Camilla Jerlang Christiani

The Danish High Risk and Resilience Study – VIA 7 - a cohort study of 520 7-year-old children born of parents diagnosed with either schizophrenia, bipolar disorder or neither of these two mental disorders

BackgroundSevere mental illnesses like schizophrenia and bipolar disorder are known to be diseases that to some extent, but not entirely can be understood genetically. The dominating hypothesis is that these disorders should be understood in a neurodevelopmental perspective where genes and environment as well as gene-environment-interactions contribute to the risk of developing the disease. We aim to analyse the influences of genetic risk and environmental factors in a population of 520 7-year-old children with either 0, 1 or 2 parents diagnosed with schizophrenia spectrum psychosis or bipolar disorder on mental health and level of functioning. We hypothesize that a larger proportion of children growing up with an ill parent will display abnormal or delayed development, behavioural problems or psychiatric symptoms compared to the healthy controls.Methods/designWe are establishing a cohort of 520 7-year-old children and both their parents for a comprehensive investigation with main outcome measures being neurocognition, behaviour, psychopathology and neuromotor development of the child. Parents and children are examined with a comprehensive battery of instruments and are asked for genetic material (saliva or blood) for genetic analyses. The participants are recruited via Danish registers to ensure representativity. Data from registers concerning social status, birth complications, somatic illnesses and hospitalization are included in the database. Psychological and relational factors like emotional climate in the family, degree of stimulation and support in the home and attachment style are also investigated.DiscussionData collection started January 1, 2013, and is successfully ongoing. By Aug 2015 424 families are included. About 20 % of the invited families decline to participate, equal for all groups.

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 Teachers 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 Childrens 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.

O12.5. GENETIC AND ENVIRONMENTAL PREDICTORS OF MAIN OUTCOMES IN THE DANISH HIGH RISK AND RESILIENCE STUDY - VIA 7. A STUDY OF 522 7-YEAR-OLD CHILDREN OF PARENTS WITH SCHIZOPHRENIA, BIPOLAR DISORDER OR NEITHER OF THESE DISORDERS

Abstract Background Studies of children born to parents with schizophrenia and affective disorders can allow us to study the processes preceding the manifestation of the disease, and thereby provide a possibility for identifying early amendable risk factors such as poor parenting, deviances in cognitive functioning, and early, subtle signs of psychopathology at a point where preventive intervention can be applied. Methods The Danish High Risk and Resilience Study - VIA7 is a representative nationwide cohort study of 522 7-year-old children of parents with schizophrenia, bipolar disorder or neither of these disorders recruited during 2013–2015. The sample consists of: 202 children with a parent diagnosed with schizophrenia spectrum psychosis, 120 children with a parent diagnosed with bipolar disorder, and 200 children with neither of the parents treated in mental health services for the above diagnoses. We have collected blood and saliva samples from the children and their parents and polygenic risk scores were calculated. We have thoroughly assessed the home environment with the instrument HOME. We have assessed main outcomes such as psychopathology, PLIKS, neurocognition and social cognition. We will analyse the influence of genetic and environmental exposures and their interaction. Results Generally, the children with a familial risk of schizophrenia had lower neurocognitive, social cognitive and neuromotor functioning, more child psychiatric diagnoses, and more severe symptoms compared to control children. In most comparisons, children of parents with bipolar disorder were not different from controls, but in some tests they performed poorer or had more symptoms compared to than control children. We will present data on genetic and environmental risk factors for these outcomes Discussion This is the largest high-risk study ever conducted. It is unique that we have access to detailed phenotyping and extensive information on environmental and genetic risk factors. Studies like this can inform about patogenesis and possibilities for future preventive interventions

F205. OLFACTORY IDENTIFICATION IN 7-YEAR OLD CHILDREN AT FAMILIAL RISK TO DEVELOP SCHIZOPHRENIA

Abstract Background Olfactory dysfunction has repeatedly been observed in individuals diagnosed with schizophrenia. The most stable and consistent finding on the behavioral level is that of smell identification deficits. However, the nature of olfactory identification abnormalities seems to extend to structural abnormalities in the underlying neurobiology of the olfactory system. Furthermore, smell identification deficits are also documented in first-episode patients and non-psychotic first-degree relatives of schizophrenia patients. Family members of schizophrenia patients also show structural abnormalities of the olfactory system, suggesting that these may serve as an endophenotype for the development of schizophrenia. Only a few studies examined the olfactory identification ability in adolescents at-risk for schizophrenia and suggested smell identification deficits as a risk marker for schizophrenia. These studies included adolescents at clinical as well as at genetic risk for schizophrenia. None of these studies focused on children at genetic risk for schizophrenia. Therefore, we investigated the olfactory identification ability in children of parents with schizophrenia in comparison to children of parents without a psychotic disorder. As we are also interested in the specificity of the olfactory impairments to schizophrenia, we included children of parents with bipolar disorder. We hypothesize that children at genetic risk for schizophrenia would have the most severe smell identification deficits and that children of bipolar disorder patients would have less severe deficits than the at-risk for schizophrenia group but more severe than the group of children without a psychotic parent. Methods Participants - The olfactory identification ability was assessed in 202 children of schizophrenia patients (‘children at familial risk for schizophrenia’) in relation to that of 200 children of parents without a psychotic disorder (‘controls’). In addition, we also assessed the B-SIT in 120 children of bipolar disorder patients (‘children at familial risk for bipolar disorder’). All children were 7 years of age at the time of assessment and they were part of the Danish High Risk and Resilience Study – VIA7. Brief Smell Identification Test - The Brief Smell Identification Test (B-SIT) contains 12 items that need to be scratched and sniffed. The test has excellent reliability (> 0.80) and demonstrates agreement for abnormal olfaction comparing B-SIT with the San Diego Odor Identification Test (SDOIT). A maximum score of 12 reflects intact olfactory identification functioning. B-SIT has been conducted in patients with neurodegenerative disorders (Parkinson’s disease and Alzheimer’s disease) and can be used for individuals above 5 years of age. Statistics - We will use analysis of covariance (ANCOVA) for analysis of the B-SIT total scores with ‘diagnosis of parent’ as the independent variable and age and sex as covariates for the three groups. Results Analyses will be performed within the next 3 months so can be presented in April 2018. Discussion Conclusion and discussion cannot be drawn at this time.

F204. THE DANISH HIGH-RISK AND RESILIENCE STUDY - VIA 7 - A PROSPECTIVE COHORTE STUDY OF 522 7 YEARS OLD CHILDREN BORN TO PARENTS DIAGNOSED WITH SCHIZOPHRENIA OR BIPOLAR DISORDER - RESULTS ON PSYCHOPATHOLOGY, COGNITION AND LIVING CONDITIONS

Abstract Background For decades familial high-risk studies have informed us about genetic and environmental risk factors for schizophrenia and recently also bipolar disorder. Familial high-risk studies are important and relevant and may represent a possible shortcut to learning more about early markers of illness, mental vulnerability and resilience. Methods The Danish High Risk and Resilience Study – VIA 7 is a prospective cohort study of 522 7-year old children, 202 of them born to at least one parent diagnosed with schizophrenia in the Danish registries, 120 of them born to a least one parent diagnosed with bipolar disorder and 200 of them born to parents without any of these diagnoses. A comprehensive battery has been used combining assessments from several domains for both parents and children. Results Results show that children born to parents with schizophrenia or bipolar disorder have higher frequencies of early mental problems. Further there are marked differences between the three groups concerning neuro cognition, motor functioning and living conditions including socioeconomic status, early risk factors and home environment - all factors that are known to be important with regard to healthy child development. Discussion First results from the VIA 7-study indicate that many children and families have unmet needs and problems. Perspectives are two-fold: we aim to follow the cohort and conduct a new assessment before puberty (at age 11). Simultaneously, we are evolving an early, integrated, specialized and family based intervention, called VIA Family, to prevent or ameliorate development of severe mental illness in individuals born to parents with schizophrenia or bipolar disorder.

F67. NEUROCOGNITION IN 7-YEAR-OLD CHILDREN OF PARENTS WITH SCHIZOPHRENIA OR BIPOLAR DISORDER

Abstract Background Children of parents with schizophrenia or bipolar disorder display neurocognitive deficits. However, studies of schizophrenia offspring and bipolar offspring at the same age are lacking. The objective was to compare neurocognitive abilities in 7-year-old children of parents with schizophrenia or bipolar disorder with neurocognitive abilities in children of parents without these disorders. Methods In this nationwide cohort study we assessed 522 7-year-old children (schizophrenia offspring: N=202, bipolar offspring: N=120, and controls=200) with a detailed and well validated neurocognitive test battery. We compared the neurocognitive test scores of the three study groups. Results Children of parents with schizophrenia showed neurocognitive deficits, whereas children of parents with bipolar disorder displayed neurocognitive abilities comparable to the control group. Discussion Neurocognitive deficits are numerous in 7-year-old children of parents with schizophrenia, which supports the neurodevelopmental model of schizophrenia. Unimpaired neurocognitive abilities in children of parents with bipolar disorder indicate different neurodevelopmental manifestations in these high risk populations at this early age. Our results call for early identification of schizophrenia offspring with cognitive dysfunctions.

Assessment of Neurocognitive Functions in 7-Year-Old Children at Familial High Risk for Schizophrenia or Bipolar Disorder: The Danish High Risk and Resilience Study VIA 7

Importance Children at familial high risk of schizophrenia spectrum disorders (FHR-SZ) or bipolar disorder (FHR-BP) exhibit neurocognitive impairments. Large studies of neurocognition in young children at familial high risk at the same age are important to differentiate the pathophysiology and developmental trajectory of these 2 groups. Objective To characterize neurocognitive functions in 7-year-old children with FHR-SZ or FHR-BP and a control population. Design, Setting, and Participants This multisite population-based cohort study collected data from January 1, 2013, to January 31, 2016, in the first wave of the Danish High Risk and Resilience Study VIA 7 at 2 university hospital research sites in Copenhagen and Aarhus using Danish registries. Participants (n = 514) included 197 children with FHR-SZ, 118 with FHR-BP, and 199 controls matched with the FHR-SZ group for age, sex, and municipality. Assessors were blinded to risk status. Exposures Parents with schizophrenia, bipolar disorder, or neither diagnosis. Main Outcomes and Measures Neurocognitive functions were measured across 23 tests. Four neurocognitive domains were derived by principal component analysis, including processing speed and working memory, verbal functions, executive and visuospatial functions, and declarative memory and attention. Results A total of 514 children aged 7 years were included in the analysis (46.3% girls), consisting of 197 children with FHR-SZ (46.2% girls), 118 with FHR-BP (46.6% girls), and 199 controls (46.2% girls). Children with FHR-SZ were significantly impaired compared with controls on processing speed and working memory (Cohen d = 0.50; P < .001), executive and visuospatial functions (Cohen d = 0.28; P = .03), and declarative memory and attention (Cohen d = 0.29; P = .02). Compared with children with FHR-BP, children with FHR-SZ performed significantly poorer in processing speed and working memory (Cohen d = 0.40; P = .002), executive and visuospatial functions (Cohen d = 0.35; P = .008), and declarative memory and attention (Cohen d = 0.31; P = .03). Children with FHR-BP and controls did not differ. Conclusions and Relevance Children with FHR-SZ had widespread neurocognitive impairments, supporting the hypothesis of neurocognitive functions as endophenotypes of schizophrenia. The absence of neurocognitive deficits in children with FHR-BP suggests distinct neurodevelopmental manifestations in these familial high-risk groups at this age. Early detection of children with FHR-SZ and cognitive impairments is warranted to investigate associations of neurocognition with transition to psychosis, add to the knowledge of their developmental pathophysiology, and inform early intervention programs.