Lanxiang Liu

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.

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.

Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus

Gut microbiota has an important role in the immune system, metabolism, and digestion, and has a significant effect on the nervous system. Recent studies have revealed that abnormal gut microbiota induces abnormal behaviors, which may be associated with the hypothalamic–pituitary–adrenal (HPA) axis. Therefore, we investigated the behavioral changes in germ-free (GF) mice by behavioral tests, quantified the basal serum cortisol levels, and examined glucocorticoid receptor pathway genes in hippocampus using microarray analysis followed by real-time PCR validation, to explore the molecular mechanisms by which the gut microbiota influences the host’s behaviors and brain function. Moreover, we quantified the basal serum cortisol levels and validated the differential genes in an Escherichia coli-derived lipopolysaccharide (LPS) treatment mouse model and fecal “depression microbiota” transplantation mouse model by real-time PCR. We found that GF mice showed antianxiety- and antidepressant-like behaviors, whereas E. coli LPS-treated mice showed antidepressant-like behavior, but did not show antianxiety-like behavior. However, “depression microbiota” recipient mice exhibited anxiety- and depressive-like behaviors. In addition, six glucocorticoid receptor pathway genes (Slc22a5, Aqp1, Stat5a, Ampd3, Plekhf1, and Cyb561) were upregulated in GF mice, and of these only two (Stat5a and Ampd3) were upregulated in LPS-treated mice, whereas the shared gene, Stat5a, was downregulated in “depression microbiota” recipient mice. Furthermore, basal serum cortisol levels were decreased in E. coli LPS-treated mice but not in GF mice and “depression microbiota” recipient mice. These results indicated that the gut microbiota may lead to behavioral abnormalities in mice through the downstream pathway of the glucocorticoid receptor. Herein, we proposed a new insight into the molecular mechanisms by which gut microbiota influence depressive-like behavior.

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.

Comparative efficacy and acceptability of bibliotherapy for depression and anxiety disorders in children and adolescents: a meta-analysis of randomized clinical trials

Background Depression and anxiety are the most common mental disorders in children and adolescents. Bibliotherapy is a treatment using written materials for mental health problems. Its main advantages are ease of use, low cost, low staffing demands, and greater privacy. Yet few meta-analyses have focused on the effect of bibliotherapy on depression and anxiety disorders in children and adolescents. Methods We included randomized controlled trials comparing bibliotherapy with control conditions for depression and anxiety in children and adolescents (aged ≤18 years). Five electronic databases (PubMed, Embase, Cochrane, Web of Science, and PsycINFO) were searched from inception to January 2017. Efficacy was defined as mean change scores in depression and anxiety symptoms. Acceptability was defined as the proportion of participants who discontinued the treatment. Random effects model was used. An intention-to-treat analysis was conducted. Results Eight studies with 979 participants were selected. At posttreatment, bibliotherapy was significantly more effective than the control conditions in reducing the symptoms of depression or anxiety (standardized mean difference, −0.52; 95% confidence interval [CI], −0.89 to −0.15). Bibliotherapy did not have statistically significantly more all-cause discontinuations than controls (risk ratios, 1.66; 95% CI, 0.93 to 2.95). We also performed subgroup analyses for efficacy outcomes in different categories (types of disorder, mean age, control conditions, and parental involvement) of studies and found that bibliotherapy has been more effective in depressive adolescents. Limitations Limited studies were eligible in this review and hence there was potential publication bias. Conclusion According to the findings in this review, bibliotherapy may be more beneficial in treating depression in adolescents, but shows less robust effects for anxiety in children. Further well-defined clinical studies should be performed to confirm these outcomes.

Polyunsaturated fatty acids metabolism, purine metabolism and inosine as potential independent diagnostic biomarkers for major depressive disorder in children and adolescents

Major depressive disorder (MDD) in children and adolescents is a recurrent and disabling condition globally but its pathophysiology remains poorly elucidated and there are limited effective treatments available. We performed metabolic profiling of plasma samples based on ultra-high-performance liquid chromatography equipped with quadrupole time-offlight mass spectrometry to explore the potential biomarkers of depression in children and adolescents with MDD. We identified several perturbed pathways, including fatty acid metabolism—particularly the polyunsaturated fatty acids metabolism, and purine metabolism—that were associated with MDD in these young patients. In addition, inosine was shown as a potential independent diagnostic biomarker for MDD, achieving an area under the ROC curve of 0.999 in discriminating drug-naive MDD patients and 0.866 in discriminating drug-treated MDD from healthy controls. Moreover, we found evidence for differences in the pathophysiology of MDD in children and adolescents to that of adult MDD, specifically with tryptophan metabolism. Through metabolomic analysis, we have identified links between a framework of metabolic perturbations and the pathophysiology and diagnostic biomarker of child and adolescent MDD.