Psychosis Endophenotypes: A Gene-Set-Specific Polygenic Risk Score Analysis.

BACKGROUND AND HYPOTHESIS: Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes. STUDY DESIGN: We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score. STUDY RESULTS: After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores. CONCLUSIONS: Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models.

Exposure to potentially morally injurious events in U.K. health and social care workers during COVID-19: Associations with PTSD and complex PTSD.

OBJECTIVE: Health and social care workers (HSCWs) have been shown to be at risk of exposure to potentially morally injurious events (PMIEs) and mental health problems during the COVID-19 pandemic. This study aimed to examine associations between exposure to PMIEs and meeting threshold criteria for probable posttraumatic stress disorder (PTSD) and probable complex PTSD (CPTSD) in U.K. HSCWs immediately after the peak of the first COVID-19 wave. METHOD: Frontline HSCWs from across the United Kingdom working in diverse roles in hospitals, nursing or care homes, and other community settings were recruited to the Frontline-COVID study via social media. Participants (n = 1,056) completed a cross-sectional online survey (May 27, 2020-July 23, 2020) which assessed exposure to PMIEs (nine-item Moral Injury Events Scale), and meeting symptom thresholds for probable PTSD and probable CPTSD (International Trauma Questionnaire). RESULTS: PMIEs related to witnessing others' wrongful actions and betrayal events were more commonly endorsed than perceived self-transgressions. The rate of probable International Classification of Diseases, 11th Revision (ICD-11) PTSD was 8.3%, and of probable ICD-11 CPTSD was 14.2%. Betrayal-related PMIEs were a significant predictor of probable PTSD or probable CPTSD, together with having been redeployed during the pandemic. The only variable that differentially predicted probable CPTSD as compared with probable PTSD was not having had reliable access to personal protective equipment; none of the PMIE types were differential predictors for screening positive for probable PTSD versus probable CPTSD. CONCLUSIONS: Exposure to PIMEs could be important for PTSD and CPTSD development. Interventions for moral injury in HSCWs should be investigated. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Adolescent Verbal Memory as a Psychosis Endophenotype: A Genome-Wide Association Study in an Ancestrally Diverse Sample.

Verbal memory impairment is one of the most prominent cognitive deficits in psychosis. However, few studies have investigated the genetic basis of verbal memory in a neurodevelopmental context, and most genome-wide association studies (GWASs) have been conducted in European-ancestry populations. We conducted a GWAS on verbal memory in a maximum of 11,017 participants aged 8.9 to 11.1 years in the Adolescent Brain Cognitive Development Study®, recruited from a diverse population in the United States. Verbal memory was assessed by the Rey Auditory Verbal Learning Test, which included three measures of verbal memory: immediate recall, short-delay recall, and long-delay recall. We adopted a mixed-model approach to perform a joint GWAS of all participants, adjusting for ancestral background and familial relatedness. The inclusion of participants from all ancestries increased the power of the GWAS. Two novel genome-wide significant associations were found for short-delay and long-delay recall verbal memory. In particular, one locus (rs9896243) associated with long-delay recall was mapped to the NSF (N-Ethylmaleimide Sensitive Factor, Vesicle Fusing ATPase) gene, indicating the role of membrane fusion in adolescent verbal memory. Based on the GWAS in the European subset, we estimated the SNP-heritability to be 15% to 29% for the three verbal memory traits. We found that verbal memory was genetically correlated with schizophrenia, providing further evidence supporting verbal memory as an endophenotype for psychosis.

Reward Processing in Children With Psychotic-Like Experiences.

Alterations to striatal reward pathways have been identified in individuals with psychosis. They are hypothesized to be a key mechanism that generate psychotic symptoms through the production of aberrant attribution of motivational salience and are proposed to result from accumulated childhood adversity and genetic risk, making the striatal system hyper-responsive to stress. However, few studies have examined whether children with psychotic-like experiences (PLEs) also exhibit these alterations, limiting our understanding of how differences in reward processing relate to hallucinations and delusional ideation in childhood. Consequently, we examined whether PLEs and PLE-related distress were associated with reward-related activation in the nucleus accumbens (NAcc). The sample consisted of children (N = 6718) from the Adolescent Brain Cognitive Development (ABCD) study aged 9-10 years who had participated in the Monetary Incentive Delay (MID) task in functional MRI. We used robust mixed-effects linear regression models to investigate the relationship between PLEs and NAcc activation during the reward anticipation and reward outcome stages of the MID task. Analyses were adjusted for gender, household income, ethnicity, depressive symptoms, movement in the scanner, pubertal development, scanner ID, subject and family ID. There was no reliable association between PLEs and alterations to anticipation- or outcome-related striatal reward processing. We discuss the implications for developmental models of psychosis and suggest a developmental delay model of how PLEs may arise at this stage of development.

The Influence of CYP2D6 and CYP2C19 Genetic Variation on Diabetes Mellitus Risk in People Taking Antidepressants and Antipsychotics.

CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics. Genetic variation in these genes may increase risk of adverse drug reactions. Antidepressants and antipsychotics have previously been associated with risk of diabetes. We examined whether individual genetic differences in CYP2D6 and CYP2C19 contribute to these effects. We identified 31,579 individuals taking antidepressants and 2699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate, or normal metabolizers of CYP2D6, and as poor, intermediate, normal, rapid, or ultra-rapid metabolizers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. CYP2D6 poor metabolizers taking paroxetine had higher Hb1Ac than normal metabolizers (mean difference: 2.29 mmol/mol; p < 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolizers had higher HbA1c levels compared to normal metabolizers (mean differences: 10.15 mmol/mol; p < 0.001. Among participants with diabetes who were taking fluoxetine, CYP2D6 intermediate metabolizers and decreased HbA1c, compared to normal metabolizers (mean difference -7.74 mmol/mol; p = 0.017). We did not observe any relationship between CYP2D6 or CYP2C19 metabolic status and HbA1c levels in participants taking antipsychotic medication. Our results indicate that the impact of genetic variation in CYP2D6 differs depending on diabetes status. Although our findings support existing clinical guidelines, further research is essential to inform pharmacogenetic testing for people taking antidepressants and antipsychotics.

Emerging models and trends in mental health crisis care in England: a national investigation of crisis care systems.

BACKGROUND: Inpatient psychiatric care is unpopular and expensive, and development and evaluation of alternatives is a long-standing policy and research priority around the world. In England, the three main models documented over the past fifty years (teams offering crisis assessment and treatment at home; acute day units; and residential crisis services in the community) have recently been augmented by several new service models. These are intended to enhance choice and flexibility within catchment area acute care systems, but remain largely undocumented in the research literature. We therefore aimed to describe the types and distribution of crisis care models across England through a national survey. METHODS: We carried out comprehensive mapping of crisis resolution teams (CRTs) using previous surveys, websites and multiple official data sources. Managers of CRTs were invited to participate as key informants who were familiar with the provision and organisation of crisis care services within their catchment area. The survey could be completed online or via telephone interview with a researcher, and elicited details about types of crisis care delivered in the local catchment area. RESULTS: We mapped a total of 200 adult CRTs and completed the survey with 184 (92%). Of the 200 mapped adult CRTs, there was a local (i.e., within the adult CRT catchment area) children and young persons CRT for 84 (42%), and an older adults CRT for 73 (37%). While all but one health region in England provided CRTs for working age adults, there was high variability regarding provision of all other community crisis service models and system configurations. Crisis cafes, street triage teams and separate crisis assessment services have all proliferated since a similar survey in 2016, while provision of acute day units has reduced. CONCLUSIONS: The composition of catchment area crisis systems varies greatly across England and popularity of models seems unrelated to strength of evidence. A group of emerging crisis care models with varying functions within service systems are increasingly prevalent: they have potential to offer greater choice and flexibility in managing crises, but an evidence base regarding impact on service user experiences and outcomes is yet to be established.

Implementation, Adoption, and Perceptions of Telemental Health During the COVID-19 Pandemic: Systematic Review.

BACKGROUND: Early in 2020, mental health services had to rapidly shift from face-to-face models of care to delivering the majority of treatments remotely (by video or phone call or occasionally messaging) due to the COVID-19 pandemic. This resulted in several challenges for staff and patients, but also in benefits such as convenience or increased access for people with impaired mobility or in rural areas. There is a need to understand the extent and impacts of telemental health implementation, and barriers and facilitators to its effective and acceptable use. This is relevant both to future emergency adoption of telemental health and to debates on its future use in routine mental health care. OBJECTIVE: To investigate the adoption and impacts of telemental health approaches during the COVID-19 pandemic, and facilitators and barriers to optimal implementation. METHODS: Four databases (PubMed, PsycINFO, CINAHL, and Web of Science) were searched for primary research relating to remote working, mental health care, and the COVID-19 pandemic. Preprint servers were also searched. Results of studies were synthesized using framework synthesis. RESULTS: A total of 77 papers met our inclusion criteria. In most studies, the majority of contacts could be transferred to a remote form during the pandemic, and good acceptability to service users and clinicians tended to be reported, at least where the alternative to remote contacts was interrupting care. However, a range of impediments to dealing optimal care by this means were also identified. CONCLUSIONS: Implementation of telemental health allowed some continuing support to the majority of service users during the COVID-19 pandemic and has value in an emergency situation. However, not all service users can be reached by this means, and better evidence is now needed on long-term impacts on therapeutic relationships and quality of care, and on impacts on groups at risk of digital exclusion and how to mitigate these. TRIAL REGISTRATION: PROSPERO International prospective register of systematic reviews CRD42021211025; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021211025.

What symptoms best predict severe distress in an online survey of UK health and social care staff facing COVID-19: development of the two-item Tipping Point Index.

OBJECTIVES: COVID-19 has altered standard thresholds for identifying anxiety and depression. A brief questionnaire to determine when individuals are at a tipping point for severe anxiety or depression would greatly help decisions about when to seek assessment or treatment. DESIGN: Data were collected as part of the Frontline-COVID Study, a cross-sectional national online survey with good coverage of health and social care settings. New questionnaire items reflecting when coping was actually breaking down were compared with standard measures of severe anxiety and depression. Data were collected between 27 May and 23 July 2020. SETTING: The majority of participants worked in hospitals (53%), in nursing or care homes (15%), or in other community settings (30%). PARTICIPANTS: Of 1194 qualifying respondents, 1038 completed the six tipping point items. Respondents included nurses, midwives, doctors, care workers, healthcare assistants, allied healthcare professionals and other non-medical staff. Over 90% were white and female. MAIN OUTCOME MEASURES: Threshold for severe anxiety according to the Generalised Anxiety Disorder Scale-7 or moderately severe depression according to the Patient Health Questionnaire-9. RESULTS: Answering yes to one of two simple questions ('Over the last week have you been often feeling panicky or on the point of losing control of your emotions?', 'Over the last week have you felt complete hopelessness about the future?') demonstrated very high sensitivity (0.95, 95% CI 0.92 to 0.97) and negative predictive value (0.97, 95% CI 0.95 to 0.98). Answering yes to both questions yielded high specificity (0.90, 95% CI 0.87 to 0.92) and positive predictive value (0.72, 95% CI 0.67 to 0.77). Results were replicated in two random subsamples and were consistent across different genders, ethnic backgrounds, and health or social care settings. CONCLUSIONS: Answering two simple yes/no questions can provide simple and immediate guidance to assist with decisions about whether to seek further assessment or treatment.

A qualitative study of stakeholder views on the use of a digital app for supported self-management in early intervention services for psychosis.

BACKGROUND: Digital tools such as Smartphones have the potential to increase access to mental health support including self-management interventions for individuals with psychosis, and ultimately to improve outcomes. Self-management strategies, including relapse prevention and crisis planning and setting personal recovery goals, are intended to assist people with long-term conditions to take an active role in their recovery, with evidence for a range of benefits. However, their implementation is inconsistent, and access and uptake need to be improved. The current study explores the acceptability of a Smartphone app (My Journey 3) that has been developed to facilitate supported self-management in Early Intervention in Psychosis (EIP) services. METHODS: Semi-structured one-to-one interviews were conducted with twenty-one EIP service users who had access to My Journey 3 as part of a feasibility trial, and with thirteen EIP service clinicians who were supporting service users with the app. Interviews focused on the acceptability and usability of My Journey 3. Data was coded to themes based on the Acceptability of Healthcare Interventions framework. RESULTS: Many service user participants found My Journey 3 to be acceptable. The symptom and medication trackers in particular were described as helpful. A smaller number of service users disliked the intervention. Individual-level factors that appeared to influence acceptability and engagement included recovery stage and symptom severity. Clinicians tended to report that My Journey 3 was a potentially positive addition to service users' care, but they often felt unable to provide support due to competing demands in their work, which in turn may have impacted acceptability and usage of the app. CONCLUSIONS: Our findings suggest that the app is perceived as having potential to improve users' capacity to self-manage and work towards recovery goals, but barriers prevented many clinicians providing consistent and effective support as intended. Further evaluation of supported self-management apps in psychosis is warranted but needs to address implementation challenges from the start.

Predictors and rates of PTSD, depression and anxiety in UK frontline health and social care workers during COVID-19.

Background: Studies have shown that working in frontline healthcare roles during epidemics and pandemics was associated with PTSD, depression, anxiety, and other mental health disorders. Objectives: The objectives of this study were to identify demographic, work-related and other predictors for clinically significant PTSD, depression, and anxiety during the COVID-19 pandemic in UK frontline health and social care workers (HSCWs), and to compare rates of distress across different groups of HCSWs working in different roles and settings. Methods: A convenience sample (n = 1194) of frontline UK HCSWs completed an online survey during the first wave of the pandemic (27 May - 23 July 2020). Participants worked in UK hospitals, nursing or care homes and other community settings. PTSD was assessed using the International Trauma Questionnaire (ITQ); Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9); Anxiety was assessed using the Generalized Anxiety Disorder Scale (GAD-7). Results: Nearly 58% of respondents met the threshold for a clinically significant disorder (PTSD = 22%; anxiety = 47%; depression = 47%), and symptom levels were high across occupational groups and settings. Logistic regression analyses found that participants who were concerned about infecting others, who could not talk with their managers if there were not coping, who reported feeling stigmatized and who had not had reliable access to personal protective equipment (PPE) were more likely to meet criteria for a clinically significant mental disorder. Being redeployed during the pandemic, and having had COVID were associated with higher odds for PTSD. Higher household income was associated with reduced odds for a mental disorder. Conclusions: This study identified predictors of clinically significant distress during COVID-19 and highlights the need for reliable access to PPE and further investigation of barriers to communication between managers and staff.

Antecedentes: Los estudios han mostrado que el trabajo en roles de primera línea de salud durante epidemias y pandemias se asoció a TEPT, depresión, ansiedad y otros trastornos de salud mental.Objetivos: Los objetivos de este estudio fueron identificar predictores demográficos, predictores relacionados al trabajo y otros, para TEPT, depresión y ansiedad clínicamente significativos durante la pandemia por COVID-19 en la primera línea de trabajadores sociales y de la salud (HSCWs), y comparar las tasas de afectación entre los diferentes grupos de HSCWs trabajando en diferentes roles y contextos.Métodos: Una muestra por conveniencia (n=1194) de la primera línea de HSCWs en Reino Unido completó un cuestionario en línea durante la primera ola de la pandemia (27 de mayo ­ 23 de julio de 2020). Los participantes trabajaban en hospitales del Reino Unido, centros asistenciales u otros contextos clínicos comunitarios. Se evaluó TEPT usando el Cuestionario Internacional de Trauma (ITQ); la depresión fue evaluada usando el Cuestionario sobre la salud del paciente 9 (PHQ-9); la ansiedad fue evaluada usando la Escala sobre Trastorno Ansioso (GAD-7).Resultados: Cerca del 58% de los participantes cumplieron el umbral para algún trastorno clínicamente significativo (TEPT = 22%; ansiedad = 47%; depresión = 47%), y los niveles de síntomas fueron altos entre los grupos y contextos ocupacionales. Los análisis de regresión logística encontraron que los participantes que estaban preocupados respecto a contagiar a otros; quienes no pudieron hablar con sus administradores cuando no se estaban adaptando a la situación; quienes reportaron sentirse estigmatizados y quienes no tuvieron acceso a elementos de protección personal (EPP) confiables, tuvieron mayor probabilidad de cumplir los criterios para un trastorno mental clínicamente significativo. Ser redistribuido a otras funciones durante la pandemia, y haber tenido COVID se asociaron a mayores probabilidades de desarrollar TEPT. Un mayor ingreso familiar se asoció con menores probabilidades de desarrollar un trastorno mental.Conclusiones: Este estudio identificó predictores para afectación clínicamente significativa durante la pandemia por COVID-19 y resalta la necesidad de un acceso confiable a EPP y de mayor investigación sobre las barreras de comunicación entre los administradores y los equipos de trabajo.

Transcriptome-wide association study reveals two genes that influence mismatch negativity.

Mismatch negativity (MMN) is a differential electrophysiological response measuring cortical adaptability to unpredictable stimuli. MMN is consistently attenuated in patients with psychosis. However, the genetics of MMN are uncharted, limiting the validation of MMN as a psychosis endophenotype. Here, we perform a transcriptome-wide association study of 728 individuals, which reveals 2 genes (FAM89A and ENGASE) whose expression in cortical tissues is associated with MMN. Enrichment analyses of neurodevelopmental expression signatures show that genes associated with MMN tend to be overexpressed in the frontal cortex during prenatal development but are significantly downregulated in adulthood. Endophenotype ranking value calculations comparing MMN and three other candidate psychosis endophenotypes (lateral ventricular volume and two auditory-verbal learning measures) find MMN to be considerably superior. These results yield promising insights into sensory processing in the cortex and endorse the notion of MMN as a psychosis endophenotype.

How has COVID-19 affected mental health nurses and the delivery of mental health nursing care in the UK? Results of a mixed-methods study.

WHAT IS KNOWN ON THE SUBJECT?: During the COVID-19 pandemic, there has been research considering the impact on medical healthcare professionals and the mental health needs of the general population. However, limited focus has been placed on mental health services or mental health staff providing care in the community and in hospitals. While nurses make up the largest section of the mental health workforce in the UK, the impact that this pandemic has had on their work has been largely ignored. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: This paper provides a unique insight into the experiences and impact that the COVID-19 pandemic has had on mental health nurses across a range of community and inpatient settings to understand what has changed in their work and the care they can and do provide during this crisis. This includes exploring how services have changed, the move to remote working, the impact of the protective equipment crisis on nurses and the difficult working conditions facing those in inpatient settings where there is minimal guidance provided. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: By understanding the impact the pandemic has had on mental health nursing care, we can understand the gaps in guidance that exist, the challenges being faced and the impact the crisis has had on care for mental health service users. By doing so, we can plan for the ongoing nature of this pandemic and the aftermath that the crisis may leave for our service users and workforce alike. ABSTRACT: Introduction While evidence has emerged concerning the impact of COVID-19 on the general population and the challenges facing health services, much less is known regarding how the pandemic has directly affected the delivery of mental health nursing care. Aim This paper aimed to explore how COVID-19 has affected the ability of mental health nurses to deliver care in community and inpatient mental health services in the UK. Method We investigated staff reports regarding the impact of the COVID-19 pandemic on mental healthcare and mental health service users in the UK, using a mixed-methods online survey. A total of 897 nurses across a range of inpatient and community settings participated. Discussion Key themes within the data explore the following: new ways of working; remote working; risks of infection/infection control challenges; and the impact on service users. Targeted guidelines are required to support mental health nurses providing care and support during a pandemic to people in severe mental distress, often in unsuitable environments. Implications for Practice Service developments need to occur alongside tailored guidance and support for staff welfare supported by clear leadership. These findings identify areas requiring attention and investment to prepare for future crises and the consequences of the pandemic.

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

The effect of CYP2D6 variation on antipsychotic-induced hyperprolactinaemia: a systematic review and meta-analysis.

Hyperprolactinemia is a known adverse drug reaction to antipsychotic treatment. Antipsychotic blood levels are influenced by cytochrome P450 enzymes, primarily CYP2D6. Variation in CYP450 genes may affect the risk of antipsychotic-induced hyperprolactinemia. We undertook a systematic review and meta-analysis to assess whether CYP2D6 functional genetic variants are associated with antipsychotic-induced hyperprolactinemia. The systematic review identified 16 relevant papers, seven of which were suitable for the meta-analysis (n = 303 participants including 134 extreme metabolisers). Participants were classified into four phenotype groups as poor, intermediate, extensive, and ultra-rapid metabolisers. A random effects meta-analysis was used and Cohen's d calculated as the effect size for each primary study. We found no significant differences in prolactin levels between CYP2D6 metabolic groups. Current evidence does not support using CYP2D6 genotyping to reduce risk of antipsychotic-induced hyperprolactinemia. However, statistical power is limited. Future studies with larger samples and including a range of prolactin-elevating drugs are needed.