| As a common mental illness,major depressive disorder(MDD)has become one of the important public health problems in the world.Modern medicine has not yet formed a unified view on the pathogenesis of MDD.Currently,first-line antidepressants can effectively treat some patients with depression,but they have limitations such as slow effect and limited effect on improving physical symptoms.However,TCM holistic syndrome differentiation can play an antidepressant role through multi-component,multi-target and multi-approach,with good clinical effect and less side effects,and can effectively improve depressive mood and physical symptoms.Professor Li Qiuyan has been in the clinic for more than 30 years.In terms of syndrome differentiation and treatment of depression,she has unique medication experience and diagnosis and treatment ideas.This study aims to explore the medication rules and diagnosis and treatment ideas of Professor Li Qiuyan in the treatment of depression,and preliminatively predict the mechanism of action through three research methods:data mining,semi-structured interview and network pharmacology.Research objectives:1 By collecting the medical records of Professor Li Qiuyan’s outpatients with MDD,a variety of data mining methods were used to explore them,summarize the rules of medication,and initially propose the core prescription.2 Combined with the semi-structured interview method and grounded theory analysis strategy,the diagnosis and treatment ideas of Professor Li Qiuyan in the treatment of MDD were discussed,and the core prescriptions proposed by data mining were verified.3 To preliminarily analyze the antidepressant mechanism of Professor Li Qiuyan’s core prescription through network pharmacology,and to predict the core targets and pathways.Research methods:1 Data mining research:The complete medical records of patients with depression in Professor Li Qiuyan’s outpatient department of Xiyuan Hospital,China Academy of Chinese Medical Sciences from February 15,2016 to June 26,2022 were extracted as research data.Patients meeting the diagnosis of MDD were screened by inclusion and exclusion criteria,medical records database was established,and symptoms and traditional Chinese medicine were treated in a standardized manner.Excel,SPSS Statistic 20.0,SPSS Modeler 18.0 and Cytoscape 3.7.2 were used for frequency statistics,association rules and cluster analysis.2 Semi-structured interview research:Referring to the research paradigm of medical ethics and leechcraft of famous and veteran Chinese medicine,Professor Li Qiuyan and her students were selected as interviewees.Through literature review,the necessity of semi-structured interview was clarified to improve the sensitivity of researchers to the theoretical framework.A pre-interview was conducted on the basis of the preliminary interview outline,and the formal interview outline was determined based on the interview results.The snowball sampling method was combined with the theoretical sampling method,and the interview subjects were interviewed,audio-recorded and recorded in the field.The interview data were transcribed in time.Based on the grounded theory research data analysis strategy,Nvivo Plus Release v1.2 software was used for three-level coding of the interview data.When the theoretical saturation was insufficient,the interview data continued to be obtained until the theoretical saturation was reached,and the core categories and complete story lines were extracted from the bottom up.To construct a theoretical model of Professor Li Qiuyan’s depression diagnosis and treatment ideas,and to confirm the clinical application of core prescriptions obtained by data mining.In the process of research,ethical review,credibility discussion,validity test and research promotion test were conducted to improve the scientific nature of the implementation of qualitative research.3 Network Pharmacology research:In this research,the network pharmacology method was used to predict the mechanism of Chaishao Kaiyu decoction,Professor Li Qiuyan’s core prescription for treating depression.The main method was to obtain six drug active ingredients,drug action targets and disease targets of depression through the database,and the intersection of drug component targets and disease targets was obtained through Venn diagram.Cytoscape 3.7.2 was used to construct the "drug-components-target" regulatory network,screen the core components,and construct the PPI protein interaction network.The core target genes were obtained by intersection of multiple analysis methods in the CytoHubba plug-in.Finally,KEGG and GO enrichment pathway analysis were performed on the intersection targets.Research results:1 Data mining research:59 MDD patients and 227 prescriptions met the inclusion and exclusion criteria were screened in this study.Patients are more female than male.In addition to depression,insomnia was the most prominent symptom of the patients.Red tongue and light purple tongue were the most common tongue,and the pulse was stringy,heavy,slippery and fast.Among the drugs,Paeoniae Radix Alba was the most frequently used,with a total of 187 times(5.17%),followed by Radix Bupleuri,Gardeniae Fructus,Curcumae Radix and Cyperi Rhizoma.The main properties of the drug were cold,flat and warm,the main flavors were sweet,bitter and pungent,and the main meridians were liver,heart,lung and spleen meridians.Among the drug-drug second-order association rules,"Paeoniae Radix Alba→Gardeniae Fructus" had the highest support(82.38%),and "Radix Bupleuri→Paeoniae Radix Alba" had the highest confidence(97.27%).Among the third-order association rules,"Radix Bupleuri-Paeoniae Radix Alba→Gardeniae Fructus" had the highest support(78.41%),and "Poria cum Radix Pini-Paeoniae Radix Alba→Radix Bupleuri","OsDraconis-Paeoniae Radix Alba→Radix Bupleuri",and" Chuanxiong Rhizoma-Radix Bupleuri→Paeoniae Radix Alba" had the highest confidence(100.00%).According to the TCM theory,the Chinese herbs with frequency ≥100 were clustered into three categories which were more suitable for clinical application.Cluster first categories:Paeoniae Radix Alba,Radix Bupleuri,Gardeniae Fructus,Curcumae Radix and Cyperi Rhizoma.Cluster second categories:Angelicae Sinensis Radix,Magnetite;Cluster third categories:Herbahypericiperforati,Ziziphi Spinosae Semen.Combined with the frequency of medication,association rules and cluster analysis,the core prescription was preliminarily proposed as Paeoniae Radix Alba,Radix Bupleuri,Gardeniae Fructus,Curcumae Radix and Cyperi Rhizoma.2 Semi-structured interview research:This study collected interview data based on Professor Li Qiuyan’s treatment ideas for depression.By the end of the interview,11 people did not have new codes and concepts,and additional 14 people did not have new codes and concepts,so the verification reached theoretical saturation.Through open coding,14 original transcribed data were coded,and 144 concepts were obtained.According to the relationship between concepts,they could be integrated into 8 categories,namely,the understanding of the cause of MDD,the understanding of the pathogenesis of MDD,the combination of four diagnostic methods and syndrome differentiation,the principle of traditional Chinese medicine treatment,common prescriptions and drugs,the adjustment of syndrome differentiation,doctor-patient communication and medical ethics cultivation.Comparison of data by axial coding,Through the comparison of the data by axial coding,three main categories were finally summarized,namely medical ethics cultivation,diagnostic ideas(four diagnosis combined with syndrome differentiation,etiology understanding of MDD,pathogenesis understanding of MDD)and treatment ideas(doctor-patient communication,treatment principles of traditional Chinese medicine,common prescriptions and drugs,syndrome differentiation adjustment prescription).Finally,through selective coding extraction,"examining the causes,treating the spirit and regulating qi and blood,relieving depression,training ethics and soothing mood" was proposed as the core category.Professor Li Qiuyan’s theoretical model of MDD diagnosis and treatment based on medical ethics cultivation,clarifying the cause of the disease,and treating the spirit and regulating qi and blood as the core was initially constructed.The core prescription derived from data mining is basically consistent with clinical application,and Herbahypericiperforati should be added to form the final core prescription,Chaishao Kaiyu prescription.3 Network pharmacology research:Based on the TCMSP database,40 active ingredients of six drugs in the core prescription were screened,of which 8 active ingredients were shared by two or more drugs,and 242 non-repetitive targets were matched.A total of 1650 disease targets were obtained based on OMIM,DisGeNET and Genecards databases,and 95 intersection targets between drug components and diseases were obtained by drawing Venn diagram.After the construction of the "drug-ingredient-target" regulatory network,12 compounds were selected as the core active ingredients by topological analysis,with quercetin,kaempferol,luteolin and beta-sitosterol ranked the top.The PPI network diagram was drawn and the topology analysis was performed.The intersection of multiple methods in the CytoHubba plug-in was used to make the Venn diagram,and four possible core target genes were obtained.They were AKT1,TNF,TP53 and CAT.GO enrichment analysis showed that the main biological processes of intersection targets were chemical synaptic transmission and regulation of secretion.The cellular components were mainly involved in postsynaptic membrane,serotonin receptor complex,vesicle lumen,and endocytic vesicle.The molecular functions are mainly involved in neurotransmitter receptor activity,cytokine activity,oxidoreductase activity,and adrenergic receptor activity.KEGG pathway enrichment analysis mainly involved neuroactive ligand-receptor interaction pathway,dopaminergic synapse pathway,serotonergic synapse pathway,etc.Conclusions:1 Data mining research:Professor Li Qiuyan think there are more female patients with MDD,and the nature of disease is more solid,with Qi stagnation,heat,blood stasis.In terms of treatment,Professor Li Qiuyan advocated the use of bitter cold to clear heat and eliminate boredom,sweet and mild drugs to strengthen the spleen and stomach,acrid and warm drugs to smooth the three jiao qi and blood,drugs of the liver meridian to regulate the qi machine,drugs of the heart meridian to reassure the spirit,with calming drugs to help sleep and relieve depression,in order to achieve the harmony of form and spirit,qi and blood.2 Semi-structured interview research:Professor Li Qiuyan’s diagnosis and treatment ideas for MDD are "examining the causes,treating the spirit and regulating qi and blood,relieving depression,training ethics and soothing mood",which mainly includes three academic viewpoints:"Medical ethics is more important than medical skill","spirit is the master of form",and "qi and blood are related to disease".3 Network Pharmacology research:The drug components of Chaishao Kaiyu decoction have an antidepressant effect.And they may improve synaptic plasticity,reduce inflammatory response,reduce oxidative stress,interfere with the process of neurotransmitter reuptake,and regulate the activity of neurotransmitter receptors through the targets of AKT1,TNF,TP53 and CAT in the neuroactive ligand-receptor interaction,dopaminergic synapse and serotonergic synapse. |
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