Wang R, Wu MX, Wang XF, Chen ZT. Meta-analysis on the efficacy of liver-soothing formulas for perimenopausal anxiety and depression. World J Psychiatry 2026; 16(1): 111471 [DOI: 10.5498/wjp.v16.i1.111471]
Corresponding Author of This Article
Zong-Tao Chen, PhD, Professor, Health Management Center, First Affiliated Hospital of Army Medical University (Third Military Medical University), No. 30 Gaotanyan Street Shapingba District, Chongqing 400038, China. zongtaochen@126.com
Research Domain of This Article
Psychiatry
Article-Type of This Article
Meta-Analysis
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Jan 19, 2026 (publication date) through Dec 31, 2025
Times Cited of This Article
Times Cited (0)
Journal Information of This Article
Publication Name
World Journal of Psychiatry
ISSN
2220-3206
Publisher of This Article
Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
Share the Article
Wang R, Wu MX, Wang XF, Chen ZT. Meta-analysis on the efficacy of liver-soothing formulas for perimenopausal anxiety and depression. World J Psychiatry 2026; 16(1): 111471 [DOI: 10.5498/wjp.v16.i1.111471]
Rui Wang, Ming-Xia Wu, Xiao-Fang Wang, Zong-Tao Chen, Health Management Center, First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing 400038, China
Author contributions: Wang R and Wu MX acquired, analyzed, and interpreted the data; Wang R and Wang XF drafted, revised, and approved the manuscript; Wang R and Chen ZT conceived and designed the study, and critically revised and approved the final manuscript.
Conflict-of-interest statement: All the authors report having no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zong-Tao Chen, PhD, Professor, Health Management Center, First Affiliated Hospital of Army Medical University (Third Military Medical University), No. 30 Gaotanyan Street Shapingba District, Chongqing 400038, China. zongtaochen@126.com
Received: August 6, 2025 Revised: September 9, 2025 Accepted: October 23, 2025 Published online: January 19, 2026 Processing time: 146 Days and 18 Hours
Abstract
BACKGROUND
Perimenopausal women are prone to anxiety and depression due to fluctuating hormone levels, which significantly impair their quality of life. The current treatments have certain limitations. In traditional Chinese medicine, liver-soothing formulas are commonly prescribed for mood-related disorders, but their overall efficacy in perimenopausal anxiety and depression remains uncertain and requires verification through meta-analysis.
AIM
To provide evidence-based support for clinical decision-making and research, a meta-analysis was conducted to evaluate the effectiveness of liver-soothing formulas in treating perimenopausal anxiety and depression.
METHODS
Relevant studies published up to April 2025 were retrieved from ClinicalTrials.gov, PubMed, Web of Science, EMBASE, and the Cochrane Library. Eligible studies were screened according to predefined inclusion and exclusion criteria. Data were extracted and analyzed using the Stata 12.0 software.
RESULTS
After searching and screening, 12 articles involving 1798 patients (922 in the treatment group and 876 in the control group) were included in the analysis. Meta-analysis showed that the standardized scores for anxiety [standardized mean difference (SMD) = -0.71, 95% confidence interval (95%CI): -1.06 to -0.36] and depression (SMD = -0.67, 95%CI: -1.06 to -0.27) of the treatment group were lower than those of the control group. Subgroup analysis results revealed that for anxiety, liver-soothing formulas used alone (SMD = -0.34, 95%CI: -0.50 to -0.18) or in combination (SMD = -0.88, 95%CI: -1.43 to -0.34) both significantly reduced scores compared with the control group. For depression, monotherapy of liver-soothing formulas showed no significant statistical difference between the treatment and control groups (SMD = -0.47, 95%CI: -1.11 to 0.17), whereas combination therapy produced significantly lower standardized scale scores in the treatment group than in the control group, with a statistically significant difference (SMD = -0.83, 95%CI: -1.39 to -0.28). Regarding Greene scores, no statistically significant difference was observed with monotherapy (SMD = 0.87, 95%CI: -0.32 to 2.06), whereas combination therapy had significantly lower Greene scores (SMD = -0.24, 95%CI: -0.44 to -0.04). No statistically significant difference was found between the groups in the occurrence of adverse reactions (odds ratio = 0.90, 95%CI: 0.57-1.43). However, liver-soothing formulas did not affect estrogen levels in perimenopausal women.
CONCLUSION
Compared with placebo, conventional Western medicine, or other interventions, the monotherapy of liver-soothing formulas demonstrates superior efficacy in treating perimenopausal anxiety. When used as an adjuvant, they exert a synergistic effect in alleviating negative emotions and improving overall perimenopausal symptoms.
Core Tip: This meta-analysis evaluates the efficacy of liver-soothing formulas for perimenopausal anxiety and depression by synthesizing data from randomized controlled trials. The results show that these formulas outperform the controls (placebo and conventional Western medicine) in reducing anxiety and depression scores, with fewer adverse reactions. When combined with other interventions, they exert synergistic effects. However, the high heterogeneity and small sample sizes in some trials limit the robustness of conclusions, requiring cautious interpretation.
Citation: Wang R, Wu MX, Wang XF, Chen ZT. Meta-analysis on the efficacy of liver-soothing formulas for perimenopausal anxiety and depression. World J Psychiatry 2026; 16(1): 111471
Perimenopause is the transitional period before and after menopause, during which women undergo marked biological and endocrine changes[1]. Declining ovarian function and reduced estrogen and progesterone levels predispose women not only to physiological symptoms—such as hot flashes, sweating, insomnia, palpitations, fatigue, headache, and mood swings—but also to psychological disorders, including anxiety and depression[2]. A survey of 19677 women aged 35-60 years showed that perimenopausal women had the highest anxiety and depression scores[3]. Among 3725 women aged 40-65 years, 47% reported depressive symptoms and 37% reported anxiety disorders[4]. Studies have shown that such psychological disturbances are associated with impaired quality of life, increased risk of cardiovascular diseases, and metabolic syndrome[5-7].
Currently, treatments for perimenopausal-related symptoms and emotional disorders include estrogen replacement therapy, sequential estrogen–progesterone therapy, and selective antidepressant and anxiolytic drugs. These treatments have short-term benefits but are limited by drug tolerance, side effects, and potential carcinogenic risks, restricting their broader clinical application[8,9]. Consequently, new therapeutic options are a research hotspot.
In recent years, significant progress has been made in applying traditional Chinese medicine (TCM) for perimenopausal anxiety and depression. Liver-soothing formulas, rooted in TCM theory of “liver soothing and depression relieving”, align with the syndrome differentiation of liver qi stagnation in perimenopausal women[10]. These formulas have demonstrated antidepressant and anxiolytic effects in animal studies and clinical trials. Moreover, compared with conventional Western medicine, such as hormone replacement therapy, they show greater efficacy in alleviating anxiety and depression scores, with fewer adverse reactions and better tolerability[11]. However, existing clinical studies are constrained by small sample sizes and varying methodological quality. To address these gaps, this study employs a meta-analysis to systematically evaluate the effectiveness of liver-soothing formulas in treating perimenopausal anxiety and depression, aiming to provide stronger evidence-based support for clinical practice.
MATERIALS AND METHODS
Inclusion and exclusion criteria
Inclusion criteria: (1) Study design: Randomized controlled trials (RCTs) published in English; (2) Subjects: Perimenopausal women with anxiety and depression; (3) Interventions: Liver-soothing formulas used alone or combined with other treatments (e.g., other TCM, Western medicine, and psychological interventions), with a minimum treatment duration of 4 weeks; (4) Control measures: Placebo, other proprietary Chinese medicines, conventional Western medicines, or psychological interventions, with treatment duration ≥ 4 weeks; (5) Outcome indicators: (a) Main outcomes: Improvement in anxiety and depression symptoms assessed using standardized scale scores, including investigator-rated scales [Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD)] and self-rated scales [Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS), Patient Health Questionnaire-9 (PHQ-9)]; hospital-based emotional scales [Hospital Anxiety and Depression Scale-Depression (HAD-D) and Hospital Anxiety and Depression Scale-Anxiety subscale (HAD-A)]; and (b) Secondary outcomes: Changes in serum hormone levels [e.g., estradiol (E2) and follicle-stimulating hormone (FSH)] and their changes from baseline; menopausal-related symptoms assessed using standardized rating scales (e.g., Greene score); and safety indicators, including all adverse events and reactions (e.g., nausea, dizziness, and elevated liver enzymes).
Exclusion criteria: (1) Literature such as meta-analyses, systematic reviews, clinical case reports, review articles, dissertations, conference papers, and animal studies; (2) Literature with incomplete data that could not be extracted or confined despite attempts to contact authors; (3) Literature with duplicate publications using the same dataset; (4) Literature lacking relevant or complete outcome indicators; (5) Literature with poorly designed methodologies or incomplete original data; and (6) Literature with unavailable full texts.
Literature retrieval
Relevant literature was searched in five databases: The Cochrane Library, PubMed, EMBASE, Web of Science, and ClinicalTrials.gov. The retrieval periods were as follows: PubMed (1996-April 2025), EMBASE (1974-April 2025), Cochrane Library (1993-April 2025), Web of Science (1969-April 2025), and ClinicalTrials.gov (2002-April 2025). A combination of subject and free-text terms was applied. Search terms included “Perimenopause”, “Menopause”, “Chinese medicine”, “Shugan”, and “xiaoyao”. The detailed PubMed search strategy is shown in Table 1.
(("Medicine, Chinese Traditional"[Mesh]) OR ((((((((((((((Zhong Yi Xue[Title/Abstract]) OR (Chung I Hsueh[Title/Abstract])) OR (Hsueh, Chung I[Title/Abstract])) OR (Traditional Medicine, Chinese[Title/Abstract])) OR (Chinese Traditional Medicine[Title/Abstract])) OR (Traditional Chinese Medicine[Title/Abstract])) OR (Chinese Medicine, Traditional[Title/Abstract])) OR (Traditional Tongue Diagnosis[Title/Abstract])) OR (Tongue Diagnoses, Traditional[Title/Abstract])) OR (Tongue Diagnosis, Traditional[Title/Abstract])) OR (Traditional Tongue Diagnoses[Title/Abstract])) OR (Traditional Tongue Assessment[Title/Abstract])) OR (Tongue Assessment, Traditional[Title/Abstract])) OR (Traditional Tongue Assessments[Title/Abstract]))))) OR ((soothing liver[Title/Abstract]) OR (liver-soothing[Title/Abstract]))) OR (Shugan[Title/Abstract])) OR ((((((((((((((xiaoyao) OR (chaihu)) OR (Longdan Xiegan Wan)) OR (Decoction for Calming the Liver and Promoting Qi Circulation)) OR (Qi - Stagnation Stomach Granules)) OR (Consistent Decoction)) OR (Yiguan Decoction)) OR (Yiguan Jian)) OR (Qiju Dihuang Wan)) OR (Sinisan)) OR (Chaihu Shugan San))) OR (Yueju)) OR (Longgu Muli)))
3
#1 OR #2
4
(("Menopause"[Mesh]) OR ("Perimenopause"[Mesh]))
5
"Anxiety"[Mesh]
6
(((((((Angst[Title/Abstract]) OR (Nervousness[Title/Abstract])) OR (Hypervigilance[Title/Abstract])) OR (Social Anxiety[Title/Abstract])) OR (Anxieties, Social[Title/Abstract])) OR (Anxiety, Social[Title/Abstract])) OR (Social Anxieties[Title/Abstract])) OR (Anxiousness[Title/Abstract])
7
"Depression"[Mesh]
8
(((((Depressive Symptoms[Title/Abstract]) OR (Depressive Symptom[Title/Abstract])) OR (Symptom, Depressive[Title/Abstract])) OR (Emotional Depression[Title/Abstract])) OR (Depression, Emotional[Title/Abstract])) OR (Depressed[Title/Abstract])
Two researchers independently screened the literature according to the inclusion and exclusion criteria, with results cross-checked for consistency. Disagreements were resolved through consultation with a third researcher. Data were then extracted from eligible studies, including: (1) Study information: First author’s name, study duration, publication year, and study design; (2) Baseline data: Sample size, participant age, intervention type and duration, and control measures; and (3) Outcome data: PHQ-9, HAMA, HAMD, SDS, SAS, HAD-D, and HAD-A scores; serum E2 and FSH levels; Greene score; and adverse events or reactions.
Literature quality evaluation
The methodological quality of the included RCTs was assessed using the Cochrane Collaboration’s Risk of Bias Assessment Tool across seven aspects: (1) Random sequence generation; (2) Allocation concealment; (3) Blinding of participants and personnel; (4) Blinding of outcome assessment; (5) Integrity of outcome data; (6) Selective reporting; and (7) Other sources of bias. Each item was rated as “low risk”, “high risk”, or “unclear risk”. Two researchers independently conducted the assessment, and disagreements were resolved through discussion with a third researcher to reach a consensus.
Statistical analysis
The Cochrane risk of bias assessment figures were generated using R v4.2.3, and Stata v12.0 was used for meta-analysis. Continuous variables are expressed as standardized mean difference (SMD) with 95% confidence interval (95%CI), whereas categorical variables are expressed as odds ratio (OR) with 95%CI. Before the meta-analysis, heterogeneity was assessed using the χ2 test and the I2 statistic. When P > 0.10 and I2 < 50%, heterogeneity was considered nonsignificant, and a fixed-effects model was applied. When P ≤ 0.10 and I2 ≥ 50%, significant heterogeneity was assumed, and a random-effects model was adopted. Sensitivity, meta-regression, and subgroup analyses were performed to investigate the causes of heterogeneity. Sensitivity analysis was performed by sequentially omitting individual studies to assess the robustness of pooled results. Publication bias was evaluated using the Egger’s linear regression and Begg’s tests. Differences were considered statistically significant at P < 0.05.
RESULTS
Results of the literature screening
A total of 555 studies were retrieved from the databases. After applying the inclusion and exclusion criteria, 12 eligible studies were included[12-23]. The screening process is illustrated in Figure 1.
Figure 1 Literature screening process.
RCT: Randomized controlled trial.
Basic information on the included articles
Twelve articles[12-23] met the criteria and were incorporated into the meta-analysis. Of these, four were multicenter RCTs and eight were single-center RCTs, involving 1798 patients. The experimental group comprised 922 patients treated with liver-soothing formulas alone or combined with other therapies, whereas the control group included 876 patients who received no liver-soothing formulas (i.e., placebos, other TCMs, conventional Western medicines, or psychological interventions). The basic characteristics of the included articles are presented in Tables 2 and 3.
Table 2 Basic characteristics of 12 included studies.
Among the 12 included studies, 10 studies[12-15,18-23] described randomized methods, including random number tables, SAS software, and Microsoft Excel functions; two studies[16,17] did not provide such descriptions. Allocation concealment was reported in six studies[12,13,18-20,23]. Five studies[12,13,19,20,23] implemented double blinding of both implementers and participants, whereas the remainder lacked blinding or allocation concealment. None of the 12 studies described blinding in outcome measurement, raising the risk of selection or implementation bias. Nine studies[12,14,15,18-23] reported dropouts or withdrawals; six studies[12,13,14,19,22,23] specified the numbers and reasons. Eight studies[12-15,18-20,23] reported adverse events/reactions during follow-up. Four of them[12,15,20,23] provided detailed descriptions, patient counts, and statistical analyses, while the others provided only brief descriptions. No study addressed other potential biases, leaving the overall risk of bias uncertain. Detailed findings of the bias risk assessment are presented in Figures 2 and 3.
Figure 2 Results of risk of bias assessment for 12 included studies.
The column of numbers on the left side of the figure corresponds to the literature ID in Table 2.
Figure 3 Results of overall risk of bias assessment for 12 included studies.
Meta-analysis of the anxiety scores
Eight studies (n = 1134)[12,14,16,18-20,22,23] evaluated the effect of liver-soothing formulas on anxiety in perimenopausal women. However, in 2020, Zhang et al[19] reported dichotomous rather than continuous data; therefore, this study was excluded from the pooled analysis. The heterogeneity test yielded P < 0.001 and I2 = 88.9%, indicating substantial heterogeneity among the seven included studies; thus, a random-effects model was applied. The findings indicated that treatment significantly reduced the anxiety scores compared with the control group (SMD = -0.71, 95%CI: -1.06 to -0.36), suggesting that liver-soothing formulas can effectively alleviate anxiety in perimenopausal women. Subgroup analysis further demonstrated that both monotherapy and combination therapy significantly reduced anxiety scores compared with the control group; liver-soothing formulas alone (SMD = -0.34, 95%CI: -0.50 to -0.18); combined with other treatments/interventions (SMD = -0.88, 95%CI: -1.43 to -0.34; Figure 4A). Sensitivity analysis revealed that excluding any single study did not change the direction of the results, supporting their relative stability and reliability (Figure 5A). However, heterogeneity remained relatively high regardless of exclusion, making it difficult to determine the source of the heterogeneity. Meta-regression analysis by assessment tools (SAS vs others), study design (single center vs multicenter), treatment duration (8 weeks vs > 8 weeks), and treatment method (liver-soothing formulas alone vs combined with others) did not account for heterogeneity. Possible sources include differences in the physical constitution of patients included in each study, baseline anxiety levels, treatment regimens, and dosage.
Among the included literature, 10 studies (n = 1649)[12,13,16,23] evaluated the effect of liver-soothing formulas on depressive symptoms in perimenopausal women. However, the anxiety score data in the study by Zhang et al[19] were dichotomous, whereas those in the other nine studies were continuous data; therefore, Zhang et al[19] was excluded from the pooled analysis. The heterogeneity test results showed P < 0.001, I2 = 92.7%, indicating significant heterogeneity among the remaining nine studies; thus, a random-effects model was applied. The findings indicated that depression scores were significantly lower in the treatment group than in the control group (SMD = -0.67, 95%CI: -1.06 to -0.27), suggesting that liver-soothing formulas can effectively alleviate depressive symptoms in perimenopausal women. Subgroup analysis indicated no statistically significant difference between the liver-soothing formulas alone group and the control group (SMD = -0.47, 95%CI: -1.11 to 0.17), whereas combined therapy significantly reduced depression scores compared with the control group (SMD = -0.83, 95%CI: -1.39 to -0.28). This suggests that liver-soothing formulas alone have limited efficacy in improving depressive symptoms during perimenopause, but when combined with other interventions, they exert synergistic effects (Figure 4B). Sensitivity analysis showed that excluding any single study did not change the overall direction of the results, confirming their relative stability and reliability (Figure 5B). However, heterogeneity remained relatively high regardless of study exclusion, making it difficult to determine the source of the heterogeneity. Meta-regression on variables, such as assessment tools (SDS vs others), study design (single center vs multicenter), treatment duration (8 weeks vs > 8 weeks), and treatment method (liver-soothing formulas alone vs. combined) indicated that none explained the heterogeneity. Potential sources of heterogeneity may include differences in patient characteristics (i.e., constitution, underlying diseases, baseline depression level, etc.); prescriptions (ingredients, duration, and dosage); and methodological diversity (measurement tools, sample size, and study design).
Meta-analysis of the Greene scores
Among the included studies, four studies (n = 498)[15,17,18,20] reported the effect of liver-soothing formulas on Greene scores in perimenopausal women. The heterogeneity test showed P < 0.001 and I2 = 87.1%, indicating significant heterogeneity; a random-effects model was therefore used. The findings showed no statistically significant difference between the treatment and control groups (SMD = 0.27, 95%CI: -0.32 to 0.88)). Subgroup analysis indicated no statistically significant difference when liver-soothing formulas were used alone (SMD = 0.87, 95%CI: -0.32 to 2.06), whereas combined therapy significantly reduced Greene scores compared with the control group (SMD = -0.24, 95%CI: -0.44 to -0.04). This suggests that liver-soothing formulas alone do not significantly improve Greene scores, but in combination with other treatments/interventions, they significantly reduce Greene scores in perimenopausal women (Figure 4C). Sensitivity analysis indicated that excluding individual studies did not change the overall direction of the pooled findings, supporting the stability and reliability of the results (Figure 5C).
Meta-analysis of perimenopausal hormone levels
Among the included studies, five studies (n = 610)[14-16,18,22] reported the effect of liver-soothing formulas on estrogen (E2) levels in perimenopausal women. The heterogeneity test showed P < 0.001 and I2 = 97.3%, indicating significant heterogeneity; thus, a random-effects model was applied. The pooled analysis suggested no significant improvement in E2 levels with liver-soothing formulas (SMD = 0.27, 95%CI: -0.32 to 0.88; Figure 4D). Sensitivity analysis revealed that excluding any single study did not change the overall direction of the results, confirming their relative stability and reliability (Figure 5D). Given that only one study reported the effect of liver-soothing formulas alone on the E2 levels of perimenopausal women, subgroup analysis by treatment method (liver-soothing formulas alone vs. in combination with others) was not performed.
FSH
Among the included studies, five studies (n = 588)[14,15,18,19,22] evaluated the effect of liver-soothing formulas on FSH levels in perimenopausal women. The heterogeneity test showed P < 0.001 and I2 = 92.2%, indicating significant heterogeneity among the five studies; thus, a random-effects model was applied. No statistically significant differences were observed between the treatment and control groups (SMD = -0.08, 95%CI: -0.77 to 0.62). Subgroup analyses indicated that neither liver-soothing formulas alone or in combination produced significant changes in FSH levels (P > 0.05; Figure 4E). Sensitivity analysis revealed that the combined results remained directionally unchanged after exclusion of most studies, supporting their stability and reliability (Figure 5E). These findings suggest no clear evidence that liver-soothing formulas improve FSH levels in perimenopausal women.
Safety of liver-soothing formulas
Eight articles[12-15,18-20,23] reported adverse events or side effects during follow-up. Among them, four studies[13,14,18,19] reported no abnormalities in biochemical safety indicators (e.g., liver and kidney function, blood, urine, and stool) and no adverse reactions. The other four[12,15,20,23] described adverse reactions and case counts. The heterogeneity test showed P = 0.275, I2 = 22.7%, indicating mild heterogeneity among the studies; thus, a fixed-effects model was applied. The findings revealed no statistically significant difference in adverse event incidence between the treatment and control groups (OR = 0.90, 95%CI: 0.57-1.43), suggesting that liver-soothing formulas did not increase the incidence of adverse reactions (Figure 4F). Sensitivity analysis revealed that excluding most of the studies did not change the overall direction of the pooled results, confirming result stability and reliability (Figure 5F). Notably, Chen et al[15] reported lower discontinuation rates due to adverse events with liver-soothing formulas than with premarin (an estrogen replacement therapy). The other three articles[12,20,23] compared liver-soothing formulas with a placebo and still found no statistically significant difference in adverse event incidence (P > 0.05).
Publication bias
Publication bias in the inclusion of articles regarding outcome indicators, including standardized anxiety and depression scores, hormone levels (E2 and FSH), Greene scores, and adverse events, was analyzed using Begg’s rank correlation and Egger’s linear regression tests. Both yielded P > 0.05 for all indicators, indicating a relatively low risk of publication bias and more stable results. For example, Begg’s rank correlation and Egger’s linear regression tests for the standardized anxiety/depression scale scores showed no evidence of publication bias (Figure 6).
Figure 6 Begg's rank correlation test and Egger's linear regression test.
A: Begg's rank correlation test for publication bias of anxiety scores; B: Begg's rank correlation test for publication bias of depression scores; C: Eegg's rank correlation test for publication bias of anxiety scores; D: Eegg's rank correlation test for publication bias of depression scores. SMD: Standardized mean difference.
DISCUSSION
In traditional Chinese medical literature, anxiety and depression are categorized as “Yu Zheng” (depression syndrome), “Bai He Bing” (lily disease), and “Zang Zao” (internal restlessness)[24]. A classic on gynecology text states that “for women, the liver is the foundation of life”. Menstruation, leukorrhea, pregnancy, and childbirth all depend on the liver, whose physiological functions rely on the smooth flow of liver qi. Impaired liver function disrupts qi dispersion, affects qi and blood regulation, and disturbs the thoroughfare and conception vessels, leading to systemic symptoms[25]. Women, described as having “abundant qi and scarce blood”, are prone to qi stagnation, which fosters diseases. During the perimenopausal period, anxiety and depression are primarily linked to the liver. Given that the liver governs qi dispersion and emotions, stagnation of liver qi results in emotional dysregulation. According to the five elements theory, wood-generating fire can influence the heart’s role in governing the mind. Therefore, in clinical practice, prescriptions that soothe the liver are commonly used to restore qi flow and regulate emotions[26].
This study comprehensively evaluated the effects of liver-soothing formulas on perimenopausal anxiety and depression. The findings indicated that these formulas effectively alleviated anxiety and depression, and when used as adjunctive therapy, further improved mood symptoms and menopausal severity. Additionally, this study found that during the treatment of perimenopausal anxiety and depression, the occurrence of adverse reactions was similar in the liver-soothing formula and the placebo groups, suggesting that liver-soothing formulas have a high level of safety. In contrast, the side effects of antidepressants and hormone drugs are mechanism related and often unavoidable. However, only one included study compared the adverse effects of hormone drugs with liver-soothing prescriptions, limiting precise risk assessment. A related meta-analysis on Xiangshao granules supports these findings, showing that compared with the control group (i.e., placebo, conventional Western medicine, or other traditional Chinese patent medicines), Xiangshao granules significantly alleviated menopausal symptoms and anxiety-depressive emotions with good safety[11]. Among the herbs frequently used for soothing, the Baishao (Paeoniae Radix Alba), Chaihu (Bupleuri Radix), Yu jin (Curcumae radix), and Xiangfu (Cyperi Rhizoma) were the most commonly used in the literature included in this study. Saikosaponins in Chaihu (Bupleuri Radix) regulate emotions by regulating monoamine neurotransmitters and brain-derived neurotrophic factors[27], and can reduce 5-hydroxytryptamine and dopamine levels in the brains of depressed rats, thereby reducing the incidence of depression[28]. Paeoniflorin in Baishao (Paeoniae Radix Alba) relieves pain, counteracts inflammation, treats depression, and enhances immunity, with anxiolytic and antidepressant effects mediated through amino acid receptor expression in brain tissue and correction of hypothalamic-pituitary-adrenal axis dysfunction[29]. Xiangfu (Cyperi Rhizoma) treats liver qi stagnation and contains volatile oils, tea polyphenols, α-cyperone, and flavonoids[30]. A study on the active components of antidepressants and action targets of Xiangfu showed that 69 compounds in Xiangfu could act on 103 biological targets, including 29 key targets, and exert antidepressant effects through eight related metabolic pathways, suggesting antidepressant effects through synergistic multicomponent, multi-target mechanisms[31]. Yu jin (Curcumae radix) is known to soothe the liver, relieve depression, promote qi and blood flow, alleviate pain, and cool the blood. Its chemical components-volatile oils, curcumin, and alkaloids-exert neurological, anti-inflammatory, analgesic, renal protective, and neurotransmitter-modulating effects[32]. Oral curcumin extract has been shown to inhibit oxidative enzyme activity in the mouse brain, counteracting depression[33]. Overall, liver-soothing formulas alleviate liver qi stagnation, soothe the spirit, and eliminate irritability. Their efficacy arises not only from individual herbs but also from synergistic, antagonistic, and complementary interactions within the formulas. This study provides evidence supporting the clinical value of liver-soothing prescriptions and can inform future research and shared decision-making between physicians and patients.
A study by Wang et al[34] showed that treating patients with polycystic ovary syndrome (PCOS) of the liver-depression type with the modified Chaihu Shugan San (a liver-soothing formula) significantly improved sex hormone levels, as evidenced by an increase in E2 level. This suggests that Chaihu Shugan San can intervene in PCOS by regulating sex hormone secretion. Estrogen receptors do not independently function but act in coordination with neurotransmitters. Serotonin, norepinephrine, and dopamine—the three main monoamine neurotransmitters—play crucial roles in modulating emotional states, maintaining sleep rhythms, and regulating pain perception[23,35]. Similarly, a meta-analysis by Tang et al[11] reported that Xiangshao granule (another liver-soothing formula) outperformed other Chinese patent medicines or placebo in increasing E2 levels. Moreover, combining Western medicine with Xiangshao Granule was more significantly effective than hormone replacement therapy or selective serotonin reuptake inhibitors alone in lowering serum luteinizing hormone level and elevating serum E2 level, with statistically significant differences (P < 0.05). However, the results of this meta-analysis also indicated that the estrogen levels in the control group and perimenopausal women receiving liver-soothing formula differed insignificantly. Therefore, further studies are needed to determine whether the observed improvements in anxiety and depression alleviation are related to changes in estrogen levels.
The standardized use of blinding is critical for reducing implementation and measurement bias. Blinding minimizes subjective interference, reduces measurement error, and increases the credibility of results[36], whereas inadequate allocation concealment can exaggerate efficacy[37]. In this study, however, most included studies paid insufficient attention to these factors: Only six reported allocation concealment, five implemented double blinding of implementers and participants, and none described blinding of outcome measures. These shortcomings may have introduced bias. Additionally, only three studies of the 12 included studies had large-sample sizes (> 250 cases), whereas the remaining nine had fewer than 200 cases, with the smallest enrolling just 38 cases. Small sample sizes increase the risk of false-negative findings and limit the generalizability and clinical applicability of the results.
Due to differences among the included studies—such as patient baseline characteristics, the types and duration of liver-soothing formulas, control medications/interventions, research settings, study designs, and outcome measures—this study has several limitations, which include the following: (1) Age distribution: The mean patient age across nine studies was 50 years, whereas two studies reported 55 years and one study reported 45 years, which increased heterogeneity in the evaluation; (2) Intervention diversity: Among the 12 studies, seven different liver-soothing formulas were used, including Xiangshao granules, Xiaoyao pills, Bushen Tiaogan formula, Modified Xiaoyao powder, Bupleurum and Cinnamon Twig, Chaihu Guizhi Longgu Muli decoction, Chaihu Guizhi Ganjiang decoction, and Shugan Bushen Huoxue decoction. These formulas differ in their composition and mechanisms of action. Treatment duration also varied significantly: Six studies applied an 8-week course, whereas the other six studies extended the course to 12 weeks or longer. Noteworthy, due to the small number of relevant existing literature, the experimental group of this study included two intervention types—liver-soothing formulas used alone and in combination with other treatments/interventions. When used alone, the action pathway is single, whereas combined interventions involve complex synergistic mechanisms, thereby reducing result comparability and complicating the attribution of effects; (3) Control-arm heterogeneity: Controls included placebo, psychological interventions, and other patented Chinese or Western medications, inherently adding variability in the pooled assessment; and (4) Study design: Only four studies were multicenter, whereas 75% were single center, limiting generalizability and increasing the risk of institution-specific selection bias. Subgroup and meta-regression analyses were performed to explore the sources of heterogeneity, but significant residual heterogeneity persisted. Therefore, extrapolation of conclusions should consider (1) differences in target populations for different formulas; (2) uncertainty regarding synergistic effects of combination therapies; and (3) limited representativeness of single-center studies.
CONCLUSION
In summary, liver-soothing formulas appear clinically effective in treating perimenopausal anxiety and depression and maintain a favorable safety profile without increasing adverse event incidence, suggesting notable therapeutic utility. However, limitations in overall study quality and sample size necessitate further validation through large-sample, multicenter, high-quality RCTs, and basic research. Future studies should prioritize the standardization of efficacy criteria, the use of objective laboratory and clinical endpoints, and more refined trial design to strengthen study credibility.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Psychiatry
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade C
Novelty: Grade B, Grade C
Creativity or Innovation: Grade B, Grade B
Scientific Significance: Grade C, Grade C
P-Reviewer: Lesicka M, PhD, Poland; Milad MR, PhD, United States S-Editor: Lin C L-Editor: A P-Editor: Yu HG
Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M; Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease.N Engl J Med. 2003;349:523-534.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 1512][Cited by in RCA: 1401][Article Influence: 63.7][Reference Citation Analysis (0)]
Chen LC, Tsao YT, Yen KY, Chen YF, Chou MH, Lin MF. A pilot study comparing the clinical effects of Jia-Wey Shiau-Yau San, a traditional Chinese herbal prescription, and a continuous combined hormone replacement therapy in postmenopausal women with climacteric symptoms.Maturitas. 2003;44:55-62.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 38][Cited by in RCA: 44][Article Influence: 2.0][Reference Citation Analysis (0)]
Xu Y, Xu L, Zheng Y. Application of Chaihu-Guizhi-Longgu-Muli decoction combined with Liuwei Dihuang Pills in the treatment of menopausal insomnia and its effect on sleep quality.Pak J Pharm Sci. 2021;34:2027-2033.
[PubMed] [DOI]
Pei F, Hu WJ, Zhao YL. Efficacy of Jiao's scalp acupuncture in combination with Xiangshao granules on chronic tension-type headache with concomitant nonalcoholic fatty liver disease in climacteric women.Menopause. 2023;30:1132-1138.
[RCA] [PubMed] [DOI] [Full Text][Cited by in RCA: 1][Reference Citation Analysis (0)]
Zhou SJ, Shi J, Han P. [Clinical Efficacy on Shugan Bushen Huoxue Decoction in Treating Perimenopausal Perio Syndrome (Kidney Deficiency and Liver Depression and Blood Stasis Syndrome)].Zhongguo Shiyan Fangjixue Zazhi. 2021;27:83-88.
[PubMed] [DOI] [Full Text]
Xie Z, Tang R, Zhang P, Shu K, Liu K, Zhang Y, Ji J, Li S, Zhuang Y, Lu L, Guo C, Zhang J, Ren Q, Meng Q, Lin Y, Huang X, Li H, Liu Y, Deng Q, Zhang P, Chen R.
Efficacy of the Traditional Chinese Medicine Xiangshao on Menopausal Anxiety: A Multi-Center, Double-Blind, Randomized Controlled Trial. 2024 Preprint.
[PubMed] [DOI] [Full Text]
Lan J, Wu C, Liang W, Shen J, Zhuo Z, Hu L, Ruan L, Zhang P, Ye X, Xu L, Li C, Lin S, Yang C, Wu S, Dong Y, Ren H, Huang H, Gao B, Yao H, Lin T, Chen X, Li C. An Effective Treatment of Perimenopausal Syndrome by Combining Two Traditional Prescriptions of Chinese Botanical Drugs.Front Pharmacol. 2021;12:744409.
[RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)][Cited by in RCA: 7][Reference Citation Analysis (0)]
Wang F, Zhang AH, Zhang N, Dai GW, Guo X, Zhao X. [Effects of modified Chaihu Shugan powder on glucose and lipid metabolism and sex hormone levels in patients with polycystic ovarian syndrome in hepatic stagnation type].Linchuang Yixue Yanjiu Yu Shijian. 2022;7:114-7.
[PubMed] [DOI] [Full Text]
Mitchell A, Moe-Byrne T, Cunningham-Burley R, Dean A, Rangan A, Roche J, Torgerson DJ. Poor allocation concealment methods are associated with heterogeneity in age and statistical significance of the primary outcome: Review of recent trials published in four general medical journals.J Eval Clin Pract. 2020;26:1316-1319.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 2][Cited by in RCA: 3][Article Influence: 0.6][Reference Citation Analysis (0)]
