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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.

Background and Hypothesis Subgroups with distinct levels of neurocognitive functioning exist in children of parents with schizophrenia or bipolar disorder. However, studies investigating the temporal stability of subgroup membership are currently lacking. We hypothesized that a minority of children at familial high-risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) would transition to a different neurocognitive subgroup from age 7 to 11 and that most transitions would be to a more impaired subgroup. Study Design Latent profile analysis was used to identify subgroups at two assessments (age 7 and 11) based on the performance of 320 children at FHR-SZ or FHR-BP across eight neurocognitive functions. Temporal stability in subgroup membership was evaluated with latent profile transition analysis. Population-based controls (age 7, n = 199; age 11, n = 178) were included as a reference group. Children transitioning to a more impaired subgroup were compared with nontransitioning children on sex, FHR-status, global functioning, and psychopathology. Study Results At both assessment points, we identified three subgroups based on neurocognitive performance: a moderately–severely impaired, a mildly impaired, and an above-average subgroup. A total of 12.8% of children transitioned to a different subgroup, of which the majority (85.2%) moved to a more impaired subgroup. Parental diagnosis of schizophrenia, but neither parental diagnosis of bipolar disorder, global functioning at age 7, psychopathology, nor sex significantly differentiated children transitioning to a more impaired subgroup from nontransitioning children. Conclusions During pre-adolescence, neurocognitive developmental lag is associated with being at FHR-SZ. Close attention to these children’s neurocognitive development is indicated.

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 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.

Background: Despite the genetic overlap between bipolar disorder and schizophrenia, working memory impairments are mainly found in children of parents with schizophrenia. However, working memory impairments are characterized by substantial heterogeneity, and it is unknown how this heterogeneity develops over time. We used a data-driven approach to assess working memory heterogeneity and longitudinal stability in children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP). Methods: Based on the performances on four working memory tasks by 319 children (FHR-SZ, N = 202, FHR-BP, N = 118) measured at age 7 and 11, latent profile transition analysis was used to test for the presence of subgroups, and the stability of subgroup membership over time. Population-based controls (VIA 7, N = 200, VIA 11, N = 173) were included as a reference group. The working memory subgroups were compared based on caregiver- and teacher ratings of everyday working memory function, and dimensional psychopathology. Results: A model with three subgroups characterized by different levels of working memory function (an impaired subgroup, a mixed subgroup, and an above average subgroup) best fitted the data. The impaired subgroup had the highest ratings of everyday working memory impairments and psychopathology. Overall, 98 % (N = 314) stayed in the same subgroup from age 7 to 11. Conclusion: Persistent working memory impairments are present in a subset of children at FHR-SZ and FHR-BP throughout middle childhood. Attention should be given to these children, as working memory impairments influence daily life, and may serve as a vulnerability marker of transition to severe mental illness.

Background and Hypothesis Suicide is a leading cause of death in youth and is often preceded by suicidal ideation (SI) and non-suicidal self-injury (NSSI). Identifying early markers of risk for SI and NSSI could improve timely identification of at-risk individuals. Study Design Children (mean age 11.9, SD 0.2) at familial high risk of schizophrenia (N = 171), or bipolar disorder (N = 104), and controls (N = 174) were assessed for psychotic experiences (PE), SI, NSSI, and Axis I mental disorders in face-to-face interviews in early and middle childhood (age 7 and 11). Study Results Having 2 types of early childhood PE predicted middle childhood SI after accounting for previous SI, NSSI, and mental disorders (OR 2.8, 95% CI 1.1–6.9; P = .03). Two PE predicted NSSI (OR 3.0, 95% CI 1.2–7.7; P = .02) in excess of previous SI, NSSI, mental disorders, and familial risk. Persistent and incident PE predicted SI (OR 3.2, 95% CI, 1.1–8.8; P = .03; OR 3.8, 95% CI, 1.3–11.5; P = .02) in the fully adjusted model. Nineteen percent of children with persistent PE reported middle childhood SI vs 3.8% of those who never reported PE. In children with early childhood mental disorders, those who reported 2 PE had 4.4-fold increased odds of later SI (95% CI, 1.2–16.7; P = .03) after adjustments. PE were nondifferentially associated with outcomes across familial risk groups. Conclusions Early childhood PE index elevated risk for subsequent SI and NSSI beyond what can be attributed to presence of mental disorders. Mental health screenings and clinical assessments should include early childhood PE.

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.

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.

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.

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.

Schizophrenia and bipolar disorder are highly heritable severe mental disorders associated with social impairments. Moreover, partners to individuals with one of these disorders display poorer functioning and more psychopathology, but their social skills and the transgenerational transmission remains uninvestigated. Therefore, we aimed to examine social responsiveness in families with parental schizophrenia or bipolar disorder. The cohort consists of 11-year-old children with at least one parent with schizophrenia (n = 179) or bipolar disorder (n = 105) and population-based controls (PBC, n = 181). Children and parents were assessed with The Social Responsiveness Scale, Second Edition. Duration of time each parent and child have lived together was ascertained through interviews. Parents with schizophrenia and parents with bipolar disorder exhibited poorer social responsiveness compared with PBC parents. Parents with schizophrenia displayed poorer social responsiveness compared with parents with bipolar disorder. Schizophrenia co-parents exhibited poorer social responsiveness compared with bipolar co-parents and PBC co-parents. We found significant positive associations between parents' and children's social responsiveness, with no interaction effect of duration of time living together. Considering that social impairments are suggested as a vulnerability marker, this knowledge calls for increased attention towards vulnerable families, particularly those where both parents have social impairments.

In bipolar disorder, dysregulation of affect is a core feature while knowledge on affective lability in schizophrenia is sparse. Research on affective lability in partners to individuals with schizophrenia or bipolar disorder is also lacking. The objective of this study was to investigate affective lability in parents with schizophrenia or bipolar disorder, and their co-parents without these disorders. The Danish High Risk and Resilience Study – VIA 7 is a population-based cohort study. This study focuses on parents diagnosed with schizophrenia (n = 148), their co-parents (n = 157), parents with bipolar disorder (n = 98), their co-parents (n = 89) and control parents (n = 359). The Affective Lability Scale – short form (ALS-SF) was used to measure affective lability. We found significantly higher levels of affective lability in parents with schizophrenia and bipolar disorder compared with controls, but no significant differences between bipolar disorder and schizophrenia. Co-parents to parents with schizophrenia had significantly higher levels of affective lability compared to controls. Our results add to the existing knowledge concerning underlying transdiagnostic factors and nonrandom mating in schizophrenia and bipolar disorder and highlight the need for studies of parental affective lability as a potential risk factor for offspring in families with parental schizophrenia or bipolar disorder.

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], pINTERPRETATION: 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.

Background Facing multiple risk factors, relative to single risk factor exposure early in life can have great implications for negative child development. Objective We aim to examine whether the prevalence of early risk factors is higher among children with familial high risk for schizophrenia or bipolar disorder compared to controls. Further, to investigate the association between number of early risk factors and level of functioning at age seven, and whether this possible association is different in children with familial high risk compared to controls. Method The Danish High Risk and Resilience Study VIA 7 is a population-based cohort study of children of parents diagnosed with schizophrenia (N = 202), bipolar disorder (N = 120) and controls (N = 200). We conducted a semi-structured anamnestic interview with the child’s primary caregiver to assess early risk factors from pregnancy to age four. We used the Children’s Global Assessment Scale to measure level of functioning at age seven. Results 13 out of 17 risk factors were more prevalent in children at familial high risk for schizophrenia and 7 out of 17 risk factors were more prevalent in children at familial high risk for bipolar disorder compared to controls. Level of functioning decreased 2.7 (95% CI, 2.2; 3.3)-points per risk factor, but the association was not significantly different across the three groups (p = 0.09). Conclusions Our results showed that children at age seven with familial high risk for schizophrenia or bipolar disorder experience a greater number of early risk factors. A higher number of early risk factors were associated with lower level of functioning at age seven. However, the association is not different for children with familial high risk or controls.

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 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.

Background and Hypothesis Familial high-risk (FHR) studies examining longitudinal associations between neurocognition and psychotic experiences are currently lacking. We hypothesized neurocognitive impairments at age 7 to be associated with increased risk of psychotic experiences from age 7 to 11 in children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and population-based controls (PBC), and further, impaired functioning in some neurocognitive functions to be associated with greater risk of psychotic experiences in children at FHR-SZ or FHR-BP relative to PBC. Study Design Neurocognition was assessed at age 7 (early childhood) and psychotic experiences from age 7 to 11 (middle childhood) in 449 children from the Danish High Risk and Resilience Study. The neurocognitive assessment covered intelligence, processing speed, attention, visuospatial and verbal memory, working memory, and set-shifting. Psychotic experiences were assessed through face-to-face interviews with the primary caregiver and the child. Study Results Set-shifting impairments at age 7 were associated with greater risk of psychotic experiences from age 7 to 11 in children at FHR-SZ. Children at FHR-BP and PBC showed no differential associations. Working memory and visuospatial memory impairments were related to increased risk of psychotic experiences across the cohort. However, adjusting for concurrent psychopathology attenuated these findings. Conclusions Early childhood neurocognitive impairments are risk markers of middle childhood psychotic experiences, of which impaired set-shifting appears to further increase the risk of psychotic experiences in children at FHR-SZ. More research is needed to examine longitudinal associations between neurocognitive impairments and psychotic experiences in FHR samples.

The cognitive control system matures gradually with age and shows age-related sex differences. To gain knowledge concerning error adaptation in familial high-risk groups, investigating error adaptation among the offspring of parents with severe mental disorders is important and may contribute to the understanding of cognitive functioning in at-risk individuals. We identified an observational cohort through Danish registries and measured error adaptation using an Eriksen flanker paradigm. We tested 497 7-year-old children with a familial high risk of schizophrenia (N = 192) or bipolar disorder (N = 116) for deficits in error adaptation compared with a control group (N = 189). We investigated whether error adaptation differed between high-risk groups compared with controls and sex differences in the adaptation to errors, irrespective of high-risk status. Overall, children exhibited post-error slowing (PES), but the slowing of responses did not translate to significant improvements in accuracy. No differences were detected between either high-risk group compared with the controls. Boys showed less PES and PES after incongruent trials than girls. Our results suggest that familial high risk of severe mental disorders does not influence error adaptation at this early stage of cognitive control development. Error adaptation behavior at age 7 years shows specific sex differences.

Background and hypothesesImpaired interference control is a potential prognostic and endophenotypic marker of schizophrenia (SZ) and bipolar disorder (BP). Assessing children with familial high-risk (FHR) of SZ or BP enables characterization of early risk markers and we hypothesize that they express impaired interference control as well as aberrant brain activation compared to population-based control (PBC) children.Study designUsing a flanker task, we examined interference control together with functional magnetic resonance imaging (fMRI) in 11-to-12-year-old children with FHR of SZ (FHR-SZ) or FHR of BP (FHR-BP) and population-based control (PBC) children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study – VIA 11.Study resultsWe included 85 (44 % female) FHR-SZ, 63 (52 % female) FHR-BP and 98 (50 % female) PBC in the analyses. Interference effects, caused by the spatial visuomotor conflict, showed no differences between groups. Bayesian ANOVA of reaction time (RT) variability, quantified by the coefficient of variation (CVRT), revealed a group effect with similarly higher CVRTin FHR-BP and FHR-SZ compared to PBC (BF10= 6.82). The fMRI analyses revealed no evidence for between-group differences in task-related brain activation. Post-hoc analyses excluding children with psychiatric illness yielded same results.ConclusionFHR-SZ and FHR-BP at age 11-to-12 show intact ability to resolve a spatial visuo-motor conflict and neural efficacy. The increased variability in RT may reflect difficulties in maintaining sustained attention. Since variability in RT was independent of existing psychiatric illness, it may reflect a potential endophenotypic marker of risk.

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.

Twin-studies of social responsiveness have reported moderate to high heritabilities, but studies using parent–child data are lacking. Additionally, social impairments have been suggested as a vulnerability marker for schizophrenia and bipolar disorder, but the heritability of social responsiveness in this context is unknown. This study is part of the Danish High Risk and Resilience Study – VIA, comprising families with one parent with schizophrenia (n = 202) or bipolar disorder (n = 120) and population-based controls (PBC, n = 200). Social responsiveness was assessed with The Social Responsiveness Scale, Second Edition (SRS-2). Heritability was estimated from variance components, and a polygenic risk score (PRS) for autism spectrum disorder (ASD) was calculated to assess the genetic relationship between ASD and SRS-2. SRS-2 heritability was moderate to high and significantly different from zero in all groups when the children were rated by the primary caregiver. With teacher ratings, the heritability was lower and only significant in the full cohort and PBC. We found no significant association between SRS-2 and PRS for ASD. Our study confirms that social responsiveness is heritable, but that heritability estimates are affected by the child-respondent relation and familial risk of mental illness. This has implications for clinical practice and research using SRS-2 and provides insight on the familial transmission of mental illness.

Cognitive heterogeneity characterizes individuals with schizophrenia and bipolar disorder; however, little is known of cognitive heterogeneity within young children at familial high-risk of schizophrenia or bipolar disorder. This study aimed to investigate heterogeneity across social cognitive and language functions in children at familial high-risk of schizophrenia or bipolar disorder, i.e. severe mental illness (FHR-SMI). This may help designate subgroups in need of intervention initiatives. A data-driven, hierarchical cluster analysis was applied across a sample of 322 children at FHR-SMI (FHR-SZ, n = 200; FHR-BP, n = 120) on measures of Theory of Mind, facial emotion recognition, social cognitive processing speed, receptive and pragmatic language. We examined differences between subgroups as well as differences between subgroups and a control group. Exploratively, the subgroups were compared in terms of social responsiveness and global functioning. A Typical-High Functioning Subgroup with intact social cognitive and language functioning (34.5%), a Mildly Impaired Subgroup with selective impairments in explicit Theory of Mind and language functioning (58.7%), and a Significantly Impaired Subgroup with social cognitive and language functioning impairments (6.8%) were identified. The subgroups differed significantly from each other and overall compares to the controls. The Significantly and Mildly Impaired Subgroups presented with poorer social responsiveness and global functioning than the Typical-High Functioning Subgroup. In young children with FHR-SMI, three subgroups with relatively homogeneous social cognitive and language functioning profiles were observed. Only a small proportion of children at FHR-SMI displayed large social cognitive and language functioning impairments in middle childhood.

OBJECTIVES: Emotion regulation is a predictor of overall life outcome. Problems of emotion regulation are associated with multiple psychiatric disorders and could be a potential treatment target for improving well-being and functioning. Children at familial high risk of severe mental illness have a markedly increased risk of various psychopathology and constitute a group at significant risk of emotion regulation problems. Investigations of emotion regulation in children at familial high risk of severe mental illness are sparse.METHODS: We applied an instrument for assessing emotion regulation, the Tangram Emotion Coding Manual (TEC-M), to a population-based cohort of 522 7-year-old children born to parents diagnosed with either schizophrenia or bipolar disorder and matched controls. The TEC-M is an ecologically valid, clinician-rated observational test measure of spontaneous emotion regulation. We aimed to compare emotion regulation between risk groups and to investigate associations between emotion regulation and psychopathology and daily life functioning, and between emotion regulation and an acknowledged questionnaire-based dysregulation profile.RESULTS: In this early developmental phase, we found no between group differences in emotion regulation. We found a significant but weak negative association between emotion regulation and both child psychopathology and the presence of a dysregulation profile on the Child Behavior Checklist and a weak positive association between emotion regulation and current level of functioning.CONCLUSIONS: These findings contribute to the understanding of emotion regulation in familial high-risk children and further studies of emotion regulation in children at familial high risk of severe mental illness are warranted.

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.

BACKGROUND: Studies of neurocognitive heterogeneity in young children at familial high-risk of bipolar disorder (FHR-BP) or schizophrenia (FHR-SZ) are important to investigate inter-individual neurocognitive differences. We aimed to identify neurocognitive subgroups, describe prevalence of FHR-BP or FHR-SZ children herein, and examine risk ratios (RR) compared with controls.METHODS: In a population-based cohort of 514 7-year-old children (197 FHR-SZ, 118 FHR-BP, and 199 matched controls) we used hierarchical cluster analyses to identify subgroups across 14 neurocognitive indices.RESULTS: Three neurocognitive subgroups were derived: A Mildly Impaired (30%), Typical (51%), and Above Average subgroup (19%). The Mildly Impaired subgroup significantly underperformed controls (Cohen d = 0.11-1.45; Ps < .001) except in set-shifting (P = .84). FHR-SZ children were significantly more prevalent in the Mildly Impaired subgroup; FHR-BP children were more so in the Above Average subgroup (X2 (2, N= 315) = 9.64, P < .01). 79.7% FHR-BP and 64.6% FHR-SZ children demonstrated typical or above average neurocognitive functions. Neurocognitive heterogeneity related significantly to concurrent functioning, psychopathology severity, home environment adequacy, and polygenic scores for schizophrenia (Ps LIMITATIONS: Limitations include the cross-sectional design and smaller FHR-BP sample size.CONCLUSIONS: Identification of neurocognitive heterogeneity in preadolescent children at FHR-BP or FHR-SZ may ease stigma and enable pre-emptive interventions to enhance neurocognitive functioning and resilience to mental illness in the impaired sub-population.

Background Sex differences in brain structure and neurodevelopment occur in non-clinical populations. We investigated whether sex had a similar effect on developmental domains amongst boys and girls with a familial risk of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP), and controls. Methods Through Danish registries, we identified 522 7-year-old children (242 girls) with FHR-SZ, FHR-BP, and controls. We assessed their performance within the domains of neurocognition, motor function, language, social cognition, social behavior, psychopathology, and home environment. Results FHR-SZ boys compared with FHR-SZ girls had a higher proportion of disruptive behavior and attention-deficit hyperactivity disorder (ADHD) and exhibited lower performance in manual dexterity, balance, and emotion recognition. No sex differences were found between boys and girls within FHR-BP group. Compared with controls, both FHR-SZ boys and FHR-SZ girls showed impaired processing speed and working memory, had lower levels of global functioning, and were more likely to live in an inadequate home environment. Compared with control boys, FHR-SZ boys showed impaired manual dexterity, social behavior, and social responsiveness, and had a higher proportion of ADHD and disruptive behavior disorder diagnoses. Stress and adjustment disorders were more common in FHR-BP boys compared with control boys. We found no differences between FHR-BP girls and control girls. Conclusions Impairment within neurodevelopmental domains associated within FHR-SZ boys v. FHR-SZ girls was most evident among boys, whereas no sex differences were found within the FHR-BP group (FHR-BP boys v. FHR-BP girls). FHR-SZ boys exhibited the highest proportion of early developmental impairments.

Objective People with schizophrenia and bipolar disorder are at increased risk of having comorbid somatic illness. This is partly due to lack of physical activity, which may originate from childhood. Sleep disturbances are associated with schizophrenia and bipolar disorder. We aimed to assess physical activity and sleep in children at familial high risk of schizophrenia or bipolar disorder and population-based controls Methods This study is part of The Danish High Risk and Resilience Study—VIA 11. Children aged 11 born to parents with schizophrenia (FHR-SZ) (N = 133), bipolar disorder (FHR-BP) (N = 84), or controls (C) (N = 150) were assessed by accelerometry for an average of 6.9 days. Results High-intensity physical activity was significantly lower in children at FHR-SZ and FHR-BP compared to controls, (mean hours per day for FHR-SZ: 0.29, SD 0.19, for FHR-BP: 0.27, SD 0.24, and for controls 0.38, SD 0.22, P = Conclusion Children at FHR-SZ or FHR-BP had less physical activity compared to controls. Our study highlights a research area that reveals a hitherto unexplored disadvantage of being born to parents with schizophrenia or bipolar disorder. Further research is needed to enhance better understanding of causal pathways and consequences of reduced physical activity in children with FHR-SZ and FHR-BP.

Background: Prior studies have shown high heritability estimates regarding within-function transmission of neurocognition, both in healthy families and in families with schizophrenia but it remains an open question whether transmission from parents to offspring is function specific and whether the pattern is the same in healthy families and families with schizophrenia or bipolar disorder. We aimed to characterize the transmission of intelligence, processing speed, and verbal working memory functions from both biological parents to their 7-year-old offspring in families with parental schizophrenia, bipolar disorder, and population-based control parents. Methods: The population-based cohort consists of 7-year-old children with one parent diagnosed with schizophrenia (n = 186), bipolar disorder (n = 114), and of parents without schizophrenia or bipolar disorder (n = 192). Children and both parents were assessed using identical, age-relevant neurocognitive tests of intelligence, verbal working memory, and processing speed. Results: In multiple regression analyses children's intelligence, verbal working memory, and processing speed scores were significantly associated with the corresponding parental cognitive function score. All associations from parents to offspring across functions were non-significant. No significant parental cognitive function by group interaction was observed. Conclusion: Transmissions of intelligence, processing speed, and verbal working memory from parents to offspring are function specific. The structure of transmission is comparable between families with schizophrenia, families with bipolar disorder and families without these disorders.

ObjectiveChildren 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.MethodIn 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.ResultsA 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).ConclusionPrecursors 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.

Cognitive impairments are strongly associated with schizophrenia (SZ) and bipolar disorder (BP) with executive functions (EF) impairments as a likely key feature. Studies of everyday behavior rated EF in young children at familial high risk of SZ (FHR-SZ) are scarce and, to our knowledge, non-existent in young children at familial high risk of BP (FHR-BP). We aimed to compare everyday behavior-rated EF of FHR-SZ, FHR-BP, and control children. A nationwide population-based cohort of 522 7-year-old children with parents diagnosed with either SZ (N = 202) or BP (N = 120) and matched controls (N = 200) were recruited using the Danish national registries. The children's EF were assessed with the Behavior Rating Inventory of Executive Functions questionnaire rated by primary caregivers and teachers. According to primary caregiver assessments, FHR-SZ children displayed widespread EF impairments and had an odds ratio of 3.7 (2.0-6.9) of having clinically significant global EF impairments compared to controls. FHR-BP children were most severely impaired regarding EF related to emotional control and had an odds ratio of 2.5 (1.2-5.1) of clinically significant global EF impairments compared to controls. Teacher assessments were overall comparable to primary caregiver assessments but teachers rated more difficulties in the FHR-SZ group than primary caregivers. Already at age 7, children with a parental history of SZ or BP displayed significant impairments of EF in everyday-life situations. FHR-SZ children displayed widespread significant impairments of EF, whereas FHR-BP children were most severely impaired on emotional control. Clinicians should be aware of potential EF impairments in FHR children.

BackgroundThe 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.MethodsAssessments 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.ResultsAt 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.ConclusionsAssessed 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.

Nonrandom mating in parents with schizophrenia or bipolar disorder increases the population-level genetic variance among the offspring generation and creates familial (risk) environments likely to be shaped by specific conditions. The objective of this study was to investigate the occurrence of mental disorder and levels of cognitive and social functioning in individuals who have children by partners with schizophrenia or bipolar disorder compared to controls. The Danish High Risk and Resilience Study VIA 7 is a population-based cohort study conducted in Denmark between 2013 and 2016. This study focus on parents diagnosed with schizophrenia (n = 150) or bipolar disorder (n = 100) and control parents (n = 182), as well as their partners without schizophrenia or bipolar disorder (n = 440). We used linear mixed-effect models, and main outcomes were mental disorders, intelligence, processing speed, verbal working memory, and social functioning. We found that parents having children by a partner with schizophrenia or bipolar disorder more often fulfilled the criteria for a mental disorder and had poorer social functioning compared to parents having children by a partner without schizophrenia or bipolar disorder. Furthermore, parents having children by a partner with schizophrenia performed poorer on processing speed compared to parents in the control group. The presence of nonrandom mating found in this study has implications for our understanding of familial transmission of these disorders and our findings should be considered in future investigations of potential risk factors for children with a parent with schizophrenia or bipolar disorder.

Language is one of the cognitive domains often impaired across many neurodevelopmental disorders. While for some disorders the linguistic deficit is the primary impairment (e.g., specific language impairment, SLI), for others it may accompany broader behavioral problems (e.g., autism). The precise nature of this phenotypic overlap has been the subject of debate. Moreover, several studies have found genetic overlaps across neurodevelopmental disorders. This raises the question of whether these genetic overlaps may correlate with phenotypic overlaps and, if so, in what manner. Here, we apply a genome‐wide approach to the study of the linguistic deficit in SLI, autism spectrum disorder (ASD), and attention deficit/hyperactivity disorder (ADHD). Using a discovery genome‐wide association study of SLI, we generate polygenic risk scores (PRS) in an independent sample which includes children with language impairment, SLI, ASD or ADHD and age‐matched controls and perform regression analyses across groups. The SLI‐trained PRS significantly predicted risk in the SLI case–control group (adjusted R 2 = 6.24%; P = 0.024) but not in the ASD or ADHD case‐control groups (adjusted R 2 = 0.0004%, 0.01%; P = 0.984, 0.889, respectively) nor for height, used as a negative control (R 2 = 0.2%; P = 0.452). Additionally, there was a significant difference in the normalized PRS between children with SLI and children with ASD (common language effect size = 0.66; P = 0.044). Our study suggests no additive common‐variant genetic overlap between SLI and ASD and ADHD. This is discussed in the context of phenotypic studies of SLI and related disorders. Autism Res 2020, 13: 369–381. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. Lay Summary Language deficits are characteristic of specific language impairment (SLI), but may also be found in other neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Many studies examined the overlaps and differences across the language deficits in these disorders, but few studies have examined the genetic aspect thereof. In this study, we use a genome‐wide approach to evaluate whether common genetic variants increasing risk of SLI may also be associated with ASD and ADHD in the same manner. Our results suggest that this is not the case, and we discuss this finding in the context of theories concerning the etiologies of these disorders.

It is well established that children with familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) have a higher risk of developing mental disorders, however, little is known of to what degree the genetic and environmental vulnerabilities affect the quality of life and self-esteem of these children. We aimed to compare the quality of life and self-esteem between children with FHR-SZ or FHR-BP and controls. We used Danish nationwide registers to retrieve a cohort of 522 7-year-old children with FHR-SZ or FHR-BP and controls. Quality of life was assessed with the 'Health-related Quality of Life Screening Instrument', KIDSCREEN-27, and the scale 'Social Acceptance (Bullying)' from the KIDSCREEN-52. Self-esteem was assessed with the self-report scale 'I think I am'. Assessors were blind to familial risk status of the children. Children with FHR-SZ displayed lower levels of the general quality of life, as well as lower scores on the 'Psychological Well-being' scale and the 'School Environment' scale of the KIDSCREEN-27 compared with controls. Both children with FHR-SZ and FHR-BP reported more bullying victimization compared with controls. Children with FHR-SZ reported lower self-esteem on the total scale of 'I think I am', as well as on the 'Skills and talents', the 'Psychological well-being', and the 'Relationships with others' subscales compared with controls. The findings of lower quality of life and self-esteem in children with FHR-SZ together with more bullying victimization in both familial high-risk groups call for studies on low risk, early intervention strategies towards this group of vulnerable children.

BACKGROUND: Slower and suboptimal decision making has been identified in adults with schizophrenia and bipolar disorder. Owing to the limited evidence on decision making in first-degree relatives, we aimed to investigate, whether alterations in decision making are present in young children at familial high risk of bipolar disorder or schizophrenia.METHODS: In this population-based cohort study we assessed decision making in 197 children at familial high risk of schizophrenia (FHR-SZ), 115 children at familial high risk of bipolar disorder (FHR-BP), and 190 controls aged seven using the Cambridge Gambling Task. Potential associations to neurocognition, psychopathology, and the home environment were investigated.RESULTS: Children at FHR-SZ or FHR-BP displayed intact decision making. Quality of decision making showed significant but weak cross-sectional associations to neurocognition and adequacy of the home environment. Associations to aspects of executive functions and the home environment differed across groups.LIMITATIONS: Due to the cross-sectional nature of this study, the predictive value of efficient and inefficient decision making remains to be investigated in planned follow-up studies of this cohort.CONCLUSIONS: Young children at FHR-SZ or FHR-BP do not differ from controls in decision making efficacy, which does not appear to be an early risk marker of bipolar disorder or schizophrenia. Decision making is weakly associated to neurocognition and the home environment, but not to general intelligence or psychopathology.

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.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.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.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.

We aimed to investigate to which degree the home environment and/or primary caregivers’ level of functioning mediate the association between parental mental illness (eg, schizophrenia) and child psychopathology. We used data from the nationwide Danish High Risk and Resilience Study—VIA7. The study sample comprised 522 seven-year-old children. The main outcome was the child psychopathology, assessed with the Child Behavior Checklist (CBCL). The exposure variable had 3 categories: children at familial high risk of schizophrenia spectrum psychosis (FHR-SZ), bipolar disorder (FHR-BP), and population-based controls. Mediators were quality of the Home Observation for Measurement of the Environment (HOME) and primary caregiver’s Personal and Social Performance Scale (primary caregiver functioning). Primary caregiver’s IQ and polygenic risk scores (PRS) for the educational attainment of the children were considered as covariates. We found a significant indirect adjusted effect of FHR status vs controls on CBCL total scores (FHR-SZ = 5.34, 95% confidence interval [CI]: 3.50–7.47 and FHR-BP = 4.54, 95% CI: 2.65–6.68), through primary caregiver functioning and HOME. Both mediators combined explained 53% and 64% variation of the total effects of FHR-SZ and FHR-BP, respectively. Adjusting for the PRS in the mediation models only resulted in minor changes in the FHR effects on the CBCL. We conclude that the HOME and the primary caregiver functioning are important mediating factors for child psychopathology, especially in children born with familial risk for severe mental illness. This knowledge may represent a window of opportunity for the development of preventive strategies (eg, intervention to improve primary caregiver functioning and home environment).

Background Children with familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) are at increased risk of developing similar disorders and show cognitive deficits during childhood. The aim of this paper is to investigate visual attention and its developmental trajectories in children with FHR-SZ and with FHR-BP to increase our knowledge about potential cognitive endophenotypes of these two disorders. Methods We compared the performance of 89 children with FHR-SZ (N = 32), FHR-BP (N = 22), and population-based controls (PBC, N = 35) at age 7 to that at age 12 as well as including 133 12-year-old children with FHR-SZ (N = 50), FHR-BP (N = 43) and PBC (N = 40) to investigate visual attention, as part of the Danish High Risk and Resilience Study. We used the TVA-based whole report paradigm, based on the Bundesen's Theory of Visual Attention (TVA) to investigate visual attention. Results Children with FHR-SZ that showed deficits in visual processing speed at age 7 improved to a level that was not significantly different from controls at age 12. All children improved over time. We found no attentional deficits in FHR children at age 12. Conclusions On visual attention, children with FHR-SZ did not show developmental deficits or lags and, together with children with FHR-BP, they develop similarly to control children between age 7 to age 12. This emphasizes the potential of beneficial neuroplastic changes in cognitive deficits found at younger ages in children with FHR-SZ. It also highlights the importance of identifying and characterizing cognitive developmental trajectories of high-risk children and provides hope that visual attention may develop appropriately in these groups.

Cognitive heterogeneity characterizes individuals with schizophrenia and bipolar disorder; however, little is known of cognitive heterogeneity within young children at familial high-risk of schizophrenia or bipolar disorder. This study aimed to investigate heterogeneity across social cognitive and language functions in children at familial high-risk of schizophrenia or bipolar disorder, i.e. severe mental illness (FHR-SMI). This may help designate subgroups in need of intervention initiatives. A data-driven, hierarchical cluster analysis was applied across a sample of 322 children at FHR-SMI (FHR-SZ, n = 200; FHR-BP, n = 120) on measures of Theory of Mind, facial emotion recognition, social cognitive processing speed, receptive and pragmatic language. We examined differences between subgroups as well as differences between subgroups and a control group. Exploratively, the subgroups were compared in terms of social responsiveness and global functioning. A Typical-High Functioning Subgroup with intact social cognitive and language functioning (34.5%), a Mildly Impaired Subgroup with selective impairments in explicit Theory of Mind and language functioning (58.7%), and a Significantly Impaired Subgroup with social cognitive and language functioning impairments (6.8%) were identified. The subgroups differed significantly from each other and overall compares to the controls. The Significantly and Mildly Impaired Subgroups presented with poorer social responsiveness and global functioning than the Typical-High Functioning Subgroup. In young children with FHR-SMI, three subgroups with relatively homogeneous social cognitive and language functioning profiles were observed. Only a small proportion of children at FHR-SMI displayed large social cognitive and language functioning impairments in middle childhood.

Cognitive impairments are strongly associated with schizophrenia (SZ) and bipolar disorder (BP) with executive functions (EF) impairments as a likely key feature. Studies of everyday behavior rated EF in young children at familial high risk of SZ (FHR-SZ) are scarce and, to our knowledge, non-existent in young children at familial high risk of BP (FHR-BP). We aimed to compare everyday behavior-rated EF of FHR-SZ, FHR-BP, and control children. A nationwide population-based cohort of 522 7-year-old children with parents diagnosed with either SZ (N = 202) or BP (N = 120) and matched controls (N = 200) were recruited using the Danish national registries. The children's EF were assessed with the Behavior Rating Inventory of Executive Functions questionnaire rated by primary caregivers and teachers. According to primary caregiver assessments, FHR-SZ children displayed widespread EF impairments and had an odds ratio of 3.7 (2.0-6.9) of having clinically significant global EF impairments compared to controls. FHR-BP children were most severely impaired regarding EF related to emotional control and had an odds ratio of 2.5 (1.2-5.1) of clinically significant global EF impairments compared to controls. Teacher assessments were overall comparable to primary caregiver assessments but teachers rated more difficulties in the FHR-SZ group than primary caregivers. Already at age 7, children with a parental history of SZ or BP displayed significant impairments of EF in everyday-life situations. FHR-SZ children displayed widespread significant impairments of EF, whereas FHR-BP children were most severely impaired on emotional control. Clinicians should be aware of potential EF impairments in FHR children.

This study aimed to compare the psychopathological profiles of children at familial high risk of schizophrenia spectrum psychosis (FHR-SZ) or bipolar disorder (FHR-BP) with population-based controls. We used Danish nationwide registers to retrieve a cohort of 522 seven-year-old children of parents with schizophrenia spectrum psychosis (N=202), bipolar disorder (N=120) or none of these disorders (N=200). Psychopathology was assessed by reports from multiple informants, including children, parents and teachers. Lifetime DSM-IV diagnoses were ascertained by blinded raters through the Schedule for Affective Disorders and Schizophrenia for School-Age Children. The dimensional assessment of psychopathology was performed by the Child Behavior Checklist, the Teacher's Report Form, a modified version of the ADHD-Rating Scale, the Test Observation Form, and the State-Trait Anxiety Inventory for Children. Current level of functioning was evaluated using the Children's Global Assessment Scale (CGAS). The prevalence of lifetime psychiatric diagnoses was significantly higher in both FHR-SZ children (38.7%, odds ratio, OR=3.5, 95% confidence interval, CI: 2.2-5.7, p