Prenatal fever and autism risk.

Some studies suggest that prenatal infection increases risk of autism spectrum disorders (ASDs). This study was undertaken in a prospective cohort in Norway to examine whether we could find evidence to support an association of the prenatal occurrence of fever, a common manifestation of infection, with ASD risk. Prospective questionnaires provided maternal exposure data; case status was established from clinical assessments and registry linkages. In a large, prospectively ascertained cohort of pregnant mothers and their offspring, we examined infants born ⩾32 weeks for associations between fever exposure in each trimester and ASD risk using logistic regression. Maternal exposure to second-trimester fever was associated with increased ASD risk, adjusting for presence of fever in other trimesters and confounders (adjusted odds ratio (aOR), 1.40; 95% confidence interval, 1.09-1.79), with a similar, but nonsignificant, point estimate in the first trimester. Risk increased markedly with exposure to three or more fever episodes after 12 weeks' gestation (aOR, 3.12; 1.28-7.63). ASD risk appears to increase with maternal fever, particularly in the second trimester. Risk magnified dose dependently with exposure to multiple fevers after 12 weeks' gestation. Our findings support a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD.

Three decades of eating disorders in Dutch primary care: decreasing incidence of bulimia nervosa but not of anorexia nervosa.

BACKGROUND: Whether the incidence of eating disorders in Western, industrialized countries has changed over time has been the subject of much debate. The purpose of this primary-care study was to examine changes in the incidence of eating disorders in The Netherlands during the 1980s, 1990s and 2000s. METHOD: A nationwide network of general practitioners (GPs), serving a representative sample (~1%) of the total Dutch population, recorded newly diagnosed patients with anorexia nervosa (AN) and bulimia nervosa (BN) in their practice during 1985-1989, 1995-1999, and 2005-2009. GPs are key players in the Dutch healthcare system, as their written referral is mandatory in order to get access to specialized (mental) healthcare, covered by health insurance. Health insurance is virtually universal in The Netherlands (99% of the population). A substantial number of GPs participated in all three study periods, during which the same case identification criteria were used and the same psychiatrist was responsible for making the final diagnoses. Incidence rates were calculated and for comparison between periods, incidence rate ratios. RESULTS: The overall incidence rate of BN decreased significantly in the past three decades (from 8.6 per 100,000 person-years in 1985-1989 to 6.1 in 1995-1999, and 3.2 in 2005-2009). The overall incidence of AN remained fairly stable during three decades, i.e. 7.4 per 100,000 person-years in 1985-1989, 7.8 in 1995-1999, and 6.0 in 2005-2009. CONCLUSIONS: The incidence rate of BN decreased significantly over the past three decades, while the overall incidence rate of AN remained stable.

Severity and persistence of asthma and mental health: a birth cohort study.

BACKGROUND: The goal of the current study was to investigate asthma and mental health among youth in the community, and to consider the role of asthma severity and persistence in this link. Method Data were drawn from the Raine Study, a population-based birth cohort study in Western Australia. Logistic regression models and generalized estimating equations were used to examine the relationship between asthma at age 5 years and the range of internalizing and externalizing mental health problems at ages 5-17 years. Analyses were stratified by asthma severity and persistence, and adjusted for a range of potential confounders. RESULTS: More severe and persistent asthma at age 5 was associated with significantly increased odds of affective, anxiety, somatic, oppositional defiant and conduct problems at ages 5-17. Mild asthma and remitted asthma were not associated with heightened vulnerability to mental disorders. CONCLUSIONS: Our results suggest that youth with symptomatic asthma are more likely to suffer from a wide range of mental health problems, and that the likelihood of mental health problems appears to increase as a function of asthma severity. Youth with poorly controlled and/or more severe and persistent asthma may be considered a vulnerable group who might benefit from mental health screening in clinical, school and community settings.

Genetics of schizophrenia in the South African Xhosa.

Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.

Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945.

We tested the hypothesis that first-trimester exposure to acute food deprivation is a risk factor for schizophrenia. A sharp and time-limited decline in the food intake of the Dutch population following a Nazi blockade in 1944 to 1945 created a unique if tragic natural experiment to test this hypothesis in three regions of Holland (west, north, and south). In the west, or famine region, birth cohorts exposed to severe food deprivation (an average daily ration under 4200 kJ) during the first trimester showed a substantial increase in hospitalized schizophrenia for women but not for men. Relative risks for women were 2.17 for "broad" and 2.56 for "restricted" schizophrenia. Moderate food deprivation during the first trimester (average daily ration under 6300 kJ) was not associated with increased risk of schizophrenia in the famine region. In the north and south regions, numbers were smaller and there was no exposure to severe famine. Birth cohorts exposed to moderate food deprivation during the first trimester showed a trend toward increased risk of schizophrenia for women. These findings give plausibility to the proposition that early prenatal nutrition can have a gender-specific effect on the risk of schizophrenia.

Advancing paternal age and the risk of schizophrenia.

BACKGROUND: A major source of new mutations in humans is the male germ line, with mutation rates monotonically increasing as father's age at conception advances, possibly because of accumulating replication errors in spermatogonial cell lines. METHOD: We investigated whether the risk of schizophrenia was associated with advancing paternal age in a population-based birth cohort of 87 907 individuals born in Jerusalem from 1964 to 1976 by linking their records to the Israel Psychiatric Registry. RESULTS: Of 1337 offspring admitted to psychiatric units before 1998, 658 were diagnosed as having schizophrenia and related nonaffective psychoses. After controlling for maternal age and other confounding factors (sex, ethnicity, education [to reflect socioeconomic status], and duration of marriage) in proportional hazards regression, we found that paternal age was a strong and significant predictor of the schizophrenia diagnoses, but not of other psychiatric disorders. Compared with offspring of fathers younger than 25 years, the relative risk of schizophrenia increased monotonically in each 5-year age group, reaching 2.02 (95% confidence interval, 1.17-3.51) and 2.96 (95% confidence interval, 1.60-5.47) in offspring of men aged 45 to 49 and 50 years or more, respectively. Categories of mother's age showed no significant effects, after adjusting for paternal age. CONCLUSIONS: These findings support the hypothesis that schizophrenia may be associated, in part, with de novo mutations arising in paternal germ cells. If confirmed, they would entail a need for novel approaches to the identification of genes involved in schizophrenia.

A.E. Bennett Research Award. Prenatal rubella, premorbid abnormalities, and adult schizophrenia.

BACKGROUND: Premorbid neurocognitive, neuromotor, and behavioral function tends to be disturbed in schizophrenia. We previously demonstrated that a birth cohort clinically and serologically documented with prenatal rubella evidenced a marked increase in risk of nonaffective psychosis. In our study, we examined whether rubella-exposed subjects destined to develop schizophrenia and other schizophrenia spectrum disorders (SSD), compared with exposed control subjects, had greater impairment in several premorbid functions. METHODS: Subjects were interviewed using a direct, comprehensive research assessment and diagnosed by consensus. We compared the degree of IQ decline, as well as premorbid neuromotor and behavioral dysfunction, between rubella-exposed subjects who developed schizophrenia spectrum psychosis (SSP) and exposed control subjects from the cohort. We also compared the gestational timing of rubella infection between the cases and control subjects. RESULTS: This rubella-exposed birth cohort evidenced a markedly increased risk of SSD (20.4% or 11/53). Rubella-exposed SSP cases, compared with rubella-exposed control subjects, demonstrated a decline in IQ from childhood to adolescence, and increased premorbid neuromotor and behavioral abnormalities. Moreover, it appears that early gestational rubella exposure may represent a period of increased vulnerability for SSD. CONCLUSIONS: These findings link a known prenatal exposure, a deviant neurodevelopmental trajectory in childhood and adolescence, and SSP in adulthood within the same individuals.

Risk factors for homelessness among patients admitted to a state mental hospital.

OBJECTIVE: This study measured the overall prevalence of homelessness and tested a priori hypothesized risk factors for homelessness among patients admitted to a state hospital. The risk factors included male gender, age under 40 years, black race, urban residence, schizophrenia-related diagnosis, alcohol abuse, and drug abuse. METHOD: For 377 patients admitted to a New York state mental hospital, the 3-month, 3-year, and lifetime prevalences of homelessness were assessed. The associations between these prevalences and the hypothesized risk factors were measured by relative risks in univariate analyses and by odds ratios derived from a logistic regression in multivariate analyses. RESULTS: The 3-month prevalence of homelessness was 19%, the 3-year prevalence was 25%, and the lifetime prevalence was 28%. In univariate analyses, significant associations included drug abuse with 3-month prevalence, 3-year prevalence, and lifetime prevalence; urban residence with 3-year prevalence and lifetime prevalence; and age under 40 years with 3-month prevalence. In the logistic regression analyses, the only significant associations were urban residence with 3-year prevalence and lifetime prevalence. Male gender, black race, alcohol abuse, and schizophrenia-related diagnosis had little or no relation to homelessness. CONCLUSIONS: The overall prevalence of homelessness in these patients was remarkably high. Several strong risk factors for homelessness in the general population had only a moderate effect or no effect on homelessness in this population. Risk factors for homelessness in psychiatric patients may be somewhat different from those in the general population.

Childhood antecedents of homelessness in psychiatric patients.

OBJECTIVE: This study examined the relationship between childhood experience and homelessness in psychiatric patients. METHOD: Three large and diverse samples of homeless patients (N = 512) were compared with a sample of patients who had never been homeless (N = 271), with respect to childhood experience of foster care, group home placement, and running away. One of the homeless samples and the never homeless sample were drawn from patients admitted to a state mental hospital. In this state hospital population, risk ratios for lifetime prevalence of homelessness could be derived. RESULTS: In the three homeless samples, over 15% had a history of foster care, over 10% had a history of group home placement, and over 20% had a history of running away. These figures compared with 2%, 1%, and 5%, respectively, in the never homeless sample. In the state hospital, the lifetime prevalence of homelessness in patients with any one of these childhood experiences was about threefold that of other patients. A history of homelessness was reported by the great majority of state hospital patients who had had one of these childhood experiences. CONCLUSIONS: These childhood experiences were strongly associated with adult homelessness in these psychiatric patients. It might be possible to prevent homelessness in some cases by interventions aimed at patients with such childhood histories.

Further evidence of relation between prenatal famine and major affective disorder.

OBJECTIVE: In a previous study, the authors demonstrated an association between prenatal famine in middle to late gestation and major affective disorders requiring hospitalization. In this study, they sought to examine the association by using newly identified cases from the Dutch birth cohort used previously to examine the gender specificity of the association and to assess whether this relation is present for both unipolar and bipolar affective disorders. METHOD: The authors compared the risk of major affective disorder requiring hospitalization in birth cohorts who were and were not exposed, in each trimester of gestation, to famine during the Dutch Hunger Winter of 1944-1945. These cases of major affective disorder requiring hospitalization were newly ascertained from a national psychiatric registry. A larger data set from this registry was used for analysis by gender and diagnostic subtype. RESULTS: For the newly ascertained cases, the risk of developing major affective disorder requiring hospitalization was increased for subjects with exposure to famine in the second trimester and was increased significantly for subjects with exposure in the third trimester, relative to unexposed subjects. For the cases from the entire period of ascertainment, the risk of developing affective disorder was significantly increased for those exposed to famine during the second and the third trimesters of gestation. The effects were demonstrated for men and women and for unipolar and bipolar affective disorders. CONCLUSIONS: These results provide support for the authors' previous findings on the association between middle to late gestational famine and affective disorder.

Homelessness among individuals with psychotic disorders hospitalized for the first time: findings from the Suffolk County Mental Health Project.

OBJECTIVE: Although data suggest that homelessness among persons with severe mental disorders is both distressing and common, several important epidemiologic questions remain unanswered. This study reports on the occurrence of homelessness in a quasi-representative sample of persons newly hospitalized with psychotic disorders. The authors also compared rates of homelessness in different diagnostic groups and among groups with differing symptom profiles. METHOD: The study was based on data from 237 first-admission patients hospitalized at 10 of the 12 inpatient facilities in eastern Long Island, N.Y. Consensus diagnoses were derived from multiple sources of information, including the Structured Clinical Interview for DSM-III-R. Patients were followed over a 24-month period after initial interview. Homelessness histories were based on subject self-reports. RESULTS: Fifteen percent of the patients had experienced at least one episode of homelessness before or within 24 months of their first psychiatric hospitalization. In more than two-thirds of these cases, the initial homeless episode had occurred before the first hospitalization. There were no significant differences in the risk of homelessness among diagnostic groups. Among subjects diagnosed with schizophrenia and related disorders, those with high levels of negative symptoms had a significantly greater risk of prehospitalization homelessness than those with low symptom levels. CONCLUSIONS: The high rate of homelessness observed must be viewed with profound concern by clinicians, consumers, and policymakers alike. The findings support the importance of intervening early in the course of disorder, particularly for persons diagnosed with psychotic illnesses.

Senile degeneration and cognitive impairment in chronic schizophrenia.

OBJECTIVE: This study was an investigation of the role of Alzheimer-type senile degenerative abnormalities in the cognitive impairment of chronic schizophrenia. METHOD: The study group comprised 145 deceased elderly institutionalized psychiatric patients: 66 with schizophrenia, 26 with mood disorders, 36 with dementia, and 17 with other psychiatric diagnoses. The comparison group included 16 deceased elderly individuals without neurologic or psychiatric disease. Psychiatric diagnoses and cognitive status were established by standardized review of medical records. Neuritic senile plaques and neurofibrillary tangles were identified immunohistochemically and counted, by investigators blind to clinical information, in standardized regions of each brain. RESULTS: Of the subjects with schizophrenia, 68% had definite cognitive impairment, but only 8% satisfied neuropathological criteria for Alzheimer's disease. Among the schizophrenia subjects without Alzheimer's disease, definite cognitive impairment was associated with higher levels of plaques and tangles. The schizophrenia subjects without definite cognitive impairment had fewer plaques and tangles than the unimpaired nonpsychiatric subjects. CONCLUSIONS: Most cases of cognitive impairment in schizophrenia could not be attributed to Alzheimer's disease. An association of mild Alzheimer-type pathology with definite cognitive impairment was unique to schizophrenia. Enhanced sensitivity to the effects of aging on the brain may be a manifestation of diminished cognitive reserve in schizophrenia.

Prenatal nutritional deprivation as a risk factor in schizophrenia: preclinical evidence.

We will review evidence from preclinical literature that prenatal nutritional deprivation produces neurochemical, morphological, and electrophysiological effects reminiscent of those seen in clinical studies of schizophrenia. We will focus on effects of nutritional deficiency that are likely to have implications for schizophrenia. These include disruption of neurotransmitter systems such as dopamine and serotonin and dysgenesis of the hippocampal formation. Preclinical studies show enhanced release and turnover of dopamine and serotonin following prenatal and early postnatal nutritional deficiency. Morphology of the hippocampus, as well as electrophysiology and hippocampally-mediated behaviors are also altered. Although intriguing, these studies have not been conducted with schizophrenia in mind, and thus, outcome measures that may be more specifically related to schizophrenia have not been examined. We propose that further preclinical studies that examine the consequences of prenatal nutritional deficiency, which may lead to altered neuronal migration and other developmental abnormalities, may be useful in understanding the etiology of schizophrenia.

Divalproex treatment of disruptive adolescents: a report of 10 cases.

BACKGROUND: To report an open trial of divalproex sodium in 10 adolescents with chronic temper outbursts and mood lability. METHOD: Ten adolescents meeting screening criteria for chronic temper outbursts and mood lability were followed for 5 consecutive weeks on open divalproex sodium treatment. Temper outburst frequency and mood swings severity at pretreatment and posttreatment were compared by using paired t tests. Subjects continued to be followed to judge persistence of response. RESULTS: All subjects showed clear improvement at 5 weeks and maintained it during follow-up while taking medication. Rapid relapse and recovery occurred in 5 of 6 patients who discontinued and then resumed medication. CONCLUSION: Divalproex sodium may be helpful in teenagers who have explosive tempers and severe mood swings, and benefits may generalize to school and family life.

Prenatal exposure to the 1957 influenza pandemic and non-affective psychosis in The Netherlands.

Second-trimester exposure to the 1957 A2 influenza pandemic is a controversial risk factor for schizophrenia. Two earlier studies of the Dutch psychiatric registry failed to find an increased risk for exposed subjects, but diagnostic misclassification within the spectrum of non-affective psychoses has not yet been ruled out as an explanation for the negative findings. Using an enlarged data-set we examined not only whether second-trimester exposure to the epidemic is associated with an increased risk of schizophrenia (ICD:295), but also whether it is associated with an increased risk of paranoid states (ICD:297) or other non-organic psychoses (ICD:298). In this retrospective cohort study the risks of the above-mentioned disorders were compared for those exposed and unexposed to A2 influenza during the second trimester of fetal life. The risks for the exposed subjects were not significantly higher than the risks for the unexposed. The power of the study to detect a significant increase in the risk of schizophrenia was sufficient. If the relative risk of a lifetime hospitalization for schizophrenia for second-trimester exposed subjects (born January-April 1958) is assumed to be 1.3, the power of the study would be 0.97 (alpha=0.05; one-tailed testing). If the relative risk for subjects born five months after the peak of the epidemic (mid-February to mid-March 1958) is assumed to be 1.88, as reported for England and Wales, the power of the study would be close to 1.00. This was the largest study of its kind in Europe: 275 subjects were born in the period January-April 1958 and had a lifetime hospitalization for schizophrenia. This study indicates that there is no relation between second-trimester exposure to the 1957 influenza pandemic and risk of non-affective psychosis in the Dutch population. It adds to a growing body of work which does not support an association between maternal influenza and schizophrenia.

Diagnosis and screening for psychotic disorders in a study of the homeless.

In a survey of homeless men, the authors found that screening scales for psychotic symptoms (Psychiatric Epidemiology Research Instrument) and signs (6-item scale of observational ratings) predicted a rating of psychosis (possible, probable, or definite) on a diagnostic interview (Structured Clinical Interview for DSM-III-R: Psychotic Disorders) reasonably well, in a sample where psychosis was common. Although the two scales performed well when used in conjunction, neither scale showed adequate predictive power when used alone. The authors conclude that screening for psychotic disorders in community studies is feasible for some purposes. They suggest approaches to the use of diagnostic interviews and screening scales in future community studies that might enhance the interpretability as results as well as the efficacy of screening.

The design of the prenatal determinants of schizophrenia study.

This paper describes the Prenatal Determinants of Schizophrenia (PDS) Study; three companion papers report the first results. The PDS Study was designed to study early antecedents of schizophrenia in a birth cohort of 1959-1967 for whom a wealth of archived prenatal data--including maternal sera--was available. Making use of the registries of a health plan into which the cohort was born, we ascertained and then diagnosed 71 cases of schizophrenia and spectrum disorders in the cohort. We describe herein the available prenatal data, the process of case diagnosis, and the strategies used to analyze prenatal determinants of schizophrenia in this cohort. Data are presented that bear on the main sources of potential bias and are important to understanding the strengths and limitations of this unique data set.

Maternal prepregnant body mass and risk of schizophrenia in adult offspring.

This study examined the relation between maternal prepregnant body mass index (BMI) and development of schizophrenia and schizophrenia spectrum disorders in adult offspring from the Prenatal Determinants of Schizophrenia Study. The study drew on a previously studied cohort of births occurring between 1959 and 1967 to women enrolled in a prepaid health plan. Computerized treatment registries were used to identify possible cases of schizophrenia and spectrum disorders in adult offspring belonging to the health plan from 1981 to 1997. Diagnostic interviews and medical record reviews resulted in diagnosis of 63 cases of schizophrenia and spectrum disorders; these cases and 6,570 unrelated and unaffected cohort members whose mothers also had prepregnancy measures of BMI comprised the sample for analyses. High (> or = 30.0), compared with average (20.0-26.9), maternal prepregnant BMI (kg/m2) was significantly associated with schizophrenia and spectrum disorders in the adult offspring (relative risk [RR] = 2.9; 95% confidence interval [CI] 1.3-6.6), independently of maternal age, parity, race, education, or cigarette smoking during pregnancy. Low (< or = 19.9) maternal BMI was not associated with schizophrenia and spectrum disorders (RR = 1.2; 95% CI 0.64-2.2). Future studies of this cohort will examine factors that may help explain the relationship of high maternal prepregnant BMI with schizophrenia, including nutritional and metabolic factors, toxic exposures, and obstetrical complications.

Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study.

We sought to examine the relationship between maternal exposure to adult respiratory infections and schizophrenia spectrum disorder (SSD) in the Prenatal Determinants of Schizophrenia (PDS) Study, a large birth cohort investigation. Previous work suggests that second trimester exposure to respiratory infection may be a risk factor for SSD. We therefore examined whether this class of infection was associated with adult SSD. For this purpose, we capitalized on several design advantages of the PDS Study, including a comprehensive, prospective data base on physician-diagnosed infections and a continuous followup in which diagnoses of SSD were made, in the majority, by face-to-face interview. Second trimester exposure to respiratory infections was associated with a significantly increased risk of SSD, adjusting for maternal smoking, education, and race (rate ratio [RR] = 2.13 [1.05-4.35], chi2 = 4.36, df= 1,p = 0.04); no associations were shown for first trimester and third trimester exposure to these respiratory infections. These findings support-and extend-previous studies suggesting that second trimester respiratory infections are risk factors for SSD. This study therefore has implications toward uncovering the etiology of schizophrenia and developing preventive strategies.

Incidence and cumulative risk of treated schizophrenia in the prenatal determinants of schizophrenia study.

The present study uses data from the Prenatal Determinants of Schizophrenia (PDS) Study to derive age- and sex-specific estimates of incidence and cumulative risk for DSM-IV schizophrenia. Although not designed as an incidence study, the PDS Study uses both a well-defined population under continuous followup and DSM-IV diagnoses. The originating cohort was established in Alameda County, California, during 1959-1967 and yielded 12,094 cohort members followed from 1981 to 1997 during the principal ages at risk for schizophrenia. Survival analytic techniques showed that schizophrenia incidence rates per 10,000 person-years for men were 9.4 for ages 15-19; 5.6 for ages 20-24; 3.3 for ages 25-29; and 0.9 for ages 30-34. Schizophrenia incidence rates per 10,000 person-years for women were 1.6 for ages 15-19; 1.3 for ages 20-24; and 4.1 for ages 25-29. The cumulative risk for schizophrenia by age 38 was 0.93 percent for men and 0.35 percent for women. These estimates of incidence rates and risk were higher than those in traditional incidence studies but similar to recent findings in other cohorts. Possible explanations for the apparently high rates of disorder include chance, design effects, and true variation in risk over time and place.