Zhang X, L., Dai WW, Jin GQ, Xia HY, Yao LA, Gong ZB, et al. Depression model rats
hippocampal receptor ion channel gene expression profile changes and modified
ganmai dazao decoction. Pharmacol Clin Chin Mater Med 2011(06):6-10.
12. American Psychiatric Association. Diagnostic and statistical manual of mental disorders.
4th ed. Washington, DC: American Psychiatric Association, 1994.
13. World Health Organisation. The ICD-10 Classification o mental and Behavioural
Disorders. Diagnostic Criteria for Research. Geneva: World Health Organisation,
1993.
14. Chinese Psychiatric Society. The Chinese classification of mental disorders [CCMD-3].
Shandong, China: Shandong Publishing House of Science and Technology, 2001.
15. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring
depression. Arch Gen Psychiatry 1961;4:561-71.
16. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.
17. Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included
studies. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0 (updated March 2011). : The Cochrane
Collaboration. Available from www.cochrane-handbook.org, 2011.
18. Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing data and undertaking meta-
Page 37 of 39
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on August 3, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2013-003690 on 6 January 2014. D
ownloaded from
For peer review only
18
analyses. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.0 (updated March 2011). : The Cochrane
Collaboration. Available from www.cochrane-handbook.org, 2011.
19. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a
simple, graphical test. BMJ 1997;315(7109):629-34.
20. Sterne JAC, Egger M, Moher D. Chapter 10: Addressing reporting biases. In: Higgins JPT,
Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version
5.1.0 (updated March 2011). : The Cochrane Collaboration. Available from
www.cochrane-handbook.org, 2011.
Page 38 of 39
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Figure legends
Figure 1. Flow diagram of the trial selection process. NRS: non randomised studies.
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ownloaded from