BMJ Open · 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

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

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Herbal medicine (Ganmai Dazao Decoction) for depression:


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

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

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instructions-for-authors/licence-forms).

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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

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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,

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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



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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:


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


BMJ Open on A

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1



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




Tel: 82-(0)42-868-9266

Fax: 82-(0)42-868-9622



Lee JA: [email protected]



Lim HJ: [email protected]


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2

License statement







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3

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


will determine the current state of evidence using unbiased methods.



databases without language restrictions.



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4

Abstract


of an herbal medicine (Gan Mai Da Zao (GMDZ) decoction) in treating depression.






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





Keywords: Depression, complementary and alternative medicine, herbal decoction, Gan Mai

Da Zao decoction, randomised clinical trials, systematic review

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5

Introduction


The prevalence of depression is as high as 10% of the population, with half of affected people


characterised by emotional depression, a loss of interest or pleasure, insomnia, increased


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,



to the World Health Organisation, depression is the leading cause of disability for all ages and





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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6

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


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


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



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.



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.


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.


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


and the Hamilton Rating Scale for Depression (HAMD) 16

Secondary outcomes

1. Quality of life

2. Adverse events

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Electronic searches






(VIP)).

Other sources





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.




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).



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.



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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.





instead of the weighted MD (WMD).


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.


If missing data are detected, we will request any missing or incomplete information from the

original study investigators.


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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







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.



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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 will be conducted according to the following criteria:




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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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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


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


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


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.


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.

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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.





1993.



15. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch

Gen Psychiatry 1961;4:561-71.







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19. Egger M, Davey Smith G, et al. Bias in meta-analysis detected by a simple, graphical test.

BMJ 1997;315(7109):629-34.


Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version

5.1.0 (updated March 2011). : The Cochrane Collaboration. Available from


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Figure legends

Figure 1. Flow diagram of the trial selection process. NRS: non randomised studies.

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213x206mm (300 x 300 DPI)

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1



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




Tel: 82-(0)42-868-9266

Fax: 82-(0)42-868-9622



Lee JA: [email protected]



Lim HJ: [email protected]


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License statement







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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


will determine the current state of evidence using unbiased methods.



databases without language restrictions.



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Abstract


of an herbal medicine (Gan Mai Da Zao (GMDZ) decoction) in treating depression.






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





Keywords: Depression, complementary and alternative medicine, herbal decoction, Gan Mai

Da Zao decoction, randomised clinical trials, systematic review

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Introduction


The prevalence of depression is as high as 10% of the population, with half of affected people


characterised by emotional depression, a loss of interest or pleasure, insomnia, increased


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,



to the World Health Organisation, depression is the leading cause of disability for all ages and





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


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


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



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.



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.


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.


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


and the Hamilton Rating Scale for Depression (HAMD) 16

Secondary outcomes

1. Quality of life

2. Adverse events

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Electronic searches






(VIP)).

Other sources





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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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).



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.




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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.





instead of the weighted MD (WMD).


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.


If missing data are detected, we will request any missing or incomplete information from the

original study investigators.


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







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.



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 will be conducted according to the following criteria:




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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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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


Medicine (K13400, K13130, K13281).

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Figure legends

Figure 1. Flow diagram of the trial selection process. NRS: non randomised studies.

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BMJ Open · 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