Depression is the most common mental disorder in menopausal women, with a prevalence ranging from 26% to 41.8% [
Antidepressants are considered the most common pharmacotherapy specifically for menopausal depression. However, the effect of antidepressants is unsatisfactory clinically, and the long-term use leads to considerable adverse effects. For example, selective serotonin reuptake inhibitors (SSRIs) are associated with sexual dysfunction, weight gain, and sleep disturbance [
Traditional Chinese medicine (TCM) is one of the oldest medicine systems in the world and has been widely used as a form of complementary and alternative medicine [
This systematic review was motivated by the large number of published clinical trials on OCHM combined with pharmacotherapy and the unresolved problems of pharmacotherapy. Our objective was to evaluate the effectiveness of OCHM combined with pharmacotherapy for menopausal depression.
We conducted and reported the systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines [
Titles and abstracts of all retrieved studies were screened, and then full texts were reviewed for eligibility by two authors (Jiju Wang and Jian Liu) independently. The data was collected by using the predefined data extraction form, including the journal title, first author, year of publication, size of study, baseline characteristics of women (e.g., age, course of disease), methodological design, intervention strategy, treatment duration, and outcomes. The dataset was validated by the third reviewer (Xiaouyn Wang).
Two reviewers independently evaluated the risk of bias by using the Cochrane Collaboration’s tool [
Meta-analysis was performed using Review Manager (the Cochrane Collaboration) software, Version 5.3.0. For dichotomous data, relative risk ratio (RR) with 95 % confidence intervals (CIs) was used to present the therapeutic effect; for continuous data, mean difference (MD) with 95 % CIs was used. The chi-square test and the Higgins I2 test were used to assess heterogeneity. If heterogeneity was low (
Publication bias was visualized by the funnel chart. Begg’s correlation test and Egger’s intercept test were used to quantify the publication bias, with a significant level at 0.05.
Databases search found 1076 articles. After duplicates were removed, 761 articles were screened by reading the title/abstract and 628 ineligible articles were removed. After reading the full texts of the remaining 133 articles, 22 trials [
Flowchart of study selection.
All included trials were conducted in China and they were published ranging from 2005 to 2016. The total sample size was 1777, including 901 women in the experimental group and 876 women in the control group. The participants ranged between 40 and 60 years. The most common diagnostic instrument was CCMD-3, and the combination of CCMD-3 and HAMD score was usually used as the inclusion criterion of RCTs. For outcome measurements, eighteen trials reported HAMD score [
Basic characteristics of the included studies.
Reference | Sample size(I/C) | Age(I/C) | Duration of disease(I/C) | Diagnosis standard | Intervention group | Control group | Treatment duration |
|
---|---|---|---|---|---|---|---|---|
Chen H, 2012 | 68/51 | 42-59 (50.20 ± 3.94) |
1.76 ± 0.99 y |
Age; |
OCHM + antidepressant | antidepressant | 8w | ①②④ |
|
||||||||
Chu YH, 2005 | 30/30 | 41-60 (47.86 ± 4.42) /41-60 (48.3 ± 4.06) | NS | Age; |
OCHM + HT | HT | 6w | ①② |
|
||||||||
Guo LH, 2016 | 43/43 | 40-55/42-55 | (1.8 ± 0.6) y/(1.6 ± 0.8) y | Age; |
OCHM + antidepressant | antidepressant | 6w | ② |
|
||||||||
Jiang LX, 2016 | 98/98 | 41-60 (51.18 ± 4.52)/46-54(48.85 ± 3.27) | (4.8 ± 1.7) y/(4.2 ± 1.0) y | Age; |
OCHM + antidepressant | antidepressant | 8w | ①②③④ |
|
||||||||
Li QY, 2009 | 34/34 | 41-56 (46.8 ± 4.1) | NS | Age; |
OCHM + pharmacotherapy | pharmacotherapy | 4w | ①②④ |
|
||||||||
Liu F, 2014 | 50/50 | 44-56 (49.3 ± 2.4) |
(2.3 ± 0.5) y/(2.1 ± 0.4)y | Age; |
OCHM + antidepressant | antidepressant | 8w | ①② |
|
||||||||
Liu R, 2007 | 30/30 | (54.32 ± 3.29) |
(11.32 ± 6.25) m/(12.12 ± 4.58)m | Age; |
OCHM + antidepressant | antidepressant | 8w | ①②④ |
|
||||||||
Ni JP, 2014 | 37/33 | (52 ± 4)/(52 ± 4) | (9 ± 5) m/ |
Age; |
OCHM + antidepressant | antidepressant | 4w | ②④ |
|
||||||||
Qu LX, 2010 | 30/30 | 45-55(51.6 ± 3.2) |
(10.5±2.7)m |
Age; |
OCHM + HT + antidepressant | HT + antidepressant | 8w | ①②④ |
|
||||||||
Shi LR, 2016 | 45/45 | 41-58(46.4 ± 4.2) |
(11.7 ± 4.5)m |
Age; |
OCHM + HT + antidepressant | HT + antidepressant | 12w | ①② |
|
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Sun GC, 2015 | 40/40 | 42.2 ± 2.60 |
(1.92 ± 1.06) y /NS | Age; |
OCHM + antidepressant | antidepressant | 4w | ① |
|
||||||||
Sun YH, 2013 | 38/38 | 43-48(44.76 ± 2.24) |
(2.38 ± 1.24) y |
Age; |
OCHM + HT + antidepressant | HT + antidepressant | 4w | ② |
|
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Wang CG, 2015 | 46/46 | 44-53(46.93 ± 6.8) |
NS | Age; |
OCHM + antidepressant | antidepressant | 6w | ①④ |
|
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Wang SF, 2015 | 40/40 | 43-50(46.45 ± 6.15) |
(2.75 ± 0.35)y |
Age; |
OCHM + HT + antidepressant | HT + antidepressant | 3w | ① |
|
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Wang XL, 2011 | 60/60 | 45-55(51.21 ± 3.17) |
NS | Age; |
OCHM + HT + antidepressant | HT + antidepressant | 8w | ① |
|
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Wang Y, 2015 | 30/30 | 45.20 ± 2.90 |
NS | Age; |
OCHM + antidepressant | antidepressant | 8w | ①②③④ |
|
||||||||
Zhang CH, 2013 | 40/40 | 43-56(46.80 ± 4.10) |
(11.50±4.30)m |
Age; |
OCHM + HT + antidepressant | HT + antidepressant | 3w | ①② |
|
||||||||
Zhang CH, 2011 | 30/30 | 45-55(43.50 ± 12.43) |
NS | Age; |
OCHM + antidepressant | antidepressant | 6w | ①② |
|
||||||||
Zhang GQ, 2009 | 38/34 | 45-56(51.63 ± 3.68) |
(9.44 ± 4.69)m |
Age; |
OCHM + antidepressant | antidepressant | 4w | ①②④ |
|
||||||||
Zhang HZ, 2014 | 20/20 | 45-53 |
(6-24)m |
Age; |
OCHM + HT | HT | 12w | ①②③ |
|
||||||||
Zhang SJ, 2012 | 27/27 | 43-54(46.5 ± 6.3) |
(3.2 ± 2.8)m |
Age; |
OCHM + antidepressant | antidepressant | 4w | ② |
|
||||||||
Zhang XH, 2014 | 27/27 | (47 ± 6.8) |
NS | Age; |
OCHM + antidepressant | antidepressant | 8w | ①② |
CCMD-3: Criteria for Classification and Diagnosis of Mental Diseases; DSM-IV: Diagnostic and Statistical Manual; ICD-10: International Classification of Disease; m = month; y = year; NS: not stated.OCHM: oral Chinese herbal medicine; HT: hormone therapy; w = week; ①: Hamilton Rating Scale for Depression (HAMD) score; ②: response rate; ③: Kupperman Menopausal Index (KMI) score; ④: adverse events (AEs).
Four forms of OCHM were investigated, consisting of decoctions, capsule, granule, and powder. Twenty-two formulas of OCHM were found. Bupleuri Radix (Chinese name: Chaihu) and Paeoniae Radix Alba (Chinese name: Baishao) were the herbs with top frequency. Details of OCHM in the included studies are summarized in Table
Chinese herbal medicine of the included studies.
Study | Formula |
|
Preparation | Dosage | Frequency |
---|---|---|---|---|---|
Chen H, 2012 | Jie Yu Jing Xin Ke Li | zhenzhumu, huaixiaomai, shoudihuang, shanzhuyu, tusizi, suanzaoren, fuling, chaihu, baishao, meiguihua, danggui, nvzhenzi | granule | 1 bag | bid |
|
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Chu YH, 2005 | Xiao Yao Jie Yu Tang | Chaihu, danggui, baishao, baizhu, fuling, weijiang, bohe, zhi gan cao, xian ling pi, nvzhenzi, shengmaiya, chaomaiya | decoction | 1 pack decocted twice | bid |
|
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Guo LH, 2016 | Bai He Di Huang Tang | Baihe, sheng di huang, long gu, muli, danggui, he huan pi, chaihu, ye jiao teng, fushen, yujin, zhi mu | decoction | 1 pack decocted twice | bid |
|
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Jiang LX, 2016 | Wu Ling Jiao Nang | wulingjun | capsule | 3 tablets | tid |
|
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Li QY, 2009 | Jie Yu Tang | Dangshen, chuanxiong, danggui, danshen, xiangfu, he huan pi, gualou, yujin | decoction | 1 pack decocted twice | bid |
|
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Liu F, 2014 | Suan Zao Ren Tang | Suanzaoren, chuanxiong, fuling, wuweizi, zhi mu, gan cao | decoction | 1 pack decocted twice | bid |
|
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Liu R, 2007 | Xue Fu Zhu Yu Jiao Nang | Taoren, honghua, chishao, chuanxiong, zhiqiao, chaihu, jiegeng, danggui, dihuang, niuxi, gan cao | capsule | 6 tablets | bid |
|
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Ni JP, 2014 | Shen Song Yang Xin Jiao Nang | Renshen, maidong, shanzhuyu, danshen, suanzaoren, sangjishen, chishao, tu bie chong, gansong, huanglian, wuweizi, long gu | capsule | 4 tablets | tid |
|
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Qu LX, 2010 | Jie Yu Zi Shen Tang | Chaihu, xiangfu, baishao, baizhu, yujin, gan cao, suanzaoren, fuling, shichangpu, shoudihuang, shanyurou, shanyao | decoction | 1 pack decocted twice | bid |
|
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Shi LR, 2016 | Zi Ni Zi Gan Yang Shen Tang | Fuling, gan cao, baishao, chaihu, chuanxiong | decoction | 1 pack decocted twice | bid |
|
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Sun GC, 2015 | Jia Wei Xiao Yao San | Chaihu, baizhu, bohe, danggui, fuling, baishao, gan cao, shengjiang, zhizi, danpi | granule | 1 bag | tid |
|
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Sun YH, 2013 | Zi Ni Shu Gan Jie Yu Tang | Chaihu, xiangfu, chuanxiong, chishao, yujin, chenpi, sheng di huang, shanzhuyu, danpi, yuanzhi, gan cao | decoction | 1 pack decocted twice | bid |
|
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Wang CG, 2015 | Zi Ni An Shen Jie Yu Tang | Huangqi, huangqin, chaihu, muxiang, zhiqiao, gan cao, sharen, peilan, dangshen, fushen, danggui, baizhu, chuanxiong, yujin, suanzaoren, ye jiao teng, long yan rou | decoction | 1 pack decocted twice | bid |
|
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Wang SF, 2015 | Zi Ni Shu Gan Jie Yu Tang | Chaihu, xiangfu, chuanxiong, baishao, yujin, chenpi, zhi mu, shengdi, shanzhuyu, danpi, suanzaoren, gan cao | decoction | 1 pack decocted twice | bid |
|
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Wang XL, 2011 | Si Hua Jie Yu Tang | He huan hua, xuanhua, meiguihua, baimeihua, suanzaoren, bai zi ren, fuxiaomai, fushen, ye jiao teng, tiandong, maidong, wuweizi, gan cao, dazao | decoction | 1 pack decocted twice | bid |
|
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Wang Y, 2015 | Zi Ni Bai He Di Huang Tang | Baihe, shengdi, maidong, wuweizi, he huan pi, ye jiao teng, fuling, yuanzhi, shichangpu, yujin, chuanxiong, gan cao | decoction | 1 pack decocted twice | bid |
|
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Zhang CH, 2013 | Wu Ling Jiao Nang | wulingjun | capsule | 3 tablets | tid |
|
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Zhang CH, 2011 | Zi Ni Zi Yin Bu Shen Tang | Chaihu, xiangfu, chuanxiong, baishao, yujin, shoudihuang, fuling, shanzhuyu, suanzaoren, gan cao | decoction | 1 pack decocted twice | bid |
|
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Zhang GQ, 2009 | Zi Ni Zao Ren Bu Xue |
Suanzaoren, fuling, chuanxiong, zhi mu, gan cao, huangqi, danggui, shanzhuyu, shoudihuang, danshen, chaihu, xiangfu, yujin, shichangpu | decoction | 1 pack decocted twice | bid |
|
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Zhang HZ, 2014 | Si Er Wu He Fang And Gan Mai Da Zao Tang | Danggui, baishao, danshen, shoudihuang, xianmao, xian ling pi, fu pen zi, tusizi, wuweizi, che qian zi, gouqi, yujin, huanglian, rougui, xiaomai, gan cao, dazao | decoction | 1 pack decocted twice | bid |
|
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Zhang SJ, 2012 | Zi Ni Bai He Di Huang Tang | Baihe, shengdi, danshen, chuanxiong, juhua | decoction | 1 pack decocted twice | bid |
|
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Zhang XH, 2014 | Kun Tai Jiao Nang | Shoudihuang, huanglian, baishao, huangqin, ejiao, fuling | capsule | 4 tablets | tid |
The risk of bias was summarized in Figures
Risk of bias across included studies.
Risk of bias of individual studies. +: low risk of bias; ?: unclear risk of bias; −: high risk of bias.
Eighteen RCTs (n = 1417 participants) used HAMD scores to measure the effect of OCHM for menopausal depression [
Forest plot of HAMD scores. HAMD: Hamilton Rating Scale for Depression; CHM: Chinese herbal medicine; HT: hormone therapy.
As the meta-analysis was heterogeneous, subgroup analysis in terms of different categories of pharmacologic agents was performed (Figure
Eighteen trials (n = 1189 participant) applied response rate of reducing HAMD scores in outcome measurement [
Forest plot of response rate.
Three RCTs [
Forest plot of Kupperman menopausal index scores.
AEs were monitored in nine studies (n = 797 participants) [
Forest plot of adverse event.
The funnel plots of HAMD scores and the response rate were asymmetrical (Figures
Funnel plot of HAMD scores.
Funnel plot of response rate.
In the present study, we reviewed 22 RCTs involving a total of 1777 participants and assessed the add-on effects and safety of OCHM to pharmacotherapy in women with menopausal depression. Meta-analysis showed that the combination of OCHM and pharmacotherapy was more effective in improving menopausal depression. In addition, the incidence of AEs in the participants treated with OCHM adjunctive therapy was less than those without OCHM adjunctive therapy. However, the risk of bias of the included RCTs may affect the evidence certainty; particularly most studies did not blind the participants or personnel.
OCHM can increase the expression level of estrogen receptors in hypothalamic pituitary ovarian (HPO) axis [
There were several limitations in this study. Firstly, the quality of the included trials was generally poor. The risks of selection bias and reporting bias were unclear most of the time. And the risk of performance bias in almost all the RCTs was high. These biases may affect the results of meta-analysis. Secondly, the heterogeneity was observed across meta-analyses and it was not resolved by subgroup analysis. This can also reduce the evidence certainty. Thirdly, none of the RCTs included considered placebo as the control. Hence the current studies were unable to conclude the efficacy of OCHM. Although it is difficult to successfully produce a placebo to CHM because of its special characteristics such as the appearance, smell, and taste, recent progress of placebo making can be applied. For example, when researchers explored the preparation method of placebo to Moron Dan, they found that the flavor characteristics and disintegration of the placebo made of soybean powder 100g, starch 100g, carbon black pigment 1g, and honey 70g were similar to the experimental drug [
Adjuvant therapy of OCHM provided additional benefits to pharmacotherapy in the people with menopausal depression. More RCTs with a rigorous design, particularly applying placebo as the control as well as blinding the participants and personnel, are needed to confirm the efficacy of OCHM for menopausal depression.
Search strategy included the following: #1 Menopause [Mesh] #2 ((((((((((Perimenopausal [ti.ab]) OR menopausal [ti.ab]) OR menopause [ti.ab]) OR perimenopause [ti.ab]) OR premenopause [ti.ab]) OR postmenopause [ti.ab]) OR menopausal transition[ti.ab]) OR premenopausal [ti.ab]) OR postmenopausal [ti.ab]) OR climacterium [ti.ab]) OR climacteric [ti.ab] #3 #1 OR #2 #4 Depression [Mesh] #5 (((((((((Depression [ti.ab]) OR Depressions [ti.ab]) OR Depressive Symptoms [ti.ab]) OR Depressive Symptom [ti.ab]) OR Symptom, Depressive [ti.ab]) OR Symptoms, Depressive [ti.ab]) OR Emotional Depression [ti.ab]) OR Depression, Emotional [ti.ab]) OR Depressions, Emotional [ti.ab]) OR Emotional Depressions [ti.ab] #6 #4 OR #5 #7 Medicine, Chinese Traditional [Mesh] #8 ((((((Medicine, Chinese Traditional [ti.ab]) OR Traditional Chinese Medicine [ti.ab]) OR Chinese Medicine, Traditional [ti.ab]) OR Chung I Hsueh [ti.ab]) OR Hsueh, Chung I [ti.ab]) OR Zhong Yi Xue [ti.ab]) OR Chinese Traditional Medicine [ti.ab]) OR Traditional Medicine, Chinese [ti.ab] #9 #7 OR #8 #10 ((randomized controlled trial [Publication Type]) OR randomized [ti.ab]) OR placebo [ti.ab] #11 #3 AND #6 AND #9 AND #10
The authors declare that there are no conflicts of interest regarding the publication of this article.
The study was conceived and designed by Xiaoyun Wang. Jiju Wang and Jian Liu independently screened literature, extracted data, and evaluated study quality. Xiaoyun Wang validated the data. Jiju Wang conducted data synthesis and analysis. Xiaoyun Wang, Xiaojia Ni, Jian Liu, and Guangning Nie finalized the results. Yuyan Zeng, Xiaojing Cao, and Xiaoyu Li participated in the discussion of data interpretation. Wang Jiju drafted the manuscript and Xiaojia Ni revised it.
This study was supported by the funding from Traditional Chinese Medicine Bureau of Guangdong Province (no. 2015KT1164 and no. 20171111) and the grant from Natural Science Foundation of Guangdong Province (no. 2017A030313728).