| PART 1: INTEGRATED METABOLOMICS AND PROTEOMICS ANALYSIS REVEALED SECOND MESSENGER SYSTEM DISTURBANCE IN HIPPOCAMPUS OF CHRONIC SOCIAL DEFEAT STRESS RATBackground:Major depression disorder(MDD)is one of the most common mental disease in the world.It is characterized by significant and persistent low mood,with high prevalence,high recurrence rate,high disability rate and high suicide rate,is the main cause of global health burden.There is a variety of factors related to depression,while its pathophysiology remains poorly elucidated.Various animal models have been used to explore the molecular mechanisms of MDD.Among these,the chronic social defeat stress(CSDS)seems to be one of the most widely used for investigating possible causes of and treatments for depression.The repeated exposure of rodents to social defeat stress causes a robust depression-like phenotype marked by anhedonia,body weight alteration,despair behavior,and altered protein expression in various brain areas.As a key brain region for emotion and motivation generation andregulation,the hippocampus plays an important role in the pathogenesis of depression.However,how these changes in hippocampus,such as atrophy of hippocampal neurons,decreased glial density,lead to depression remain unclear.Uncovering these molecular events is critical to the understanding of the etiology of depression.In recent decades,omics technologies have become a powerful tool for molecular profiling,biomarkers identification,characterization of complex biochemical systems,and to uncover the pathophysiology of neuropsychiatric disorders.Metabolomics enables quantification of low-molecular-weight metabolites within a particular biological sample,and is widely used to capture disease-specific metabolite signatures.Proteomics – the analysis of protein expression in biological samples – can provide insights into the pathophysiological mechanisms of several disease states.However,the result from a single omics has to be a great challenge due to complex biochemical regulation at multiple levels for disease.Thus,integrated analysis by combining multiple types of omics data is promising and may help to elucidate potential biological relationships,improve understanding of the pathophysiological mechanism of disease,discover biomarkers and conduct early diagnosis of diseases.Among different integrated analysis by combining multiple types of omics data,protein-metabolism integration analysis is the most commonly used and effective.Metabolomics informed functional interpretations of proteomicdata,while proteomics contributed to a better understanding of metabolomics data by highlighting the involvement of specific enzymatic and/or enzymatic pathways.In this study,we applied an integrated analysis of GC–MS-based metabolomics and iTRAQ-based proteomics to investigate molecular changes in the hippocampus of rats induced by CSDS.Furthermore,we used Ingenuity pathway analysis(IPA)to integrate potential relationships among differentially expressed metabolites and proteins to gain a better understanding of the pathophysiology of depression.Objective:1.Induced depression-like behavior in rats by exposing them to chronic social defeat stress.Non-targeted gas chromatography-mass spectrometry(GC-MS)-based metabolomic approaches with isobaric tags for relative and absolute quantitation(iTRAQ)-based proteomic analysis were used to compare the metabolites and proteins of rats' hippocampus of CSDS group with non-stressed control(CON)group2.Integrate metabolomics and proteomics analyses to investigate the molecular mechanisms of depression in the hippocampus.Methods:1.CSDS model of rats was established.After the chronic social defeat stress model,behavioral tests such as body weight and sucrose preference test were carried out.2.Using non-targete GC–MS-based metabolomics to investigate the metabolite changes in rats' hippocampus of CSDS group compare with CON group.3.Using iTRAQ-based proteomic to investigate the protein changes in rats' hippocampus of CSDS group compare with CON group.4.IPA was used to analyze the canonical pathway and network function of CSDS model of rats,and to explore the possible pathogenesis of depression.Results:1.After 3 weeks of chronic social defeat stress,there were significant differences for the results of body weight,sucrose preference test and forced swimming test(FST)between CSDS and CON group(p<0.05).While there was no difference in the total distance of movement,the time of the central area,the number of standings in the open field test(OFT),and the number of open/closed arms of the elevated plus maze(EPM).It suggested that rats in the CSDS group showed significant change in depression-like behaviors,but not in anxiety-like behaviors.2.Twenty-five significantly different metabolites were identified in the hippocampus between CSDS and control groups,most are primarily involved in amino acid metabolism,carbohydrate metabolism,and lipid metabolism.3.234 differentially expressed proteins were identified in thehippocampus between CSDS and control groups,most proteins are associated with protein transport,positive regulation of neuron death,and nervous system development.4.IPA canonical pathway and network analyses of integrated metabolites and proteins revealed that intracellular second messenger/signal transduction cascades were the most significantly altered in the hippocampus of CSDS rats.Conclusions:Complementary omics strategies(GC–MS-based metabolomics and iTRAQ-based proteomics)were applied to obtain a comprehensive view of the rat hippocampal response to CSDS.The results suggest that disturbances in several different secondary messenger systems(cAMP,phosphoinositol,arachidonic acid,and tyrosine kinase)are involved in the hippocampus of CSDS rodents.The results contribute to a better understanding of biological mechanisms and pathophysiology of depression,and may help identify novel targets for antidepressant treatment.PART 2: EFFICACY AND ACCEPTABILITY OF COGNITIVE BEHAVIORAL THERAPY FOR DEPRESSION IN CHILDREN: A SYSTEMATIC REVIEW AND META-ANALYSISBackground:Depression is one of the most common mental disorders among children(?13 years old).The lifetime prevalence of depression in preschool children is about 1%,and in school children about 3%.1Compared with adults,children with major depression are often underdiagnosed and undertreated because depression in children may be expressed in unspecific symptoms,e.g.,somatic complaints,headache,social withdrawal and hopelessness.2 Some researchers have found that the average duration of a major depressive episode in children is approximately6–9 months.3,4 Although this duration is similar to that in adults,it may have a more severe effect on children because of the impact upon their academic and social development.Moreover,depressed children have an increased risk of psychological and physiological ill-health in adolescence and adulthood,and of suicide attempts,alcohol and drug use,and social adjustment problems.5,6 Thus,the extent,impact and long-term sequelae of childhood depression highlights the need for effective treatment.Currently,several international guidelines recommend that psychological treatments,especially cognitive behavioral therapy(CBT)and interpersonal therapy,are still considered the first-line treatments for depression in children and adolescents,7,8 and CBT is the most studied psychosocial intervention for the treatment of depression in children and adolescents.9-12 Nonetheless,few systematic reviews and meta-analyses have focused on the effect of CBT in children.13-15 The degree of cognitive maturity is less in children than in adolescents,and debate continues as to what degree of cognitive maturity is required for successful engagement in CBT in children.Hence,the aim of the current meta-analysis was to compare the efficacy and acceptability of CBT with wait-list,non-treatment or psychological placebo in the treatment of depression in children.Objective:The aim of the current meta-analysis was to compare the efficacy and acceptability of CBT with wait-list,non-treatment or psychological placebo in the treatment of depression in children.Methods:Seven electronic databases(Pub Med,Embase,Cochrane Library,Web of Science,Psyc INFO,CINAHL,and Li LACS)were searched from inception to September 2015.Randomized controlled trials comparing CBT with control conditions for depression in children(?13 years old)were included.The primary efficacy was defined as mean change scores in depressive symptoms,and the second efficacy(remission)was a score below the threshold for a diagnosis of depression,at both post-treatment and the end of follow-up.We also measured acceptability,by the proportion of participants who discontinued treatment up to post-treatment.Results:Nine studies with 306 participants were selected for this analysis.At post-treatment,CBT was significantly more effective than control conditions in terms of primary efficacy(SMD=-0.41,95%CI-0.64 to-0.18)and secondary efficacy(OR=2.16,95%CI 1.24 to 3.78).At follow-up,the results were consistent with those of efficacy outcomes at post-treatment,with an SMD of-0.34 and OR of 2.04.CBT had no statistical more all-cause discontinuations than control group(OR=0.69,95% CI 0.26 to 1.82).However,subgroup analyses found that CBT was only significantly more effective than the non-treatment condition,while it was not better than wait-list or psychological placebo.Conclusions:CBT seems to be more beneficial than a non-treatment condition in the treatment of depression in children;however,this finding is limited by the small size of the trials and low literature quality. |
PDF Full Text Request