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Bacterial dysbiosis has been demonstrated in patients with schizophrenia (SCH). The aim of the present study was to investigate alterations in mycobiota composition and fungi-bacteria correlation network in drug-naïve, first episode SCH. We recruited 205 SCH patients and 125 healthy controls (HCs), whose gut bacterial and fungal compositions were characterized by 16S and 18S ribosomal RNA gene amplicon sequencing, respectively. Fungal-bacterial relative correlation network analysis was performed using the Spearman's test and distance correlation. We also computed relative networks connectedness, which represents the ratio of significant interactions (edges) and taxa (nodes) in the network. SCH patients showed lower fungal α-diversity compared with that of HCs. Furthermore, we identified 29 differential fungal markers at multiple taxonomies between SCH patients and HCs. SCH patients also showed a significantly lower fungi-to-bacteria α-diversity ratio compared with that of HCs (p = 1.81 × 10

Background and Hypothesis Schizophrenia (SCZ) is associated with complex crosstalk between the gut microbiota and host metabolism, but the underlying mechanism remains elusive. Investigating the aberrant neurotransmitter processes reflected by alterations identified using multiomics analysis is valuable to fully explain the pathogenesis of SCZ. Study Design We conducted an integrative analysis of multiomics data, including the serum metabolome, fecal metagenome, single nucleotide polymorphism data, and neuroimaging data obtained from a cohort of 127 drug-naïve, first-episode SCZ patients and 92 healthy controls to characterize the microbiome–gut–brain axis in SCZ patients. We used pathway-based polygenic risk score (PRS) analyses to determine the biological pathways contributing to genetic risk and mediation effect analyses to determine the important neuroimaging features. Additionally, a random forest model was generated for effective SCZ diagnosis. Study Results We found that the altered metabolome and dysregulated microbiome were associated with neuroactive metabolites, including gamma-aminobutyric acid (GABA), tryptophan, and short-chain fatty acids. Further structural and functional magnetic resonance imaging analyses highlighted that gray matter volume and functional connectivity disturbances mediate the relationships between Ruminococcus_torgues and Collinsella_aerofaciens and symptom severity and the relationships between species Lactobacillus_ruminis and differential metabolites l-2,4-diaminobutyric acid and N-acetylserotonin and cognitive function. Moreover, analyses of the Polygenic Risk Score (PRS) support that alterations in GABA and tryptophan neurotransmitter pathways are associated with SCZ risk, and GABA might be a more dominant contributor. Conclusions This study provides new insights into systematic relationships among genes, metabolism, and the gut microbiota that affect brain functional connectivity, thereby affecting SCZ pathogenesis.

Objective Cognitive symptoms are associated with significant dysfunction in schizophrenia. Oxidative stress and inflammation involving histone deacetylase (HDAC) have been implicated in the pathophysiology of schizophrenia. Sulforaphane has antioxidant properties and is an HDAC inhibitor. The objective of this study was to determine the efficacy of sulforaphane on cognition dysfunction for patients with schizophrenia. Methods This double-blind randomized 22-week trial of patients with first-episode schizophrenia was conducted in four psychiatric institutions in China. Patients were randomized to three groups (two doses of sulforaphane vs. placebo) and symptomatic and cognitive assessments were completed at multiple times. The primary outcome measure was change in the MATRICS Composite score. The secondary outcomes were change in MATRICS Domain scores, PANSS Total Scores and change in side-effects. Results A total of 172 patients were randomized and 151 patients had at least one follow up evaluation. There were no significant effects of sulforaphane, on the primary outcome, MATRICS overall composite score. However, on secondary outcomes, sulforaphane did significantly improve performance scores on MATRICS battery Domains of spatial working memory (F = 5.68, P = 0.004), reasoning-problem solving (F = 2.82, P = 0.063), and verbal learning (F = 3.56, P = 0.031). There were no effects on PANSS symptom scores. Sulforaphane was well tolerated. Conclusion Although the primary outcome was not significant, improvement in three domains of the MATRICS battery, suggests a positive cognitive effect on some cognitive functions, which warrants further clinical trials to further assess whether sulforaphane may be a useful adjunct for treating some types of cognitive deficits in schizophrenia.

Brain-derived neurotrophic factor (BDNF) may be related to the pathophysiology of schizophrenia. This study aims to examine the relation between plasma BDNF levels and the cognition of patients with schizophrenia. We recruited 31 patients with chronic schizophrenia, 34 first-episode patients, and 35 healthy control subjects. We examined the MATRICS Consensus Cognitive Battery (MCCB) and the plasma BDNF levels in all groups. The schizophrenic symptoms were assessed using the positive and negative syndrome scale. The BDNF levels of schizophrenic patients were remarkably lower than those of the controls. The cognitive MCCB global composite scores and part index scores of schizophrenic patients were remarkably lower than those of the controls. Moreover, remarkable correlations were observed between BDNF levels and partial cognitive dimensions, such as visual learning, memory, and processing speed. Therefore, BDNF may be involved in the pathophysiology and cognitive impairment of schizophrenia.

Patients with schizophrenia consistently present pervasive cognitive deficits, but the neurobiological mechanism of cognitive impairments remains unclear. By analyzing regional homogeneity (ReHo) of resting-state functional Magnetic Resonance Imaging, this study aimed to explore the association between brain functional alterations and cognitive deficits in first-episode schizophrenia (FES) with a relatively large sample.A total of 187 patients with FES and 100 healthy controls from 3 independent cohorts underwent resting-state functional magnetic resonance scans. The MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognitive function. Partial correlation analysis was performed between abnormal ReHo values and the severity of symptoms and cognitive deficits.Compared with healthy controls, ReHo values increased in right superior frontal cortex and decreased in right anterior cingulate cortex (ACC), left middle occipital gyrus (MOG), left cuneus, right posterior cingulate cortex (PCC), and right superior occipital gyrus in schizophrenia patients. ReHo values in ACC, PCC and superior occipital gyrus were correlated with PANSS scores. In addition, ReHo values in ACC and MOG were negatively correlated with working memory; left cuneus was positively correlated with multiple cognitive domains (speed of processing, attention/vigilance and social cognition); PCC was positively correlated with verbal learning; right superior occipital gyrus was positively correlated with speed of processing and social cognition.In conclusion, we found widespread ReHo alterations and cognitive dysfunction in FES. And the pathophysiology mechanism of a wide range of cognitive deficits may be related to abnormal spontaneous brain activity.

Background: Schizophrenia is a severe mental disease which characterized by positive symptom, negative symptom, general pathology syndrome and cognitive deficits. In recent years, many studies have investigated the relationship between cognitive deficits and clinical characteristics in schizophrenia, but relatively few studies have been performed on first-episode drug-naïve patients.Methods: Eighty seven first-episode drug-naïve schizophrenia patients were assessed for positive symptom, negative symptom, general pathology symptom and cognitive deficits from the Positive and Negative Symptom Scale and MATRICS Consensus Cognitive Battery. Psychotics depression were assessed using the Calgary depressing scale for schizophrenia. The relationship between clinical characteristics and cognitive deficits were assessed using correlation analysis and linear regression analysis.Results: The prevalence of cognitive deficits among the patients in our study was 85.1% (74/87) which was much higher than that in the general population. According to correlation analysis, negative symptom was negatively correlated with speed of processing and social cognition, and general pathology showed a negative correlation with attention/vigilance. In addition, a positive correlation was found between age and speed of processing. No correlation was found between cognitive deficits and positive symptom.Conclusions: This study confirmed that negative symptom is negatively related with some domains of cognitive function in first-episode drug naïve schizophrenia patients.Trail Registration: NCT02880462. Registered August 26, 2016.

Introduction: Affecting ~1% of the world population, schizophrenia is known as one of the costliest and most burdensome diseases worldwide. Antipsychotic medications are the main treatment for schizophrenia to control psychotic symptoms and efficiently prevent new crises. However, due to poor compliance, 74% of patients with schizophrenia discontinue medication within 1.5 years, which severely affects recovery and prognosis. Through research on intra and interindividual variability based on a psychopathology–neuropsychology–neuroimage–genetics–physiology-biochemistry model, our main objective is to investigate an optimized and individualized antipsychotic-treatment regimen and precision treatment for first-episode schizophrenic patients.Methods and Analysis: The study is performed in 20 representative hospitals in China. Three subprojects are included. In subproject 1, 1,800 first-episode patients with schizophrenia are randomized into six different antipsychotic monotherapy groups (olanzapine, risperidone, aripiprazole, ziprasidone, amisulpride, and haloperidol) for an 8-week treatment. By identifying a set of potential biomarkers associated with antipsychotic treatment response, we intend to build a prediction model, which includes neuroimaging, epigenetics, environmental stress, neurocognition, eye movement, electrophysiology, and neurological biochemistry indexes. In subproject 2, apart from verifying the prediction model established in subproject 1 based on an independent cohort of 1,800 first-episode patients with schizophrenia, we recruit patients from a verification cohort who did not get an effective response after an 8-week antipsychotic treatment into a randomized double-blind controlled trial with minocycline (200 mg per day) and sulforaphane (3 tables per day) to explore add-on treatment for patients with schizophrenia. Two hundred forty participants are anticipated to be enrolled for each group. In subproject 3, we tend to carry out one trial to construct an intervention strategy for metabolic syndrome induced by antipsychotic treatment and another one to build a prevention strategy for patients at a high risk of metabolic syndrome, which combines metformin and lifestyle intervention. Two hundred participants are anticipated to be enrolled for each group.Ethics and Dissemination: The study protocol has been approved by the Medical Ethics committee of the Second Xiangya Hospital of Central South University (No. 2017027). Results will be disseminated in peer-reviewed journals and at international conferences.Trial Registration: This trial has been registered on Clinicalrials.gov (NCT03451734). The protocol version is V.1.0 (April 23, 2017).

Antipsychotic medication is the primary treatment for schizophrenia, which is effective on ameliorating positive symptoms and can reduce the risk of recurrence, but it has limited efficacy for negative symptoms and cognitive dysfunction. The negative symptoms and cognitive dysfunction seriously affects the life quality and social function for the patients with schizophrenia. Currently, there is plenty evidence that antipsychotic drugs combined with adjuvant therapy drugs can effectively improve the negative symptoms and cognitive dysfunction. These drugs include anti-oxidants, nicotinic acetylcholine receptors and neuro-inflammatory drugs (anti-inflammatory drugs, minocycline), which show potential clinical effects.抗精神病药物是治疗精神分裂症的主要方法，可有效缓解阳性症状和减少复发风险，但对阴性症状和认知功能障碍的临床疗效有限，而阴性症状和认知功能障碍严重影响精神分裂症患者的社会功能和生活质量。目前有较多的研究支持抗精神病药物联合辅助治疗药物可有效改善阴性症状和认知功能障碍。其中，作用于氧化应激、烟碱能乙酰胆碱受体和神经炎症的药物(抗炎药、米诺环素)有潜在的临床疗效。.

IntroductionMany patients with frontal brain damage show serious cognitive function deficits, which hamper their quality of life and result in poor clinical outcomes. Preclinical research has shown that sulforaphane can significantly improve spatial localisation and working memory impairment after brain injury. The primary aim of this double-blind randomised controlled clinical trial is to assess the efficacy of sulforaphane for improving cognitive function in patients with frontal brain damage.Methods and analysisNinety eligible patients will be randomly allocated to an active treatment or a placebo group in a 2:1 ratio. Participants will undergo a series of cognitive and neuropsychiatric tests at baseline (week 0) and after 12 weeks to determine the effect of sulforaphane on cognition. Magnetic resonance spectrum of the brain will be studied using the 3T MRIs of the brain to detect brain metabolites markers, including N-acetyl aspartate, glutamate (Glu), glutathione (GSH) and γ-aminobutyric acid (GABA). Blood brain-derived neurotrophic factor, Glu, GSH and GABA levels and gut microbiota will also be assessed over this period. This study will also evaluate long-term outcomes of brain trauma, brain tumours and cerebrovascular disease via exploratory analyses. The primary outcome will be the difference in scores of a battery of cognitive tests after 12 weeks of sulforaphane treatment. The secondary outcomes will be changes in the Functional Activities Questionnaire (FAQ), the Patient Health Questionnaire (PHQ-9), the Self-Rating Anxiety Scale, the changes in T1-weighted MRI and resting-state functional MRI findings, and changes in brain and blood metabolic markers and gut microbiota at weeks 0 and 12. We expect that sulforaphane will yield favourable results in treating memory and learning deficits for patients with frontal brain damage. Cognitive functional treatment may also improve brain trauma, brain tumours and cerebrovascular outcomes.Ethics and disseminationThe study protocol has been approved by the Medical Ethics committee of the Xiangya Hospital of Central South University (No. 2017121019). The results will be disseminated in peer-reviewed journals and at international conferences.Trial registration numberThis trial was registered on Clinicaltrials.gov on 31 January 2020 (NCT04252261). The protocol version is V.1.0 (20 December 2019).

This study was to examine the alterations in metabolic parameters, anti-oxidant superoxide dismutase (SOD), inflammatory marker high-sensitivity C-reactive protein (hs-CRP) and microbiota after 24-week risperidone treatment in drug naïve, normal weight, first episode schizophrenia patients; the study further examined the relationship between metabolic changes and changes in microbiota.Forty-one patients completed the 24-week study and 41 controls were enrolled in this study. Metabolic parameters, SOD, hs-CRP and the copy numbers of 5 fecal bacteria were measured at baseline (both groups) and at different time points (patients only).Patients had significantly lower numbers of fecal Bifidobacterium spp., Escherichia coli, Lactobacillus spp. compared with healthy controls (HC) (ps 0.001); in contrast, the numbers of fecal Clostridium coccoides group were significantly higher in the patient group compared with HC (p 0.001). After 24-week risperidone treatment, there were significant increases in body weight, BMI, fasting blood-glucose, triglycerides, LDL, hs-CRP, SOD and HOMA-IR (p 0.001), significant increases in the numbers of fecal Bifidobacterium spp. and E. coli (ps 0.001), and significant decreases in the numbers of fecal Clostridium coccoides group and Lactobacillus spp. (ps 0.001). Hierarchical multiple linear regression analysis shows that after controlling for potential confounding variables, only the changes in fecal Bifidobacterium spp., among 4 types of fecal bacteria, entered into the model and significantly correlated with the changes in weight (unstandardized coefficient B = 4.413, RDrug naïve, first episode schizophrenia patients show abnormalities in microbiota composition. Risperidone treatment causes significant changes in certain fecal bacteria, which are likely associated with antipsychotic medication induced metabolic changes.

The negative symptoms and cognitive symptoms of schizophrenia patients are still clinical problems to be solved. Schizophrenia patients are abnormal in oxidative stress, immune regulation, and anti-histone deacetylase (HDAC), while sulforaphane plays a role in anti-oxidative stress, anti-inflammation, and anti-HDAC. Therefore, the sulforaphane could improve the negative symptoms and cognitive deficits of schizophrenia.精神分裂症患者的阴性症状与认知缺陷的治疗仍然是临床难题。精神分裂症患者存在氧化应激、免疫调节、抗组蛋白去乙酰化酶(histone deacetylase，HDAC)等方面的异常，而萝卜硫素具有抗氧化应激、抗炎、抗HDAC等作用。因此，萝卜硫素可能通过上述作用改善精神分裂症的阴性症状及认知缺陷。.

To explore the association between serum concentrations of folic acid and homocysteine (HCY), 5, 10-methylenetetrahydrofolate reductase (MTHFR) C667T polymorphism and schizophrenia.A total of 130 schizophrenics (schizophrenia group) from our hospital and 80 healthy individuals (control group) were enrolled. The serum concentration of homocysteine was measured by the electrochemical luminescence method, the concentration of serum folic acid by enzymatic cycling assay and MTHFR C667T genotype by PCR-DNA microarray. And positive and negative syndrome scale (PANSS) was used to evaluate the mental symptoms.(1) Serum HCY level in schizophrenia group was higher than that in control group [(20 ± 10) vs (11 ± 3) µmol/L; P0.001] while serum folate level in schizophrenia group was lower than that in control group [(6 ± 4) vs (9 ± 3) ng/ml; P0.001]; (2) the frequencies of CC, CT and TT in MTHFR C677T alleles were 13.1%, 50.0% and 36.9% in schizophrenia group versus 30.0%, 47.5% and 22.5% in control group respectively. Statistical significant inter-group difference existed in the frequencies of genotypes (χ² = 36.806, P0.05) . The frequencies of T and C alleles were 61.9%, 38.1% in schizophrenia group versus 46.25%, 53.75% in control group respectively. Statistical significant inter-group difference existed in the frequency of T allele (χ² = 9.872, P0.05). The frequency of TT genotype in schizophrenia group was 61.9% versus 22.5% in control group. Statistically significant inter-group difference existed in the frequency of TT homozygous mutation (χ² = 4.780, P0.05); (3) correlation analysis showed that serum folate level in schizophrenia group had a negative correlation with HCY level (r = -0.418, P0.001) . Serum HCY level had a positive correlation with negative symptoms scores (r = 0.345, P0.001) and serum folate level was negatively correlated with negative symptoms scores (r = -0.386, P0.001); (4) the serum HCY level in schizophrenia group with TT genotype was significantly higher than those with CC and CT genotypes (P0.05).There is a certain correlation between the serum levels of folate and HCY and the symptoms of schizophrenia. And MTHFR C677T polymorphism is a possible risk factor for schizophrenia.