Parsing components of risk of premature mortality in the children of mothers with severe mental illness.

INTRODUCTION: Children of mothers with severe mental illness are at increased risk of premature death including in infancy and early childhood. Importantly, these children are also more likely to be exposed to adverse socio-demographic risk factors and serious obstetric complications which, of themselves, may increase risk for childhood mortality. We examined mortality outcome at different ages up to 5 years taking account of these risks. METHOD: We used linked data across Western Australian whole-population psychiatric, inpatient, death, and midwives' registers to identify 15,486 births to mothers with severe mental illness and 452,459 births to mothers with no mental illness. Multivariable models were adjusted for exposure to adverse socio-demographic risk factors and serious obstetric complications. RESULTS: Overall risk of premature death was increased amongst children of mothers with severe mental illness (2.3%, 354 deaths) compared with children of mothers with no mental illness (1.4%, 6523 deaths); the same was true for specific risk of stillbirth, neonatal, post­neonatal and early childhood deaths. Risk was substantially attenuated after adjustment for adverse socio-demographic exposures, and further still after adjustment for exposure to serious obstetric complications. We observed no effects for the timing of maternal illness diagnosis. CONCLUSIONS: To minimise the risk of premature mortality in the children of mothers with severe mental illness, priority should be given to the prompt diagnosis of maternal mental illness with targeted delivery of high quality antenatal and psychiatric care, as well as social and structural supports for affected families that continue after birth.

Intellectual Disability and Psychotic Disorders in Children: Association With Maternal Severe Mental Illness and Exposure to Obstetric Complications in a Whole-Population Cohort.

OBJECTIVE: Children of mothers with severe mental illness are at significantly increased risk of developing intellectual disability. Obstetric complications are also implicated in the risk for intellectual disability. Moreover, children of mothers with severe mental illness are more likely to be exposed to obstetric complications. The purpose of this study was to examine the independent and joint contributions of familial severe mental illness and obstetric complications to the risk of intellectual disability. METHOD: Record linkage across Western Australian whole-population psychiatric, inpatient, birth, and midwives' registers identified 15,351 children born between 1980 and 2001 to mothers with severe mental illness and 449,229 children born to mothers with no mental illness. Multivariable models were adjusted for paternal psychiatric status, parental intellectual disability, and other family and sociodemographic covariates. RESULTS: The risk of intellectual disability was increased among children of mothers with severe mental illness compared with children of unaffected mothers. The impact varied across maternal diagnostic groups. For children of mothers with schizophrenia, the unadjusted odds ratio was 3.8 (95% CI=3.0, 4.9) and remained significant after simultaneous adjustment for exposure to obstetric complications and other covariates (odds ratio=1.7, 95% CI=1.3, 2.3). The odds ratio for exposure to obstetric complications also remained significant after adjustment (odds ratio=1.7, 95% CI=1.6, 1.8). For intellectual disability of a genetic basis, the adjusted odds ratio for maternal schizophrenia was elevated but not statistically significant. Among children with intellectual disability, 4.2% later developed a psychotic disorder, compared with 1.1% of children without intellectual disability. CONCLUSIONS: Maternal severe mental illness and exposure to obstetric complications contribute separately to the risk of intellectual disability, suggesting potentially different causal pathways.

Risk of neurological, eye and ear disease in offspring to parents with schizophrenia or depression compared with offspring to healthy parents.

BACKGROUND: Neurological, visual and hearing deviations have been observed in the offspring of parents with schizophrenia. This study test whether children to parents hospitalized with schizophrenia have increased the likelihood of childhood neurological disorder. METHODS: Among all parents in Sweden born 1950-1985 and with offspring born 1968-2002: 7107 children with a parent hospitalized for schizophrenia were compared to 172 982 children with no parents hospitalized for schizophrenia or major depression, as well as to 32 494 children with a parent hospitalized for major depression as a control population with another severe psychiatric outcome. We estimated relative risks (RR) and two-sided 95% confidence intervals calculated from Poisson regression. RESULTS: Children to parents with schizophrenia were more likely than controls to have been hospitalized before the age of 10 with a diagnosis of cerebral palsy, RR = 1.76 (95% CI: 1.15-2.69); epilepsy, RR = 1.78 (95% CI: 1.33-2.40), combined neurological disease, RR = 1.33 (95% CI: 1.11-1.60) and certain diseases of the eye, RR = 1.92 (95% CI: 1.17-3.15) and ear, RR = 1.18 (95% CI: 1.05-1.32). Similar disease-risk-pattern was found for children to parents hospitalized with a diagnosis of major depression. A specific risk increase for strabismus RR = 1.21 (95%CI: 1.05-1.40) was found for off-spring with parental depression. CONCLUSIONS: Compared with children to healthy parents, children to parents with schizophrenia have increased risk of a variety of neurological disorders as well as visual and hearing disorders at an early age. The risk increase was not specific to schizophrenia but was also seen in children to parents with a diagnosis of major depression.

Barbara Fish and a Short History of the Neurodevelopmental Hypothesis of Schizophrenia.

The neurodevelopmental hypothesis of schizophrenia has become a paradigm broadly accepted in today's research in schizophrenia and its spectrum. This article traces the historical development of the neurodevelopmental hypothesis of schizophrenia up until the time of its explicit formulation in 1987, by Weinberger and by Murray and Lewis, with a main focus on the seminal contribution of Barbara Fish to its conception and elaboration.

Prediction of adaptation difficulties by country of origin, cumulate psychosocial stressors and attitude toward integrating: a Swedish study of first-generation immigrants from Somalia, Vietnam and China.

BACKGROUND: Different types of accumulated stress have been found to have negative consequences for immigrants' capacity to adapt to the new environment. It remains unclear which factors have the greatest influence. AIMS: The study investigated whether immigrants' experience of great difficulty in adapting to a new country could best be explained by (1) country of origin, (2) exposure to accumulated stressors before arrival or (3) after arrival in the new country and/or (4) reserved attitude toward integrating into the new society. METHODS: The 119 first-generation immigrants from Somalia, Vietnam and China, living in Malmö, Sweden, were interviewed in a standardized manner. RESULTS: Experiencing great difficulty in adapting to Sweden was independent of length of residence, but significantly related to all four influences, studied one at a time. Country of origin was also related to stressors and attitude. When the effects of the other influences were mutually controlled for, only exposure to accumulated stressors in Sweden (and especially experiencing discrimination/xenophobia/racism) accounted for great adaptation difficulty. Stressors in Sweden had a greater effect if the immigrant had been exposed to stressors earlier. CONCLUSIONS: Immigrants' long-term experiences of great difficulty in adapting to a new country were explained primarily by exposure to accumulated stressors while moving to and living in the new country, rather than by their backgrounds or attitudes toward integrating. This suggests promoting strategies to avoid discrimination and other stressors in the host country.

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.

Prospective study of pandysmaturation and adult mental disorder in high-risk and normal-risk offspring.

More than 50 years ago, Fish postulated that a special form of early abnormal neurodevelopment, "pandysmaturation", defined a priori as constituting retarded cranial development in the first year of life, combined with delay in early motor milestone attainment, was related to genetic risk for schizophrenia, and was associated with schizophrenia-spectrum disorders in young adulthood. Fish confirmed this in a very small sample. We retested Fish's postulation in a larger prospective study. Pandysmaturation was blindly investigated through medical records and prospective researcher and maternal observations, studying 75 "high-risk" offspring of women with a history of schizophrenia or affective psychosis and 91 "normal-risk" offspring. Subjects were studied prospectively from mother's pregnancy to 22 years of age, at which time the offspring were independently assessed for schizophrenia-spectrum and affective disorders. Pandysmaturation (n = 13, with 10 "definite" and 3 "probable" degrees) was significantly related to genetic risk for schizophrenia (Odds Ratio 4.9, p = 0.02) but not to genetic risk for affective disorders (OR 1.2, p = 0.81). Pandysmaturation was significantly associated with schizophrenia-spectrum (OR 6.2, p = 0.02), but not affective (OR 0.9, p = 0.90), disorders in young adulthood. Pandysmaturation was more strongly associated than was retarded cranial development, motor milestone delay, or social/cognitive milestone delay by itself. Pandysmaturation has efficacy as an early life risk-indicator of schizophrenia-spectrum disorder in young adulthood at least in subjects at genetic risk, strengthening the evidence for a generally genetic-based neurodevelopmental model of schizophrenia-spectrum (as contrasted with affective) disorders. Pandysmaturation is a risk-indicator for future schizophrenia-spectrum disorder, for potential use in scientific studies and clinical practice.

Schizophrenia: from the brain to peripheral markers. A consensus paper of the WFSBP task force on biological markers.

Objective. The phenotypic complexity, together with the multifarious nature of the so-called "schizophrenic psychoses", limits our ability to form a simple and logical biologically based hypothesis for the disease group. Biological markers are defined as biochemical, physiological or anatomical traits that are specific to particular conditions. An important aim of biomarker discovery is the detection of disease correlates that can be used as diagnostic tools. Method. A selective review of the WFSBP Task Force on Biological Markers in schizophrenia is provided from the central nervous system to phenotypes, functional brain systems, chromosomal loci with potential genetic markers to the peripheral systems. Results. A number of biological measures have been proposed to be correlated with schizophrenia. At present, not a single biological trait in schizophrenia is available which achieves sufficient specificity, selectivity and is based on causal pathology and predictive validity to be recommended as diagnostic marker. Conclusions. With the emergence of new technologies and rigorous phenotypic subclassification the identification of genetic bases and assessment of dynamic disease related alterations will hopefully come to a new stage in the complex field of psychiatric research.

Neurobehavioral deficits in young adult offspring with heightened risk for psychosis who developed schizophrenia-spectrum disorder.

Neurobehavioral deficits in neuromotor function, verbal memory, executive function and attention found in patients with schizophrenia and their relatives have been suggested to be liability indicators or predictors of schizophrenia. It remains uncertain which of these neurobehavioral deficits are components of the illness itself or characteristics associated with genetic risk for it. The purpose of this study was to investigate the relation between these neurobehavioral deficits and schizophrenia-spectrum disorder in young adults at genetic risk for psychosis. A 93%-effective follow-up (total n=166, mean 22.4 yr of age) of a sample longitudinally investigated since fetal age provided complete data for mental disturbance, neuropsychological performance and neurological abnormality for 74 offspring at increased risk for psychosis (38 offspring of mothers with schizophrenia and 36 offspring of mothers with affective psychosis) and 88 normal-risk offspring. Abnormal glabella reflex and deficits in verbal memory, attention and complex executive functions seem specifically to be related to schizophrenia-spectrum disorder (primarily Cluster A personality disorders) among offspring at genetic risk for psychosis, while neurobehavioral deficits in general characterized offspring at heightened (vs. normal) genetic risk for psychosis, with no relation to schizophrenia-spectrum disorders. The two patterns of neurobehavioral deficits observed here may possibly reflect different causes and different aspects of a deviant neurodevelopmental process, and potentially contribute to a more nuanced version of this all-pervasive (but often non-specific) "model" of schizophrenia's development.

A morphometric magnetic resonance method for measuring cranial, facial and brain characteristics for application to schizophrenia: part 1.

Serious psychopathology in adulthood may be associated with disturbed foetal brain development, which potentially shows lingering "fossil marks" in the cranial and facial regions. Several methods exist for assessing external craniofacial and internal brain distances but, to our knowledge, no method yet provides simultaneous measurement of cranial, facial and brain dimensions in live subjects. In this article we describe a method to identify landmarks on magnetic resonance images (MRI) for simultaneous measurement of cranial, facial and brain characteristics potentially associated with psychosis. To test the method itself, 30 patients with chronic schizophrenia and 31 healthy comparison subjects, mean age 41 years, were randomly selected from a larger cohort recruited at the Karolinska Hospital, Sweden. Participants were investigated with MRI, and 60 landmarks in the cranial, facial and brain regions were identified in the images. An independent anthropometric examination measured external craniofacial characteristics for study in relation to measurements produced through MRI. High inter-scorer and re-test reliabilities were obtained for two independent scorers of the landmarks in the MR images. Measurements of potentially comparable craniofacial distances showed high alignment with an established anthropometric method. This new method can provide simultaneous investigation of multiple aspects of cranial, facial and brain morphology in MR images originally collected for other purposes. In a second article we will use this method to compare 3D craniofacial measurements and shape between schizophrenia patients and healthy controls.

Is craniofacial dysmorpholgy correlated with structural brain anomalies in schizophrenia?

This study aimed to examine the relationship between craniofacial dysmorphology and anomalies of brain morphology in schizophrenia. Assessments of craniofacial dysmorphology and magnetic resonance imaging of brain were performed independently of each other and blind to each other in 24 males with schizophrenia and 16 male controls. Ventricular cerebrospinal fluid volume was negatively correlated with total dysmorphology score in males with schizophrenia (i.e., the larger the ventricular cerebrospinal fluid volume, the lower the total dysmorphology score) but not in male controls. These findings suggest that craniofacial dysmorphology and anomalies of brain morphology may be associated with independent processes in the etiology of schizophrenia.

Increased risk of psychotic disorder among immigrants in Malmö: a 3-year first-contact study.

BACKGROUND: Previous findings of increased rates of psychotic disorders among immigrants to Sweden are primarily based on hospital samples. The aim of the current study was to compare the risks of first contact for psychotic and schizophrenic disorders among first- and second-generation immigrants to the risks in native 'Swedes'. METHOD: During a 3-year period, diagnostic information was collected on all patients with a possible psychotic disorder who made a first-in-lifetime contact with both in-patient and out-patient psychiatric services in Malmö. RESULTS: First-generation immigrants to Sweden had an increased risk of developing psychotic and schizophrenic disorders compared to Swedes (age- and gender-adjusted relative risk, RR 2.9, 95 % CI 2.0-4.0 and RR 4.0, 95 % CI 1.8-8.6 respectively). Risks for these disorders were not significantly increased in second-generation immigrants. The highest risks of developing psychotic disorder compared to Swedes were found in first-generation immigrants with 'black' (versus 'neither black nor white', or 'white') skin colour (RR 5.8, 95 % CI 2.8-13.4) and birthplace in a developing (versus developed) country (RR 3.3, 95 % CI 2.3-4.8). CONCLUSION: The increased risks of psychosis obtained especially in immigrant groups having relatively disadvantaged status in Sweden suggest that psychosocial factors may contribute to the development of psychotic disorders.

Neuropsychological impairment and its neurological correlates in adult offspring with heightened risk for schizophrenia and affective psychosis.

OBJECTIVE: Schizophrenia is generally considered to be a neurodevelopmental disorder reflected in findings of neuropsychological impairments and neurological abnormality in patients and their relatives. The authors investigated whether neuropsychological impairments are related to neurological abnormality and whether such deficits also characterize risk for affective psychosis. METHOD: In a longitudinal study with a 93% rate of effective follow-up, the authors investigated neuropsychological impairment and its relation to neurological abnormality at a mean age of 22.3 years in 74 offspring of mothers with a history of psychotic disorders (38 offspring with heightened risk for schizophrenia and 36 with risk for affective psychosis) and 88 normal-risk offspring born to mothers with no history of psychosis. RESULTS: Offspring with genetically heightened risk for schizophrenia showed significantly impaired verbal memory, selective attention, and grammatical reasoning, compared with normal-risk offspring. Having impaired verbal memory, attention, and grammatical reasoning functions identified a significantly larger subgroup (16%) among offspring with heightened risk for schizophrenia than among offspring with heightened risk for affective psychosis (0%) and among normal-risk offspring (3%). Multiple neuropsychological functions were significantly related to neurological abnormality in offspring with heightened risk for schizophrenia and in normal-risk offspring but not among offspring with heightened risk for affective psychosis. The extension of schizophrenia and affective psychosis risk groups to include additional offspring of mothers with psychosis-spectrum disorders yielded results similar to those for the core risk groups. CONCLUSIONS: The neurocognitive dysfunction attending heightened risk for schizophrenia is likely based on genetically mediated neurodevelopmental factors, with schizophrenia and affective psychosis belonging to different biological spheres.

Health and development in the first 4 years of life in offspring of women with schizophrenia and affective psychoses: Well-Baby Clinic information.

The investigation of genetic high-risk (HR) groups provides the opportunity to study diathesis characteristics associated with schizophrenia (Sc) and affective psychoses. High-risk offspring of women with a history of schizophrenia, affective and other psychoses (n = 84), as well as normal-risk control (NC) offspring (n = 100), were studied from 0 to 4 years of age, using prospectively recorded information from Well-Baby Clinic (WBC) records. Blind assessment of an average of 25 contacts per subject yielded data concerning early life developmental, physical and behavioral characteristics associated with psychosis risk. As compared with controls, offspring of women with schizophrenia showed significantly increased rates of delayed walking, visual dysfunction, language skill disorders, enuresis, disturbed behavior (especially poor social competence), and multiple accumulated risk characteristics. Significant Sc-risk characteristics did not include impaired hearing, minor malformations, biological dysfunctions, or physical illness leading to treatment. Offspring of mothers with affective psychosis (Aff) showed only a significantly increased rate of delayed walking, with no significantly increased total aggregation of risk characteristics, compared with controls. The results suggest a limited overlap in the diathesis characteristics associated with risk for Sc vs. Aff psychosis. The importance of these early risk characteristics for the later development of psychopathology is being investigated in this sample.

Prospective study of neurological abnormalities in offspring of women with psychosis: birth to adulthood.

OBJECTIVE: The authors prospectively investigated neurological abnormalities in 75 young adult offspring of mothers with psychotic disorders and 91 offspring of comparison mothers with no psychosis history. They also studied the stability of these abnormalities from birth to adulthood. METHOD: Neurological abnormalities were previously studied in infancy and at 6 years of age. In this study, they were blindly assessed with a comprehensive neurological assessment scale at a mean age of 22.4 years in a 93.3% effective follow-up of the sample. RESULTS: In relation to the comparison subjects (N=88) and offspring of mothers with affective psychosis (N=22), the adult offspring of mothers with schizophrenia (N=28) had significantly more neurological abnormalities. More soft signs, primitive reflexes, involuntary movements, and cranial nerve abnormalities characterized a subgroup (32%) among these offspring. The offspring of mothers with affective psychosis were not different from comparison subjects. The extension of schizophrenia and affective psychosis risk groups to include additional maternal "spectrum cases" (N=10 and N=14, respectively) generally yielded similar results. Neurological abnormalities at 22 years were significantly associated with neurological abnormalities at age 6, but not in infancy, among the total high-risk group, offspring of mothers with schizophrenia, and comparison offspring. CONCLUSIONS: High levels of neurological abnormalities are found in a substantial proportion of offspring of mothers with schizophrenia but not offspring of mothers with affective psychosis. This suggests that familial risk for schizophrenia is associated with neurodevelopmental disturbance that is manifest throughout life and belongs to a different biological continuum from that of affective psychosis.

Paternal and maternal age as risk factors for psychosis: findings from Denmark, Sweden and Australia.

BACKGROUND: While the association between increased maternal age and congenital disorders has long been recognized, the offspring of older fathers are also at increased risk of congenital disorders related to DNA errors during spermatogenesis. Recent studies have drawn attention to an association between increased paternal age and increased risk of schizophrenia. The aim of the current study was to examine both paternal and maternal age as risk factors for the broader category of psychosis. METHOD: We used data from three sources examining psychosis: a population-based cohort study (Denmark), and two case-control studies (Sweden and Australia). RESULTS: When controlling for the effect of maternal age, increased paternal age was significantly associated with increased risk of psychosis in the Danish and Swedish studies. The Australian study found no association between adjusted paternal age and risk of psychosis. When controlling for the effect of paternal age, younger maternal age was associated with an increased risk of psychoses in the Danish study alone. CONCLUSIONS: The offspring of older fathers are at increased risk of developing psychosis. The role of paternally derived mutations and/or psychosocial factors associated with older paternal age warrants further research.

Psychiatric admissions for psychosis in Malmö during the NATO bombing of Kosovo.

Little is known about the possible mechanisms contributing to increased risk for psychosis found among immigrants. We used the NATO bombing campaign of Kosovo as a naturalistic experiment to explore the role of potentially stressful aspects of minority group status. We examined all patient admissions to the psychiatric clinic in Malmö during the months of the NATO campaign in Kosovo in 1999 and during control months in 1997. Admission rates showed significantly differing trends over time, with an increasing proportion of immigrant patients with psychosis admitted during the NATO campaign months and a decreasing proportion of such patients admitted during control months. A significantly greater proportion of the immigrant patients admitted for psychosis during the NATO campaign months versus control months had been exposed to extreme duress before migration. Cumulative adversity, either solely or in combination with current stress, may possibly contribute to increased risk for psychosis among immigrants.