Serum Metabolic Profile in Schizophrenia Patients With Antipsychotic-Induced Constipation and Its relationship With Gut Microbiome.

BACKGROUND AND HYPOTHESIS: Antipsychotics (APs), the cornerstone of schizophrenia treatment, confer a relatively high risk of constipation. However, the mechanisms underpinning AP-induced constipation are poorly understood. Thus, we hypothesized that (1) schizophrenia patients with AP-induced constipation have distinct metabolic patterns; (2) there is more than one mechanism at play in producing this adverse drug effect; and (3) AP-associated changes in the gut microbiome are related to the altered metabolic profiles. STUDY DESIGN: Eighty-eight schizophrenia patients, including 44 with constipation (C) and 44 matched patients without constipation (NC), were enrolled in this study. Constipation was diagnosed by Rome IV criteria for constipation and colonic transit time using radiopaque markers (ROMs) while severity was evaluated with the Bristol Stool Form Scale (BSS) and Constipation Assessment Scale (CAS). Fasting blood samples were drawn from all participants and were subjected to non-targeted liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis. STUDY RESULTS: Eleven metabolites were significantly altered in AP-induced constipation which primarily disturbed sphingolipid metabolism, choline metabolism, and sphingolipid signaling pathway (P value < .05, FDR < 0.05). In the C group, changes in the gut bacteria showed a certain degree of correlation with 2 of the significantly altered serum metabolites and were associated with alterations in choline metabolism. CONCLUSIONS: Our findings indicated that there were disturbances in distinct metabolic pathways that were associated with AP-induced constipation. In addition, this study presents evidence of a link between alterations in the gut microbiome and host metabolism which provides additional mechanistic insights on AP-induced constipation.

Association of Interleukin-6 Polymorphisms with Schizophrenia and Depression: A Case-Control Study.

OBJECTIVE: Growing evidence suggests a crossover in genetic susceptibility to schizophrenia and depression. We aimed to investigate the association of the rs1800795 and rs1800796 polymorphisms of the IL-6 gene with schizophrenia and depression in the Han Chinese population, combined with IL-6 serum levels. METHODS: Gene sequencing and enzyme-linked immunosorbent assay were performed on 113 subjects with schizophrenia, 114 subjects with depression, and 110 healthy controls. RESULTS: Our findings showed that IL-6 concentrations in schizophrenia and depression groups were significantly higher than in the control group. The rs1800796 CC genotype and C allele were significantly associated with depression (P = .012 and P < .05, respectively). The rs1800796 CC and CG genotype was significantly associated with chronic schizophrenia (P = .020 and P = .009, respectively). Regarding the rs1800795 polymorphism, only one case of CG genotype was detected. The remainder were of the GG genotype. CONCLUSION: The IL-6 rs1800796 might serve as a protective factor for depression and schizophrenia in the Han Chinese population.

Correlation of Blood Biochemical Markers with Tardive Dyskinesia in Schizophrenic Patients.

Objective: Oxidative stress factors and proinflammatory cytokines had been found to be involved in the pathogenesis of patients with tardive dyskinesia (TD). This study assumes that blood biochemical markers would have a link with TD in schizophrenia patients. To explore the correlation between blood biochemical markers and tardive dyskinesia in patients with schizophrenia (SCH). Methods: From January 2010 to August 2021, the inpatients who met the diagnostic criteria of schizophrenia in the Chinese Classification and Diagnosis Criteria of Mental Disorders (DSM-4) and the American Diagnostic and Statistical Manual of Mental Disorders (DSM-4) were followed up in the psychiatric outpatient department of Jinxia Street Community Health Service Center, Longhu District, Shantou City. The diagnostic criteria of Abnormal Involuntary Movement Scale (AIMS) used in the TD study of Schooler and Kane were used to screen the patients. Patients were divided into the schizophrenia (SCH group) and the schizophrenia with TD groups (TD group). Oxidative stress factors including Superoxide Dismutase1 (SOD1), Glutathione Peroxidase1 (GPX1), Malondialdehyde1 (MDA1), Catalase Activity1 (CAT1), and brain-derived neurotrophic factor 1 (BDNF1) and some inflammatory cytokines including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), serum tumor necrosis factor (TNF-α), prolactin, estrogen, and cortisol were measured in 121 schizophrenic patients with tardive dyskinesia and 118 schizophrenic patients. The correlation analysis was conducted on the data. Results: Age and female were immutable risk factors for the development of TD, and there were significant differences in blood biochemical indices GPX1, MDA1, CAT1, and TNF-α in schizophrenic patients with and without TD. Conclusion: This study supports that oxidative stress and immune disorders are associated with TD patients. Blood biochemical markers GPX1, MDA1, CAT1, and TNF-α may play an important role in the pathogenesis of schizophrenia combined with TD patients, and they may be useful in the diagnosis of schizophrenia with tardive dyskinesia.

Changes of Mental State and Serum Prolactin Levels in Patients with Schizophrenia and Depression after Receiving the Combination Therapy of Amisulpride and Chloroprothixol Tablets.

OBJECTIVE: To investigate the changes in mental state and serum prolactin levels in patients with schizophrenia and depression after receiving the combination therapy of amisulpride and chloroprothixol tablets. METHODS: A total of 148 schizophrenic patients with depression were randomly divided into control group (N = 73) and study group (N = 75). The control group was treated with clopidothiol, and the study group was treated with amisulpride. Symptom scores, sleep quality, adverse reactions, therapeutic effects, prolactin, and progesterone levels, HAMD, PANSS, and PSP scores were compared between the two groups. RESULTS: The symptom scores of both groups were significantly reduced, but when compared to the control group, the symptom scores of the research group were significantly reduced more significantly (P < 0.05); serum GDNF levels of both groups were significantly increased, while serum NSE, IL-1, and MBP levels were significantly reduced (P < 0.05). However, the research group altered more substantially (P < 0.05) than the control group; the overall PSQI score of the research group was lower (P < 0.05) than the control group; and the incidence of adverse responses in the control and study groups was 12.3 percent and 4.0 percent. The research group had a lower rate of adverse responses (P < 0.05) than the control group, and the effective treatment of the control and research groups was 82.2 percent and 98.7%, respectively. The research group had a lower rate of adverse reactions (P < 0.05) than the control group, while the control and research groups' successful treatment rates were 82.2 percent and 98.7%, respectively. When compared to the control group, the research group had a greater treatment efficiency (P < 0.05); blood prolactin and progesterone levels were considerably lowered in both groups, but the reductions in the research group were more evident (P < 0.05). Both groups had considerably lower HAMD and PANSS scores, and both had significantly higher PSP scores, although the difference in the research group was more evident (P < 0.05). CONCLUSION: For people with schizophrenia and depression, a combination of amisulpride and chloroprothixol pills has a considerable effect. It can help patients with their clinical symptoms and sleep quality while also lowering their serum prolactin levels, which is favorable to their illness recovery. As a result, the combined treatment of amisulpride and chloroprothixol pills deserves to be promoted and used.

The role of BDNF and NGF plasma levels in first-episode schizophrenia: A longitudinal study.

Neurotrophins have been proposed to be involved in biological mechanisms which might underlie different clinical outcomes in schizophrenia. The aims of the present study were to examine the BDNF/NGF plasma levels in a cohort of first-episode schizophrenia (FES) patients in remission as potential biological predictors of relapse; to study the associations between these neurotrophins and the symptomatology severity through different stages after a FES in two independent cohorts. 2EPs-Cohort: 69 first-episode in clinical remission were included. BDNF/NGF plasma levels and symptom severity were measured at enrollment and at 3-year or at the time of the second episode/relapse. FLAMM-PEPs-Cohort: 65 first-episodes were also included. BDNF/NGF and symptom severity were obtained at enrollment and 2-year follow-up. Symptomatology was assessed with the Marder-PANSS-Factor scores. Plasma neurotrophins did not differ significantly over time and neither BDNF/NGF were predictors of relapse. Besides, in remission stages, baseline BDNF levels showed significant correlations with both positive and negative symptoms (p<0.05); NGF, with negative symptomatology (p<0.01). Similarly, in the FLAMM-PEPs-Cohort, baseline BDNF/NGF levels showed significant correlations with negative symptoms (and not positive symptomatology) at follow-up (p<0.05). In both cohorts, lower levels correlated with higher symptom severity. Findings did not support a role for BDNF/NGF plasma levels as biomarkers of relapse in FES patients. Nevertheless, baseline BDNF/NGF may lead to be considered potentially useful biomarkers of long-term severity in schizophrenia and of the underlying illness traits, specially of negative symptomatology severity. More longitudinal studies in FES samples and adding a control group are warranted to replicate these findings.

Relationship of selective complement markers with schizophrenia.

Immune system dysregulation may be involved in schizophrenia, but biomarker studies have thus far reported inconsistent findings. The relationship of plasma levels of complement markers C3 and C4, with schizophrenia, sociodemographic and clinico-psychological factors were here studied in 183 patients and 212 controls. C3 and C4 levels were significantly higher in the patients and in subjects with elevated C-reactive protein (CRP), and positively correlated with body mass index (BMI) (p < 0.05). Schizophrenia, BMI, and CRP were significant predictors for C3 and C4 levels in multivariate analyses (p < 0.001). In conclusion, complements C3 and C4 are potential peripheral biomarkers in schizophrenia.

Pro-inflammatory cytokine levels are elevated in female patients with schizophrenia treated with clozapine.

RATIONALE AND OBJECTIVE: In this study, we hypothesized that the chronic use of clozapine affects cytokine expression and has a greater effect on female patients than on male patients. The aims of this study were to detect (1) whether serum cytokine levels were altered in patients with chronic schizophrenia after clozapine treatment compared with age- and sex-matched healthy controls, (2) whether there was a gender difference in serum cytokine levels after clozapine treatment, and (3) whether there was a correlation between serum cytokine levels and clozapine daily dosage in patients with schizophrenia. METHODS: Forty-nine inpatients with schizophrenia treated with clozapine and fifty-three sex- and age-matched healthy controls were recruited. The patients' psychiatric symptoms were measured by the Positive and Negative Syndrome Scale (PANSS). Blood samples from both patients and healthy controls were collected. Serum IL-1ß, IL-2, IL-6, IL-17, IFN-γ, and TNF-α levels were measured in duplicate by sandwich enzyme-linked immunosorbent assay. RESULTS: We found that chronic clozapine treatment in patients with schizophrenia resulted in the abnormal expression of serum cytokines, such as IL-2, IL-6, IL-17, and TNF-α, compared with the healthy controls. In addition, there was a gender difference in the abnormal expression of cytokines between male and female patients with schizophrenia. In the female group, IL-2 serum levels were lower than those in the male group. Interestingly, there was a positive correlation between serum IL-2 levels and the daily clozapine dosage in female patients with schizophrenia. CONCLUSION: Findings from our study have shown clear evidence that clozapine had a greater effect on immune function in female patients with schizophrenia.

Skewing of the antibody repertoire in cerebrospinal fluid B cells from healthy controls and patients with schizophrenia.

Autoantibodies play a role in the etiology of some neuropsychiatric disorders. To address the possibility that B cells and their antibodies may be involved in the pathophysiology of schizophrenia, we examined B cells in cerebrospinal fluid (CSF) and peripheral blood (PB) of 4 schizophrenic patients (SP) and 4 healthy control (HC) volunteers by analyzing immunoglobulin VH gene usage. All CSF samples contained measurable levels of B cells. We found for both SP and HC, CSF B cells represented a select subset of, and were not the same as, B cells in PB. Moreover, we found statistically significant differences in antibodies generated by CSF B cells in SP compared to CSF B cells in HC. Although binding characteristics of CSF SP-associated B cell antibodies is unknown, the study number is small, and pathophysiology has not been established, these results suggest the value of focusing further study on the distinctly separate population of CSF B cells in SP.

Distinctively lower DISC1 mRNA levels in patients with schizophrenia, especially in those with higher positive, negative, and depressive symptoms.

BACKGROUND: The issue of genetic influence on schizophrenia has received considerable attention. The DISC1 gene has been shown in several studies to play a role in the pathophysiology of schizophrenia. However, the relationship between DISC1 mRNA expression vs. schizophrenia and its clinical symptoms is uncertain. METHODS: Fifty-six subjects (32 patients with schizophrenia and 24 healthy controls) were enrolled. Peripheral blood was obtained from all subjects to exam the DISC1 mRNA expression. Schizophrenia patients were evaluated with Hamilton Rating Scale for Depression (HAMD), Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS) and Scale for the Assessment of Negative Symptoms (SANS) scales. Healthy subjects were assessed with HAMD scale. RESULTS: Patients with schizophrenia had significantly lower levels of the DISC1 mRNA expression than the healthy control (P = 0.002). We also found that lower DISC1 mRNA levels in schizophrenia patients were associated with higher degree of depression in HAMD (P = 0.037), severer positive symptoms in PANSS (P = 0.032) and more negative symptoms in SANS (P = 0.038). CONCLUSION: The results showed that schizophrenia patients had lower levels of DISC1 mRNA than healthy individuals, and that the schizophrenia patients with lower DISC1 mRNA levels were more likely to manifest more marked symptoms, including positive, negative, and depressive symptoms. The findings suggest that lower DISC1 expression may be related with the pathogenesis and phenotypes of schizophrenia. Future studies are needed to replicate the results and to further establish its potential role in clinical application of early diagnosis and outcome follow-up.

Effect of Valproic Acid on the Metabolic Spectrum of Clozapine in Patients With Schizophrenia.

BACKGROUND: Valproic acid (VPA) is frequently used with clozapine (CLZ) as mood stabilizer and/or seizure prophylaxis. Valproic acid is known to reduce N-desmethylclozapine (N-DMC) but not CLZ levels. This leads to the hypothesis that VPA induces the CLZ metabolism via non-N-desmethylation pathways. Therefore, we aimed to investigate the effect of concurrent VPA use on the serum concentrations of a spectrum of CLZ metabolites in patients, adjusting for smoking. METHODS: In total, 288 patients with an overall number of 737 serum concentration measurements of CLZ and metabolites concurrently using VPA (cases, n = 22) or no interacting drugs (controls, n = 266) were included from a routine therapeutic drug monitoring service. Linear mixed model analyses were performed to compare the dose-adjusted concentrations (C/D) of CLZ, N-DMC, CLZ 5N/N+-glucuronides, and metabolite-to-parent ratios in cases versus controls. RESULTS: After adjusting for covariates, the N-DMC (-40%, P < 0.001) and N+-glucuronide C/Ds (-78%, P < 0.001) were reduced in cases versus controls, while the CLZ C/D was unchanged (P > 0.7). In contrast, the 5N-glucuronide C/D (+250%, P < 0.001) and 5N-glucuronide-to-CLZ ratios (+120%, P = 0.01) were increased in cases versus controls. CONCLUSIONS: Our findings show that complex changes in CLZ metabolism underly the pharmacokinetic interaction with VPA. The lower levels of N-DMC seem to be caused by VPA-mediated induction of CLZ 5N-glucuronide formation, subsequently leading to reduced substrate availability for N-desmethylation. Whether the changes in CLZ metabolism caused by VPA affects the clinical outcome warrants further investigation.

A Real-World Study of Risk Factors for QTc Prolongation in Schizophrenia Patients Receiving Atypical Antipsychotics.

PURPOSE: The risk of sudden cardiac death in patients receiving atypical antipsychotics may be related to QTc prolongation. The aim of this study was to investigate the risk factors for QTc prolongation to prevent QTc prolongation and guide clinical practice. METHODS: All electrocardiogram recordings of 913 schizophrenia patients who were receiving atypical antipsychotics were reviewed for prolonged QTc and associated conditions. Binary logistic regression analysis was used to investigate risk factors for QTc prolongation. RESULTS: Logistic regression analysis demonstrated that sex (odds ratio [OR], 0.386; P = 0.010), age (OR, 1.047; P = 0.000), high-density lipoprotein (OR, 0.257; P = 0.014), and antipsychotics dose (OR, 1.040; P = 0.036) were significantly associated with QTc prolongation. CONCLUSIONS: In patients with male sex, elder age, low high-density lipoprotein, or large antipsychotics dose, QTc should be monitored more frequently.

Plasma Levels of the Cytokines B Cell-Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) in Schizophrenia, Bipolar, and Major Depressive Disorder: A Cross Sectional, Multisite Study.

BACKGROUND: Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. METHODS: We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. RESULTS: Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen's d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10). CONCLUSIONS: These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.

Cerebrospinal Fluid Pathologies in Schizophrenia-Spectrum Disorder-A Retrospective Chart Review.

BACKGROUND: The role of inflammatory processes in the etiology of schizophrenia is increasingly being investigated. A link between psychosis and inflammation measured with different biomarkers has been reported in the literature and needs to be further explored. To investigate the presence of inflammatory biomarkers in first-episode psychosis (FEP) we analyzed the largest available FEP cohort to date regarding routine CSF and blood diagnostics. METHODS: We report a retrospective analysis of clinical data from all inpatients that were admitted to our tertiary care hospital with a ICD-10 diagnosis of F2x (schizophrenia-spectrum) between January 1, 2008 and August 1, 2018 and underwent a lumbar puncture. RESULTS: A total of n = 314 FEP patients were included in our sample. 42.7% patients (134/314) showed cerebrospinal fluid (CSF) alterations. Oligoclonal bands in the CSF were present in 21.8% of patients (67/307) with 12.4% (27/217) of patients presenting OCBs type 2 or 3. 15.8% (49/310) of our cohort revealed signs of blood-brain-barrier (BBB) dysfunction with increased albumin ratios. Mean serum CRP levels were 2.4 mg/l (SD = 9.5). CRP elevation was present in 116/280 cases (41.4%). CONCLUSIONS: This large retrospective analysis on FEP cohort greatly enriches the clinical data available on this population and contributes to the discussion around inflammation in psychosis. Of note, even though several inflammatory alterations were found both in CSF and in blood tests, we found no evidence for a significant relationship between peripheral inflammation and inflammatory CSF. Furthermore, no significant relationship between CSF alterations and peripheral inflammation measured with CRP could be established.

Comparison of thyroid-stimulating hormone levels in adolescents with schizophrenia, bipolar disorder, unipolar depression, conduct disorders, and hyperkinetic disorders.

ABSTRACT: The aim of this study was to retrospectively compare values of thyroid-stimulating hormone (TSH) in adolescent patients diagnosed with schizophrenia, bipolar disorder, unipolar depression (UNI-DEP), conduct disorders (CD), and hyperkinetic disorders.The research involved 1122 patients (718 women, 64%); aged 12 to 18 hospitalized in the Department of Adolescent Psychiatry, Medical University of Lodz. We analyzed TSH levels in the whole study population and compared it between the above-mentioned subgroups of diagnoses.Mean serum TSH concentration in the studied population (n = 1122) was 2.06 µIU/mL. The values of percentiles were as follows: 2.5th - 0.53 µIU/mL, 10th - 0.89 µIU/mL, 25th - 1.31 µIU/mL, 50th - 1.9 µIU/mL, 75th - 2.6 µIU/mL, 90th - 3.43 µIU/mL, 97.5th - 4.72 µIU/mL. TSH values were negatively correlated with patients' age (P = .00001). Patients with bipolar depression had higher TSH levels than patients with CD (P = .002). Also, when male and female groups were examined separately we found that female patients with UNI-DEP and bipolar disorder had higher TSH levels than female patients with CD (P = .001; P = .001).Our results confirm that there may be a higher prevalence of thyroid dysfunctions in bipolar and UNI-DEP subgroups among adolescents and that it is worthy to consider some kind of interventions regarding thyroid function in depressed individuals.

Mapping the serum proteome to neurological diseases using whole genome sequencing.

Despite the increasing global burden of neurological disorders, there is a lack of effective diagnostic and therapeutic biomarkers. Proteins are often dysregulated in disease and have a strong genetic component. Here, we carry out a protein quantitative trait locus analysis of 184 neurologically-relevant proteins, using whole genome sequencing data from two isolated population-based cohorts (N = 2893). In doing so, we elucidate the genetic landscape of the circulating proteome and its connection to neurological disorders. We detect 214 independently-associated variants for 107 proteins, the majority of which (76%) are cis-acting, including 114 variants that have not been previously identified. Using two-sample Mendelian randomisation, we identify causal associations between serum CD33 and Alzheimer's disease, GPNMB and Parkinson's disease, and MSR1 and schizophrenia, describing their clinical potential and highlighting drug repurposing opportunities.

Effect of CYP2C19 polymorphisms on serum valproic level acid in Chinese Han patients with schizophrenia.

Valproic acid is an anticonvulsant, which is also widely used for treating psychiatric disorders. Some clinical trials have demonstrated benefits of valproic acid augmentation therapy in schizophrenia. Interindividual variability in valproic acid dose and serum concentration may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes. The aim of this study was to determine the relationship between serum concentrations of valproic acid and single nucleotide polymorphisms of the cytochrome P450 (CYP) 2C19 gene in patients with schizophrenia. All patients had been receiving fixed dose of valproic acid for at least 2 weeks. The daily doses were 0.5-1.5 g. No other drugs except olanzapine were coadministered. Serum concentrations of valproic acid were measured using the ultra-high performance liquid chromatography method with mass-spectrometric detection. The CYP2C19 (CYP2C19*2 G681A rs4244285 and CYP2C19*3 G636A rs4986893) genotypes were identified by real-time PCR analyses. The mean concentration/dose ratios of valproic acid were significantly higher in patients with CYP2C19 *1/*2 genotype (P < 0.01) or CYP2C19 *2/*3 genotype (P < 0.01) than in those with CYP2C12 *1/*1 genotype. The mean concentration/dose ratios of valproic acid were significantly higher in patients with 1 (P < 0.01) or 2 (P < 0.01) mutated alleles for CYP2C19 than in those without mutated alleles. And the post hoc analysis revealed that the result has acceptable statistical (power (1 - ß) = 0.8486 at type I level of 0.05) to support the observed significant associations for CYP2C19 SNPs and serum C/D ratios of valproic acid. The findings of this study suggest that the genetic polymorphisms of CYP2C19 significantly affect the steady-state serum concentrations of valproic acid in Chinese Han population. The determination of the CYP2C19 genotypes may be useful for dosing adjustment in schizophrenia patients on valproic acid therapy.

Associations between plasma fatty acid concentrations and schizophrenia: a two-sample Mendelian randomisation study.

BACKGROUND: Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia. METHODS: We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides. FINDINGS: Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75-0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98-1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58-0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02-1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71-1·01]). INTERPRETATION: Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia. FUNDING: National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.

Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice.

Importin α1/KPNA1 is a member of the Importin α family widely present in the mammalian brain and has been characterized as a regulator of neuronal differentiation, synaptic functionality, and anxiety-like behavior. In humans, a de novo mutation of the KPNA1 (human Importin α5) gene has been linked with schizophrenia; however, the precise roles of KPNA1 in disorder-related behaviors are still unknown. Moreover, as recent studies have highlighted the importance of gene-environment interactions in the development of psychiatric disorders, we investigated the effects of Kpna1 deletion and social isolation stress, a paradigm that models social stress factors found in human patients, on psychiatric disorder-related behaviors in mice. Through assessment in a behavioral battery, we found that Kpna1 knockout resulted in the following behavioral phenotype: (1) decreased anxiety-like behavior in an elevated plus maze test, (2) short term memory deficits in novel object recognition test (3) impaired sensorimotor gating in a prepulse inhibition test. Importantly, exposure to social isolation stress resulted in additional behavioral abnormalities where isolated Kpna1 knockout mice exhibited: (1) impaired aversive learning and/or memory in the inhibitory avoidance test, as well as (2) increased depression-like behavior in the forced swim test. Furthermore, we investigated whether mice showed alterations in plasma levels of stress-associated signal molecules (corticosterone, cytokines, hormones, receptors), and found that Kpna1 knockout significantly altered levels of corticosterone and LIX (CXCL5). Moreover, significant decreases in the level of prolactin were found in all groups except for group-housed wild type mice. Our findings demonstrate that Kpna1 deletion can trigger widespread behavioral abnormalities associated with psychiatric disorders, some of which were further exacerbated by exposure to adolescent social isolation. The use of Kpna1 knockout mice as a model for psychiatric disorders may show promise for further investigation of gene-environment interactions involved in the pathogenesis of psychiatric disorders.

DNA Methylation and Schizophrenia: Current Literature and Future Perspective.

Schizophrenia is a neuropsychiatric disorder characterized by dissociation of thoughts, idea, identity, and emotions. It has no central pathophysiological mechanism and precise diagnostic markers. Despite its high heritability, there are also environmental factors implicated in the development of schizophrenia. Epigenetic factors are thought to mediate the effects of environmental factors in the development of the disorder. Epigenetic modifications like DNA methylation are a risk factor for schizophrenia. Targeted gene approach studies attempted to find candidate gene methylation, but the results are contradictory. Genome-wide methylation studies are insufficient in literature and the available data do not cover different populations like the African populations. The current genome-wide studies have limitations related to the sample and methods used. Studies are required to control for these limitations. Integration of DNA methylation, gene expression, and their effects are important in the understanding of the development of schizophrenia and search for biomarkers. There are currently no precise and functional biomarkers for the disorder. Several epigenetic markers have been reported to be common in functional and peripheral tissue. This makes the peripheral tissue epigenetic changes a surrogate of functional tissue, suggesting common epigenetic alteration can be used as biomarkers of schizophrenia in peripheral tissue.

Association between plasma homocysteine levels and cognitive deficits in Han Chinese patients with schizophrenia across age groups.

It was still unclear how homocysteine (Hcy) levels and cognitive deficits change in patients with schizophrenia of various ages. The present article attempts to assess the relationship between Hcy levels and cognitive deficits in patients with schizophrenia across age groups, especially in young people. Totals of 103 patients and 122 healthy controls were included. All participants were stratified into four groups according to their age: 18-29 years, 30-39 years, 40-49 years, and 50-59 years. Clinical data, plasma Hcy levels, and cognitive function score were collected. Cognitive function was evaluated using the MATRICS Consensus Cognitive Battery of tests assessing speed of processing, verbal learning and memory, visual learning and memory, working memory, and attention/vigilance. Compared with the healthy group, Hcy levels increased significantly, and all the measured cognitive function score were significantly lower in all age groups of patients with schizophrenia (p < 0.001). Hcy levels were negatively associated with speed of processing (SoP), working memory (WM), and visual learning and memory (Vis Lrng) score in 18-29 years. Further multiple regression analysis showed that SoP were independently associated with Hcy levels in patients with schizophrenia aged 18-29 years (B = 0.74, t = 3.12, p = 0.008). Based on our results, patients with schizophrenia performed worse on cognitive assessments and Hcy levels were more closely related to cognition in young patients.