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

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

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

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

Suicidal Ideation and Non-Suicidal Self-Injury Following Early Childhood Psychotic Experiences in Preadolescent Children at Familial High Risk of Schizophrenia or Bipolar Disorder-The Danish High Risk and Resilience Study, VIA 11.

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.

Mismatch negativity and P3a amplitude in children with familial high risk of schizophrenia or bipolar disorder - A Danish register-based EEG study.

BACKGROUND: Infrequent deviants in a rapid sequence of sounds elicit a negative cortical potential over the frontocentral midline (mismatch negativity, MMN) followed by a positive deflection (P3a). Both cortical potentials are consistently attenuated in patients with schizophrenia (SZ), and, to a lesser degree, in patients with bipolar disorder (BP). OBJECTIVE: Since it is unclear when MMN and P3a deficits arise relative to the emergence of symptoms, we examined whether MMN and P3a alterations are already detectable in children with familial high risk. METHODS: Using 128-channel electroencephalography, we recorded auditory MMN and P3a evoked by a deviation in sound duration, frequency, or both in 51 children with familial high-risk for SZ (FHR-SZ), 41 children with familial high-risk for BP (FHR-BP), and 39 population-based children (PBC) at a mean age of 12.10. RESULTS: MMN amplitude evoked by a duration deviant was larger in children with FHR-BP compared to PBC and FHR-SZ. P3a amplitude in response to a duration ∗ frequency deviant was larger in children with FHR-BP compared to children with FHR-SZ, but not compared to PBC. MMN- and P3a-peak latency did not differ between groups. CONCLUSIONS: At an age of around 12 years, children with FHR-BP display enhanced neural sensitivity to change detection of duration deviants, while FHR-SZ showed a normal response pattern. Longitudinal recordings in high-risk children during adolescence are required to elucidate the temporal trajectories of MMN and P3a responses and how they relate to the emergence of first clinical symptoms in SZ and BP.

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

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

Development of visual attention from age 7 to age 12 in children with familial high risk for schizophrenia or bipolar disorder.

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.

Odor identification in 7-year-old children at familial high risk of schizophrenia or bipolar disorder - the Danish high risk and resilience study VIA 7.

BACKGROUND: Odor identification deficits occur in individuals with schizophrenia and their unaffected first-degree relatives, while deficits are less pronounced in individuals with bipolar disorder. We hypothesized that children at familial high-risk for schizophrenia (FHR-SZ) show odor identification deficits compared to population-based controls and that children at familial high-risk for bipolar disorder (FHR-BP) perform intermediate. METHODS: Odor identification was assessed at age 7 in 184 children with FHR-SZ, 106 children with FHR-BP, and 186 population-based controls with the Brief Smell Identification Test. Dimensional and predefined categorical outcomes were used in the analyses. Potential relationships with psychopathological, cognitive, and home environmental variables were conducted using hierarchical and logistic multiple regression analyses. RESULTS: ANOVA revealed no between-group differences in odor identification. Using the recommended cut-off (below 5), we found a significantly greater proportion of boys at FHR-SZ than population-based boys with an abnormal odor identification (p = .013). However, a supplementary analysis using a Danish-based cut-off (below 4) did not support this. All children showed significant, positive associations of odor identification with female gender, social responsiveness, and verbal working memory. Lower social responsiveness predicted abnormal odor identification in boys at FHR-SZ, only using the recommended cut-off. CONCLUSIONS: Odor identification efficacy and risk status appear independent in this early developmental phase. Using the recommended threshold, abnormal odor identification is more frequent in young boys at FHR-SZ than in population-based boys and is linked to lower social responsiveness. The validity of these results is questioned by non-significant differences in the rates when using an exploratory Danish-based threshold.

Psychopathology in 7-year-old children with familial high risk of developing schizophrenia spectrum psychosis or bipolar disorder - The Danish High Risk and Resilience Study - VIA 7, a population-based cohort study.

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 < 0.001) and FHR-BP children (35.6%, OR=3.1, 95% CI: 1.8-5.3, p < 0.001) compared with controls (15.2%). FHR-SZ children displayed significantly more dimensional psychopathology on all scales and subscales compared with controls except for the Anxious subscale of the Test Observation Form. FHR-BP children showed higher levels of dimensional psychopathology on several scales and subscales compared with controls, but lower levels compared with FHR-SZ children. Level of functioning was lower in both FHR-SZ children (CGAS mean score = 68.2; 95% CI: 66.3-70.2, p < 0.0001) and FHR-BP children (73.7; 95% CI: 71.2-76.3, p < 0.05) compared with controls (77.9; 95% CI: 75.9-79.9). In conclusion, already at the age of seven, FHR-SZ and FHR-BP children show a higher prevalence of a broad spectrum of categorical and dimensional psychopathology compared with controls. These results emphasize the need for developing early intervention strategies towards this vulnerable group of children.