Inflammatory markers, somatic complaints, use of medication and health care in 11-year-old children at familial high risk of schizophrenia or bipolar disorder compared with population-based controls. The Danish High Risk and Resilience Study - via 11.

PURPOSE: Patients with schizophrenia or bipolar disorder are at increased risk of somatic illnesses and have more somatic complaints compared with the general population. Schizophrenia and bipolar disorder are highly heritable. Already during childhood, children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BD) are at increased risk of psychiatric disorders and cognitive and social impairments. Knowledge about physical conditions is sparse. MATERIALS AND METHODS: Through blood tests (n = 293), interviews, and questionnaires, we assessed inflammatory markers, somatic complaints, medication - and health care use in 11-year-old children at FHR-SZ, FHR-BD, and population-based controls (PBC). RESULTS: Children at FHR-SZ had higher concentrations of leucocytes (mean 6.41, SD 0.73) compared with PBC (mean 5.78, SD 0.27, p = 0.005) and of neutrophilocytes (FHR-SZ: mean 3.11, SD 1.32, PBC: mean 2.70, SD 0.96, p = 0.024). Compared with PBC (26.6%), more children at FHR-SZ (40.5%, p = 0.007) reported somatic complaints. So did caregivers and teachers to children at FHR-BD. Somatic complaints, higher concentrations of leucocytes, and neutrophilocytes were associated with lower levels of physical activity. Children at FHR-BD with psychiatric disorders reported more somatic complaints compared with those without. CONCLUSION: Children at FHR-SZ had higher concentrations of leucocytes and neutrophilocytes than PBC. Children at FHR-SZ or FHR-BP displayed more somatic complaints than controls. Our study highlights rarely explored disadvantage of being born to parents with schizophrenia or bipolar disorder. To enhance understanding of how physical conditions in childhood may interplay with later transition to mental disorders in children at FHR-SZ and FHR-BD, further research is needed.

Exploring the relationship between attributional style measured in virtual reality and bullying among children at familial high risk of schizophrenia or bipolar disorder compared with controls.

BACKGROUND: Children of parents with severe mental illness report bullying more often compared with controls. We hypothesized that deviations in attributional styles may explain the increased prevalence of bullying experiences. We aimed to assess real-time responses to standardized ambiguous social situations, bullying experiences by children, their primary caregivers, and teachers, and to investigate potential associations between attributional styles and bullying. METHOD: The study included 465 children aged 11-12, born to parents with schizophrenia, N =179, bipolar disorder, N = 105, or population-based controls, N = 181. Attributional style was evaluated using virtual reality environments depicting ambiguous social everyday situations. We created a tailored assessment since no suitable assessments were found. Bullying was assessed through self-reports and reports from primary caregivers and teachers. RESULTS: We observed no group differences in the attributional style of the children. Reports from children, primary caregivers, and teachers revealed that compared with controls, children born to parents with schizophrenia were more likely to perceive bullying victimization, with high consistency among reports. No associations were found between bullying reports and attributional style. CONCLUSIONS: Children of parents with schizophrenia consistently experienced more bullying, as reported by the children themselves, primary caregivers, and teachers. No differences in attributional style were found, indicating that attributional style did not explain the increased prevalence of bullying reports. While it cannot be ruled out that our virtual environments were insufficient to trigger a sense of social exclusion, the results suggest that the observed differences in reported bullying are genuine and not a result of the child's attributional style.

The development in rating-based executive functions in children at familial high risk of schizophrenia or bipolar disorder from age 7 to age 11: the Danish high risk and resilience study.

Executive functions (EF) deficits are well documented in children at familial high risk of schizophrenia (FHR-SZ), and to a lesser degree in children at familial high risk of bipolar disorder (FHR-BP). The aim of this study was to assess EF development in preadolescent children at FHR-SZ, FHR-BP and population-based controls (PBC) using a multi-informant rating scale. A total of 519 children (FHR-SZ, n = 201; FHR-BP, n = 119; PBC, n = 199) participated at age 7, at age 11 or at both time points. Caregivers and teachers completed the Behavior Rating Inventory of Executive Functions (BRIEF). The developmental pattern from age 7 to age 11, did not differ between groups. At age 11, caregivers and teachers rated children at FHR-SZ as having widespread EF deficits. A higher proportion of children at FHR-SZ had clinically significant scores on the General executive composite (GEC) and all BRIEF indices compared to PBC. According to the caregivers, children at FHR-BP had significantly more EF deficits than PBC on 9 out of 13 BRIEF scales, whereas according to teachers, they only had significantly more deficits on one subdomain (Initiate). Likewise, caregivers rated a significantly higher proportion of children at FHR-BP above the clinical cut-off on the GEC and Metacognition index, compared to PBC, whereas there were no significant differences according to teachers. This study highlights the relevance of including multi-informant rating scales in the assessment of EF in children at FHR-SZ and FHR-BP. The results imply a need to identify children at high risk who would benefit from targeted intervention.

Pubertal timing, sex hormone levels, and associations between early life adversity and accelerated development amongst 11-year-old children of parents with schizophrenia or bipolar disorder and controls: The Danish high risk and Resilience study via 11.

Background: Children of parents with severe mental illness have several known risk factors for altered pubertal timing. Pubertal timing is important for children's physical and emotional development. We aimed to examine pubertal timing and associations between pubertal timing, early life adversity and child problem behavior including psychiatric diagnoses among children of parents with schizophrenia or bipolar disorder and controls. Methods: Self-reported Tanner stage (mean age 11.9, range 10.87-12.67), sex hormone levels, home environment, placement out of home, and problem behavior including psychiatric diagnoses of children at familial high-risk (FHR) of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP) and population-based controls (PBC) were assessed. Results: A total of 465 children participated in the study (Tanner assessment N = 417, sex hormones N = 293). Assessed with self-reported Tanner, no difference in pubertal timing was found between groups (p = 0.09). Hormone levels did not differ between groups except for inhibin B (mean (SD) = 55.86 (29.13) pg/mL for FHR-SZ girls vs 84.98 (47.98) pg/mL) for PBC girls (p < 0.001)) and for follicle stimulating hormone (FSH) (mean (SD) = 5.82 (1.45) U/L for FHR-BP girls vs 4.54 (1.68) U/L for PBC girls (p < 0.001)). FHR children who were placed out of home (17 children, 3.8% of participants) had higher Tanner stages than those living at home (p < 0.001). Timing was not associated with level of problem behavior or psychiatric diagnoses. Conclusions: FHR children did not differ from controls in pubertal timing. Early life adversity assessed as placement out of home may be associated with accelerated pubertal timing among children of parents with schizophrenia or bipolar disorder.

Attachment representations in 7-year-old children at familial high risk of schizophrenia or bipolar disorder: Associations with mental disorders and daily functioning: The Danish High Risk and Resilience Study, VIA 7-A population-based cohort study.

BACKGROUND: Attachment quality may affect psychological functioning. However, evidence on attachment representations and their correlates in children born to parents with schizophrenia and bipolar disorder is sparse. METHODS: We compared attachment representations in a Danish sample of 482 children aged 7 years at familial high risk of schizophrenia, bipolar disorder, and population-based controls and examined associations between attachment and mental disorders and daily functioning. Attachment representations were examined with the Story Stem Assessment Profile (SSAP). Mental disorders were ascertained in diagnostic interviews. Daily functioning was assessed with the Children's Global Assessment Scale. RESULTS: We found no between-group differences in attachment. Higher levels of secure attachment were associated with decreased risk of concurrent mental disorders in the schizophrenia high-risk group. Higher levels of insecure and disorganized attachment were associated with increased risk of mental disorders across the cohort. Higher levels of secure and insecure attachment were associated with better and poorer daily functioning, respectively. In the current study, results regarding defensive avoidance could not be reported due to methodological limitations. CONCLUSION: Familial high risk of schizophrenia (FHR-SZ) or bipolar disorder is not associated with less secure or more insecure attachment at age 7. Insecure and disorganized attachment representations index risk of mental disorders and poorer functioning. Secure attachment may be a protective factor against mental disorders in children at FHR-SZ. Validation of the SSAP is needed.

Home environment of 11-year-old children born to parents with schizophrenia or bipolar disorder - a controlled, 4-year follow-up study: The Danish High Risk and Resilience Study - VIA 11.

BACKGROUND: The home environment has a major impact on child development. Parental severe mental illness can pose a challenge to the home environment of a child. We aimed to examine the home environment of children of parents with schizophrenia or bipolar disorder and controls longitudinally through at-home assessments. METHODS: Assessments were conducted within The Danish High Risk and Resilience Study, a nationwide multi-center cohort study of children of parents with schizophrenia or bipolar disorder and population-based controls. The level of at-home stimulation and support was measured at age 7 (N = 508 children) and age 11 (N = 430 children) with the semi-structured HOME Inventory. Results from the 11-year follow-up study were analyzed and compared with 7-year baseline results to examine change across groups. RESULTS: At age 11, children of parents with schizophrenia and bipolar disorder had lower levels of stimulation and support than controls (mean (s.d.) = 46.16 (5.56), 46.87 (5.34) and 49.25 (4.37) respectively, p < 0.001). A higher proportion of children with parental schizophrenia or bipolar disorder lived in inadequate home environments at age 11, compared with controls (N (%) = 24 (15.0), 12 (12.2) and 6 (3.5) respectively, p < 0.003). The changes in home environment scores did not differ across groups from age 7 to age 11. CONCLUSIONS: Assessed longitudinally from the children's age of 7 to 11, children of parents with schizophrenia or bipolar disorder had lower levels of stimulation and support in their homes than controls. Integrated support which can target practical, economic, social and health issues to improve the home environment is indicated.

Hair cortisol concentrations and daily life stress in 7-year-old children at familial high-risk of schizophrenia or bipolar disorder. The Danish High Risk and Resilience Study - VIA 7.

BACKGROUND: Dysregulation of the HPA-axis, perceived stress and interpersonal trauma are associated with an elevated risk for schizophrenia and bipolar disorder. Being at familial high-risk of these two mental disorders also constitutes an increased risk. In this study, we aimed to investigate hair cortisol concentrations and perceived stress among 7-year-old children at familial high-risk of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP), and population-based controls (controls). METHODS: A total of 515 children (mean age 7.8, SD 0.2) from baseline assessment of the Danish High Risk and Resilience Study - VIA 7 participated in this study. Hair cortisol concentrations were analyzed among 322 children (FHR-SZ; N = 111, FHR-BP; N = 82, controls; N = 129). Perceived stress was assessed with the Daily Life Stressor Scale including 512 children (FHR-SZ; N = 195, FHR-BP; N = 118, controls; N = 199). Interpersonal trauma was measured with face-to-face interviews. RESULTS: Seven-year-old children at FHR-SZ or FHR-BP did not have a higher level of hair cortisol concentrations compared with controls (FHR-SZ: mean: 5.10, 95%CI 3.69-6.52; FHR-BP: mean: 5.01, 95%CI 3.27-6.72; controls: mean: 4.51, 95%CI 3.61-5.40; p = 0.77). Self-reported perceived stress was higher among children at FHR-SZ and FHR-BP compared with controls (FHR-SZ: mean: 12.09, 95%CI 10.99-13.19; FHR-BP: mean: 10.69, 95%CI 9.38-11.99; controls: mean: 8.90, 95%CI 8.13-9.68; p < 0.001). There was no significant association between hair cortisol concentrations and perceived stress (p = 0.84). Exploratory analyses revealed that interpersonal trauma exposure was neither associated with elevated hair cortisol nor perceived stress. CONCLUSIONS: Children at FHR-SZ and FHR-BP did not exhibit higher levels of hair cortisol concentrations at age 7, while both FHR-groups had higher level of self-reported perceived stress compared with controls. Early attention to stress in children at FHR is crucial and these vulnerabilities should be targeted in future interventions studies.

Associations between exposure to early childhood adversities and middle childhood psychotic experiences in children at familial high risk of schizophrenia, bipolar disorder, and population-based controls: The Danish high risk and resilience study - VIA 7 and VIA 11.

BACKGROUND: Exposure to adversities in early childhood is associated with psychotic experiences and disorders in adulthood. We aimed to examine whether early childhood adversities are associated with middle childhood psychotic experiences in a cohort of children at familial high risk of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP) and population-based controls (controls). METHODS: Four hundred and forty-six children from The Danish High Risk and Resilience Study - VIA7 and VIA11 participated in this study (FHR-SZ = 170; FHR-BP = 103; controls = 173). Exposure to early childhood adversities and psychotic experiences were assessed using face-to-face interviews. Having childhood adversities assessed at baseline (age 7) was used as predictor. Psychotic experiences assessed at follow-up (age 11) were used as outcome. RESULTS: Across the sample, exposure to early childhood interpersonal adversities was associated with an increased risk for any middle childhood psychotic experiences and subclinical delusions when adjusting for relevant confounders (OR 1.8, 95% CI 1.0-3.1, p = 0.05; OR 3.0, 95% CI 1.6-5.6, p < 0.001). There was no significant dose-response effect of exposure to multiple types of childhood adversities on any psychotic experiences. There were no interaction effects between early childhood adversities and FHR on middle childhood psychotic experiences. Exploratory analyses revealed that experiencing domestic violence in early childhood was associated with any middle childhood psychotic experiences (OR 2.8, 95% CI 1.5-5.1, p = 0.001). CONCLUSIONS: Exposure to interpersonal adversities during early childhood is associated with an increased risk for middle childhood psychotic experiences including specifically subclinical delusions. Future studies should examine associations between exposure to childhood adversities and conversion to psychosis within this cohort.

Impaired motor development in children with familial high risk of schizophrenia or bipolar disorder and the association with psychotic experiences: a 4-year Danish observational follow-up study.

BACKGROUND: Motor abnormalities have clinical relevance as a component of psychotic illness; they are not only a proxy of altered neurodevelopment, but also intimately related to psychotic risk. We aimed to assess motor development and its association with psychotic experiences in children with familial high risk (FHR) of schizophrenia or bipolar disorder compared with controls. METHODS: The Danish High Risk and Resilience Study is a prospective longitudinal cohort study, for which participants were extracted from Danish registers. Children born in Denmark between Sept 1, 2004, and Aug 31, 2009, with no, one, or two parents born in Denmark with schizophrenia or bipolar disorder, could be included in the study. No ethnicity data were collected. Children with no biological parent diagnosed with schizophrenia spectrum disorder or bipolar disorder were matched to children with FHR of schizophrenia (one or two parents with schizophrenia spectrum disorder) on the basis of sex, age, and municipality. Children with FHR of bipolar disorder (one or two parents with bipolar disorder) were included as a non-matched group. We assessed motor function in children with FHR of schizophrenia, children with FHR of bipolar disorder, and children in the control group at approximately age 8 years (baseline; 2013-16) and age 12 years (follow-up; 2017-20) using the Movement Assessment Battery for Children-Second Edition (Movement ABC-2). Psychotic experiences were assessed using the psychosis section of the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Raters were masked regarding familial risk status. Motor development from baseline to follow-up in the different groups was assessed using a linear mixed model. Logistic regression examined the relationship between definite motor problems (≤5th percentile on Movement ABC-2) and psychotic experiences. FINDINGS: Between March 1, 2017, and June 30, 2020, we studied 437 children (234 [54%] boys, 203 [46%] girls; mean age 11·99 years [SD 0·26, range 11·08-12·86]). Children with FHR of schizophrenia showed stable motor developmental deficits in manual dexterity (difference in intercept -1·62 [95% CI -2·39 to -0·85], p<0·0001; difference in slope 0·17 [-0·48 to 0·81], p=0·61) and balance (difference in intercept -1·58 [-2·34 to -0·82], p<0·0001; difference in slope 0·32 [-0·34 to 0·99], p=0·34), and a developmental lag in aiming and catching (difference in slope -1·07 [-1·72 to -0·41], p=0·0015; difference in intercept -0·59 [-1·35 to 0·17], p=0·13) compared with controls. Children with FHR of bipolar disorder showed no motor developmental differences on a group basis. Compared with controls, children with FHR of schizophrenia were more likely to have definite motor problems (odds ratio [OR] 2·86 [95% CI 1·60 to 5·11], p=0·0004), as were children with FHR of bipolar disorder (OR 2·45 [1·28 to 4·70], p=0·0068). Children with definite motor problems across all groups were more likely (OR 1·90 [1·12 to 3·21, p=0·017] to have had psychotic experiences than children with no definite motor problems. INTERPRETATION: Clinicians should be aware that motor impairment in childhood can reflect neurodevelopmental vulnerability to psychosis. Our findings contribute to the identification of early risk markers for severe mental illness, both for use by clinicians and for establishing a basis for future primary preventive intervention studies in the premorbid phase. FUNDING: The Independent Research Fund Denmark, the Mental Health Services of the Capital Region of Denmark, the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University, the Beatrice Surovell Haskell Fund, the Tryg Foundation, and the Innovation Fund Denmark. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

Experiences of helplessness and fear among caregivers diagnosed with severe mental illness and co-caregivers: The Danish High Risk and Resilience Study - VIA 7.

This study investigates indicators of disorganized caregiving among caregivers of children who have a familial predisposition of schizophrenia spectrum psychosis (SZ) or bipolar disorder (BP), and whether indicators of disorganized caregiving are associated with the caregivers' and children's level of functioning as well as the children's internalizing and externalizing behavior problems. Indicators of disorganized caregiving were assessed with the Caregiving Helplessness Questionnaire (CHQ). Level of functioning was evaluated using the Children's Global Assessment Scale and the Personal and Social Performance Scale, while dimensional psychopathology were measured with the Child Behavior Checklist. 185 caregivers belonging to a SZ combined group (i.e., SZ-I + SZ co-caregiver), 110 caregivers to a BP combined group (i.e., BP-I + BP co-caregiver), and 184 caregivers to a population-based control group provided data on CHQ. Having a history of SZ or BP or being a co-caregiver to a parent with SZ or BP was associated with higher levels of experiences of helplessness and fear. Higher scores on helplessness were associated with lower level of functioning among caregivers and children and with children having externalizing/internalizing behavior problems. These results emphasize the need for interventions addressing indicators of disorganized caregiving in families with SZ or BP.

Examining selection bias in a population-based cohort study of 522 children with familial high risk of schizophrenia or bipolar disorder, and controls: The Danish High Risk and Resilience Study VIA 7.

PURPOSE: Knowledge about representativity of familial high-risk studies of schizophrenia and bipolar disorder is essential to generalize study conclusions. The Danish High Risk and Resilience Study (VIA 7), a population-based case-control familial high-risk study, creates a unique opportunity for combining assessment and register data to examine cohort representativity. METHODS: Through national registers, we identified the population of 11,959 children of parents with schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and controls from which the 522 children participating in The VIA 7 Study (202 FHR-SZ, 120 FHR-BP and 200 controls) were selected. Socio-economic and health data were obtained to compare high-risk groups and controls, and participants versus non-participants. Selection bias impact on results was analyzed through inverse probability weights. RESULTS: In the total sample of 11,959 children, FHR-SZ and FHR-BP children had more socio-economic and health disadvantages than controls (p < 0.001 for most). VIA 7 non-participants had a poorer function, e.g. more paternal somatic and mental illness (p = 0.02 and p = 0.04 for FHR-SZ), notifications of concern (FHR-BP and PBC p < 0.001), placements out of home (p = 0.03 for FHR-SZ), and lower level of education (p ≤ 0.01 for maternal FHR-SZ and FHR-BP, p = 0.001 for paternal FHR-BP). Inverse probability weighted analyses of results generated from the VIA Study showed minor changes in study findings after adjustment for the found selection bias. CONCLUSIONS: Familial high-risk families have multiple socio-economic and health disadvantages. In The VIA 7 Study, although comparable regarding mental illness severity after their child's birth, socioeconomic and health disadvantages are more profound amongst non-participants than amongst participants.

A family-based study of genetic and epigenetic effects across multiple neurocognitive, motor, social-cognitive and social-behavioral functions.

Many psychiatric and neurodevelopmental disorders are known to be heritable, but studies trying to elucidate the genetic architecture of such traits often lag behind studies of somatic traits and diseases. The reasons as to why relatively few genome-wide significant associations have been reported for such traits have to do with the sample sizes needed for the detection of small effects, the difficulty in defining and characterizing the phenotypes, partially due to overlaps in affected underlying domains (which is especially true for cognitive phenotypes), and the complex genetic architectures of the phenotypes, which are not wholly captured in traditional case-control GWAS designs. We aimed to tackle the last two issues by performing GWASs of eight quantitative neurocognitive, motor, social-cognitive and social-behavioral traits, which may be considered endophenotypes for a variety of psychiatric and neurodevelopmental conditions, and for which we employed models capturing both general genetic association and parent-of-origin effects, in a family-based sample comprising 402 children and their parents (mostly family trios). We identified 48 genome-wide significant associations across several traits, of which 3 also survived our strict study-wide quality criteria. We additionally performed a functional annotation of implicated genes, as most of the 48 associations were with variants within protein-coding genes. In total, our study highlighted associations with five genes (TGM3, CACNB4, ANKS1B, CSMD1 and SYNE1) associated with measures of working memory, processing speed and social behavior. Our results thus identify novel associations, including previously unreported parent-of-origin associations with relevant genes, and our top results illustrate new potential gene → endophenotype → disorder pathways.

Developmental Pathways and Clinical Outcomes of Early Childhood Psychotic Experiences in Preadolescent Children at Familial High Risk of Schizophrenia or Bipolar Disorder: A Prospective, Longitudinal Cohort Study - The Danish High Risk and Resilience Study, VIA 11.

OBJECTIVE: Psychotic experiences are common in children and adolescents and are associated with concurrent and subsequent psychopathology. Most findings originate from general population studies, whereas little is known of the clinical outcomes of psychotic experiences in children and adolescents at familial high risk of psychosis. We examined the prevalence of psychotic experiences in middle childhood and whether early childhood psychotic experiences and developmental pathways of psychotic experiences predicted mental disorders in middle childhood in children at familial high risk of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP), and a population-based control group. METHODS: In a longitudinal population-based cohort study children at FHR-SZ (N=170), FHR-BP (N=103), and the control group (N=174) were assessed for psychotic experiences and axis I disorders with face-to-face interviews in early and middle childhood (at 7 and 11 years of age). RESULTS: Psychotic experiences were more prevalent in children at FHR-SZ (31.8%, odds ratio 2.1, 95% CI 1.3-3.4) than in the control group (18.4%) in middle childhood. Early childhood psychotic experiences predicted mental disorders in middle childhood after adjusting for early childhood disorders and familial risk (odds ratio 2.0, 95% CI 1.2-3.1). Having three or more psychotic experiences increased odds the most (odds ratio 2.5, 95% CI 1.1-5.7). Persistent psychotic experiences were associated with increased odds of middle childhood disorders (odds ratio 4.1, 95% CI 2.1-8.4). Psychotic experiences were nondifferentially associated with mental disorders across the three familial risk groups. CONCLUSIONS: Early childhood psychotic experiences predict mental disorders in middle childhood. Psychotic experiences index vulnerability for psychopathology nondifferentially in children at familial high risk and the control group. Psychotic experiences should be included in mental health screenings including children at familial high risk.

Jumping to Conclusions and Its Associations With Psychotic Experiences in Preadolescent Children at Familial High Risk of Schizophrenia or Bipolar Disorder-The Danish High Risk and Resilience Study, VIA 11.

BACKGROUND: The jumping to conclusions (JTC) bias, ie, making decisions based on inadequate evidence, is associated with psychosis in adults and is believed to underlie the formation of delusions. Knowledge on the early manifestations of JTC and its associations with psychotic experiences (PE) in children and adolescents is lacking. DESIGN: Preadolescent children (mean age 11.9 y, SD 0.2) at familial high risk of schizophrenia (FHR-SZ, n = 169) or bipolar disorder (FHR-BP, n = 101), and controls (n = 173) were assessed with the Beads Task to examine JTC. The number of beads drawn before making a decision, "draws to decision" (DTD) was used as a primary outcome. PE were ascertained in face-to-face interviews. General intelligence was measured with Reynolds Intellectual Screening Test. RESULTS: Children at FHR-SZ took fewer DTD than controls (4.9 vs 5.9, Cohen's d = 0.31, P = .004). Differences were attenuated when adjusting for IQ (Cohen's d = 0.24, P = .02). Higher IQ was associated with a higher number of DTD (B = 0.073, P < .001). Current subclinical delusions compared with no PE were associated with fewer DTD in children at FHR-SZ (P = .04) and controls (P < .05). Associations between delusions and DTD were nullified when accounting for IQ. CONCLUSIONS: JTC marks familial risk of psychosis in preadolescence, not reducible to general intelligence. JTC is associated with subclinical delusions, but this may be an expression of intellectual impairment. Future studies should establish temporality between JTC and delusion formation and examine JTC as a target for early intervention.

The Danish High-Risk and Resilience Study-VIA 15 - A Study Protocol for the Third Clinical Assessment of a Cohort of 522 Children Born to Parents Diagnosed With Schizophrenia or Bipolar Disorder and Population-Based Controls.

Background: Children born to parents with severe mental illness have gained more attention during the last decades because of increasing evidence documenting that these children constitute a population with an increased risk of developing mental illness and other negative life outcomes. Because of high-quality research with cohorts of offspring with familial risk and increased knowledge about gene-environment interactions, early interventions and preventive strategies are now being developed all over the world. Adolescence is a period characterized by massive changes, both in terms of physical, neurologic, psychological, social, and behavioral aspects. It is also the period of life with the highest risk of experiencing onset of a mental disorder. Therefore, investigating the impact of various risk and resilience factors in adolescence is important. Methods: The Danish High-Risk and Resilience Study started data collection in 2012, where 522 7-year-old children were enrolled in the first wave of the study, the VIA 7 study. The cohort was identified through Danish registers based on diagnoses of the parents. A total of 202 children had a parent diagnosed with schizophrenia, 120 children had a parent diagnosed with bipolar disorder, and 200 children had parents without these diagnoses. At age 11 years, all children were assessed for the second time in the VIA 11 study, with a follow-up retention rate of 89%. A comprehensive assessment battery covering domains of psychopathology, neurocognition, social cognition and behavior, motor development and physical health, genetic analyses, attachment, stress, parental functioning, and home environment was carried out at each wave. Magnetic resonance imaging scans of the brain and electroencephalograms were included from age 11 years. This study protocol describes the third wave of assessment, the VIA 15 study, participants being 15 years of age and the full, 3-day-long assessment battery this time including also risk behavior, magnetoencephalography, sleep, and a white noise paradigm. Data collection started on May 1, 2021. Discussion: We will discuss the importance of longitudinal studies and cross-sectional data collection and how studies like this may inform us about unmet needs and windows of opportunity for future preventive interventions, early illness identification, and treatment in the future.

Neurocognitive Development in Children at Familial High Risk of Schizophrenia or Bipolar Disorder.

Importance: Neurocognitive impairments exist in children at familial high risk (FHR) of schizophrenia and bipolar disorder. Studies on preadolescent developmental courses of neurocognition are important to describe shared and distinct neurodevelopmental pathways in these groups. Objective: To assess the development in specific neurocognitive functions from age 7 to 11 years in children at FHR of schizophrenia or bipolar disorder compared with children in a population-based control (PBC) group. Design, Setting, and Participants: The Danish High Risk and Resilience Study is a prospective, longitudinal, cohort study that collected data from January 1, 2013, to January 31, 2016 (phase 1), and from March 1, 2017, to June 30, 2020 (phase 2). Data were collected at 2 university hospitals in Denmark, and participants included 520 children at FHR of schizophrenia or bipolar disorder along with a PBC group matched with the group of children at FHR of schizophrenia by age, sex, and municipality. Exposures: Parental schizophrenia, bipolar disorder, or neither. Main Outcomes and Measures: Neurocognitive functioning was assessed with validated tests of intelligence, processing speed, attention, memory, verbal fluency, and executive functioning. Multilevel mixed-effects linear regression models with maximum likelihood estimation were used to estimate neurocognitive development from age 7 to 11 years. Results: At 4-year follow-up, a total of 451 children (mean [SD] age; 11.9 [0.2] years; 208 girls [46.1%]) underwent neurocognitive testing. There were a total of 170 children at FHR of schizophrenia (mean [SD] age, 12.0 [0.3]; 81 girls [47.7%]), 103 children at FHR of bipolar disorder (mean [SD] age, 11.9 [0.2] years; 45 girls [43.7%]), and 178 children in the PBC group (mean [SD] age, 11.9 [0.2] years; 82 girls [46.1%]). At either age 7 or 11 years or at both assessments, 520 children participated in the neurocognitive assessment and were therefore included in the analyses. When correcting for multiple comparisons, no statistically significant time × group interactions were observed across the 3 groups. Compared with the PBC group at 4-year follow-up, children at FHR of schizophrenia showed significant neurocognitive impairment in 7 of 24 neurocognitive measures (29.2%; Cohen d range, 0.29-0.37). Compared with children at FHR of bipolar disorder, children at FHR of schizophrenia had significant neurocognitive impairment in 5 of 24 measures (20.8%; Cohen d range, 0.29-0.38). Children at FHR of bipolar disorder and those in the PBC group did not differ significantly. Conclusions and Relevance: In this cohort study, findings suggest that neurocognitive maturation was comparable across groups of children at FHR of schizophrenia or bipolar disorder compared with PBCs from age 7 to 11 years. Compared with the PBC group, children at FHR of schizophrenia demonstrated widespread, stable, neurocognitive impairments during this period, whereas children at FHR of bipolar disorder showed no neurocognitive impairments, which may indicate distinct neurodevelopmental pathways in children at FHR of schizophrenia and bipolar disorder.

Childhood trauma in children at familial high risk of schizophrenia or bipolar disorder: A longitudinal study. The Danish High Risk and Resilience Study - VIA 7 and VIA 11.

OBJECTIVES: Childhood trauma increases the risk of developing mental illness as does being born to parents with schizophrenia or bipolar disorder. We aimed to compare prevalence of lifetime childhood trauma among 11-year-old children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) compared with population-based controls (PBCs). DESIGN: The study is a longitudinal, prospective cohort study of children at FHR-SZ, FHR-BP, and PBCs. METHODS: A cohort of 512 children at FHR-SZ (N = 199), FHR-BP (N = 118), and PBCs (N = 195) were examined at baseline (mean age 7.8, SD 0.2) and 451 children at FHR-SZ (N = 172), FHR-BP (N = 104), and PBCs (N = 175) were examined at four-year follow-up (mean age 11.9, SD 0.2, retention rate 87.3%). Childhood trauma was measured with a semi-structured interview. RESULTS: Children at FHR-BP had an elevated risk of exposure to any lifetime trauma (age 0-11 years) compared with PBCs (OR 2.082, 95%CI 1.223-3.545, p = .007) measured with binary logistic regression. One-way ANOVA revealed that both FHR-groups had a higher lifetime prevalence of exposure to a greater number of types of trauma compared with PBCs (FHR-SZ: observed mean: 1.53, 95%CI 1.29-1.77; FHR-BP: observed mean: 1.56, 95%CI 1.26-1.85; PBCs: observed mean: 0.99, 95%CI 0.82-1.17; p < .001). Binary logistic regression showed that the lifetime risk of exposure to interpersonal trauma (age 0-11 years) was elevated for both FHR-groups (FHR-SZ: OR 3.773, 95%CI 2.122-6.710, p < .001; FHR-BP: OR 3.602, 95%CI 1.913-6.783, p < .001). CONCLUSIONS: Children at FHR-SZ and FHR-BP are at increased risk for being exposed to childhood trauma compared with PBCs. This study underscores the need for early detection, support, and prevention of childhood trauma in children at FHR-SZ and FHR-BP.

Development of social responsiveness and theory of mind in children of parents with schizophrenia or bipolar disorder.

Social impairments are suggested as vulnerability markers for schizophrenia and bipolar disorder. Therefore, we investigated the development of social responsiveness and theory of mind (ToM) in children at familial high-risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP). This study is part of The Danish High Risk and Resilience Study, a longitudinal cohort study of children at FHR-SZ or FHR-BP and population-based controls (PBC). Social responsiveness was measured with the Social Responsiveness Scale (SRS-2), completed by teachers and primary caregivers. ToM was measured using The Animated Triangles Task (ATT). Both SRS-2 and ATT were applied at age 7 and 11. A total of 520 children participated (FHR-SZ, n = 201; FHR-BP, n = 119; PBC, n = 200). Results showed no significant time by group interactions. At follow-up, children at FHR-SZ exhibited impaired social responsiveness compared with PBC regardless of the informant. At both timepoints, a higher proportion of children at FHR-SZ were rated at a clinically significant level, implying inference in everyday social interactions. Compared with PBC, primary caregivers reported impairments in social responsiveness in children at FHR-BP at follow-up. The three groups did not differ in ToM at follow-up. Social responsiveness and ToM do not develop differently in children at FHR-SZ, FHR-BP and PBC from age 7 to 11, but impairments in social responsiveness remain stable and may constitute a vulnerability marker particularly in children at FHR-SZ, but also FHR-BP. ToM abilities seem to improve and remain intact, but ToM development and ToM task properties should be taken into consideration.

Mental disorders in preadolescent children at familial high-risk of schizophrenia or bipolar disorder - a four-year follow-up study: The Danish High Risk and Resilience Study, VIA 11.

BACKGROUND: Children at familial high-risk of schizophrenia and bipolar disorder have an elevated prevalence of mental disorders but studies of children within a narrow age range are lacking and there are few conjoint studies of these two groups. Knowledge on their mental health is important for prevention and early intervention. METHODS: The authors examined mental disorders and global functioning in children at familial high-risk of schizophrenia (FHR-SZ) and bipolar disorder (FHR-BP) compared with population-based controls. In a longitudinal cohort study, 450 children (FHR-SZ, n = 171; FHR-BP, n = 104; controls, n = 175), were assessed for Axis I disorders at baseline and four-year follow-up (mean age 11.9, SD 0.2) with the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children and for global functioning with Children's Global Assessment Scale. RESULTS: Cumulative incidence of Any Axis I disorder was elevated by age 11 in children at FHR-SZ (54.4%, OR 3.0, 95% CI 1.9-4.7, p < .001) and children at FHR-BP (52.9%, OR 2.8, 95% CI 1.7-4.7, p < .001) compared with controls (28.6%). Children at FHR-SZ and FHR-BP had higher rates of affective disorders (OR 4.4, 95% CI 1.4-13.5, p = .009; OR 5.1, 95% CI 1.6-16.4, p = .007), anxiety disorders (OR 2.1, 95% CI 1.1-4.0, p = .02; OR 3.0, 95% CI 1.5-6.1, p = .002), and stress and adjustment disorders (OR 3.3, 95% CI 1.4-7.5, p = .006; OR 5.3, 95% CI 2.2-12.4, p < .001). Disruptive behavior disorders (OR 2.8, 95% CI 1.0-7.3, p = .04) and ADHD (OR 2.9, 95% CI 1.6-5.3, p < .001) were elevated in children at FHR-SZ. Both FHR groups had lower global functioning than controls. Cumulative incidence of disorders increased equally across the three groups from early childhood to preadolescence and level of functioning did not change differentially. CONCLUSIONS: Children at FHR-SZ and FHR-BP have an elevated prevalence of mental disorders and poorer functioning than controls. Vulnerability in children at FHR manifests early and remains stable throughout childhood. Early attention toward their mental health and identification of those in need of intervention is warranted.

Accumulation of Disadvantages Across Multiple Domains Amongst Subgroups of Children of Parents With Schizophrenia or Bipolar Disorder: Clustering Data from the Danish High Risk and Resilience Study VIA 7.

Objective: Children with familial high-risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) are frequently affected in a range of domains known to be precursors of severe mental illness. No previous studies have gathered known precursors to examine whether they distribute evenly across familial high risk (FHR) children or if they cluster among a smaller group. Since such examination holds the potential to identify high and low risk of severe mental illness groups, we aimed to cluster FHR and control children affected to various degrees. Method: In The Danish High Risk and Resilience Study VIA 7, a clinical cohort study, 514 7-year-old children with FHR-SZ or FHR-BP and matched controls were assessed in domains of motor function, neurocognition, emotional control, behavior, social cognition, self-perception, language, psychotic experiences, and psychopathology, and grouped using cluster analysis. Associations between clusters and parents' level of education, functioning, caregiver status, child's level of stimulation and support in the home, and polygenic risk scores were examined. Results: A total of four groups including one of broadly affected children were identified. The broadly affected group was represented 4-5-fold (18.1%) amongst FHR-SZ children and 2-3-fold (10.2%) amongst FHR-BP children, compared to controls (4.1%) (P < .001), and the broadly affected group had lower levels of caregiver functioning (P < .001) and stimulation and support at home (P < .001). Conclusion: Precursors of severe mental illness distribute unevenly among FHR children; while approximately half are not affected in any domains, the other half are affected to various degrees. Targeted support towards the affected groups is indicated.