Clinical illness course and family-related outcomes among parents with a first episode of schizophrenia spectrum disorder: a 20-year follow-up of the OPUS trial.

BACKGROUND: Studies investigating parenthood and how it affects long-term outcomes are lacking among individuals with schizophrenia spectrum disorders. This study aimed to examine the life of participants 20 years after their first diagnosis with a special focus on parenthood, clinical illness course, and family-related outcomes. METHODS: Among 578 individuals diagnosed with first-episode schizophrenia spectrum disorder between 1998 and 2000, a sample of 174 participants was reassessed at the 20-year follow-up. We compared symptom severity, remission, clinical recovery, and global functioning between 75 parents and 99 non-parents. Also, family functioning scored on the family assessment device, and the children's mental health was reported. We collected longitudinal data on psychiatric admission, supported housing, and work status via the Danish registers. RESULTS: Participants with offspring had significantly lower psychotic (mean (s.d.) of 0.89 (1.46) v. 1.37 (1.44), p = 0.031) negative (mean [s.d.] of 1.13 [1.16] v. 1.91 [1.07], p < 0.001) and disorganized symptom scores (mean [s.d.] of 0.46 [0.80] v. 0.85 [0.95], p = 0.005) and more were in remission (59.5% v. 22.4%, p < 0.001) and in clinical recovery (29.7% v. 11.1%, p = 0.002) compared to non-parents. When investigating global functioning over 20 years, individuals becoming parents after their first diagnosis scored higher than individuals becoming parents before their first diagnosis and non-parents. Regarding family-related outcomes, 28.6% reported unhealthy family functioning, and 10% of the children experienced daily life difficulties. CONCLUSIONS: Overall, parents have more favorable long-term outcomes than non-parents. Still, parents experience possible challenges regarding family functioning, and a minority of their children face difficulties in daily life.

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.

Children at Familial High risk of Schizophrenia and Bipolar Disorder Exhibit Altered Connectivity Patterns During Pre-attentive Processing of an Auditory Prediction Error.

BACKGROUND AND HYPOTHESIS: Individuals with schizophrenia or bipolar disorder have attenuated auditory mismatch negativity (MMN) responses, indicating impaired sensory information processing. Computational models of effective connectivity between brain areas underlying MMN responses show reduced connectivity between fronto-temporal areas in individuals with schizophrenia. Here we ask whether children at familial high risk (FHR) of developing a serious mental disorder show similar alterations. STUDY DESIGN: We recruited 67 children at FHR for schizophrenia, 47 children at FHR for bipolar disorder as well as 59 matched population-based controls from the Danish High Risk and Resilience study. The 11-12-year-old participants engaged in a classical auditory MMN paradigm with deviations in frequency, duration, or frequency and duration, while we recorded their EEG. We used dynamic causal modeling (DCM) to infer on the effective connectivity between brain areas underlying MMN. STUDY RESULTS: DCM yielded strong evidence for differences in effective connectivity among groups in connections from right inferior frontal gyrus (IFG) to right superior temporal gyrus (STG), along with differences in intrinsic connectivity within primary auditory cortex (A1). Critically, the 2 high-risk groups differed in intrinsic connectivity in left STG and IFG as well as effective connectivity from right A1 to right STG. Results persisted even when controlling for past or present psychiatric diagnoses. CONCLUSIONS: We provide novel evidence that connectivity underlying MMN responses in children at FHR for schizophrenia and bipolar disorder is altered at the age of 11-12, echoing findings that have been found in individuals with manifest schizophrenia.

Predictors of transfer and prognosis after transfer from child and adolescent mental health services to adult mental health services-a Danish nationwide prospective register-based cohort study.

Onset of mental health disorder peaks during adolescence making continuity of care during this period of life crucial both to ensure a smooth treatment course and high quality of mental health services for adolescents. We aimed to examine which clinical and sociodemographic features predict transfer from child and adolescent mental health services to adult mental health services and if transfer is associated with prognosis. A Danish register study including all 16-17-year-olds with an outpatient contact in child and adolescent mental health services, who were discharged in the period of 1/1/06-10/05/15. Out of 27,170 Danish adolescents, 16% transferred to adult mental health services. Transfer was predicted by schizophrenia (OR 6.16; 95% CI 5.51-6.90) and personality disorders (OR 2.08; 95% CI 1.84-2.34), while hyperkinetic (OR 0.54; 95% CI 0.49-0.59) and pervasive developmental disorders (OR 0.42; 95% CI 0.31-0.58) decreased likelihood of transfer. Transfer was also substantially predicted by inpatient admission (OR 3.37; 95% CI 3.14-3.61) and psychiatric medication (OR 2.07; 95% CI 1.92-2.23). Transfer was associated with higher rates of inpatient admission to adult mental health services (IRR 5.83; 95% CI 4.37-7.77), more psychiatric emergency contacts (IRR 12.0; 95% CI 10.7-13.4), more convictions (IRR 1.40; 95% CI 1.23-1.59) and suicide attempts (IRR 5.70; 95% CI 4.72-6.90). Policy-makers and clinicians should push for improvements and open a discussion of how to ensure continuity of care for adolescents with psychiatric disorders.

Association of maternal and paternal personality disorders with risk of mental disorders in children: A nationwide, register-based cohort study of 1,406,965 children.

BACKGROUND: Knowledge of the association between parental personality disorders and mental disorders in children is limited. To examine the association between parental personality disorders and the risk of mental disorders in offspring. METHODS: We linked Danish health registers to create a cohort of children born from January 1, 1995, to December 31, 2016. Children were followed until their 18th birthday, diagnosis set, emigration, death, or December 31, 2016. Parental personality disorders according to the International Classification of Diseases (ICD) Eighth or 10th Revision. Poisson regression analyses were used to estimate the incidence risk ratio (IRR) and cumulative incidence of ICD 10th mental disorders in offspring (age 0-17). RESULTS: The study cohort included 1,406,965 children. For girls, maternal or paternal personality disorder (MPD/PPD) was associated with mental disorders: MPD girls (IRR, 2.74; 95% CI, 2.59-2.89) and PPD girls (IRR, 2.10; 95% CI, 1.94-2.27). Likewise, the risk was increased for both MPD boys (IRR, 2.44; 95% CI, 2.33-2.56) and PPD boys (IRR, 2.04; 95% CI, 1.91-2.18). For girls and boys combined, exposure to two parents with a personality disorder was associated with the highest risk (IRR, 3.69; 95% CI, 3.15-4.33). At age 18, the cumulative incidence of any mental disorder in children of one or two parents with a personality disorder was 34.1% (95% CI, 33.0-35.1), which was twice the cumulative incidence of mental disorders in nonexposed children (15.2% [95% CI, 15.1-15.3]). CONCLUSION: Children of parents with a personality disorder were at a 2 to 3.5 times higher risk of mental disorders compared with nonexposed offspring. Possible mechanisms of transmission of mental disorders from parent to child involve genetic, environmental, and gene-environment pathways. More research into these mechanisms and research into preventive interventions is warranted.

Executive Control and Associated Brain Activity in Children With Familial High-Risk of Schizophrenia or Bipolar Disorder: A Danish Register-based Study.

BACKGROUND AND HYPOTHESES: Impaired executive 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 executive control as well as aberrant brain activation compared to population-based control (PBC) children. STUDY DESIGN: Using a flanker task, we examined executive 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 PBC children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study-VIA 11. STUDY RESULTS: We included 85 (44% female) FHR-SZ, 63 (52% female) FHR-BP and 98 (50% female) PBC in the analyses. Executive control 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 CVRT in 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. CONCLUSION: FHR-SZ and FHR-BP at age 11-12 show intact ability to resolve a spatial visuomotor 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.

Development of social functioning in preadolescent children at familial high-risk of schizophrenia or bipolar disorder - a 4-year follow-up study from age 7 to 11.

Social functioning is a major indicator of psychosis risk and evidence is lacking regarding social functioning development during preadolescence in children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP). We aimed to investigate development of social functioning from age 7 to 11 in children at FHR-SZ or FHR-BP compared with population-based controls. At 4-year follow-up, 179 children at FHR-SZ (mean age 12.0 y, SD 0.3), 105 children at FHR-BP (mean age 11.9 y, SD 0.2), and 181 controls (mean age 11.9 y, SD 0.2) participated. We used the Vineland-II to measure social functioning. Development of social functioning was non-significantly different across groups on the Socialization Composite score as well as the subscales Interpersonal Relations, Play and Leisure, and Coping Skills. At 4-year follow-up, children at FHR-SZ demonstrated impaired social functioning, whereas children at FHR-BP displayed social functioning comparable to controls except from impaired coping skills. From age 7 to 11, the maturational pace of social functioning in children at FHR-SZ and FHR-BP is parallel to that of controls. Children at FHR-SZ show stable social functioning deficits, whereas children at FHR-BP show normal social functioning except from emergence of discretely impaired coping skills at age 11.

A study of the genetic architecture of social responsiveness in families with parental schizophrenia or bipolar disorder and population-based controls.

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.

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.

Working memory heterogeneity from age 7 to 11 in children at familial high risk of schizophrenia or bipolar disorder- The Danish High Risk and Resilience Study.

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.

Social responsiveness in families with parental schizophrenia or bipolar disorder-The Danish High Risk and Resilience Study.

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.

Mental Health Is a Family Affair-Systematic Review and Meta-Analysis on the Associations between Mental Health Problems in Parents and Children during the COVID-19 Pandemic.

As a multidimensional and universal stressor, the COVID-19 pandemic negatively affected the mental health of children, adolescents, and adults worldwide. In particular, families faced numerous restrictions and challenges. From the literature, it is well known that parental mental health problems and child mental health outcomes are associated. Hence, this review aims to summarize the current research on the associations of parental mental health symptoms and child mental health outcomes during the COVID-19 pandemic. We conducted a systematic literature search in Web of Science (all databases) and identified 431 records, of which 83 articles with data of over 80,000 families were included in 38 meta-analyses. A total of 25 meta-analyses resulted in significant small to medium associations between parental mental health symptoms and child mental health outcomes (r = 0.19 to 0.46, p < 0.05). The largest effects were observed for the associations of parenting stress and child mental health outcomes. A dysfunctional parent-child interaction has been identified as a key mechanism for the transmission of mental disorders. Thus, specific parenting interventions are needed to foster healthy parent-child interactions, to promote the mental health of families, and to reduce the negative impacts of the COVID-19 pandemic.

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.

Early Childhood Neurocognition in Relation to Middle Childhood Psychotic Experiences in Children at Familial High Risk of Schizophrenia or Bipolar Disorder and Population-Based Controls: The Danish High Risk and Resilience Study.

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.

Neurocognitive Subgroups in Children at Familial High-risk of Schizophrenia or Bipolar disorder: Subgroup Membership Stability or Change From Age 7 to 11-The Danish High Risk and Resilience Study.

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.

Familial load of psychiatric disorders and overall functioning in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives.

BACKGROUND: Overall functioning is already impaired in patients newly diagnosed with bipolar disorder (BD) and, to a lesser degree, also in their unaffected first-degree relatives (UR). Further, aggregation of psychiatric disorders among the patients' first-degree relatives seems to be associated with higher illness burden and poorer prognosis. However, whether this aggregation of psychiatric disorders among first-degree relatives, the familial load (FL), impacts overall functioning in patients newly diagnosed with BD and their UR remains unresolved. METHODS: In total, 388 patients newly diagnosed with BD, 144 of their UR and 201 healthy control individuals were included. Overall functioning was assessed using three different assessment methods: The interviewer based "Functioning Assessment Short Test" (FAST), the questionnaire "Work and Social Adjustment Scale" (WSAS) and six outcome measures covering the participants' socio-economic status (SES); educational achievement, employment, work ability, relationship, cohabitation and marital status. Familial load of psychiatric disorder was assessed using the "Family History Research Diagnostic Criteria" interview. Associations between FL and overall functioning in patients and UR were investigated categorically using logistic and continuously in linear regression models. RESULTS: Contrasting with the hypotheses, the FL of psychiatric disorders was not associated with impaired overall functioning, neither in patients newly diagnosed with BD nor in their UR. CONCLUSION: The findings indicate that impaired functioning in the early phase of BD is not associated with aggregation of psychiatric disorders among first-degree relatives. The observed functional impairment in patients newly diagnosed with BD seems driven by the personal impact of the disorder rather than the impact of having first-degree relatives with psychiatric disorders.

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.