Evaluation of the Clinical Efficacy of the Classic Prescription “Baihe Dihuang Decoction” Based on Meta-Analysis

Purpose To explore the clinical application of Baihe Dihuang Decoction. To provide certain data support and theoretical basis for the clinical application of Baihe Dihuang Decoction in the future. Methods With “Baihe Rehmannia Tang” as the search term, the search was carried out on CNKI, VIP, Wanfang, PubMed and other databases. The statistical analysis of Baihe Dihuang decoction for treating diseases was obtained. Meta-analysis of the data was performed using RevMan 5.3 software to analyze the main therapeutic indicators of the disease. Results According to the 83 valid literature that can be found, it is shown that 17 are used for the treatment of depression, 14 are used for the treatment of menopausal syndrome, 24 are used for the treatment of insomnia, and 28 are used for the treatment of other diseases. Conclusion In the treatment of depression, menopausal syndrome, and insomnia combined with Baihe Dihuang Decoction can have a better therapeutic effect and diminish the incidence of adverse reactions. It provides a theoretical basis for the study and experimental study of its active components.


Introduction
e development of classic traditional Chinese medicine prescriptions has gradually become one of the hot spots in the field of traditional Chinese medicine. e "classical prescriptions" of the "Supplementary Regulations Regarding the Administration of Printing and Distributing the Registration of Traditional Chinese Medicines" promulgated in 2008 refer to the prescriptions recorded in the medical records of the Qing Dynasty and before the Qing Dynasty that are still widely used, have clear curative effects, and have obvious advantages. Subsequently, the "Ancient Classic Famous Prescriptions Catalog (First Batch)" and the "Ancient Classic Famous Prescriptions Chinese Medicine Compound Preparation Simplified Registration and Approval Management Regulations" were successively released. e introduction of these policies has brought new opportunities to the research and development of the classical prescriptions. e first batch of classical prescriptions included Baihe Dihuang Decoction [1]. Baihe Dihuang Decoction originated from Synopsis of the Golden Chamber of the Golden Chamber by Zhang Zhongjing. Baihe Dihuang Decoction is composed of lily and rehmannia glutinosa, which has the effect of nourishing Yin, clearing heat and nourishing heart and lung.
Traditional Chinese medicine generally works in the body through multiple components-multiple targets-multiple pathways. Meta analysis can objectively evaluate the effect indicators, Heterogeneity and significance between different trial outcomes can also be explained, erefore, we used evidence-based medicine to comprehensively search the published literature in both Chinese and English, collect the clinical trials of Baihe Dihuang Decoction, and discuss its therapeutic effects, so as to provide some evidence-based evidence for future clinical treatment. ese provided theoretical basis for the one-step treatment of the disease.

Literature Analysis and Statistics
With "Baihe Dihuang Decoction" as the key words, Wanfang, CNKI Figure 1. It can be seen that Baihe Dihuang Decoction is mainly used clinically to treat depression, menopausal syndrome, and insomnia. Meta-analysis was used to evaluate the efficacy and safety of Baihedihuang Decoction in the treatment of depression, menopausal syndrome and insomnia, so as to provide evidence-based reference for clinical application.

Meta Analysis and Methods.
e key words "Baihe Dihuang Decoction" and "depression," "Baihe Dihuang Decoction" and "menopause syndrome" or "climacteric syndrome," "Baihe Dihuang Decoction" and "insomnia" were searched in Wanfang, CNKI, VIP and PubMed databases, and the retrieval time was from the database establishment to March 27, 2021. Two researchers independently searched, screened literatures, evaluated quality and extracted data according to the inclusion and exclusion criteria, and used RevMan 5.3 software for analysis. All relevant literature were downloaded to Endnote software for further discussion. Duplicate records were deleted, the full text was reviewed, and the title/abstract is considered to be thematic. e above work was carried out independently by two investigators. Conflicts were resolved through consensus and discussion. e experimental group was treated with Baihe Dihuang Decoction or Baihe Dihuang Decoction combined with other drugs, and the control group was treated with conventional methods. (4) e outcome measure of each study must include at least one of the following indicators: e screening indicators for depression are HAMD, or the total effective rate (TER), or Incidence of adverse reactions (IAR), or KMI, or National Institutes of Health Stroke Scale (NIHSS), or Bathel Index, or QOL-100, or Symptoms of traditional Chinese medicine (STCM), or Social function evaluation (OHS), or Post-stroke depression (PSD), or Neurological deficit score (NDS), or PSQI, or Social dysfunction scale (SDSS), or 5-HT, or Norepinephrine (NE), or Follicle Stimulating Hormone (FSH), or Luteinizing hormone (LH), or Estradiol (E 2 ). e screening indicators for menopausal syndrome are TER, or menopause-specific quality of life questionnaire (MENQOL), or Simpson-Angus scale (SAS), or Anxiety Self-Rating Scale (SDS), or PSQI, or Yin Deficiency and Fire Prosperity Syndrome (YDFPS), or KMI, or Quality of Life (QL), or Hamilton depression scale (HAMD), or Hamilton anxiety scale (HAMA), or Luteinizing hormone (LH), or follicle Stimulating Hormone (FSH), or Estradiol (E 2 ), or Testosterone (T), or Prolactin (PRL), or Norepinephrine (NE), or 5-HT, or Nitric oxide (NO), or Endothelin-1 (ET-1), or calcitonin gene-related peptide (CGRP), or CD-3,4,8, or IL-2. e screening indicators for insomnia are TER, or Incidence of adverse reactions (IAR), or PSQI, or TCM symptom score (TSS), or sleeping time (ST), or Falling asleep time (FAT), or number of night wakes (NNW), or sleep depth (SD), or sleep efficiency (SE), or sleep quality (SQ), or Dreaminess or nightmares (DN), or Drowsiness, Lack of energy (LE), or HAMD, or HAMA, or Asberg Sideeffect Rating Scale for Antidepressant (ASRSA), or glycosylated serum protein (GSP). e exclusion criteria were designed as follows: (1) References, such as reviews, case reports, animal experiments, reviews that were considered irrelevant to the subject. (2) Diagnostic standard in statement was ambiguous. (3) e intervention of patients was not based on Baihe Dihuang Decoction. (4) Provide incomplete information and duplicate literatures.

Data Selection and Quality Assessment.
e literature that met the requirements was screened, and the information, including author, year of publication, sample size, intervention and measurement results, was tabulated. e quality of the included studies was independently evaluated by two investigators according to the Cochrane Intervention System Evaluation Manual. Disagreements were resolved by consensus. e quality assessment is as follows: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) and other bias. Each semester is judged at three levels. e "low risk" of prejudice means that the description of the method or procedure is adequate. An inadequate or incorrect description of a method or procedure means "High risk," while the absence of a description of a method or procedure means "unclear risk."

Data Analysis.
We analyzed the data using Review Manager 5.3 (Cochrane Collaboration). Outcome measures such as TER were treated as dichotomous variables and emerged as the odds ratio (OR) with 95% confidence intervals (95% CI). We evaluated the heterogeneity between the studies by using Q statistics and I 2 tests. e data with low heterogeneity (P ≥ 0.1% and I 2 ≤ 50%) were analyzed by using a fixed-effects model, while the data with high heterogeneity (P < 0.1 or I 2 > 50%) were estimated by using the random-effects model. Funnel plots reveal potential publication bias.
A total of 878 patients (451 cases in the experimental group and 427 cases in the control group) were enrolled in Baihedihuang decoction for depression treatment. e age of the patients ranged from 29 to 85years old, and there was no significant difference between the two groups by sex or sex. All trials were conducted before March 27, 2021, All reports are about comparing conventional treatment and conventional treatment combined with Baihe Dihuang Decoction treatment. In eligible trials, the conventional treatment plan is slightly different. Conventional antidepressants are generally psychotropic drugs and 5-HT, NE reuptake inhibitors. In some cases, Ganmai Dazao Decoction, Ginkgo biloba, etc are used. 13 studies reported treatment durations ranging from 2 weeks to 8 weeks. Baihe Dihuang Decoction for the treatment of menopausal syndrome selected 579 patients (290 cases in the test group, 289 cases in the control group), and the age of the patients was 40 to 60 years old. All reports are about comparing conventional treatment and conventional treatment combined with

Evidence-Based Complementary and Alternative Medicine
Baihe Dihuang Decoction treatment. In eligible trials, the conventional treatment plan is slightly different. Conventional treatment is generally given with hormonal drugs, and in some cases, hypoglycemic drugs, Huanglian Ejiao Decoction, etc are also given. e duration of treatment is 4 weeks to 12 weeks. Baihe Dihuang Decoction for the treatment of insomnia selected 1086 patients (554 cases in the test group, 532 cases in the control group). e age of the patient is 30 to 87 years old, and there was no significant difference between the two groups by sex or sex. All trials were conducted before March 27, 2021, All reports are about comparing conventional treatment and conventional treatment combined with Baihe Dihuang Decoction treatment. In eligible trials, the conventional treatment plan is slightly different. Conventional treatment drugs mostly use sedative, hypnotic and anxiolytic drugs, and in some cases Suanzaoren Decoction, acupuncture, etc are used. e duration of treatment is 2 to 8 weeks, as shown in Tables 1 and 2.

Quality of Included Trials.
According to Cochrane's risk of bias estimates, 12 trials mentioned randomly assigned participants and 1 did not mention it. None of the studies mentioned blindness of subjects and outcome evaluation. All of the literature had a low risk of allocation concealment, selective reporting and data integrity, as shown in Figure 3(a). Cure: e symptoms disappear, the spirit is normal: Effective: the symptoms are alleviated, and the mood is stable; Ineffective: there is no improvement in the mental and physical symptoms. Healed and effective are included in the total effective. e overall effective rate refers to the proportion of patients receiving rehabilitation and efficacy evaluation in the total group. 11 articles reported the total effective rate. Meta-analysis using a fixed-effect model (P � 0.34, I 2 � 11%) showed that combined Baihe Dihuang Decoction could significantly augment the efficacy of depression treatment (MD � 0.33, 95%CI: 0.21, 0.53; P < 0.00001), as shown in Figure 3(b). Five studies provided a description of the incidence of adverse reactions after conventional treatments combined with Baihe Dihuang Decoction, such as nausea, constipation, drowsiness, fatigue and dizziness. Meta-analysis using a fixed-effect model (P � 0.18, I 2 � 35%) showed that combined Baihe Dihuang Decoction could reduce the incidence of adverse reactions in the treatment of depression. (MD � 0.47, 95%CI:0.25, 0.91; P � 0.02), as shown in Figure 3(c).   Evidence-Based Complementary and Alternative Medicine 5  Table 3. It shows that compared with    Table 4.

Quality of Included Trials.
According to Cochrane's risk of bias estimates, 4 trials mentioned randomly assigned participants and 2 did not mention it. None of the studies mentioned blindness of subjects and outcome evaluation. 5 trials had low data integrity risks. 6 articles had a low risk of allocation concealment and selective reporting, as shown in Figure 4(a).          If symptoms such as hot flashes, sweating, irritability, insomnia and palpitation are not enhanced or worsened, it is invalid. Healed and effective are included in the total effective. e total effective rate refers to the proportion of patients receiving rehabilitation and efficacy evaluation in the total group. 6 articles reported the total effective rate. Random effects model (P � 0.01, I 2 � 66%) meta-analysis results showed that combining Baihe Dihuang Decoction in the treatment of menopausal syndrome could significantly enhance the efficacy (MD � 0.10, 95%CI: 0.03, 0.34; P � 0.0002), as shown in Figure 4(b).  Table 5.  Table 6. Insomnia.

Quality of Included Trials.
According to Cochrane's risk of bias estimates, 11 trials mentioned randomly assigned participants and 1 did not mention it. 1 article did not randomly assign participants. 1 article mentioned blindness of the subject, and the other 12 did not mention it. All studies had a low risk of allocation concealment. All studies did not mention blinding result evaluation. 11 trials all had low data integrity risks. 12 trials had a low risk of selective reporting, as shown in Figure 5(a).

Total Effective Rate and Incidence of Adverse Reactions of Conventional Treatment Drugs and Conventional Treatment Drugs Combined with Baihe Dihuang Decoction in the
Treatment of Insomnia. Judgement criteria for overall efficiency: Significantly effective: fall asleep fast, sleep quality is good, and nerve function is normal; Effective: fall asleep faster, sleep quality is average, and nerve function is basically normal; Invalid: slow falling asleep, poor sleep quality, severe neurological deficits. Healed and effective are included in the total effective. e overall effective rate refers to the proportion of patients receiving rehabilitation and efficacy evaluation in the total group. 11 studies reported the total effective rate.
e fixed-effect model (P � 1.00, I 2 � 0%) meta-analysis results showed that the combination of Baihe Dihuang Decoction in the treatment of insomnia could significantly augment the efficacy (MD � 0.20, 95%CI: 0.13, 0.33; P < 0.00001), as shown in Figure 5(b). 4 studies provided descriptions of adverse reactions after treatment with commonly used anti-insomnia drugs, such as dreaminess, irritability, dry mouth and lack of energy.
e fixed-effect model (P � 0.20, I 2 � 36%) meta-analysis results showed that the combination of Baihe Dihuang Decoction in the treatment of

PSQI of Conventional Treatment Drugs and Conventional Treatment Drugs Combined with Baihe Dihuang
Decoction in the Treatment of Insomnia. PSQI is an important indicator reflecting the sleep status of patients with insomnia included in the study. Five literature reported the detection of PSQI indicators. Random effects model (P < 0.00001, I 2 � 99%) meta-analysis results showed that combining Baihe Dihuang Decoction could reduce PSQI in the treatment of depression (MD � −2.10, 95%CI: −6.37, 2.17; P � 0.33), as shown in Figure 5(d).   Table 7. e results showed that insomnia was enhanced after combined Baihe Dihuang Decoction.

Publication Bias.
e publication bias is represented by a funnel chart. List in turn the total effective rate of conventional anti-depressant drugs combined with Baihe

Discussion
e World Health Organization (WHO) report shows that as of 2015, there are as many as 322 million depressed patients worldwide, the global prevalence rate of depression is about 4.4%, and the prevalence rate in my country is about 4.2%. Depression is the world's fourth most common disease and is expected to become the second most common disease by 2030 [34]. Depression is the disease with the heaviest burden among non-communicable diseases. It is a kind of psychotic mood disorder. Its main clinical feature is longlasting and significant depression. e main performance for negative emotions, slow thinking, loss of will, cognitive impairment, pessimism and even more likely to commit suicide [35].
erefore, how to improve the cognitive function of patients with depression, maintain the treatment effect, relieve and control the symptoms of depression, and avoid the recurrence of depression is the key topic of clinical research [36]. e common pathogenesis of depression may be because the insufficiency of neurotransmitters such as serotonin and norepinephrine in the brain is the main factor leading to depression, and dopamine is also involved in the pathogenesis of depression, 5HT and norepinephrine reuptake inhibitors are often used clinically to treat depression, and depression is treated by increasing the content of neurotransmitters such as 5-HT and norepinephrine [37]. Although these drugs have good anti-anxiety and anti-depressant effects, they also have side effects such as arrhythmia [38].  concluded that compared with the use of conventional drugs alone, the combination of Baihe Dihuang Decoction on the basis of it has a positive effect on the treatment and prognosis of patients with depression.
Foreign research shows that about 78% of women will have menopausal symptoms. Domestic research has found that the incidence of menopausal syndrome now fluctuates in the range of 50% to 80%. According to the survey, women have the highest incidence rate between 51 and 55 years old, and the degree of symptoms reaches moderate to severe.At the same time, if the patient is accompanied by other underlying diseases, the incidence is even higher, up to 64% [39]. During menopause, the gonads in the human body begin to shrink, and the original endocrine function begins to undergo a series of changes [40], In addition to the more typical symptoms, most menopausal women will have obvious neuropsychiatric symptoms, which are mainly manifested as suspiciousness, memory loss, emotional instability, and decreased work ability [16], Some women also often have a series of visceral functions.

Evidence-Based Complementary and Alternative Medicine
Disordered symptoms, collectively referred to as "menopausal syndrome" in medicine [41]. e common pathogenesis of menopausal syndrome may be caused by the imbalance of H-P-O axis neuroendocrine function after ovarian function decline, and the decrease of serum monoamine transmitters [42]. At present, drugs such as estradiol, norethindrone acetate, oryzanol are generally used clinically [43]. Although these drugs have achieved certain effects, the overall effect is average and cannot achieve the expected results of patients. erefore, more effective and reasonable treatment methods need to be studied in depth in order to improve hormone levels, relieve clinical symptoms, and improve quality of life. e vasomotor factor NO and ET-1 are reproductive hormone regulatory peptides, which have a good regulatory effect on the thalamus-pituitary-ovarian axis (HPOA) [42], and the disorder of HPOA can be manifested by abnormal levels of NE and 5-HT. After combining with Baihe Dihuang Decoction, the levels of NO, NE, 5-HT in the patient's body increased, and the content of ET-1 decreased, indicating that it can regulate HPOA and improve the symptoms of menopausal syndrome. Improve immune function by increasing the content of CD-3, CD-4 and IL-2. Comparing conventional treatment combined with Baihe Dihuang Decoction and conventional treatment of MENQOL, Kupperman and other evaluation indicators can show that the combination of Baihe Dihuang Decoction has a better therapeutic effect and can improve the overall effective rate. erefore, it can be concluded that the combination of Baihe Dihuang Decoction has a positive effect on the treatment of menopausal syndrome patients compared with the conventional drugs alone. e global incidence of insomnia is 10% to 50%, and it is currently the sleep disorder with the highest prevalence rate. e World Health Organization estimates that there are nearly 700 million people suffering from insomnia worldwide. Insomnia is a sleep initiation disorder or sleep maintenance disorder that occurs repeatedly when there is sufficient sleep time and a good sleep environment [44]. It is often characterized by the inability to get normal sleep, and it usually becomes difficult to fall asleep, dreamy, easy to wake up, etc [45]. Long-term insomnia can lead to a series of health and psychological problems, which can induce heart and brain diseases, diabetes, etc [46]. It can be accompanied by depression, which seriously affects the patient's health and quality of life [47]. e common pathogenesis of insomnia may be caused by the enhanced activity of the hypothalamic-pituitary-adrenal (HPA) axis and the changes of cytokines such as interleukin (IL) and tumor necrosis factor (TNF), At present, the treatment of insomnia with anxiety in modern medicine mainly focuses on improving sleep quality and anti-anxiety treatment, and mostly uses sedative hypnosis and anti-anxiety drugs [48]. But its therapeutic effect is not good. In recent years, Chinese medicine has made some progress in the treatment of insomnia, and obtained good treatment results. Baihe Dihuang Decoction works by modulating pathways related to the nervous system, endocrine system, inflammation and immune system Comparing the PSQI, ZYZZJF, SMSJ and other evaluation indicators of conventional treatment combined with Baihe Dihuang Decoction and conventional treatment can show that the combination of Baihe Dihuang Decoction has a better therapeutic effect, and can significantly improve the total effective rate while significantly reducing the incidence of adverse reactions. erefore, it can be concluded that the combination of Baihe Dihuang Decoction has a positive effect on the treatment and prognosis of patients with insomnia compared with the use of conventional drugs alone.
From the above discussion, it is easy to find that depression, menopausal syndrome and insomnia are all neuropsychiatric disorders, and their common pathological processes involve various aspects of neurotransmitter release, anti-inflammatory and immune regulation. e mechanism of action of Baihe Dihuang Decoction includes promoting monoamine neurotransmitter release, inhibiting monoamine oxidase activity, regulating hypothalamic-pituitary-adrenal (HPA) axis function, anti-inflammation, immunomodulation and neuroprotection, etc. ese findings provide some scientific basis for future pharmacological studies in the treatment of depression, menopausal syndrome and insomnia with Baihe Dihuang Decoction. e results of Meta-analysis also showed that the combination of Baihe Dihuang Decoction for the treatment of depression, menopausal syndrome and insomnia could improve the efficacy and reduce the incidence of adverse reactions, which is worthy of clinical promotion and application.
e limitations of Meta are as follows: (1) Among the included 44 articles, only one mentions allocation concealment, and none of the studies mentions blindness and outcome evaluation of subjects, which is likely to lead to a certain degree of bias. Since this study only included Chinese literature and did not include literature in other languages, it will have a certain impact on the comprehensiveness of the research. (2) ere is no uniform standard for the dosage of Baihe Dihuang Decoction, the treatment period and the evaluation standard of patients' curative effect. (3) All the included literature lacks the observation of long-term curative effect, and the index such as recurrence rate is not used as one of the curative effect evaluation criteria, and its longterm effect and curative effect cannot be clarified. (4) Most of the included studies are small sample trials and there are differences in race, ethnicity, and regional conditions, and lack of representativeness. It is necessary to increase the sample size to make the research results closer to the overall authenticity.

Conflicts of Interest
e authors declare that they have no conflicts of interest.