Hindawi Publishing Corporation

Evidence-Based Complementary and Alternative Medicine

Volume 2012, Article ID 931636, 13 pages
doi:10.1155/2012/931636

Review Article
Chinese Herbal Formula Xiao Yao San for
Treatment of Depression: A Systematic Review of
Randomized Controlled Trials

Yuqing Zhang,1, 2 Mei Han,2 Zhijun Liu,2 Jie Wang,1 Qingyong He,1 and Jianping Liu2
1 Guang’anmen Hospital, China Academy of Chinese Medical Science, Beijing 100053, China
2 Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China

Correspondence should be addressed to Jianping Liu, jianping l@hotmail.com

Received 21 March 2011; Revised 24 May 2011; Accepted 2 June 2011

Academic Editor: Jenny M. Wilkinson

Copyright © 2012 Yuqing Zhang et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objectives. To assess the beneficial and adverse effects of Xiaoyaosan for depression. Search Strategy. Electronic databases were
searched until December 2009. Inclusion Criteria. We included randomized clinical trials testing Xiaoyaosan against placebo,
antidepressants, or combined with antidepressants against antidepressants alone. Data Extraction and Analyses. Study selection,
data extraction, quality assessment, and data analyses were conducted according to the Cochrane standards. Results. 26 randomized
trials (involving 1837 patients) were included and the methodological quality was evaluated as generally low. The pooled results
showed that Xiaoyaosan combined with antidepressants was more effective in comprehensive effect, the score of HAMD and
the score of SDS compared with antidepressants alone. Xiaoyaosan was superior to antidepressants for the score of HAMD.
However, Xiaoyaosan was not different from placebo for the score of SDS. There was no adverse effects reported in the trials
from Xiaoyaosan. Conclusions. Xiaoyaosan appears to be effective on improving symptoms in patients with depression. However,
due to poor methodological quality in the majority of included trials, the potential benefit from Xiaoyaosan need to be confirmed
in rigorous trials and the design and reporting of trials should follow international standards.

1. Introduction “unseen burden” [1, 2]. It was the 4th leading contributor
to the global burden of disease when measured by Disability
Depression is a common mental disorder that presents Adjusted Life Years (DALYs) in 2000. By the year 2020,
with depressed mood, loss of interest or pleasure, feelings depression is projected to reach 2nd place of the ranking of
of guilt or low self-worth, disturbed sleep or appetite, DALYs calculated for all ages in both sexes. Today, depression
insomnia or hypersomnia, fatigue or loss of energy, and
is already the 2nd cause of DALYs in the age category 15–
poor concentration or difficulty making decisions. These
44 years for both sexes combined. Mood disorders have been
problems can become chronic or recurrent and lead to
shown to have a greater impact on quality of life compared
substantial impairments in an individual’s ability to take care
of his or her everyday responsibilities. with conditions such as hypertension and cardiac disease [3].
Depression is recognized as a major public health In China, depression is now one of the top three public
problem, which has a substantial impact on individuals and health problems. Statistics show that 5 per cent of Chinese
society. Depressive disorders are common in the general people suffer from the disease and 13 out of 1,000 Chinese
population. It affecting about 121 million people worldwide. have mental health issues [4]. Until 2003, China has over
At its worst, depression can lead to suicide, a tragic fatality 26 million depression patients, for which discrimination and
associated with the loss of about 850 000 thousand lives neglect are the two major obstacles to curing them, thus
every year. Depression is the leading cause of disability incurring an annual loss of over 64 billion yuan, according
as measured by Years Lived with Disability (YLD). The to a reserved estimation made at the Seminar on Attention
World Health Organization has described depression as an to the Socio-Economic Burden of Depression held [5].
2 Evidence-Based Complementary and Alternative Medicine

Depression is most commonly treated with antidepres- were included. RCTs combined xiaoyansan with antidepres-
sants in primary care [6]. In addition, there are other kind of sants compared with antidepressants and all the modified
psychological interventions, such as cognitive behavior ther- xiaoyaosan formula were included as well. There were
apies, interpersonal therapy, psychotherapy, and counseling. no restrictions on population characteristics, language and
The most widely prescribed antidepressants come from a publication type.
class of medications known as selective serotonin reuptake Outcome measures include Clinical Comprehensive Effect,
inhibitors (SSRIs). Besides of that “atypical” antidepressants, Hamilton depression scale (HAMD) scores, self-rating
the older tricyclic antidepressants and monoamine oxidase depression scale (SDS) scores, self-rating anxiety scale (SAS)
inhibitors (MAOIs). The common side effects include sex- scores, Hamilton Anxiety Scale (HAMA), scores, clinical
ual problems, drowsiness, fatigue, sleep difficulties, nausea global impression (CGI) scores, the scale for TCM syndrome
weight gain, nervousness, dry mouth, and blurred vision. and symptom differentiation (TCM-SSD) scores and so
Stop taking drugs abruptly may cause “antidepressant dis- forth, the criteria “recover, significant effective, effective, or
continuation syndrome” such as spells, extreme restlessness, not effective” was also include in the outcome measurement.
dizziness, fatigue, and aches and pains. Duplicated publications reporting the same groups of partic-
The Xiaoyaosan (XYS) decoction containing eight com- ipants were excluded.
monly used herbs (Bupleurum root, Chinese angelica root,
white peony root, poria, bighead atractylodes rhizome, 2.3. Data Extraction and Quality Assessment. Two authors (J.
roasted ginger, prepared licorice root, menthol and pepper- P. Liu and Y. Q. Zhang) extracted the data from the included
min) been used for treatment of mental disorders such as trials independently. The methodological quality of trials was
depression for centuries in China. The mechanism of the assessed using the 6 criteria 6 election bias (study design,
description maybe soothing the liver, invigorating the spleen, confounders, blinding, data collection methods, withdrawals
nourishing the blood to restore the normal menstruation, and dropouts) to following 3 categories: Category A (strong
and clearing away the liver fire due to blood deficiency. quality): four strong ratings with no weak ratings above.
Category B (moderate quality): less than four strong ratings
Biochemically, the XYS decoction also reversed CIS-induced
and one weak rating. Category C (weak quality): two or more
decreases in brain-derived neurotrophic factor (BDNF) and
weak ratings.
increases in tyroxine hydroxylase (TrkB), and neurotrophin
Quality assessment of included randomized controlled
3 (NT-3) in the frontal cortex, and the hippocampal CA trials: sequence generation, allocation concealment, blinding
subregion. of participants personnel and outcome assessors, incom-
Currently, xiaoyaosan used alone or integrated with plete outcome data, selective outcome reporting, and other
antidepressants has been widely used as an alternative and sources of bias.
effective method for the treatment of depression in China.
Many clinical studies reported the effectiveness ranging from 2.4. Data Synthesis. The statistical package (RevMan 4.3.2)
case reports and case series to controlled observational was used for data analyses, which was provided by The
studies and randomized clinical trials, but the evidence for Cochrane Collaboration. Dichotomous data were presented
its effect is not clear. The present paper aims to evaluate as risk ratio (RR) and continuous outcomes as mean
the beneficial and harmful effects of xiaoyaosan (wan) for difference (MD), both with 95% confidence interval (CI).
treatment of depression in randomized trials. Meta-analysis was performed if the intervention, control,
and outcome were the same or similar. The statistical
2. Methods heterogeneity was presented as significant when I square (I 2 )
is over 50% or P < 0.1. Random effect model was used for
2.1. Database and Search Strategies. Literature searches the meta-analysis if there was significant heterogeneity (I 2 >
were conducted in National Knowledge Infrastructure 50%) and fixed effect model was used when the heterogeneity
(1999–2009), VIP Database for Chinese Technical Period- was not significant (I 2 < 50%) [7].
icals (1989–2009), Chinese Biomedical Literature Database
(1995–2009), PubMed (1950–2009), and Cochrane library 3. Result
(Issue 3, 2009) and searched the reference list of retrieved
papers. All of those searches ended the end of November 3.1. Description of Included Trials. After primary search of
2009. We used the search terms “depression,” “xiaoyaowan,” 5 databases, 263 trials were screen out from electronic and
“xiaoyaosan,” and “xiaoyaotang.” Various combinations of manual searches (Figure 1), and the majority were excluded
the terms were used, depending on the database searched. due to obvious ineligibility which including irrelevant
The bibliographies of included studies were searched for titles and abstract (some papers being found from more
additional references. than one database). 141 trials with full text papers were
retrieved. 122 RCTs were excluded because of reporting
2.2. Inclusion Criteria. All the parallel randomized con- the depression complicated with other disease such as
trolled trials (RCTs) of all the prescriptions based on stroke and postpartum, 60 trials were excluded because of
“xiaoyaosan” including pills, powder, decoction dosage form duplicated publication, 22 trials were excluded due to the
compared with antidepressants in patients with depression animal studies, and the rest 41 trials were noncontrolled
Evidence-Based Complementary and Alternative Medicine 3

CNKI VIP CBM Cochrane library PubMed

N = 173 N = 52 N = 38 N =8 N = 13

Total
N = 263

Repetitions n = 60
Title, abstract Animal study n = 22
Case report, case series
traditional review n = 41

Full text
N = 140

114 studies excluded based

on the inclusion criteria

RCT included
N = 26

Figure 1: Study selection process.

clinical trials including case report, case series traditional based on “xiaoyaosan” using alone [9, 17–19, 23, 30] or
review. 114 out of the rest of 140 articles were excluded plus placebo [12, 15] versus antidepressants, one three-arm
based on the inclusion criteria. The treatment for depressive trial and the rest sixteen trials [7, 8, 10, 11, 13, 14, 16, 20–
neurosis, bipolar disorders, and depression in patients with 22, 24–29, 31, 32] compared the prescriptions based on
psychological stress insomnia were excluded. In the end, 26 “xiaoyaosan” plus antidepressants versus antidepressants.
RCTs were reviewed. The characteristics of 26 randomized The total treatment duration ranged from 30 days to 3
trials are summarized in Table 1. month. The variable prescriptions are presented in Table 1.
The 26 RCTs involved 1837 patients with depression. The different composition of formula Xiaoyaosan are pre-
There was a wide variation in the age of subjects (17–80 sented in Table 2. Nineteen (19) of the 26 trials used the
years). Twenty-six (26) trials specified six diagnostic criteria, hamilton depression scale (HAMD) as the outcome measure,
four trials [7, 17, 22, 25, 31, 32] used the China classification other 4 kinds of scales including self-rating depression
and diagnostic criteria for mental disorder (second edition scale (SDS), self-rating anxiety scale (SAS), the scale for
CCMD-2-R) alone, six [8, 9, 11, 18, 20, 24, 26–28, 30] TCM syndrome and symptom differentiation (TCM-SSD),
trials used the third edition (CCMD-3) alone, three trials the hamilton anxiety scale (HAMA) were also be used.
combined international classification on the diagnosis of Side effect was evaluated by asberg side effect scale and
depression (ICD-10) with CCMD-2-R [19] or CCMD-3 treatment-emergent symptom side effect (TESS) scale or
[12, 15], one trials [21] combined the depression standard described in details. Eleven (11) trials used four classes
in “internal medicine of Chinese medicine” and CCMD- to evaluate treatment effects including cure, significant
3 together, one trial [16] used CCMD-3 and affective effective, effective, ineffective, while ten (10) trials used three
disorder in the western medicine and Chinese medicine classes (except of cure) according to the scores reducing rate.
classification and diagnostic criteria on depression breaks
out, two trials [10, 29] used CCMD-3 and the diagnostic
criteria of Chinese medicine on depression and stagnation of 3.2. Methodological Quality of Included Trials. Six [10, 12,
liver qi, one trial [23] used CCMD-3 and depression of liver- 15, 16, 23, 26] out of 26 trials (23.08%) were evaluated as
qi stagnation and spleen deficiency, the last trial [13] used strong quality, the rest of 20 trials (76.928%) were evaluated
the depression standard in TCM on liver-qi stagnation and as moderate quality. The majority of the included trials were
spleen deficiency. assessed to be moderate methodological quality. The sample
The interventions included all the prescriptions based size of including trials varied from 24 to 200 patients. None
on “xiaoyaosan” including pills, powder, decoction dosage of the 26 trials reported sample size calculation. Ten trials
form alone, with Maprotiline placebo or with antide- described the randomization procedure, six [10, 12, 15, 16,
pressants. The controls included antidepressants alone or 23, 26] trials used random number table, four trials [8, 17, 25,
the combination of danzhiXiaoyaosan (DXS) placebo and 30] used visiting time to realize the randomization. One trial
antidepressants. Eight trials investigated the prescriptions [23] used opaque envelopes to allocate concealment. Only
4 Evidence-Based Complementary and Alternative Medicine

Table 1: Characteristics and methodological quality of included studies.

Diagnosis Course Followup

Study ID Sample Intervention Control Outcome measure
standard (week) (month)
Du et al. xiaoyao pill plus amitriptyline HAMD and TESS
120 CCMD-3 6–8
[8] fluoxetine paroxetine score, side effect
Huang and Shugan jieyu clinical effect, side
69 ICD-10 amitriptyline 6
Gan [9] formula effect
clinical effect,
danzhi xiaoyao
Huo et al. HAMD, HAMA
72 CCMD-3 decoction plus fluoxetine 6
[10] and CJI score, side
fluoxetine
effect
clinical effect,
J. Li et al. xiaoyao pill plus
60 CCMD-3 imipramine 8 HAMD score, side
[11] imipramine
effect
HAMD score,
Y. J. Li et CCMD-3, danzhixiaoyao
66 maprotiline 6 5-HT, NE, EDNF,
al. [12] ICD-10 powder
CORT, IL-6, IL-1β
clinical effect,
H. Li et al. xiaoyao powder
80 Unclear fluoxetine 6 12 HAMD, SDS score,
[13] plus fluoxetine
side effect
“practice
Liu and danzhixiaoyao
of internal clinical effect,
Chen 2007 78 powder plus amitriptyline 8
medicine”- HAMD score
[14] amitriptyline
3
symptoms, clinical
effect, HAMD,
Luo et al. CCMD-3, danzhixiaoyao
66 maprotiline 6 SDS, SAS and
2006 [15] ICD-10 powder
Asberg score, side
effect
clinical effect,
Ma 2007 xiaoyao pill plus
60 CCMD-3 citalopram 8 12 HAMD and Tess
[16] citalopram
score, side effect
C. Y. Wang
CCMD-2- guipi xiaoyao clinical effect, SDS
et al. 2004 200 venlafaxine 4
R pill score, side effect
[17]
R. C. clinical effect,
modifiedxiaoyao
Wang 2008 60 CCMD-3 amitriptyline 6 HAMD score, side
powder
[18] effect
CCMD-2-
T. Y. Wang danzhixiaoyao clinical effect, SDS
61 R fluoxetine 6
2001 [19] decoction score, side effect
ICD-10
clinical effect,
W. A.
xiaoyao pill plus HAMD and
Wang et al. 68 CCMD-3 fluoxetine 6
doxepin HAMA score, side
2005 [20]
effect
clinical effect,
Y. Wang danzhixiaoyao
HAMD and
and Liu 60 CCMD-3 powder plus fluoxetine 8
CGI-SI score, side
[21] fluoxetine
effect
xiaoyao powder
Wei et al. CCMD-2-
60 plus amitriptyline 4 clinical effect
1999 [22] R
amitriptyline
symptoms, clinical
Xian et al.
60 CCMD-3 xiaoyao powder fluoxetine 6 effect, HAMD
[23]
score
danzhixiaoyao
Xiao [24] 66 CCMD-3 powder plus clomipramine 8 clinical effect
clomipramine
Evidence-Based Complementary and Alternative Medicine 5

Table 1: Continued.
Diagnosis Course Followup
Study ID Sample Intervention Control Outcome measure
standard (week) (month)
xiaoyao powder
Yang and plus amitriptyline or clinical effect, TESS
58 CCMD-2 12
Xie [25] amitriptyline or clomipramine score, side effect
clomipramine
modified clinical effect,
Yang et al.
64 CCMD-3 xiaoyao pill plus fluoxetine 12 3 HAMD score, side
[26]
amitriptyline effect
clinical effect,
Zhai et al. CCMD-2- xiaoyao powder
24 doxepin 8 HAMD and TESS
[7] R plus doxepin
score, side effect
clinical effect,
Zhang et xiaoyao pill plus
59 CCMD-3 fluoxetine 6 HAMD and TESS
al. [27] fluoxetine
score, side effect
Zhang xiaoyao pill plus HAMD score, side
50 CCMD-3 fluoxetine 6
[28] fluoxetine effect
modified
symptoms, clinical
Zhao and xiaoyao powder
66 CCMD-3 amitriptyline 12 effect, HAMD
Jiang [29] plus
score, side effect
amitriptyline
symptoms, clinical
Zhou and effect, HAMD and
90 CCMD-3 xiaoyao powder fluoxetine 8
Li [30] SDS score, side
effect
xiaoyao pill plus HAMD score, side
Zhu [31] 60 CCMD-2 venlafaxine 10
venlafaxine effect
xiaoyao powder
Zhu and Li clinical effect, side
60 CCMD-2 plus amitriptyline 8
[32] effect
amitriptyline

four [12, 15, 23, 27] of the 26 trials employed a blinding control group on the four criteria outcome measurement
procedure: three of them using patients blinding, doctors Two [17, 19] trials compared the effectiveness using the
blinding, and assessors blinding, and the other one [27] three criteria outcome measurement: significant effective
mentioned single-blind without further details. Seven trials (SDS scores reduced rate ≥ 50%), effective (50 > SDS scores
[8, 10–12, 15, 21, 25] reported the withdrawals/dropouts reduced rate ≥ 30%), not effective (SDS scores reduced
information. Three trials [13, 16, 26] mentioned follow-up, rate < 30%). The Total effective rate is the combination
and neither of them used intention to treat method. The of “cure”, “significant effective “and” effective rate”. We
reporting quality of 26 trials according to quality assessment put these two different kinds of measurements together
tool for quantitative studies varied among different trials to evaluate the general effectiveness. The meta-analysis
(Table 3). showed no significant difference between xiaoyaosan and
antidepressants on the Total effective rate (RR: 1.05 [1.00,
3.3. Effect of the Interventions (Tables 4–6) 1.11]; P = 0.07) (Table 4).
3.3.1. “Xiaoyaosan” versus Antidepressants (Western Medi-
cine). Eight [9, 12, 15, 17–19, 23, 30] trials compared HAMD Scores Decrease. Meanwhile four trials [12, 15, 18,
xiaoyaosan with antidepressants. 30] reported there are no significant difference on the HAMD
scores decrease nor on the HAMD scores reduced rate [15]
Clinical Comprehensive Effect. Seven of the eight trials used after 6 weeks treatment. Meta-analysis of three trials showed
clinical comprehensive effect to evaluate the outcome. Five the same result in the fixed effects model (WMD: 0.59
trials [9, 15, 18, 23, 30] used the percentage of HAMD scores [−0.51, 1.70]; P = 0.29) and random effects model (WMD:
reduced rate to measure the outcome: cure (HAMD scores 0.43 [−2.14, 2.99]; P = 0.74) with significant heterogeneity
reduced rate more than 75%), significant effective (HAMD (I 2 = 68.7%) (Table 5).
scores reduced rate between 51% and 75%), effective
(HAMD scores reduced rate from 25 to 50%) and ineffective SDS Scores Decrease. Four trails [15, 17, 19, 30] reported the
(HAMD scores reduced rate less than 25%). None of the five SDS scores decreasing. Meta-analysis of four trials showed
trials showed significant difference between treatment and significant difference in favor of modified xiaoyao powder or
6 Evidence-Based Complementary and Alternative Medicine

Table 2: Composition of formula.

ID Formulation Composition of formula

Du et al. [8] pill Chinese patent medicine
Bupleuri 10 g, Paeoniae lactiflorae 15 g, Poriae cocos pararadicis 30 g, Atractylodis macrocephalae 15 g,
Moutan radicis 10 g, Curcumae 10 g, Angelicae sinensis 15 g, Menthae haplocalycis 10 g, Tritici aestivi
levis 30 g, Polygoni multiflory 30 g, Pseudostellariae heterophyllae 20 g. Menstrual period remove Moutan
Huang and radicis, Pseudostellariae heterophyllae, Menthae haplocalycis, plus Ligustici chuanxiong 10 g, Persicae 10 g,
decoction
Gan [9] Leonuri heterophylli 30 g, Guanzhong 10 g, typhae 10 g, Trogopteri seu pteromi 10 g; Follicular phase
remove Moutan radicis, Menthae haplocalycis, plus Cervi 15 g, Epimedii 15 g, Chrysanthemi indici 15 g,
Lycii 15 g; Luteal phase plus Gardeniae jasminoidis 10 g, Ligustri lucidi 20 g, Liquidam baris taiwanianae
15 g, Cyperi rotundi 10 g, Rhapontici seu echinops 10 g
Bupleuri 10 g, Paeoniae lactiflorae 12 g, Angelicae sinensis 12 g, Poriae cocos 20 g, Atractylodis macro-
cephalae 10 g, Moutan radicis 12 g, Gradeniae jasminodidis 10 g, Curcumae l2 g, Acori graminei 10 g,
Fructus aurantii 10 g, Draconis 30 g, Ostreae 30 g, Polygalae tenuifoliae 12 g, Cizyphi spinosae 30 g, Tritici
Huo et al.
decoction aestivi levis 30 g, Glycyrrhizae uralensis 10 g, Zizyphi jujubae 5. Blood stasis plus Ligustici chuanxiong 12 g,
[10]
Salviae milgiorrhizae 20∼30 g; Phelgm and dampness plus Citri reticulatae 10 g, Pinelliae ternatae 10 g; Yin
deficiency plus Lilii 30 g, Anemarrhenae asphodeloibis 10 g; Qi deficiency remove Gradeniae jasminodidis,
plus Pseudostellariae heterophyllae 15 g; Astriction plus Cannabis sativae 10 g or Radix et rhizome 10 g
Li et al. [11] pill Chinese patent medicine
Li et al. 2007 Chinese patent medicine (bupleuri, angelicae sinensis, poriae cocos, atractylodis macrocephalae, gradeniae
powder
[12] jasminodidis, moutan radicis)
Bupleuri 15 g, Angelicae sinensis 15 g, Atractylodis macrocephalae 15 g, Paeoniae lactiflorae 10 g, Poriae
Li et al. [13] decoction
cocos 10 g, Menthae haplocalycis 6 g, Glycyrrhizae uralensis 6 g
Bupleuri 8 g, Gradeniae jasminodidis 6 g, Ligustici chuanxiong 6 g, Glycyrrhizae uralensis 6 g, Moutan
radicis 10 g, Taeoniae rubrae 10 g, Atractylodis macrocephalae 10 g, Draconis 30 g, Ostreae 30 g, Poriae
cocos 15 g. Liver qi stagnation and abdominal distention plus Aucklandiae lappae 10 g, Citri reticulatae
Liu and Chen
decoction 10 g, Cyperi rotundi 6 g; Insomnia plus Albizziae julibrissin 15 g, Polygoni multiflory 15 g, Poriae cocos
[14]
pararadicis 15 g, Polygalae tenuifoliae 10 g; Cizyphi spinosae 10 g; Spleen and stomach deficiency plus
Pseudostellariae heterophyllae 10 g, Citri reticulatae 10 g; Phlegm and dampness and no appetite plus
Pinelliae ternatae 10 g, Bambusae in taeniis 10 g, Citri reticulatae 10 g, Amomi 6 g
Bupleuri, Angelicae sinensis, Paeoniae lactiflorae, Poriae cocos, Atractylodis macrocephalae, Moutan
Luo et al. [15] powder
radicis, Gradeniae jasminodidis
Ma [16] pill Chinese patent medicine
Bupleuri, Astragali membranacei, Codonotsitis pilosulae, Angelicae sinensis, Paeoniae lactiflorae, Rehman-
Wang et al. niae glutinosae, Artemisiae yinchenhao, Atractylodis macrocephalae, Poriae cocos, Aucklandiae lappae,
pill
[17] Cizyphi spinosae, Polygalae tenuifoliae, Schisandrne chinensis, Acori graminei, Moutan radicis, Moschus,
Menthae haplocalycis, Glycyrrhizae uralensis
Bupleuri 12 g, Angelicae sinensis 20 g, Paeoniae lactiflorae 12 g, Atractylodis macrocephalae 12 g, Lilii
15 g, Albizziae julibrissin 15 g, Citri aurantii 10 g, Pinelliae ternatae 12 g, Gradeniae jasminodidis 10 g,
Wang [18] decoction
Scutellariae baicalensis 10 g, Bambusae textillis 15 g, Curcumae 12 g, Acori graminei 12 g, Glycyrrhizae
uralensis 6 g, Zizyphi jujubae 6
Bupleuri 10 g, Paeoniae lactiflorae 12 g, Angelicae sinensis 12 g, Poriae cocos 20 g, Atractylodis macro-
cephalae 10 g, Moutan radicis 12 g, Gradeniae jasminodidis 10 g, Curcumae 12 g, Acori graminei 10 g,
Fructus aurantii 10 g, Draconis 30 g, Ostreae 30 g, Polygalae tenuifoliae 12 g, Cizyphi spinosae 30 g, Tritici
Wang [19] decoction aestivi levis 30 g, Glycyrrhizae uralensis 10 g, Zizyphi jujubae 5. Blood stasis plus Ligustici chuanxiong 12 g,
Salviae milgiorrhizae 20–30 g; Phlegm and dampness plus Citri reticulatae 10 g, Pinelliae ternatae 10 g; Yin
deficiency plus Lilii 30 g, Anemarrhenae asphodeloibis 10 g; Qi deficiency remove Gradeniae jasminodidis,
plus Pseudostellariae heterophyllae 15 g; Astriction plus Cannabis sativae 10 g or Radix et rhizome 10 g
Wang et al.
pill Chinese patent medicine
[20]
Angelicae sinensis 10 g, Paeoniae lactiflorae 12 g, Bupleuri 12 g, Atractylodis macrocephalae 10 g, Poriae
Wang and
decoction cocos 12 g, Zingiberis officinalis recens 10 g, Glycyrrhizae uralensis 10 g, Moutan radicis 10 g, Gradeniae
Liu [21]
jasminodidis 10 g
Qi stagnation and blood stasis plus Salviae milgiorrhizae, Cyperi rotundi, Linger strychnifoliae, Ligustici
chuanxiong, Taeoniae rubrae; Qi stagnation leading to fire plus Salviae milgiorrhizae, Gardeniae
jasminoidis; Qi and blood deficiency plus Codonotsitis pilosulae, Astragali membranacei, Rehmanniae
Wei et al. [22] decoction
glutinosae conquitae; Palpitation plus Cizyphi spinosae, Draconis, ostreae, Polygalae tenuifoliae, Biotae
orientalin; Spleen and kidney deficiency plus Morindae officinalis, Curculiginis orchioidis, Epimedii,
Zingberis officinalis, Aconiticarmichaeli praeparata, Corneum gigeriae galli
Evidence-Based Complementary and Alternative Medicine 7

Table 2: Continued.

ID Formulation Composition of formula

Xian et al. Angelicae sinensis, Paeoniae lactiflorae, Poriae cocos, Atractylodis macrocephalae, Menthae haplocalycis,
decoction
[23] Bupleuri, Zingiberis officinalis recens, Glycyrrhizae uralensis
Bupleuri 30 g, Menthae haplocalycis 12 g, Atractylodis macrocephalae 10 g, Poriae cocos 15 g, Moutan
radicis 12 g, Gradeniae jasminodidis 12 g, Angelicae sinensis 12 g, Paeoniae lactiflorae 10 g, Zingiberis
officinalis recens, Glycyrrhizae uralensis 6 g. Blood stasis Ligustici chuanxiong 12 g; Phelgm and dampness
Xiao [24] decoction
plus Citri reticulatae 10 g, Pinelliae ternatae 10 g; Yin deficiency plus Anemarrhenae asphodeloibis 10 g;
Qi deficiency plus Pseudostellariae heterophyllae 15 g; Astriction plus Cannabis sativae 10 g or Radix et
rhizome l0 g
Bupleuri l5 g, Atractylodis macrocephalae l0 g, Paeoniae lactiflorae l0 g, Angelicae sinensis l0 g, Poliae cocos
l0 g. Menthae haplocalycis 6 g, Glycyrrhizae uralensis 6 g. Qi stagnation leading to fire plus Gradeniae
Yang and Xie jasminodidis, Moutan radicis, Fructus aurantii; Heart and spleen deficiency plus Codonotsitis pilosulae,
decoction
[25] Astragali membranacei, Polygalae tenuifoliae, Dioscoreae oppositae; Phlegm and Qi stagnation plus
Trichosanthis, Pinelliae ternatae, Madnoliae officinalis; Blood stasis plus Persicae, Salviae milgiorrhizae,
Ligustici chuanxiong; Insomnia plus Cizyphi spinosae, Polygoni multiflori, Succinum
Yang et al. Bupleuri, Angelicae sinensis, Paeoniae lactiflorae, Poriae cocos, Atractylodis macrocephalae, Moutan
pill
[26] radicis, Gradeniae jasminodidis, Menthae haplocalycis, Glycyrrhizae uralensis
Zhai et al. [7] pill Chinese patent medicine
Zhang et al. Bupleuri, Angelicae sinensis, Paeoniae lactiflorae, Atractylodis macrocephalae, Poriae cocos, Menthae
pill
[27] haplocalycis, Zingiberis officinalis recens, Glycyrrhizae uralensis
Zhang [28] pill Chinese patent medicine
Bupleuri 15 g, Angelicae sinensis 15 g, Paeoniae lactiflorae 15 g, Atractylodis macrocephalae 15 g, Poriae
Zhao and
decoction cocos 15 g, Moutan radicis 10 g, Gradeniae jasminodidis 10 g, Glycyrrhizae uralensis 10 g, Menthae
Jiang [29]
haplocalycis 10 g, Zingiberis officinalis recens 10 g
Bupleuri 12 g, Angelicae sinensis 12 g, Atractylodis macrocephalae 9 g, Poriae cocos 15 g, Paeoniae
Zhou and Li lactiflorae 12 g, Cizyphi spinosae 15 g, Salviae milgiorrhizae 30 g, Ligustici chuanxiong 12 g, Carthami
decoction
[30] tinctolii 12 g, Persicae 9 g, Gradeniae jasminodidis 12 g, Citri reticulatae viride 9 g, Glycyrrhizae uralensis
6g
Zhu [31] pill Chinese patent medicine
Heart and spleen deficiency plus Codonotsitis pilosulae, Astragali membranacei, Salviae milgiorrhizae,
Polygalae tenuifoliae, Cizyphi spinosae, Asini. liver and kidney yin deficiency plus Draconis, Ostreae,
Zhu and Li Amydae sinensis, Asinilycii, Moutan radicis, Gradeniae jasminodidis. Liver qi stagnation plus Curcumae,
decoction
[32] Citri sarcodactylis, Citri reticulatae, Trichosanthis, Massa fermentata, Agastaches seu pogostemi, Eupatorii
fortunei. Spleen and kidney yang deficiency plus Cinnamomi cassiae, Rehmanniae glutinosae conquitae,
Corni officinalis, Schisandrne chinensis, Acori graminei

decoction compare to antidepressants (WMD: −3.97 [−5.52, Clinical Comprehensive Effect. Meta-analysis of fourteen
−2.41]; P < 0.00001) (Table 6). trials showed significant difference in favor of combination
group on clinical comprehensive effect (RR: 1.10 [1.04, 1.17];
Other Outcomes (TCM-SSD Scores, SAS Scores, 5-HT, BDNF, P = 0.0007) (Table 4).
etc.) One trial [15] showed that there are no significant
differences on TCM-SSD and SAS scores. One trial [12] HAMD Scores Decrease. Fourteen trials reported the HAMD
showed that after 6 weeks of treatment, the serum level of 5- scores decrease. The meta-analysis of fifteen trials showed
hydroxytryptamine (5-HT) and brain-derived neurotrophic there are significant beneficial effect on the combination
factor (BDNF) increased (P < 0.01) and the Interleukin- group compare to the antidepressants using alone both in
6 (IL-6) level decreased in both groups without significant the fixed effects model (WMD: −0.51 [−0.71, −0.31]; P <
difference between two groups, the cortisol (CORT) level 0.0001) and random effects model (WMD: −0.69 [−1.25,
reduced significantly in the DXP group compared to Mapro- −0.13]; P = 0.02) with significant heterogeneity (I 2 =
tiline group. 76.3%).

3.3.2. “Xiaoyaosan” Plus Antidepressants versus Antidepres- SDS Scores Decrease. One trial [13] showed significant
sants. Seventeen trials [7, 10, 11, 13, 14, 16, 20–22, 24–29, benefit on SDS scores decreased in favor of combination
31, 32] compared the combination of xiaoyaosan or modified group after 6 (MD: −3.6 [−4.65, −2.55]; P < 0.00001) weeks
xiaoyaosan plus antidepressants with antidepressants. treatment (Table 6).
8 Evidence-Based Complementary and Alternative Medicine

Table 3: Quality assessment of included randomized controlled trials.

Blinding of
participants Selective
Included Sequence Allocation Incomplete Other
personnel and outcome Risk of bias
trials generation concealment outcome data sourcesof bias
outcome reporting
assessors
Du et al.
Unclear Unclear Unclear Yes No Unclear High
[8]
Huang and
Unclear Unclear Unclear No No Unclear High
Gan [9]
Table of
Huo et al.
random Unclear Unclear No No Unclear Unclear
[10]
number
J. Li et al.
Unclear Unclear Unclear Yes No Unclear Unclear
[11]
Liu and
Unclear Unclear Double blind Yes No Unclear Unclear
Chen [14]
Li et al.
Unclear Unclear Unclear Yes No Unclear High
[13]
Liu and
Unclear Unclear Unclear No No Unclear High
Chen [14]
Table of
Luo et al.
random Unclear Double blind Yes No Unclear Unclear
[15]
number
Table of
Ma [16] random Unclear Unclear Yes Yes Unclear Unclear
number
Wang et al.
Unclear Unclear Unclear No No Unclear High
[17]
Wang [18] Unclear Unclear Unclear No No Unclear High
Wang [19] Unclear Unclear Unclear No No Unclear High
Wang et al.
Unclear Unclear Unclear No Yes Unclear High
[20]
Wang and
Unclear Unclear Unclear No Yes Unclear High
Liu [21]
Wei et al.
Unclear Unclear Unclear No Yes Unclear High
[22]
Table of
Xian et al.
random Yes Unclear No Yes Unclear Unclear
[23]
number
Xiao [24] Unclear Unclear Unclear No No Unclear High
Yang and
Unclear Unclear Unclear No Yes Unclear High
Xie [25]
Table of
Yang et al.
random Unclear Unclear No No Unclear Unclear
[26]
number
Zhai et al.
Unclear Unclear Unclear No No Unclear High
[7]
Zhang et
Unclear Unclear Single-blind No No Unclear Unclear
al. [27]
Zhang
Unclear Unclear Unclear No No Unclear High
[28]
Zhao and
Unclear Unclear Unclear No No Unclear High
Jiang [29]
Zhou and
Unclear Unclear Unclear No No Unclear High
Li [30]
Zhu [31] Unclear Unclear Unclear No No Unclear High
Zhu and Li
Unclear Unclear Unclear No No Unclear High
[32]
Evidence-Based Complementary and Alternative Medicine 9

Table 4: Analyses of clinical comprehensive effect.

Intervention
Trials Control (n/N) RR [95% CI] P Value
(n/N)
Xiaoyao powder versus antidepressants
Xiaoyao powder versus amitriptyline 1 41/42 25/27 1.05 [0.94, 1.18] 0.37
Danzhi Xiaoyao powder versus
1 28/32 30/31 0.90 [0.78, 1.05] 0.18
maprotiline
Guipi Xiaoyao powder versus
1 94/100 86/100 1.09 [1.00, 1.20] 0.06
venlafaxine
Modified Xiaoyao powder versus
1 29/30 28/30 1.04 [0.92, 1.16] 0.55
amitriptyline
Danzyhih Xiaoyao decoction versus
1 29/34 22/27 1.05 [0.83, 1.31] 0.69
fluoxetine
Xiaoyao powder versus fluoxetine 2 66/75 61/75 1.08 [0.94, 1.24] 0.25
Meta-Analysis 7 287/313 252/290 1.05 [1.00, 1.11] 0.07
Xioayao powder plus antidepressants
versus antidepressants
Xiaoyao pills/powder plus
2 56/60 45/60 1.24 [1.06, 1.46] 0.008
amitriptyline versus amitriptyline
Danzhi Xiaoyao decoction/powder
2 51/66 38/66 1.34 [1.05, 1.72] 0.02
plus fluoxetine versus fluoxetine
Xiaoyao pills plus imipramine versus
1 26/30 25/29 1.01 [0.82, 1.23] 0.96
imipramine
Xiaoyao pills plus fluoxetine versus
2 56/71 54/66 0.97 [0.82, 1.14] 0.69
fluoxetine
Danzhi Xiaoyao powder plus
1 38/40 28/38 1.29 [1.05, 1.58] 0.01
amitriptyline versus amitriptyline
Xiaoyao pills plus citalopram versus
1 28/30 28/30 1.00 [0.87, 1.14] 1.00
citalopram
Xiaoyao pills plus doxepin versus
1 32/35 29/33 1.04 [0.88, 1.22] 0.63
fluoxetine
Danzhi Xiaoyao powder plus
1 30/33 25/33 1.20 [0.96, 1.50] 0.11
clomipramine versus clomipramine
Modified Xiaoyao pills plus
1 29/32 30/32 0.97 [0.84, 1.12] 0.64
amitriptyline versus fluoxetine
Modified Xiaoyao powder plus
1 31/33 30/33 1.03 [0.90, 1.19] 0.64
amitriptyline versus amitriptyline
Xiaoyao powder plus doxepin versus
1 9/12 10/12 0.90 [0.60, 1.36] 0.62
doxepin
Meta-Analysis 14 386/442 342/432 1.10 [1.04, 1.17] 0.001

Other Outcomes (HAMA Scores, CGI Scores). One trial [10] mouth, Bloating, constipation, tachycardia, blurred vision,
showed significant benefit on HAMA scores decreased in insomnia, prolonged QT, naupathia, fatigue, anxiety, tremor,
favor of combination group after 6 (MD: −2.4 [−4.23, anorexia, palpitation, asthenia, oscitancy, sweat, akathisia,
−0.57]; P = 0.01) weeks treatment. tetter, excitation, hypertension, bellyache, dysuria, transami-
One trial [10] reported the outcome of CGI scores. nase increased, and sexual dysfunction (Figure 3).
It used modified DanzhiXiaoyao decoction plus fluoxetine Amitriptyline showed main side effect including dry
versus fluoxetine showed better effect on the combination mouth, constipation, dizziness, blurred vision, tachycardia,
group (MD: 0.8 [−1.2, −0.4]; P < 0.0001). somnolence and so forth, [8, 9, 14, 18, 22, 25, 32].
Imipramine, chlorimipramine, doxepin showed main side
3.4. Publication Bias. A funnel plot analysis of the 14 trials effect including dry mouth, constipation and other symp-
comparing xiaoyaosan plus antidepressants to antidepres- toms in alimentary canal [11]. Fluoxetine, paroxetine, citalo-
sants on Clinical Comprehensive Effect was generated, and pram showed main side effect including anxiety, insomnia,
it showed a significant asymmetry (Figure 2). headache, naupathia, sexual dysfunction, and tremor, [8, 13,
16, 19–21, 23, 26–28, 30]. Venlafaxine showed main side
3.5. Adverse Effect. Twenty-four out of twenty-six trials men- effect including dry mouth, sweat, insomnia, headache, and
tioned the adverse effect except two trials [22, 24]. Twenty- anxiety, [17, 31].
four trials reported the twenty-seven specific symptoms Four trials [9, 17, 19, 23] reported no side effect in
including diarrhea, dizziness and headache, somnolence, dry the herbal medicine group compared to the antidepressants
10 Evidence-Based Complementary and Alternative Medicine

Table 5: Analyses of score of HAMD.

Trials WMD [95% CI] P value
Xiaoyao powder versus antidepressants
Danzhi Xiaoyao powder versus
2 2.39 [−0.55, 5.33] 0.11
maprotiline
Modified Xiaoyao powder versus
1 1.11 [−0.21, 2.43] 0.10
amitriptyline
Xiaoyao powder versus fluoxetine 1 −3.30 [−6.07, −0.53] 0.02
Meta-Analysis [FEM] 4 0.59 [−0.51, 1.70] 0.29
Meta-Analysis [REM] 4 0.43 [−2.14, 2.99] 0.74
Xiaoyao powder plus antidepressants
versus antidepressants
Xiaoyao pills plus fluoxetine versus
1 0.06 [−1.50, 1.62] 0.94
amitriptyline
Xiaoyao pills plus fluoxetine versus
1 1.88 [0.20, 3.56] 0.03
paroxetine
Danzhi Xiaoyao decoction/powder
2 −0.18 [−0.49, 0.13] 0.25
plus fluoxetine versus fluoxetine
Xiaoyao pills plus imipramine versus
1 −0.10 [−2.35, 2.15] 0.93
imipramine
Xiaoyao pills plus fluoxetine versus
3 −1.41 [−2.17, −0.65] 0.0003
fluoxetine
Danzhi Xiaoyao powder plus
1 −5.84 [−8.76, −2.92] <0.0001
amitriptyline versus amitriptyline
Xiaoyao pills plus citalopram versus
1 −0.30 [−2.06, 1.46] 0.74
citalopram
Xiaoyao pills plus doxepin versus
1 −0.88 [−1.38, −0.38] 0.0006
fluoxetine
Modified Xiaoyao pills plus
1 0.17 [−1.29, 1.63] 0.82
amitriptyline versus fluoxetine
Xiaoyao powder plus doxepin versus
1 −0.80 [−4.84, 3.24] 0.70
doxepin
Modified Xiaoyao powder plus
1 −0.76 [−1.16, −0.36] 0.0002
amitriptyline versus amitriptyline
Meta-Analysis [FEM] 14 −0.51 [−0.71, −0.31] <0.00001
Meta-Analysis [REM] 14 −0.69 [−1.25, −0.13] 0.02
FEM: fixed effects model, REM: random effects model.

Table 6: Analyses of score of SDS.

Trials WMD [95% CI] P value

Xiaoyao powder versus antidepressants
Danzhi Xiaoyao powder versus maprotiline 1 −1.19 [−10.84, 8.46] 0.81
Guipi Xiaoyao powder versus venlafaxine 1 −5.00 [−7.07, −2.93] <0.00001
Danzyhih Xiaoyao decoction versus fluoxetine 1 −5.14 [−9.54, −0.74] 0.02
Xiaoyao powder versus fluoxetine 1 −1.70 [−4.59, 1.19] 0.25
Meta-Analysis [FEM] 4 −3.97 [−5.52, −2.41] <0.00001
Xioayao powder plus antidepressants versus antidepressants
Xiaoyao pills plus fluoxetine versus fluoxetine 1 −3.60 [−4.65, −2.55] <0.00001

group. Three trials reported side effect in xiaoyaosan group 30, 31] used treatment-emergent symptom side effect (TESS)
including headache, dizziness, and slightly diarrhea [15, 18, scale scores, one trial [15] used asberg side effect scale scores,
30]. Fifteen out of eighteen trials reported the combination the rest three trials [17, 19, 29] did not mentioned the tools
group has less side effect compare to the antidepressants they used to evaluate the side effect.
group. Twelve trials [7, 15–19, 21, 25, 29–31] mentioned A meta-analysis of four trials [7, 8, 16, 27] with
the side effect are significant reduced in intervention group five comparison using TESS scale scores showed less side
compared to control group. Seven trials [7, 16, 18, 21, 25, effect (WMD: −2.51 [−3.18, −1.84]; P < 0.00001) using
Evidence-Based Complementary and Alternative Medicine 11

Review: xiaoyao powder for depression (version 01) 70

Comparison: 04 xiaoyaosan plus antidepressants
versus antidepressants
60
Outcome: 02 scores of HAMD
0
50

Number of patients
1
40
SE(WMD)

3 30

4 20

−10 −5 0 5 10 10
WMD (fixed)
0

Wang and Liu [26]

Li et al. [13]

Zhao and Jiang [29]

Luo et al. [25]
Huo et al. [28]
Wang [23]
Zhang [14]
Wang et al. [8]

Yang et al. [16]

Ma [27]
Zhu [9]
Li et al. [31]
Yang and Xie [10]
Figure 2: Funnel plot.

xiaoyaosan plus antidepressants compare to antidepressants

using alone with significant heterogeneity (I 2 = 87.2%).
There is another trial [18] showed modified xiaoyao decoc-
tion had less side effect compared to amitriptyline (WMD:
−1.86 [−2.57, −1.15]; P < 0.00001). Trials
Hypertension Insomnia
Excitation Blurred vision
4. Discussion Tetter Tachycardia
Akathisia Constipation
Based on this paper and meta-analyses of the outcome on Sweat Bloating
Clinical Comprehensive Effect, HAMD scores, SDS scores, Oscitancy Dry mouth
HAMA scores, and CGI scores, the prescriptions based Asthenia Diarrhea
on “xiaoyaosan” including pills, powder, decoction dosage Palpitation Transaminase increased
form using alone or combined with antidepressants may Anorexia Dysuria
have beneficial effects on patients with depression. The Fatigue Bellyache
Naupathia Dizziness and headache
prescription xiaoyaosan may have the same effectiveness as
Prolonged QT
antidepressants at the end point of the treatment with fewer
side effects. The combination group may have significant Figure 3: Side effect of including studies (“xiaoyaosan” versus
beneficial effect compared to the antidepressants group antidepressants).
variable on onset time with less side adverse events. We
tried to analysis the trend of “xiaoyaosan”’s effectiveness by Two meta-analysis on HAMD scores showed significant
different followup time points as well. heterogeneity. It may due to the different intervention and
The SAS scales scores, TCM-SSD scales scores and the treatment time or the methodology quality. The significant
outcome of the four criteria outcome measurement “cure, heterogeneity on TESS scales may due to the dosage of the
significant effective, effective, or ineffective” showed that antidepressants.
there are no significant differences between the prescription According to the twenty-six trials the xiaoyansan pre-
group and antidepressants group. Meanwhile the xiaoyaosan scription group and the combination of xiaoyaosan and
prescriptions [12, 15] using alone may not as effective as antidepressants group have less adverse events compared
antidepressants after 2 weeks treatment but after 4 or 6 to antidepressants group with significant differences which
weeks treatment the effectiveness tend to be no significant were showed by the TESS scales and Asberg side effect scales.
difference between two groups. We could clearly tell the We should consider several limitations before accepting
trend from the HAMD scores and the reduced rate [15] the findings of this paper. First, the quality of the included
of HAMD scores [12, 15]. The SDS scores showed the studies is generally moderate according to the quality
xiaoyansan prescriptions are significantly more effective after assessment tool for quantitative Studies (Effective Public
4 weeks [17] and 6 weeks [19] treatment compared to Health Practice Project 2007) which was recommended
antidepressants. on the Cochrane Handbook. It also indicated that there
The combination of xiaoyaosan prescription plus antide- are moderate risk of bias in most of the trials. Due to
pressants group may have significant beneficial effect com- inadequate reporting of the allocation sequence, allocation
pared to the antidepressants group. The onset time are concealment, blinding, intention to treat analysis and drop
variable may depended on the form of prescription such as outs account in the majority of trials, it was possible
pills and decoctions. that there was performance bias and detection bias due
12 Evidence-Based Complementary and Alternative Medicine

to patients and researchers being aware of the therapeutic with well design and adequate sample size are warranted
interventions for the subjective outcome measures. Most to support or refute the positive findings. Trials should be
of the trials provided limited descriptions of study design, reported according to the CONSORT Statement [34].
randomization were mentioned but without further details In general, comparing to three categories (tricyclic-
after randomly assignment of patients which do not allow a tertiary amines, nontricyclic, specific serotonin reup-
proper judgment of the conduct of the trials. Therefore, we take inhibitors (SSRIs)) of antidepressant drugs such as
canot draw a confident conclusion that there are significant Amitriptyline, venlafaxine and Fluoxetine, the prescription
beneficial effects in patients with depression on combined based on xiaoyaosan in different forms appears to improve
groups or xiaoyaosan prescriptions using alone comparing
the symptoms with less adverse event. The combination
to antidepressants. The number of trials identified limits us
of xiaoyaosan and antidepressants may have shorter onset
to perform meaningful subgroup or sensitivity analyses to
time compare to antidepressants using alone. The mech-
illuminate robustness of the results in the review. Sixteen
out of twenty-seven trials didnot described the blinding in anism [12] may due to the regulating the levels of 5-
details, only two trials [12, 15] used double-dummy in their HT, CORT, BDNF, IL-6. Since depression may occurred
study design. recurrently with or without treatment, a longer follow-
Second, Liu et al. [33] found that some Asian countries up period with serial measurement of outcomes after the
including China publish unusually high proportions of treatment is important to determine the effectiveness and
positive results, considering all of the nineteen trials included long term effect of the xiaoyaosan prescription. Considering
are in Chinese the publication bias possibly existed. We there are not sufficient amount of high-quality trials on
cannot explore quantitatively the possibility of publication xiaoyaosan prescription treating patients with depression,
bias due to the small number of trials. the effectiveness of xiaoyaosan prescription need further
Third, different modified xiaoyao prescriptions and rigorous trials to prove.
different form of the prescriptions were used in the trials:
eight trials [7, 8, 11, 16, 20, 27, 28, 31] used fixed
xiaoyaowan throughout the treatment, five trials used mod-
Conflict of Interest
ified xiaoyaowan, and one trial used modified xiaoyansan The authors declare that there is no conflict of interest.
based on menstruation period of young female [9]. The rest
thirteen trials [10, 13, 14, 18, 19, 21–24, 29, 32] used modi-
fied xiaoyao decoction according to syndrome differentiation Acknowledgment
based on Chinese medicine theory, the herbal compound This work is supported by a grant from the Ministry of
varied from 7 to 17 herbs (Table 2). The treatment duration Science Project “The Study of Clinical Evaluation of Tradi-
varied from 30 days to 3 months. tional Chinese Medicine in China and Australia” ( Program,
Fourth, the use of composite outcome measures in 26 no. 2009DFA31460). Y. Zhang and J. Wang have contributed
trials to evaluate overall improvement of symptoms limits equally to the work.
the generalization of the findings. The classification of cure,
significant effective, effective, or ineffective and the Total
effective rate are not internationally recognized, and these References
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