A meta-analysis of the efficacy and safety of traditional Chinese medicine formula Ganmai Dazao decoction for depression

Journal of Ethnopharmacology 153 (2014) 309–317

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Review

A meta-analysis of the efficacy and safety of traditional Chinese medicine formula Ganmai Dazao decoction for depression Wing-Fai Yeung a, Ka-Fai Chung a,n, Ka-Yan Ng a, Yee-Man Yu a, Eric Tat-Chi Ziea b, Bacon Fung-Leung Ng b a b

Department of Psychiatry, University of Hong Kong, Hong Kong SAR, China The Chinese Medicine Department, Hospital Authority, Hong Kong SAR, China

art ic l e i nf o

a b s t r a c t

Article history: Received 23 December 2013 Received in revised form 24 February 2014 Accepted 25 February 2014 Available online 12 March 2014

Ethnopharmacological relevance: Ganmai Dazao (GMDZ) decoction is a traditional Chinese herbal formula commonly used for the treatment of depression. The objective of this study was to assess the efficacy and safety of GMDZ, either alone or as co-therapy, for depression. Materials and methods: We systematically searched key databases (9 Chinese and 7 English) up until May 2013 for randomized controlled trials (RCTs). The primary outcomes were effective rate and self-rated or clinician-rated severity of depression. The secondary outcome was the occurrence of adverse events. Methodological quality of the RCTs was assessed by the Cochrane's risk of bias assessment. Results: Ten RCTs were included. All were written in Chinese and the methodological quality was generally low. Pooled analysis of 5 studies which compared GMDZ with antidepressants showed that GMDZ was significantly more efficacious than antidepressants in effective rate (risk ratio: 1.14, 95% CI: 1.02 to 1.27, P ¼0.02, I2 ¼ 0%), but comparable in Hamilton Depression Rating Scale (HDRS) score (mean difference:  2.10, 95% CI: 4.62 to  0.41, P¼ 0.10, I2 ¼92%). With regard to the other 5 studies which compared GMDZ plus antidepressants with antidepressants alone, there was no significant difference in effective rate (risk ratio: 1.24, 95% CI: 0.99 to 1.55, P ¼0.07, I2 ¼93%), but the end-point HDRS score was significantly lower in GMDZ antidepressants combination (mean difference:  4.25, 95% CI:  6.50 to  2.00, P ¼0.0002, I2 ¼ 96%). Adverse events were more common with antidepressants than GMDZ (rate ratio: 0.52, 95% CI: 0.32 to 0.82, P¼ 0.005, I2 ¼37%) and in antidepressants alone compared to GMDZ antidepressants combination (rate ratio: 0.23, 95% CI: 0.08 to 0.68, P ¼0.08, I2 ¼0%). Conclusion: The overall results suggest that GMDZ has few side effects and the potential as an antidepressant. Adding GMDZ to antidepressants reduces side effects and enhances efficacy of antidepressants. However, due to the small number of studies and their limitations, further studies with better methodological quality and more comprehensive safety assessment are needed to determine the benefits and risks of GMDZ in the treatment of depression. & 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Ganmai Dazao decoction Depression Meta-analysis Randomized controlled trials

Contents 1. 2.

3.

n

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Result . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Characteristics of the included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Treatment intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Correspondence to: Department of Psychiatry, University of Hong Kong, Pokfulam Road, Hong Kong SAR, China. Tel.: þ 852 22554487; fax: þ852 28551345. E-mail address: [email protected] (K.-F. Chung).

http://dx.doi.org/10.1016/j.jep.2014.02.046 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.

310 310 310 311 311 311 311 311 313

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3.3. 3.4.

Assessment by the Cochrane's risk of bias assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Efficacy assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. GMDZ decoction vs. antidepressants (Studies 3–4, 7 and 9–10) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. GMDZ decoction plus antidepressants vs. antidepressants alone (Studies 1–2, 5–6 and 8). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. GMDZ decoction vs. no treatment (Study 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Major depressive disorder (MDD) is characterized by pervasive low mood, marked loss of interest, fatigue, sleep difficulties, irritability, poor concentration, suicidal ideation, feeling worthless, excessive guilt and loss of appetite for at least one month which causes clinically significant distress or functional impairment (American Psychiatric Association., 2013). Depressive disorders were the second leading cause of years lived with disability in 2010 (Ferrari et al., 2013). According to the World Mental Health Survey Initiative, the average lifetime prevalence for DSM-IV major depressive episode was 14.6% in 10 high-income countries and 11.1% in 8 low- to middle-income countries (Bromet et al., 2011). MDD not only affects people's performance at work, school and in daily life, but also their life satisfaction and perceived well-being. As the number of depressed people across the world is rapidly increasing (Baxter et al., 2014), effective and safe treatments should be identified in order to reduce the potential harms MDD brings to sufferers' lives. Pharmacotherapy is currently the most commonly used treatment for MDD due to its reported effectiveness. Yet, complaints such us nausea, sexual dysfunction, headache, insomnia, daytime somnolence, agitation and weight gain have often been reported by patients during the course of treatment, which can lead to treatment termination. Psychological treatments for depression are also commonly used, especially in middle to high-income countries (World Health Organization, 2011). Despite its proven effectiveness, the limitations of psychotherapy include limited access to skilled providers, high cost, time-intensive nature and requirement of patients' participation and motivation. Faced with the limitations of the currently available treatments, the use of complementary and alternative medicine for depression is common. A national representative survey in the United States showed that 53.6% of people with self-reported depression used some forms of complementary and alternative therapies to treat depression during the past 12 months (Kessler et al., 2001). Many studies have been conducted to test the effectiveness of complementary and alternative therapies for mood disorders (Qureshi and AI-Bedah, 2013), suggesting that the demand for treatments other than pharmacotherapy and psychotherapy is present. Chinese herbal medicine is one of the potential complementary and alternative therapies for depression and is widely used in Chinese culture (Hsu et al., 2008). Chaihu-Shugan-San (Bupleurum Soothe the Liver powder), Xiao-Yao-San (Free and Easy powder), and Ganmai Dazao decoction (Licorice, Wheat and Red Dates, GMDZ) are the commonly used and recommended herbal formulas for depression (China Academy of Chinese Medical Sciences, 2011). Systematic reviews have been conducted on ChaihuShugan-San (Wang et al. 2012) and Xiao-Yao-San (Qin et al., 2011; Zhang et al., 2012a, 2012b); however, studies summarizing the efficacy and safety of other commonly used herbal formulas have not been published. A recent study showed that 46 among 310 herbal formulas for MDD were GMDZ-based (Xiong, 2011),

313 313 313 314 315 315 315 316 316 316

confirming that GMDZ is one of the commonly used herbal formulas for treating depression. GMDZ decoction has Gan Cao (Glycyrrhiza uralensis Fisch.), Xiao Mai (Triticum aestivum L.) and Da Zao (Ziziphus jujuba Mill.) as its major ingredients, in a ratio of 3:5:5 (Yan, 2001). It was first documented in Jin-Gui-Yao-Lue (Synopsis of Prescriptions of the Golden Chamber) written by Zhang Zhongjing (AD 152–219) for treating “Zangzao” (visceral irritation), in which female patients presented with low mood, a tendency to cry, possession-like behavior and frequent yawning (Chen and Zhang, 2000). However, the book did not describe why these botanical drugs were used. In Qing dynasty (AD 1644–1912), Chinese medicine practitioners proposed that these botanical drugs, especially Xiao Mai, could be used together to nourish the heart (He, 2011). In terms of contemporary traditional Chinese medicine (TCM) theory, the onset of depression is due to damage by extreme emotions. The liver qi thus becomes depressed gradually, which leads to disharmony of the qi mechanism of the five viscera, and particularly the liver, spleen and heart, causing loss of regulation of the qi and blood. The liver depression may repress the spleen and result in consumption and damage of the heart qi. The heart then loses its nourishment (heart deficiency) and disquietude of the heart shen (spirit) occurs, resulting in unstable and depressed mood. If qi depression is prolonged, it may accumulate and transform into fire (depressed qi transforming into fire). If the spleen fails to transform and transport body fluid, it may result in dampness brewing and engendering phlegm. This then leads to qi stagnation and phlegm depression (binding of phlegm and qi) (Schnyer and Flaws, 1998; Wang et al., 1997). GMDZ decoction, one of the formulas that nourish the heart, is believed to be effective for depression caused by heart deficiency. Current evidence supporting the use of GMDZ decoction for depression is largely based on anecdotal reports (Chen and Zhang, 2000; He, 2011). Only recently several controlled trials on GMDZ decoction for depression have been published. Given the common use of GMDZ decoction for depression, it is worthwhile to conduct a systematic review and meta-analysis on the potential role of GMDZ decoction as treatment for depression. We aimed to assess the efficacy and safety of GMDZ, either alone or as co-therapy, for depression.

2. Materials and methods 2.1. Search strategy Nine Chinese language databases and seven English language databases were searched by two researchers (KN and YY) independently. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine, PsycINFO and ProQuest Dissertations and Theses A&I from inception to May 2013 using the grouped terms (depressionn OR depressiven OR dysthymian OR mood disordern OR affective

W.-F. Yeung et al. / Journal of Ethnopharmacology 153 (2014) 309–317

disordern OR affective symptoms OR MDD) AND (Chinese herbn OR herbal medicinen OR traditional Chinese medicinen OR TCM OR Chai-Hu-Shu-Gan-San OR ChaiHuShuGann OR Xiao-Yao-San OR XiaoYaon OR Ban-Xia-Hou-Pu-Tang OR BanXiaHouPun OR GanMai-Da-Zao-Tang OR GanMaiDaZaon OR Gui-Pi-Tang OR GuiPin OR Wen-Dan-Tang OR WenDan OR Yue-Ju-Wan OR Yue-Ju). With regard to Chinese databases, we searched the China Journals Full-text Database, China Proceedings of Conference Full-text Database, Chinese Biomedical Literature Database, China Doctor Dissertations Full-text Database, China Master Theses Full-text Database, Chinese Science and Technology Documents Database, Chinese Dissertation Document Bibliography Database, Taiwan Electronic Periodical Services, and WanFang Database using equivalent Chinese terms. The reference lists of the included papers and previous systematic reviews (Wang et al., 2012; Qin et al., 2011; Butler and Pilkington, 2013; Zhao et al., 2009a) were further searched for relevant articles. There was no language restriction in our search. We followed the PRISMA statement guidelines in the report of this systematic review and meta-analysis (Moher et al., 2009). 2.2. Inclusion criteria Studies included in this review were randomized or quasirandomized clinical trials that examined participants with depression according to one of the following diagnostic criteria: the Diagnostic and Statistical Manual, Forth Edition (DSM-IV, American Psychiatric Association, 1994), Research Diagnostic Criteria (RDC, Spitzer et al., 1989), Chinese Classification of Mental Disorders, Second-Revised/ Third Edition (CCMD-2-R/3, Chinese Psychiatric Society, 2001) or other relevant criteria. The included studies should have one of the following comparisons: (1) GMDZ alone vs. antidepressants alone, (2) GMDZ and antidepressants vs. antidepressants alone or (3) GMDZ and routine care or psychotherapy vs. antidepressants and routine care or psychotherapy. Studies comparing GMDZ vs. GMDZ plus antidepressants were excluded because GMDZ plus antidepressants is not a standard treatment for comparison with GMDZ alone. In addition, at least one of the following outcome measures was used: (1) self-rating scales on depression, (2) clinician-rated scales on depression or (3) effective rate, which was often defined as the proportion of subjects who had at least some improvement in depression. The secondary outcome was the frequency of adverse events (AE). Any disagreement about the eligibility of a study was resolved by discussion between the two independent researchers (KN and YY) and consultation with the senior authors (WY and KC). One researcher (KN) extracted the data and the other (YY) checked the extracted data. For each study, the following variables were extracted: study design, patients' characteristics including age, gender, and duration of depression, GMDZ decoction treatment protocol, control interventions and outcome parameters.

outcome. Mean difference (MD) or standardized mean difference (SMD) with 95% CI was presented for continuous outcome. Heterogeneity was tested using the Q and I² statistics. We used fixed effects model when statistical heterogeneity was absent (heterogeneity test, P Z0.10) and random effects model when heterogeneity was present (heterogeneity test, P o0.10). The occurrence of AE was summarized using RR with 95% CI, but the incidence of any AE was summarized using rate ratio, as the total number of events could theoretically exceed the number of participants, rendering the results nonsensical (Higgins and Green, 2011).

3. Result 3.1. Characteristics of the included studies The search yielded 5030 potential titles for review, of which 894 were duplicate records and 3588 were excluded for reasons of irrelevance. The full texts of 548 articles were retrieved for detailed assessment, and 269 were excluded for various reasons (Fig. 1). Of the remaining 279 studies, 14 studies examined the efficacy of GMDZ decoction, yet, only 10 were included in this review. The other four studies averaged the effective rates of GMDZ decoction with other formulas; despite repeated enquiries to the authors, we did not receive replies regarding the effective rate of GMDZ decoction alone. Full details of the excluded studies are available from the authors upon request. Table 1 summarizes the characteristics of the 10 included studies. Sample size ranged from 31 to 209, with a total of 968 subjects. All studies were carried out in China and published in Chinese. Nine of the 10 studies were 2-arm studies, and the remaining one study was a 3-arm study. All studies used antidepressants as comparators. Three studies recruited subjects with depression in general; four studies were on post-stroke depression, one study on depression with suicidal attempt, one on subjects with depression and anxiety, and one on depression in

2.3. Quality assessment We analyzed the studies using the Cochrane's risks of bias assessment (Higgins and Green, 2011). The risks of bias assessment appraises a study in six domains: adequate sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting and other sources of bias. Each domain was rated as “yes” (low risk of bias), “no” (high risk of bias), or “unclear” (uncertain risk). 2.4. Data analysis We used the Cochrane Collaboration Review Manager software (RevMan 5.1) for statistical analysis. Data were summarized using risk ratio (RR) with 95% confidence intervals (CI) for binary

311

Fig. 1. Flowchart of this systematic review.

312

Table 1 Randomized controlled trials of GMDZ decoction for depression. Control intervention

Outcome measure

Results reported

Risk of biasa

(GMDZ þAD;

76 (38/38) 209 (139/ 70) 98 (34/32/ 32) 60 (30/30)

Effective rate, HARS, HDRS Effective rate

GMDZ þ AD 4AD

(GMDZ þAD;

Fluoxetine or paroxetine 20 mg/d Fluoxetine 20 mg/d Deanxit 1tablet/d

Effective rate, HDRS Effective rate, HDRS, SDS Effective rate, HDRS, SDS HDRS, MESSS

U, U, H, L, LU H, H, H, L, L, L L, U, H, L, L, L U, U, H, L, L, L U, U, H, L, H, L U, U, H, L, L, L U, U, H, L, L, L U, U, H, L, L, L U, U, H, L, L, L U, U, H, L, L, L

Country/type of case

Mean age (range)/ % female

Diagnostic system

Design

1

Gong (2008)

2

Liu et al. (2008) Meng et al., 2008 Wang et al. (2008) Wu et al. (2012) Xin and He (2010) Xu and Wan (2011) Yin (2010)

China/inpatients with depression and anxiety China / depression with suicidal attempt China/ post-stroke depression China/depression in cancer patients China / post-stroke depression China / post-stroke depression China/outpatients with depression China/patients with depression China / post-stroke depression China/outpatients with depression

58.6 (47–76)/ 50% 30.0 (15–49)/ 56% 64.5 (50–85)/ 43.9% 51.9 (NR)/62%

HARS, HDRS (4 20) NR CCMD2-R, HDRS ( Z 8) CCMD3

2 parallel arms AD) 2 parallel arms AD) 3 parallel arms no treatment) 2 parallel arms

CCMD3, TCM textbook CCMD3, HDRS (4 20) HDRS

2 parallel arms (GMDZ þAD; AD) 2 parallel arms (GMDZ þAD; AD) 2 parallel arms (GMDZ; AD)

120 (60/ 60) 60 (30/30)

Fluoxetine 20 mg/d

70 (35/35)

Fluoxetine 20 mg/d

CCMD3, HDRS (Z 17) CCMD3, HDRS

2 parallel arms (GMDZ þAD; AD) 2 parallel arms (GMDZ; AD)

186 (93/ 93) 58 (30/28)

Clomipramine 50 mg/d Fluoxetine 20 mg/d

DSM-IV, HDRS (Z 16)

2 parallel arms (GMDZ; AD)

31 (16/15)

Citalopram 20 mg/d

3 4 5 6 7 8 9

Zhao et al. (2009b) 10 Zhao et al. (2012)

56.0 (35–70)/ 45.8% 63.7 (NR)/ 41.7% 46.9 (NR)/ 38.6% 24.9 (NR)/ 33.3% NR (45–70)/ 56.9% 45.2 (NR)/ 58.1%

(GMDZ; AD; (GMDZ; AD)

Fluoxetine 20 mg/d Fluoxetine 20 mg/d

Effective rate, HDRS,TESS Effective rate, HDRS Effective rate, HDRS Effective rate, HDRS

GMDZ þ AD 4AD GMDZ ¼ AD; both GMDZ and AD 4no treatment GMDZ 4AD GMDZ þ AD 4AD GMDZ þ AD 4AD GMDZ ¼ AD GMDZ þ AD ¼AD GMDZ ¼ AD GMDZ ¼ AD

AD, antidepressant; CCMD, Chinese classification of mental disorder; GMDZ, Ganmai Dazao; HARS, Hamilton anxiety rating scale; HDRS, Hamilton depression rating scale; MESSS, modified Edinburgh-Scandinavian Stroke scale; NR, not reported; SDS, Zung self-rating depression scale; TESS, treatment emergent symptoms scale. a Cochrane risk of bias assessment in 6 domains: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; complete collection and reporting of outcome data; selective outcome reporting; and adequate attention to other sources of bias; H, high risk; L, low risk; U, unclear risk.

W.-F. Yeung et al. / Journal of Ethnopharmacology 153 (2014) 309–317

Sample size (GMDZ/ control)

No 1st Author (year)

W.-F. Yeung et al. / Journal of Ethnopharmacology 153 (2014) 309–317

313

Table 2 Major herbal components of GMDZ decoction. No

1st author (year)

Botanical drug selection

Dose and treatment period

1 2

Gong (2008) Liu et al. (2008)

Standardized Individualized

Not reported; 8 wk C 1 dose/d for 10 d C

3

Meng et al., 2008

Individualized

1 dose/d for 8 wk

C

4

Wang et al. (2008) Individualized

1 dose/d for 8 wk

C

5

Wu et al. (2012)

Individualized

1 dose/d for 60 d

C

6

Xin and He (2010)

Individualized

1 dose/d for 8 wk

C

7

Xu and Wan (2011) Standardized

1 dose/d for 6 wk

C

8

Yin (2010)

Standardized

1 dose/d for 60 d

C

9

Zhao et al. (2009b) Standardized

1 dose/d for 4 wk

C

10

Zhao et al. (2012)

1 dose/d for 6 wk

C

Standardized

Adequate reporting on botanical materialsa

Major botanical drugs

Not reported Gan Cao (Glycyrrhiza uralensis Fisch.), Xiao Mai (Triticum aestivum L.), Da Zao (Ziziphus jujuba Mill.) Gan Cao (Glycyrrhiza uralensis Fisch.), Xiao Mai (Triticum aestivum L.), Da Zao (Ziziphus jujuba Mill.) Gan Cao (Glycyrrhiza uralensis Fisch.), Xiao Mai (Triticum aestivum L.), Da Zao (Ziziphus jujuba Mill.), Suan Zao Ren (Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F.Chow), He Huan Hua (Acacia julibrissin (Durazz.) Willd.), Bo Zi Ren (Platycladus orientalis (L.) Franco), Fu Shen (Poria Cocos (Schw.) Wolf) Gan Cao (Glycyrrhiza uralensis Fisch.), Xiao Mai (Triticum aestivum L), Da Zao (Ziziphus jujuba Mill.), Chai Hu (Bupleurum chinense DC.), Yu Jin (Curcuma wenyujin Y.H.Chen & C.Ling), Fu Shen (Poria Cocos (Schw.) Wolf), Suan Zao Ren (Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F.Chow), Chen Pi (Citrus reticulata Blanco), Shui Zhi (Hirudo niponia Whitman), De Long (Pheretima aspergillum (Perrier)) Gan Cao (Glycyrrhiza uralensis Fisch.), Xiao Mai (Triticum aestivum L.), Da Zao (Ziziphus jujuba Mill.) Gan Cao (Glycyrrhiza uralensis Fisch.), Xiao Mai (Triticum aestivum L.), Da Zao (Ziziphus jujuba Mill.), De Long (Pheretima asiatica (Perrier)), He Huan Pi (Acacia julibrissin (Durazz.) Willd.) Gan Cao (Glycyrrhiza uralensis Fisch.), Xiao Mai (Triticum aestivum L.), Da Zao (Ziziphus jujuba Mill.), Shi Chang Pu (Acorus tatarinowii Schott), Suan Zao Ren (Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F.Chow), Zhu Ye (Phyllostachys nigra (Lodd. ex Lindl.) Munro), Mai Dong (Ophiopogon japonicus (Thunb.) Ker Gawl.) Gan Cao (Glycyrrhiza uralensis Fisch.), Xiao Mai (Triticum aestivum L.), Da Zao (Ziziphus jujuba Mill.), Yu Jin (Curcuma wenyujin Y.H.Chen & C.Ling), He Huan Pi (Acacia julibrissin (Durazz.) Willd.) Gan Cao (Glycyrrhiza uralensis Fisch.), Xiao Mai (Triticum aestivum L.), Da Zao (Ziziphus jujuba Mill.), He Huan Pi (Acacia julibrissin (Durazz.) Willd.)

a The reporting was rated by three levels: A, full information about the botanical material is provided including a voucher specimen; B, only partial information about the botanical material is provided but a voucher specimen is missing and there are taxonomic inaccuracies; C, inadequate information and overall taxonomically inadequate.

cancer patients. The studies used different diagnostic systems and cutoff scores as inclusion criteria. Seven studies reported using the Hamilton Depression Rating Scale (HDRS) total score, ranging from eight to 21, as cutoff score for subject inclusion; six studies used the CCMD-2-R or CCMD-3 criteria, one used the DSM-IV, and one used the Hamilton Anxiety Rating Scale. A total of 479 males and 433 females were assessed. With regard to the participants' age, five studies had reported the age range and eight studies the mean age. Overall, the participants had a mean age of 43.3 years and an age range from 15 to 85 years. The HDRS is the most commonly used outcome measure (all studies except Study 2); other outcome measures include the Hamilton Anxiety Rating Scale (Study 1), Zung Self-Rating Depression Scale (Studies 4 & 5) and a TCM symptom severity scale (Study 2).

3.2. Treatment intervention Of the 10 included studies, five used standardized formulas and five used individualized formulas. Table 2 presents the ingredients and dosages of the formulas. Although the ingredients were slightly different from each other, all contained Gan Cao, Xiao Mai and Da Zao as major components. The amount of Gan Cao ranged from 9 g to 30 g, Xiao Mai from 15 g to 30 g, and Da Zao from 5 to 20 pieces. The number of Chinese botanical drugs in the formulas varied from 3 to 7 with an average of 4.4. The other Chinese botanical drugs commonly used in GMDZ decoction were Suan Zao Ren and He Huan Pi, which were used in 3 studies. GMDZ was prescribed once daily in all 10 studies. The treatment duration ranged from 28 to 60 days, with an average of 50.7 days.

None of the included studies reported the Latin scientific names and voucher specimens of the botanical drugs used. 3.3. Assessment by the Cochrane's risk of bias assessment Table 1 presents the quality of the included studies. Only one study (Study 3) reported using an adequate randomization method by means of random digit table. Study 2 used alternation as randomization, but it is considered an inadequate randomization method; hence there was a high risk of bias in random sequence generation. The other eight studies did not report the randomization method. None of the studies reported whether an adequate concealment method was used. All the included studies did not have subject blinding and none of the studies mentioned whether the assessors were blinded to treatment allocation. However, the included studies had addressed all outcome data. Regarding other sources of bias, nine studies reported that there were no baseline differences, but Study 1 did not have the information. 3.4. Efficacy assessment 3.4.1. GMDZ decoction vs. antidepressants (Studies 3–4, 7 and 9–10) The antidepressants used include fluoxetine 20 mg/day (Studies 4, 7 and 9), deanxit (flupentixol 0.5 mg plus melitracen 10 mg) 1 tablet/day (Study 3) and citalopram 20 mg/day (Study 10). Only one of these five studies showed that GMDZ decoction was more effective than antidepressants. Study 4 found that treatment using GMDZ decoction resulted in significantly lower HDRS scores than using fluoxetine (MD: 10.70, 95% CI:  14.10 to

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7.30, P o0.0001), but there was no significant difference in effective rate between GMDZ and fluoxetine (RR: 1.39, 95% CI: 1.00 to 1.94, P¼ 0.05). Pooled analysis of these five studies showed that GMDZ decoction was significantly more efficacious than antidepressants in terms of effective rate (RR: 1.14, 95% CI: 1.02 to 1.27, P ¼0.02, I2 ¼0%), but not in HDRS score (MD: 2.10, 95% CI: 4.62 to  0.41, P¼ 0.10, I2 ¼92%) (Table 3). Both Studies 7 and 10 involved outpatients with major depression. Pooled analysis could not find any significant difference in effective rate (RR: 1.04, 95% CI: 0.84 to 1.27, P ¼0.73, I2 ¼ 0%) and

HDRS score (MD:  0.40, 95% CI:  0.97 to 0.16, P ¼0.16, I2 ¼0%) between GMDZ and antidepressants.

3.4.2. GMDZ decoction plus antidepressants vs. antidepressants alone (Studies 1–2, 5–6 and 8) The antidepressants used in these studies include fluoxetine 20 mg/day (Studies 2 and 5–6), clomipramine 50 mg/day (Study 8) and fluoxetine or paroxetine 20 mg/day (Study 1). Studies 1–2 and 5–6 reported that GMDZ decoction plus antidepressants was more

Table 3 GMDZ decoction versus antidepressants as treatment for depression. Study

GMDZ Events

Total

Events

GMDZ Mean

32 30 35 28 15 140

26.7 16.7 26.9 21.1 8.6 100

Antidepressants SD

More effective with antidepressant

More effective with GMDZ

Total

Meng et al., 2008 33 34 28 Wang et al. (2008) 25 30 18 Xu and Wan, 2011 30 35 29 Zhao et al. (2009b) 27 30 22 Zhao et al. (2012) 10 16 9 Total (95%CI) 145 Total events 125 106 Heterogeneity: χ2 ¼ 2.44, df ¼4 (P ¼0.66); I2 ¼ 0% Test for overall effect: Z¼2.27 (P¼ 0.02)

Study

Weight (%) Risk ratio, fixed, 95%CI

Antidepressants

Mean

1.11 [0.96, 1.28] 1.39 [1.00, 1.94] 1.03 [0.84, 1.27] 1.15 [0.91, 1.44] 1.04 [0.59, 1.83] 1.14 [1.02, 1.27]

Weight (%) Mean difference, Random, More effective with GMDZ 95% CI

More effective with antidepressant

SD

Meng et al., 2008 11.12 2.15 10.87 2.45 Liu et al. (2008) 8.20 6.20 18.90 7.20 Xu and Wan, 2011 7.10 6.20 6.90 5.80 Zhao et al. (2012) 15.5 0.63 15.93 0.96 Total (95%CI) Heterogeneity: τ2 ¼5.43, χ2 ¼ 36.61, df ¼3 (Po 0.00001); I2 ¼92% Test for overall effect: Z¼1.64 (P¼ 0.10)

0.25 [  0.86, 1.36]  10.70 [  14.10,  7.30] 0.20 [  2.61, 3.01]  0.43 [  1.01, 0.15]  2.10 [  4.62, 0.41]

28.6 19.5 22.0 29.9 100

Table 4 GMDZ decoction plus antidepressants versus antidepressants as treatment for depression. Study

GMDZ plus antidepressants

Antidepressants

Events

Events

Total

GMDZ plus antidepressants

Antidepressants

Mean

Mean

SD

Gong 2008 8.65 1.09 15.32 Wu et al. (2012) 12.10 3.10 15.20 Xin and He (2010) 5.47 1.33 10.75 Yin 2010 6.58 3.25 8.53 Total (95%CI) Heterogenity: τ2 ¼5.07, χ2 ¼ 78.42, df¼ 3 (Po 0.00001); Test for overall effect: Z ¼3.70 (P¼ 0.0002)

Risk ratio, random, 95% CI

17.1 21.9 19.8 18.3 22.9 100

1.48 [1.12, 1.95] 1.17 [1.05, 1.31] 1.32 [1.09, 1.60] 1.38 [1.08, 1.76] 0.99 [0.94,1.04] 1.24 [0.99, 1.55]

More effective with antidepressants

More effective with GMDZ

More effective with GMDZ

More effective with antidepressants

Total

Gong 2008 34 38 23 38 Liu et al. (2008) 135 139 58 70 Wu et al. (2012) 54 60 41 60 Xin and He (2010) 29 30 21 30 Yin 2010 90 93 91 93 Total (95%CI) 360 291 Total events 342 234 Heterogeneity: τ2 ¼0.06 χ2 ¼55.55, df ¼4 (Po 0.00001); I2 ¼ 93% Test for overall effect: Z ¼1.84 (P ¼0.07)

Study

Weight (%)

Weight (%)

Mean difference, Random, 95% CI

25.2 24.9 24.8 25.1 100

 6.67 [  7.41,  5.93]  3.10 [  4.05,  2.15]  5.28 [  6.32,  4.24]  1.95 [  2.79,  1.11]  4.25 [  6.50,  2.00]

SD 2.07 2.09 2.57 2.56 I2 ¼ 96%

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315

Table 5 Risk ratios and rate ratios of adverse events associated with GMDZ decoction. Total events/total n

Dry mouth Melancholia Constipation Insomnia Irritation Blurred vision Tachycardia Dizziness Headache Sweating Incidence of any adverse event

Nausea Daytime somnolence Fatigue Incidence of any adverse event

Risk ratio (95% CI)

GMDZ

Antidepressants

9/82 4/32 2/82 3/32 1/32 0/32 0/32 0/50 0/32 0/16

17/78 0/31 11/78 1/31 0/31 10/31 7/31 2/47 1/31 1/15

GMDZ plus antidepressants

Antidepressants

3/93 0/93 0/93

0/93 7/93 4/93

effective than antidepressants alone, while Study 8 found no significant advantage of GMDZ plus antidepressants. Pooled analysis of all five studies showed that there was no significant difference between GMDZ decoction plus antidepressants and antidepressants alone in effective rate (RR: 1.24, 95% CI: 0.99 to 1.55, P¼ 0.07, I2 ¼93%), but the end-point HDRS score was significantly lower with GMDZ decoction plus antidepressants (MD: 4.25, 95% CI: 6.50 to  2.00, P ¼0.0002, I2 ¼96%) (Table 4). Both Studies 5 and 6 assessed the efficacy of GMDZ decoction in post-stroke depression. Pooled analysis showed that GMDZ decoction plus antidepressants resulted in significantly higher effective rate (RR: 1.34, 95% CI: 1.15 to 1.56, Po 0.0001) and lower HDRS score (MD:  4.18, 95% CI:  6.32 to  2.04, P¼ 0.0001). We also pooled Studies 1 and 2 because both used selective serotonin reuptake inhibitors as antidepressants. The results showed that GMDZ decoction plus antidepressants was significantly more efficacious compared to antidepressants alone (RR: 1.27, 95% CI: 1.01 to 1.60, P¼ 0.04, I2 ¼61%). Since Study 2 did not use HDRS as outcome measure, pooled analysis was not possible.

3.4.3. GMDZ decoction vs. no treatment (Study 3) Participants allocated to routine care in Study 3 received no treatment for their post-stroke depression. It was found that GMDZ decoction was significantly better than no treatment for post-stroke depression (Effective rate: RR: 1.76, 95% CI: 1.22 to 2.55, P ¼0.002; HDRS score: MD: 10.11, 95% CI: 11.44 to  8.78, P o0.0001).

3.5. Adverse events Adverse events were recorded based on self-report (Studies 3, 5 and 8–10) and the Treatment Emergent Symptoms Scale (Study 7). In Studies 3 and 10, no adverse events related to GMDZ decoction were reported. Table 5 summaries the adverse events associated with GMDZ decoction, which include dry mouth, constipation, melancholia, insomnia and irritability. Statistical analysis showed that adverse events were more common in participants taking antidepressants than those taking GMDZ decoction (Rate Ratio: 0.52, 95% CI: 0.32 to 0.82, P¼ 0.005, I2 ¼37%). It was also found that GMDZ decoction plus antidepressants was associated with less adverse events compared to

0.54 (0.28, 1.03) 8.73 (0.49,155.62) 0.24 (0.07, 0.81) 6.79 (0.36,126.24) 2.91 (0.12, 68.81) 0.05 (0.00, 0.76) 0.06 (0.00, 1.09) 0.31 (0.03, 2.90) 0.32 (0.01, 7.65) 0.31 (0.01, 7.15) Pooled rate ratio 0.52 (0.32, 0.82)

7.00 (0.37, 133.66) 0.07 (0.00, 1.15) 0.11 (0.01, 2.04) Pooled rate ratio 0.23 (0.08, 0.68)

antidepressants alone (Rate Ratio: 0.23, 95% CI: 0.08 to 0.68, P¼ 0.08, I2 ¼0%).

4. Discussion To our knowledge, this is the first systematic review on the use of GMDZ decoction for the treatment of depression. Of the 10 RCTs included in this review, four studies compared GMDZ decoction alone (Studies 4, 7 and 9–10) and five studies in combination with antidepressants (Studies 1–2, 5–6 and 8) against antidepressants. Only one three-arm study (Study 3) examined GMDZ vs. antidepressants and no treatment, while no studies had used placebo as controls. Of the studies (Studies 3–4, 7 and 9–10) examining GMDZ vs. antidepressants (including deanxit, fluoxetine and citalopram), pooled analysis found that GMDZ was more efficacious than antidepressants in terms of effective rate (Risk ratio: 1.14), but there was no significant difference in HDRS scores between the two groups. Of the other studies (Studies 1–2, 5–6 and 8) on GMDZ plus antidepressants vs. antidepressants alone (including fluoxetine, paroxetine and clomipramine), pooled analysis showed a 4.25 points greater reduction in the end-point HDRS score when using GMDZ plus antidepressants; however, no significant difference in effective rate was found. The overall results suggested that GMDZ decoction was at least as effective as antidepressants, while the GMDZ antidepressant combination was slightly better than antidepressants alone in the treatment of depression. In addition, GMDZ decoction was found to have fewer side effects than antidepressants and the GMDZ antidepressants combination helped to reduce the side effects of antidepressants. However, due to the small number of studies and their limitations, further studies with better methodological quality and more comprehensive safety assessment are definitely needed to accurately determine the indication of GMDZ decoction for depression. This review found that the methodologic quality of the studies was poor. The randomization and allocation concealment procedures were not described in a majority of the included RCTs, thus it was not possible to assess whether the randomization process was properly conducted and whether allocation was adequately concealed. Another limitation was the blinding of the patients and investigators. Placebo design and the blinding of outcome assessment were not practiced. It may be hard to prepare a placebo, especially in decoction form, to taste, smell, and look similar to

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real Chinese herbal medicine. Although decoction is the favored method of extraction of herbal material, it is preferable to prepare herbal formulas and placebo in pills or granules in order to achieve the placebo design, which allows an examination of the specific therapeutic effects of Chinese herbal medicine. In addition, the reviewed studies did not include the Latin scientific names and voucher specimen of botanical drugs. As the lack of precise and appropriate use of botanical scientific nomenclature can easily lead to taxonomic ambiguity (Rivera et al., 2013), future studies on Chinese herbal medicine should follow the recommended reporting guidelines and present the Latin scientific names of the Chinese botanical drugs (Chan et al., 2012; Uzuner et al., 2012). Other methodological limitations included imprecise enrollment criteria and a lack of standardized diagnostic procedure, outcome measures and adverse event monitoring. Pharmacologic actions of GMDZ decoction have been explored using the unpredictable chronic mild stress model in rats. GMDZ treatment reversed depressive-like behaviors, possibly via pathways involving glutamate, N-methyl-D-aspartate receptor, proinflammatory cytokines, hypothalamic–pituitary–adrenal axis, nitric oxide and brain-derived neurotrophic factor (Hu, 2011; Tong et al., 2005; Zhang et al., 2012a, 2012b). Future human studies on the mechanism of GMDZ decoction are definitely needed. We noted that standardized GMDZ formula and individualized GMDZ formula based on TCM pattern differentiation were both commonly used. However, we had not compared the efficacy between standardized and individualized treatment due to differences in methodology between the studies. Results of previous studies in other medical conditions are inconsistent whether individualized herbal treatment fares better than standardized formulas (Bensoussan et al., 1998; Zhu et al., 2008). Although further studies are needed to examine the usefulness of individualized herbal treatment based on TCM pattern differentiation, it is also important to tackle the key shortcomings of the TCM diagnostic process, including the lack of standardization in terminology and disagreement of pattern differentiation among Chinese medicine practitioners (Hogeboom et al., 2001; Sung et al., 2004; Zhang et al., 2004; Zell et al., 2000). We found that the incidence of any adverse events in patients receiving GMDZ decoction was lower than individuals taking antidepressants (Rate ratio: 0.52). The common side effects of GMDZ decoction included dry month, melancholia, and constipation. Melancholia as an adverse event was only reported in participants treated with GMDZ; hence, further studies are needed to determine the possible risk of worsening in depression and suicidal ideation associated with GMDZ. No serious adverse events were reported in the reviewed studies. However, a majority of the studies had not used standardized rating scales for treatment emergent adverse events and the number of studies was too small to provide a reliable assessment. The long-term safety of GMDZ decoction, the effects of overdose and the use in pregnancy and during lactation were not recorded and this merits further investigation. In this review, GMDZ decoction for depression was most frequently taken once a day for four to eight weeks. Little research is available to judge the speed of onset of antidepressant action of GMDZ decoction and its long-term efficacy. Therefore, further pharmacokinetic and pharmacodynamic studies to find out the dosing regimens and treatment duration of GMDZ decoction are necessary. There are strengths as well as limitations of the study. We conducted a systematic literature review and screened through more than 500 articles to derive a comprehensive summary of the efficacy and safety of GMDZ decoction. In addition, we also assessed the adequacy of botanical material reporting, which is

critical in phytomedical research but had not been evaluated in previous systematic reviews of Chinese herbal medicine for depression. The major limitations are that our conclusion is limited by the dearth of high quality studies. Only 10 randomized trials were included in our review and the meta-analysis was performed irrespective of the studies' methodological quality; hence the pooled results should be treated with caution. Although we imposed no language restriction to our search, relevant studies were all published in Chinese and performed in China. As suggested by some researchers, there may be a publication bias in China (Vickers et al., 1998); hence the positive results in this review require further replication.

5. Conclusion In summary, previous RCTs suggest that GMDZ decoction has fewer side effects and is at least as effective as antidepressants in the acute treatment of depression. GMDZ antidepressant combination is found to be more efficacious and have fewer side effects than antidepressants alone. However, owing to the shortcoming of the reviewed RCTs and the lack of adequate safety data, future studies with better methodological quality are needed to determine the benefits and risks of GMDZ decoction for depression.

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