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.

Implementing Predictive Models Within an Electronic Health Record System: Lessons from an External Validation of a Suicide Risk Model.

Over the past 5 years, there has been an increase in the development of EHR-based models for predicting suicidal behaviour. Using the McGinn (2000) framework for creating clinical prediction rules, this study discusses the broad validation of one such predictive model in a context external to its derivation. Along with reporting performance metrics, our paper high-lights five practical challenges that arise when trying to undertake such a project including (i) validation sample sizes, (ii) availability and timeliness of data, (iii) limited or incomplete documentation for predictor variables, (iv) reliance on structured data and (v) differences in the source context of algorithms. We also discuss our study in the context of the current literature.

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.

Novel intranasal treatment for anxiety disorders using amiloride, an acid-sensing ion channel antagonist: Pharmacokinetic modeling and simulation.

OBJECTIVE: To develop a physiologically based pharmacokinetic (PBPK) model for amiloride, an acid-sensing ion channel (ASIC) antagonist, and to simulate its pharmacokinetics in plasma and the central nervous system following intranasal administration in a virtual human population. MATERIALS AND METHODS: We first developed a PBPK model of amiloride after oral administration and optimized the model using data from five clinical studies. Next, we added a nasal compartment to the amiloride oral PBPK model and parameterized using data from previous clinical studies. We simulated amiloride's pharmacokinetics in plasma, brain, and cerebrospinal fluid (CSF) after intranasal administration of amiloride at various doses in a virtual human population. RESULTS: The target amiloride concentration in the central nervous system required for maximal ASIC inhibition was achieved with a 75-mg intranasal amiloride dose. However, this finding is based on simulations performed using a mathematical model and needs to be further validated with appropriate clinical data. CONCLUSION: The nasal PBPK model of amiloride could be used to design future clinical studies and allow for successful clinical translation of intranasal amiloride formulation.

Exploring Uniformity of Clinical Judgment: A Vignette Approach to Understanding Healthcare Professionals' Suicide Risk Assessment Practices.

OBJECTIVES: Suicide risk assessment often requires health professionals to consider a complex interplay of multiple factors, with a significant reliance on judgment, which can be influenced by factors such as education and experience. Our study aimed at assessing the uniformity of decision making around suicide risk within healthcare professionals. METHODS: We used a factorial survey approach to gather information on healthcare professionals' demographics, clinical experience, and their decision on 3 vignettes of patients with suicidal ideation. We used Kruskal-Wallis tests for determining if there were significant differences between groups for continuous variables and Spearman rank correlation for measuring the association between continuous variables. Content analysis was used for analyzing free-text comments. RESULTS: Responses were gathered from 79 healthcare professionals (nurses, nurse practitioners, physicians) who worked in primary care, mental health, or emergency department settings. Median suicide risk rates across all respondents were 90%, 50%, and 53% for vignettes 1, 2, and 3, respectively. Confidence in healthcare professionals' decisions was significantly associated with the clinical designation and personal risk profile of the healthcare professional in certain vignettes, with nurses and those willing to take more risks having a higher confidence in their decisions for vignettes 1 and 3, respectively. Treatment decision was significantly associated with mental health experience (i.e., those with lengthier mental health experiences were less likely to choose "admit to psychiatry ward" for vignette 2), clinical designation (i.e., nurses were more likely to "admit to psychiatry ward" for vignette 1), and practice setting. It should be noted that these associations were not consistent across all 3 vignettes, and results for each association were only specific to 1 of the 3 vignettes. DISCUSSION: Findings compare decision-making practices for suicide risk assessment across several types of healthcare professions over a range of practice settings, with the high-risk vignette showing the least variability. Insights from this study are relevant when building clinical decision support systems for suicide risk assessment. Designers should think about incorporating tailored messaging and alerts to health professionals' mental health experience and/or designation. CONCLUSIONS: Within our Canadian sample, there was considerable variability among healthcare professionals assessing the risk of suicide, with important implications for tailoring education and decision support.

Links Between Mortality and Socioeconomic Characteristics, Disease Burden, and Biological and Physical Functioning in the Aging Chinese Population.

OBJECTIVES: Determinants of mortality may depend on the time and place where they are examined. China provides an important context in which to study the determinants of mortality at older ages because of its unique social, economic, and epidemiological circumstances. This study uses a nationally representative sample of persons in China to determine how socioeconomic characteristics, early-life conditions, biological and physical functioning, and disease burden predict 4-year mortality after age 60. METHODS: We used data from the China Health and Retirement Longitudinal Study. We employed a series of Cox proportional hazard models based on exact survival time to predict 4-year all-cause mortality between the 2011 baseline interview and the 2015 interview. RESULTS: We found that rural residence, poor physical functioning ability, uncontrolled hypertension, diabetes, cancer, a high level of systemic inflammation, and poor kidney functioning are strong predictors of mortality among older Chinese. DISCUSSION: The results show that the objectively measured indicators of physical functioning and biomarkers are independent and strong predictors of mortality risk after accounting for several additional self-reported health measures, confirming the value of incorporating biological and performance measurements in population health surveys to help understand health changes and aging processes that lead to mortality. This study also highlights the importance of social and historical context in the study of old-age mortality.

CARIBOU-1: A pilot controlled trial of an Integrated Care Pathway for the treatment of depression in adolescents.

Background: To co-ordinate a multidisciplinary team in the delivery of guideline recommendations using a measurement-based care framework, our group previously developed a care pathway for the treatment of depression in adolescents. Core components of the pathway were: assessment, education, cognitive-behavioural therapy, a caregiver intervention group, a medication algorithm, and monthly measurement-based care "team reviews" with the adolescent present. The aim of this study was to test the feasibility of conducting a controlled clinical trial of the pathway. Method: We conducted a 20-week pilot controlled clinical trial of the care pathway relative to treatment as usual. Participants were adolescents (age 14-18) with a primary diagnosis of Major Depressive Disorder recruited from one of two outpatient psychiatric clinics at academic hospitals. Site of presentation was the method of allocation. Thirty-five youth were allocated to the pathway and 31 were allocated to treatment as usual. As this is a pilot study, trial feasibility outcomes were of primary interest, including clinician fidelity to the care pathway. Results: Our target sample size was recruited over a 15-month time interval. Clinician fidelity and adolescent engagement in the care pathway components on a priori checklists were high (95% and 80%, respectively). We collected baseline and 20-week endpoint data for our primary outcome of the Children's Depression Rating Scale - Revised (CDRS-R) for 83% of the sample. On linear mixed effects modelling, we observed a linear decrease in CDRS-R across 4-week intervals up to the 20-week endpoint in both groups (ß = -2.07; 95% CI -3.14 to -1.01). Conclusion: A controlled clinical trial of a complex, multi-component intervention for the treatment of depression in adolescents is feasible. Given the need to find optimal strategies to deliver effective care for adolescents with depression, a definitive randomized controlled trial of the pathway is warranted.Trial is registered at Clinicaltrials.gov: NCT03428555.

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.

"This Is ME": Promoting Person-Centred Care within the Digital Health Environment.

In this paper, we describe the implementation of an initiative called "This Is ME," which involves a change in the summary page of a patient's electronic health record in order to include their story and provide a more humanistic perspective. The change includes information related to their family, hobbies and interests - a change that has important implications for facilitating conversation and relationship-building between providers and patients. Since implementation, 1,246 (and counting) patient stories were shared with over 300 healthcare providers, including nurses, social workers, physicians and others. We also share the results of our evaluation of the initiative and provide recommendations for organizations embarking on similar initiatives.

Genome-wide association study of suicidal behaviour severity in mood disorders.

OBJECTIVE: Suicide is a major public health problem and it has a prominent genetic component. We performed a genome-wide association study (GWAS) of suicidal behaviour severity. METHODS: Suicide behaviour severity was assessed within the Schedules for Clinical Assessment in Neuropsychiatry in our mood disorder sample (n = 3506) for the GWAS. We also performed polygenic risk score analyses to explore genetic sharing between suicidal behaviour severity and a number of phenotypes, including bipolar disorder, major depressive disorder, alcoholism, post-traumatic stress disorder, impulsivity, insomnia, educational attainment, loneliness, maltreatment, and amygdala volume. RESULTS: We did not detect genome-wide significant findings at the single-marker or gene level. We report a number of suggestive single-marker and gene-based findings. Our polygenic risk score analyses did not yield significant findings with these phenotypes. CONCLUSIONS: Larger sample sizes are required to detect moderate effects.

Biological aging in schizophrenia and psychosis severity: DNA methylation analysis.

The physiological changes associated with normal aging are known to occur earlier in individuals with schizophrenia (SCZ). One of the phenomena linked with normal aging is the change in patterns of epigenetic modifications. We recruited 138 individuals with SCZ spectrum disorders and extracted DNA from white blood cells. The combinations of pre-selected DNA methylation sites were utilized to estimate the 'methylation age' (DNAm age) and evaluate evidence of epigenetic age acceleration. We investigated the correlation between the epigenetic age acceleration measures and psychosis severity; furthermore, we estimated blood cell counts based on DNA methylation levels. The extrinsic epigenetic age acceleration showed a significant correlation with the Brief Psychiatric Rating Scale (BPRS) disorganization subscale(r=0.222, p=0.039).Both Horvath age acceleration and Hannum age acceleration showed a significant correlation (r=0.221, p=0.029; r=0.242, p=0.017 respectively) with the Symptom Checklist 90 (SCL-90) psychotic domain. Overall, this study shows some evidence of epigenetic age acceleration associated with psychosis severity using two different algorithms for DNAm age analysis.

Genome-wide methylation association with current suicidal ideation in schizophrenia.

In this study, we investigate the epigenetic mechanisms associated with current suicidal ideation. Gene expression changes have been found in post-mortem brain of suicide victims. However, it is not clear how in-vivo gene expression change confers risk for suicide. DNA methylation is a form of epigenetic modification that regulates gene expression. Our primary aim is to investigate genome-wide methylation in conferring risk for current suicidal ideation (SI) in schizophrenia. The presence of current SI and genome-wide methylation patterns were assessed in 107 patients with schizophrenia. DNA methylation has been measured in white blood cells as a possible peripheral biomarker of SI. SI was the primary outcome variable in a model including methylation status of white blood cells using the Illumina 450 array. We have tested the association with genome-wide methylation levels in 19 subjects with current SI and 88 subjects without current SI and we found that higher methylation level in the CpG cg06121808 located in the gene SLC20A1 on chromosome 2 was associated with current SI (p = 0.000003; beta difference = 0.06). Furthermore, the distal promoter analysis showed that the gene SMPD2 was hypermethylated in suicide ideators (p = 0.0001; beta difference = 0.02). Thus, molecular biomarkers could advance our understanding of the molecular mechanisms of stress-related SI. Furthermore, the methylation sites that we have identified should be replicated in other suicide related phenotypes to generate robust biomarkers with high translational value for proof of concept interventions aiming at reducing SI.

Stability of extemporaneously compounded amiloride nasal spray.

Anxiety disorders (AD) are the most common mental conditions affecting an estimated 40 million adults in the United States. Amiloride, a diuretic agent, has shown efficacy in reducing anxious responses in preclinical models by inhibiting the acid-sensing ion channels (ASIC). By delivering amiloride via nasal route, rapid onset of action can be achieved due to direct "nose-to-brain" access. Therefore, this study reports the formulation, physical, chemical, and microbiological stability of an extemporaneously prepared amiloride 2 mg/mL nasal spray. The amiloride nasal spray was prepared by adding 100 mg of amiloride hydrochloride to 50 mL of sterile water for injection in a sterile reagent bottle. A stability-indicating high-performance liquid chromatography (HPLC) method was developed and validated. Forced-degradation studies were performed to confirm the ability of the HPLC method to identify the degradation products from amiloride distinctively. The physical stability of the amiloride nasal spray was assessed by pH, clarity, and viscosity assessments. For chemical stability studies, samples of nasal sprays stored at room temperature were collected at time-points 0, 3 hr., 24 hr., and 7 days and were assayed in triplicate using the stability-indicating HPLC method. Microbiological stability of the nasal spray solution was evaluated for up to 7 days based on the sterility test outlined in United States Pharmacopoeia (USP) chapter 71. The stability-indicating HPLC method identified the degradation products of amiloride without interference from amiloride. All tested solutions retained over 90% of the initial amiloride concentration for the 7-day study period. There were no changes in color, pH, and viscosity in any sample. The nasal spray solutions were sterile for up to 7 days in all samples tested. An extemporaneously prepared nasal spray solution of amiloride hydrochloride (2 mg/mL) was physically, chemically, and microbiologically stable for 7 days when stored at room temperature.

Identifying indicators of meaningful patient portal use by psychiatric populations.

The primary objective of this study was to identify meaningful indicators of patient portal use deemed important to psychiatric consumers. The secondary objectives were to uncover: 1) barriers and facilitators to patient portal use; and, 2) desired functionality of the technology by psychiatric consumers.A qualitative descriptive study was conducted using focus groups consisting of psychiatric consumers, their family members/caregivers, and Peer Support Workers. Two members of the research team independently performed a content analysis, and came to agreement on the identified coding hierarchy and themes. A total of twenty-three participants took part in one of five focus groups. Engagement and empowerment, consumer experience and satisfaction, and quality of care were identified as outcome indicators. Privacy and security, portal usage, and usability were identified as important process indicators. A number of barriers and facilitators were identified. Finally, psychiatric consumers desired functionality of a patient portal were discussed.Findings suggest that patient portal research among psychiatric populations can be conducted using many of the indicators that have previously been used for physical health populations. However, this study identified other unique considerations that should be accounted for when evaluating a patient portal among psychiatric populations.

Ascertaining cause of mortality among middle-aged and older persons using computer-coded and expert review verbal autopsies in the China Health and Retirement Longitudinal Study.

BACKGROUND: Verbal autopsy is designed to ascertain causes of death that are not registered or certified. Verbal autopsy has been validated in multiple settings but has not been as widely evaluated for older populations as for younger age groups. OBJECTIVE: This study aims to provide empirical evidence of the value of verbal autopsy interviews in the context of population-based surveys of older adults by comparing the cause-of-death assignments derived from two methods of interpreting verbal autopsy data. METHODS: Data used in this study come from the China Health and Retirement Longitudinal Study, a nationally representative longitudinal survey of older Chinese. We compared 407 causes of death determined using InterVA, which is a computer-coded method, and causes of death as assigned by experts; then evaluated factors that affect the results of the two approaches. RESULTS: Among the 407 deaths, neoplasms, cardiac disease, and stroke are the leading causes of death according to both approaches. The consistency of the two approaches is about 45% at the individual level. The primary reason for the mismatch is that no cause of death could be assigned for more than 25% of the sample based on expert review. A higher likelihood of mismatch is associated with advanced age and a long period between death and verbal autopsy interview. CONCLUSION: Both approaches identify the same leading causes of death at the aggregate level, but consistency is relatively low at the individual level. InterVA works well when causes of death are characterized by distinctive signs and symptoms. Grouping the various causes of death with shared etiology or common risk factors may help improve the quality of the ascertainment of causes of death. Open-ended narratives are helpful because they provide information about the circumstances surrounding the death that are not available in the structured verbal autopsy interviews.

Genome-wide association study of aggression and violence in schizophrenia.

Schizophrenia patients are at higher risk of engaging in violent behavior than the general population. Schizophrenia is also regarded as a highly heritable disorder. This study aimed to analyze genome-wide the effect of SNPs on violence in schizophrenia. We recruited 205 subjects between the age of 18-75 from the Centre for Addiction and Mental Health (CAMH), who had a diagnosis of schizophrenia or schizoaffective disorder. We recorded physical, verbal and lifetime violence scores indicating any violent actions to inflict pain, bodily harm, or death on another individual from the standardized scale, Modified Overt Aggression Scale (MOAS). We genotyped each participant's DNA using the Illumina Omni 2.5, and the SNPs were analyzed using the whole genome analysis tool-set, PLINK. We probed for single nucleotide polymorphisms (SNPs) correlated with violence in schizophrenia patients. We found one SNP (rs2188177) on chromosome 7 which showed a trend for association with physical violence (p = 7.80E-06). This study is the first of its kind to investigate genome-wide, the polymorphisms associated with violence in schizophrenia. The findings of this study may promote collaborative efforts to understand the genetic basis of violent behavior in psychosis.

Mobile and wearable technology for monitoring depressive symptoms in children and adolescents: A scoping review.

BACKGROUND: There has been rapid growth of mobile and wearable tools that may help to overcome challenges in the diagnosis and prediction of Major Depressive Disorder in children and adolescents, tasks that rely on clinical reporting that is inherently based on retrospective recall of symptoms and associated features. This article reviews more objective ways of measuring and monitoring mood within this population. METHODS: A scoping review of peer-reviewed studies examined published research that employs mobile and wearable tools to characterize depression in children and/or adolescents. Our search strategy included the following terms: (1) monitoring or prediction (2) depression (3) mobile apps or wearables and (4) children and youth (including adolescents), and was applied to five databases. RESULTS: Our search produced 829 citations (2008- Feb 2019), of which 30 (journal articles, conference papers and abstracts) were included in the analysis, and 2 reviews included in our discussion. The majority of the evidence involved smartphone apps, with very few studies using actigraphy. Mobile and wearables captured a variety of data including unobtrusive passive analytics, movement and light data, plus physical and mental health data, including depressive symptom monitoring. Most studies also examined feasibility. LIMITATIONS: This review was limited to published research in the English language. The review criteria excluded any apps that were mainly treatment focused, therefore there was not much of a focus on clinical outcomes. CONCLUSIONS: This scoping review yielded a variety of studies with heterogeneous populations, research methods and study objectives, which limited our ability to address our research objectives cohesively. Certain mobile technologies, however, have demonstrated feasibility for tracking depression that could inform models for predicting relapse.