APOA-I: a possible novel biomarker for metabolic side effects in first episode schizophrenia

The purpose of this study was to investigate the change in plasma protein expression in first episode schizophrenia after an 8-week treatment with risperidone, and to explore potential biomarkers for metabolic side effects associated with risperidone treatment. Eighty first-episode schizophrenia patientswere enrolled in the study. Fifteen of the 80 patients were randomly selected to undergo proteomic analysis. Plasma proteins were obtained before and after the 8-week risperidone treatment, and measured using two-dimensional gel electrophoresis (2-DE), Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry(MALDI-TOF/TOF) and peptide mass fingerprinting.Proteins with the highest fold changes after risperidone treatment were then measured for all 80 patients using enzyme linked immunosorbent assay (ELISA). The relationship between changes in plasma protein levels and changes in metabolic parameters after risperidone treatment was examined. In 15 randomly selected patients, approximately 1,500 protein spots were detected in each gel by 2-DE. Of those proteins, 22 spots showed significant difference in abundance after risperidone treatment (p\u27s \u3c 0.05). After MALDI-TOF peptide mass fingerprinting, apolipoprotein A-I (APOA-I) and Guanine Nucleotide Binding Protein, Alpha Stimulating (GNAS), were found to have the highest fold changes.The content of APOA-I was significantly increased, and the content of GNAS was significantly decreased after risperidone treatment (p\u27s\u3c0.05). The analysis in the entire study sample showed similar findings in changes of APOA-I and GNAS after risperidone treatment. Further analysis showed significant relationships between changesin APOA-1 and changes in triglyceride, total cholesterol, and body mass index after controlling for age, gender and family history of diabetes. Similar analysis showed a trend positive relationship between changes in GNAS and changes in BMI. Using proteomic analysis, the study suggested that APOA-I might be a novel biomarkers related to metabolic side effects in first episode schizophrenia treated with risperidone

The nuclear factor-κB inhibitor pyrrolidine dithiocarbamate reduces polyinosinic-polycytidilic acid-induced immune response in pregnant rats and the behavioral defects of their adult offspring

<p>Abstract</p> <p>Background</p> <p>Epidemiological studies have indicated that maternal infection during pregnancy may lead to a higher incidence of schizophrenia in the offspring. It is assumed that the maternal infection increases the immune response, leading to neurodevelopmental disorders in the offspring. Maternal polyinosinic-polycytidilic acid (PolyI:C) treatment induces a wide range of characteristics in the offspring mimicking some schizophrenia symptoms in humans. These observations are consistent with the neurodevelopmental hypothesis of schizophrenia.</p> <p>Methods</p> <p>We examined whether suppression of the maternal immune response could prevent neurodevelopmental disorders in adult offspring. PolyI:C or saline was administered to early pregnant rats to mimic maternal infection, and the maternal immune response represented by tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) levels was determined by enzyme-linked immunosorbent assays (ELISA). The NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) was used to suppress the maternal immune response. Neurodevelopmental disorders in adult offspring were examined by prepulse inhibition (PPI), passive avoidance, and active avoidance tests.</p> <p>Results</p> <p>PolyI:C administration to early pregnant rats led to elevated serum cytokine levels as shown by massive increases in serum TNF-α and IL-10 levels. The adult offspring showed defects in prepulse inhibition, and passive avoidance and active avoidance tests. PDTC intervention in early pregnant rats suppressed cytokine increases and reduced the severity of neurodevelopmental defects in adult offspring.</p> <p>Conclusions</p> <p>Our findings suggest that PDTC can suppress the maternal immune response induced by PolyI:C and partially prevent neurodevelopmental disorders of adult offspring.</p

Fat-mass and obesity-associated gene polymorphisms and weight gain after risperidone treatment in first episode schizophrenia

BACKGROUND: Obesity induced by antipsychotics severely increases the risk of many diseases and significantly reduces quality of life. Genome Wide Association Studies has identified fat-mass and obesity-associated (FTO) gene associated with obesity. The relationship between the FTO gene and drug-induced obesity is unclear. METHOD: Two hundred and fifty drug naive, Chinese Han patients with first-episode schizophrenia were enrolled in the study, and genotyped for four single nucleotide polymorphisms (SNPs rs9939609, rs8050136, rs1421085 and rs9930506) by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing. Body weight and body mass index (BMI) were measured at baseline and six months after risperidone treatment. RESULTS: At baseline, body weight and BMI of TT homozygotes were lower than those of A allele carriers in rs9939609; body weight of AA homozygotes was higher than those of G allele carriers in rs9930506 (p\u27s \u3c 0.05). After 6 months of risperidone treatment, body weight and BMI of TT homozygotes were lower than those of A allele carriers in rs9939609 (p\u27s \u3c 0.01); body weight and BMI of CC homozygotes were lower than those of A allele carriers in rs8050136 (p\u27s \u3c 0.05); body weight of AA homozygotes was higher than those of G allele carriers in rs9930506 (p\u27s \u3c 0.05). After controlling for age, gender, age of illness onset, disease duration, weight at baseline and education, weight gain of TT homozygotes at 6 months remained to be lower than those of A allele carriers in rs9939609 (p \u3c 0.01); weight gain of CC homozygotes at 6 months was lower than those of A allele carriers in rs8050136 (p = 0.01). Stepwise multiple regression analysis suggested that, among 4 SNPs, rs9939609 was the strongest predictor of weight gain after 6 months of risperidone treatment (p = 0.001). CONCLUSIONS: The FTO gene polymorphisms, especially rs9939609, seem to be related to weight gain after risperidone treatment in Chinese Han patients with first episode schizophrenia

Association between Ghrelin gene (GHRL) polymorphisms and clinical response to atypical antipsychotic drugs in Han Chinese schizophrenia patients

<p>Abstract</p> <p>Background</p> <p>Ghrelin (<it>GHRL</it>) is a pivotal peptide regulator of food intake, energy balance, and body mass. Weight gain (WG) is a common side effect of the atypical antipsychotics (AAPs) used to treat schizophrenia (SZ). Ghrelin polymorphisms have been associated with pathogenic variations in plasma lipid concentrations, blood pressure, plasma glucose, and body mass index (BMI). However, it is unclear whether <it>GHRL </it>polymorphisms are associated with WG due to AAPs. Furthermore, there is no evidence of an association between <it>GHRL </it>polymorphisms and SZ or the therapeutic response to AAPs. We explored these potential associations by genotyping <it>GHRL </it>alleles in SZ patients and controls. We also examined the relation between these SNPs and changes in metabolic indices during AAP treatment in SZ subgroups distinguished by high or low therapeutic response.</p> <p>Methods</p> <p>Four SNPs (Leu72Met, -501A/C, -604 G/A, and -1062 G > C) were genotyped in 634 schizophrenia patients and 606 control subjects.</p> <p>Results</p> <p>There were no significant differences in allele frequencies, genotype distributions, or the distributions of two SNP haplotypes between SZ patients and healthy controls (<it>P </it>> 0.05). There was also no significant difference in symptom reduction between genotypes after 8 weeks of AAP treatment as measured by positive and negative symptom scale scores (PANSS). However, the -604 G/A polymorphism was associated with a greater BMI increase in response to AAP administration in both APP responders and non-responders as distinguished by PANSS score reduction (<it>P </it>< 0.001). There were also significant differences in WG when the responder group was further subdivided according to the specific AAP prescribed (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>These four <it>GHRL </it>gene SNPs were not associated with SZ in this Chinese Han population. The -604 G/A polymorphism was associated with significant BW and BMI increases during AAP treatment. Patients exhibiting higher WG showed greater improvements in positive and negative symptoms than patients exhibiting lower weight gain or weight loss.</p

Decreased Functional Connectivity of Insular Cortex in Drug Naive First Episode Schizophrenia: In Relation to Symptom Severity

BACKGROUND: This study was to examine the insular cortical functional connectivity in drug naive patients with first episode schizophrenia and to explore the relationship between the connectivity and the severity of clinical symptoms. METHODS: Thirty-seven drug naive patients with schizophrenia and 25 healthy controls were enrolled in this study. A seed-based approach was used to analyze the resting-state functional imaging data. Insular cortical connectivity maps were bilaterally extracted for group comparison and validated by voxel-based morphometry (VBM) analysis. Clinical symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). RESULTS: There were significant reductions in the right insular cortical connectivity with the Heschl\u27s gyrus, anterior cingulate cortex (ACC), and caudate (p\u27s \u3c 0.001) in the patient group compared with the healthy control (HC) group. Reduced right insular cortical connectivity with the Heschl\u27s gyrus was further confirmed in the VBM analysis (FDR corrected p \u3c 0.05). Within the patient group, there was a significant positive relationship between the right insula-Heschl\u27s connectivity and PANSS general psychopathology scores (r = 0.384, p = 0.019). CONCLUSION: Reduced insula-Heschl\u27s functional connectivity is present in drug naive patients with first episode schizophrenia, which might be related to the manifestation of clinical symptoms

Gut microbial biomarkers for the treatment response in first-episode, drug-naive schizophrenia: a 24-week follow-up study

Preclinical studies have shown that the gut microbiota can play a role in schizophrenia (SCH) pathogenesis via the gut-brain axis. However, its role in the antipsychotic treatment response is unclear. Here, we present a 24-week follow-up study to identify gut microbial biomarkers for SCH diagnosis and treatment response, using a sample of 107 first-episode, drug-naive SCH patients, and 107 healthy controls (HCs). We collected biological samples at baseline (all participants) and follow-up time points after risperidone treatment (SCH patients). Treatment response was assessed using the Positive and Negative Symptoms Scale total (PANSS-T) score. False discovery rate was used to correct for multiple testing. We found that SCH patients showed lower alpha-diversity (the Shannon and Simpson\u27s indices) compared to HCs at baseline (p = 1.21 x 10(-9), 1.23 x 10(-8), respectively). We also found a significant difference in beta-diversity between SCH patients and HCs (p = 0.001). At baseline, using microbes that showed different abundance between patients and controls as predictors, a prediction model can distinguish patients from HCs with an area under the curve (AUC) of 0.867. In SCH patients, after 24 weeks of risperidone treatment, we observed an increase of alpha-diversity toward the basal level of HCs. At the genus level, we observed decreased abundance of Lachnoclostridium (p = 0.019) and increased abundance Romboutsia (p = 0.067). Moreover, the treatment response in SCH patients was significantly associated with the basal levels of Lachnoclostridium and Romboutsia (p = 0.005 and 0.006, respectively). Our results suggest that SCH patients may present characteristic microbiota, and certain microbiota biomarkers may predict treatment response in this patient population

Solute Carrier Family 1 (SLC1A1) Contributes to Susceptibility and Psychopathology Symptoms of Schizophrenia in the Han Chinese Population

Objective: Schizophrenia (SZ) is a common and complex psychiatric disorder that has a significant genetic component. The glutamate hypothesis describes one possible pathogenesis of SZ. The solute carrier family 1 gene (SLC1A1) is one of several genes thought to play a critical role in regulating the glutamatergic system and is strongly implicated in the pathophysiology of SZ. In this study, we identify polymorphisms of the SLC1A1 gene that may confer susceptibility to SZ in the Han Chinese population. Methods: We genotyped 36 single-nucleotide polymorphisms (SNPs) using Illumina GoldenGate assays on a BeadStation 500G Genotyping System in 528 paranoid SZ patients and 528 healthy controls. Psychopathology was rated by the Positive and Negative Symptom Scale. Results: Significant associations were found in genotype and allele frequencies for SNPs rs10815017 (p = 0.002, 0.030, respectively) and rs2026828 (p = 0.020, 0.005, respectively) between SZ and healthy controls. There were significant associations in genotype frequency at rs6476875 (p = 0.020) and rs7024664 (p = 0.021) and allele frequency at rs3780412 (p = 0.026) and rs10974573 (p = 0.047) between SZ and healthy controls. Meanwhile, significant differences were found in genotype frequency at rs10815017 (p = 0.015), rs2026828 (p = 0.011), and rs3780411 (p = 0.040) in males, and rs7021569 in females (p = 0.020) between cases and controls when subdivided by gender. Also, significant differences were found in allele frequency at rs2026828 (p = 0.003), and rs7021569 (p = 0.045) in males, and rs10974619 in females (p = 0.044). However, those associations disappeared after Bonferroni\u27s correction (p\u27s \u3e 0.05). Significant associations were found in the frequencies of four haplotypes (AA, CA, AGA, and GG) between SZ and healthy controls (chi (2) = 3.974, 7.433, 4.699, 4.526, p = 0.046, 0.006, 0.030, 0.033, respectively). There were significant associations between rs7032326 genotypes and PANSS total, positive symptoms, negative symptoms, and general psychopathology in SZ (p = 0.002, 0.011, 0.028, 0.008, respectively). Conclusion: The present study provides further evidence that SLC1A1 may be not a susceptibility gene for SZ. However, the genetic variations of SLC1A1 may affect psychopathology symptoms

Aberrant Dynamic Functional Network Connectivity and Graph Properties in Major Depressive Disorder

Major depressive disorder (MDD) is a complex mood disorder characterized by persistent and overwhelming depression. Previous studies have identified abnormalities in large scale functional brain networks in MDD, yet most of them were based on static functional connectivity. In contrast, here we explored disrupted topological organization of dynamic functional network connectivity (dFNC) in MDD based on graph theory. One hundred and eighty-two MDD patients and 218 healthy controls were included in this study, all Chinese Han people. By applying group information guided independent component analysis (GIG-ICA) to resting-state functional magnetic resonance imaging (fMRI) data, the dFNCs of each subject were estimated using a sliding window method and k-means clustering. Network properties including global efficiency, local efficiency, node strength and harmonic centrality, were calculated for each subject. Five dynamic functional states were identified, three of which demonstrated significant group differences in their percentage of state occurrence. Interestingly, MDD patients spent much more time in a weakly-connected State 2, which includes regions previously associated with self-focused thinking, a representative feature of depression. In addition, the FNCs in MDD were connected differently in different states, especially among prefrontal, sensorimotor, and cerebellum networks. MDD patients exhibited significantly reduced harmonic centrality primarily involving parietal lobule, lingual gyrus and thalamus. Moreover, three dFNCs with disrupted node properties were commonly identified in different states, and also correlated with depressive symptom severity and cognitive performance. This study is the first attempt to investigate the dynamic functional abnormalities in MDD in a Chinese population using a relatively large sample size, which provides new evidence on aberrant time-varying brain activity and its network disruptions in MDD, which might underscore the impaired cognitive functions in this mental disorder

Common and Specific Functional Activity Features in Schizophrenia, Major Depressive Disorder, and Bipolar Disorder

Objectives: Schizophrenia (SZ), major depressive disorder (MDD), and bipolar disorder (BD) are serious mental disorders with distinct diagnostic criteria. They share common clinical and biological features. However, there are still only few studies on the common and specific brain imaging changes associated with the three mental disorders. Therefore, the aim of this study was to identify the common and specific functional activity and connectivity changes in SZ, MDD, and BD.Methods: A total of 271 individuals underwent functional magnetic resonance imaging: SZ (n = 64), MDD (n = 73), BD (n = 41), and healthy controls (n = 93). The symptoms of SZ patients were evaluated by the Positive and Negative Syndrome Scale. The Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI) were used to evaluate the symptoms of MDD patients. The BDI, BAI, and Young Mania Rating Scale were used to evaluate the symptoms of MDD and BD patients. In addition, we compared the fALFF and functional connectivity between the three mental disorders and healthy controls using two sample t-tests.Results: Significantly decreased functional activity was found in the right superior frontal gyrus, middle cingulate gyrus, left middle frontal gyrus, and decreased functional connectivity (FC) of the insula was found in SZ, MDD, and BD. Specific fALFF changes, mainly in the ventral lateral pre-frontal cortex, striatum, and thalamus were found for SZ, in the left motor cortex and parietal lobe for MDD, and the dorsal lateral pre-frontal cortex, orbitofrontal cortex, and posterior cingulate cortex in BD.Conclusion: Our findings of common abnormalities in SZ, MDD, and BD provide evidence that salience network abnormality may play a critical role in the pathogenesis of these three mental disorders. Meanwhile, our findings also indicate that specific alterations in SZ, MDD, and BD provide neuroimaging evidence for the differential diagnosis of the three mental disorders