Drug-naive Schizophrenia Patients Research Articles

Peak width of skeletonized mean diffusivity as a neuroimaging biomarker in first-episode schizophrenia.

Peak width of skeletonized mean diffusivity (PSMD), a fully automated diffusion tensor imaging (DTI) biomarker of white matter (WM) microstructure damage, has been shown to be associated with cognition in various WM pathologies. However, its application in schizophrenic disease remains unexplored. This study aims to investigate PSMD along with other DTI markers in first-episode schizophrenia patients compared to healthy controls (HCs), and explore the correlations between these metrics and clinical characteristics. A total of 56 first-episode drug-naive schizophrenia patients and 64 HCs were recruited for this study. Participants underwent structural imaging and DTI, followed by comprehensive clinical assessments, including the Positive and Negative Syndrome Scale (PANSS) for patients and cognitive function tests for all participants. We calculated PSMD, peak width of skeletonized fractional anisotropy (PSFA), axial diffusivity (PSAD), radial diffusivity (PSRD) values, skeletonized average mean diffusivity (MD), average fractional anisotropy (FA), average axial diffusivity (AD), and average radial diffusivity (RD) values as well as structural network global topological parameters, and examined between-group differences in these WM metrics. Furthermore, we investigated associations between abnormal metrics and clinical characteristics. Compared to HCs, patients exhibited significantly increased PSMD values (t = 2.467, p = 0.015), decreased global efficiency (Z = -2.188, p = 0.029), and increased normalized characteristic path length (lambda) (t = 2.270, p = 0.025). No significant differences were observed between the groups in the remaining metrics, including PSFA, PSAD, PSRD, average MD, FA, AD, RD, local efficiency, normalized cluster coefficient, small-worldness, assortativity, modularity, or hierarchy (p > 0.05). After adjusting for relevant variables, both PSMD and lambda values exhibited a significant negative correlation with reasoning and problem-solving scores (PSMD: r = -0.409, p = 0.038; lambda: r = -0.520, p = 0.006). No statistically significant correlations were observed between each PANSS score and the aforementioned metrics in the patient group (p > 0.05). Multivariate linear regression analysis revealed that increased PSMD (β = -0.426, t = -2.260, p = 0.034) and increased lambda (β = -0.490, t = -2.994, p = 0.007) were independently associated with decreased reasoning and problem-solving scores respectively ( = 0.295, F = 2.951, p = 0.029). But these significant correlations did not withstand FDR correction (p_FDR > 0.05). PSMD can be considered as a valuable neuroimaging biomarker that complements conventional diffusion measurements for investigating abnormalities in WM microstructural integrity and cognitive functions in schizophrenia.

Plasma G72 protein in schizophrenia: A comparative analysis of drug-naive schizophrenia patients, patients in acute exacerbation and healthy controls

ObjectivesSchizophrenia is a complex psychiatric disorder with an unclear etiopathogenesis. This study investigates the plasma G72 protein levels in drug-naive schizophrenia patients (DNS), those in acute psychotic episodes (AES), and healthy controls (HC). It also examines the correlation between the plasma G72 protein levels and Positive and Negative Syndrome Scale (PANSS) scores. MethodsThe study included 138 schizophrenia patients (84 DNS, 54 AES) and 83 HCs. Plasma G72 protein levels were measured by ELISA. Statistical analyses, including log-transformation and correlation analysis, were conducted. ResultsSchizophrenia patients had significantly lower plasma G72 levels than HCs (4.39 ± 5.38 vs. 8.06 ± 10.27 ng/mL, p < 0.001), while DNS and AES groups did not differ significantly. Log-transformed data confirmed these differences. Negative correlation was found between plasma G72 levels and age (r = −0.258, p = 0.02), PANSS-G (r = −0.249, p = 0.004), and total PANSS scores (r = −0.226, p = 0.008). ROC analysis showed poor discrimination between schizophrenia patients and controls (AUC: 0.587, p = 0.031). ConclusionsThis study's novel findings reveal that plasma G72 protein levels are significantly lower in schizophrenia patients and inversely correlated with age and symptom severity. However, the poor diagnostic accuracy observed in the ROC analysis suggests that G72 may not be a reliable biomarker for schizophrenia at this stage. These results underscore the need for further research to explore the potential clinical implications of these findings.

White matter microstructure alterations of the posterior limb of internal capsule in first-episode drug naive schizophrenia patients

ObjectivesPrevious studies have shown that microstructural alterations in white matter (WM) could contribute to the symptom manifestation and support the dysconnectivity hypothesis in schizophrenia patients. These alterations were pervasive, non-specific, and reported inconsistently across the literature. This study aimed to specifically investigate the microstructure alterations of the posterior limb of the internal capsule (PLIC) in first-episode, drug-naive schizophrenia patients. Utilizing a multicompartmental biophysical model, we further explored the correlation between these alterations and syndrome scale scores. MethodsThirty-two individuals with first-episode, drug-naive schizophrenia (FES) and thirty demographically matched healthy controls were enrolled. High-resolution multi-shell diffusion MRI data were collected, followed by the application of a three-compartment Neurite Orientation Dispersion and Density Imaging (NODDI) model to scrutinize the alterations in white matter microstructure. Changes in sensory and motor fibers within the PLIC were specifically focused on. Additionally, the correlation between these pathological changes and scores on the Positive and Negative Syndrome Scale (PANSS) was investigated. ResultsThe Neurite density index (NDI) in the left PLIC was significantly lower in FES patients compared to healthy individuals, and positively correlated with PANSS positive syndrome scores (r = 0.0379, p = 0.046). In the sensory component (left superior thalamic radiation within PLIC, STR_P), the NDI was significantly elevated (p < 0.0001). Conversely, the NDI in the motor component (left corticospinal tract within PLIC, CST_P) was reduced (p = 0.007) in FES patients compared to healthy individuals, and strongly correlated with PANSS positive syndrome scores (p < 0.020) and PANSS total scores (p < 0.045). Moreover, the NDI deviation of STR from total PLIC (fSTR_P) and NDI deviation in STR_P and CST_P compared to PLIC region (fPLIC) were significantly higher in FES patients than in healthy controls (p < 0.00001), with an area under the curve (AUC) of fPLIC reaching 0.872. ConclusionThe study’s findings provided new insights into the discrepancy of white matter microstructure changes associated with the sensory and motor fibers in the PLIC region in FES patients. These results contribute to the growing body of evidence suggesting that WM microstructural alterations play a critical role in schizophrenia pathophysiology.

Neutrophil gelatinase-associated lipocalin (NGAL) and inflammatory markers in schizophrenia: A comparative analysis of drug-naive schizophrenia patients, remitted patients, and healthy controls

This study aims to examine the plasma concentrations of NGAL and other inflammatory parameters, including TNF-α, IL-1β, and IFN-γ, in schizophrenia patients and healthy volunteers. It also investigates potential associations between these biomarkers and symptom severity in schizophrenia and the utility of NGAL as a potential diagnostic and monitoring biomarker for schizophrenia. The study included 49 drug-naive schizophrenia patients (DNS), 59 patients with schizophrenia in remission (REM) on antipsychotic treatment, and 58 healthy volunteers (HC). The Positive and Negative Symptoms Evaluation Scale (PANSS) was utilized to assess the severity of symptoms in schizophrenia patients. Plasma levels of TNF-α, IL-1β, IFN-γ, and NGAL were measured for all participants. NGAL levels were significantly lower in the DNS group than in HC. Significantly lower TNF-α levels were observed in both the DNS and REM groups compared to the HC group. Notably, a statistically significant positive correlation was detected between TNF-α and NGAL levels. The findings of this study are noteworthy, as they demonstrate that drug-naive individuals with schizophrenia exhibit significantly diminished levels of NGAL and TNF-α compared to healthy controls. These identified biomarkers hold promise for providing valuable insights into the complex and evolving pathophysiology of schizophrenia.

Differentiation value of miR-26b for major depressive disorder, schizophrenia, generalized anxiety disorder.

First episode and drug naive schizophrenia (SZ) patients comorbid with major depressive episode and generalized anxiety disorder (GAD) comorbid with major depressive disorder (MDD) are common in clinical practice, overlapping symptomatology during first presentation of MDD, SZ and GAD challenged the diagnostic process. This study aimed to investigate the differentiation value of peripheral microRNA-26b expression in 52 patients of MDD, SZ, and GAD, respectively, and 52 controls. Quantitative real-time reverse transcription polymerase chain reaction was used to further verify aberrant miRNAs of previous identified in MDD and investigate expression level of these peripheral miRNAs in SZ and GAD. The expression levels of miR-26b and miR-4743 were significantly upregulated and of miR-4498, miR-4485, and miR-1972 had no significant difference. There were no significant differences of expression levels of miR-26b, miR-4498, miR-4485, and miR-1972 except miR-4743 between SZ patients and control group and of miR-26b, miR-1972, miR-4498, and miR-4485 between GAD group and the controls. The receiver operating characteristic (ROC) curve of miR-26b in MDD patients showed that its sensitivity and specificity for diagnosis were 0.540 and 0.830, respectively, with the area under curve (AUC) being 0.728; the ROC of miR-26b for SZ and MDD differentiation showed that its sensitivity and specificity were 0.580 and 0.710, respectively, with AUC being 0.631; the ROC of miR-26b for GAD and MDD differentiation suggested that sensitivity and specificity were 0.560 and 0.750, respectively, with AUC being 0.637. MiR-26b might have potential value of differentiation biomarker for MDD, SZ, and GAD.

Altered controllability of white matter networks and related brain function changes in first-episode drug-naive schizophrenia.

Understanding how structural connectivity alterations affect aberrant dynamic function using network control theory will provide new mechanistic insights into the pathophysiology of schizophrenia. The study included 140 drug-naive schizophrenia patients and 119 healthy controls (HCs). The average controllability (AC) quantifying capacity of brain regions/networks to shift the system into easy-to-reach states was calculated based on white matter connectivity and was compared between patients and HCs as well as functional network topological and dynamic properties. The correlation analysis between AC and duration of untreated psychosis (DUP) were conducted to characterize the controllability progression pattern without treatment effects. Relative to HCs, patients exhibited reduced AC in multiple nodes, mainly distributed in default mode network (DMN), visual network (VN), and subcortical regions, and increased AC in somatomotor network. These networks also had impaired functional topology and increased temporal variability in dynamic functional connectivity analysis. Longer DUP was related to greater reductions of AC in VN and DMN. The current study highlighted potential structural substrates underlying altered functional dynamics in schizophrenia, providing a novel understanding of the relationship of anatomic and functional network alterations.

Effect of Risperidone and Olanzapine on blood glucose levels and lipid profile among individuals with schizophrenia

Background: Treatment of schizophrenia requires use of antipsychotics for considerable time. Studies established that patients have risk of metabolic side effects. Objectives: To study fasting blood glucose levels and lipid profile in schizophrenic patients and to see that same was present in study population. Methods: This study was conducted at psychiatry outpatient department, Nobel Medical College and Teaching Hospital Kanchanbari Biratnagar from October 2018 till august 2019 after due approval from college ethics committee. A total of 50 consenting drug naive schizophrenia patients 17- 60 years of age, with no comorbidity, were divided alternatively into two groups. group 1 was treated with olanzapine, group 2 with risperidone for eight weeks. With flexible dosage for ease of the therapy and individual patient requirement. Fasting blood glucose and lipid profile was measured at day baseline, four, eight weeks. Results: There was rise of fasting blood glucose in both groups but more in olanzapine group with no statistically significant intergroup difference (The p-value after eight weeks was 0.504). In lipid profile, mean total cholesterol levels were higher in the group 1, (p = 0.005 after eight weeks). Triglycerides, on intergroup comparison significant difference (p = 0.002) was noted. Higher values in group 1 were recorded. However, very low-density lipoprotein was elevated (p = 0.003) in group1 only. Conclusion: olanzapine and risperidone cause non-significant rise in fasting blood sugar. Olanzapine caused statistically significant rise of total cholesterol, triglycerides, very low-density lipoprotein as compared to risperidone.

Abnormal functional connectivity of the striatum in first-episode drug-naive early-onset Schizophrenia.

Abnormal brain network connectivity is strongly implicated in the pathogenesis of schizophrenia. The striatum, consisting of the caudate and putamen, is the major treatment target for antipsychotics, the primary treatments for schizophrenia; however, there are few studies on the functional connectivity (FC) of striatum in drug‐naive early‐onset schizophrenia (EOS) patients. We examined the FC values of the caudate nucleus and putamen with whole brain by resting‐state functional magnetic resonance imaging (RS‐fMRI) and the associations with indices of clinical severity. Patients demonstrated abnormal FC between subregions of the putamen and both the visual network (left middle occipital gyrus) and default mode network (bilateral anterior cingulate, left superior frontal, and right middle frontal gyri). Furthermore, FC between dorsorostral putamen and left superior frontal gyrus correlated with both positive symptom subscore and total score on the Positive and Negative Syndrome Scale (PANSS). These findings demonstrate abnormal FC between the striatum and other brain areas even in the early stages of schizophrenia, supporting neurodevelopmental disruption in disease etiology and expression.

Lack of neural load modulation explains attention and working memory deficits in first-episode schizophrenia

ObjectiveAlthough working memory (WM) deficits are well-recognized core features of schizophrenia, the underlying pathophysiological substrates of impairment in early psychosis before medication remain unclear. One possibility is that deficits in selective attention contribute to WM impairment. MethodsEEG was acquired from 25 first-episode drug-naive schizophrenia patients and 26 matched controls while they performed a WM task. ResultsCompared with controls, schizophrenia patients showed a deficit in WM capacity in both behavioral and electrophysiological measures. Notably, the increased parieto-occipital pre-encoding stimulus alpha power in patients with schizophrenia predicted their subsequent reduced N2pc and symptom severity, whereas this relationship was absent in controls. Moreover, lacking load effect in neural activities predicted the serious impairment in behavior for schizophrenia. ConclusionsThis pilot study provides preliminary evidence that the lack of load effect in neural activities may serve as potential underlying mechanisms for the impaired selective attention and WM capacity in schizophrenia. Our results emphasize the importance of pre-encoding stimulus alpha power in first-episode drug-naive schizophrenia. SignificanceThese findings provide a neurophysiological correlate for the subjective reports of working memory deficits in schizophrenia and indicate the potential effective targets for clinical intervention.

Association Between Hippocampal Subfields and Clinical Symptoms of First-Episode and Drug Naive Schizophrenia Patients During 12 Weeks of Risperidone Treatment

Small hippocampal size may be implicated in the pathogenesis and psychopathology of schizophrenia (SCZ). However, does the volume of hippocampal subfields in SCZ patients affect response to antipsychotic treatment? In this study, we used risperidone to treat first-episode drug naïve (FEDN) SCZ patients for 12 weeks, and then explored the relationship between baseline hippocampal subfield volumes, as well as any changes in these hippocampal subfield volumes during treatment, and improvement in their psychopathological symptoms. By adopting a state-of the-art automated algorithm, the hippocampal subfields were segmented in 43 FEDN SCZ inpatients at baseline and after 12 weeks of risperidone monotherapy, as well as in 30 matched healthy controls. We adopted the Positive and Negative Syndrome Scale (PANSS) to assess psychopathological symptoms in patients at baseline and at post-treatment. Before treatment, SCZ patients had no significant differences in total or subfield hippocampal volumes compared with healthy volunteers. However, we found a significant correlation between a smaller left CA1 at baseline and a lower PANSS total score and general psychopathology sub-score at post-treatment (both p < 0.05). Furthermore, the left CA1 at baseline was significantly smaller in responders, who had >50% improvement in PANSS total score, than in non-responders (p < 0.05). Our results suggest that smaller left CA1 volume may be a predicator for improvement in psychotic symptoms of FEDN SCZ patients.

METABOLIC EFFECTS OF ANTIPSYCHOTIC TREATMENT IN SCHIZOPHRENIA

BACKGROUND: It is well established that morbidity and mortality of Schizophrenia is signicantly increased due to the metabolic derangements caused by anti-psychotic medications which in turn are potent cardiovascular risk factors. Despite this widespread knowledge of metabolic risks of antipsychotic treatment, the metabolic parameters of the patients are rarely taken into consideration while prescribing antipsychotic medications in India. AIM:To determine the effects of antipsychotic treatment on the metabolic parameters in drug naïve patients of schizophrenia. METHOD: Eighty consecutive drug naive schizophrenia patients were assessed for 05 metabolic parameters which form the criteria of metabolic syndrome (NCEP- ATPIII). These parameters were again assessed after 06 months of treatment in the same set of patients. The data was then analyzed for changes in metabolic parameters in context of treatment with rst and second generation antipsychotics. RESULT: Our study found that there were signicant changes in the metabolic parameters after 06 months of treatment with anti-psychotic medications. CONCLUSION:Antipsychotic medications, both rst and second generation, cause signicant derangements in the metabolic parameters. Thus, metabolic parameters should always be taken into consideration before starting of antipsychotic treatment as well as during follow up.

Differences in patterns of metabolic abnormality and metabolic syndrome between early-onset and adult-onset first-episode drug-naive schizophrenia patients

Although metabolic abnormalities and metabolic syndrome (MetS) often occur in schizophrenia, few studies have investigated them in early-onset schizophrenia (EOS) patients. To our knowledge, this was the first to compare clinical correlates of metabolic abnormalities between first-episode drug-naïve (FEDN) EOS and adult-onset schizophrenia (AOS) patients. A total of 489 Chinese FEDN schizophrenia patients (116 EOS and 373 AOS) and 451 healthy controls were recruited in this cross-sectional study. Blood pressure, waist circumference (WC), Body mass index (BMI), total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), glucose, hemoglobin A1c (HbA1c), insulin and insulin resistance were measured. The Positive and Negative Syndrome Scale (PANSS) was applied to evaluate the clinical symptoms of schizophrenia patients, and higher scores on PANSS indicate increased severity. EOS patients had lower rates of: MetS, elevated WC, hypertriglyceridemia, hypercholesterolemia, and hyper-LDLC than EOS patients (all p < 0.05). In EOS patients, WC was positively associated with PANSS general psychopathology score (p = 0.04). In AOS patients, WC (p = 0.01; p = 0.02) and glucose (p < 0.001; p < 0.001) were positively associated with PANSS general psychopathology and total score. HOMA-IR was positively associated with PANSS total score (p = 0.04). Systolic BP, triglycerides and HDLC were main contributors to MetS in AOS (all p < 0.05), but not in EOS. BMI was a risk factor of MetS in EOS, while BMI and HOMA-IR were risk factors of MetS in AOS (all p < 0.05). Our results indicate differences in metabolic abnormalities patterns, risk factors and their association with clinical characteristics between Chinese EOS and AOS patients. Data Availability StatementThe datasets that support the findings of this study are not publically available due to ongoing analyses for further publications, but are available from the corresponding author X.Z. upon reasonable request.

ATP-binding cassette transporter 13 mRNA expression level in schizophrenia patients

The objective of this study was to investigate the expression and clinical role of ATP-binding cassette transporter 13 (ABCA13) gene previously shown to be associated with schizophrenia (SZ) through Genome-wide association studies studies. Thirty-two first-episode drug-naive SZ patients and forty-eight age and gender-matched healthy controls were enrolled in this study. We measured ABCA13 mRNA expression levels using quantitative real-time PCR at baseline and 12 weeks after antipsychotic therapy. Moreover, clinical symptoms were measured by the Positive and Negative Syndrome Scale (PANSS) at baseline and 12-week follow-up. We found that ABCA13 mRNA levels were significantly lower in SZ patients compared with healthy controls at baseline. SZ patients’ symptoms were decreased, but ABCA13 mRNA levels were increased after 12 weeks antipsychotic therapy. In addition, there was a significant difference in ABCA13 mRNA levels among SZ patients at baseline and 12-week follow-up. The ABCA13 mRNA levels were not associated with age, BMI, years of education. Of the clinical symptoms measured, the ABCA13 mRNA levels were negatively associated with the PANSS scores at baseline and 12-week follow-up. The results indicated that the ABCA13 mRNA expression level is of interest, and upon further studies, it could be used as a biomarker for SZ treatment outcome.

Different serum protein factor levels in first-episode drug-naive patients with schizophrenia characterized by positive and negative symptoms.

The clinical features of schizophrenia can be mainly divided into two symptom domains: positive and negative. Patients in each symptom domain respond differently to treatments, and their prognoses vary accordingly. Serum protein factors, such as nerve growth factor (NGF), neurotrophin-3 (NT-3), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and the calcium-binding protein, S100β, have been reported to be involved in the pathogenesis of schizophrenia. However, their roles in the positive and negative symptom domains have not been determined. In this study, we investigated whether the serum levels of these five protein factors differed among first-episode drug-naive schizophrenia patients in each symptom domain and in healthy controls. Double-antibody sandwich ELISA were used to quantify the amounts of the five protein factors in serum. Compared with the levels in the controls (n = 60), increased serum levels of IL-6, IL-1β, and S100β and decreased serum levels of NGF and NT-3 were observed in first-episode drug-naive schizophrenia patients. Additionally, the serum levels of IL-6 and IL-1β were significantly higher in schizophrenia patients characterized by negative symptoms (negative group, n = 37) than in those characterized by positive symptoms (positive group, n = 46). Based on multivariate regression analyses, serum levels of IL-1β were positively associated with the Negative Symptom subscore of the Positive and Negative Syndrome Scale in the negative group and in all patients with schizophrenia. The two subtypes of schizophrenia may have different pathological mechanisms. Patients characterized by negative symptoms probably have more serious disturbances in neuroimmunology.

Methods to Handle Incomplete Data

Context: The major question for data analysis is determining the appropriate analytic approach in the presence of incomplete observations. The most common solution to handle missing data in a data set is imputation, where missing values are estimated and filled in. An important problem of imputation is to maintain the statistical significance of the data set. Aim: To compare different imputation techniques − complete case analysis, last observation carried forward (LOCF), mean imputation, hot deck Imputation, regression imputation, and multiple imputation (MI). Settings and Design: The data for the study were collected from a prospective study to find out the predictors of early response to treatment in drug naive schizophrenia patients from a tertiary care centre, India. Methods and Material: The present study tries to compare four imputation methods: complete case analysis, LOCF, mean imputation, hot deck Imputation, regression imputation and MI, in filling up the missing values of the outcome variable. Statistical analysis used: Paired t test was used to compare the imputation methods. Results: At the fourth week, the positive and negative syndrome scale scores were missing for about a minority of the subjects (41%). Mean imputation differed significantly from LOCF (P = 0.001), regression imputation (P = 0.010) and MI (P = 0.002). LOCF differed significantly from all these methods − regression imputation (P = 0.001), hot deck imputation (P = 0.011) and MI (P = 0.001). Conclusions: LOCF and mean imputation methods are different from other imputation methods, and there is no difference between hot deck imputation, MI, and regression imputation.

Impact of antipsychotic medication on IL-6/STAT3 signaling axis in peripheral blood mononuclear cells of drug-naive schizophrenia patients.

Immunopathogenesis remains a widely appreciated etiopathological model of schizophrenia. Persistent efforts have aimed to identify schizophrenia biomarkers indexing immune system abnormalities and also immuno-dampening effects of antipsychotic medications. Although data arising from published reports are encouraging, such studies are limited to a few immune parameters and not focused on a specific pathway. Th17 cells-mediated immuno-inflammatory responses have emerged as a potential mechanism in various neuropsychiatric conditions, including schizophrenia. The Th17 pathway is distinctly regulated through a coordinated action of multiple cytokines and transcription factors. In this study, we explored whether antipsychotic medication has any effect on the cytokines and transcription factors of the Th17 pathway. A total of 27 drug-naive schizophrenia patients were recruited and followed up for 3 months after initiation of antipsychotic medication. Lymphocyte gene expression levels of two transcription factors (STAT3 and RORC) and one of their upstream regulators, IL6, were quantified before and after treatment. Plasma levels of cytokines, such as interleukin (IL)-1β, IL-6, IL-17A, IL-23, and IL-33, were also analyzed before and after treatment. Treatment with antipsychotic medication for 3 months resulted in significant downregulation of STAT3 gene expression as well as reduction in plasma levels of IL-1β, IL-6, and IL-17A. Significant reduction in total scores for the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms was also observed in schizophrenia patients after 3 months of antipsychotic treatment. Our findings suggest possible immuno-modulatory effects of antipsychotic medication on the critical regulators, such as IL-6 and STAT3, of the Th17 pathway in schizophrenia patients. The IL-6/STAT3 signaling axis involved in the transcriptional regulation of Th17 cells might appear as an important target of antipsychotic treatment in schizophrenia patients. Alternatively, irrespective of the effect of antipsychotic drugs, the IL-6/STAT3 signaling axis might be crucially involved in ameliorating psychotic symptoms.

Multimodel inference for biomarker development: an application to schizophrenia

In the present study, to improve the predictive performance of a model and its reproducibility when applied to an independent data set, we investigated the use of multimodel inference to predict the probability of having a complex psychiatric disorder. We formed training and test sets using proteomic data (147 peptides from 77 proteins) from two-independent collections of first-onset drug-naive schizophrenia patients and controls. A set of prediction models was produced by applying lasso regression with repeated tenfold cross-validation to the training set. We used feature extraction and model averaging across the set of models to form two prediction models. The resulting models clearly demonstrated the utility of a multimodel based approach to make good (training set AUC > 0.80) and reproducible predictions (test set AUC > 0.80) for the probability of having schizophrenia. Moreover, we identified four proteins (five peptides) whose effect on the probability of having schizophrenia was modified by sex, one of which was a novel potential biomarker of schizophrenia, foetal haemoglobin. The evidence of effect modification suggests that future schizophrenia studies should be conducted in males and females separately. Future biomarker studies should consider adopting a multimodel approach and going beyond the main effects of features.

Regulation of obesity-associated metabolic disturbance by the antipsychotic drug olanzapine: Role of the autophagy-lysosome pathway

Metabolic disturbance is commonly observed in schizophrenia patients, and the metabolic impacts of atypical antipsychotics such as olanzapine (OLA) have received much attention. Drug naive schizophrenia patients display metabolic abnormality to varying degrees, but how this shapes the metabolic responses to chronic OLA exposure is unknown. Using high-fat diet (HFD, 8 weeks) induced obesity, here we explored the metabolic outcome of chronic OLA exposure in conditions of pre-existing metabolic disturbance. OLA treatment (2 mg/kg) for 4 weeks led to markedly reduced body weight and adiposity in obese mice, concomitant with reduced adipose inflammation and hepatic steatosis. No significant change was observed on insulin sensitivity or energy expenditure after OLA exposure. Mechanistically, OLA restored autophagic clearance in the subcutaneous adipose tissue of obese mice, in line with its potentiation of lysosomal function in adipocytes. The metabolic phenotypes induced by OLA were partially reversed by chemical suppression of autolysosome. Together, these data uncover distinct metabolic effects of OLA in obesity involving the regulation of adipose tissue autophagy, and suggest a complicated link between OLA therapy and metabolic disturbance in schizophrenia.

Prevalence and Clinical Correlates of and Cognitive Function at the Time of Suicide Attempts in First-Episode and Drug-Naive Patients With Schizophrenia.

It is well established that patients with chronic schizophrenia have a substantially higher rate of attempted and completed suicide than the general population. However, the actual prevalence of suicide attempts at first-episode psychosis is relatively unknown. Previous studies showed that suicidal schizophrenia patients demonstrate higher cognitive function than nonsuicidal patients, though with inconsistent results. The aims of the study were to examine the prevalence of suicide attempts and the association of this prevalence with demographic and clinical variables and cognitive function in Chinese first-episode, drug-naive (FEDN) schizophrenia patients using a cross-sectional and case-control design. A total of 357 FEDN inpatients meeting DSM-IV criteria for schizophrenia and 380 healthy controls were enrolled and completed a detailed in-house questionnaire. The suicide attempt data were collected from medical records and interviews with the patients and their family members. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was administered to measure cognition in the 28 patients with and 95 patients without a history of suicide attempt and 151 healthy controls. Also, patients were rated on the Positive and Negative Syndrome Scale (PANSS). This study was conducted from June 2013 to December 2015. A suicide attempt rate of 12.0% was found in inpatients with first-episode schizophrenia. The attempters were more likely to smoke (34.4% vs 17.9%; χ² = 5.49, P = .019) and had lower severity of negative symptoms (F₁,₃₅₄ = 4.12, P = .043) as compared to FEDN patients without a suicide attempt. All 5 RBANS subscales (all P < .001) except for the Visuospatial/Constructional index (P > .05) showed significantly lower cognitive performance for FEDN patients than for healthy controls. Among the FEDN patients, the suicide attempters performed better than nonattempters on attention (F₁,₁₂₁ = 5.12, P = .025), with an effect size of 0.49. The following variables were independently associated with suicide attempt as shown by multivariate regression analysis: PANSS negative symptom subscale score (Wald χ²₁ = 7.90 P = .005; adjusted OR = 0.807, 95% CI, 0.696-0.936) and Attention (Wald χ²₁ = 4.69, P = .03; adjusted OR = 0.957, 95% CI, 0.918-0.997). FEDN patients with schizophrenia attempt suicide more often than the general population. The suicidal patients were more likely to smoke, had lower severity of negative symptoms, and showed better attention than nonsuicidal patients.

Treatment response prediction and individualized identification of first-episode drug-naïve schizophrenia using brain functional connectivity.

Identifying biomarkers in schizophrenia during the first episode without the confounding effects of treatment has been challenging. Leveraging these biomarkers to establish diagnosis and make individualized predictions of future treatment responses to antipsychotics would be of great value, but there has been limited progress. In this study, by using machine learning algorithms and the functional connections of the superior temporal cortex, we successfully identified the first-episode drug-naive (FEDN) schizophrenia patients (accuracy 78.6%) and predict their responses to antipsychotic treatment (accuracy 82.5%) at an individual level. The functional connections (FC) were derived using the mutual information and the correlations, between the blood-oxygen-level dependent signals of the superior temporal cortex and other cortical regions acquired with the resting-state functional magnetic resonance imaging. We also found that the mutual information and correlation FC was informative in identifying individual FEDN schizophrenia and prediction of treatment response, respectively. The methods and findings in this paper could provide a critical step toward individualized identification and treatment response prediction in first-episode drug-naive schizophrenia, which could complement other biomarkers in the development of precision medicine approaches for this severe mental disorder.