Copy Number Variation Analysis of Aggressive Behaviour in Schizophrenia.

INTRODUCTION: An increased proclivity towards violence is often associated with those diagnosed with schizophrenia (SCZ), despite contradictory findings from prior studies exploring the association between violence and SCZ. Evidence has shown that certain comorbidities, specifically the presence of a substance use disorders, can result in increased aggression in those with SCZ. Copy number variation (CNV) load has also previously been implicated in the genetic vulnerability of individuals with SCZ. For this study, we aimed to determine whether CNV load correlates with increased violence in SCZ. METHODS: Community-dwelling patients diagnosed with SCZ spectrum disorders (n = 203) were recruited from a non-forensic population. The assessment for aggression was completed using a cross-sectional and retrospective design, and CNV analysis was conducted analysing genomic DNA using the Illumina Omni 2.5 array. RESULTS: No correlation between the number of CNV events (either deletion or duplication) and the severity of the physical violence episode index was found. However, there was a significant association between larger deletion events across the violent behaviours under investigation. DISCUSSION: These results need to be confirmed in more extensive studies using standardized tools developed for non-forensic populations, such as the Brown-Goodwin Scale of Aggression.

Dynamic change in genome-wide methylation in response to increased suicidal ideation in schizophrenia spectrum disorders.

Suicide is a significant public health crisis, with 800,000 people dying annually. Most people completing suicide have previous psychiatric conditions, and those with psychotic and mood disorders are particularly vulnerable. Unfortunately, there are currently no biomarkers available for accurately detecting suicidal ideation. Given the genetic and environmental factors that play a role in suicidal ideation, we attempted to determine epigenetic modifications, specifically DNA methylation, in response to changes in suicidal ideation. Using a longitudinal study design, 31 participants with schizophrenia spectrum disorders were interviewed at a baseline visit and again at a follow-up visit 3-12 months later. Current suicidal ideation was recorded at both visits with the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicide Ideation, and whole blood was collected for methylation analysis. Our analysis shows a significant negative correlation between cg26910920 methylation and increasing Columbia Suicide Severity Rating Scale scores and a positive correlation between cg13673029 methylation and increasing Beck Scale for Suicide Ideation scores. This pilot study indicates that there is  the possibility  that DNA methylation can respond to changes in suicidal ideation over time and potentially be used as a biomarker of suicidal ideation in the future.

GWAS of biological aging to find longevity genes in schizophrenia.

Schizophrenia (SCZ) is a severe psychotic disorder associated with premature mortality and aging. Moreover, the symptoms and progression of psychiatric disorders in general are associated with decreased lifespan, biological aging, and poorer medical outcomes. In this study, we investigated the relationship between several epigenetic clocks and scanned the entire genome for association in a cohort of SCZ individuals (n = 107). Biological age was computed from blood DNA methylation (DNAm) and tested for association against  common  variants across the genome using general linear models. Genes affecting epigenetic age acceleration in our cohort were found mainly when using the telomeric length clock rather than the other biological clocks. These findings pair with existing evidence that there are some genes associated with longevity and suggest further investigations of  putative biological mechanisms for morbidity and premature mortality, not only in patients with SCZ but also in the general population.

Mediating effect of genome-wide DNA methylation on suicidal ideation induced by stressful events.

OBJECTIVE: Schizophrenia is a debilitating disease that is associated with higher rates of death by unnatural causes including suicide. Exposure to stressful events is an important risk factor for suicidal ideation (SI); however, the mechanisms that link stress, SI, and suicide remain unclear. Epigenetic processes are involved in both vulnerability to suicidal behavior and stress. Therefore, we sought to study the relationship between epigenetic modifications and suicidal behavior and stress. METHODS: This pilot study was conducted on 39 patients diagnosed with schizophrenia (54% men and age 45.5 ± 12.7). We analyzed the effects of (a) stress exposure and (b) the mediation of DNA methylation [via an epigenetic wide association study (EWAS) of more than 450 000 CpG sites across the genome] on SI severity. RESULTS: The top CpG site mediating the effect of global stress exposure on SI was cg27660192 located in an intergenic region on chromosome 11, exerting a facilitating effect on worsening SI through DNA hypomethylation. CONCLUSION: These preliminary results indicate that DNA methylation in peripheral tissues can shed light on the complex relationship between stress and SI in schizophrenia.

Genome-wide methylation analysis of treatment resistant schizophrenia.

Various studies have investigated the relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug response. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and treatment resistance schizophrenia. The primary aim of this pilot study is to investigate the association between treatment resistance status and genome-wide DNA methylation in schizophrenia patients. Treatment resistance status was determined for 109 patients with schizophrenia. Treatment resistance was the primary outcome variable in a model, including methylation status of white blood cells using the Illumina 450 array. The genome-wide DNA methylation levels in 109 Schizophrenia subjects did not show that DNA methylation sties were associated with resistance status. From our study, it is evident the importance of continuing to investigate the relationship between DNA methylation and antipsychotic response to personalize treatment in schizophrenia. Future studies require larger prescription databases to build on the results presented in this pilot study.

Concordance between the Columbia-Suicide Severity Rating Scale and Beck Scale for Suicide Ideation in assessing suicide behaviour in young adults with schizophrenia spectrum disorders.

The Columbia Suicide Severity Rating Scale (C-SSRS) is considered the gold standard for collecting information on suicidal ideation and behavior by the Food and Drug Administration (FDA) of the United States. To determine the accuracy of the C-SSRS compared to the Beck Scale for Suicidal Ideation (BSS) for collecting suicide attempt history in the schizophrenia population, 202 participants aged 18-40 with schizophrenia spectrum disorders were administered the C-SSRS, followed by the BSS. Medical charts were reviewed to confirm the lifetime history of actual suicide attempts. The BSS had an 83.5% accuracy in reporting single suicide attempts and 81.7% for multiple suicide attempts; while the C-SSRS had 84.1% and 83.9% accuracy respectively. This difference was not statistically significant (p = 0.849). Both the BSS and C-SSRS demonstrated high sensitivity and specificity in collecting suicide attempt history for young patients with psychosis, with no significant differences. Future investigators may choose the scale that is best suited to the level of detail required.

Protein Nanoparticles for Enhanced Oral Delivery of Coenzyme-Q10: in Vitro and in Silico Studies.

Coenzyme-Q10 (CoQ10) is a hydrophobic benzoquinone with antioxidant and anti-inflammatory properties. It is known to reduce oxidative stress in various health conditions. However, due to the low solubility, permeability, stability, and poor oral bioavailability, the oral dose of CoQ10 required for the desired therapeutic effect is very high. In the present study, CoQ10 is encapsulated into two milk derived proteins ß-lactoglobulin and lactoferrin (BLG and LF) to produce self-assembled nanostructures of around 100-300 nm with high encapsulation efficiency (5-10% w/w). Both CoQ10-BLG and CoQ10-LF nanoparticles (NPs) significantly improved the aqueous solubility of CoQ10 60-fold and 300-fold, compared to CoQ10 alone, which hardly dissolves in water. Insight into the difference in solubility enhancement between BLG and LF was obtained using in silico modeling, which predicted that LF possesses multiple prospective CoQ10 binding sites, potentially enabling greater loading of CoQ10 on LF compared to BLG, which was predicted to be less capable of binding CoQ10. At pH 7.4, CoQ10-LF NPs showed a burst release between 30 min and 2 h then plateaued at 12 h with 30% of the total drug released over 48 h. However, pure CoQ10-BLG and pure CoQ10 had a significantly lower release rate with less than 15% and 8% cumulative release in 48 h, respectively. Most importantly, both BLG and LF NPs significantly improved CoQ10 permeability compared to the pre-dissolved drug across the Caco-2 monolayer with up to 2.5-fold apparent permeability enhancement for CoQ10-LF─further confirming the utility of this nanoencapsulation approach. Finally, in murine macrophage cells (J774A.1), CoQ10-LF NPs displayed significantly higher anti-ROS properties compared to CoQ10 (predissolved in DMSO) without affecting the cell viability. This study paves the way in improving oral bioavailability of poorly soluble drugs and nutraceuticals using milk-based self-assembled nanoparticles.

Epigenetic age dysregulation in individuals with bipolar disorder and schizophrenia.

Bipolar disorder (BD) and schizophrenia (SCZ) are debilitating disorders that are associated with significant burden and reduced quality of life. In this study, we leveraged microarray data derived from both the Illumina HumanMethylation450 platform to investigate the epigenetic age of individuals with SCZ (n = 40), BD (n = 40), and healthy controls (n = 38), across five epigenetic clocks. Various statistical metrics were used to identify discrepancies between epigenetic and chronological age across the three groups. We observed a significant increase in epigenetic age compared to chronological age in the BD group. Mean epigenetic age acceleration was also higher in individuals with bipolar disorder compared to healthy controls across four different epigenetic clocks (p<0.05). Despite the study's relatively small sample size, these findings suggest that both individuals with bipolar disorder and schizophrenia may have epigenetic markers associated with a premature aging phenotype, which could be suggestive of negative outcomes associated with the disease. In our future studies, we hope to elucidate this finding further by elucidating the precise link between epigenetic age, symptomatology and disease progression.

Genome-wide methylation analysis of early-onset schizophrenia.

OBJECTIVE: Schizophrenia (SCZ) is a debilitating disease with a complex genetic cause in which age at onset may reflect genetic vulnerability. Though there has been some association between genetic polymorphisms and age of onset, there has been little exploration of the role of epigenetic processes. We sought to explore the influence of DNA methylation, a key epigenetic mechanism, and its association with the age of onset of illness. METHODS: One hundred thirty-eight participants aged 18-75 years and previously diagnosed with SCZ spectrum disorders by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID DSM-5) were recruited. Venous blood was collected and genome-wide DNA methylation was quantified using the Illumina Infinium HumanMethylation450 BeadChip array. Individual CpG sites and regions of differential methylation were explored by the age of onset; covariates included age, sex, as well as white blood cell composition. RESULTS: Binary grouping (early vs. late onset) revealed four intergenic CpG sites on chromosome 2 that were above the expected P-value threshold, with hypermethylation of the CpG site cg10392614 most strongly associated with early-onset SCZ. The four most strongly associated CpG sites, including cg 10392614, were intergenic. Continuous analysis revealed the top CpG site to be cg11723066 , which is linked to the JAM3 gene, with hypomethylation associated with earlier onset; however, results were below the expected P-value threshold. CONCLUSION: Studies on DNA methylation in the first-episode psychosis population may help further our understanding of the role of epigenetics in the age of onset of SCZ.

Differential Methylation Analysis of Suicidal Ideation Severity in Schizophrenia with the Illumina MethylationEPIC Array.

There is a multitude of factors that makes difficult to identify those at risk for suicide, especially among schizophrenia patients. Suicide cannot be explained by genetics alone, therefore epigenetic mechanisms including DNA methylation are thought to play a role. DNA methylation could be a valuable tool in helping predict those at-risk individuals. This cross-sectional study comprised 112 subjects diagnosed with schizophrenia spectrum disorders, and were grouped according to the current suicidal ideation severity. DNA methylation across the genome was measured with the Infinium® MethylationEPIC BeadChip. We utilized the dmpFinder and bumphunter functions within the Bioconductor minfi package to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs), respectively. Following quality control, we removed one sample from the analysis and reported the most significant DMPs and DMRs associated with suicidal ideation severity. All positions and regions identified in this analysis were only found to have suggestive levels of significance at the genome-wide level. The present study was one of the first to investigate genome-wide methylation and suicidal ideation severity. While there were many strengths of our study, including investigating both differentially methylated positions and regions, further larger-scale studies are necessary to replicate, support, and validate our findings presented here.

Encapsulation and Controlled Release of Resveratrol Within Functionalized Mesoporous Silica Nanoparticles for Prostate Cancer Therapy.

Resveratrol (RES) is a naturally existing polyphenol which exhibits anti-oxidant, anti-inflammatory, and anti-cancer properties. In recent years, RES has attracted attention for its synergistic effect with other anti-cancer drugs for the treatment of drug resistant cancers. However, RES faces the issues of poor pharmacokinetics, stability and low solubility which limits its clinical application. In present study, RES has been loaded onto uniformly sized (~60 nm) mesoporous silica nanoparticles (MSNs) to improve its in vitro anti-proliferative activity and sensitization of Docatexal in hypoxia induced drug resistance in prostate cancer. RES was efficiently encapsulated within phosphonate (negatively charged) and amine (positively charged) modified MSNs. The effect of surface functionalization was studied on the loading, in vitro release, anti-proliferative and cytotoxic potential of RES using prostate cancer cell line. At pH 7.4 both free and NH2-MSNs loaded RES showed burst release which was plateaued with almost 90% of drug released in first 12 h. On the other hand, PO3-MSNs showed significantly slower release kinetics with only 50% drug release in first 12 h at pH 7.4. At pH 5.5, however, both the PO3-MSNs and NH2-MSNs showed significant control over release (around 40% less release compared with free RES in 24 h). Phosphonate modified MSNs significantly enhanced the anti-proliferative potential of RES with an IC50 of 7.15 µM as compared to 14.86 µM of free RES whereas amine modified MSNs didn't affect proliferation with an IC50 value higher than free RES (20.45 µM). Furthermore, RES loaded onto PO3-MSNs showed robust and dose dependent sensitization of Docatexal in hypoxic cell environment which was comparable to pure RES solution. This study provides an example of applicability of MSNs loaded with polyphenols such as RES as next generation anticancer formulations for treating drug resistant cancers such as prostate cancer.

Efficient photoacoustic imaging using indocyanine green (ICG) loaded functionalized mesoporous silica nanoparticles.

Photoacoustic (PA) imaging is gaining momentum due to its greater depth of field, low background, and 3D imaging capabilities. However, traditional PA imaging agents (e.g. dyes, quantum dots, etc.) are usually unstable in plasma and bind to serum proteins, and thus cleared rapidly. Because of this, the nanoparticle encapsulation of PA imaging agents is becoming increasingly popular. Therefore, the rational design of carrier nanoparticles for this purpose is necessary for strong imaging signal intensity, high biosafety, and precise targeting. Herein, we systematically evaluate the influence of the chemical and physical surface functionalization of mesoporous silica nanoparticles (MSNs) on the photo-stability, loading, release, and photoacoustic (PA) signal strength of the FDA approved small molecule contrast agent, indocyanine green (ICG). Chemical functionalization involved the modification of MSNs with silanes having amine (NH2) or phosphonate (PO3) terminal groups, whereas physical modifications were performed by capping the ICG loaded MSNs with lipid bilayer (LB) or layer-by-layer (LBL) polyelectrolyte coatings. The NH2-MSNs display the highest ICG mass loading capacity (16.5 wt%) with a limited release of ICG (5%) in PBS over 48 h, while PO3-MSNs only loaded ICG around 3.5 wt%. The physically modified MSNs (i.e. LBMSNs and LBLMSNs) were vacuum loaded resulting in approximately 9 wt% loading and less than 10% ICG release in 48 h. Pure ICG was highly photo-unstable and showed 20% reduction in photoluminescence (PL) within 3 h of exposure to 800 nm, while the ICG loaded onto functionalized MSNs did not photo-degrade. Among the tested formulations, NH2-MSNs and LBLMSNs presented 4-fold in vitro PA signal intensity enhancement at a 200 µg mL-1 equivalent ICG dose. Similar to the in vitro PA imaging, NH2-MSNs and LBLMSNs performed the best when subcutaneously injected into mouse cadavers with 1.29- and 1.43-fold PA signal enhancement in comparison to the pure ICG, respectively.