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.

Negative emotionality as a candidate mediating mechanism linking prenatal maternal mood problems and offspring internalizing behaviour.

Negative emotionality (NE) was evaluated as a candidate mechanism linking prenatal maternal affective symptoms and offspring internalizing problems during the preschool/early school age period. The participants were 335 mother-infant dyads from the Maternal Adversity, Vulnerability and Neurodevelopment project. A Confirmatory Bifactor Analysis (CFA) based on self-report measures of prenatal depression and pregnancy-specific anxiety generated a general factor representing overlapping symptoms of prenatal maternal psychopathology and four distinct symptom factors representing pregnancy-specific anxiety, negative affect, anhedonia and somatization. NE was rated by the mother at 18 and 36 months. CFA based on measures of father, mother, child-rated measures and a semistructured interview generated a general internalizing factor representing overlapping symptoms of child internalizing psychopathology accounting for the unique contribution of each informant. Path analyses revealed significant relationships among the general maternal affective psychopathology, the pregnancy- specific anxiety, and the child internalizing factors. Child NE mediated only the relationship between pregnancy-specific anxiety and the child internalizing factors. We highlighted the conditions in which prenatal maternal affective symptoms predicts child internalizing problems emerging early in development, including consideration of different mechanistic pathways for different maternal prenatal symptom presentations and child temperament.

Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood.

BACKGROUND: Polygenic risk scores (PRSs) operationalize genetic propensity toward a particular mental disorder and hold promise as early predictors of psychopathology, but before a PRS can be used clinically, explanatory power must be increased and the specificity for a psychiatric domain established. To enable early detection, it is crucial to study these psychometric properties in childhood. We examined whether PRSs associate more with general or with specific psychopathology in school-aged children. Additionally, we tested whether psychiatric PRSs can be combined into a multi-PRS score for improved performance. METHODS: We computed 16 PRSs based on GWASs of psychiatric phenotypes, but also neuroticism and cognitive ability, in mostly adult populations. Study participants were 9,247 school-aged children from three population-based cohorts of the DREAM-BIG consortium: ALSPAC (UK), The Generation R Study (Netherlands), and MAVAN (Canada). We associated each PRS with general and specific psychopathology factors, derived from a bifactor model based on self-report and parental, teacher, and observer reports. After fitting each PRS in separate models, we also tested a multi-PRS model, in which all PRSs are entered simultaneously as predictors of the general psychopathology factor. RESULTS: Seven PRSs were associated with the general psychopathology factor after multiple testing adjustment, two with specific externalizing and five with specific internalizing psychopathology. PRSs predicted general psychopathology independently of each other, with the exception of depression and depressive symptom PRSs. Most PRSs associated with a specific psychopathology domain, were also associated with general child psychopathology. CONCLUSIONS: The results suggest that PRSs based on current GWASs of psychiatric phenotypes tend to be associated with general psychopathology, or both general and specific psychiatric domains, but not with one specific psychopathology domain only. Furthermore, PRSs can be combined to improve predictive ability. PRS users should therefore be conscious of nonspecificity and consider using multiple PRSs simultaneously, when predicting psychiatric disorders.

Effectiveness and Predictors of Outcomes in a Psychiatric Day Treatment Program for Elementary-Age.

OBJECTIVE: In this study, we aimed to (1) assess the effectiveness of an intensive multimodal day treatment program in improving externalizing problems and function in elementary-age children and (2) examine 3 predictors of the treatment outcome (i.e., family functioning, baseline severity, and comorbid disorders). METHODS: The sample included 261 children (80.9% boys) between ages of 5 and 12. A retrospective chart review, from 2013 to 2018, and a prospective chart review, from 2018 to 2019, were conducted to extract all relevant data for the present study. Parents and teachers provided reports on children's externalizing problems (i.e., aggressive behavior, attention problems, and rule-breaking behavior) and their level of function across different domains. The level of family functioning was also reported by parents, while clinicians assessed children's severity of disturbance and their diagnoses at intake. RESULTS: Based on both parents' and teachers' reports, children showed significant improvement in their externalizing problems. Moreover, children showed functional improvement at home, at school, with peers, and in hobbies by the end of the program. Based on teacher's reports, children with lower level of severity showed less improvement in their attention problems, and those with comorbid developmental problems showed less improvement in their aggressive and rule-breaking behaviors. Family functioning did not predict any treatment outcome. CONCLUSION: An intensive multimodal day treatment program was effective in reducing the symptoms of externalizing problems in elementary-age children. However, children with less severe difficulties and comorbid developmental problems showed less improvement in their externalizing problems.

Frequent follow-up of suicidal youth assessed in the emergency room: Long-term trajectory and predictors of suicidality.

Suicide was the second­leading cause of US deaths in 2018 among 15-24-year-olds. Suicide attempts, a risk factor for completions, and suicide ideation have doubled among pediatric emergency room (ER) patients during the past decade. Borderline Personality Disorder (BPD), a comorbid condition, has a 10% suicide rate. We examined the 4-year outcome of a cohort of suicidal adolescents, many also suffering from BPD and having undergone some form of treatment, to identify baseline factors which could inform intervention that would minimize suicidality 4 years post-discharge. METHODS: We conducted a prospective longitudinal study of suicidality at twelve points (four assessment occasions) for 286 suicidal youth presenting to a pediatric ER, most suffering from BPD, with 36 suicide ratings from baseline to 2-, 6- and 48-month follow-up evaluations. We examined the trajectory and predictors of persisting suicidality. RESULTS: Suicidality rapidly decreased within 2 months post-ER-discharge, subsequently remaining low throughout 48 months. Baseline functioning, female sex, stressful life events and BPD impulsiveness were most predictive of persisting suicidality at 48-month follow-up. CONCLUSION: Most suicidal youth, many meeting BPD criteria, no longer feel suicidal 2 months after ER discharge. Management of participants' baseline poor functioning stressful life events and the impulsiveness component of BPD specifically in females could impact suicidality 4 years later, and guide treatment options. The absence of the BPD cognitive and affective subscales as predictors of suicidality at 4-year follow-up may reflect treatment received. Further investigation of treatment effects is warranted and under way.

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.

Measuring resilience in children: a review of recent literature and recommendations for future research.

PURPOSE OF REVIEW: Understanding variability in developmental outcomes following exposure to early life adversity (ELA) has been an area of increasing interest in psychiatry, as resilient outcomes are just as prevalent as negative ones. However, resilient individuals are understudied in most cohorts and even when studied, resilience is typically defined as an absence of psychopathology. This review examines current approaches to resilience and proposes more comprehensive and objective ways of defining resilience. RECENT FINDINGS: Of the 36 studies reviewed, the most commonly used measure was the Strengths and Difficulties Questionnaire (n = 6), followed by the Child Behavior Checklist (n = 5), the Resilience Scale for Chinese Adolescents (n = 5), the Rosenberg Self-Esteem Scale (n = 4), and the Child and Youth Resilience Scale (n = 3). SUMMARY: This review reveals that studies tend to rely on self-report methods to capture resilience which poses some challenges. We propose a complementary measure of child resilience that relies on more proactive behavioral and observational indicators; some of our preliminary findings are presented. Additionally, concerns about the way ELA is characterized as well as the influence of genetics on resilient outcomes prompts further considerations about how to proceed with resiliency research.

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.

Effects of maternal depression and prenatal SSRI exposure on executive functions and susceptibility to household chaos in 6-year-old children: prospective cohort study.

BACKGROUND: Maternal depressed mood during pregnancy may shape a child's adaptation to their environment and engagement in goal-directed behaviour such as executive functions. Whether everyday household context also alters executive functions in children with prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure remains to be determined. AIMS: To examine the impact of prenatal depressed maternal mood and SSRI exposure on child executive functions and to determine whether these exposures shape a susceptibility to household chaos. METHOD: A prospective cohort study of mothers and their children (118 mother-children dyads (47 SSRI-exposed, 71 non-exposed)) followed from the second trimester to 6 years. Regression models examined relationships between maternal depressed mood and household chaos on maternal report of child executive functions. Competitive-confirmatory regression models examined whether children were susceptible to household chaos or were positively influenced by less chaos. RESULTS: Prenatal SSRI exposure, third-trimester maternal depressed mood and household chaos in a three-way interaction were associated with executive functions within a model of differential susceptibility. When household chaos was low, children of non-prenatally depressed mothers had better executive function than children of prenatally depressed mothers, regardless of whether the mothers were SSRI-treated. However, when household chaos was high, SSRI-exposed children of mothers who were not depressed during pregnancy had poorer executive functions at 6 years of age compared with SSRI-exposed children whose mothers were symptomatic during pregnancy. CONCLUSIONS: The impact of household chaos depended on whether mothers were prenatally depressed and whether mothers were SSRI-treated.

Distinguishing differential susceptibility, diathesis-stress, and vantage sensitivity: Beyond the single gene and environment model.

Currently, two main approaches exist to distinguish differential susceptibility from diathesis-stress and vantage sensitivity in Genotype × Environment interaction (G × E) research: regions of significance (RoS) and competitive-confirmatory approaches. Each is limited by its single-gene/single-environment foci given that most phenotypes are the product of multiple interacting genetic and environmental factors. We thus addressed these two concerns in a recently developed R package (LEGIT) for constructing G × E interaction models with latent genetic and environmental scores using alternating optimization. Herein we test, by means of computer simulation, diverse G × E models in the context of both single and multiple genes and environments. Results indicate that the RoS and competitive-confirmatory approaches were highly accurate when the sample size was large, whereas the latter performed better in small samples and for small effect sizes. The competitive-confirmatory approach generally had good accuracy (a) when effect size was moderate and N ≥ 500 and (b) when effect size was large and N ≥ 250, whereas RoS performed poorly. Computational tools to determine the type of G × E of multiple genes and environments are provided as extensions in our LEGIT R package.

General psychopathology, internalising and externalising in children and functional outcomes in late adolescence.

BACKGROUND: Internalising and externalising problems commonly co-occur in childhood. Yet, few developmental models describing the structure of child psychopathology appropriately account for this comorbidity. We evaluate a model of childhood psychopathology that separates the unique and shared contribution of individual psychological symptoms into specific internalising, externalising and general psychopathology factors and assess how these general and specific factors predict long-term outcomes concerning criminal behaviour, academic achievement and affective symptoms in three independent cohorts. METHODS: Data were drawn from independent birth cohorts (Avon Longitudinal Study of Parents and Children (ALSPAC), N = 11,612; Generation R, N = 7,946; Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN), N = 408). Child psychopathology was assessed between 4 and 8 years using a range of diagnostic and questionnaire-based measures, and multiple informants. First, structural equation models were used to assess the fit of hypothesised models of shared and unique components of psychopathology in all cohorts. Once the model was chosen, linear/logistic regressions were used to investigate whether these factors were associated with important outcomes such as criminal behaviour, academic achievement and well-being from late adolescence/early adulthood. RESULTS: The model that included specific factors for internalising/externalising and a general psychopathology factor capturing variance shared between symptoms regardless of their classification fits well for all of the cohorts. As hypothesised, general psychopathology factor scores were predictive of all outcomes of later functioning, while specific internalising factor scores predicted later internalising outcomes. Specific externalising factor scores, capturing variance not shared by any other psychological symptoms, were not predictive of later outcomes. CONCLUSIONS: Early symptoms of psychopathology carry information that is syndrome-specific as well as indicative of general vulnerability and the informant reporting on the child. The 'general psychopathology factor' might be more relevant for long-term outcomes than specific symptoms. These findings emphasise the importance of considering the co-occurrence of common internalising and externalising problems in childhood when considering long-term impact.

Alternating optimization for G × E modelling with weighted genetic and environmental scores: Examples from the MAVAN study.

Motivated by the goal of expanding currently existing Genotype × Environment interaction (G × E) models to simultaneously include multiple genetic variants and environmental exposures in a parsimonious way, we developed a novel method to estimate the parameters in a G × E model, where G is a weighted sum of genetic variants (genetic score) and E is a weighted sum of environments (environmental score). The approach uses alternating optimization, an iterative process where the genetic score weights, the environmental score weights, and the main model parameters are estimated in turn, assuming the other parameters are constant. This technique can be used to construct relatively complex interaction models that are constrained to a particular structure, and hence contain fewer parameters. We present the model as a 2-way interaction longitudinal mixed model, for which ordinary linear regression is a special case, but it can easily be extended to be compatible with k-way interaction models and generalized linear mixed models. The model is implemented in R (LEGIT package) and using SAS macros (LEGIT_SAS). Through simulations, we demonstrate the power and validity of this approach even with small sample sizes. Furthermore, we present examples from the Maternal Adversity, Vulnerability, and Neurodevelopment (MAVAN) study where we improve significantly upon already existing models using alternating optimization. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The dopamine D4 receptor gene, birth weight, maternal depression, maternal attention, and the prediction of disorganized attachment at 36 months of age: A prospective gene×environment analysis.

BACKGROUND: Efforts to understand the developmental pathways for disorganized attachment reflect the importance of disorganized attachment on the prediction of future psychopathology. The inconsistent findings on the prediction of disorganized attachment from the dopamine D4 receptor (DRD4) gene, birth weight, and maternal depression as well as the evidence supporting the contribution of early maternal care, suggest the importance of exploring a gene by environment model. METHODS: Our sample is from the Maternal Adversity, Vulnerability, and Neurodevelopment project; consisting of 655 mother-child dyads. Birth weight was cross-referenced with normative data to calculate birth weight percentile. Infant DRD4 genotype was obtained with buccal swabs and categorized according to the presence of the 7-repeat allele. Maternal depression was assessed with the Center for Epidemiologic Studies Depression Scale at the prenatal, 6-, 12-, and 24-month assessments. Maternal attention was measured at 6-months using a videotaped session of a 20-min non-feeding interaction. Attachment was assessed at 36-months using the Strange Situation Procedure. RESULTS: The presence of the DRD4 7-repeat allele was associated with less disorganized attachment, ß=-1.11, OR=0.33, p=0.0008. Maternal looking away frequency showed significant interactions with maternal depression at the prenatal assessment, ß=0.003, OR=1.003, p=0.023, and at 24 months, ß=0.004, OR=1.004, p=0.021, as at both time points, women suffering from depression and with frequent looking away behavior had an increased probability of disorganized attachment in their child, while those with less looking away behavior had a decreased probability of disorganized attachment in their child at 36 months. CONCLUSIONS: Our models support the contribution of biological and multiple environmental factors in the complex prediction of disorganized attachment at 36 months.

Prenatal maternal depression and child serotonin transporter linked polymorphic region (5-HTTLPR) and dopamine receptor D4 (DRD4) genotype predict negative emotionality from 3 to 36 months.

Prenatal maternal depression and a multilocus genetic profile of two susceptibility genes implicated in the stress response were examined in an interaction model predicting negative emotionality in the first 3 years. In 179 mother-infant dyads from the Maternal Adversity, Vulnerability, and Neurodevelopment cohort, prenatal depression (Center for Epidemiologic Studies Depressions Scale) was assessed at 24 to 36 weeks. The multilocus genetic profile score consisted of the number of susceptibility alleles from the serotonin transporter linked polymorphic region gene (5-HTTLPR): no long-rs25531(A) (LA: short/short, short/long-rs25531(G) [LG], or LG/LG] vs. any LA) and the dopamine receptor D4 gene (six to eight repeats vs. two to five repeats). Negative emotionality was extracted from the Infant Behaviour Questionnaire-Revised at 3 and 6 months and the Early Child Behavior Questionnaire at 18 and 36 months. Mixed and confirmatory regression analyses indicated that prenatal depression and the multilocus genetic profile interacted to predict negative emotionality from 3 to 36 months. The results were characterized by a differential susceptibility model at 3 and 6 months and by a diathesis-stress model at 36 months.

Preschool children without 7-repeat DRD4 gene more likely to develop disorganized attachment style.

BACKGROUND: The current paper aimed to explore the effects of birth weight and the 7-repeat allele in Exon III of the dopamine D4 receptor (DRD4) gene on the development of disorganized attachment, a potential endophenotype of depression. Infants born with low birth weight have been shown to be at higher risk for later neurological impairments, psychological disorders or behavioural problems. The DRD4 gene is critical for the cognitive and emotional processes that are sub-served by neural circuits in the prefrontal cortex. This paper examined the main effect of birth weight and DRD4 on the development of disorganized attachment. METHODS: Data was used from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project. The sample consisted of 251 mother-child dyads with complete data. Attachment style was assessed using the modified separation-reunion procedure. RESULTS: There was no main effect for birth weight on disorganized attachment, (b = -0.001, p = 0.998). There was, however, a main effect for the DRD4 7-repeat polymorphism on disorganized attachment (b = -1.120, p = 0.004). LIMITATIONS: Compared to studies of similar design, the sample size in this study was relatively small. Additionally, a significant number of subjects did not have complete data. CONCLUSIONS: Children without the DRD4 7-repeat allele were more likely to have disorganized attachment than children with the DRD4 7-repeat allele. This indicates that the 7-repeate allele of the DRD4 gene may actually serve as a protective factor against disorganized attachment.