Giulietta Valuri

Intellectual disability and other neuropsychiatric outcomes in high-risk children of mothers with schizophrenia, bipolar disorder and unipolar major depression

BACKGROUND Recent evidence points to partially shared genetics of neuropsychiatric disorders. AIMS We examined risk of intellectual disability and other neuropsychiatric outcomes in 3174 children of mothers with schizophrenia, bipolar disorder or unipolar major depression compared with 3129 children of unaffected mothers. METHOD We used record linkage across Western Australian population-based registers. The contribution of obstetric factors to risk of intellectual disability was assessed. RESULTS Children were at significantly increased risk of intellectual disability with odds ratios (ORs) of 3.2 (95% CI 1.8-5.7), 3.1 (95% CI 1.9-4.9) and 2.9 (95% CI 1.8-4.7) in the maternal schizophrenia, bipolar disorder and unipolar depression groups respectively. Multivariate analysis suggests familial and obstetric factors may contribute independently to the risk. Although summated labour/delivery complications (OR = 1.4, 95% CI 1.0-2.0) just failed to reach significance, neonatal encephalopathy (OR = 7.7, 95% CI 3.0-20.2) and fetal distress (OR = 1.8, 95% CI 1.1-2.7) were independent significant predictors. Rates of rare syndromes in children of mothers with mental disorder were well above population rates. Risk of pervasive developmental disorders, including autism, was significantly elevated for children of mothers with bipolar disorder. Risk of epilepsy was doubled for children of mothers with unipolar depression. CONCLUSIONS Our findings provide epidemiological support for clustering of neuropsychiatric disorders. Further larger epidemiological studies are warranted.

Cohort Profile: Pathways of risk from conception to disease: the Western Australian schizophrenia high-risk e-Cohort

Schizophrenia is a severely disabling disorder with a lifetime risk of 1% and a point prevalence of about 5 per 1000. Schizophrenia accounts for 2.3% of the global burden of disease. The aetiology of schizophrenia is complex. While there appears to be a significant genetic contribution, it is possible that many genes of small effect contribute to the disorder and that environmental risk factors interact with the genetic susceptibility. The impact of environmental risks appears to be complex, with no single environmental risk factor of major effect isolated to date. Putative candidate exposures include winter/spring season of birth, pregnancy and birth complications; prenatal starvation; urbanicity; migration and ethnicity, with the incidence apparently higher in second-generation migrants; stress and cannabis use. There have also been reports of possible age-related germ-line mutations such as those associated with older fathers. Much of the research into environmental risk factors has focused on the role of obstetric complications. While the level of reported risk associated with obstetric complications varies, Geddes and Lawrie, in a meta-analysis of published research, reported a pooled odds ratio of 2, a figure corroborated a few years later by Cannon et al., who calculated the individual odds ratio of 2 and under for the majority of the many complications that they reviewed. It appears that changes in the uterine environment such as increased maternal cytokines in response to hypoxia or infection, and stress-induced elevation of circulating corticosteroid levels may predispose some infants to psychopathology. In particular, much attention has been focused on hypoxic/ischemic events associated with and/or resulting in placentation abnormalities leading to fetal growth retardation and neonatal encephalopathy. In order to examine the role of genes, environment and their interaction in the expression of schizophrenia, a number of studies have adopted a prospective, longitudinal approach focusing on so-called ‘strategic’ populations of ‘high-risk’ children. These are children who are at genetically increased risk of developing schizophrenia because they have at least one parent with the disease and are therefore a priori enriched for predisposing genes. High-risk samples offer researchers the opportunity to address efficiently and parsimoniously key questions about risk factors and vulnerability. By parcelling out the separate contribution of genetic liability and environmental exposures, their relative contribution to the onset of schizophrenia and other neuropsychiatric outcomes can be assessed. One of the earliest of the longitudinal investigations of developmental pathways in the children of parents with schizophrenia was initiated by Barbara Fish in the early 1950s. Fish proposed that developmental retardation and neurological soft signs observed amongst the high-risk children in her sample were early markers of an inherited neurointegrative defect in schizophrenia which she named ‘pandysmaturation’. Dr Fish’s seminal work on pandysmaturation laid the groundwork for the formulation of the neurodevelopmental hypothesis of schizophrenia in the late 1980s. In its simplest form, the hypothesis states that critical circuits in the brain are affected by subtle disease processes in early development, with full-blown consequences Published by Oxford University Press on behalf of the International Epidemiological Association

Impact of social disadvantage and parental offending on rates of criminal offending among offspring of women with severe mental illness

Objective: Children of parents with severe mental illness have an increased risk of offending. Studies suggest that risk factors such as parental offending and social disadvantage may be associated with the increased risk. This paper assesses the impact of these risk factors on offending rates in the offspring of women with severe mental illness compared to offspring of unaffected women. Methods: This is part of a longitudinal record-linked whole-population study of 467,945 children born in Western Australia from 1980 to 2001 to mothers with severe mental illness and mothers with no recorded psychiatric illness. These data were linked to Western Australia corrective services data producing a dataset of 12,999 people with at least one offence (3.7% of birth cohort). Cox proportional hazard was used to calculate incidence rate ratios of offspring offending. Results: The offending rate for offspring of mothers with severe mental illness (cases) was almost three times the rate for offspring of unaffected mothers (comparison) with an unadjusted incidence rate ratio of 2.75 (95% confidence interval: [2.58, 2.93]). Adjusting for sex, indigenous status, socio-economic status and geographical remoteness reduced the rate ratio by 24% to incidence rate ratio 2.10, 95% confidence interval: [1.97, 2.23]. Adjusting for parental offending further reduced the rate ratio by 23% to incidence rate ratio 1.62, 95% confidence interval: [1.52, 1.72]. The mean age at first recorded offence was significantly lower for cases compared to comparison offspring. Conclusion: Children of mothers with a severe mental illness have a higher rate of offending than children of unaffected mothers, and social disadvantage and parental offending have a major impact on this rate. Services supporting these vulnerable children need to focus on improving the social environment in which they and their families live in.

The offspring of women with severe mental disorder

Schizophrenia is a severely disabling disorder with a lifetime risk of about 1%. The aetiology of schizophrenia is complex. Evidence from twin, adoptive and family studies indicates that the disorder involves a significant genetic contribution: children of women with schizophrenia have an 8- to 10-fold higher risk of developing the disorder compared with the general population [1], with the risk in a monozygotic co-twin increased to about 50-fold [2]. The pattern of inheritance in schizophrenia is not a simple Mendelian one. It is likely that multiple genes of small to moderate effect contribute to the disorder, and that environmental risk factors interact with this genetic susceptibility. However, the precise nature of the genetic and environmental risk factors remains unclear. It has long been suspected that disruptions to early brain development may be associated with an increased risk of adult-onset schizophrenia [3]. In the 1980s, these speculations became more clearly articulated under the generic label of the ‘neurodevelopmental hypothesis’ of schizophrenia [4]. It was proposed that critical circuits in the brain were affected in early development by a disease process, with full-blown consequences evident many years later in adolescence or early adulthood as schizophrenia [5]. The original theory is open as to whether the ‘disease process’ affecting neuronal development is genetically or environmentally determined. There are a number of indicators of neurodevelopmental disruption in schizophrenia including: (a) an increased risk of schizophrenia following obstetric complications at birth with good evidence that the risk is increased 2- to 7-fold [6]; (b) a history of neurointegrative defect in children who later develop schizophrenia [7], and (c) an increased frequency of minor physical anomalies [8] and neurological soft signs [9] in affected

Congenital blindness is protective for schizophrenia and other psychotic illness. A whole-population study.

Congenital/early blindness is reportedly protective against schizophrenia. Using a whole-population cohort of 467,945 children born in Western Australia between 1980 and 2001, we examined prevalence of schizophrenia and psychotic illness in individuals with congenital/early blindness. Overall, 1870 children developed schizophrenia (0.4%) while 9120 developed a psychotic illness (1.9%). None of the 66 children with cortical blindness developed schizophrenia or psychotic illness. Eight of the 613 children with peripheral blindness developed a psychotic illness other than schizophrenia and fewer had developed schizophrenia. Our results support findings from small case studies that congenital/early cortical but not peripheral blindness is protective against schizophrenia.

THE HIGH RISK CHILDREN OF MOTHERS WITH SCHIZOPHRENIA AND OTHER SEVERE MENTAL ILLNESS: DOES A MOTHER'S MENTAL ILLNESS INCREASE THE RISK OF SUDDEN INFANT DEATH SYNDROME?

psychosis following traumatic brain injury or allowed calculation of prevalence rates from data provided in the paper. We did computerassisted searches, scanned reference lists, searched journals and correspondedwith authorswherenecessary.We includedcase-control studies, cohort studies and family studies. Estimates of prevalence of psychosis from different studies were combined using fixed or random-effects meta-analysis, as appropropriate, with the data presented in forest plots. Heterogeneity among studies was estimated. Results: Our literature search and search of reference lists yielded 10015 references. The search was then limited to humans, which resulted in 9131 studies. Of these, 162 were considered to be potentially relevant. We excluded 154 studies, which did not meet inclusion criteria. We identified 8 studies which met our inclusion criteria, of which two were family studies, two were nested casecontrol studies and four were cohort studies. The overall pooled data revealed a significant association between TBI and subsequent psychosis (adjusted odds ratio=1.15, 1.04-1.26). However there was significant heterogeneity between the studies (Heterogeneity x=30.70 (d.f.=7) p=0.000; I=77.2%). Therefore,we decided to examine the family studies and case-control/cohort studies separately. Overall pooled data from the 6 population-based cohort and case-control studies showed an increased risk of development of schizophrenia or psychotic disorder in individuals who had been exposed to TBI (adjusted odds ratio=1.1, 1.005-1.231). However there was significant heterogeneity between the studies (Heterogeneity x=26.43 (d.f.=5); p<0.000; I=81.1%). Pooled data from the two family studies show an increased risk of schizophrenia after TBI in individuals who have a family history of schizophrenia (adjusted odds ratio=1.43, 1.14-1.8). There was no significant heterogeneity between the two studies. We were not able to examine the influence of location or age at onset of head injury. Discussion: We report an increased risk of psychosis following TBI. The increase among the general population is small about 10%but the risk ismore substantial among individualswhohave a family historyof schizophrenia or psychosis – about 43% increased risk. In particular, our findings point to the importance of gene-environment interaction in the etiology of psychosis following traumatic brain injury. Acknowledgements: Thisworkwas supportedbya Clinician Scientist Award to M. Cannon from the Health Research Board (Ireland).