Efficacy and safety of Shugan Jieyu Decoction in the treatment of coronary heart disease complicated with depression

Abstract

Background: 

Coronary heart disease combined with depression is 1 of the 2 major diseases affecting physical and mental health. It has become a hot spot at the intersection of psychiatry and internal medicine. Most doctors call double heart medicine, which has a high incidence rate and a low diagnostic rate. Clinical research shows that Shugan Jieyu Decoction (SJD) has a better curative effect, increased safety, and fewer adverse reactions, but it lacks systematic evaluation. This study aims to integrate clinical data through network meta-analysis and provide more evidence-based medical evidence for clinical medication.

Methods: 

We searched 8 electronic databases: China knowledge network database, Wanfang, VIP, SinoMed, PubMed, Embase, WebofScience, Cochrane Library, and selected 22 randomized controlled trials from January 2012 to January 2022. The common primary endpoint was the relief of angina pectoris and the improvement of depression. Two researchers used Endnote9.1 software to conduct literature screening and information extraction according to the developed nano-passage standard, used Cochrane collaborative tool to evaluate the bias risk in the experiment, and then used RevMan5.3 software to assess the literature and data analysis synthesis.

Results: 

In 1908 patients with coronary heart disease and depression, the total effective rate of SJD in the treatment of angina pectoris was 3.49 (95% confidence interval, 1.93–6.29), as well as the network meta-analysis of improving depressive symptoms, anxiety, depression scores (SAS, SDS) and quality of life scores (HAMD), and reducing the indicators related to CPR and homocysteine.

Conclusion: 

The analysis of this study shows that SJD can reduce the frequency of angina pectoris in patients with coronary heart disease and depression, alleviate anxiety and depression, provide a reference basis for clinical treatment, and select more effective intervention therapy.

1. Introduction

Coronary heart disease and depression are the main problems that endanger human health worldwide. Epidemiological studies have shown that depression is a psychological risk factor for coronary heart disease, and nearly 30% of patients with affective disorders have coronary heart disease.^[1] The strong association between depression and coronary artery disease has led many to recommend universal screening for depression in all patients with coronary artery disease. It has been endorsed by the American Psychiatric Association.^[2] There is a bidirectional causal relationship between psychological and somatic factors and the pathogenesis of coronary artery disease.^[3] The current clinical treatment of coronary artery disease through coronary surgery or drugs is to correct patients’ physical symptoms, such as chest tightness, weakness, and chest pain; however, treatment is scarce for psychosomatic disorders, and patients have difficulty truly recovering.^[4] Whether successful treatment of depression is associated with reduced morbidity or mortality from coronary heart disease remains unknown.

Currently, the clinical treatment of coronary heart disease combined with depression is primarily unilateral, mainly conventional western medicine for coronary heart disease, with less attention or treatment of depression and many side effects. Patients have long-term drug dependence. Given the current coronary heart disease, combined with depression, as a significant threat to human health, it is urgent to solve the safe and effective treatment of coronary heart disease combined with depression. In today’s world, traditional Chinese medicine has attracted more and more attention in the complementary and alternative treatment of patients with coronary heart disease and depression, as well as in clinical practice.

Shugan Jieyu Decoction (SJD) has the functions of soothing the liver and relieving depression, regulating qi, and activating blood. It has a good effect on improving angina pectoris and depression symptoms of coronary heart disease complicated by depression. It is composed of 9 kinds of medicines, including Cyperus Cypress (Xiangfu), Qingpi, Bupleurum (Chaihu), golden bell charcoal (Jinlingtan), Turmeric(Yujin), Salvia (Danshen), Chuanxiong, Hongzelan, and Corydalis (Yanhusuo). Some literature points out that SJD can significantly reduce blood homocysteine, triacylglycerol, and C-reactive protein levels. Some literature pointed out that SJD can dramatically lower blood homocysteine, triacylglycerol, and C-reactive protein levels. At the same time, it can further alleviate vascular endothelial injury, control vascular inflammation, inhibit vasoconstriction, enhance the body’s antioxidant capacity, and even reduce sympathetic nerve excitability, so it has an excellent therapeutic effect on the treatment of patients with coronary heart disease complicated by depression.^[5] Some studies have pointed out that the antidepressant targets of Bupleurum Chinese mainly involve MAPK, FoxO, Rap1, PI3K-AKT, neurotrophin, and other signal pathways.^[6] Ligustrazine can down-regulate the expression of Bax mRNA in CIR hippocampal neurons and inhibit neuronal apoptosis and cerebral ischemia-reperfusion injury after cardiac arrest and resuscitation.^[7]

In recent ten years, several randomized controlled clinical trials have suggested that SJD has specific efficacy in treating coronary heart disease complicated with depression. Still, there is no evidence evaluation or literature report on the clinical effectiveness of SJD in treating coronary heart disease confused with depression. Therefore, this study investigated the therapeutic effect of SJD commonly used in clinical practice on coronary heart disease complicated with depression and used network meta-analysis to integrate relevant clinical evidence, summarize the intervention measures in the evidence, conduct a comprehensive quantitative analysis, and compare the clinical efficacy of SJD and conventional Western Medicine in the treatment of coronary heart disease complicated with depression. The purpose is to provide a reference for the clinical treatment of coronary heart disease combined with depression to choose a suitable and safe intervention.

2. Data and methods

2.1. Study registration

The protocol and registration information are available at PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php? ID = CRD42022353121, registration number: CRD42022353121). This study was conducted and reported under the preferred reporting items for systematic reviews and meta-analyses protocols (PRISMA-P) statement.^[8]

2.2. Literature inclusion criteria

2.2.1. Type of study.

This study includes a randomized controlled trial of Shugan Jieyu Decoction in treating coronary heart disease complicated with depression. Exclusion trials were not randomized and did not use a control group; literature published before 2012 was excluded; duplicate publications and plagiarized studies were excluded.

2.2.2. Research objects.

Patients with coronary heart disease and depression who meet the clinical diagnostic criteria are eligible to be included in this study, regardless of age, gender, or nationality.

2.2.3. Intervention measures.

The experimental group was treated with SJD, the control group was treated with conventional western medicine; the experimental group was treated with traditional western medicine + SJD, the control group was treated with conventional western medicine. Conventional western drugs are aspirin, nitrates, beta-blockers, and statins. Clopidogrel is given in patients with unstable coronary artery disease; nitroglycerin 0.5 mg is included during angina attacks.

2.2.4. Outcome indicators.

Primary outcome: total effective rate of angina pectoris improvement, the effective rate of depression improvement; Secondary outcome: SDS score, HAMD score, and CPR and homocysteine (HCY) test index scores.

2.2.5. Exclusion criteria.

Pieces of literature with incomplete data or serious errors; works of literature whose full text cannot be obtained; self-made soothing liver SJD.

2.3. Literature search strategy

A systematic review was conducted according to the meta-analysis of epidemiological observational studies guidelines.^[9] Eight electronic databases were searched from January 2012 to January 2022, a comprehensive search of the China knowledge network database, Wanfang database, VIP database, China Biomedical Literature database (SinoMed), PubMed, Embase, Web of Science, and Cochrane Library was conducted. Formulate specific retrieval formulas according to different databases, and use the combination of keywords and article titles to retrieve documents using the intersection of subject headings and free words. The specific search terms are “coronary heart disease,” “angina pectoris,” “chest pain,” “anxiety,” “depression,” “SJD,” “Shugan Jieyu Capsule,” “randomized controlled trial,” “clinical study” and so on. The search strategy for PubMed is shown in Table 1. This search strategy was modified as required for other electronic databases.

Table 1 - Pubmed retrieval type.

Search number	Query
18	(((((“Coronary Disease”[Mesh]) OR ((((((((Disease, Coronary[Title/Abstract]) OR (Diseases, Coronary[Title/Abstract])) OR (Coronary Heart Disease[Title/Abstract])) OR (Coronary Heart Diseases[Title/Abstract])) OR (Disease, Coronary Heart[Title/Abstract])) OR (Diseases, Coronary Heart[Title/Abstract])) OR (Heart Disease, Coronary[Title/Abstract])) OR (Heart Diseases, Coronary[Title/Abstract]))) AND ((“Depression”[Mesh]) OR ((((((Depressive Symptoms[Title/Abstract]) OR (Depressive Symptom[Title/Abstract])) OR (Symptom, Depressive[Title/Abstract])) OR (Symptoms, Depressive[Title/Abstract])) OR (Emotional Depression[Title/Abstract])) OR (Depression, Emotional[Title/Abstract])))) AND ((“Anxiety”[Mesh]) OR ((((((((Angst[Title/Abstract]) OR (Social Anxiety[Title/Abstract])) OR (Anxieties, Social[Title/Abstract])) OR (Anxiety, Social[Title/Abstract])) OR (Social Anxieties[Title/Abstract])) OR (Hypervigilance[Title/Abstract])) OR (Nervousness[Title/Abstract])) OR (Anxiousness[Title/Abstract])))) AND ((((Shugan Jieyu Decoction) OR (Soothing the Liver and Relieving Depression)) OR (Shugan Jieyu Capsules)) OR (Soothing Liver and Relieving Depression Chinese Medicine))) AND (randomized controlled trial[Publication Type] OR randomized[Title/Abstract] OR placebo[Title/Abstract])
17	(((((“Coronary Disease”[Mesh]) OR ((((((((Disease, Coronary[Title/Abstract]) OR (Diseases, Coronary[Title/Abstract])) OR (Coronary Heart Disease[Title/Abstract])) OR (Coronary Heart Diseases[Title/Abstract])) OR (Disease, Coronary Heart[Title/Abstract])) OR (Diseases, Coronary Heart[Title/Abstract])) OR (Heart Disease, Coronary[Title/Abstract])) OR (Heart Diseases, Coronary[Title/Abstract]))) AND ((“Depression”[Mesh]) OR ((((((Depressive Symptoms[Title/Abstract]) OR (Depressive Symptom[Title/Abstract])) OR (Symptom, Depressive[Title/Abstract])) OR (Symptoms, Depressive[Title/Abstract])) OR (Emotional Depression[Title/Abstract])) OR (Depression, Emotional[Title/Abstract])))) AND ((“Anxiety”[Mesh]) OR ((((((((Angst[Title/Abstract]) OR (Social Anxiety[Title/Abstract])) OR (Anxieties, Social[Title/Abstract])) OR (Anxiety, Social[Title/Abstract])) OR (Social Anxieties[Title/Abstract])) OR (Hypervigilance[Title/Abstract])) OR (Nervousness[Title/Abstract])) OR (Anxiousness[Title/Abstract])))) AND ((((Shugan Jieyu Decoction) OR (Soothing the Liver and Relieving Depression)) OR (Shugan Jieyu Capsules)) OR (Soothing Liver and Relieving Depression Chinese Medicine))) AND (randomized controlled trial[Publication Type] OR randomized[Title/Abstract] OR placebo[Title/Abstract]) - Schema: all
16	randomized controlled trial[Publication Type] OR randomized[Title/Abstract] OR placebo[Title/Abstract]
15	(((Shugan Jieyu Decoction) OR (Soothing the Liver and Relieving Depression)) OR (Shugan Jieyu Capsules)) OR (Soothing Liver and Relieving Depression Chinese Medicine)
14	Soothing Liver and Relieving Depression Chinese Medicine
13	Shugan Jieyu Capsules
12	Soothing the Liver and Relieving Depression
11	Shugan Jieyu Decoction
10	(((“Coronary Disease”[Mesh]) OR ((((((((Disease, Coronary[Title/Abstract]) OR (Diseases, Coronary[Title/Abstract])) OR (Coronary Heart Disease[Title/Abstract])) OR (Coronary Heart Diseases[Title/Abstract])) OR (Disease, Coronary Heart[Title/Abstract])) OR (Diseases, Coronary Heart[Title/Abstract])) OR (Heart Disease, Coronary[Title/Abstract])) OR (Heart Diseases, Coronary[Title/Abstract]))) AND ((“Depression”[Mesh]) OR ((((((Depressive Symptoms[Title/Abstract]) OR (Depressive Symptom[Title/Abstract])) OR (Symptom, Depressive[Title/Abstract])) OR (Symptoms, Depressive[Title/Abstract])) OR (Emotional Depression [Title/Abstract])) OR (Depression, Emotional[Title/Abstract])))) AND ((“Anxiety”[Mesh]) OR ((((((((Angst [Title/Abstract]) OR (Social Anxiety [Title/Abstract])) OR (Anxieties, Social [Title/Abstract])) OR (Anxiety, Social [Title/Abstract])) OR (Social Anxieties [Title/Abstract])) OR (Hypervigilance [Title/Abstract])) OR (Nervousness [Title/Abstract])) OR (Anxiousness [Title/Abstract])))
9	(“Anxiety” [Mesh]) OR ((((((((Angst [Title/Abstract]) OR (Social Anxiety [Title/Abstract])) OR (Anxieties, Social [Title/Abstract])) OR (Anxiety, Social [Title/Abstract])) OR (Social Anxieties [Title/Abstract])) OR (Hypervigilance [Title/Abstract])) OR (Nervousness [Title/Abstract])) OR (Anxiousness [Title/Abstract]))
8	(((((((Angst [Title/Abstract]) OR (Social Anxiety [Title/Abstract])) OR (Anxieties, Social [Title/Abstract])) OR (Anxiety, Social [Title/Abstract])) OR (Social Anxieties [Title/Abstract])) OR (Hypervigilance [Title/Abstract])) OR (Nervousness [Title/Abstract])) OR (Anxiousness [Title/Abstract])
7	“Anxiety” [Mesh]
6	(“Depression” [Mesh]) OR ((((((Depressive Symptoms [Title/Abstract]) OR (Depressive Symptom [Title/Abstract])) OR (Symptom, Depressive [Title/Abstract])) OR (Symptoms, Depressive [Title/Abstract])) OR (Emotional Depression [Title/Abstract])) OR (Depression, Emotional [Title/Abstract]))
5	(((((Depressive Symptoms [Title/Abstract]) OR (Depressive Symptom [Title/Abstract])) OR (Symptom, Depressive [Title/Abstract])) OR (Symptoms, Depressive [Title/Abstract])) OR (Emotional Depression [Title/Abstract])) OR (Depression, Emotional [Title/Abstract])
4	“Depression” [Mesh]
3	(“Coronary Disease” [Mesh]) OR ((((((((Disease, Coronary [Title/Abstract]) OR (Diseases, Coronary [Title/Abstract])) OR (Coronary Heart Disease [Title/Abstract])) OR (Coronary Heart Diseases [Title/Abstract])) OR (Disease, Coronary Heart [Title/Abstract])) OR (Diseases, Coronary Heart [Title/Abstract])) OR (Heart Disease, Coronary [Title/Abstract])) OR (Heart Diseases, Coronary [Title/Abstract]))
2	(((((((Disease, Coronary [Title/Abstract]) OR (Diseases, Coronary [Title/Abstract])) OR (Coronary Heart Disease [Title/Abstract])) OR (Coronary Heart Diseases [Title/Abstract])) OR (Disease, Coronary Heart [Title/Abstract])) OR (Diseases, Coronary Heart [Title/Abstract])) OR (Heart Disease, Coronary [Title/Abstract])) OR (Heart Diseases, Coronary [Title/Abstract])
1	“Coronary Disease” [Mesh]

2.4. Study selection and data extraction

2.4.1. Study selection.

According to the selected electronic database search strategy, the 6 retrieved literature titles were first imported into EndNoteX9.1 software by 2 researchers to check to exclude duplicate literature. Preliminary screening was carried out by reading the titles and abstracts, excluding the literature that did not meet the inclusion criteria, and downloading the full text of the appropriate literature; finally, fine screening was carried out by reading the complete text, and the data were presented according to a predetermined table. In disagreements, third-party experts are invited to conduct discussions and research and finally make a decision. The PRISMA flow chart selected for this process is shown in Figure 1.

Figure 1.: PRISMAflow diagram. PRISMA = preferred reporting items for systematic review and meta-analysis.

2.4.2. Data extraction and management.

Table 2 summarizes the literature extraction information. Two researchers independently extracted data. The extracted content includes: basic information on literature research (author, research title, publication journal, year, and region); study characteristics (sample size, age, sex, course of disease, diagnostic criteria, inclusion, and exclusion criteria); intervention measures (drug formulation, dose, and duration); study methods (random protocol generation, completeness of outcome data, outcome reporting, and other sources of bias); outcome measurement. If the study provided insufficient data or the information was uncertain, the appropriate author was contacted, a consensus was reached through discussion with a third reviewer.

Table 2 - Characteristics of the 22 trials included in the meta-analysis.

First author/yr	Country	Sample size (experimental/control)	Mean age (SD)	Experimental	Control	Duration	Outcome measure
Cheng YJ 2020	Zunyi, Guizhou, China	28/28	T:66.15 ± 0.73 C:66.21 ± 0.62	Conventional therapy + SJD	Conventional therapy	1 mo	A, C, D
Cui XN 2018	Liaoyang, Liaoning, China	50/50	T:65.4 ± 4.7 C:67.7 ± 5.5	Conventional therapy + SJD	Conventional therapy	4 w	A, C, D
Gao ZX 2019	Yuncheng, Shanxi, China	46/46	T:57.14 ± 4.85/C:57.30 ± 4.89	Conventional therapy + SJD	Conventional therapy + Flupentixol and Melitracen Tablets	6 w	A, C, D, E, M, N
Gu YQ 2014	Nantong, Jiangsu, China	30/30	T:63.32 ± 8.16 C:64.12 ± 7.33	Conventional therapy + SJD	Conventional therapy	4 w	A, B, G, K, L
Hao JY 2017	Yutian, Hebei, China	40/40	T:60.5 ± 12.8 C:60.9 ± 12.8	Conventional therapy + SJD	Conventional therapy	4 w	A, B
Huang G 2020	Liuyang, Hunan, China	29/29	T:65.87 ± 5.21 C:65.32 ± 5.74	Conventional therapy + SJD	Conventional therapy	1 mo	A, C, D
Jiang CS 2017	Zhijiang, Hubei, China	40/40	T:65 ± 2.1 C:55.38 ± 4.22	Conventional therapy + SJD	Conventional therapy	4 w	A, C, D
Jin L 2019	Yanji, Jilin, China	44/44	T:65.50 ± 4.22 C:66.00 ± 4.1	Conventional therapy + SJD	Conventional therapy + Nitrates,Statins	4 w	A, C, D, I
Lei XF 2017	Yinchuan, Ningxia, China	40/40	T:62.7 ± 3.6 C:63.4 ± 4.1	Conventional therapy + SJD	Conventional therapy		C, D, I
Liu Y 2021	Linyi, Shandong, China	43/43	T:66.91 ± 4.26 C:66.95 ± 4.31	SJD	Conventional therapy	4 w	A, C, D
Pan D 2018	Liaocheng, Shandong, China	43/43	T:56.5 ± 3.8S C:57.1 ± 3.3	SJD	Conventional therapy	60 d	C, D, J
Qi ZP 2020	Gansu Province, China	60/60	T:65.73 ± 3.52 C:66.55 ± 3.93	Conventional therapy + SJD	Conventional therapy	21 d	A, C, D
Ren HJ 2018	Zhengzhou, Henan, China	102/98	T:63.50 ± 5.20 C:63.45 ± 5.17	Conventional therapy + SJD	Conventional therapy	4 w	A, D, G
Ruan JT 2020	Zhangzhou, Fujian, China	46/46	T:52.86 ± 4.59 C:53.45 ± 4.67	SJD	Conventional therapy + Clopidogrel	4 w	A, C, D
Sun J 2019	Daqing, Heilongjiang, China	48/48	T:53.48 ± 4.58 C:54.12 ± 4.62	SJD	Conventional therapy + Clopidogrel	4 w	A, C, D, I
Wang XQ 2017	Lincang, Yunnan, China	40/40	T:55.38 ± 4.22 C:56.70 ± 5.10	Conventional therapy + SJD	Conventional therapy	4 w	A, I
Wang ZM 2020	Hebei Province, China	28/28	T:67.84 ± 1.37 C:67.53 ± 1.39	Conventional therapy + SJD	Conventional therapy	1 mo	C, D
Wang F 2018	Hefei, Anhui, China	40/40	T:38.73 ± 6.34 C:37.86 ± 7.56	Conventional therapy + SJD	Conventional therapy	10 w	A, B, G
Wang JC 2018	Xinglong, Hebei, China	50/50	T:54.1 ± 0.6 C:54.8 ± 0.2	Conventional therapy + SJD	Conventional therapy	1 mo	A, C, D
Xuan ZH 2019	Zhuji, Zhejiang, China	42/42	T:65.5 ± 0.4 C:65.4 ± 0.5	Conventional therapy + SJD	Conventional therapy	4w	A, C, D
Ye G 2021	Bijie, Guizhou, China	30/30	T:71.4 ± 7.3 C:73.4 ± 8.3	Conventional therapy + SJD	Conventional therapy	4 w	H, B, C, D
Zhang HM 2020	Rongcheng, Shandong, China	37/37	T:65.02 ± 2.05 C:64.98 ± 2.03	Conventional therapy + SJD	Conventional therapy	1 mo	A, C, D

A = efficacy comparison, B = depression efficacy comparison, C = SAS score, D = SDS score, E = comparison of TCM symptom scores, F = comparison of the efficacy of electrocardiogram, G = comparison of CRP and HCY levels, H = angina recurrence rate, I = HAMD total score comparison, J = blood lipid index comparison, K = angina pectoris efficacy comparison, L = blood lipid level comparison, M = comparison of adverse drug reactions, N = cardiovascular adverse event rate comparison, SJD = Shugan Jieyu Decoction.

2.5. Evaluation of literature quality

The quality of the included literature was evaluated by 2 researchers using the risk of the bias assessment tool in the Cochrane reviewer’s handbook^[10]: method of randomization, allocation concealment, whether it was performed on patients, researchers or not. Blinding, completeness of outcome data, selective reporting, and other biases. The quality assessment results of each project can be divided into 3 categories: high risk, low risk, and uncertainty risk.

2.6. Statistical analysis

RevMan5.3 software was used for data analysis. Continuous variables and dichotomous results were all from the included trials, the relative risk (RR) was the effect value, and the 95% confidence interval (CI) for each effect size was obtained to describe the dichotomous results. The effect size of the comparison between groups was defined as mean difference (MD) 7% and 95% CI. The heterogeneity was determined according to the results of the I² test. A fixed-effects model was used if I² < 50% indicated low heterogeneity between studies. When I² > 50%, the heterogeneity between studies was high, and a random-effects model was used. Random-effect models were also used to generate estimates for direct and mixed-treatment comparisons. Subgroup analysis was performed according to whether the experimental group was combined with conventional western medicine and the different treatment methods of the control group. A funnel plot was made to analyze publication bias for outcome indicators with the number of pieces of literature ≥ 10.^[11]

3. Results

3.1. Literature search results

According to the search strategy formulated in advance, n = 170 related pieces of literature were searched in 8 databases, and 80 articles were obtained through the endnote 9.1 software check. After reading the titles and abstracts, the first round of screening was performed; 45 articles were deleted, 35 articles were finally read in full text, and 22 Chinese articles were finally included.^[5,12–32] The specific screening of all PRISMA literature has been completed, and the included trials have been published as full texts.

3.2. Basic characteristics of included studies

Two researchers summarized the essential attributes of 22 qualified trials and analyzed 1908 patients with coronary heart disease and depression. Sample sizes ranged from 56 to 200. In the included trials, there were 4 items of SJD versus conventional western medicine; 18 items of traditional western medicine + SJD versus traditional western medicine. In the primary outcome, 17 trials reported overall response rates for angina, and 4 tests reported overall response rates for depression. Among secondary outcomes, 18 problems said SDS scores, 17 said SAS scores, 3 reported quality of life scores, and 3 reported comparisons of CPR and HCY indicators. Only 1 of the included trials did not report treatment duration; all others said treatment duration, ranging from 21 days to 10 weeks.

3.3. The included studies were assessed for risk of bias

Figure 2 summarizes the methodological quality of the 22 eligible trials and assesses the risk of bias in studies by 2 8 investigators using criteria from the Cochrane Handbook for Systematic Reviews of Interventions.^[10] Although the included trials were declared randomized, 9 shots^{[14–16,18,21,23,25,26,32]} were assigned using the randomized number table method and were therefore rated as “Low risk of bias,” 11 trials^{[5,12,13,17,19,20,22,27–31]} did not explicitly describe the random assignment method. They were therefore rated as having an “Unclear risk of bias,” and 1 trial^[24] used a systematic randomization method and was consequently rated as having a “High risk of bias.” None of the 22 trials^[5,12–32] mentioned allocation concealment, blinding of participants, investigators, outcome assessments, selective reporting, and missing reporting.

Figure 2.: Risk of bias graph.

3.4. Clinical total effective rate

3.4.1. Angina pectoris improvement total effective rate.

For the improvement of angina pectoris, refer to the “cardiovascular disease diagnosis and treatment standards,”^[33] and its efficacy criteria are divided into 3 aspects: markedly effective, effective, and ineffective, to evaluate the clinical efficacy of SJD. Seventeen trials^{[5,13,15–18,20,22–28,30–32]} provide test results. In addition, subgroup analysis shows that SJD can significantly improve the clinical efficacy of coronary heart disease; its efficacy was 1.23 times that of conventional western medicine (17 trials; n = 1538; RR; 1.23; 95% CI [1.17, 1.28]). Among them, there are 14 trials in the experimental group and the control group^{[5,13,15–18,22,23,26–28,30–32]} using conventional western medicine + SJD and conventional western medicine to treat participants, 3 trials^[20,24,25]The participants were treated with SJD and conventional western medicine. Subgroup analysis showed that conventional western medicine and SJD or single use of SJD could significantly improve the clinical efficacy of angina pectoris. Compared with conventional western medicine, the results were 1.23 (17 trials; n = 1264; RR; 1.23; 95% CI [1.17, 1.30]) and 1.19 (3 trials; n = 274; RR; 1.19; 95% CI [1.09, 1.29]); (Fig. 3).

Figure 3.: Forest plot of the trials shows the clinical effects of different interventions.

3.4.2. Depression improvement total effective rate.

The progress of depression refers to the “classification and diagnostic criteria of mental disorders in China”^[34]; its efficacy criteria are divided into 4 aspects: cure, markedly effective, effective, and ineffective, to 9 evaluate the clinical efficacy of SJD. It has 4 reports,^[5,15,26,31] and the meta-analysis shows that CWM + SJD can significantly improve the clinical efficacy of depression, and its efficacy is 1.35 (4 trials, n = 280, RR = 1.35; 95% CI [1.17, 1.55], P < .0001); (Fig. 4)

Figure 4.: Total effective rate of depression improvement: forest plot for meta-analysis.

3.5. Clinically relevant scores

3.5.1. SDS score.

The SDS score was scored according to the Depression Self-Rating Scale to evaluate the curative effect of SJD. Eighteen trials^{[12–14,16–25,27,29–32]} give scores, and subgroup analysis shows whether conventional western medicine + SJD or single use of SJD can improve the scores. Improve SDS score. Results were (18 trials; n = 1608; SMD; −3.91; 95% CI [−4.79, −3.02]). Among them, there are 14 trials in the experimental group and the control group, respectively,^{[12–14,16–19,22,23,27,29–32]} using conventional western medicine + SJD and conventional western medicine to treat participants, 4 trials^{[20,21,24,25]} using SJD and conventional western medicine to treat participants. Subgroup analysis showed that SJD improved SDS scores, whether used alone or with SJD + CWM, compared with conventional western medicine treatment with a result of −3.99 (14 trials; n = 1248; SMD; −3.99; 95% CI [−5.03, −2.95]) and −3.79 (4 trials; n = 360; SMD; −3.79; 95% CI [−5.04, −2.54]); (Fig. 5).

Figure 5.: SDS scores for different interventions: forest plot of meta-analysis.

3.5.2. HAMD score.

The quality of life score includes 4 aspects: psychological, physiological, social, and emotional. Three trials^[18,19,25] reported, and the meta-analysis showed that CWM + SJD could significantly improve HAMD scores (3 trials; n = 264; SMD; 2.84; 95% CI [2.40, 3.27]). Its psychological function was 3.39 (3 trials, n = 264, SMD, 3.39; 95% CI [2.37, 4.40], P < .0001), and its physiological function was 2.71 (3 trials, n = 264, SMD, 2.71; 95% CI [1.70, 3.71], P < .0001), social function 2.85 (3 trials, n = 264, SMD, 2.85; 95% CI [2.10, 3.60], P < .0001), affective function 2.27 (2 trials, n = 184, SMD, 2.27, 95% CI = [1.61, 2.94], P < .0001); (Fig. 6).

Figure 6.: HAMD score: forest plot for meta-analysis.

3.5.3. CPR and HCY level.

Three trials^[15,23,26]reported CPR and HCY index levels at baseline and after the intervention. The meta-analysis assessed that CWM + SJD could significantly reduce CPR and HCY index levels. The results were (SMD, −1.71, 95% CI = [−1.90, −1.52]), CPR (2 trials n = 340, 10 SMD, −1.81, 95% CI = [−2.06, −1.55]) and HCYP (2 trials n = 160, SMD, −1.59, 95% CI = [−1.87, −1.31], P < .0001); (Fig. 7).

Figure 7.: CPR and HCY score: forest plot for meta-analysis. HCY = homocysteine.

3.6. Ethics and communication

The network meta-analysis plan was approved by the local institutional review committee and the Ethics Committee; It does not involve private information, nor does it require further ethical approval or informed consent.

4. Discussion

The mechanism of action of SJD in treating coronary heart disease complicated with depression: Coronary heart disease with depression, also known as double-heart medicine, is a disease state caused by psychological disorders and cardiovascular abnormalities. In Chinese medicine, coronary heart disease belongs to the category of “chest pain,” “chest paralysis and heart pain,” and “heart pain,” and depression belong to the type of “depression evidence.” Anxiety and depression are highly prevalent in patients with coronary heart disease, which often persists and affects the treatment and prognosis of the disease.^[35,36] Its pathogenesis is based on deficiency of the standard; the qi is not smooth, the blood stasis leads to the lack of nourishment, and abnormal emotions such as heart and chest pain, palpitations, upset, insomnia, worry, and anger hurt the heart and spleen, and further aggravate the coronary heart disease itself. For clinical symptoms, the treatment should be based on clearing the deficiency and excess of the specimen, and it is based on promoting blood circulation and removing blood stasis, soothing the liver and regulating qi, and adding nourishing and tranquilizing drugs. In SJD, Bupleurum and Xiangfu are good at soothing the liver and relieving stagnation; Qingpi has the effects of soothing the liver, breaking qi, promoting phlegm, dispelling suffocation and removing stagnation, and helping Bupleurum to soothe the liver and relieve stagnation. Chuanxiong and Corydalis have to Widen the chest and regulate qi, promote blood circulation, and ease pain; Salvia, tulip, turmeric, and neem have analgesic effects; licorice harmonizes various medicines. All the prescriptions play the functions of soothing the liver, regulating qi, promoting blood circulation, and relieving pain. It has an excellent theoretical basis for traditional Chinese 11 medicine in treating coronary heart disease complicated with depression, and it is safe and reliable. This study comprehensively analyzed SJD combined with conventional western medicine to treat coronary heart disease confused with depression. We explored improving the frequency and duration of angina pectoris SDS score, SAS score, and HAMN score. The potential mechanism of decoction in treating coronary heart disease is complicated by depression.

Modern research has found that the pathogenesis of coronary heart disease complicated with depression is mainly caused by stimulating platelet function, activating inflammatory response, and hyperfunction of the sympathetic nervous system, leading to depression and social-psychological mechanisms and genetic factors.^[37,38] Modern pharmacology found that Bupleurum in SJD achieved the analgesic effect by affecting the release of related pain factors; achieved antibacterial and antiinflammatory effects by inhibiting the production of related pro-inflammatory factors or inflammatory mediators; by down-regulating the expression of miR-124 and inflammatory mediators. The inhibition of MAPK14 and Gria3 signaling pathways releases antidepressants and other effects.^[39,40] The alkaloid extract in Corydalis has been used to improve blood circulation, relieve pain caused by blood stasis, resist myocardial ischemia, inhibit gastric acid secretion, and have promising therapeutic effects on coronary heart disease, arrhythmia, and other diseases.^[41,42] Tanshinone IIA inhibits the activation of phospholipase C and protein kinase C by blocking the binding of angiotensin II to G protein-coupled receptors, reducing the level of cardiomyocytes (Ca2+) and blocking the signaling of cardiac hypertrophy to the nucleus. Internal conduction inhibits phosphodiesterase activity, increasing cAMP in platelets and thereby inhibiting platelet aggregation.^[43] Chuanxiong can protect vascular endothelial cells, inhibit the abnormal proliferation of smooth muscle, protect cardiomyocytes from damage, and reduce blood lipids. While protecting liver cells, Curcuma can inhibit platelet aggregation, reduce blood viscosity, reduce plasma fibrin formation, and reduce blood triacylglycerol.^[44] Therefore, SJD can treat patients with coronary heart disease complicated by depression through multiple targets and pathways, improve 12 blood lipid metabolism, protect vascular endothelial cells, antiinflammatory, analgesic, and inhibit platelet aggregation even reduce sympathetic nerve excitation. It can improve clinical symptoms such as anxiety and depression and has an excellent pharmacological basis.

5. Conclusion

To sum up, this study used multiple results to systematically evaluate the total clinical efficacy of SJD in treating coronary heart disease complicated with depression, relieving the frequency and duration of angina pectoris, improving SAS score, SDS score, and HAMN score. All have certain advantages, the effect is remarkable, and there is no apparent adverse reaction. The sites of this study are all in China, and there are certain geographical risks; the sample size of the included studies is small, and the treatment period is short, which slightly impacts the reliability of the study results. Therefore, the clinical efficacy of SJD in treating coronary heart disease complicated with depression needs to be confirmed by more high-quality multi-center and large-sample RCTs to provide a more reliable basis for clinical guidance.

Author contributions

Conceptualization: Haijun Wang.

Data curation: Zhenzhen Li, Xiaojin Wang.

Formal analysis: Zhenzhen Li, Xiaojin Wang, Jianying Zhang.

Funding acquisition: Haijun Wang, Mingqi Qiao, Yinghui Guo.

Investigation: Zhenzhen Li, Xiaojin Wang, Jianying Zhang.

Methodology: Zhenzhen Li, Xiaojin Wang.

Project administration: Zhenzhen Li.

Resources: Zhenzhen Li, Xiaojin Wang.

Software: Zhenzhen Li, Xiaojin Wang, Jianying Zhang.

Supervision: Xiaojin Wang Yinghui Guo, Haijun Wang, Mingqi Qiao.

Validation: Zhenzhen Li, Xiaojin Wang, Yinghui Guo, Haijun Wang, Jianying Zhang, Mingqi Qiao.

Visualization: Zhenzhen Li, Xiaojin Wang.

Writing – original draft: Zhenzhen Li, Jianying Zhang.

Writing – review & editing: Xiaojin Wang, Yinghui Guo, Haijun Wang, Mingqi Qiao.