Association Between Mental Health and Reproductive System Disorders in Women: A Systematic Review and Meta-analysis.

Importance: Reproductive system and mental health disorders are commonly comorbid in women. Although the causes of this overlap remain elusive, evidence suggests potential shared environmental and genetic factors associated with risk. Objective: To investigate the comorbidity between psychiatric and reproductive system disorders, both as broad diagnostic categories and among specific pairs of diagnoses. Data Source: PubMed. Study Selection: Observational studies published between January 1980 and December 2019 assessing prevalence of psychiatric disorders in women with reproductive system disorders and prevalence of reproductive system disorders in women with psychiatric disorders were included. The study did not include psychiatric and reproductive disorders triggered by life events (eg, trauma, infection, surgery) to address potential confounding. Data Extraction and Synthesis: A search yielded 1197 records, of which 50 met the inclusion criteria for the qualitative and 31 for the quantitative synthesis in our study. A random-effects model was used for data synthesis and Egger test and I2 to assess study bias and heterogeneity. Data were analyzed from January to December 2022. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Main Outcomes and Measures: Psychiatric and reproductive system disorders. Results: A total of 1197 records were identified, of which 50 met the inclusion criteria for qualitative and 31 for quantitative synthesis. Diagnosis of a reproductive system disorder was associated with a 2- to 3-fold increased odds of having a psychiatric disorder (lower bound odds ratio [OR], 2.00; 95% CI, 1.41-2.83; upper bound OR; 2.88; 95% CI, 2.21-3.76). The analysis focused on specific diagnoses described in the literature and found that polycystic ovary syndrome was associated with increased odds of depression (population-based studies OR, 1.71; 95% CI, 1.19-2.45; clinical studies OR, 2.58; 95% CI, 1.57-4.23) and anxiety (population-based studies OR, 1.69; 95% CI, 1.36-2.10; clinical studies OR, 2.85; 95% CI, 1.98-4.09). Chronic pelvic pain was also associated with both depression (OR, 3.91; 95% CI, 1.81-8.46) and anxiety (OR, 2.33; 95% CI, 1.33-4.08). Few studies investigated risk of other reproductive system disorders in women with psychiatric disorders, or reverse associations (risk of reproductive system disorder among women with a psychiatric diagnosis). Conclusions and Relevance: In this systematic review and meta-analysis, a high rate of reported co-occurrence between psychiatric and reproductive disorders overall was observed. However, data for many disorder pairs were limited. The available literature focused overwhelmingly on affective disorders in polycystic ovary syndrome, overlooking a substantial portion of disease overlap. As such, the associations between the majority of mental health outcomes and conditions of the female reproductive system are largely unknown.

Familial clustering of psychiatric disorders and low IQ.

BACKGROUND: Although the ICD and DSM differentiate between different psychiatric disorders, these often share symptoms, risk factors, and treatments. This was a population-based, case-control, sibling study examining familial clustering of all psychiatric disorders and low IQ, using data from the Israel Draft-Board Registry on all Jewish adolescents assessed between 1998 and 2014. METHODS: We identified all cases with autism spectrum disorder (ASD, N = 2128), severe intellectual disability (ID, N = 9572), attention-deficit hyperactive disorder (ADHD) (N = 3272), psychotic (N = 7902), mood (N = 9704), anxiety (N = 10 606), personality (N = 24 816), or substance/alcohol abuse (N = 791) disorders, and low IQ (⩾2 SDs below the population mean, N = 31 186). Non-CNS control disorders were adolescents with Type-1 diabetes (N = 2427), hernia (N = 29 558) or hematological malignancies (N = 931). Each case was matched with 10 age-matched controls selected at random from the Draft-Board Registry, with replacement, and for each case and matched controls, we ascertained all full siblings. The main outcome measure was the relative recurrence risk (RRR) of the sibling of a case having the same (within-disorder RRR) or a different (across-disorder RRR) disorder. RESULTS: Within-disorder RRRs were increased for all diagnostic categories, ranging from 11.53 [95% confidence interval (CI): 9.23-14.40] for ASD to 2.93 (95% CI: 2.80-3.07) for personality disorders. The median across-disorder RRR between any pair of psychiatric disorders was 2.16 (95% CI: 1.45-2.43); the median RRR between low IQ and any psychiatric disorder was 1.37 (95% CI: 0.93-1.98). There was no consistent increase in across-disorder RRRs between the non-CNS disorders and psychiatric disorders and/or low IQ. CONCLUSION: These large population-based study findings suggest shared etiologies among most psychiatric disorders, and low IQ.

Cancer risk in individuals with intellectual disability in Sweden: A population-based cohort study.

BACKGROUND: A knowledge gap exists about the risk of cancer in individuals with intellectual disability (ID). The primary aim of this study was to estimate the cancer risk among individuals with ID compared to individuals without ID. METHODS AND FINDINGS: We conducted a population-based cohort study of all children live-born in Sweden between 1974 and 2013 and whose mothers were born in a Nordic country. All individuals were followed from birth until cancer diagnosis, emigration, death, or 31 December 2016 (up to age 43 years), whichever came first. Incident cancers were identified from the Swedish Cancer Register. We fitted Cox regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of cancer risk in relation to ID after adjusting for several potential confounders. We analyzed ID by severity, as well as idiopathic ID and syndromic ID separately. We performed a sibling comparison to investigate familial confounding. The study cohort included a total of 3,531,305 individuals, including 27,956 (0.8%) individuals diagnosed with ID. Compared with the reference group (individuals without ID and without a full sibling with ID), individuals with ID were in general more likely to be male. The median follow-up time was 8.9 and 23.0 years for individuals with ID and individuals without ID, respectively. A total of 188 cancer cases were identified among individuals with ID (incidence rate [IR], 62 per 1,000 person-years), and 24,960 among individuals in the reference group (IR, 31 per 1,000 person-years). A statistically significantly increased risk was observed for any cancer (HR 1.57, 95% CI 1.35-1.82; P < 0.001), as well as for several cancer types, including cancers of the esophagus (HR 28.4, 95% CI 6.2-130.6; P < 0.001), stomach (HR 6.1, 95% CI 1.5-24.9; P = 0.013), small intestine (HR 12.0, 95% CI 2.9-50.1; P < 0.001), colon (HR 2.0, 95% CI 1.0-4.1; P = 0.045), pancreas (HR 6.0, 95% CI 1.5-24.8; P = 0.013), uterus (HR 11.7, 95% CI 1.5-90.7; P = 0.019), kidney (HR 4.4, 95% CI 2.0-9.8; P < 0.001), central nervous system (HR 2.7, 95% CI 2.0-3.7; P < 0.001), and other or unspecified sites (HR 4.8, 95% CI 1.8-12.9; P = 0.002), as well as acute lymphoid leukemia (HR 2.4, 95% CI 1.3-4.4; P = 0.003) and acute myeloid leukemia (HR 3.0, 95% CI 1.4-6.4; P = 0.004). Cancer risk was not modified by ID severity or sex but was higher for syndromic ID. The sibling comparison showed little support for familial confounding. The main study limitations were the limited statistical power for the analyses of specific cancer types, and the potential for underestimation of the studied associations (e.g., due to potential underdetection or delayed diagnosis of cancer among individuals with ID). CONCLUSIONS: In this study, we found that individuals with ID showed an increased risk of any cancer, as well as of several specific cancer types. These findings suggest that extended surveillance and early intervention for cancer among individuals with ID are warranted.

Risk and protective factors for mental disorders beyond genetics: an evidence-based atlas.

Decades of research have revealed numerous risk factors for mental disorders beyond genetics, but their consistency and magnitude remain uncer-tain. We conducted a "meta-umbrella" systematic synthesis of umbrella reviews, which are systematic reviews of meta-analyses of individual studies, by searching international databases from inception to January 1, 2021. We included umbrella reviews on non-purely genetic risk or protective factors for any ICD/DSM mental disorders, applying an established classification of the credibility of the evidence: class I (convincing), class II (highly suggestive), class III (suggestive), class IV (weak). Sensitivity analyses were conducted on prospective studies to test for temporality (reverse causation), TRANSD criteria were applied to test transdiagnosticity of factors, and A Measurement Tool to Assess Systematic Reviews (AMSTAR) was employed to address the quality of meta-analyses. Fourteen eligible umbrella reviews were retrieved, summarizing 390 meta-analyses and 1,180 associations between putative risk or protective factors and mental disorders. We included 176 class I to III evidence associations, relating to 142 risk/protective factors. The most robust risk factors (class I or II, from prospective designs) were 21. For dementia, they included type 2 diabetes mellitus (risk ratio, RR from 1.54 to 2.28), depression (RR from 1.65 to 1.99) and low frequency of social contacts (RR=1.57). For opioid use disorders, the most robust risk factor was tobacco smoking (odds ratio, OR=3.07). For non-organic psychotic disorders, the most robust risk factors were clinical high risk state for psychosis (OR=9.32), cannabis use (OR=3.90), and childhood adversities (OR=2.80). For depressive disorders, they were widowhood (RR=5.59), sexual dysfunction (OR=2.71), three (OR=1.99) or four-five (OR=2.06) metabolic factors, childhood physical (OR=1.98) and sexual (OR=2.42) abuse, job strain (OR=1.77), obesity (OR=1.35), and sleep disturbances (RR=1.92). For autism spectrum disorder, the most robust risk factor was maternal overweight pre/during pregnancy (RR=1.28). For attention-deficit/hyperactivity disorder (ADHD), they were maternal pre-pregnancy obesity (OR=1.63), maternal smoking during pregnancy (OR=1.60), and maternal overweight pre/during pregnancy (OR=1.28). Only one robust protective factor was detected: high physical activity (hazard ratio, HR=0.62) for Alzheimer's disease. In all, 32.9% of the associations were of high quality, 48.9% of medium quality, and 18.2% of low quality. Transdiagnostic class I-III risk/protective factors were mostly involved in the early neurodevelopmental period. The evidence-based atlas of key risk and protective factors identified in this study represents a benchmark for advancing clinical characterization and research, and for expanding early intervention and preventive strategies for mental disorders.

Systematic review and meta-analysis identify significant relationships between clinical anxiety and lower urinary tract symptoms.

BACKGROUND: Lower urinary tract symptoms (LUTS), such as voiding symptoms, overactive bladder, and interstitial cystitis, and anxiety disorders are often comorbid conditions in patients. However, the existing evidence regarding the rates and nature of the co-occurrence of these conditions has not been systematically evaluated. The aim of this study was to examine these relationships. METHODS: We conducted a systematic review and meta-analysis to examine the relationship between LUTS and anxiety. We searched for articles published from January 1990 to July 2019 in PubMed, CENTRAL, PsycINFO, and Google Scholar. Outcomes were anxiety-related disorders and symptoms (clinically significant anxiety) and LUTS. We performed random-effects meta-analyses, inspected funnel plots, and applied the Egger's test to evaluate publication bias. We followed PRISMA guidelines and recorded our protocol on PROSPERO (ID = CRD42019118607). RESULTS: We identified 814 articles, of which 94 fulfilled inclusion criteria, and 23 had sufficient data for meta-analysis. The odds ratio (OR) for clinically significant anxiety among individuals with LUTS was 2.87 (95% CI: 2.38,3.46, p < .001). The OR for LUTS among individuals with clinically significant anxiety was 2.87 (95% CI: 1.07,7.74, p < .001), although very few studies examined this relationship. A large value of I2 index suggests high heterogeneity between studies. CONCLUSION: The results demonstrate a significant association between clinically significant anxiety and LUTS in both females and males. There were limited studies on younger individuals and on individuals ascertained for clinically significant anxiety, which should motivate further study in these areas. Understanding the co-occurrence of these conditions will lead to better prevention and interventions to ameliorate the progression of the symptoms and improve the quality of life. A thorough assessment of anxiety may provide more optimal care for LUTS patients.

Linked patterns of biological and environmental covariation with brain structure in adolescence: a population-based longitudinal study.

Adolescence is a period of major brain reorganization shaped by biologically timed and by environmental factors. We sought to discover linked patterns of covariation between brain structural development and a wide array of these factors by leveraging data from the IMAGEN study, a longitudinal population-based cohort of adolescents. Brain structural measures and a comprehensive array of non-imaging features (relating to demographic, anthropometric, and psychosocial characteristics) were available on 1476 IMAGEN participants aged 14 years and from a subsample reassessed at age 19 years (n = 714). We applied sparse canonical correlation analyses (sCCA) to the cross-sectional and longitudinal data to extract modes with maximum covariation between neuroimaging and non-imaging measures. Separate sCCAs for cortical thickness, cortical surface area and subcortical volumes confirmed that each imaging phenotype was correlated with non-imaging features (sCCA r range: 0.30-0.65, all PFDR < 0.001). Total intracranial volume and global measures of cortical thickness and surface area had the highest canonical cross-loadings (|ρ| = 0.31-0.61). Age, physical growth and sex had the highest association with adolescent brain structure (|ρ| = 0.24-0.62); at baseline, further significant positive associations were noted for cognitive measures while negative associations were observed at both time points for prenatal parental smoking, life events, and negative affect and substance use in youth (|ρ| = 0.10-0.23). Sex, physical growth and age are the dominant influences on adolescent brain development. We highlight the persistent negative influences of prenatal parental smoking and youth substance use as they are modifiable and of relevance for public health initiatives.

Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight.

There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean = 6.08 days; s.d. = 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p < 1 × 10-7. Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR. Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.

Infertility treatments during pregnancy and the risk of autism spectrum disorder in the offspring.

We aimed to examine the effects of infertility treatments on the risk of Autism Spectrum Disorder (ASD). Data were from a representative national registry on 110,093 male live births in Israel (born: 1999-2008; and ASD: 975, 0.9%). Infertility treatments included In Vitro Fertilization (IVF), and five hormone treatments. Relative risk (RR) was estimated with multivariable logistic models. Results showed that IVF treatment compared with spontaneous conception was not statistically significantly associated with the risk of ASD. Only progesterone hormone treatment was associated with a statistically significant (p < .05) increased risk of ASD (RR = 1.51, 95% CI 1.22, 1.86) compared to the group with no progesterone treatment. In conclusion, progesterone exposure during the critical period of fetal life elevated the risk of ASD, possibly reflecting epigenetic modification.

Elevated polygenic burden for autism is associated with differential DNA methylation at birth.

BACKGROUND: Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth. METHODS: We quantified neonatal methylomic variation in 1263 infants-of whom ~ 50% went on to subsequently develop ASD-using DNA isolated from archived blood spots taken shortly after birth. We used matched genotype data from the same individuals to examine the molecular consequences of ASD-associated genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings. RESULTS: We identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots. Although we did not identify specific loci showing robust differences in neonatal DNA methylation associated with later ASD, there was a significant association between increased polygenic burden for autism and methylomic variation at specific loci. Each unit of elevated ASD polygenic risk score was associated with a mean increase in DNA methylation of - 0.14% at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8. CONCLUSIONS: This study is the largest analysis of DNA methylation in ASD undertaken and the first to integrate genetic and epigenetic variation at birth. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants.

Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses.

BACKGROUND: According to recent evidence, up to 40-50% of variance in autism spectrum disorder (ASD) liability might be determined by environmental factors. In the present paper, we conducted a review of systematic reviews and meta-analyses of environmental risk factors for ASD. We assessed each review for quality of evidence and provided a brief overview of putative mechanisms of environmental risk factors for ASD. FINDINGS: Current evidence suggests that several environmental factors including vaccination, maternal smoking, thimerosal exposure, and most likely assisted reproductive technologies are unrelated to risk of ASD. On the contrary, advanced parental age is associated with higher risk of ASD. Birth complications that are associated with trauma or ischemia and hypoxia have also shown strong links to ASD, whereas other pregnancy-related factors such as maternal obesity, maternal diabetes, and caesarian section have shown a less strong (but significant) association with risk of ASD. The reviews on nutritional elements have been inconclusive about the detrimental effects of deficiency in folic acid and omega 3, but vitamin D seems to be deficient in patients with ASD. The studies on toxic elements have been largely limited by their design, but there is enough evidence for the association between some heavy metals (most important inorganic mercury and lead) and ASD that warrants further investigation. Mechanisms of the association between environmental factors and ASD are debated but might include non-causative association (including confounding), gene-related effect, oxidative stress, inflammation, hypoxia/ischemia, endocrine disruption, neurotransmitter alterations, and interference with signaling pathways. CONCLUSIONS: Compared to genetic studies of ASD, studies of environmental risk factors are in their infancy and have significant methodological limitations. Future studies of ASD risk factors would benefit from a developmental psychopathology approach, prospective design, precise exposure measurement, reliable timing of exposure in relation to critical developmental periods and should take into account the dynamic interplay between gene and environment by using genetically informed designs.

Prenatal Maternal Smoking and Increased Risk for Tourette Syndrome and Chronic Tic Disorders.

OBJECTIVE: We assessed the role of prenatal maternal smoking in risk for Tourette syndrome and chronic tic disorder (TS/CT) and pediatric-onset obsessive-compulsive disorder (OCD). METHOD: In an analysis of 73,073 singleton pregnancies from the Danish National Birth Cohort, we calculated incidence rates (IR) per 1,000 person-year for TS/CT and OCD. We then determined crude and adjusted hazard ratios and 95% CIs associated with prenatal maternal smoking, considering smoking as a dichotomous (yes/no) variable or a stratified variable (no smoking, light smoking, and heavy smoking [≥10 cigarettes/day]). Additional analyses examined the effect of maternal smoking on risk for TS/CT with other comorbid psychiatric conditions. RESULTS: In final adjusted analyses, heavy smoking was associated with a 66% increased risk for TS/CT (adjusted hazard ratio = 1.66, 95% CI = 1.17-2.35). In addition, heavy smoking was associated with a 2-fold increased risk for TS/CT with comorbid attention-deficit/hyperactivity disorder (ADHD), and both light and heavy smoking were associated with a more than 2-fold increased risk for TS/CT with any non-ADHD psychiatric comorbidity. Our parallel analyses of pediatric-onset OCD were likely underpowered but showed similar relationships. CONCLUSION: Prenatal maternal smoking was associated with increased risk for TS/CT as well as TS/CT with comorbid psychiatric conditions, even after adjustment for several important variables, including maternal psychiatric history, socioeconomic status, and partner smoking. Our findings point to a pathway linking prenatal tobacco exposure and altered brain development to TS/CT.

Impaired Gas Exchange at Birth and Risk of Intellectual Disability and Autism: A Meta-analysis.

We conducted meta-analyses of 67 studies on the association between neonatal proxies of impaired gas exchange and intellectual disability (ID) or autism spectrum disorders (ASD). Neonatal acidosis was associated with an odds ratio (OR) of 3.55 [95 % confidence interval (95 % CI) 2.23-5.49] for ID and an OR of 1.10 (95 % CI 0.91-1.31) for ASD. Children with a 5-min Apgar score of <7 had an OR of 5.39 (95 % CI 3.84-7.55) for ID and an OR of 1.67 (95 % CI 1.34-2.09) for ASD. O2 treatment was associated with an OR of 4.32 (95 % CI 3.23-5.78) for ID and an OR of 2.02 (95 % CI 1.45 to 2.83) for ASD. Our meta-analysis demonstrates an increased risk of ID and (to a lesser extent) ASD in children with neonatal hypoxia. Moreover, our findings raise the possibility that concomitant ID might account for the observed association between the gas exchange proxies and ASD.

Study of resilience and environmental adversity in midlife health (STREAM).

PURPOSE: The Jerusalem study of resilience and environmental adversity in midlife health (STREAM) was established to examine the prevalence of common mental and physical health issues in mid-adulthood in the inner city of Jerusalem, and to examine their association with lifespan psychosocial factors of vulnerability and resilience. METHOD: Participants were 811 randomly selected individuals from 7000 individuals who were born and grew up in inner-Jerusalem. Participants were 34-44 years old during first wave of STREAM assessment. Initial telephone surveys took place in 2007-2008 and participants were followed-up for a second survey 1 year later. Upon funding, a new wave is planned for 2017-2018. Survey topics comprised common health problems (e.g., type 2 diabetes/migraine), health markers (e.g., BMI), and psychiatric vulnerabilities (e.g., anxiety, post-traumatic stress, depressive symptoms, psychosis). Other measures included socioeconomic status, creativity, life style behavior (e.g., smoking, exercise), social contact and adaptation to change. Survey data were retrospectively merged with data of national registry sources that included adverse psychosocial factors, psychiatric and social measures assessed across all developmental stages through midlife. This includes data available on birth factors, school achievement and adjustment, cognitive and behavioral functioning during young adulthood, psychiatric hospitalizations, immigration and socioeconomic status. RESULTS: Results on health outcomes of the first STREAM wave indicate that prevalence rates of health problems are comparable to recent World Mental Health Surveys. CONCLUSIONS: Apart from measures on adverse psychosocial factors, STREAM provides a cohort to examine resilience to developing health problems and having a poor health and functional outcome.

Adversity, cannabis use and psychotic experiences: evidence of cumulative and synergistic effects.

BACKGROUND: There is robust evidence that childhood adversity is associated with an increased risk of psychosis. There is, however, little research on intervening factors that might increase or decrease risk following childhood adversity. AIMS: To investigate main effects of, and synergy between, childhood abuse and life events and cannabis use on odds of psychotic experiences. METHOD: Data on psychotic experiences and childhood abuse, life events and cannabis use were collected from 1680 individuals as part of the South East London Community Health Study (SELCoH), a population-based household survey. RESULTS: There was strong evidence that childhood abuse and number of life events combined synergistically to increase odds of psychotic experiences beyond the effects of each individually. There was similar, but weaker, evidence for cannabis use (past year). CONCLUSIONS: Our findings are consistent with the hypothesis that childhood abuse creates an enduring vulnerability to psychosis that is realised in the event of exposure to further stressors and risk factors.

A nationwide study of the association between celiac disease and the risk of autistic spectrum disorders.

IMPORTANCE: Most case reports suggest an association between autistic spectrum disorders (ASDs) and celiac disease (CD) or positive CD serologic test results, but larger studies are contradictory. OBJECTIVE: To examine the association between ASDs and CD according to small intestinal histopathologic findings. DESIGN AND SETTING: Nationwide case-control study in Sweden. MAIN OUTCOMES AND MEASURES: Through 28 Swedish biopsy registers, we collected data about 26,995 individuals with CD (equal to villous atrophy, Marsh stage 3), 12,304 individuals with inflammation (Marsh stages 1-2), and 3719 individuals with normal mucosa (Marsh stage 0) but positive CD serologic test results (IgA/IgG gliadin, endomysium, or tissue transglutaminase) and compared them with 213,208 age- and sex-matched controls. Conditional logistic regression estimated odds ratios (ORs) for having a prior diagnosis of an ASD according to the Swedish National Patient Register. In another analysis, we used the Cox proportional hazards regression model to estimate hazard ratios (HRs) for future ASDs in individuals undergoing small intestinal biopsy. RESULTS: A prior ASD was not associated with CD (OR, 0.93; 95% CI, 0.51-1.68) or inflammation (OR 1.03; 95% CI, 0.40-2.64) but was associated with a markedly increased risk of having a normal mucosa but a positive CD serologic test result (OR, 4.57; 95% CI, 1.58-13.22). Restricting our data to individuals without a diagnosis of an ASD at the time of biopsy, CD (HR, 1.39; 95% CI, 1.13-1.71) and inflammation (HR, 2.01; 95% CI, 1.29-3.13) were both associated with moderate excess risks of later ASDs, whereas the HR for later ASDs in individuals with normal mucosa but positive CD serologic test results was 3.09 (95% CI, 1.99-4.80). CONCLUSIONS AND RELEVANCE: Although this study found no association between CD or inflammation and earlier ASDs, there was a markedly increased risk of ASDs in individuals with normal mucosa but a positive CD serologic test result.

The relationship between risk of hospitalization for schizophrenia, SES, and cognitive functioning.

Although most studies find low socioeconomic status (SES) to be associated with prevalence of schizophrenia, incidence studies do not generally support this, and some even report an inverse association. The objective of the current historical prospective study was to examine the relationship between SES, cognitive functioning, and risk of hospitalization for schizophrenia in a population-based sample of Israeli adolescents. Subjects were 811 487 adolescents, assessed by the Israeli military draft board for socio-demographic factors and cognitive functioning. Data on later hospitalization for schizophrenia were obtained from a population-based hospitalization registry. Findings indicated that when simply examining SES and schizophrenia, lower SES was associated with greater risk of hospitalization for schizophrenia (Hazard Ratio [HR] = 1.193, 95% CI = 1.091-1.303). When dividing the cohort into low, average, and high cognitive functioning, SES did not influence the risk for schizophrenia among individuals with high and average cognitive functioning, whereas among individuals with low cognitive functioning, high SES was found to slightly increase the risk for schizophrenia (HR = 1.21, 95% CI = 1.03-1.42). One possible explanation for this finding might be that among individuals from low socioeconomic backgrounds, low IQ may reflect decreased opportunities related to SES, whereas among individuals from high SES backgrounds, low IQ might reflect risk for later psychopathology.

Psychiatric neuroimaging: joining forces with epidemiology.

Severe mental illnesses such as schizophrenia and mood disorders have a major impact on public health. Disease prevalence and phenotypic expression are the products of environment and gene interactions. However, our incomplete understanding of their aetiology and pathophysiology thwarts primary prevention and early diagnosis and limits the effective application of currently available treatments as well as the development of novel therapeutic approaches. Neuroimaging can provide detailed in vivo information about the biological mechanisms underpinning the relationship between genetic variation and clinical phenotypes or response to treatment. However, the biological complexity of severe mental illness results from unknown or unpredictable interactions between multiple genetic and environmental factors, many of which have only been partially identified. We propose that the use of epidemiological principles to neuroimaging research is a necessary next step in psychiatric research. Because of the complexity of mental disorders and the multiple risk factors involved only the use of large epidemiologically defined samples will allow us to study the broader spectrum of psychopathology, including sub-threshold presentation and explore pathophysiological processes and the functional impact of genetic and non-genetic factors on the onset and persistence of psychopathology.

Cytokines and cholinergic signals co-modulate surgical stress-induced changes in mood and memory.

Inflammatory cytokines and the cholinergic system have been implicated in the effects of stressors on mood and memory; however, the underlying mechanisms involved and the potential interrelationships between these pathways remain unclear. To address these questions, we administered neuropsychological tests to 33 generally healthy surgery patients who donated blood samples several days prior to undergoing moderate surgery (baseline), on the morning of the surgery (i.e., a psychological stressor), and one day after surgery. Eighteen control subjects were similarly tested. Serum levels of inflammatory cytokines, acetylcholinesterase (AChE) activity, and the stressor-inducible AChE-R variant were measured. An elevation in anxiety levels, an increase in depressed mood, and a decline in declarative memory were observed on the morning of the surgery, prior to any medical intervention, and were exacerbated one day after surgery. The surgical stressor-induced elevated IL-1 beta levels, which contributed to the increased depressed mood and to the post-surgery increase in AChE-R expression. The latter increase, which was also predicted by pre-surgery AChE-R and post-surgery mood disturbances, was associated with exacerbated memory impairments induced by surgery. In addition, elevated levels of AChE-R on the morning of the surgery predicted the post-surgery elevation in IL-6 levels, which was associated with amelioration of the memory impairments induced by surgery. Taken together, these findings suggest that exposure to a surgical stressor induces a reciprocal up-regulation of AChE-R and pro-inflammatory cytokines, which are involved in regulating the surgery-induced mood and memory disturbances.

Subtle cognitive dysfunction in nonaffected siblings of individuals affected by nonpsychotic disorders.

BACKGROUND: Previous studies have reported that as a group, individuals affected by psychotic and nonpsychotic disorders perform below norms on cognitive tests. Other studies have indicated that unaffected siblings of individuals affected by psychotic disorders also perform below norms on the same tests. We investigated cognitive performance on a large, population-based sample of individuals, affected at the time of testing by nonpsychotic disorders, and their unaffected siblings. METHODS: Subjects were taken from a population-based cohort of 523,375, 16- to 17-year-old male adolescents who had been assessed by the Israeli Draft Board. Cognitive test scores were examined in sib-pairs discordant for nonpsychotic (n = 19,489) and psychotic (n = 888) disorders and compared with 224,082 individuals from sibships with no evidence of mental illness. RESULTS: There appears to be a gradient in cognitive performance (worst to best) from individuals currently affected by psychotic illnesses (Cohen's d = -.82), followed by individuals currently affected by nonpsychotic illness (Cohen's d = -.58), unaffected siblings of individuals affected by psychotic illness (Cohen's d = -.37), unaffected siblings of individuals affected by nonpsychotic illness (Cohen's d = -.27), and members of sibships with no evidence of mental illness. Unaffected siblings of both psychotic and nonpsychotic individuals from multiple affected sibships (more then one affected sibling) had worse cognitive test scores compared with unaffected siblings from simplex sibships (only one affected sibling). CONCLUSIONS: The results support, but do not prove, the notion that cognitive impairment in psychiatric disorders is familial and cuts across diagnostic entities.

Impaired reading comprehension and mathematical abilities in male adolescents with average or above general intellectual abilities are associated with comorbid and future psychopathology.

Research indicates that persons with learning disorders often suffer from psychopathology. We assessed current and future psychopathology in male adolescents with discrete impairments in reading comprehension (IRC) or arithmetic abilities (IAA) but with average or above-average general intellectual abilities. Subjects were a population-based cohort of 174,994 male adolescents screened by the Israeli Draft Board with average or above-average intellectual abilities but with low scores (8.6th and 10th lowest percentile respectively) on reading or arithmetic tests. They were compared with adolescents who scored in the 10th percentile and above on these tests (comparison group). Relative to the comparison group, male adolescents with IRC, IAA, or IRC and IAA (0.69%), had poorer scores on most behavioral assessments and higher prevalence of current psychopathology: 4.2% (comparison group), 8.0% (IRC), 7.0% (IAA), and 9.8% (IRC and IAA). Adolescents with IRC were also at increased risk for later hospitalization for schizophrenia (hazard ratios = 1.8, 95% confidence interval: 1.3-2.6). Male adolescents with average and above-average general intellectual abilities but with IRC or IAA are more likely to have current and future psychopathology. Impairments in intellectual functioning and abnormal behaviors leading to mental illnesses may share common neurobiological substrates. The results support screening male adolescents with learning disorders for psychopathology.