| Aims:Depression(classified in Chinese medicine as "dirty mania","depression" and"lily disease")is a mental illness that endangers physical health.Chinese herbal compound can exert pharmacological effects through multiple targets,with more obvious efficacy and safer action,which has more advantages for the treatment of depression.KaiXin-San is composed of four herbs often used to alleviate psychiatric disorders,and preclinical trials and clinical trials have reported the effects of Kai-Xin-San in the treatment of depression.Ginsenoside Rgl is a steroidal compound derived from ginseng,and preclinical trials have reported the potential of ginsenoside Rg1 for the rapid treatment of depression.The potential of ketamine and esketamine are N-methyl-Daspartic acid receptor channel blockers that exert rapid and long-lasting antidepressant effects,and their clinical application has been shown to have rapid antidepressant efficacy in depression.To assess the efficacy and safety of the antidepressant effects of Kai-XinSan and the main active ingredient ginsenoside Rg1 and on experimental animal models of depression using systematic evaluation and Meta-analysis,followed by Meta-analysis of prospective clinical randomized controlled trials incorporating some ketamine and esketamine for the treatment of suicidal ideation in depression from the perspective of preventive medicine,in order to investigate its effectiveness as a novel rapid antidepressant for the treatment of suicidal ideation in clinically refractory depression.Methods:By using keywords "Kai-Xin-San"、"ginsenoside Rg1","depression"."ketamine","esketamine","suicidal ideation" in China National Knowledge Infrastructure,CBMdisc,VIP Information Database,Wan Fang Database,PubMed,Web of Science,Embase Cochrane Library and other electronic databases,we also collected information by hand since the establishment of the database to June 28,2022.According to the inclusion and exclusion criteria,the retrieved literature was screened out for the preclinical experiments of ginsenoside Rgl and compound Kai-Xin-San in the treatment of depression animal models,and ketamine and esketamine in patients with treatmentresistant depression.The quality of the included literature was evaluated using ARRIVE guidelines or Cochrane collaboration criteria.Animal experiments were evaluated using the behavioral tests of animal depression as the outcome index,and clinical trials were evaluated using suicidal ideation in relevant depression scales as the outcome index.The researchers used Review Manager 5.3 software to conduct a meta-analysis on the valid data independently extracted from the included literature,and the corresponding results were expressed in the form of mean and 95%confidence interval,and presented in the form of a forest map.Q test and I2 test were used to test the heterogeneity of the studies.When I2>50%,the heterogeneity between the studies was indicated,and the random effects model was used for analysis.Otherwise,the fixed effect model is used.The larger the I2,the higher the inter-study heterogeneity.Methods for identifying sources of potential confounding factors with high heterogeneity are commonly used using subgroup analysis and sensitivity analysis.Subgroup analysis refers to dividing the subjects into multiple subgroups according to certain characteristics of the subjects(such as gender,age,disease diagnostic criteria,etc.)in the included studies,and then comparing the subgroups according to the effect values of the multiple groups.Sensitivity analysis,also known as sensitivity analysis,checks the robustness of meta-analysis conclusions by observing different models and different selection criteria.Therefore,subgroup analysis by category grouping and sensitivity analysis by single study exclusion was used to obtain more accurate results.The funnel plot indicates whether publication bias exists in the behavioral outcomes of included studies.If the funnel plot is asymmetric,the results are biased,and the degree of asymmetry indicates the degree of bias.For example,the greater the degree of dispersion asymmetry,the greater the bias.Otherwise,there is no or no obvious publication bias.Results:1)Kai-Xin-San:Twenty-four studies and 608 animals were included in this systematic review and meta-analysis.A remarkable effect of KXS in depression behavioral tests,including sucrose consumption test(MD=27.55,95%CI:(17.28,37.81);Z=5.26,P<0.0001),forced swimming test(MD=-60.52,95%CI:(-89.04,-31.99);Z=4.16,P<0.0001),rearing times(MD=4.48,95%CI:(3.39,5.57);Z=8.05,P<0.00001)and crossing times(MD=-33.7,95%CI:(25.74,41.67);Z=8.29,P<0.00001)in the open field test,showing KXS’s excellent efficiency in improving depressive-like symptoms of animals.2)Ginsenoside Rg1:a total of 24 studies,including 678 animals,were included in this meta-analysis.The results showed remarkable effects of Rg1 in improving depressive-like symptoms of depressed rodents,including the sucrose preference test(MD:25.08,95%CI:20.17-30.00,Z=10.01,P<0.00001),forced swimming test(MD=-37.69,95%CI:(-45.18,-30.2);Z=9.86,P<0.00001),and the tail suspension test(MD=-22.93,95%CI:(-38.49,-7.37);Z=2.89,P=0.004).3)Ketamine and esketamine:A total of 12 studies,representing 5 independent double-blind,placebo-controlled RCTs,which is eligible for inclusion.No statistically significant interaction on the subscales of suicide ideation(MD=-0.94,95%CI:(-2.03,0.15);Z=1.69,P=0.09),and antidepressant effects MD=-1.19,95%CI:(-3.28,0.9);Z=1.12,P=0.26)based on the results of ketamine and esketamine,compared with placebo groups.Conclusions:The results of systematic evaluation and Meta-analysis showed that both ginsenoside Rgl and Kai-Xin-San were effective in improving depression-like behavior in animals,suggesting them as potential future antidepressants.Clinical use of ketamine and esketamine has been shown to have a rapid antidepressant effect on depression.Meta-analysis of ketamine and esketamine and suicidal ideation in depression,including some prospective clinical randomized controlled trials,showed that ketamine and esketamine did not significantly reduce suicidal ideation in refractory depression,which suggests that more clinical studies are needed to further explore and give hints on the prevention of suicide in depression,considering the limitations of the number of trials. |
