Genetic contribution to disease-course severity and progression in the SUPER-Finland study, a cohort of 10,403 individuals with psychotic disorders.

Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic shifts in the SUPER-Finland study, encompassing 10 403 genotyped individuals with a psychotic disorder. To longitudinally track the study participants' past disease-course severity, we created a psychiatric hospitalization burden metric using the full-coverage and nation-wide Finnish in-hospital registry (data from 1969 and onwards). Using a hierarchical model, ranking the psychotic diagnoses according to clinical severity, we show that high schizophrenia PGS (SZ-PGS) was associated with progression from lower ranked psychotic disorders to schizophrenia (OR = 1.32 [1.23-1.43], p = 1.26e-12). This development manifested already at psychotic illness onset as a higher psychiatric hospitalization burden, the proxy for disease-course severity. In schizophrenia (n = 5 479), both a high SZ-PGS and a low educational attainment PGS (EA-PGS) were associated with increased psychiatric hospitalization burden (p = 1.00e-04 and p = 4.53e-10). The SZ-PGS and the EA-PGS associated with distinct patterns of hospital usage. In individuals with high SZ-PGS, the increased hospitalization burden was composed of longer individual hospital stays, while low EA-PGS associated with shorter but more frequent hospital visits. The negative effect of a low EA-PGS was found to be partly mediated via substance use disorder, a major risk factor for hospitalizations. In conclusion, we show that high SZ-PGS and low EA-PGS both impacted psychotic disease-course development negatively but resulted in different disease-course trajectories.

Visual memory and alcohol use in a middle-aged birth cohort.

Light and moderate alcohol use has been reported to be associated with both impaired and enhanced cognition. The purpose of this study was to explore whether there was a linear relationship between visual memory and alcohol consumption in males and females in a large middle-aged birth cohort population in cross-sectional and longitudinal settings. Data were collected from 5585 participants completing 31-year (1997-1998) and 46-year (2012-2014) follow-ups including Paired Associate Learning (PAL) test at 46-years follow-up. The participants were originally from 12,231 study population of the Northern Finland Birth Cohort 1966 (NFBC1966). The PAL test was conducted to assess visual memory. Reported alcohol use was measured as total daily use of alcohol, beer, wine, and spirits converted into grams and as frequency and amount of use of beer, wine, and spirits. The total daily alcohol use was not associated with reduced visual memory. The frequency of use of beer and wine in males was associated with better visual memory in cross-sectional and longitudinal settings. Using six or more servings of spirits was associated with worse visual memory in males in cross-sectional and longitudinal settings. Using six or more servings of spirits was associated with worse visual memory in males in cross-sectional and longitudinal setting. The study suggested a lack of a linear association between drinking and visual memory in the middle-aged population.

Parental suicide attempts and offspring's risk of attempting or dying by suicide: does the timing of a parental suicide attempt matter?

BACKGROUND: Studies on the transmission of suicide risk have focused on parental history of suicide attempts (SAs), overlooking when the attempt happened. This study examined how the offspring's risk of attempting or dying by suicide varied by the timing of a first parental SA and the sex of the parent who attempted suicide. METHODS: Participants were 59 469 members of the 1987 Finnish Birth Cohort. The Finnish Hospital Discharge and Cause of Death Registers were the sources for parental and offspring SAs and offspring suicide. Timing of parental SA was coded as before (pre-pregnancy and pregnancy) and after the child's birth [infant/toddler years (0-2 years), childhood (3-11 years), adolescence (12-17 years), and young adulthood (18-26 years)]. RESULTS: In the multivariate models, having a parent who attempted suicide increased the offspring's risk of attempting suicide (odds ratio (OR) = 1.77, 95% confidence interval (CI) 1.39-2.25), but not of dying by suicide. Compared to unexposed offspring, those exposed after child's birth were at higher risk of attempting suicide (OR = 1.90, 95% CI 1.46-2.47), specifically when the parent attempted during offspring's childhood, adolescence, and young adulthood. A first maternal SA increased offspring's risk of attempting suicide regardless of the timing. CONCLUSIONS: The impact of a parental SA on offspring's risk of attempting suicide differed depending on the timing and sex of the parent who attempted suicide, suggesting that the transmission of suicide risk may occur through genetic as well as environmental factors. Our findings call for an intergenerational approach in suicide risk assessment.

Body mass index in the middle-aged offspring of parents with severe mental illness.

BACKGROUND: People with severe mental illness (SMI) have an elevated risk of obesity but the causes and mechanisms are unclear. We explored the familial association between parental SMI and body mass index (BMI) in middle-aged offspring. Our objective was to determine if the offspring of either parent with SMI have an increased risk for obesity. METHODS: The Northern Finland Birth Cohort 1966 is a cohort study of offspring with expected date of birth in 1966. The data include originally 12 068 mothers and 12 231 children from the provinces of Lapland and Oulu in Finland. The final study sample included 5050 middle-aged offspring. Parental SMI was used as exposure in the study. BMI measured at the age of 46 years was used as a primary outcome. RESULTS: Risk for obesity was elevated in the offspring of mothers with SMI [overweight: adjusted odds ratio (OR) 1.93 (1.29-2.90), obese class I: 1.97 (1.20-3.25), obese classes II-III: 2.98 (1.67-5.33)]. For the offspring of either parent with SMI, statistically significant results were found in obese class I and obese classes II-III [overweight: adjusted OR 1.21 (0.94-1.54), obese class I: 1.52 (1.03-1.08), obese classes II-III: 1.53 (1.01-2.32)]. CONCLUSIONS: We found an elevated risk of obesity in the middle-aged offspring of either parent with SMI, especially in the offspring of mothers with SMI. Thus, there might be a common familial pathway leading to the co-occurrence of obesity and SMI.

Parental suicide attempts and offspring mental health problems in childhood and adolescence.

BACKGROUND: The relationship between parental suicide attempts and offspring suicide risk has been established. However, the impact of parental suicide attempts on mental health problems in offspring as youth remains unexplored. This study examined the prospective association between parental suicide attempts and offspring internalizing, externalizing, and attention/hyperactivity problems in childhood and adolescence. We also examined how offspring mental health problems in childhood mediated the association between parental suicide attempts and offspring mental health problems in adolescence. METHODS: A subsample of 6,381 (48.4% female) cohort members with complete data on mental health problems in childhood and adolescence was extracted from the Northern Finland Birth Cohort 1986 Study. Offspring mental health problems were assessed via teacher's Rutter B2 scale during the childhood assessment (child's age of 8) and the Youth Self-Report scale (child's age of 15/16). Information about first parental suicide attempts was collected using ICD codes from hospital discharge records. RESULTS: Lifetime parental suicide attempts during the study period (N = 95) were associated with offspring internalizing, externalizing, and attention/hyperactivity problems in adolescence. Parental suicide attempts before the childhood assessment (N = 55) were associated with offspring behavioral problems in childhood [B (95% CI) = .64 (0.08-1.28)]. In the mediation models, parental suicide attempts before the childhood assessment had a significant indirect effect on offspring externalizing [B (95% CI) = .03 (0.01-0.05)] and attention/hyperactivity problems [B (95% CI) = .02 (0.01-0.04)] in adolescence via offspring behavioral problems in childhood. CONCLUSIONS: Our findings highlight the importance of assessing and monitoring mental health problems in offspring whose parents have been hospitalized for attempting suicide. Among children with behavioral problems, clinicians should inquire about parental history of suicide attempts, as children with familial vulnerability to suicide may develop externalizing and attention/hyperactivity problems in adolescence.

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder.

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.

Cardiometabolic Disorders in the Offspring of Parents With Severe Mental Illness.

OBJECTIVE: The elevated prevalence of cardiometabolic disorders is consistently reported in patients with severe mental illness (SMI). We explored the association between parental SMI and offspring cardiometabolic morbidity. Our hypothesis was that offspring of people with SMI have increased morbidity risk. METHOD: The Northern Finland Birth Cohort 1966 is a study of offspring whose date of birth was expected in 1966. The follow-up lasted until 2015 (49 years). The final study sample included 11,175 children. We used parental SMI as the exposure in the study. The following cardiometabolic disorders were used as outcome measures: diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease, obesity, and cerebrovascular disorders. RESULTS: There were 139 (14.7%; hazard ratios [HR] = 1.63; 95% confidence interval [CI] = 1.36-1.94) children of parents with SMI who developed cardiometabolic disorder during follow-up and 957 (9.4%) in the comparison cohort. Statistically significant HRs were found in males (HR = 1.95; 95% CI =1.56-2.44), but not in females (HR = 1.29; 95% CI = 0.96-1.73). CONCLUSIONS: Having a cardiometabolic disorder was associated with male offspring of parents with SMI. Our findings suggest that there is an elevated risk of coronary artery disease, hyperlipidemia, obesity, and hypertension in the male offspring of parents with SMI. Our results suggest that the somatic health of offspring of parents with SMI should also be considered in addition to their mental health in clinical practice.

Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants.

Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66-0.89]) and lower household income (OR = 0.77 [0.66-0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38-0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32-0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26-0.37]), lower-income (OR = 0.66 [0.57-0.77]), lower subjective health (OR = 0.72 [0.61-0.83]), and increased mortality (Cox's HR = 1.55 [1.21-1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.

Cumulative incidences of hospital-treated psychiatric disorders are increasing in five Finnish birth cohorts.

OBJECTIVE: The aim of this study was to explore changes in the incidences of childhood and early adulthood hospital-treated psychiatric disorders in five large Finnish birth cohorts of individuals born between 1966 and 1997. METHODS: The five birth cohorts were as follows: Northern Finland Birth Cohort 1966 (NFBC 1966) and 1986 (NFBC 1986), 1987 Finnish Birth Cohort (FBC 1987) and 1997 (FBC 1997), and Finnish 1981 Birth Cohort Study (FBCS 1981). Incidences of hospital-treated psychiatric disorders in each cohort were calculated separately for males (N = 71,209) and females (N = 65,190). Poisson regression was used to test difference in proportions of psychiatric disorders in wide range of diagnosis classes separately in childhood and adolescence, and early adulthood. RESULTS: The total incidences of psychiatric disorders in childhood and adolescence among males has increased in the birth cohorts over decades (Incidence Rate Ratio, IRR = 1.04 (1.04-1.05); p < 0.001). Similar result was seen among females (IRR = 1.04 (1.03-1.04); p < 0.001). In early adulthood, there was significant increase among females (IRR = 1.04 (1.03-1.05); p < 0.001), but among males, the change was not significant (IRR = 0.99 (0.99-1.00), p = 0.051). CONCLUSIONS: The main finding was that the cumulative incidence of hospital-treated psychiatric disorders increased over the decades in Finland. The increasing trend in hospital-treated psychiatric disorders in early adulthood was detected in females but not in males. In the youngest cohorts, the cumulative incidence of hospital-treated psychiatric disorders was at the same level in males and females, whereas in oldest cohort, males had higher incidence than females.

Inflammation, hippocampal volume, and cognition in schizophrenia: results from the Northern Finland Birth Cohort 1966.

Increased blood interleukin-6 (IL-6) levels are a replicated abnormality in schizophrenia, and may be associated with smaller hippocampal volumes and greater cognitive impairment. These findings have not been investigated in a population-based birth cohort. The general population Northern Finland Birth Cohort 1966 was followed until age 43. Subjects with schizophrenia were identified through the national Finnish Care Register. Blood IL-6 levels were measured in n = 82 subjects with schizophrenia and n = 5373 controls at age 31. Additionally, 31 patients with schizophrenia and 63 healthy controls underwent brain structural MRI at age 34, and cognitive testing at ages 34 and 43. Patients with schizophrenia had significantly higher median (interquartile range) blood IL-6 levels than controls (5.31, 0.85-17.20, versus 2.42, 0.54-9.36, p = 0.02) after controlling for potential confounding factors. In both schizophrenia and controls, higher blood IL-6 levels were predictors of smaller hippocampal volumes, but not cognitive performance at age 34. We found evidence for increased IL-6 levels in patients with midlife schizophrenia from a population-based birth cohort, and replicated associations between IL-6 levels and hippocampal volumes. Our results complement and extend the previous findings, providing additional evidence that IL-6 may play a role in the pathophysiology of schizophrenia and associated brain alterations.

Antisocial and borderline personality disorders in the offspring of antenatally depressed mothers - a follow-up until mid-adulthood in the Northern Finland 1966 birth cohort.

Background: Maternal depression is common during pregnancy, affecting 10-15% of mothers. In previous reports, the offspring of antenatally depressed mothers have had an elevated risk for antisocial, criminal and violent behaviour in adolescence, and for borderline personality features in childhood, but long-term outcomes are unknown.Aims: To study whether the adult offspring of antenatally depressed mothers have an elevated risk for antisocial (ASPD) or borderline personality disorder (BPD) when followed until mid-adulthood.Methods: In the general population-based Northern Finland 1966 Birth Cohort, mothers of 12,058 children were asked during mid-gestation if they felt depressed. Of the mothers, 14% reported being depressed. The offspring were followed for 49 years. The diagnoses of in- and outpatient-treated ASPD and BPD in the offspring were detected using the Finnish Care Register for Healthcare. Maternal antenatal smoking, newborn´s low birthweight or short gestational age, father's social class, and family type at birth were considered as confounding variables. Logistic regression analyses on the potential confounders were performed. Maternal postnatal depression and paternal ASPD information was not available.Results: In the male offspring of antenatally depressed mothers, the risk for ASPD was elevated (adjusted odds ratio 5.6; 95% confidence interval 1.8-17.8), but not in female offspring. The risk for BPD was not elevated in the offspring of antenatally depressed mothers in this study.Conclusions: The sons of antenatally depressed mothers had an increased risk for ASPD. Prevention and treatment of antenatal depression might present an opportunity to decrease the risk of antisocial personality in the offspring.

Maternal prepregnancy body mass index and offspring white matter microstructure: results from three birth cohorts.

BACKGROUND AND AIMS: Prepregnancy maternal obesity is a global health problem and has been associated with offspring metabolic and mental ill-health. However, there is a knowledge gap in understanding potential neurobiological factors related to these associations. This study explored the relation between maternal prepregnancy body mass index (BMI) and offspring brain white matter microstructure at the age of 6, 10, and 26 years in three independent cohorts. SUBJECTS AND METHODS: The study used data from three European birth cohorts (n = 116 children aged 6 years, n = 2466 children aged 10 years, and n = 437 young adults aged 26 years). Information on maternal prepregnancy BMI was obtained before or during pregnancy and offspring brain white matter microstructure was measured at age 6, 10, or 26 years. We used magnetic resonance imaging-derived fractional anisotropy (FA) and mean diffusivity (MD) as measures of white matter microstructure in the brainstem, callosal, limbic, association, and projection tracts. Linear regressions were fitted to examine the association of maternal BMI and offspring white matter microstructure, adjusting for several socioeconomic and lifestyle-related confounders, including education, smoking, and alcohol use. RESULTS: Maternal BMI was associated with higher FA and lower MD in multiple brain tracts, for example, association and projection fibers, in offspring aged 10 and 26 years, but not at 6 years. In each cohort maternal BMI was related to different white matter tract and thus no common associations across the cohorts were found. CONCLUSIONS: Maternal BMI was associated with higher FA and lower MD in multiple brain tracts in offspring aged 10 and 26 years, but not at 6 years of age. Future studies should examine whether our observations can be replicated and explore the potential causal nature of the findings.

Cognition, psychosis risk and metabolic measures in two adolescent birth cohorts.

BACKGROUND: Psychoses, especially schizophrenia, are often preceded by cognitive deficits and psychosis risk states. Altered metabolic profiles have been found in schizophrenia. However, the associations between metabolic profiles and poorer cognitive performance and psychosis risk in the population remain to be determined. METHODS: Detailed molecular profiles were measured for up to 8976 individuals from two general population-based prospective birth cohorts: the Northern Finland Birth Cohort 1986 (NFBC 1986) and the Avon Longitudinal Study of Parents and Children (ALSPAC). A high-throughput nuclear magnetic resonance spectroscopy platform was used to quantify 70 metabolic measures at age 15-16 years in the NFBC 1986 and at ages 15 and 17 years in ALSPAC. Psychosis risk was assessed using the PROD-screen questionnaire at age 15-16 years in the NFBC 1986 or the psychotic-like symptoms assessment at age 17 years in ALSPAC. Cognitive measures included academic performance at age 16 years in both cohorts and general intelligence and executive function in ALSPAC. Logistic regression measured cross-sectional and longitudinal associations between metabolic measures and psychosis risk and cognitive performance, controlling for important covariates. RESULTS: Seven metabolic measures, primarily fatty acid (FA) measures, showed cross-sectional associations with general cognitive performance, four across both cohorts (low density lipoprotein diameter, monounsaturated FA ratio, omega-3 ratio and docosahexaenoic acid ratio), even after controlling for important mental and physical health covariates. Psychosis risk showed minimal metabolic associations. CONCLUSIONS: FA ratios may be important in marking risk for cognitive deficits in adolescence. Further research is needed to clarify whether these biomarkers could be causal and thereby possible targets for intervention.

Rsu1 regulates ethanol consumption in Drosophila and humans.

Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons to modulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption, across phyla.

Early adversity and brain response to faces in young adulthood.

Early stressors play a key role in shaping interindividual differences in vulnerability to various psychopathologies, which according to the diathesis-stress model might relate to the elevated glucocorticoid secretion and impaired responsiveness to stress. Furthermore, previous studies have shown that individuals exposed to early adversity have deficits in emotion processing from faces. This study aims to explore whether early adversities associate with brain response to faces and whether this association might associate with the regional variations in mRNA expression of the glucocorticoid receptor gene (NR3C1). A total of 104 individuals drawn from the Northern Finland Brith Cohort 1986 participated in a face-task functional magnetic resonance imaging (fMRI) study. A large independent dataset (IMAGEN, N = 1739) was utilized for reducing fMRI data-analytical space in the NFBC 1986 dataset. Early adversities were associated with deviant brain response to fearful faces (MANCOVA, P = 0.006) and with weaker performance in fearful facial expression recognition (P = 0.01). Glucocorticoid receptor gene expression (data from the Allen Human Brain Atlas) correlated with the degree of associations between early adversities and brain response to fearful faces (R2 = 0.25, P = 0.01) across different brain regions. Our results suggest that early adversities contribute to brain response to faces and that this association is mediated in part by the glucocorticoid system. Hum Brain Mapp 38:4470-4478, 2017. © 2017 Wiley Periodicals, Inc.

Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: A prospective birth cohort study.

OBJECTIVE: Meta-analyses of cross-sectional studies confirm an increase in circulating inflammatory markers during acute psychosis. Longitudinal studies are scarce but are needed to understand whether elevated inflammatory markers are a cause or consequence of illness. We report a longitudinal study of serum C-reactive protein (CRP) in adolescence and subsequent risk of schizophrenia and related psychoses in adulthood in the Northern Finland Birth Cohort 1986. METHOD: Serum high-sensitivity CRP was measured at age 15/16 years in 6362 participants. ICD-10 diagnoses of schizophrenia and related psychoses were obtained from centralised hospital inpatient and outpatient registers up to age 27 years. Logistic regression calculated odds ratios (ORs) for psychotic outcomes associated with baseline CRP levels analysed as both continuous and categorical variables using American Heart Association criteria. Age, sex, body mass index, maternal education, smoking, and alcohol use were included as potential confounders. RESULTS: By age 27years, 88 cases of non-affective psychosis (1.38%), of which 22 were schizophrenia (0.35%), were identified. Adolescent CRP was associated with subsequent schizophrenia. The adjusted OR for schizophrenia by age 27yearsfor each standard deviation (SD) increase in CRP levels at age 15/16yearswas 1.25 (95% CI, 1.07-1.46), which was consistent with a linear, dose-response relationship (P-value for quadratic term 0.23). Using CRP as a categorical variable, those with high (>3mg/L) compared with low (<1mg/L) CRP levels at baseline were more likely to develop schizophrenia; adjusted OR 4.25 (95% CI, 1.30-13.93). There was some indication that higher CRP was associated with earlier onset of schizophrenia (rs=-0.40; P=0.07). CONCLUSIONS: A longitudinal association between adolescent CRP levels and adult schizophrenia diagnosis indicates a potentially important role of inflammation in the pathogenesis of the illness, although the findings, based on a small number of cases, need to be interpreted with caution and require replication in other samples.

Long-term antipsychotic use and brain changes in schizophrenia - a systematic review and meta-analysis.

OBJECTIVE: The association between long-term antipsychotic treatment and changes in brain structure in schizophrenia is unclear. Our aim was to conduct a systematic review and a meta-analysis on long-term antipsychotic effects on brain structures in schizophrenia focusing on studies with at least 2 years of follow-up between MRI scans. DESIGN: Studies were systematically collected using 4 databases, and we also contacted authors for unpublished data. We calculated correlations between antipsychotic dose and/or type and brain volumetric changes and used random effect meta-analysis to study correlations by brain area. RESULTS: Thirty-one publications from 16 samples fulfilled our inclusion criteria. In meta-analysis, higher antipsychotic exposure associated statistically significantly with parietal lobe decrease (studies, n = 4; r = -.14, p = .013) and with basal ganglia increase (n = 4; r = .10, p = .044). Most of the reported correlations in the original studies were statistically nonsignificant. There were no clear differences between typical and atypical exposure and brain volume change. The studies were often small and highly heterogeneous in their methods and seldom focused on antipsychotic medication and brain changes as the main subject. CONCLUSIONS: Antipsychotic medication may associate with brain structure changes. More long-term follow-up studies taking into account illness severity measures are needed to make definitive conclusions.

Longitudinal Pathways from Cumulative Contextual Risk at Birth to School Functioning in Adolescence: Analysis of Mediation Effects and Gender Moderation.

Children and adolescents exposed to multiple contextual risks are more likely to have academic difficulties and externalizing behavior problems than those who experience fewer risks. This study used data from the Northern Finland Birth Cohort 1986 (a population-based study; N = 6961; 51 % female) to investigate (a) the impact of cumulative contextual risk at birth on adolescents' academic performance and misbehavior in school, (b) learning difficulties and/or externalizing behavior problems in childhood as intervening mechanisms in the association of cumulative contextual risk with functioning in adolescence, and (c) potential gender differences in the predictive associations of cumulative contextual risk at birth with functioning in childhood or adolescence. The results of the structural equation modeling analysis suggested that exposure to cumulative contextual risk at birth had negative associations with functioning 16 years later, and academic difficulties and externalizing behavior problems in childhood mediated some of the predictive relations. Gender, however, did not moderate any of the associations. Therefore, the findings of this study have implications for the prevention of learning and conduct problems in youth and future research on the impact of cumulative risk exposure.

Neuropeptide precursor VGF is genetically associated with social anhedonia and underrepresented in the brain of major mental illness: its downregulation by DISC1.

In a large Scottish pedigree, disruption of the gene coding for DISC1 clearly segregates with major depression, schizophrenia and related mental conditions. Thus, study of DISC1 may provide a clue to understand the biology of major mental illness. A neuropeptide precursor VGF has potent antidepressant effects and has been reportedly associated with bipolar disorder. Here we show that DISC1 knockdown leads to a reduction of VGF, in neurons. VGF is also downregulated in the cortices from sporadic cases with major mental disease. A positive correlation of VGF single-nucleotide polymorphisms (SNPs) with social anhedonia was also observed. We now propose that VGF participates in a common pathophysiology of major mental disease.

Smoking in pregnancy, adolescent mental health and cognitive performance in young adult offspring: results from a matched sample within a Finnish cohort.

BACKGROUND: The association between prenatal exposure to maternal cigarette smoking (PEMCS) and adult cognition is debated, including if there are differences according to sex. We aimed to determine if there are associations between PEMCS and cognition in early adulthood in men and women and examine if observed associations were mediated by adolescent mental health factors that are associated with cognition, namely psychotic-like experiences (PLEs), inattention and hyperactivity, and other externalizing behaviors. METHODS: Participants were 471 individuals drawn from the general population-based Northern Finland 1986 Birth Cohort (NFBC 1986) followed up from pregnancy and birth to early adulthood; individuals with PEMCS were matched with those without PEMCS by socioeconomic and demographic factors. Cognitive performance in adulthood was assessed with a range of tests and their association with PEMCS was measured by sex using hierarchical linear regression, unadjusted and then controlling for potential confounders, mediators and moderators, including adolescent mental health factors. RESULTS: There were no associations between PEMCS and cognitive scores in females. In males, there were associations with vocabulary (beta = -0.444, 95% CI: -0.783, -0.104) and matrix reasoning (beta = -0.379, 95% CI: -0.711, -0.047). CONCLUSIONS: While associations between PEMCS and cognition were limited, observed findings with measures of general intelligence in males contribute to suggestions of differences in response to PEMCS by sex. Furthermore, observed associations may be partly mediated by earlier inattention and hyperactivity. Findings add support to efforts aimed to eliminate smoking in pregnancy.