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Background: Two distinct subtypes of treatment-resistant schizophrenia (TRS) have been recently reported, including early-treatment resistance (E-TR) as the dominant subtype and late-treatment resistance (L-TR). However, the response rate to clozapine, incidence of clozapine-induced prediabetes/diabetes, and effects of metformin at preventing clozapine-induced prediabetes/diabetes in patients with schizophrenia E-TR subtype need investigating. To assess clozapine-induced metformin-resistant prediabetes/diabetes and its correlation with clinical efficacy in schizophrenia E-TR subtype. Methods: This prospective cohort study enrolled 230 patients with schizophrenia E-TR subtype from Tianjin Kangtai Hospital between January 2015 and December 2020.The patients were treated with adequate doses of clozapine for 16 weeks, during which patients with prediabetes/diabetes were assigned to receive add-on metformin. Incidence of clozapine-induced prediabetes/diabetes and metformin-resistant prediabetes/diabetes and the efficacy of clozapine as assessed by the Positive and Negative Syndrome Scale (PANSS) score. Findings: Clozapine-induced prediabetes/diabetes occurred in 176 patients (170 prediabetes and 6 diabetes), with 76.52% incidence. The blood sugar of 43 (24.43%) patients was controlled with metformin. Despite add-on metformin, 47.06% (74/170) of patients with clozapine-induced prediabetes progressed to diabetes. In total, the incidence of clozapine-induced metformin-resistant prediabetes/diabetes was 75.57% (133/176). On completion of 16-week clozapine treatment, 16.52% (38/230) patients showed clinical improvement with PANSS scores of ≥50% declining. Furthermore, clozapine-induced prediabetes/diabetes was significantly correlated with the poor clinical efficacy of clozapine for schizophrenia E-TR subtype. In comparison with patients that did not have clozapine-induced prediabetes/diabetes, clinical efficacy was significantly lower in patients with clozapine-induced prediabetes/diabetes. Of note, the lowest clinical efficacy detected in patients with clozapine-induced diabetes [odds ratio (OR) of 0.18; 95% confidence interval (CI), 0.07–0.44]. Interpretation: The incidence of clozapine-induced metformin-resistant prediabetes/diabetes was considerably high in the schizophrenia E-TR subtype. Clozapine-induced metformin-resistant prediabetes/diabetes represents an independent risk factor that adversely affects the clinical efficacy of clozapine for the schizophrenia E-TR subtype. This study provided new evidence for re-evaluating the use of clozapine for TRS, especially E-TR subtype, and the use of metformin for the glycemic control of clozapine-induced prediabetes/diabetes. Funding: This study was supported by the National Natural Science Foundation of China (81871052 and 81571319). Declaration of Interests: All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and there is no conflict of interest to disclose. Ethics Approval Statement: The study protocol was reviewed and approved by the Ethic Committee of Tianjin Kangtai Hospital (Tianjin, China).

A novel self-supervised deep learning (DL) method is developed for computing bias-free, personalized brain functional networks (FNs) that provide unique opportunities to better understand brain function, behavior, and disease. Specifically, convolutional neural networks with an encoder-decoder architecture are employed to compute personalized FNs from resting-state fMRI data without utilizing any external supervision by optimizing functional homogeneity of personalized FNs in a self-supervised setting. We demonstrate that a DL model trained on fMRI scans from the Human Connectome Project can identify canonical FNs and generalizes well across four different datasets. We further demonstrate that the identified personalized FNs are informative for predicting individual differences in behavior, brain development, and schizophrenia status. Taken together, self-supervised DL allows for rapid, generalizable computation of personalized FNs.

Schizophrenic patients often experience visual hallucinations (VHs) and auditory hallucinations (AHs); however, brain aberrations associated with combined VH and AH in schizophrenic patients remains poorly documented. Changes to the brain and cognition during the first episode of untreated schizophrenic patients (FUSCH) with both VHs and AHs (FUSCHVA) were evaluated. One-hundred and fifty-seven patients were enrolled that had FUSCH (1) with VHs but not AHs (FUSCHV), and (2) with AHs but not VHs (FUSCHA), plus FUSCHVA and healthy controls (n = 30). Gray matter volume (GMV) and MATRICS Consensus Cognitive Battery (MCCB) was measured to reflect impairments to the brain and cognition, respectively. FUSCHVA patients had the severest cognitive impairment for all components of the MCCB, followed by FUSCHV and FUSCHA patients. Compared to healthy patients, FUSCHVA patients had reduced GMV in the occipital, parietal, frontal, and temporal cortex, and increased GMV in the hippocampus and striatum. Compared to FUSCHV patients, FUSCHVA patients had reduced GMV in the occipital cortex and postcentral gyrus, and increased GMV in the posterio-parietal lobe. Compared to patients with FUSCHA, the GMV in patients with FUSCHVV was reduced in the occipital cortex and posterio parietal lobe. In conclusion, visual and auditory hallucinations appear to deteriorate reciprocally in FUSCHVA patients, accompanied with sever cognitive impairments. Compared to AHs, VHs might be accompanied with severe GMV impairment in the brain, especially in the primary visual cortex and higher perception integration cortex (posterio parietal lobe) in patients with FUSCH.

Background : The influence of depression on the recurrence of atrial fibrillation (AF) after catheter ablation remains unclear. We performed a meta-analysis to evaluate the association between depression and AF recurrence after catheter ablation. Methods : Cohort studies that evaluated depression at baseline and correlated depression with AF recurrence after catheter ablation were identified by searching the PubMed and Embase databases. Heterogeneity was determined using the Cochrane's Q test and calculating the I2 statistic. A random-effect model was applied to incorporate the potential influence of heterogeneity. Results : Our analysis included seven cohort studies with 1,070 AF patients who underwent catheter ablation by circumferential pulmonary vein isolation. No significant heterogeneity was detected among the included studies (p for Cochrane's Q test = 0.20, I2 = 29%). Pooled results showed that depression before procedure was independently associated with increased risk of AF recurrence after catheter ablation (adjusted relative risk [RR]: 2.24, 95% confidence interval [CI]: 1.75 - 2.88, p Limitations : This analysis included a limited number of studies and various instruments applied to measure depression. Conclusions : Depression is an independent risk factor of AF recurrence after catheter ablation.

Due to recent advances in human genomic technologies, there have been explosive interests and extensive research on the genomics of schizophrenia, a severe psychiatric disorder characterized by social cognitive deficits, hallucinations, and delusions. These new technologies, including next-generation sequencing (NGS), genome-wide association studies (GWAS), and the Clustered Regularly Interspaced Short Palindromic Repeats-associated nuclease 9 (CRISPR/Cas9) genome editing platform are capable of interrogating and editing the genome directly. In the past few years, these efforts have led to the identification of important loci and genes susceptible to schizophrenia. The findings have increased our understanding of the underlying genetic causes of schizophrenia and aided in the development of new approaches for more effectively diagnosing and treating schizophrenia. Despite the substantial progress, there are several unanswered questions about the genomics of schizophrenia, and there are a number of potential shortcomings in the current literature considering the complexity of the disease and limits of the current technologies. In the present review, we assessed the existing literature on the genomics of schizophrenia, identifying the strengths and study design shortcomings from the following aspects: elucidation of the pathogenesis, early risk prediction and diagnosis, and the treatment of schizophrenia. Moreover, we have proposed solutions to overcome the shortcomings of past studies. Lastly, we have discussed the importance of developing multidisciplinary teams and global research groups in order to improve the lives of schizophrenic patients globally.

Background Schizophrenia (SZ) is a complex psychiatric disorder and the exact mechanisms that underpin SZ remain poorly understood despite decades of research. Genetic, epigenetic, and environmental factors are all considered to play a role. The importance of gut flora and its influence on the central nervous system has been recognized in recent years. We hypothesize that gut flora may be a converging point where environmental factors interact with epigenetic factors and contribute to SZ pathogenesis. Aim To summarize the current understanding of genetic and epigenetic factors and the possible involvement of gut flora in the pathogenesis of schizophrenia. Results We searched PubMed and Medline with a combination of the key words schizophrenia, microbiome, epigenetic factors to identify studies of genetic and epigenetic factors in the pathogenesis of schizophrenia. Numerous genes that encode key proteins in neuronal signaling pathways have been linked to SZ. Epigenetic modifications, particularly, methylation and acetylation profiles, have been found to differ in individuals that present with SZ from those that don't. Gut flora may affect epigenetic modifications by regulation of key metabolic pathway molecules, including methionine, florate, biotin, and metabolites that are acetyl group donors. Despite a lack of direct studies on the subject, it is possible that gut flora may influence genetic and epigenetic expression and thereby contribute to the pathogenesis of SZ. Conclusion Gut flora is sensitive to both internal and environmental stimuli and the synthesis of some key molecules that participate in the epigenetic modulation of gene expression. Therefore, it is possible that gut flora is a converging point where environmental factors interact with genetic and epigenetic factors in the pathogenesis of SZ.

Disease heterogeneity is a significant obstacle to understanding pathological processes and delivering precision diagnostics and treatment. Clustering methods have gained popularity for stratifying patients into subpopulations (i.e., subtypes) of brain diseases using imaging data. However, unsupervised clustering approaches are often confounded by anatomical and functional variations not related to a disease or pathology of interest. Semi-supervised clustering techniques have been proposed to overcome this and, therefore, capture disease-specific patterns more effectively. An additional limitation of both unsupervised and semi-supervised conventional machine learning methods is that they typically model, learn and infer from data using a basis of feature sets pre-defined at a fixed anatomical or functional scale (e.g., atlas-based regions of interest). Herein we propose a novel method, "Multi-scAle heteroGeneity analysIs and Clustering" (MAGIC), to depict the multi-scale presentation of disease heterogeneity, which builds on a previously proposed semi-supervised clustering method, HYDRA. It derives multi-scale and clinically interpretable feature representations and exploits a double-cyclic optimization procedure to effectively drive identification of inter-scale-consistent disease subtypes. More importantly, to understand the conditions under which the clustering model can estimate true heterogeneity related to diseases, we conducted extensive and systematic semi-simulated experiments to evaluate the proposed method on a sizeable healthy control sample from the UK Biobank (N = 4403). We then applied MAGIC to imaging data from Alzheimer's disease (ADNI, N = 1728) and schizophrenia (PHENOM, N = 1166) patients to demonstrate its potential and challenges in dissecting the neuroanatomical heterogeneity of common brain diseases. Taken together, we aim to provide guidance regarding when such analyses can succeed or should be taken with caution. The code of the proposed method is publicly available at https://github.com/anbai106/MAGIC.

Previous studies using resting-state functional magnetic resonance imaging (fMRI) have found abnormal functional connectivity in patients with major depressive disorder (MDD). Yet, effect of distance thresholds on local functional connectivity changes in MDD is largely unknown. Here, we used resting-state fMRI data and functional connectivity strength (FCS) method to test local functional connectivity differences at different distance thresholds between 47 drug-naive patients with MDD and 47 healthy controls. For the distribution of functional brain hubs with high local FCS, the overall changing trend from distance thresholds of 10mm to 100mm was from lateral to medial. Compared to controls, MDD patients exhibited decreased local FCS independent of distance threshold in the sensorimotor system (postcentral gyrus, paracentral lobule, and supplementary motor area). MDD Patients exhibited increased local FCS in the inferior temporal gyrus at two lower distance thresholds (20mm and 30mm) and a higher distance threshold (100mm). In addition, MDD patients showed increased local FCS in the putamen at higher distance thresholds (80-100mm). These findings suggest that local functional connectivity abnormalities in MDD are dependent on distance thresholds and that future studies should take the distance thresholds into account when measuring local functional connectivity in MDD.

Structural and functional alterations in the inferior parietal lobule (IPL) in schizophrenia have been frequently reported; however, the IPL connectivity changes in schizophrenia remain largely unknown. Based on heterogeneity of the IPL in structure, connection and function, we hypothesize that the resting-state functional connectivities (rsFCs) of the IPL subregions are differentially affected in schizophrenia. This study included 95 schizophrenia patients and 104 healthy controls. The IPL subregions were defined according to a previous in vivo connection-based parcellation study. We calculated the rsFC of each IPL subregion and compared them between the two groups while controlling for the effects of age, gender, and grey matter volume. Among the six subregions of the left IPL and the five subregions of the right IPL, only the bilateral PFm (a transition zone of the IPL) subregions exhibited abnormal rsFC in schizophrenia. Specifically, the left PFm showed increased rsFC with the bilateral lingual gyri in schizophrenia patients than in healthy controls. The right PFm exhibited increased rsFC with the right lingual gyrus and inferior occipital gyrus, and bilateral mid-cingulate and sensorimotor cortices in schizophrenia patients. These findings suggest a selective rsFC abnormality in the IPL subregions in schizophrenia, characterized by the increased rsFC between the PFm subregion of the IPL and the visual and sensorimotor areas., Highlights • Investigation of the subregional-level rsFC changes of the IPL in schizophrenia • The PFm is only IPL subregion with significant rsFC changes in schizophrenia. • Suggesting a selective rsFC abnormality in the IPL subregions in schizophrenia

New methods for using ketamine in patients with propofol-electroconvulsive therapy-resistant depression (ECT-RD) are needed in the clinic. This study aimed to investigate the therapeutic efficacy of ketamine plus ECT in ECT-RD patients, along with the treatment-induced brain alterations. A total of 28 ECT-RD patients were intravenously injected with ketamine six times and treated with propofol-ECT six times alternately within two weeks. The Hamilton Depression Scale was used to assess the treatment effect. Global functional connectivity density (gFCD) and functional connectivity strength (FCS) were used to evaluate functional brain alterations. As compared with the propofol-ECT treatment group, the addition of ketamine could improve the therapeutic outcomes in patients with ECT-RD. The treatment increased gFCD in the left temporal and subgenual anterior cingulated cortex. Simultaneously, the treatment decreased FCS within the default mode network. Although increased functional connectivity could be sustained for 10 days, the clinical effect was only sustained 7 days, indicating that the clinical effect and functional brain alterations were disjointed. Ketamine plus propofol-ECT can obviously improve the effects of propofol-ECT in ECT-RD patients. However, the effect is limited in 7 days, suggesting the benefit is short-term.

Define changes in the visual cortex and retina in first-episode schizophrenia patients with visual disturbance (FUSCHVD) accompanied by antipsychotic agent treatment is important for guiding treatment. We examined the visual system prior to and after 3 years of antipsychotic-agent treatment in 48 patients with FUSCHVD and 50 healthy controls, and after 3.5 years of antipsychotic-agent treatment in 12 patients with FUSCHVD and 12 healthy subjects who came from the cohort with 3 years of follow up. Reduction of the visual cortex gray matter volume (GMV) was observed in patients compared to healthy controls, and impairments deteriorated accompanied with 3 years' treatment with antipsychotic agents. Total retinal thickness was also reduced in patients but did not deteriorated with treatment with antipsychotic agents. However, in the 12 patients who performed the additional 6-month follow-up, GMV and total retinal thickness reductions did not demonstrate any further trend in deterioration. These findings indicate that the reductions of GMV and retinal thickness may be self-limited. Although these findings were consistent with previous reports, it was only observed in a small number of patients. Therefore, clinicians should remain pay greater attention to visual system impairment in FUSCHVD.

Depression is a highly prevalent risk factor for both the onset of cardiovascular disease (CVD) and the mortality of CVD patients, and people suffering from CVD are more likely to develop depression than healthy individuals. The aim of this review is to summarize recent findings regarding the underlying relationship between CVD and depression. Literature search and review were conducted using PubMed, Google Scholar, Wanfang Med Online, and Baidu Scholar databases. CVD and depression are intimately related and researchers from around the world have proposed and validated various mechanisms that may potentially explain the comorbidity of CVD and depression. Recent studies have suggested that depression and CVD may manifest as two distinct clinical conditions in two different organs, the brain and the heart, respectively, but may also be linked by shared mechanisms. Of these, inflammation involving the immune system is thought to be a common mechanism of depression and heart disease, with specific inflammatory cytokines or pathways being potential targets for the prevention and treatment of the concurrent diseases. Therefore, inflammation may play an important role in bridging the link between depression and CVD, a finding that can have important clinical implications for the prevention and early intervention of these conditions.

Patients with schizophrenia have a higher incidence of coronary artery disease. This meta-analysis was performed to evaluate the influence of a prior diagnosis of schizophrenia on mortality following acute coronary syndrome (ACS). Relevant longitudinal follow-up studies were obtained via systematic search of PubMed and Embase databases. A random effect model was used to perform the meta-analysis. This meta-analysis included 3,611,343 hospitalized patients with ACS from nine follow-up studies. The results show that, in patients with schizophrenia, ACS was associated with a significantly higher risk of mortality (multivariate adjusted risk ratio [RR]: 1.66, p .001) with significant heterogeneity (I2 = 93%) compared to the results of mentally healthy patients. Subgroup analyses demonstrated that patients with schizophrenia were associated with higher ACS mortality within one month (RR: 1.68, p .001) and during a follow-up period of ≥one year (RR: 1.71, p = .01), in studies with (RR: 1.65, p = .06) and without the adjustment of revascularization treatments (RR: 1.68, p = .004), as compared with the results of mentally healthy patients. These results indicate that patients with schizophrenia have a higher than expected mortality risk in the case of acute coronary events.

Auditory verbal hallucination (AVH), defined as the auditory perception of speech in the absence of a real external stimulus, occurs in individuals with and without mental illness. The distribution of functional abnormalities in patients with AVH suggests aberrant brain network connectivity. However, no study has measured the global functional connectivity density (gFCD) associated with AVH in patients with major depressive disorder (MDD); gFCD is used widely to examine the density distribution of whole-brain resting-state functional connectivity and can serve as an index reflecting brain metabolism disturbance. In this study, we involved drug-naive patients with first-episode MDD with (n = 35) and without (n = 40) AVH and healthy controls (n = 50).Whole-brain resting-state functional magnetic resonance imaging data were acquired and gFCD was calculated and compared among groups. We found the following gFCD alterations that were shared by both MDD groups: (1) decreased gFCD in the bilateral postcentral gyrus, precentral gyrus, insular cortices and occipital lobe; and (2) increased gFCD in the left middle cingulate cortex. More importantly, we found AVH-specific gFCD changes in patients with MDD: increased gFCD in the left Wernicke's brain regions and bilateral hippocampus and thalamus, and decreased gFCD in the bilateral lateral prefrontal lobule. These findings reflect the disturbance of brain information communication and metabolism in patients with MDD and AVH, related mainly to the language and memory processing circuits, and to some extent provide further support for the “VOICE” model of AVH.

Background: Antipsychotic drugs may lead to side effects such as obesity, diabetes, dyslipidemia, and cardiovascular disease. The current systematic review and network meta-analysis analyzes and provides an update on the clinical performance of these add-ons in comparison to placebo on body weight and body mass index (BMI) reductions. Methods: A comprehensive literature search was performed on electronic databases: PubMed (1946-), Embase (1974-), Cochrane library (1992-), and OpenGrey (2000-) until 31 July 2018. Network meta-analyses, comparing the body weight change, BMI change and withdrawn due to adverse events of different pharmacological add-ons, was performed using a multivariate meta-regression model with random-effects, adopting a frequentist approach. To rank the prognosis for all add-ons, we used surface under the cumulative ranking (SUCRA) values. Outcomes: From 614 potential studies identified, 27 eligible studies (n = 1,349 subjects) were included. All the studies demonstrated low to moderate risk of bias. For the analysis of body weight change, all add-ons except Ranitidine showed significant weight reductions comparing to placebo. The effectiveness rank based on SUCRA results from highest to lowest was Sibutramine, Topiramate, Metformin, Reboxetine, Ranitidine, and placebo. A similar pattern was seen for BMI change. The analysis of safety outcome did not detect significantly increased withdrawn number from the add-ons. Current evidence showed relatively good tolerance and safety of using the pharmacological add-ons. Interpretation: Topiramate and Metformin are effective add-on treatments in controlling antipsychotic-induced weight gain, comparing to placebo. They are well tolerated in short-term period. Although Sibutramine has the highest rank of the effectiveness, its licence has been withdrawn in many countries due to its adverse effects. Hence, Sibutramine should not be adopted to treat antipsychotic-induced weight gain. Funding Statement: This work was supported by grants from the Tianjin Health Bureau Foundation (2014KR02 to C.Z.) , National Natural Science Foundation of China ( 81871052 to C.Z.) and the Key Projects of the Natural Science Foundation of Tianjin, China (17JCZDJC35700 to C.Z.). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: Missing

Small sample sizes and large inter-subject variations result in inconsistent findings in resting-state cerebral blood flow (CBF) in schizophrenia. The CBF connectivity alterations in schizophrenia remain unclear. Recently, three-dimensional pseudo-continuous arterial spin labeling (pcASL) imaging was performed to measure the resting-state CBF in 100 schizophrenia patients and 94 healthy comparison subjects. The normalized CBF was used to reduce the inter-subject variations. Both group comparisons in the CBF and correlations between the CBF alterations and clinical parameters were assessed. The CBF connectivity of the brain regions with regional CBF differences was also compared between the groups. Compared with the healthy controls, the schizophrenia patients exhibited increased CBF in the bilateral inferior temporal gyri, thalami and putamen and decreased CBF in the left insula and middle frontal gyrus and the bilateral anterior cingulate cortices and middle occipital gyri. In the schizophrenia patients, significant correlations were identified between the CBF and clinical parameters. Importantly, the schizophrenia patients exhibited CBF disconnections between the left thalamus and right medial superior frontal gyrus and between the left insula and left postcentral gyrus. Our results suggest that schizophrenia patients may exhibit both regional CBF abnormalities and deficits in CBF connectivity, which may underlie the clinical symptoms of schizophrenia.