Juncai Pu

The identification of metabolic disturbances in the prefrontal cortex of the chronic restraint stress rat model of depression.

Major depressive disorder, with serious impairment in cognitive and social functioning, is a complex psychiatric disorder characterized by pervasive and persistent low mood and a loss of interest or pleasure. However, the underlying molecular mechanisms of depression remain largely unknown. In this study, we used a non-targeted metabolomics approach based on gas chromatography-mass spectrometry of the prefrontal cortex in chronic restraint stress (CRS)-treated rats. CRS was induced in the stress group by restraining rats in a plastic restrainer for 6h every day. This stress paradigm continued for 21 days. Body weight measurement and behavior tests were applied, including the sucrose preference test for anhedonia, the forced swimming test for despair-like behavior, and open field test and the elevated plus-maze to test for anxiety-like behaviors in rats after CRS. Differentially expressed metabolites associated with CRS-treated rats were identified by combining multivariate and univariate statistical analysis and corrected for multiple testing using the Benjamini-Hochberg procedure. A heat map of differential metabolites was constructed using Matlab. Ingenuity Pathways Analysis was applied to identify the predicted pathways and biological functions relevant to the bio-molecules of interest. Our findings showed that CRS induces depression-like behaviors and not anxiety-like behaviors. Thirty-six metabolites were identified as potential depression biomarkers involved in amino acid metabolism, energy metabolism and lipid metabolism, as well as a disturbance in neurotransmitters. Consequently, this study provides useful insights into the molecular mechanisms of depression.

Efficacy and feasibility of antidepressant treatment in patients with post-stroke depression

Background:Depression greatly impacts the quality of life in most stroke survivors. Therefore, effective treatment of post-stroke depression (PSD) is critically important. However, evidence supporting the effectiveness and feasibility of antidepressant treatment in this population is limited and somewhat confusing. Methods:A comprehensive literature search of the Cochrane, PubMed, Web of Science, and Embase databases from inception up to November 2015 was conducted. We reviewed all randomized controlled trials (RCTs) that assigned patients with a clinical diagnosis of PSD to antidepressant or placebo treatment. Reduction in depression rating scale scores and response rate to antidepressants were defined as the efficacy outcomes. Rates of dropout for any reason and for adverse effects were defined as the acceptability outcomes. We also assessed improvements in activities of daily living (ADL) as functional outcomes. Results:In total, 11 trials consisting of 740 participants were indentified. A significant advantage of antidepressants compared with placebo treatment in PSD was observed in overall pooled effect size analysis (SMD = −0.96; 95% CI = −1.41 to −0.51; P <0.0001). In addition, patients receiving antidepressants presented a much greater improvement in various depressive symptoms than those with placebo (RR = 1.36; 95% CI = 1.01–1.83; P = 0.04). However, antidepressants were less well tolerated than placebo because of some adverse events (RR = 2.72; 95% CI = 1.37–5.43; P = 0.04). Intriguingly, no consistent evidence was found for a positive effect of antidepressants on ADL in our analysis. Conclusions:This meta-analysis suggests that antidepressants treatment confers potentially positive effects in patients with PSD as compared with simple placebo treatment. However, this must be carefully considered in light of its possible adverse events in some individual patients.

Hippocampal metabolic differences implicate distinctions between physical and psychological stress in four rat models of depression

Major depressive disorder (MDD) is a heterogeneous and multi-factorial disorder, and the underlying molecular mechanisms remain largely unknown. However, many studies have indicated that the molecular mechanisms underlying depression in response to different stress may differ. After screening, 28–30 rats were included in each model of depression (chronic unpredictable mild stress (CUMS); learned helplessness (LH); chronic restraint stress (CRS); or social defeat (SD)). Non-targeted gas chromatography-mass spectrometry was used to profile the metabolic changes in the hippocampus. As a result, all four models exhibited significant depression-like behavior. A total of 30, 24, 19, and 25 differential metabolites were identified in the CUMS, LH, CRS, and SD models, respectively. Interestingly, the hierarchical clustering results revealed two patterns of metabolic changes that are characteristic of the response to cluster 1 (CUMS, LH) and cluster 2 (CRS, SD) stress, which represent physical and psychological stress, respectively. Bioinformatic analysis suggested that physical stress was mainly associated with lipid metabolism and glutamate metabolism, whereas psychological stress was related to cell signaling, cellular proliferation, and neurodevelopment, suggesting the molecular changes induced by physical and psychological stress were different. Nine shared metabolites were opposite in the directions of change between physical and psychological models, and these metabolites were associated with cellular proliferation and neurodevelopment functions, indicating the response to physical and psychological stress was different in the activation and deactivation of the final common pathway to depression. Our results provide a further understanding of the heterogeneity in the molecular mechanisms of MDD that could facilitate the development of personalized medicine for this disorder.

Gender differences in psychological morbidity, burnout, job stress and job satisfaction among Chinese neurologists: a national cross-sectional study

Abstract Women are an important part of the medical workforce, yet little is known about gender differences in psychological morbidity, burnout, job stress and job satisfaction among neurologists. This study assessed gender differences in a large national sample of Chinese neurologists. Multivariate analyses were performed to examine associations. A total of 5558 neurologists were included in the analysis. Compared with their male counterparts, female neurologists were generally younger; were less likely to be married or to have children; had higher levels of education; were in practice for a shorter period of time; were less likely to hold senior roles; and had lower incomes. Male and female neurologists worked similar hours and spent a similar number of nights on call. No gender differences were found in psychological morbidity, burnout, and high levels of job stress for female and male, respectively. Women had higher emotional exhaustion scores, while men were more likely to have low levels of job satisfaction. The multivariate analysis showed that factors independently associated with psychological morbidity, burnout, high levels of job stress and low levels of job satisfaction were generally similar for women and men. These findings increase our understanding of gender differences in psychological morbidity, burnout, job stress, and job satisfaction among neurologists. As more women join the medical profession, these differences may be useful in designing medical training and practice.

Integrated Metabolomics and Proteomics Analysis of Hippocampus in a Rat Model of Depression

Major depressive disorder (MDD) is a prevalent and serious mental disorder with high rates of suicide and disability. However, the underlying pathogenesis of MDD is complicated and remains largely unclear. An integrated analysis of multiple types of omics data may improve comprehensive understanding of the entire molecular mechanism of MDD. In this study, we applied an integrated analysis of gas chromatography/mass spectrometry (GC-MS)-based metabolomics and isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics to investigate changes in the hippocampus in the chronic unpredictable mild stress (CUMS) rat model of depression. Only the stress-susceptible rats in the CUMS group were selected for profiling against controls. Differential analysis identified 30 metabolites and 170 proteins between the two groups. The integrated analyses revealed four major changes in the hippocampus of CUMS rats: (1) impairment in amino acid metabolism and protein synthesis/degradation; (2) dysregulation of glutamate and glycine metabolism and their transport/catabolism related proteins; (3) disturbances in fatty acid and glycerophospholipid metabolism accompanied by alterations in the corresponding metabolic enzymes; (4) abnormal expression of synapse-associated proteins. These results provide further important insights into the pathophysiology of depression and may help identify potential targets for antidepressant drugs.

Efficacy and acceptability of interpersonal psychotherapy for depression in adolescents: A meta-analysis of randomized controlled trials

In this study, we evaluate the efficacy and safety of interpersonal psychotherapy (IPT) for adolescents with depression. We searched our existing database and electronic databases, including PubMed, Cochrane, EMBASE, PsycINFO, Web of Science, and CINAHL databases (from inception to May 2016). We included randomized controlled trials comparing IPT with various control conditions, including waitlist, psychological placebo, treatment as usual, and no treatment, in adolescents with depression. Finally, we selected seven studies comprising 538 participants comparing IPT with three different control conditions. Pooled analyses suggested that IPT was significantly more effective than control conditions in reducing depressive symptoms at post-treatment and follow-up, and increasing the response/remission rate at post-treatment. IPT was also superior to control conditions for all-cause discontinuation and quality of life/functioning improvement outcomes. However, there was no evidence that IPT reduces the risk of suicide from these data. Meta-analysis demonstrated publication bias for primary efficacy, while the adjusted standardized mean difference using the trim-and-fill method indicated IPT was still significantly superior to the control conditions. Current evidence indicates IPT has a superior efficacy and acceptability compared with control conditions in treating adolescents with depression.

Social defeat stress causes depression-like behavior with metabolite changes in the prefrontal cortex of rats

Major depressive disorder is a serious mental disorder with high morbidity and mortality. The role of social stress in the development of depression remains unclear. Here, we used the social defeat stress paradigm to induce depression-like behavior in rats, then evaluated the behavior of the rats and measured metabolic changes in the prefrontal cortex using gas chromatography-mass spectrometry. Within the first week after the social defeat procedure, the sucrose preference test (SPT), open field test (OFT), elevated plus maze (EPM) and forced swim test (FST) were conducted to examine the depressive-like and anxiety-like behaviors. For our metabolite analysis, multivariate statistics were applied to observe the distribution of all samples and to differentiate the socially defeated group from the control group. Ingenuity pathway analysis was used to find the potential relationships among the differential metabolites. In the OFT and EPM, there were no significant differences between the two experimental groups. In the SPT and FST, socially defeated rats showed less sucrose intake and longer immobility time compared with control rats. Metabolic profiling identified 25 significant variables with good predictability. Ingenuity pathways analysis revealed that “Hereditary Disorder, Neurological Disease, Lipid Metabolism” was the most significantly altered network. Stress-induced alterations of low molecular weight metabolites were observed in the prefrontal cortex of rats. Particularly, lipid metabolism, amino acid metabolism, and energy metabolism were significantly perturbed. The results of this study suggest that repeated social defeat can lead to metabolic changes and depression-like behavior in rats.

Comparative efficacy and tolerability of new-generation antidepressants for major depressive disorder in children and adolescents: Protocol of an individual patient data meta-analysis

Introduction Although previous conventional meta-analyses and network meta-analyses have provided some important findings about pharmacological treatments for children and adolescents with depressive disorders in the past decades, several questions still remain unsolved by the aggregate data from those meta-analyses. Individual participant data meta-analysis (IPD-MA) enables exploration of the impacts of individual characteristics on treatment effects, allowing matching of treatments to specific subgroups of patients. We will perform an IPD-MA to assess the efficacy and tolerability of new-generation antidepressants for major depressive disorder in children and adolescents. Methods and analysis We will systematically search for all double-blind randomised controlled trials (RCTs) that have compared any new-generation antidepressant with placebo for the acute treatment of major depressive disorder in children and adolescents, in the following databases: PubMed, EMBASE, the Cochrane Library, PsycINFO, Web of Science, CINAHL, LILACS and ProQuest Dissertations. We will contact all corresponding authors of included RCTs and ask for their cooperation in this project by providing individual participant data from the original trials. The primary outcomes will include efficacy, measured as the mean change of depression symptoms by Children’s Depression Rating Scale Revised (CDRS-R), and tolerability, measured as the proportion of patients who withdrew from the trials early due to adverse effects. The secondary outcomes will include response rates, remission rates, deterioration rate, all-cause discontinuation, suicidal-related outcomes and global functioning outcome. Using the raw de-identified study data, we will use mixed-effects logistic and linear regression models to perform the IPD-MAs. The risk of bias of included studies will be assessed using the Cochrane risk of bias tool. We will also detect the publication bias and effects of non-participation of eligible studies. Dissemination Ethical approval is not required given that informed consent has already been obtained from the patients by the trial investigators before the included trials were conducted. This study may have considerable implications for practice and help improve patient care. PROSPERO registration number CRD42016051657.

Comparative efficacy and acceptability of antidepressants, psychological interventions, and their combination for depressive disorder in children and adolescents: protocol for a network meta-analysis

Introduction Depressive disorder is common in children and adolescents, with important consequences and serious impairments in terms of personal and social functioning. While both pharmacological and psychological interventions have been shown to be effective, there is still uncertainty about the balance between these and what treatment strategy should be preferred in clinical practice. Therefore, we aim to compare and rank in a network meta-analysis (NMA) the commonly used psychological, pharmacological and combined interventions for depressive disorder in children and adolescents. Methods and analysis We will update the literature search of two previous NMAs for the identification of trials of antidepressant and psychotherapy alone for depressive disorder in children and adolescents. For identification of trials of combination interventions, seven databases (PubMed, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, PsycINFO, CINAHL, LiLACS) will be searched from date of inception. We will also search ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform and check relevant reports on the US Food and Drug Administration website for unpublished data. Building on our previous findings in the field, we will include any commonly prescribed oral antidepressants and any manualised or structured psychotherapies, as well as their combinations. Randomised controlled trials assessing any active intervention against active comparator or pill placebo/psychological controls in acute treatment for depressive disorder in children and adolescents will be included. The primary outcomes will be efficacy (mean change in depressive symptoms), and acceptability of treatment (dropout rate due to any cause). The secondary outcomes will be remission rate, tolerability of treatment (dropouts for adverse events), as well as suicide-related outcomes (suicidal behaviour or ideation). We will perform Bayesian NMAs for all relative outcome measures. Subgroup analyses and sensitivity analyses will be conducted to assess the robustness of the findings. Dissemination This NMA will provide the most up to date and clinically useful information about the comparative efficacy and acceptability of antidepressants, psychological intervention and their combination in the acute treatment of children and adolescents with depressive disorder. This is the newest NMA and therefore these results are very important in terms of evidence-based medicine. The results will be disseminated through peer-reviewed publication. Protocol registration PROSPERO CRD42015020841.

Plasma disturbance of phospholipid metabolism in major depressive disorder by integration of proteomics and metabolomics

Introduction Major depressive disorder (MDD) is a highly prevalent mental disorder affecting millions of people worldwide. However, a clear causative etiology of MDD remains unknown. In this study, we aimed to identify critical protein alterations in plasma from patients with MDD and integrate our proteomics and previous metabolomics data to reveal significantly perturbed pathways in MDD. An isobaric tag for relative and absolute quantification (iTRAQ)-based quantitative proteomics approach was conducted to compare plasma protein expression between patients with depression and healthy controls (CON). Methods For integrative analysis, Ingenuity Pathway Analysis software was used to analyze proteomics and metabolomics data and identify potential relationships among the differential proteins and metabolites. Results A total of 74 proteins were significantly changed in patients with depression compared with those in healthy CON. Bioinformatics analysis of differential proteins revealed significant alterations in lipid transport and metabolic function, including apolipoproteins (APOE, APOC4 and APOA5), and the serine protease inhibitor. According to canonical pathway analysis, the top five statistically significant pathways were related to lipid transport, inflammation and immunity. Conclusion Causal network analysis by integrating differential proteins and metabolites suggested that the disturbance of phospholipid metabolism might promote the inflammation in the central nervous system.