Profiles and diagnostic value of intestinal microbiota in schizophrenia patients with metabolic syndrome.

Aims/hypothesis: It is widely thought that the intestinal microbiota plays a significant role in the pathogenesis of metabolic disorders. However, the gut microbiota composition and characteristics of schizophrenia patients with metabolic syndrome (MetS) have been largely understudied. Herein, we investigated the association between the metabolic status of mainland Chinese schizophrenia patients with MetS and the intestinal microbiome. Methods: Fecal microbiota communities from 115 male schizophrenia patients (57 with MetS and 58 without MetS) were assessed by 16S ribosomal RNA gene sequencing. We assessed the variations of gut microbiome between both groups and explored potential associations between intestinal microbiota and parameters of MetS. In addition, the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) based on the KEGG database was used to predict the function of intestinal microbiota. We also conducted Decision Tree Analysis to develop a diagnostic model for the MetS in patients with schizophrenia based on the composition of intestinal microbiota. Results: The fecal microbial diversity significantly differed between groups with or without MetS (α-diversity (Shannon index and Simpson index): p=0.0155, p=0.0089; ß-diversity: p=0.001). Moreover, the microbial composition was significantly different between the two groups, involving five phyla and 38 genera (p<0.05). In addition, a significant correlation was observed between the metabolic-related parameters and abundance of altered microbiota including HDL-c (r2 = 0.203, p=0.0005), GLU (r2 = 0.286, p=0.0005) and WC (r2 = 0.061, p=0.037). Furthermore, KEGG pathway analysis showed that 16 signaling pathways were significantly enriched between the two groups (p<0.05). Importantly, our diagnostic model based on five microorganisms established by decision tree analysis could effectively distinguish between patients with and without MetS (AUC = 0.94). Conclusions/interpretation: Our study established the compositional and functional characteristics of intestinal microbiota in schizophrenia patients with MetS. These new findings provide novel insights into a better understanding of this disease and provide the theoretical basis for implementing new interventional therapies in clinical practice.

Differing Prevalence and Correlates of Metabolic Syndromes Between Chlorpromazine and Clozapine: A 10-year Retrospective Study of a Male Chinese Cohort.

BACKGROUND: Antipsychotics are known to be associated with metabolic syndromes (MetS). Chlorpromazine (CPZ) and Clozapine (CLZ) are currently the most commonly used antipsychotics in low-income districts of China. However, potential differences in the long-term effects of CPZ and CLZ on MetS in schizophrenia inpatients are not well understood. Here, we aimed to identify any MetS profile differences between long-term schizophrenia patients who were prescribed either CPZ or CLZ at a primary psychiatric hospital. METHODS: We recruited a total of 204 male schizophrenia patients who received either CPZ or CLZ. We measured their weight, height, body mass index (BMI), waist circumference (WC), diastolic blood pressure (DBP), and systolic blood pressure (SBP), as well as their biochemical indicators, including fasting blood glucose (FBS), triglycerides (TG), cholesterol (TC), high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c). RESULTS: The MetS prevalence in the CPZ and CLZ groups was 31% and 37.5%, respectively. The CLZ group had significantly higher DBP levels and a higher incidence of dyslipidemia (HDL-c) but lower HDL-c and TC levels than the CPZ group. We also determined that smoking history, BMI, and duration of hospitalisation were risk factors for the development of MetS. Moreover, we found that CPZ and CLZ were correlated with the same risk for developing MetS and that BMI was a vital risk factor of MetS for both the CPZ and CLZ groups. CONCLUSION: Long-term CPZ and CLZ prescriptions were associated with similar profiles for developing MetS of schizophrenia patients.

Reduced NLRP3 inflammasome expression in the brain is associated with stress resilience.

Increased expression of the Nod-like receptor pyrin containing 3 (NLRP3) inflammasome and proinflammatory cytokines is associated with depressive behaviors. This study aimed to explore potential differences in neuroinflammation associated with stress resilience, as well as associated changes in autophagy, in a mouse model of chronic unpredictable mild stress (CUMS). Animals were classified as CUMS resilient or CUMS susceptible based on performance on behavioral tests following the CUMS protocol. Then the expression levels of NLRP3 inflammasome-related proteins, interleukin-1 beta (IL-1ß), and Beclin 1 in stress-related brain regions (e.g., prefrontal cortex and hippocampus) were determined. Results showed that stress exposure triggered significant NLRP3 inflammasome increase in CUMS susceptible mice but not in CUMS resilient mice. These changes were accompanied by altered IL-1ß and Beclin 1 expression levels. These findings indicate that stress resilience is associated with reduced pro-inflammatory signaling and autophagy activation, and suggest that therapeutically targeting these pathways might promote stress resilience.

The interaction of ASAH1 and NGF gene involving in neurotrophin signaling pathway contributes to schizophrenia susceptibility and psychopathology.

The neurodevelopmental hypothesis of schizophrenia has been widely accepted. In light of our previous microarray data, two neurodevelopment-related genes were focused on inclduing the N-acylsphingosine amidohydrolase 1 gene (ASAH1) and the nerve growth factor gene (NGF). The evidence that ASAH1 and NGF are associated with schizophrenia is far from conclusive. Furthermore, their interactions in schizophrenia have not been investigated. Total 413 patients and 578 controls were included. Eleven single-nucleotide polymorphisms (SNPs) in ASAH1 and NGF were selected. A multifactor dimensionality reduction (MDR) was applied to investigate gene-gene interactions in schizophrenia, and the traditional odds ratio methods was applied to validate it. The effects of ASAH1, NGF and their interaction on the severity of the disease were analyzed by 3 × 3 covariance analysis of (ANCOVA). The biological interaction between ASAH1 and NGF was examined. KEGG was used to identify the related signaling pathways. After correction by Bonferroni, there were no differences in the genotypic, allelic, or haplotypic frequencies of 11 SNPs between patients and controls. However, the interaction of certain SNPs had effect on susceptibility to schizophrenia, including two high-risk and one low-risk genotypic combinations (OR = 1.49 [1.11-2.00]; OR = 1.45 [1.09-1.92], and OR = 0.64 [0.41-0.98]). ASAH1-rs7830490 and its interaction with NGF-rs4332358 were associated with the general psychopathological subscale score (F adjusted = 3.94, p adjusted = 0.01; F adjusted = 2.36, p adjusted = 0.03). We also found that ASAH1 and NGF interacted with CaMK2B involving in the neurotrophin signaling pathway. Our results suggest that the interaction of ASAH1 and NGF with CaMK2B involved in neurotrophin signaling pathway may contribute to schizophrenia susceptibility and psychopathology.

[Clinical phenotype and genetic analysis of a Chinese patient featuring X-linked Claes-Jensen type syndromic mental retardation].

OBJECTIVE: To explore the genetic basis of a Chinese patient featuring global developmental delay. METHODS: Peripheral venous blood samples from the proband and his parents and sister were taken for the extraction of DNA. Target capture and next generation sequencing was carried out to detect genetic variants associated with the disease. Suspected variant was validated by Sanger sequencing. RESULTS: Genetic testing discovered that the proband has carried hemizygous c.150G>T and c.150+1G>T variants of the KDM5C gene which are inherited from his mother. His younger sister also carried the variants. The c.150+1G>A variant was unreported previously, which has altered a splice site and was predicted to be pathogenic by bioinformatics analysis. CONCLUSION: The hemizygous c.150+1G>T variant of the KDM5C gene, known to underlie X-linked Claes-Jensen type syndromic mental retardation, probably accounts for the disorder in the patient. Identification of this variant has enriched the variant spectrum of the KDM5C gene.

Antipsychotics-associated obsessive-compulsive symptoms: individualized treatments and clinical benefits of memantine: a case report.

Antipsychotics with a prominent anti-serotoninergic profile have risks of obsessive-compulsive symptoms (OCS). These types of OCS are remain mostly intractable to existing treatments because of the dilemma between the antipsychotic effects and the OCS adverse effects, both of which brought by serotoninergic-blocking profile. This state forced us to seek non-serotonergic system pharmaceuticals. Memantine, as a glutamatergic drug, is the adjunctive agent most consistently showing an effective impact in primary OCD, however its benefit in antipsychotics-associated OCS has not been reported. Herein, we presented a case of a 34-year-old male schizophrenia patient who experienced antipsychotics-associated OCS which could not be relieved by routine managements. He had fallen into dilemma of either aggravated OCS or poorly controlled schizophrenia. Eventually his condition got significant relief by individualized utilization of antipsychotics to control psychosis and by memantine to deal with his OCS. This is the first case to report the benefit of memantine in SGAs-associated OCS. It suggests that memantine is a worth considering approach, especially when the OCS are resistant to routine managements. Moreover, this case would be helpful for clinicians to know the etiology of SGAs-associated OCS, as indicated by the interesting changes after every adjustment of antipsychotics in the whole therapeutic course.

Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy.

Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti-MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.

Increased plasma leptin as a novel predictor for psychopathological depressive symptoms in chronic schizophrenia.

BACKGROUND: Depressive symptoms are often seen in schizophrenia. The overlap in presentation makes it difficult to distinguish depressive symptoms from the negative symptoms of schizophrenia. The adipokine leptin was found to be altered in both depression and schizophrenia. There are few studies focusing on the prediction of leptin in diagnosis and evaluation of depressive symptoms in schizophrenia. OBJECTIVEAIMS: To assess the plasma leptin level in patients with schizophrenia and its relationships with depressive symptoms. METHODS: Cross-sectional studies were applied to (1) compare the levels of plasma leptin between schizophrenia (n=74) and healthy controls (n=50); and (2) investigate the relationship between plasma leptin levels and depressive subscores. RESULTS: (1) Plasma leptin levels were significantly higher in patients with schizophrenia than in healthy controls. (2) Correlation analysis revealed a significant negative association between leptin levels and the depressed factor scores on the Positive and Negative Syndrome Scale (PANSS). (3) Stepwise multiple regression analyses identified leptin as an influencing factor for depressed factor score on PANSS. CONCLUSION: Leptin may serve as a predictor for the depressive symptoms of chronic schizophrenia.

The Interaction of TXNIP and AFq1 Genes Increases the Susceptibility of Schizophrenia.

Although previous studies showed the reduced risk of cancer in patients with schizophrenia, whether patients with schizophrenia possess genetic factors that also contribute to tumor suppressor is still unknown. In the present study, based on our previous microarray data, we focused on the tumor suppressor genes TXNIP and AF1q, which differentially expressed in patients with schizophrenia. A total of 413 patients and 578 healthy controls were recruited. We found no significant differences in genotype, allele, or haplotype frequencies at the selected five single nucleotide polymorphisms (SNPs) (rs2236566 and rs7211 in TXNIP gene; rs10749659, rs2140709, and rs3738481 in AF1q gene) between patients with schizophrenia and controls. However, we found the association between the interaction of TXNIP and AF1q with schizophrenia by using the MDR method followed by traditional statistical analysis. The best gene-gene interaction model identified was a three-locus model TXNIP (rs2236566, rs7211)-AF1q (rs2140709). After traditional statistical analysis, we found the high-risk genotype combination was rs2236566 (GG)-rs7211(CC)-rs2140709(CC) (OR = 1.35 [1.03-1.76]). The low-risk genotype combination was rs2236566 (GT)-rs7211(CC)-rs2140709(CC) (OR = 0.67 [0.49-0.91]). Our finding suggested statistically significant role of interaction of TXNIP and AF1q polymorphisms (TXNIP-rs2236566, TXNIP-rs7211, and AF1q-rs2769605) in schizophrenia susceptibility.

Guidelines concordance of maintenance treatment in euthymic patients with bipolar disorder: Data from the national bipolar mania pathway survey (BIPAS) in mainland China.

BACKGROUND: Although the treatment guidelines of bipolar disorders (BPD) have spread more than a decade, the concordance with evidence-based guidelines was typically low in routine clinical practice. This study is to present the data on the maintenance treatment of BPD in mainland China. METHODS: One thousand and twenty-three patients who had experienced a euthymia were eligible for entry into this survey on the maintenance treatment of BPD. Guidelines disconcordance was determined by comparing the medication(s) that patients were prescribed with the recommendations in the guidelines of the Canadian Network for Mood and Anxiety Treatments. RESULTS: Three hundred and sixty-four patients (35.6%) had not been prescribed with the maintenance treatment as guidelines recommendations, and 208 patients (20.3%) were prescribed with the antidepressants. A longer duration of BPD, a depressive episode at first onset, and a recent depressive or mixed episode significantly increased the risk for guidelines disconcordance and prescribing antidepressant. In contrast, a hospitalization history due to manic episode was associated with a significant decrease in the risk for guidelines disconcordance and prescribing antidepressant. LIMITATION: This study was a cross-sectional and retrospective investigation based on medical records. CONCLUSIONS: Considering the potentially hazardous effects of inappropriate treatment, individualized psychoeducational strategies for subjects with BPD are necessary to enhance treatment adherence and close the gap between guidelines and clinical practice in mainland China.

Pharmacotherapy for acute mania and disconcordance with treatment guidelines: bipolar mania pathway survey (BIPAS) in mainland China.

BACKGROUND: With the recent attention to evidence-based medicine in psychiatry, a number of treatment guidelines for bipolar disorders have been published. This survey investigated prescribing patterns and predictors for guideline disconcordance in the acute treatment of a manic and mixed episode across mainland China. METHODS: The pharmacological treatments of 2828 patients with a recent hypomanic/manic episode or mixed state were examined. Guidelines disconcordance was determined by comparing the medication(s) patients were prescribed with the recommendation(s) in the guidelines of the Canadian Network for Mood and Anxiety Treatments. RESULTS: The most common pattern of pharmacological treatments for an acute manic or mixed episode was a mood stabilizer plus an atypical antipsychotic (n = 1345, 47.6%), and the rate of guideline-disconcordant treatments was 11.1%. The patients who were treated in general hospitals were more likely to receive guideline-disconcordant treatments than those who were treated in psychiatric hospitals, with an OR of 1.84 (95% CI 1.44-2.36). Similarly, the patients with a mixed episode at study entry were more likely to receive guideline-disconcordant treatments than those with a manic episode, with an OR of 1.69 (95% CI 1.22-2.35). In contrast, the patients with a longer duration of disease (>5 years) were less likely to receive guideline-disconcordant treatments than those with a short duration, with an OR of 0.47 (95% CI 0.36-0.60). CONCLUSIONS: In mainland China, the disconcordance with treatment guidelines for a most recent acute manic or mixed episode was modest under naturalistic conditions. The higher risk for disconcordance in general hospitals than in psychiatric hospitals suggests that special education based on treatment guidelines to practitioners in general hospitals is necessary in order to reduce the risk for disconcordant treatments.

Guidelines disconcordance in acute bipolar depression: data from the national Bipolar Mania Pathway Survey (BIPAS) in mainland China.

With the recent attention to the importance of evidence-based medicine in psychiatry, a number of treatment guidelines have been published. This survey investigated prescribing pattern and predictors for guideline disconcordance in the acute treatment of bipolar depression across mainland China. Pharmacological treatments of 1078 patients with bipolar depression were examined. Guidelines disconcordance was determined by comparing the medication(s) patients were prescribed with the recommendation(s) in the guidelines of the Canadian Network for Mood and Anxiety Treatments. Predictors for guidelines discordance were analyzed with logistic regression. Of the 1078 patients, 50.2% patients were treated against treatment guidelines recommendations. The patients who were treated in general hospitals (OR = 1.53, 95% CI 1.18-1.97), with a depressive episode (OR = 1.67, 95% CI 1.27-2.19) and an older age at first onset (OR = 1.62, 95% CI 1.15-2.28) were more likely to receive guideline-disconcordant treatment than their counterparts. In contrast, the patients with current mental comorbidity, an older age at study entry, a longer duration of disease, and more frequent episodes in past year were less likely to receive guideline-disconcordant treatments than their counterparts with an OR of 0.43 (95% CI 0.24-0.77), 0.52 (95CI% 0.36-0.75), 0.48 (95% CI 0.36-0.65), and 0.50 (95% CI 0.38-0.64), respectively. Our finding suggested the disconcordance with treatment guidelines in patients with an acute bipolar depression is common under naturalistic conditions in mainland China, and the predicting factors correlated with guidelines disconcordance include both psychiatrist-specific (clinicians from general hospitals) and patient-specific features (a depressive episode at first onset, no current co-morbidity with mental disorders, a younger age at study entry, an older age at first onset, shorter duration of disease, and non-frequent episodes in past year).

The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia.

The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2) is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia) and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445) and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445) and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605), in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605) may be involved in the susceptibility to paranoid schizophrenia.

MK-801 induces schizophrenic behaviors through downregulating Wnt signaling pathways in male mice.

Wnt signaling is important in various neuropsychiatric diseases. However, its actions on modulating schizophrenia are largely unknown. Our previous study found that three SNPs in adenomatous polyposis coli (APC), a negative regulator of the Wnt signaling, were associated with schizophrenia, and the mRNA levels of APC in blood leucocytes of patients with schizophrenia were significantly increased. This prompted us to further investigate the effects of Wnt signaling components on the pathogenesis of schizophrenia. In our current study, mouse schizophrenia was induced by i.p. injection of MK-801 for 7days and the brain prefrontal cortex (PFC) and ventral tegmental area (VTA) were isolated to investigate the Wnt signaling pathway. Compared with control, schizophrenic mice had increased inhibitory phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) in PFC and VTA, which is disassociated with augmented beta-catenin phosphorylation. However, APC mRNA and protein in the PFC and VTA isolated from the schizophrenic group were increased and matched with increased beta-catenin phosphorylation. The total dendritic length was significantly increased in both PFC and VTA from MK-801-treated mice compared to control. By using cultured SK-N-SH and PC12 cells with and without transfection of APC siRNA, we found that the APC protein facilitates neurite growth in vitro. Our data suggested that MK-801-induced schizophrenia is associated with attenuated Wnt signaling pathway in the brain, which may be due to augmented APC protein during schizophrenia. APC facilitates neurite growth, potentially contributing to the pathology of schizophrenia.