Assessing past suicidal behaviour in schizophrenia spectrum disorders using the Columbia-Suicide Severity Rating Scale and the Beck Scale for Suicide Ideation: Analysis across the life-span.

Assessing the number of past suicide attempts is vital in clinical and research settings, as it is a significant variable in assessing suicide risk. This study sought to compare the accuracy of the C-SSRS and the BSS in reporting past suicide attempts in schizophrenia spectrum disorders . Six hundred participants were recruited from the Centre for Addiction and Mental Health in Toronto, and completed the BSS and C-SSRS. A medical chart review was performed to determine the number of past suicide attempts. In addition, receiver operating characteristic curves were generated to compare the accuracy of both tests under various stratifications. Based on our findings, there were no significant differences (P = 0.8977) between the BSS and CSSRS in detecting a history of past suicide attempts. The BSS exhibited a sensitivity of 0.847 and a specificity of 0.841, while the C-SSRS had a slightly lower sensitivity of 0.795 and a slightly higher specificity of 0.889. Additionally, repeating the analysis to determine the accuracy of detecting multiple past suicide attempts, the BSS demonstrated a sensitivity of 0.704 and a specificity of 0.959, whereas the C-SSRS had a sensitivity of 0.787 and a specificity of 0.927. We further contrasted the two scales, stratified by different demographic variables such as age and sex. The accuracy of both tools, which is defined as the ability to identify true positive cases while minimizing false positives, increased as age increased, but these differences were not statistically significant. Therefore, both tools show a high level of accuracy in reporting past suicide attempt history and should be utilized to fit the specific needs of the research or clinical teams. These findings can inform clinical practice and future research, highlighting the importance of selecting assessment tools that fit the population's needs and context.

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.

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.

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.

Epigenetics for Drug Discovery: Dissecting the Effect of High Antipsychotic Dosage and D2 Blockage on Peripheral DNA Methylation.

INTRODUCTION: The relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug receptors has been often investigated. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and antipsychotic dosage. The primary aim of this pilot study was to investigate the association between antipsychotic dosage and genome-wide DNA methylation in patients with schizophrenia (SCZ). METHODS: Current dosage of antipsychotic medications was assessed in 136 patients with SCZ. Dosage was standardized using three different methods: chlorpromazine equivalent dose (CPZe), defined daily dose (DDD), and percentage of Lexicomp maximum dose (PM%). DNA methylation was measured in white blood cells. Antipsychotic dosage was the primary outcome variable in a model, including genome-wide methylation status as the main predictor. RESULTS: This study did not show any association between DNA methylation and dosage variation for CPZe, PM%, and DDD. However, the probe cg271403389 was consistently associated with antipsychotic dosage across the three standardization methods. When looking at the genomic location of the most significant probes, we found that 15% were intergenic, 23% were in the distal promoter, 9% in the 3'untranslated region, 32% in the gene body, 3% in the 5' untranslated region, 15% in the proximal promoter, and 3% in the first exon. DISCUSSION: This study shows the importance of investigating the relationship between DNA methylation and optimal antipsychotic dosage to personalize treatment in SCZ. Future studies require larger prescription databases to build on the results of this analysis.

Sex differences in schizophrenia: a longitudinal methylome analysis.

DNA methylation analysis at the genome-wide level is a useful tool to explore potential sex differences in SCZ patients. The primary aim of the current study was to identify differentially methylated regions of DNA between males and females with schizophrenia. We collected DNA samples from 134 schizophrenia patients to measure genome-wide methylation at single-base resolution in 96 males and 38 females. We further repeated the analysis in 13 subjects (9 females, 4 males) to confirm the sex differences and to reduce the effect of potential confounders. The longitudinal methylation analysis found significant replication of several genes across the genome. These genes included RFTN1, TLE1, DAZL, PRR4, UTP14C, RNU12, and LOC644649. The overall results showed robust association between autosomal CpG sites and sex. Longitudinal methylation analysis can be used as internal replication to confirm epigenetic variants that are stable over time.

Recent Stressful Life Events and Suicidal Ideation in Schizophrenia: A 1-Year Follow-up Study.

ABSTRACT: Half of patients with schizophrenia experience suicidal ideation. Only few studies have examined the effects of recent stress on both current and emergent suicidal ideation.A cohort of 85 patients with schizophrenia spectrum disorders was assessed. The study was divided into a cross-sectional and longitudinal arms to test the effect of recent stress on suicidal ideation. Analysis was done using logistic regression models.After correcting for covariates, recent stress had no significant effect on current suicidal ideation. However, increased total stress (odds ratio [OR] = 1.099 [1.032-1.170], p = 0.003) and health-related stress (OR = 1.331 [1.074-1.650], p = 0.009) at follow-up were predictive of emergent suicidal ideation.With this sample size, we were unable to draw firm conclusions regarding the effect of specific life events on suicidal ideation. Further studies involving larger samples that investigate the interplay between several risk factors are needed.

Association Between the Visual N1-P2 Complex and Neuroticism.

Neuroticism is a personality trait associated with impaired attention, memory, and error detection. Thus, the present study investigated the visual N100 and P200 event-related potentials components associated with attention using a 2-back working memory task in healthy neurotic and nonneurotic participants, evaluated using the Neuroticism, Extraversion, Openness Five Factor Inventory. A total of 35 healthy participants were asked to perform the 2-back task while recording electroencephalographic activity from 64 electrodes on the scalp. Analysis of the N100 and P200 amplitude and latency in high neuroticism and low neuroticism subjects showed an increased P200 amplitude and latency for high neuroticism subjects in the frontal and parietal regions, respectively. However, there were no significant performance differences between the high and low neuroticism subjects for the 2-back working memory task. Therefore, the results suggest that neuroticism is associated with the P200 component elicited in the context of a working memory task.

Head-to-head comparison of various antipsychotic agents on genome-wide methylation in schizophrenia.

Aim: To explore possible differences in genome-wide methylation between schizophrenia patients who consume various antipsychotics. Methods: We compared DNA methylation in leukocytes between the following cohorts: clozapine (n = 19) versus risperidone (n = 19), clozapine (n = 12) versus olanzapine (n = 12), clozapine (n = 9) versus quetiapine (n = 9) and clozapine (n = 33) versus healthy controls (n = 33). Subjects were matched for age, sex, ethnicity, smoking status and leukocyte proportions. Results: No single CpG site reached genome-wide significance for clozapine versus risperidone/olanzapine/quetiapine. For clozapine versus quetiapine, one significantly differentially methylated region was found - ch5: 176797920-176798049 (fwer = 0.075). Clozapine versus healthy controls yielded thousands of significantly differentially methylated CpG sites. Conclusions: Establishing antipsychotic induced genome-wide methylation patterns will further elucidate the biological and clinical effects of antipsychotic administration.

Epigenetic studies in suicidal ideation and behavior.

Most psychiatric disorders are associated with an elevated risk of suicide. Suicidal behavior is the product of the interaction of many risk factors, such as genetics and environmental factors. Hence, epigenetics research may help to understand the mechanisms leading to suicidal ideation and behavior. This review will discuss epigenetic studies in both suicidal ideation and behavior. Epigenetic modifications are likely to be important in both suicidal ideation and behavior. Most of the reviewed studies found significant epigenetic modifications linked with suicidal behavior rather than ideation. Although sizable research has been carried out on this topic, most studies have been done on small-scale samples, and future research is required in larger samples with better clinical characterization of suicide phenotypes to investigate these epigenetic modifications further.

Epigenetics of Schizophrenia.

Schizophrenia (SCZ) is a chronic psychotic disorder that contributes significantly to disability, affecting behavior, thought, and cognition. It has long been known that there is a heritable component to schizophrenia; studies in both the pre-genomic and post-genomic era, however, have failed to elucidate fully the genetic basis for this complex disease. Epigenetic processes - broadly, those which contribute to changes in gene expression without altering the genetic code itself - may help to understand better the mechanisms leading to development of SCZ. The objective of this review is to synthesize current knowledge of the epigenetic mechanisms involved in schizophrenia. Specifically, DNA methylation studies in both peripheral and post-mortem brain samples in SCZ are reviewed, as are epigenetic mechanisms including histone modification. The promising role of non-coding RNA including micro-RNA (miRNA) and its role as a potential diagnostic and therapeutic biomarker is outlined, as are epigenetic age acceleration and telomere shortening. Finally, we discuss limitations in current knowledge and propose future research directions.

Mediating effect of genome-wide DNA methylation on suicidal ideation induced by perceived stress.

Stress is an important risk factor for suicidal ideation, but the mechanisms that link stress, suicidal ideation and neurobiology remain unclear. Epigenetic mechanisms are involved in both vulnerability to suicidal behavior and stress. This is a pilot study of 60 patients with schizophrenia spectrum disorders (36 men and 24 women), with an average age of 43.75 ± 12.24 years. We analyzed the effects of (1) perceived stress and (2) the mediation of genome-wide methylation (~450 000 CpG sites) on suicidal ideation severity. The top CpG site mediating the effect of stress on suicidal ideation was the cg10782349 located in the ZNF701 gene on chromosome 19, facilitating the effect through DNA hypermethylation. These preliminary results indicate that DNA methylation in peripheral tissues can clarify the complex relationship between stress and suicidal ideation in schizophrenia.

Chromosome 22 Deletions and Suicidal Behavior in Schizophrenia.

BACKGROUND: Studies have shown that the overall copy number variant (CNV) load is associated with schizophrenia. Schizophrenia is a mental disorder that is frequently associated with suicidal behavior. METHODS: We recruited 263 patients with schizophrenia from the Centre for Addiction and Mental Health. The Columbia Suicide Severity Rating Scale was used to assess the presence of lifetime suicide attempt. Genotyping was completed using the Illumina Omni 2.5 chip. We tested the association between deletion events on chromosome 22 with suicide attempt in our schizophrenia sample. RESULTS: There was no significant difference between suicide attempters and non-attempters considering the presence/absence of deletion events on chromosome 22. CONCLUSION: Although our results did not show a significant association between deletions on chromosome 22 and suicide attempt in schizophrenia, CNV studies may reveal important, novel insights and open further investigation for the treatment of neuropsychiatric diseases.