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Are familial liability for schizophrenia and obstetric complications independently associated with risk of psychotic illness, after adjusting for other environmental stressors in childhood?
Abstract
Objective
The interplay between genetic and environmental factors on risk for psychotic illness remains poorly understood. The aim of this study was to estimate independent and combined effects of familial liability for schizophrenia and exposure to obstetric complications on risk for developing psychotic illness, covarying with exposure to other environmental stressors.
Methods
This whole-population birth cohort study used record linkage across Western Australian statewide data collections (midwives, psychiatric, hospital admissions, child protection, mortality) to identify liveborn offspring ( n = 1046) born 1980–1995 to mothers with schizophrenia, comparing them to offspring of mothers with no recorded psychiatric history ( n = 298,370).
Results
Both maternal schizophrenia and pregnancy complications were each significantly associated with psychotic illness in offspring, with no interaction. Non-obstetric environmental stressors significantly associated with psychotic illness in offspring included the following: being Indigenous; having a mother who was not in a partnered relationship; episodes of disrupted parenting due to hospitalisation of mother, father or child; abuse in childhood; and living in areas of greatest socioeconomic disadvantage and with elevated rates of violent crime. Adjustment for these other environmental stressors reduced the hazard ratio for maternal schizophrenia substantially (from hazard ratio: 5.7, confidence interval: 4.5–7.2 to hazard ratio: 3.5, confidence interval: 2.8–4.4), but not the estimate for pregnancy complications (hazard ratio: 1.1, confidence interval: 1.0–1.2). The population attributable fraction for maternal schizophrenia was 1.4 and for pregnancy complications was 2.1.
Conclusion
Our finding of a substantial decrease in risk of psychotic illness associated with familial liability for psychosis following adjustment for other environmental stressors highlights potentially modifiable risk factors on the trajectory to psychotic illness and suggests that interventions that reduce or manage exposure to these risks may be protective, despite a genetic liability.
... After going through the complete text, we excluded four more studies and finally included 27 articles that met our eligibility criteria. We removed the articles by Ahmad et al. (2022), Morgan et al. (2019), Giovanelli & Reynolds (2021), and Kazeem (2020) after a comprehensive reading to align the search results with the eligibility criteria of the present study. Figure 1 indicates the course of the studies included in this review as per the PRISMA guidelines. ...
A complex interlink between childhood maltreatment and later life delinquency is evident in different studies. This systematic review examines the intricate relationship between childhood maltreatment and the subsequent engagement of individuals in violent exposures. A comprehensive search of the Web of Science (WoS) core collection synthesises several empirical studies published over the last 18 years. Through a meticulous screening process and stringent inclusion criteria, 27 studies were finally selected for analysis using the PRISMA guidelines. The synthesised findings highlight the nuanced interplay between various forms of childhood maltreatment and other confounding factors that predict violence. The USA and China were the most pragmatic in studying this issue. Different statistical techniques, e.g., correlation, regression, and structural equation modelling, were used in these studies. It was found that different forms of maltreatment directly affect violent behaviours. Other factors like psychopathy,drug abuse, conduct disorder, impulsivity, narcissistic vulnerability, and other psychosocial factors often confound it or act as mediators. Gender differences were also examined in some studies. Females were found to be more prone to violent exposure as the outcome of their maltreatment experience in some studies. Findings reveal that neighbourhood factors (neighbourhood disorganisation and social capital) are less represented here.
... A common approach to modelling adversities in the study of schizophrenia has been to include them as separate terms in multivariable explanatory models (Morgan et al., 2019;Veling et al., 2015) with some studies allowing for the possibility of interactions between risk factors (Zammit et al., 2010). Some summary exposure scores have also been proposed. ...
Background
Additional to a child's genetic inheritance, environmental exposures are associated with schizophrenia. Many are broadly described as childhood adversity; modelling the combined impact of these is complex. We aimed to develop and validate a scale on childhood adversity, independent of genetic and other environmental liabilities, for use in schizophrenia risk analysis models, using data from cross-linked electronic health and social services registers.
Method
A cohort of N = 428 970 Western Australian children born 1980–2001 was partitioned into three samples: scale development sample ( N = 171 588), and two scale validation samples (each N = 128 691). Measures of adversity were defined before a child's 10th birthday from five domains: discontinuity in parenting, family functioning, family structure, area-level socioeconomic/demographic environment and family-level sociodemographic status. Using Cox proportional hazards modelling of follow-up time from 10th birthday to schizophrenia diagnosis or censorship, weighted combinations of measures were firstly developed into scales for each domain, then combined into a final global scale. Discrimination and calibration performance were validated using Harrell's C and graphical assessment respectively.
Results
A weighted combination of 42 measures of childhood adversity was derived from the development sample. Independent application to identical measures in validation samples produced Harrell's Concordance statistics of 0.656 and 0.624. Average predicted time to diagnosis curves corresponded with 95% CI limits of observed Kaplan–Meier curves in five prognostic categories.
Conclusions
Our Early Adversity Scale for Schizophrenia (EAS-Sz), the first using routinely collected register data, predicts schizophrenia diagnosis above chance, and has potential to help untangle contributions of genetic and environmental liability to schizophrenia risk.
... 21 years), outcomes studied included depression and anxiety disorders (Dahl et al., 2017;Scott et al., 2012), attentional problems (Boyd et al., 2019), internalising and externalising behaviours (Kisely et al., 2018;Scott et al., 2010), posttraumatic stress disorder , alcohol or substance use disorders Scott et al., 2010Scott et al., , 2012, and low quality of life (Abajobir, Kisely, Williams, Strathearn, Clavarino, & Najman, 2017). In later adulthood, outcomes studied included schizophrenia and psychotic disorders (Cutajar et al., 2010a(Cutajar et al., , 2010bMorgan et al., 2019;Spataro et al., 2004). ...
Background
This scoping review aimed to overview studies that used administrative data linkage in the context of child maltreatment to improve our understanding of the value that data linkage may confer for policy, practice, and research.
Methods
We searched MEDLINE, Embase, PsycINFO, CINAHL, and ERIC electronic databases in June 2019 and May 2020 for studies that linked two or more datasets (at least one of which was administrative in nature) to study child maltreatment. We report findings with numerical and narrative summary.
Results
We included 121 studies, mainly from the United States or Australia and published in the past decade. Data came primarily from social services and health sectors, and linkage processes and data quality were often not described in sufficient detail to align with current reporting guidelines. Most studies were descriptive in nature and research questions addressed fell under eight themes: descriptive epidemiology, risk factors, outcomes, intergenerational transmission, predictive modelling, intervention/service evaluation, multi-sector involvement, and methodological considerations/advancements.
Conclusions
Included studies demonstrated the wide variety of ways in which data linkage can contribute to the public health response to child maltreatment. However, how research using linked data can be translated into effective service development and monitoring, or targeting of interventions, is underexplored in terms of privacy protection, ethics and governance, data quality, and evidence of effectiveness.
... Three European sites (Denmark, Norway, Sweden) and three non-European sites (Canadian province of Manitoba, Taiwan, Australian state of Western Australia) have the unique capability to define familial relationships and objectively-measured health histories from administrative and healthcare electronic records. Studies from these sites have made important contributions to understanding associations between familial health histories and individual outcomes for a broad range of health conditions or life events [6][7][8][9][10][11][12][13][14]. ...
Family health history is a well-established risk factor for many health conditions but the systematic collection of health histories, particularly for multiple generations and multiple family members, can be challenging. Routinely-collected electronic databases in a select number of sites worldwide offer a powerful tool to conduct multigenerational health research for entire populations. At these sites, administrative and healthcare records are used to construct familial relationships and objectively-measured health histories. We review and synthesize published literature to compare the attributes of routinely-collected, linked databases for three European sites (Denmark, Norway, Sweden) and three non-European sites (Canadian province of Manitoba, Taiwan, Australian state of Western Australia) with the capability to conduct population-based multigenerational health research. Our review found that European sites primarily identified family structures using population registries, whereas non-European sites used health insurance registries (Manitoba and Taiwan) or linked data from multiple sources (Western Australia). Information on familial status was reported to be available as early as 1947 (Sweden); Taiwan had the fewest years of data available (1995 onwards). All centres reported near complete coverage of familial relationships for their population catchment regions. Challenges in working with these data include differentiating biological and legal relationships, establishing accurate familial linkages over time, and accurately identifying health conditions. This review provides important insights about the benefits and challenges of using routinely-collected, population-based linked databases for conducting population-based multigenerational health research, and identifies opportunities for future research within and across the data-intensive environments at these six sites.
... 26 A different study examining the relationship between familial history of schizophrenia, pregnancy complications, and environmental stressors on risk for psychosis among offspring found substantial covariation between family history of schizophrenia and environmental stressors, but not with pregnancy complications. 27 Though we attempted to account for maternal obstetric complications and environmental factors in our analyses, we were not able to analyze genetic data due to the age of our samples and cannot rule in or out the relevance of our finding to these debates. ...
Background:
Schizophrenia has been associated with pregnancy and birth complications and fetal exposure to inflammation is thought to be a common underlying mechanism. However, whether the risk is specific to particular phases of pregnancy is unclear. The aim of this study was to characterise and compare longitudinal patterns of maternal serum concentrations of cytokines across pregnancy between offspring who were later ascertained to have a psychotic disorder, non-psychotic siblings of these cases, and unrelated, non-psychotic individuals who served as controls.
Methods:
The National Collaborative Perinatal Project was a large-scale prospective longitudinal study that assessed the effects of perinatal factors on infant and child development. At sites across the USA, over 50 000 pregnant women were enrolled during prenatal clinical visits between 1959 and 1965. The present study draws from the Philadelphia cohort, which includes 9236 surviving offspring of 6753 pregnant women. Psychotic disorder diagnoses in adulthood were assessed with review of medical records and were confirmed with a validation study. Concentrations of TNFα, IL-1β, IL-5, IL-6, IL-8, IL-10, and IL-17a were assessed using a multiplex bead assay in archived maternal serum samples collected across prenatal visits and birth. We characterized cytokine patterns with linear mixed models.
Findings:
Our final sample comprised 90 cases, 79 siblings (of 40 cases), and 273 matched controls. Concentrations of proinflammatory cytokines TNFα, IL-1β, and IL-6 were significantly higher in maternal serum of offspring who later developed psychosis compared with maternal serum of matched controls. These differences were greatest in the first half of pregnancy (7-20 weeks), with no difference observed during the second half of pregnancy.
Interpretation:
Our results suggest that exposure to high maternal proinflammatory cytokine concentrations in early pregnancy might play a part in psychosis. These findings place the timing of risk associated with maternal inflammation much earlier in prenatal development than previously documented in humans and provide insight into a potential developmental pathway to the disorder.
Funding:
National Institute of Mental Health (P50) Silvio O Conte Center at Johns Hopkins, Stanley Foundation, March of Dimes, Yale University, National Science Foundation, and National Institute of Child Health and Human Development/Division of Intramural Population Health Research.
Objective
Offspring of parents with schizophrenia spectrum disorders (SSD) have an increased risk of neurodevelopmental disturbances. However, the ability to provide very early interventions to support these children and their families requires profound knowledge regarding characteristic features of both the parents and their offspring. Information on this subject is currently sparse. The aim of the present study is to investigate clinical and sociodemographic variables in offspring in the age range of 0–3 years of mothers diagnosed with SSD.
Methods
The study is descriptive with a cross‐sectional design and includes parent‐child dyads consisting of mothers diagnosed with SSD (ICD‐10: F20‐29) and their offspring aged 0‐3 years, who were referred for examination and intervention at the infant and toddler psychiatric units, at the Mental Health Services, Capital Region, Copenhagen University Hospitals in two locations (Bispebjerg and Glostrup). Clinical and sociodemographic data were extracted from the Copenhagen “Infant Psychiatric Database” and processed by descriptive analysis.
Results
Out of 95 parent–child dyads considered for the study population, 85 were included. 27.8% of the mothers had psychiatric comorbidities, and 18.9% of the fathers had a psychiatric diagnosis at the time of investigation. Of the children, 89.7% were born full term (≥37th week) and most of them had a birth weight of ≥2500 g (81.8%). Of the mothers, 50% had experienced pregnancy complications of varying severity. Birth complications were seen in 62.9% of the dyads. Psychopathology was identified in 50% of the children at age 0–3 years, and 62.2% of the parent–child dyads appeared to have an affected relationship.
Conclusion
Results show widespread psychopathology in offspring aged 0–3 years of mothers with SSD. Moreover, several psychosocial stressors, clinical parental features, and relational disturbances are identified. These results contribute to a better understanding and identification of early risk markers of long‐term psychopathology in this infant patient group, and hence serve as potential targets for early interventions.
Objective:
Familial, obstetric, and early-life environmental risks for schizophrenia spectrum disorder (SSD) alter normal cerebral development leading to formation of characteristic brain deficit patterns prior to onset of symptoms. We hypothesized that the insidious effects of these risks may increase brain similarity to adult SSD deficit patterns in prepubescent children.
Methods:
We used data collected by the Adolescent Brain and Cognitive Development study (ABCD; N=8,940, age=9.9±0.1 years, 4,633/4,307 M/F), including N=727 (age=9.9±0.1 years, 376/351 M/F) children with family history of SSD, to evaluate unfavorable cerebral effects of ancestral SSD history, prenatal and perinatal environment, and negative early life environment. We used a Regional Vulnerability Index (RVI) to measure the alignment of a child's cerebral patterns with the adult-SSD pattern derived from a large meta-analysis of case-control differences.
Results:
In children with a family history of SSD, the RVI captured significantly more variance in ancestral history than traditional whole-brain and regional brain measurements. In children with and without family history of SSD, RVI also captured more variance associated with negative prenatal and perinatal environment and early life experiences than traditional brain measurements.
Conclusions:
In summary, in a cohort where most children will not develop SSD, familial, pre and perinatal, and early developmental risks can alter brain patterns in the direction observed in adult SSD patients. Individual similarity to adult SSD patterns may provide an early biomarker of the effects of genetic and developmental risks on the brain prior to psychotic or prodromal symptom onset.
While genetic factors play a critical role in the risk for schizophrenia and other psychotic disorders, increasing evidence points to the role of childhood adversity as one of several environmental factors that can significantly impact the development, manifestations and outcome of these disorders. This paper reviews the epidemiological evidence linking childhood adversity and psychotic disorders and explores various theoretical models that seek to explain the connection. We discuss neurobiological parallels between the impact of childhood trauma and psychosis on the brain and then explore the impact of childhood adversity on different domains of clinical presentation. Finally, implications for prevention and treatment are considered, both on individual and structural levels.
Introduction:
An association between schizophrenia and urbanicity has long been observed, with studies in many countries, including several from Denmark, reporting that individuals born/raised in densely populated urban settings have an increased risk of developing schizophrenia compared to those born/raised in rural settings. However, these findings have not been replicated in all studies. In particular, a Western Australian study showed a gradient in the opposite direction which disappeared after adjustment for covariates. Given the different findings for Denmark and Western Australia, our aim was to investigate the relationship between schizophrenia and urbanicity in these two regions to determine which factors may be influencing the relationship.
Methods:
We used population-based cohorts of children born alive between 1980 and 2001 in Western Australia (N = 428,784) and Denmark (N = 1,357,874). Children were categorised according to the level of urbanicity of their mother's residence at time of birth and followed-up through to 30 June 2015. Linkage to State-based registers provided information on schizophrenia diagnosis and a range of covariates. Rates of being diagnosed with schizophrenia for each category of urbanicity were estimated using Cox proportional hazards models adjusted for covariates.
Results:
During follow-up, 1618 (0.4%) children in Western Australia and 11,875 (0.9%) children in Denmark were diagnosed with schizophrenia. In Western Australia, those born in the most remote areas did not experience lower rates of schizophrenia than those born in the most urban areas (hazard ratio = 1.02 [95% confidence interval: 0.81, 1.29]), unlike their Danish counterparts (hazard ratio = 0.62 [95% confidence interval: 0.58, 0.66]). However, when the Western Australian cohort was restricted to children of non-Aboriginal Indigenous status, results were consistent with Danish findings (hazard ratio = 0.46 [95% confidence interval: 0.29, 0.72]).
Discussion:
Our study highlights the potential for disadvantaged subgroups to mask the contribution of urban-related risk factors to risk of schizophrenia and the importance of stratified analysis in such cases.
Psychosis is a heterogeneous psychiatric condition for which a multitude of risk and protective factors have been suggested. This umbrella review aimed to classify the strength of evidence for the associations between each factor and psychotic disorders whilst controlling for several biases. The Web of Knowledge database was searched to identify systematic reviews and meta-analyses of observational studies which examined associations between socio-demographic, parental, perinatal, later factors or antecedents and psychotic disorders, and which included a comparison group of healthy controls, published from 1965 to January 31, 2017. The literature search and data extraction followed PRISMA and MOOSE guidelines. The association between each factor and ICD or DSM diagnoses of non-organic psychotic disorders was graded into convincing, highly suggestive, suggestive, weak, or non-significant according to a standardized classification based on: number of psychotic cases, random-effects p value, largest study 95% confidence interval, heterogeneity between studies, 95% prediction interval, small study effect, and excess significance bias. In order to assess evidence for temporality of association, we also conducted sensitivity analyses restricted to data from prospective studies. Fifty-five meta-analyses or systematic reviews were included in the umbrella review, corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders. Only the ultra-high-risk state for psychosis (odds ratio, OR=9.32, 95% CI: 4.91-17.72) and Black-Caribbean ethnicity in England (OR=4.87, 95% CI: 3.96-6.00) showed convincing evidence of association. Six factors were highly suggestive (ethnic minority in low ethnic density area, second generation immigrants, trait anhedonia, premorbid IQ, minor physical anomalies, and olfactory identification ability), and nine were suggestive (urbanicity, ethnic minority in high ethnic density area, first generation immigrants, North-African immigrants in Europe, winter/spring season of birth in Northern hemisphere, childhood social withdrawal, childhood trauma, Toxoplasma gondii IgG, and non-right handedness). When only prospective studies were considered, the evidence was convincing for ultra-high-risk state and suggestive for urbanicity only. In summary, this umbrella review found several factors to be associated with psychotic disorders with different levels of evidence. These risk or protective factors represent a starting point for further etiopathological research and for the improvement of the prediction of psychosis.
Importance
The negative effects of socioeconomic disadvantage on lifelong functioning are pronounced, with some evidence suggesting that these effects are mediated by changes in brain development. To our knowledge, no research has investigated whether parenting might buffer these negative effects.
Objective
To establish whether positive parenting behaviors moderate the effects of socioeconomic disadvantage on brain development and adaptive functioning in adolescents.
Design, Setting, and Participants
In this longitudinal study of adolescents from schools in Melbourne, Australia, data were collected at 3 assessments between 2004 and 2012. Data were analyzed between August 2016 and April 2017.
Exposures
Both family (parental income-to-needs, occupation, and education level) and neighborhood measures of socioeconomic disadvantage were assessed. Positive maternal parenting behaviors were observed during interactions in early adolescence.
Main Outcomes and Measures
Structural magnetic resonance imaging scans at 3 times (early, middle, and late adolescence) from ages 11 to 20 years. Global and academic functioning was assessed during late adolescence. We used linear mixed models to examine the effect of family and neighborhood socioeconomic disadvantage as well as the moderating effect of positive parenting on adolescent brain development. We used mediation models to examine whether brain developmental trajectories predicted functional outcomes during late adolescence.
Results
Of the included 166 adolescents, 86 (51.8%) were male. We found that neighborhood, but not family, socioeconomic disadvantage was associated with altered brain development from early (mean [SD] age, 12.79 [0.425] years) to late (mean [SD] age, 19.08 [0.460] years) adolescence, predominantly in the temporal lobes (temporal cortex: random field theory corrected; left amygdala: B, −0.237; P < .001; right amygdala: B, −0.209; P = .008). Additionally, positive parenting moderated the effects of neighborhood disadvantage on the development of dorsal frontal and lateral orbitofrontal cortices as well as the effects of family disadvantage on the development of the amygdala (occupation: B, 0.382; P = .004; income-to-needs: B, 27.741; P = .004), with some male-specific findings. The pattern of dorsal frontal cortical development in males from disadvantaged neighborhoods exposed to low maternal positivity predicted increased rates of school noncompletion (indirect effect, −0.018; SE, 0.01; 95% CI, −0.053 to −0.001).
Conclusions and Relevance
Our findings highlight the importance of neighborhood disadvantage in influencing brain developmental trajectories. Further, to our knowledge, we present the first evidence that positive maternal parenting might ameliorate the negative effects of socioeconomic disadvantage on frontal lobe development (with implications for functioning) during adolescence. Results have relevance for designing interventions for children from socioeconomically disadvantaged backgrounds.
Background:
Twin and multiplex family studies have established significant heritability for schizophrenia (SZ), often summarized as 81%. The Consortium on the Genetics of Schizophrenia (COGS-1) family study was designed to deconstruct the genetic architecture of SZ using neurocognitive and neurophysiological endophenotypes, for which heritability estimates ranged from 18% to 50% (mean = 30%). This study assessed the heritability of SZ in these families to determine whether there is a "heritability gap" between the diagnosis and related endophenotypes.
Methods:
Nuclear families (N = 296) with a SZ proband, an unaffected sibling, and both parents (n = 1366 subjects; mean family size = 4.6) underwent comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives of interviewed subjects (N = 3304 subjects; mean family size = 11.2). Heritability estimates of psychotic disorders were computed for both nuclear and extended families.
Results:
The heritability of SZ was 31% and 44% for nuclear and extended families. The inclusion of bipolar disorder increased the heritability to 37% for the nuclear families. When major depression was added, heritability estimates dropped to 34% and 20% for nuclear and extended families, respectively.
Conclusions:
Endophenotypes and psychotic disorders exhibit comparable levels of heritability in the COGS-1 family sample. The ascertainment of families with discordant sibpairs to increase endophenotypic contrast may underestimate diagnostic heritability relative to other studies. However, population-based studies also report significantly lower heritability estimates for SZ. Collectively, these findings support the importance of endophenotype-based strategies and the dimensional view of psychosis.
Research has demonstrated that exposure to violence can result in many negative consequences for youth, but the degree to which neighborhood conditions may foster resiliency among victims is not well understood. This study tests the hypothesis that neighborhood collective efficacy attenuates the relationship between adolescent exposure to violence, substance use, and violence. Data were collected from 1,661 to 1,718 adolescents participating in the Project on Human Development in Chicago Neighborhoods, who were diverse in terms of sex (51 % male, 49 % female), race/ethnicity (48 % Hispanic, 34 % African American, 14 % Caucasian, and 4 % other race/ethnicity), and age (mean age 12 years; range 8-16). Information on neighborhood collective efficacy was obtained from adult residents, and data from the 1990 US. Census were used to control for neighborhood disadvantage. Based on hierarchical modeling techniques to adjust for the clustered data, Bernoulli models indicated that more exposure to violence was associated with a greater likelihood of tobacco, alcohol, and marijuana use and perpetration of violence. Poisson models suggested that victimization was also related to a greater variety of substance use and violent behaviors. A moderating effect of collective efficacy was found in models assessing the variety of substance use; the relationship between victimization and substance use was weaker for youth in neighborhoods with higher versus lower levels of collective efficacy. These findings are consistent with literature indicating that social support can ameliorate the negative impact of victimization. This investigation extends this research to show that neighborhood social support can also help to promote resiliency among adolescents.
Objective:
Using longitudinal and prospective measures, the authors assessed the relationship between childhood trauma and psychotic experiences, addressing the following questions: 1) Does exposure to trauma predict incident psychotic experiences? 2) Does cessation of trauma predict cessation of psychotic experiences? 3) What is the direction of the relationship between childhood trauma and psychotic experiences?
Method:
This was a nationally representative prospective cohort study of 1,112 school-based adolescents 13-16 years of age, assessed at baseline and at 3-month and 12-month follow-ups for childhood trauma (physical assault and bullying) and psychotic experiences.
Results:
A bidirectional relationship was observed between childhood trauma and psychosis, with trauma predicting psychotic experiences over time and vice versa. However, even after accounting for this bidirectional relationship with a number of strict adjustments (only newly incident psychotic experiences occurring over the course of the study following exposure to traumatic experiences were examined), trauma was strongly predictive of psychotic experiences. A dose-response relationship was observed between severity of bullying and risk for psychotic experiences. Moreover, cessation of trauma predicted cessation of psychotic experiences, with the incidence of psychotic experiences decreasing significantly in individuals whose exposure to trauma ceased over the course of the study.
Conclusions:
After a series of conservative adjustments, the authors found that exposure to childhood trauma predicted newly incident psychotic experiences. The study also provides the first direct evidence that cessation of traumatic experiences leads to a reduced incidence of psychotic experiences.
Evidence suggests that adverse experiences in childhood are associated with psychosis. To examine the association between childhood adversity and trauma (sexual abuse, physical abuse, emotional/psychological abuse, neglect, parental death, and bullying) and psychosis outcome, MEDLINE, EMBASE, PsychINFO, and Web of Science were searched from January 1980 through November 2011. We included prospective cohort studies, large-scale cross-sectional studies investigating the association between childhood adversity and psychotic symptoms or illness, case-control studies comparing the prevalence of adverse events between psychotic patients and controls using dichotomous or continuous measures, and case-control studies comparing the prevalence of psychotic symptoms between exposed and nonexposed subjects using dichotomous or continuous measures of adversity and psychosis. The analysis included 18 case-control studies (n = 2048 psychotic patients and 1856 nonpsychiatric controls), 10 prospective and quasi-prospective studies (n = 41,803) and 8 population-based cross-sectional studies (n = 35,546). There were significant associations between adversity and psychosis across all research designs, with an overall effect of OR = 2.78 (95% CI = 2.34-3.31). The integration of the case-control studies indicated that patients with psychosis were 2.72 times more likely to have been exposed to childhood adversity than controls (95% CI = 1.90-3.88). The association between childhood adversity and psychosis was also significant in population-based cross-sectional studies (OR = 2.99 [95% CI = 2.12-4.20]) as well as in prospective and quasi-prospective studies (OR = 2.75 [95% CI = 2.17-3.47]). The estimated population attributable risk was 33% (16%-47%). These findings indicate that childhood adversity is strongly associated with increased risk for psychosis.
Studies of the major psychoses, schizophrenia (SZ) and bipolar disorder (BD), have traditionally focused on genetic and environmental risk factors, although more recent work has highlighted an additional role for epigenetic processes in mediating susceptibility. Since monozygotic (MZ) twins share a common DNA sequence, their study represents an ideal design for investigating the contribution of epigenetic factors to disease etiology. We performed a genome-wide analysis of DNA methylation on peripheral blood DNA samples obtained from a unique sample of MZ twin pairs discordant for major psychosis. Numerous loci demonstrated disease-associated DNA methylation differences between twins discordant for SZ and BD individually, and together as a combined major psychosis group. Pathway analysis of our top loci highlighted a significant enrichment of epigenetic changes in biological networks and pathways directly relevant to psychiatric disorder and neurodevelopment. The top psychosis-associated, differentially methylated region, significantly hypomethylated in affected twins, was located in the promoter of ST6GALNAC1 overlapping a previously reported rare genomic duplication observed in SZ. The mean DNA methylation difference at this locus was 6%, but there was considerable heterogeneity between families, with some twin pairs showing a 20% difference in methylation. We subsequently assessed this region in an independent sample of postmortem brain tissue from affected individuals and controls, finding marked hypomethylation (>25%) in a subset of psychosis patients. Overall, our data provide further evidence to support a role for DNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD.
This study ascertained the incidence of complications during pregnancy, labor, and delivery and the neonatal characteristics of infants born to women with schizophrenia, bipolar disorder, or major depression in a population-based cohort.
Based on records linkage across a psychiatric case register and prospectively recorded obstetric data, the study comprised women with schizophrenia or major affective disorders who had given birth to 3,174 children during 1980-1992 in Western Australia. A comparison sample of 3,129 births to women without a psychiatric diagnosis was randomly selected from women giving birth during 1980-1992. Complications were scored with the McNeil-Sjöström Scale. Odds ratios were calculated for specific reproductive events.
Both schizophrenic and affective disorder patients had increased risks of pregnancy, birth, and neonatal complications, including placental abnormalities, antepartum hemorrhages, and fetal distress. Women with schizophrenia were significantly more likely to have placental abruption, to give birth to infants in the lowest weight/growth population decile, and to have children with cardiovascular congenital anomalies. Neonatal complications were significantly more likely to occur in winter; low birth weight peaked in spring. Complications other than low birth weight and congenital anomalies were higher in pregnancies after psychiatric illness than in pregnancies preceding the diagnosis.
While genetic liability and gene-environment interactions may account for some outcomes, maternal risk factors and biological and behavioral concomitants of severe mental illness appear to be major determinants of increases in reproductive pathology in this cohort. Risk reduction in these vulnerable groups may be achievable through antenatal and postnatal interventions.
Numerous studies have reported high rates of psychosis in the Black Caribbean and Black African populations in the UK. However, few studies have investigated the role of specific risk factors in different ethnic groups. We sought to investigate the relationship between long-term separation from, and death of, a parent before the age of 16 and risk of adult psychosis in different ethnic groups.
All patients with a first episode of psychosis who made contact with psychiatric services in defined catchment areas in London and Nottingham, UK and a series of community controls were included in the AESOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses) study. Data relating to clinical and social variables, including parental separation and loss, were collected from patients and controls.
Separation from, and death of, a parent before the age of 16 were both strongly associated with a two- to threefold increased risk of psychosis. The strength of these associations were similar for White British and Black Caribbean (but not Black African) subjects. Separation from (but not death of) a parent was more common among Black Caribbean controls than White British controls.
Early separation may have a greater impact in the Black Caribbean population, because it is more common, and may contribute to the excess of psychosis in this population.
The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia.
Objective:
The objective is to summarise recent findings from the 2010 Australian Survey of High Impact Psychosis (SHIP) and examine their implications for future policy and planning to improve mental health, physical health and other circumstances of people with a psychotic disorder.
Methods:
Survey of High Impact Psychosis collected nationally representative data on 1825 people with psychotic illness. Over 60 papers have been published covering key challenges reported by participants: financial problems, loneliness and social isolation, unemployment, poor physical health, uncontrolled symptoms of mental illness, and lack of stable, suitable housing. Findings are summarised under the rubric of participant-ranked top challenges.
Results:
The main income source for the majority (85%) of participants was a government benefit. Only one-third was employed, and the most appropriate employment services for this group were under-utilised. High rates of loneliness and social isolation impacted mental and physical health. The rate of cardiometabolic disease was well above the general population rate, and associated risk factors were present from a very young age. Childhood abuse (30.6%), adult violent victimisation (16.4%) and alcohol and substance abuse/dependence (lifetime rates of 50.5% and 54.5%, respectively) complicated the clinical profile. Treatment with medication was suboptimal, with physical health conditions undertreated, a high rate of psychotropic polypharmacy and underutilisation of clozapine in chronic persistent psychotic illness. Only 38.6% received evidence-based psychosocial therapies. In the previous year, 27.4% had changed housing and 12.8% had been homeless, on average for 155 days.
Conclusion:
Money, social engagement and employment are the most important challenges for people with psychotic illness, as well as good physical and mental health. An integrated approach to recovery is needed to optimise service delivery and augment evidence-based clinical practice with measures to improve physical health and social circumstances. Meeting these challenges has the potential to reduce costs to government and society, as well as promote recovery.
There is a substantial body of research reporting evidence of associations between various forms of childhood adversity and psychosis, across the spectrum from experiences to disorder. This has been extended, more recently, to include studies of cumulative effects, of interactions with other factors, of specific effects, and of putative biological and psychological mechanisms. In this paper we evaluate this research and highlight the remaining methodological issues and gaps that temper, but do not dismiss, conclusions about the causal role of childhood adversity. We also consider the emerging work on cumulative, synergistic, and specific effects and on mechanisms; and discuss the broader implications of this line of research for our understanding of psychosis. We conclude that the current balance of evidence is that childhood adversities - particularly exposure to multiple adversities involving hostility and threat - do, in some people, contribute to the onset of psychotic experiences and psychotic disorders.
Background:
Environmental factors such as urban birth and ethnic minority position have been related to risk for psychotic disorders. There is some evidence that not only individual, but also neighborhood characteristics influence this risk. The aim of this study was to investigate social disorganization of neighborhoods and incidence of psychotic disorders.
Method:
The research was a 7-year first-contact incidence study of psychotic disorders in The Hague. Neighborhood characteristics included continuous, dichotomous and cumulative measures of socio-economic level, residential mobility, ethnic diversity, proportion of single person households, voter turnout, population density and crime level. Using multilevel Poisson regression analysis, incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of psychotic disorders were calculated for the indicators of neighborhood social disorganization.
Results:
A total of 618 incident cases were identified. Neighborhood socio-economic level and residential mobility had the strongest association with incidence of psychotic disorders [individual-level adjusted Wald χ2 1 = 13.03 (p = 0.0003) and 5.51 (p = 0.02), respectively]. All but one (proportion of single person households) of the dichotomous neighborhood indicators were significantly associated with a higher IRR. The cumulative degree of neighborhood social disorganization was strongly and linearly associated with the incidence of psychotic disorders (trend test, Wald χ2 5 = 25.76, p = 0.0001). The IRR in neighborhoods with the highest degree of social disorganization was 1.95 (95% CI 1.38-2.75) compared with the lowest disorganization category.
Conclusions:
The findings suggest that the risk for developing a psychotic disorder is higher for people living in socially disorganized environments. Longitudinal studies are needed to investigate causality.
Although several studies have examined the relative contributions of familial and environmental risk factors for schizophrenia, few have additionally examined the predictive power on the individual level and simultaneously examined the population impact associated with a wide range of familial and environmental risk factors. The authors present rate ratios (IRR), population-attributable risks (PAR) and sex-specific cumulative incidences of the following risk factors: parental history of mental illness, urban place of birth, advanced paternal age, parental loss and immigration status. We established a population-based cohort of 2,486,646million persons born in Denmark between 1 January 1955 and 31 December 1993 using Danish registers. We found that PAR associated with urban birth was 11.73%; PAR associated with one, respectively 2, parent(s) with schizophrenia was 2.67% and 0.12%. PAR associated with second-generation immigration was 0.70%. Highest cumulative incidence (CI=20.23%; 95% CI=18.10-22.62) was found in male offspring of 2 parents with schizophrenia. Cumulative incidences for male offspring or female offspring of a parent with schizophrenia were 9.53% (95% CI=7.71-11.79), and 4.89%, (95% CI 4.50-5.31). The study showed that risk factors with highest predictive power on the individual level have a relatively low population impact. The challenge in future studies with direct genetic data is to examine gene-environmental interactions that can move research beyond current approaches and seek to achieve higher predictive power on the individual level and higher population impact.
Importance Although increased risk for schizophrenia among immigrants is well established, knowledge of the broader spectrum of psychiatric disorders associated with a foreign migration background is lacking.
Objective To examine the full range of psychiatric disorders associated with any type of foreign migration background among persons residing in Denmark, including foreign-born adoptees, first- and second-generation immigrants, native Danes with a history of foreign residence, and persons born abroad to Danish expatriates.
Design and Setting Danish population-based cohort study. Persons were followed up from their 10th birthday for the development of mental disorders based on outpatient and inpatient data.
Participants All persons born between January 1, 1971, and December 31, 2000 (N = 1 859 419) residing in Denmark by their 10th birthday with follow-up data to December 31, 2010.
Main Outcome Measures Incidence rate ratios (IRRs) and cumulative incidences for psychiatric outcomes.
Results All categories of foreign migration background, except persons born abroad to Danish expatriates, were associated with increased risk for at least 1 psychiatric disorder. Foreign-born adoptees had increased IRRs for all psychiatric disorders and had the highest IRRs for these disorders compared with other foreign migration categories. First- and second-generation immigrants having 2 foreign-born parents had significantly increased IRRs for schizophrenia and schizophrenia spectrum disorders and had similar risk magnitudes. Second-generation immigrants having 1 foreign-born parent had significantly increased IRRs for all psychiatric disorders. Native Danes with a history of foreign residence had increased IRRs for bipolar affective disorder, affective disorders, personality disorders, and schizophrenia spectrum disorders.
Conclusions and Relevance The extent to which a background of foreign migration confers an increased risk for the broad spectrum of psychiatric disorders varies according to parental origin, with greatest risks for foreign-born adoptees. The spectrum of psychiatric disorders showed greater variation within the second-generation immigrant group than between first-generation vs second-generation immigrants, and the spectrum differed according to whether individuals had 1 or 2 foreign-born parents.
The association between urbanicity and risk of schizophrenia is well established. The incidence of schizophrenia has been observed to increase in line with rising levels of urbanicity, as measured in terms of population size or density. This association is expressed as Incidence Rate Ratio (IRR), and the results are usually presented by comparing the most urban with the most rural environment. In this study, we undertook to express the effect of urbanicity on the risk of schizophrenia in a linear form and to perform a meta-analysis of all available evidence. We first employed a simple regression analysis of log (IRR) as given in each study on the urbanicity category, assuming a uniform distribution and a linear association. In order to obtain more accurate estimates, we developed a more sophisticated method that generates individual data points with simulation from the summary data presented in the original studies, and then fits a logistic regression model. The estimates from each study were combined with meta-analysis. Despite the challenges that arise from differences between studies as regards to the number and relative size of urbanicity levels, a linear association was observed between the logarithm of the odds of risk for schizophrenia and urbanicity. The risk for schizophrenia at the most urban environment was estimated to be 2.37 times higher than in the most rural environment. The same effect was found when studies measuring the risk for nonaffective psychosis were included.
A large proportion of children across the globe suffer abuse or neglect. 1 , 2 Therefore, studies that shed light on the health consequences of adverse childhood experiences and examine the potential for resilience are of great importance. The meta-analysis by Varese et al. 3 in this volume is a welcome addition to these studies.
The 2010 Survey of High Impact Psychosis (SHIP) is Australia's second national psychosis survey. This paper provides an overview of its findings, including comparisons with the first psychosis survey and general population data.
The survey covered 1.5 million people aged 18-64 years, approximately 10% of Australians in this age group. A two-phase design was used. In phase 1, screening for psychosis took place in public mental health services and non-government organizations supporting people with mental illness. In phase 2, 1825 of those screen-positive for psychosis were randomly selected and interviewed. Data collected included symptomatology, substance use, functioning, service utilization, medication use, education, employment, housing, and physical health including fasting blood samples.
The estimated 1-month treated prevalence of psychotic disorders in public treatment services was 3.1 people per 1000 population; the 12-month treated prevalence was 4.5 people per 1000. The majority (63.0%) of participants met ICD-10 criteria for schizophrenia/schizoaffective disorder. One-half (49.5%) reported attempting suicide in their lifetime and two-thirds (63.2%) were rated as impaired in their ability to socialize. Over half (54.8%) had metabolic syndrome. The proportion currently smoking was 66.1%. Educational achievement was low. Only 21.5% were currently employed. Key changes in the 12 years since the first survey included: a marked drop in psychiatric inpatient admissions; a large increase in the proportion attending community mental health clinics; increased use of rehabilitation services and non-government organizations supporting people with mental illness; a major shift from typical to atypical antipsychotics; and large increases in the proportions with lifetime alcohol or drug abuse/dependence.
People with psychotic illness face multiple challenges. An integrated approach to service provision is needed to ensure that their living requirements and needs for social participation are met, in addition to their very considerable mental and physical health needs.
Studies of couples of psychiatric patients with children allow us to calculate the effects of double predispositions on morbid risk in the offspring, which is of interest for molecular genetic research and for genetic counseling.
To determine the risks in offspring of receiving a diagnosis of schizophrenia, bipolar disorder, unipolar depressive disorder, or any diagnosis from parents who both have received a diagnosis of schizophrenia or bipolar disorder.
National register-based cohort study.
Denmark.
A population-based cohort of 2.7 million persons born in Denmark, alive in 1968 or born later than 1968, with a register link to their mother and father and aged 10 years or older in 2007.
Risk of schizophrenia or bipolar disorder, calculated as cumulative incidences by age 52 years.
The risk of schizophrenia in 270 offspring of 196 parent couples who were both admitted to a psychiatric facility with a diagnosis of schizophrenia was 27.3% (increasing to 39.2% when schizophrenia-related disorders were included) compared with 7.0% in 13 878 offspring from 8006 couples with only 1 parent ever admitted for schizophrenia and 0.86% in 2 239 551 offspring of 1 080 030 couples with neither parent ever admitted. The risk of bipolar disorder was 24.9% in 146 offspring of 83 parent couples who were ever admitted with bipolar disorder (increasing to 36.0% when unipolar depressive disorder was included) compared with 4.4% in 23 152 offspring from 11 995 couples with only 1 parent ever admitted and 0.48% in 2 239 553 offspring of 1 080 030 couples with neither parent ever admitted. Risks of schizophrenia and bipolar disorder in offspring of couples with 1 parent with schizophrenia and the other with bipolar disorder were 15.6% and 11.7%, respectively. The maximal risks of any psychiatric disorders in the offspring of parents both with schizophrenia or both with bipolar disorder were 67.5% and 44.2%, respectively.
Derived risks may be informative for counseling. Patterns of transmission may support evolving assumptions about genetic overlap for traditional categories.
Numerous studies have reported high rates of psychosis in the Black Caribbean population in the UK. Recent speculation about the reasons for these high rates has focused on social factors. However, there have been few empirical studies. We sought to compare the prevalence of specific indicators of social disadvantage and isolation, and variations by ethnicity, in subjects with a first episode of psychosis and a series of healthy controls.
All cases with a first episode of psychosis who made contact with psychiatric services in defined catchment areas in London and Nottingham, UK and a series of community controls were recruited over a 3-year period. Data relating to clinical and social variables were collected from cases and controls.
On all indicators, cases were more socially disadvantaged and isolated than controls, after controlling for potential confounders. These associations held when the sample was restricted to those with an affective diagnosis and to those with a short prodrome and short duration of untreated psychosis. There was a clear linear relationship between concentrated disadvantage and odds of psychosis. Similar patterns were evident in the two main ethnic groups, White British and Black Caribbean. However, indicators of social disadvantage and isolation were more common in Black Caribbean subjects than White British subjects.
We found strong associations between indicators of disadvantage and psychosis. If these variables index exposure to factors that increase risk of psychosis, their greater prevalence in the Black Caribbean population may contribute to the reported high rates of psychosis in this population.
This paper reviews the literature on obstetric complications as a risk factor for schizophrenia. The authors trace the evolution of this literature through different methods and carry out a quantitative review of the results from prospective, population-based studies.
Relevant papers were identified by a MEDLINE search, by examination of reference lists of published papers, and through personal contact with researchers in the field. Studies were grouped in chronological order according to common themes or methods. Meta-analytic techniques were used to summarize the findings of prospective population-based studies.
The meta-analytic synthesis of the prospective population-based studies revealed that three groups of complications were significantly associated with schizophrenia: 1) complications of pregnancy (bleeding, diabetes, rhesus incompatibility, preeclampsia); 2) abnormal fetal growth and development: (low birthweight, congenital malformations, reduced head circumference), and 3) complications of delivery (uterine atony, asphyxia, emergency Cesarean section). Pooled estimates of effect sizes were generally less than 2.
Current methods of investigating the relationship between obstetric complications and schizophrenia are reaching the limit of their usefulness. Lack of statistical power to measure small and interactive effects and lack of detailed information about the prenatal period are major problems with current approaches. A combination of disciplines and approaches will be needed to elucidate the mechanisms underlying these small but important associations.
There is conflicting evidence concerning the association of social childhood factors and subsequent psychosis. Previous studies have had inadequate designs. The aim of the present study was to describe a broad range of social factors during childhood and the risk of developing psychosis later in life in a national cohort.
The study population consisted of all children born in Sweden in 1963-1983-2.1 million persons-in family households participating in the national census of 1970, 1980, 1985, or 1990. Hazard ratios were estimated for five different indicators of socioeconomic position (living in rented apartments, low socioeconomic status, single-parent households, unemployment, and households receiving social welfare benefits) from hospital admissions for schizophrenia and other psychoses during 1987-2002.
Increased age- and sex-adjusted hazard ratios for schizophrenia and other psychoses were found for all childhood socioeconomic indicators, ranking from lowest to highest hazard ratio: rented apartments, low socioeconomic status, single-parent households, unemployment, and households receiving social welfare benefits. Hazard ratios increased with an increasing number of adverse social factors present. Those with four measures of adversity had a 2.7-fold higher risk of schizophrenia than those with none.
The results indicate that social adversity in childhood and fetal life is independently associated with the risk of developing schizophrenia and other psychoses later in life. The risks increased with an increasing number of exposures, suggesting a dose-response relationship.
Obstetric complications and schizophrenia: A meta-analysis
- J R Geddes
- Lawrie
- Sm
Validation study of the Western Australian Midwives’ Notification System 1992
- V Gee
- V Dawes
Ontogenetic de novo copy number variations (CNVs)
- S Maiti
- K H Kumar
- C A Castellani
A National Approach for Child Protection Project Report
- L Bromfield
- P Holzer