The Toronto Adolescent and Youth Cohort Study: Study Design and Early Data Related to Psychosis Spectrum Symptoms, Functioning, and Suicidality.

BACKGROUND: Psychosis spectrum symptoms (PSSs) occur in a sizable percentage of youth and are associated with poorer cognitive performance, poorer functioning, and suicidality (i.e., suicidal thoughts and behaviors). PSSs may occur more frequently in youths already experiencing another mental illness, but the antecedents are not well known. The Toronto Adolescent and Youth (TAY) Cohort Study aims to characterize developmental trajectories in youths with mental illness and understand associations with PSSs, functioning, and suicidality. METHODS: The TAY Cohort Study is a longitudinal cohort study that aims to assess 1500 youths (age 11-24 years) presenting to tertiary care. In this article, we describe the extensive diagnostic and clinical characterization of psychopathology, substance use, functioning, suicidality, and health service utilization in these youths, with follow-up every 6 months over 5 years, including early baseline data. RESULTS: A total of 417 participants were enrolled between May 4, 2021, and February 2, 2023. Participants met diagnostic criteria for an average of 3.5 psychiatric diagnoses, most frequently anxiety and depressive disorders. Forty-nine percent of participants met a pre-established threshold for PSSs and exhibited higher rates of functional impairment, internalizing and externalizing symptoms, and suicidality than participants without PSSs. CONCLUSIONS: Initial findings from the TAY Cohort Study demonstrate the feasibility of extensive clinical phenotyping in youths who are seeking help for mental health problems. PSS prevalence is much higher than in community-based studies. Our early data support the critical need to better understand longitudinal trajectories of clinical youth cohorts in relation to psychosis risk, functioning, and suicidality.

Accumbal µ-opioid receptors and salt taste-elicited hedonic responses in a rodent model of prenatal adversity, and their correlates using human functional genomics.

Prenatal adversity is associated with behavioral obesogenic features such as preference for palatable foods. Salt appetite may play a role in the development of adiposity and its consequences in individuals exposed to prenatal adversity, and sodium consumption involves individual differences in accumbal µ-opioid receptors function. We investigated the hedonic responses to salt and the levels of µ-opioid receptors and tyrosine hydroxylase in the nucleus accumbens (Nacc) of pups from an animal model of prenatal dietary restriction. In children, we evaluated the interaction between fetal growth and the genetic background associated with the accumbal µ-opioid receptor gene (OPRM1) expression on sodium consumption during a snack test. Sprague-Dawley dams were randomly allocated from pregnancy day 10 to receive an ad libitum (Adlib) or a 50% restricted (FR) diet. The pups' hedonic responses to a salt solution (NaCl 2%) or water were evaluated on the first day of life. FR and Adlib pups differ in their hedonic responses to salt, and there were decreased levels of accumbal µ-opioid and p-µ-opioid receptors in FR pups. In humans, a test meal and genotyping from buccal epithelial cells were performed in 270 children (38 intrauterine growth restricted-IUGR) at 4 years old from a Canadian prospective cohort (MAVAN). The OPRM1 genetic score predicted the sodium intake in IUGR children, but not in controls. The identification of mechanisms involved in the brain response to prenatal adversity and its consequences in behavioral phenotypes and risk for chronic diseases later in life is important for preventive and therapeutic purposes.

Maternal major depression during early pregnancy is associated with impaired child executive functioning at 4.5 years of age.

BACKGROUND: Maternal depression is a serious condition that affects up to 1 in 7 pregnancies. Despite evidence linking maternal depression to pregnancy complications and adverse fetal outcomes, there remain large gaps in its identification and treatment. More work is needed to define the specific timing and severity of depression that most urgently requires intervention, where feasible, to protect maternal health and the developing fetus. OBJECTIVE: This study aimed to examine whether the timing and severity of maternal depression and/or anxiety during pregnancy affect child executive functioning at age 4.5 years. Executive functioning in the preschool years is a strong predictor of both school readiness and long-term quality of life. STUDY DESIGN: This longitudinal observational pregnancy cohort study included a sample of 323 mother-child dyads taking part in the Ontario Birth Study, an open pregnancy cohort in Toronto, Ontario, Canada. Maternal symptoms of depression and anxiety were assessed at 12 to 16 and 28 to 32 weeks of gestation and at the time of child testing at age 4.5 years using the 4-item Patient Health Questionnaire. Child executive functioning was measured during a home visit using standardized computerized administration of the Flanker test (a measure of attention) and the Dimensional Change Card Sort (a measure of cognitive flexibility). Stepwise linear regressions, controlling for possible confounding variables, were used to assess the predictive value of continuous measures of maternal depression and/or anxiety symptoms at each assessment time on the Flanker test and Dimensional Change Card Sort. Posthoc general linear models were used to assess whether maternal depression severity categories (no symptom, mild symptoms, or probable major depressive disorder) were helpful in identifying children at risk. RESULTS: Across all children, after controlling for potential confounds, greater maternal depressive symptoms at weeks 12 to 16 weeks of gestation predicted worse performance on both the Flanker test (ΔR2=0.058; P<.001) and the Dimensional Change Card Sort (ΔR2=0.017; P=.018). Posthoc general linear modeling further demonstrated that the children of mothers meeting the screening criteria for major depression in early pregnancy scored 11.3% lower on the Flanker test and 9.8% lower on the Dimensional Change Card Sort than the children of mothers without maternal depressive symptoms in early pregnancy. Mild depressive symptoms had no significant effect on executive function scores. There was no significant effect of anxiety symptoms or maternal antidepressant use in early pregnancy or pandemic conditions or maternal symptoms in later pregnancy or at the time of child testing on either the Flanker or Dimensional Change Card Sort results. CONCLUSION: This study demonstrated that fetal exposure to maternal major depression, but not milder forms of depression, at 12 to 16 weeks of gestation is associated with impaired executive functioning in the preschool years. Child executive functioning is crucial for school readiness and predicts long-term quality of life. This emphasizes an urgent need to improve the recognition and treatment of maternal major depression, particularly in early pregnancy, to limit its negative effects on the patient and on child cognitive development.

Cognitive and Emotional Well-Being of Preschool Children Before and During the COVID-19 Pandemic.

Importance: The association between COVID-19 social disruption and young children's development is largely unknown. Objective: To examine associations of pandemic exposure with neurocognitive and socioemotional development at 24 and 54 months of age. Design, Setting, and Participants: This cross-sectional study evaluated associations between pandemic exposure vs nonexposure and developmental outcomes with covariate adjustment using data from the Ontario Birth Study collected between February 2018 and June 2022. Eligible participants were children aged 24 and 54 months. Data were analyzed from June to November 2022. Exposure: COVID-19 pandemic exposure defined as assessment after March 11, 2020. Main Outcome and Measures: Neurodevelopmental assessment using the ASQ-3 (Ages and Stages Questionnaire, Third Edition) and MCHAT-R (Modified Checklist for Autism in Toddlers, Revised) at 24 months of age, and neurocognitive and socioemotional assessment using the National Institutes of Health Toolbox at 54 months of age. Results: A total of 718 children at age 24 months (mean [SD] age, 25.6 [1.7] months; 342 female [47.6%]; 461 White [64.2%]) and 703 at age 54 months (mean [SD] age, 55.4 [2.6] months; 331 female [47.1%]; 487 White [69.3%]) were included. At 24 months of age, 460 participants (232 female [50.4%]) were assessed during the pandemic (March 17, 2020, to May 17, 2022) and 258 (110 female [42.6%]) were assessed prepandemic (April 17, 2018, to March 10, 2020). At 54 months of age, 286 participants (129 female [45.1%]) were assessed from March 14, 2020, to June 6, 2022, and 417 (202 female [48.4%]) were assessed from February 8, 2018, to March 10, 2020. At 24 months of age, pandemic-exposed children had reduced risk of problem-solving difficulties using cutoff scores (odds ratio [OR], 0.33; 95% CI, 0.18-0.62; P = .005) and higher problem-solving (B, 3.93; 95% CI, 2.48 to 5.38; P < .001) compared with nonexposed children. In contrast, pandemic-exposed children had greater risk for personal-social difficulties using cutoff scores (OR, 1.67; 95% CI, 1.09-2.56; P = .02) and continuous scores (B, -1.70; 95% CI, -3.21 to -0.20; P = .02) compared with nonexposed children. At 54 months of age, pandemic-exposed children had higher receptive vocabulary (B, 3.16; 95% CI, 0.13 to 6.19; P = .04), visual memory (B, 5.95; 95% CI, 1.11 to 10.79; P = .02), and overall cognitive performance (B, 3.89; 95% CI, 0.73 to 7.04; P = .02) compared with nonexposed children, with no differences in socioemotional development. Conclusions and Relevance: This cross-sectional study found both positive and negative associations between pandemic exposure and preschool children's cognitive and emotional well-being within a relatively socioeconomically advantaged sample.

Associations between rumination, depression, and distress tolerance during CBT treatment for depression in a tertiary care setting.

BACKGROUND: Rumination is strongly associated with depressive symptom severity and course. However, changes in rumination during outpatient cognitive behavioral therapy (CBT), and their links to baseline features such as distress tolerance and clinical outcomes, have received limited attention. METHODS: 278 outpatients with depression received group or individual CBT. Measures of rumination, distress tolerance, and depression symptom severity were assessed at baseline and periodically during treatment. Mixed effect and regression-based models evaluated changes over time, and associations between rumination, distress tolerance and depression severity. RESULTS: Depression and rumination decreased throughout acute treatment. Rumination reduction was concurrently associated with depressive symptom reduction. Lower levels of rumination at each time point prospectively predicted lower depressive symptoms at the next time point. Distress tolerance measured at baseline was positively associated with depression symptom severity; the indirect effect on post-treatment depression symptoms via rumination measured mid-treatment was nonsignificant when rumination at baseline was accounted for. Changes in and associations between depression and rumination were replicated in sensitivity analyses; although changes in depression and rumination were smaller in magnitude in patients receiving treatment during COVID-19. LIMITATIONS: Additional assessment points would permit a more nuanced assessment of the role rumination may play in mediating the associations between distress tolerance and depression severity. Additional investigation of treatments in community settings may also further our understanding of variability in rumination during depression treatment. CONCLUSIONS: The current study provides unique real-world support for variability in rumination as a key indicator of change over the course of CBT for depression.

Maternal prenatal depression is associated with dysregulation over the first five years of life moderated by child polygenic risk for comorbid psychiatric problems.

Dysregulation is a combination of emotion, behavior, and attention problems associated with lifelong psychiatric comorbidity. There is evidence for the stability of dysregulation from childhood to adulthood, which would be more fully characterized by determining the likely stability from infancy to childhood. Early origins of dysregulation can further be validated and contextualized in association with environmental and biological factors, such as prenatal stress and polygenic risk scores (PRS) for overlapping child psychiatric problems. We aimed to determine trajectories of dysregulation from 3 months to 5 years (N = 582) in association with maternal prenatal depression moderated by multiple child PRS (N = 232 pairs with available PRS data) in a prenatal cohort. Mothers reported depression symptoms at 24-26 weeks' gestation and child dysregulation at 3, 6, 18, 36, 48, and 60 months. The PRS were for major depressive disorder, attention deficit hyperactivity disorder, cross disorder, and childhood psychiatric problems. Covariates were biological sex, maternal education, and postnatal depression. Analyses included latent classes and regression. Two dysregulation trajectories emerged: persistently low dysregulation (94%), and increasingly high dysregulation (6%). Stable dysregulation emerged at 18 months. High dysregulation was associated with maternal prenatal depression, moderated by PRS for child comorbid psychiatric problems. Males were at greater risk of high dysregulation.

Omega-3 polygenic score protects against altered eating behavior in intrauterine growth-restricted children.

BACKGROUND: Alterations in eating behavior are common in infants with intrauterine growth restriction (IUGR); omega-3 polyunsaturated fatty acids (PUFA) could provide protection. We hypothesized that those born IUGR with a genetic background associated with increased production of omega-3-PUFA will have more adaptive eating behaviors during childhood. METHODS: IUGR/non-IUGR classified infants from MAVAN and GUSTO cohorts were included at the age of 4 and 5 years, respectively. Their parents reported child's eating behaviors using the child eating behavior questionnaire-CEBQ. Based on the GWAS on serum PUFA (Coltell 2020), three polygenic scores were calculated. RESULTS: Significant interactions between IUGR and polygenic score for omega-3-PUFA on emotional overeating (ß = -0.15, P = 0.049 GUSTO) and between IUGR and polygenic score for omega-6/omega-3-PUFA on desire to drink (ß = 0.35, P = 0.044 MAVAN), pro-intake/anti-intake ratio (ß = 0.10, P = 0.042 MAVAN), and emotional overeating (ß = 0.16, P = 0.043 GUSTO) were found. Only in IUGR, a higher polygenic score for omega-3-PUFA associated with lower emotional overeating, while a higher polygenic score for omega-6/omega-3-PUFA ratio was associated with a higher desire to drink, emotional overeating, and pro-intake/anti-intake. CONCLUSION: Only in IUGR, the genetic background for higher omega-3-PUFA is associated with protection against altered eating behavior, while the genetic score for a higher omega-6/omega-3-PUFA ratio is associated with altered eating behavior. IMPACT: A genetic background related to a higher polygenic score for omega-3 PUFA protected infants born IUGR against eating behavior alterations, while a higher polygenic score for omega-6/omega-3 PUFA ratio increased the risk of having eating behavior alterations only in infants born IUGR, irrespective of their adiposity in childhood. Genetic individual differences modify the effect of being born IUGR on eating outcomes, increasing the vulnerability/resilience to eating disorders in IUGR group and likely contributing to their risk for developing metabolic diseases later in life.

Maternal acetaminophen use and cognitive development at 4 years: the Ontario Birth Study.

BACKGROUND: Studies have suggested a link between prenatal maternal acetaminophen use and adverse developmental outcomes in children. However, there exists a knowledge gap regarding overall cognitive development and use of acetaminophen, especially concerning the timing of use in pregnancy. This study aimed to characterize the relationship between maternal acetaminophen use and cognitive development at 4 years. METHODS: This analysis included data collected throughout pregnancy and delivery from women in the Ontario Birth Study prospective cohort from 2013 to 2019 and from the NIH Toolbox Early Childhood Cognition battery administered to 4-year-old children between 2018 and 2021 (n = 436). The exposure was maternal acetaminophen use and the primary outcome was a cognition composite score. The relationship between exposure and outcome was determined using Poisson regression with a robust error variance. RESULTS: We did not observe any association between maternal acetaminophen intake any time before or during pregnancy and low cognition composite score of offspring. The IRR of suboptimal overall cognition was 1.38 (0.78-2.45), 1.22 (0.67-2.22), 0.80 (0.44-1.47), and 1.56 (0.74-3.29) for maternal use of acetaminophen before, in early, late, or overall pregnancy, respectively. CONCLUSION: Current data do not provide evidence to support a relationship of maternal acetaminophen use during pregnancy with adverse cognitive effects at 4 years. IMPACT: Acetaminophen use during pregnancy may influence the risk of child neurocognitive disorders, but there is conflicting evidence of its relationship to sub-clinical measures of cognitive development such as executive function. The study design allowed us to examine the role of timing of acetaminophen use in its relationship with cognitive development, based on a validated and standardized tablet-administered instrument for children, instead of a teacher or parent report. We did not observe a clear relationship between maternal acetaminophen use at different timepoints during pregnancy and child cognitive development.

Increasing maternal age predicts placental protein expression critical for fetal serotonin metabolism: Potential implications for neurodevelopmental research.

High fetal exposure to serotonin and increasing maternal age both contribute to the risk for neurodevelopmental disorders. While identifying covariates for a study of placental protein expression, we found a significant negative correlation between maternal age and the expression of monoamine oxidase A (MAOA), and a significant positive correlation between maternal age and the expression of the serotonin transporter SERT. MAOA and SERT play key roles in placental serotonin metabolism relevant to fetal neurodevelopment. These preliminary findings suggest that the effect of increasing maternal age on neurodevelopmental risk may be mediated in part by changes in placental protein expression relevant to fetal serotonin metabolism.

Leptin receptor co-expression gene network moderates the effect of early life adversity on eating behavior in children.

Leptin influences eating behavior. Exposure to early adversity is associated with eating behaviour disorders and metabolic syndrome, but the role of the leptin receptor on this relationship is poorly explored. We investigated whether individual differences in brain region specific leptin receptor (LepR) gene networks could moderate the effects of early adversity on eating behavior and metabolism. We created an expression-based polygenic risk score (ePRS) reflecting variations in the function of LepR gene network in prefrontal cortex and hypothalamus to investigate the interactions between a cumulative index of postnatal adversity on eating behavior in two independent birth cohorts (MAVAN and GUSTO). To explore whether variations in the prefrontal cortex or hypothalamic genetic scores could be associated with metabolic measurements, we also assessed the relationship between LepR-ePRS and fasting blood glucose and leptin levels in a third independent cohort (ALSPAC). We identified significant interaction effects between postnatal adversity and prefrontal-based LepR-ePRS on the Child Eating Behavior Questionnaire scores. In MAVAN, we observed a significant interaction effect on food enjoyment at 48 months (ß = 61.58, p = 0.015) and 72 months (ß = 97.78, p = 0.001); food responsiveness at 48 months (ß = 83.79, p = 0.009) satiety at 48 months (ß = -43.63, p = 0.047). Similar results were observed in the GUSTO cohort, with a significant interaction effect on food enjoyment (ß = 30.48, p = 0.006) food fussiness score (ß = -24.07, p = 0.02) and satiety score at 60 months (ß = -17.00, p = 0.037). No effects were found when focusing on the hypothalamus-based LepR-ePRS on eating behavior in MAVAN and GUSTO cohorts, and there was no effect of hypothalamus and prefrontal cortex based ePRSs on metabolic measures in ALSPAC. Our study indicated that exposure to postnatal adversity interacts with prefrontal cortex LepR-ePRS to moderate eating behavior, suggesting a neurobiological mechanism associated with the development of eating behavior problems in response to early adversity. The knowledge of these mechanisms may guide the understanding of eating patterns associated with risk for obesity in response to fluctuations in stress exposure early in life.

Thrifty-Eating Behavior Phenotype at the Food Court - Programming Goes Beyond Food Preferences.

Introduction: Prenatal growth impairment leads to higher preference for palatable foods in comparison to normal prenatal growth subjects, which can contribute to increased body fat mass and a higher risk for developing chronic diseases in small-for-gestational-age (SGA) individuals throughout life. This study aimed to investigate the effect of SGA on feeding behavior in children and adolescents, as well as resting-state connectivity between areas related to reward, self-control, and value determination, such as orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), amygdala and dorsal striatum (DS). Methods: Caregivers and their offspring were recruited from two independent cohorts in Brazil (PROTAIA) and Canada (MAVAN). Both cohorts included anthropometric measurements, food choice tasks, and resting-state functional magnetic resonance imaging (fMRI) data. Results: In the Brazilian sample (17 ± 0.28 years, n=70), 21.4% of adolescents were classified as SGA. They exhibited lower monetary-related expenditure to buy a snack compared to controls in the food choice test. Decreased functional connectivity (n=40) between left OFC and left DL-PFC; and between right OFC and: left amygdala, right DS, and left DS were observed in the Brazilian SGA participants. Canadian SGA participants (14.9%) had non-significant differences in comparison with controls in a food choice task at 4 years old ( ± 0.01, n=315). At a follow-up brain scan visit (10.21 ± 0.140 years, n=49), SGA participants (28.6%) exhibited higher connectivity between the left OFC and left DL-PFC, also higher connectivity between the left OFC and right DL-PFC. We did not observe significant anthropometric neither nutrients' intake differences between groups in both samples. Conclusions: Resting-state fMRI results showed that SGA individuals had altered connectivity between areas involved in encoding the subjective value for available goods and decision-making in both samples, which can pose them in disadvantage when facing food options daily. Over the years, the cumulative exposure to particular food cues together with the altered behavior towards food, such as food purchasing, as seen in the adolescent cohort, can play a role in the long-term risk for developing chronic non-communicable diseases.

Evaluating depression and anxiety throughout pregnancy and after birth: impact of the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic presents unique social, economic, and psychological challenges for individuals globally. Thus, women who are pregnant face unprecedented mental health challenges. OBJECTIVE: We sought to determine the impact of the pandemic on perinatal depression and anxiety in a longitudinal pregnancy cohort. We hypothesized increased depression and anxiety scores in women during pregnancy and after birth in the pandemic at all time points. STUDY DESIGN: Participants were enrolled in the Ontario Birth Study, a pregnancy cohort embedded in clinical care at Mount Sinai Hospital, Toronto, Canada. Perinatal depression and anxiety were assessed using the 2-Item Patient Health Questionnaire and 2-Item Generalized Anxiety Disorder Questionnaire in early pregnancy, whereas the Edinburgh Postnatal Depression Scale and 2-Item Generalized Anxiety Disorder Questionnaire were used in late pregnancy and after birth. Logistic regression models were created to examine the association of the pandemic with clinically elevated mental health scores in the prepandemic group vs pandemic group while adjusting for covariates. RESULTS: A total of 1159 survey responses from 649 participants between March 1, 2019, and February 28, 2021, were used to conduct this study. Participants were assessed in early pregnancy (n=416), in late pregnancy (n=373), and after birth (n=370). Responses received on or before February 29, 2020, were considered the "prepandemic" responses, whereas responses after the aforementioned date were considered the "pandemic" responses. Mean rank scores of depression and anxiety were significantly higher in the pandemic group (P=.02 and P=.003, respectively) in the postpartum period. There was no significant association between pandemic time and antenatal scores. However, postnatally, mothers were 2.6 times more likely to score ≥13 on the Edinburgh Postnatal Depression Scale during the pandemic than before the pandemic (95% confidence interval, 1.2-5.7; P=.02). Adjustment for ethnicity and income strengthened this association as the odds ratio increased to 3.3 (95% confidence interval, 1.4-8.0; P=.007). CONCLUSION: Pandemic-associated increases in depression and anxiety scores were confined to the postpartum period, highlighting a need for increased screening and interventions for perinatal mood and anxiety disorders postnatally as this pandemic continues.

Interactions between a polygenic risk score for plasma docosahexaenoic fatty acid concentration, eating behaviour, and body composition in children.

BACKGROUND: The relationship between eating behaviour and current body weight has been described. However little is known about the effect of polyunsaturated fatty acids (PUFA) in this relationship. Genetic contribution to a certain condition is derived from a combination of small effects from many genetic variants, and polygenic risk scores (PRS) summarize these effects. A PRS based on a GWAS for plasma docosahexaenoic fatty acid (DHA) has been created, based on SNPs from 9 genes. OBJECTIVE: To analyze the interaction between the PRS for plasma DHA concentration, body composition and eating behaviour (using the Children Eating Behaviour Questionnaire) in childhood. SUBJECTS/METHODS: We analyzed a subsample of children from the Maternal, Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort with PRS and measurements of eating behaviour performed at 4 years of age (n = 210), 6 y (n = 177), and body fat determined by bioelectric impedance at 4 y and 6 y or by air displacement plethysmography and dual-energy X-ray absorptiometry at 8 y (n = 42 and n = 37). PRS was based on the GWAS from Lemaitre et al. 2011 (p threshold = p < 5*10-6), and a median split created low and high PRS groups (high PRS = higher DHA level). RESULTS: In ALSPAC children, we observed an association between PRS and plasma DHA concentration (ß = 0.100, p < 0.01) and proportion (ß = 0.107, p < 0.01). In MAVAN, there were interactions between PRS and body fat on pro-intake scores in childhood, in which low PRS and higher body fat were linked to altered behaviour. There were also interactions between PRS and pro-intake scores early in childhood on body fat later in childhood, suggesting that the genetic profile and eating behaviour influence the development of adiposity at later ages. CONCLUSIONS: A lower PRS (lower plasma PUFA) can be a risk factor for developing higher body fat associated with non-adaptive eating behaviour in childhood; it is possible that the higher PRS (higher plasma PUFA) is a protective feature.

Low socioeconomic status, parental stress, depression, and the buffering role of network social capital in mothers.

BACKGROUND: Pathways underlying the stress-depression relationship in mothers, and the factors that buffer this relationship are not well understood. AIMS: Drawing from the Stress Process model, this study examines (1) if parental stress mediates the association between socioeconomic characteristics and depressive symptoms, and (2) if social support and network capital moderate these pathways. METHOD: Data came from 101 mothers from Montreal. Generalized structural equation models were conducted, with depressive symptoms (CES-D scores) as the outcome, socioeconomic stressors as independent variables, parental stress as the mediator, and social support and network social capital as moderators. RESULTS: Parental stress partially mediated the association between household income and depressive symptoms (indirect effect: ß = -0.09, Bootstrap SE = 0.03, 95% CI = -0.15 to -0.03 p = 0.00). Network diversity moderated the relationship between parental stress and depressive symptoms (ß = -0.25, 95% CI = -0.42 to -0.09, p = 0.00); at high levels of stress, mothers with high compared to low network diversity reported fewer symptoms. CONCLUSION: Findings highlight the role that socioeconomic factors play in influencing women's risk of depression and shaping the benefits that ensue from social resources. Addressing these factors requires interventions that target the social determinants of depression.

Functional outcomes with bright light in monotherapy and combined with fluoxetine in patients with major depressive disorder: Results from the LIFE-D trial.

BACKGROUND: Bright light therapy has been shown to improve depressive symptoms in patients with nonseasonal major depressive disorder (MDD) but there are few studies examining functional outcomes. METHODS: We examined secondary functional outcomes in the 8-week randomized, placebo-sham-controlled LIFE-D trial comparing light therapy, fluoxetine, and the combination in patients with nonseasonal MDD. Functional assessments included the Sheehan Disability Scale (SDS) and, for employed participants, the Lam Employment Absence and Productivity Scale (LEAPS). Analysis of covariance (ANCOVA) was conducted with SDS and LEAPS change scores from baseline to week 8 as dependent variables, treatment modality (light, fluoxetine) as an independent variable, and baseline SDS and LEAPS scores as covariates. RESULTS: Of 122 randomized participants, SDS data were available for 105 and LEAPS data for 70. For the SDS, there were no interaction effects, but there was a significant small- to medium-sized main effect of light treatment on total SDS scores with corresponding significant effects in the Social Life and Family Life domains, but not in the Work/Study domain. There were no significant interaction or main effects with LEAPS scores. CONCLUSION: Light therapy significantly improved social and family life functioning in patients with MDD. However, work functioning was not significantly improved despite large effect sizes; these results were limited by low statistical power because of small sample sizes. Future studies should use longer treatment durations and be powered to detect clinically relevant differences in functional outcomes.

Early Life Adversity and Polygenic Risk for High Fasting Insulin Are Associated With Childhood Impulsivity.

While the co-morbidity between metabolic and psychiatric behaviors is well-established, the mechanisms are poorly understood, and exposure to early life adversity (ELA) is a common developmental risk factor. ELA is associated with altered insulin sensitivity and poor behavioral inhibition throughout life, which seems to contribute to the development of metabolic and psychiatric disturbances in the long term. We hypothesize that a genetic background associated with higher fasting insulin interacts with ELA to influence the development of executive functions (e.g., impulsivity in young children). We calculated the polygenic risk scores (PRSs) from the genome-wide association study (GWAS) of fasting insulin at different thresholds and identified the subset of single nucleotide polymorphisms (SNPs) that best predicted peripheral insulin levels in children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort [N = 467; p t- initial = 0.24 (10,296 SNPs), p t- refined = 0.05 (57 SNPs)]. We then calculated the refined PRS (rPRS) for fasting insulin at this specific threshold in the children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort and investigated its interaction effect with adversity on an impulsivity task applied at 36 months. We found a significant effect of interaction between fasting insulin rPRS and adversity exposure predicting impulsivity measured by the Snack Delay Task at 36 months [ß = -0.329, p = 0.024], such that higher PRS [ß = -0.551, p = 0.009] was linked to more impulsivity in individuals exposed to more adversity. Enrichment analysis (MetaCoreTM) of the SNPs that compose the fasting insulin rPRS at this threshold was significant for certain nervous system development processes including dopamine D2 receptor signaling. Additional enrichment analysis (FUMA) of the genes mapped from the SNPs in the fasting insulin rPRS showed enrichment with the accelerated cognitive decline GWAS. Therefore, the genetic background associated with risk for adult higher fasting insulin moderates the impact of early adversity on childhood impulsivity.

Metabolic variables associated with response to cognitive behavioural therapy for depression in females: A Canadian biomarker integration network for depression (CAN-BIND) study.

INTRODUCTION: Cognitive behavioural therapy (CBT) is an established first-line treatment for depression; however, it remains unclear which factors predict a positive outcome with this approach. Prior work suggests that co-morbid obesity predicts a poorer response to antidepressant medication. The current study examined whether there is an association between weight parameters and improvement of depressive symptoms with CBT. METHODS: This was a secondary analysis of data from the "Clinical and Biological Markers of Response to Cognitive Behavioural Therapy for Depression - 6" (CANBIND-6; https://clinicaltrials.gov/ct2/show/NCT02883257) study. Adult participants (n = 41) with a diagnosis of Major Depressive Disorder (MDD) or Persistent Depressive Disorder (PDD) were recruited from an outpatient tertiary psychiatric centre in Canada. Participants completed 20 individual sessions of CBT over 16 weeks. The primary measure for treatment outcome was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 16. RESULTS: Thirty-seven participants completed assessments pre and post CBT. Baseline weight parameters were not correlated with treatment response to CBT in the entire group. There was a significant sex*waist circumference (WC) (B:-1.34; p = 0.004) and sex*body mass index (BMI) interaction (B:-2.03; p:0.009). In female participants, baseline waist circumference, but not BMI, significantly predicted week 16 MADRS after controlling for age and baseline MADRS (B:0.422 p:0.049). LIMITATIONS: The major limitation of our preliminary finding is the small sample size. CONCLUSION: Our preliminary findings suggest that higher waist circumference may be associated with a better treatment response to CBT for depression in females. This result could be of clinical relevance and warrants further investigation in larger and independent samples.

The Interplay Between Prenatal Adversity, Offspring Dopaminergic Genes, and Early Parenting on Toddler Attentional Function.

Background: Few studies have explored the complex gene-by-prenatal environment-by-early postnatal environment interactions that underlie the development of attentional competence. Here, we examined if variation in dopamine-related genes interacts with prenatal adversity to influence toddler attentional competence and whether this influence is buffered by early positive maternal behavior. Methods: From the Maternal Adversity, Vulnerability and Neurodevelopment cohort, 134 participants (197 when imputing missing data) had information on prenatal adversity (prenatal stressful life events, prenatal maternal depressive symptoms, and birth weight), five dopamine-related genes (DAT1, DRD4, DRD2, COMT, BDNF), observed maternal parenting behavior at 6 months and parent-rated toddler attentional competence at 18 and 24 months. The Latent Environmental and Genetic Interaction (LEGIT) approach was used to examine genes-by-prenatal environment-by-postnatal environment interactions while controlling for sociodemographic factors and postnatal depression. Results: Our hypothesis of a three-way interaction between prenatal adversity, dopamine-related genes, and early maternal parenting behavior was not confirmed. However, consistent two-way interactions emerged between prenatal adversity and dopamine-related genes; prenatal adversity and maternal parenting behavior, and dopamine-related genes and maternal parenting behavior in relation to toddler attentional competence. Significant interaction effects were driven by the DAT1, COMT, and BDNF genotypes; prenatal stressful life events; maternal sensitivity, tactile stimulation, vocalization, and infant-related activities. Conclusions: Multiple dopamine-related genes affected toddler attentional competence and they did so in interaction with prenatal adversity and the early rearing environment, separately. Effects were already visible in young children. Several aspects of early maternal parenting have been identified as potential targets for intervention.

Dopamine D4 receptor gene polymorphism (DRD4 VNTR) moderates real-world behavioural response to the food retail environment in children.

BACKGROUND: Evidence for the impact of the food retailing environment on food-related and obesity outcomes remains equivocal, but only a few studies have attempted to identify sub-populations for whom this relationship might be stronger than others. Genetic polymorphisms related to dopamine signalling have been associated with differences in responses to rewards such as food and may be candidate markers to identify such sub-populations. This study sought to investigate whether genetic variation of the dopamine D4 receptor gene (DRD4 exon III 48 bp VNTR polymorphism) moderated the association between local exposure to food retailers on BMI and diet in a sample of 4 to12-year-old children. METHODS: Data collected from a birth cohort and a community cross-sectional study conducted in Montreal, Canada, were combined to provide DRD4 VNTR polymorphism data in terms of presence of the 7-repeat allele (DRD4-7R) for 322 children aged between 4 and 12 (M (SD): 6.8(2.8) y). Outcomes were Body Mass Index (BMI) for age and energy density derived from a Food Frequency Questionnaire. Food environment was expressed as the proportion of local food retailers classified as healthful within 3 km of participants' residence. Linear regression models adjusted for age, sex, income, cohort, and geographic clustering were used to test gene*environment interactions. RESULTS: A significant gene*food environment interaction was found for energy density with results indicating that DRD4-7R carriers had more energy dense diets than non-carriers, with this effect being more pronounced in children living in areas with proportionally more unhealthy food retailers. No evidence of main or interactive effects of DRD4 VNTR and food environment was found for BMI. CONCLUSIONS: Results of the present study suggest that a genetic marker related to dopamine pathways can identify children with potentially greater responsiveness to unhealthy local food environment. Future studies should investigate additional elements of the food environment and test whether results hold across different populations.

Maternal Prenatal Mood, Pregnancy-Specific Worries, and Early Child Psychopathology: Findings From the DREAM BIG Consortium.

OBJECTIVE: Few studies have attempted to identify how distinct dimensions of maternal prenatal affective symptoms relate to offspring psychopathology. We defined latent dimensions of women's prenatal affective symptoms and pregnancy-specific worries to examine their association with early offspring psychopathology in three prenatal cohorts. METHOD: Data were used from three cohorts of the DREAM-BIG consortium: Avon Longitudinal Study of Parents and Children (ALSPAC [N = 12,515]), Generation R (N = 6,803), and the Canadian prenatal cohort Maternal Adversity, Vulnerability, and Neurodevelopment (MAVAN [N = 578]). Maternal prenatal affective symptoms and pregnancy-specific worries were assessed using different measures in each cohort. Through confirmatory factor analyses, we determined whether comparable latent dimensions of prenatal maternal affective symptoms existed across the cohorts. We used structural equation models to examine cohort-specific associations between these dimensions and offspring psychopathology at 4 to 8 years of age (general psychopathology, specific internalizing and externalizing previously derived using confirmatory factor analyses). Cohort-based estimates were meta-analyzed using inverse variance-weighing. RESULTS: Four prenatal maternal factors were similar in all cohorts: a general affective symptoms factor and three specific factors-an anxiety/depression factor, a somatic factor, and a pregnancy-specific worries factor. In meta-analyses, both the general affective symptoms factor and pregnancy-specific worries factor were independently associated with offspring general psychopathology. The general affective symptoms factor was further associated with offspring specific internalizing problems. There were no associations with specific externalizing problems. CONCLUSION: These replicated findings of independent and adverse effects for prenatal general affective symptoms and pregnancy-specific worries on child mental health support the need for specific interventions in pregnancy.