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Attention-deficit hyperactivity disorder (ADHD) is associated with later depression and there is considerable genetic overlap between them. This study investigated if ADHD and ADHD genetic liability are causally related to depression using two different methods.
First, a longitudinal population cohort design was used to assess the association between childhood ADHD (age 7 years) and recurrent depression in young-adulthood (age 18–25 years) in N = 8310 individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC). Second, two-sample Mendelian randomization (MR) analyses examined relationships between genetic liability for ADHD and depression utilising published Genome-Wide Association Study (GWAS) data.
Childhood ADHD was associated with an increased risk of recurrent depression in young-adulthood (OR 1.35, 95% CI 1.05–1.73). MR analyses suggested a causal effect of ADHD genetic liability on major depression (OR 1.21, 95% CI 1.12–1.31). MR findings using a broader definition of depression differed, showing a weak influence on depression (OR 1.07, 95% CI 1.02–1.13).
Our findings suggest that ADHD increases the risk of depression later in life and are consistent with a causal effect of ADHD genetic liability on subsequent major depression. However, findings were different for more broadly defined depression.
Attention deficit hyperactivity disorder (ADHD) is highly heritable and is associated with lower educational attainment. ADHD is linked to family adversity, including hostile parenting. Questions remain regarding the role of genetic and environmental factors underlying processes through which ADHD symptoms develop and influence academic attainment.
This study employed a parent-offspring adoption design (N = 345) to examine the interplay between genetic susceptibility to child attention problems (birth mother ADHD symptoms) and adoptive parent (mother and father) hostility on child lower academic outcomes, via child ADHD symptoms. Questionnaires assessed birth mother ADHD symptoms, adoptive parent (mother and father) hostility to child, early child impulsivity/activation, and child ADHD symptoms. The Woodcock–Johnson test was used to examine child reading and math aptitude.
Building on a previous study (Harold et al., 2013, Journal of Child Psychology and Psychiatry, 54(10), 1038–1046), heritable influences were found: birth mother ADHD symptoms predicted child impulsivity/activation. In turn, child impulsivity/activation (4.5 years) evoked maternal and paternal hostility, which was associated with children's ADHD continuity (6 years). Both maternal and paternal hostility (4.5 years) contributed to impairments in math but not reading (7 years), via impacts on ADHD symptoms (6 years).
Findings highlight the importance of early child behavior dysregulation evoking parent hostility in both mothers and fathers, with maternal and paternal hostility contributing to the continuation of ADHD symptoms and lower levels of later math ability. Early interventions may be important for the promotion of child math skills in those with ADHD symptoms, especially where children have high levels of early behavior dysregulation.
Few personalised medicine investigations have been conducted for mental health. We aimed to generate and validate a risk tool that predicts adult attention-deficit/hyperactivity disorder (ADHD).
Using logistic regression models, we generated a risk tool in a representative population cohort (ALSPAC – UK, 5113 participants, followed from birth to age 17) using childhood clinical and sociodemographic data with internal validation. Predictors included sex, socioeconomic status, single-parent family, ADHD symptoms, comorbid disruptive disorders, childhood maltreatment, ADHD symptoms, depressive symptoms, mother's depression and intelligence quotient. The outcome was defined as a categorical diagnosis of ADHD in young adulthood without requiring age at onset criteria. We also tested Machine Learning approaches for developing the risk models: Random Forest, Stochastic Gradient Boosting and Artificial Neural Network. The risk tool was externally validated in the E-Risk cohort (UK, 2040 participants, birth to age 18), the 1993 Pelotas Birth Cohort (Brazil, 3911 participants, birth to age 18) and the MTA clinical sample (USA, 476 children with ADHD and 241 controls followed for 16 years from a minimum of 8 and a maximum of 26 years old).
The overall prevalence of adult ADHD ranged from 8.1 to 12% in the population-based samples, and was 28.6% in the clinical sample. The internal performance of the model in the generating sample was good, with an area under the curve (AUC) for predicting adult ADHD of 0.82 (95% confidence interval (CI) 0.79–0.83). Calibration plots showed good agreement between predicted and observed event frequencies from 0 to 60% probability. In the UK birth cohort test sample, the AUC was 0.75 (95% CI 0.71–0.78). In the Brazilian birth cohort test sample, the AUC was significantly lower –0.57 (95% CI 0.54–0.60). In the clinical trial test sample, the AUC was 0.76 (95% CI 0.73–0.80). The risk model did not predict adult anxiety or major depressive disorder. Machine Learning approaches did not outperform logistic regression models. An open-source and free risk calculator was generated for clinical use and is available online at https://ufrgs.br/prodah/adhd-calculator/.
The risk tool based on childhood characteristics specifically predicts adult ADHD in European and North-American population-based and clinical samples with comparable discrimination to commonly used clinical tools in internal medicine and higher than most previous attempts for mental and neurological disorders. However, its use in middle-income settings requires caution.
There is an enormous interest in identifying the causes of psychiatric disorders but there are considerable challenges in identifying which risks are genuinely causal. Traditionally risk factors have been inferred from observational designs. However, association with psychiatric outcome does not equate to causation. There are a number of threats that clinicians and researchers face in making causal inferences from traditional observational designs because adversities or exposures are not randomly allocated to individuals. Natural experiments provide an alternative strategy to randomized controlled trials as they take advantage of situations whereby links between exposure and other variables are separated by naturally occurring events or situations. In this review, we describe a growing range of different types of natural experiment and highlight that there is a greater confidence about findings where there is a convergence of findings across different designs. For example, exposure to hostile parenting is consistently found to be associated with conduct problems using different natural experiment designs providing support for this being a causal risk factor. Different genetically informative designs have repeatedly found that exposure to negative life events and being bullied are linked to later depression. However, for exposure to prenatal cigarette smoking, while findings from natural experiment designs are consistent with a causal effect on offspring lower birth weight, they do not support the hypothesis that intra-uterine cigarette smoking has a causal effect on attention-deficit/hyperactivity disorder and conduct problems and emerging findings highlight caution about inferring causal effects on bipolar disorder and schizophrenia.
Identifying prenatal environmental factors that have genuinely causal effects on psychopathology is an important research priority, but it is crucial to select an appropriate research design. In this review we explain why and what sorts of designs are preferable and focus on genetically informed/sensitive designs. In the field of developmental psychopathology, causal inferences about prenatal risks have not always been based on evidence generated from appropriate designs. We focus on reported links between maternal smoking during pregnancy and offspring attention-deficit/hyperactivity disorder or conduct problems. Undertaking a systematic review of findings from genetically informed designs and “triangulating” evidence from studies with different patterns of bias, we conclude that at present findings suggest it is unlikely that there is a substantial causal effect of maternal smoking in pregnancy on either attention-deficit/hyperactivity disorder or conduct problems. In contrast, for offspring birth weight (which serves as a positive control) findings strongly support a negative causal effect of maternal smoking in pregnancy. For maternal pregnancy stress, too few studies use genetically sensitive designs to draw firm conclusions, but continuity with postnatal stress seems important. We highlight the importance of moving beyond observational designs, for systematic evaluation of the breadth of available evidence and choosing innovative designs. We conclude that a broader set of prenatal risk factors should be examined, including those relevant in low- and middle-income contexts. Future directions include a greater use of molecular genetically informed designs such as Mendelian randomization to test causal hypotheses about prenatal exposure and offspring outcome.
Previous studies find that both schizophrenia and mood disorder risk alleles contribute to adult depression and anxiety. Emotional problems (depression or anxiety) begin in childhood and show strong continuities into adult life; this suggests that symptoms are the manifestation of the same underlying liability across different ages. However, other findings suggest that there are developmental differences in the etiology of emotional problems at different ages. To our knowledge, no study has prospectively examined the impact of psychiatric risk alleles on emotional problems at different ages in the same individuals.
Data were analyzed using regression-based analyses in a prospective, population-based UK cohort (the National Child Development Study). Schizophrenia and major depressive disorder (MDD) polygenic risk scores (PRS) were derived from published Psychiatric Genomics Consortium genome-wide association studies. Emotional problems were assessed prospectively at six time points from age 7 to 42 years.
Schizophrenia PRS were associated with emotional problems from childhood [age 7, OR 1.09 (1.03–1.15), p = 0.003] to mid-life [age 42, OR 1.10 (1.05–1.17), p < 0.001], while MDD PRS were associated with emotional problems only in adulthood [age 42, OR 1.06 (1.00–1.11), p = 0.034; age 7, OR 1.03 (0.98–1.09), p = 0.228].
Our prospective investigation suggests that early (childhood) emotional problems in the general population share genetic risk with schizophrenia, while later (adult) emotional problems also share genetic risk with MDD. The results suggest that the genetic architecture of depression/anxiety is not static across development.
Objectives: Previous studies have found that oxytocin (OXT) can improve the recognition of emotional facial expressions; it has been proposed that this effect is mediated by an increase in attention to the eye-region of faces. Nevertheless, evidence in support of this claim is inconsistent, and few studies have directly tested the effect of oxytocin on emotion recognition via altered eye-gaze Methods: In a double-blind, within-subjects, randomized control experiment, 40 healthy male participants received 24 IU intranasal OXT and placebo in two identical experimental sessions separated by a 2-week interval. Visual attention to the eye-region was assessed on both occasions while participants completed a static facial emotion recognition task using medium intensity facial expressions. Results: Although OXT had no effect on emotion recognition accuracy, recognition performance was improved because face processing was faster across emotions under the influence of OXT. This effect was marginally significant (p<.06). Consistent with a previous study using dynamic stimuli, OXT had no effect on eye-gaze patterns when viewing static emotional faces and this was not related to recognition accuracy or face processing time. Conclusions: These findings suggest that OXT-induced enhanced facial emotion recognition is not necessarily mediated by an increase in attention to the eye-region of faces, as previously assumed. We discuss several methodological issues which may explain discrepant findings and suggest the effect of OXT on visual attention may differ depending on task requirements. (JINS, 2017, 23, 23–33)
It is well-established that offspring of depressed mothers are at increased risk for suicidal ideation. However, pathways involved in the transmission of risk for suicidal ideation from depressed mothers to offspring are poorly understood. The aim of this study was to examine the contribution of potential mediators of this association, including maternal suicide attempt, offspring psychiatric disorder and the parent–child relationship.
Data were utilized from a population-based birth cohort (ALSPAC). Three distinct classes of maternal depression symptoms across the first 11 years of the child's life had already been identified (minimal, moderate, chronic-severe). Offspring suicidal ideation was assessed at age 16 years. Data were analysed using structural equation modelling.
There was evidence for increased risk of suicidal ideation in offspring of mothers with chronic-severe depression symptoms compared to offspring of mothers with minimal symptoms (odds ratio 3.04, 95% confidence interval 2.19–4.21). The majority of this association was explained through maternal suicide attempt and offspring psychiatric disorder. There was also evidence for an independent indirect effect via the parent–child relationship in middle childhood. There was no longer evidence of a direct effect of maternal depression on offspring suicidal ideation after accounting for all three mediators. The pattern of results was similar when examining mechanisms for maternal moderate depression symptoms.
Findings highlight that suicide prevention efforts in offspring of depressed mothers should be particularly targeted at both offspring with a psychiatric disorder and offspring whose mothers have made a suicide attempt. Interventions aimed at improving the parent–child relationship may also be beneficial.
Stress has been shown to have a causal effect on risk for depression. We investigated the role of cognitive ability as a moderator of the effect of stressful life events on depressive symptoms and whether this varied by gender. Data were analyzed in two adolescent data sets: one representative community sample aged 11–12 years (n = 460) and one at increased familial risk of depression aged 9–17 years (n = 335). In both data sets, a three-way interaction was found whereby for girls, but not boys, higher cognitive ability buffered the association between stress and greater depressive symptoms. The interaction was replicated when the outcome was a diagnosis of major depressive disorder. This buffering effect in girls was not attributable to coping efficacy. However, a small proportion of the variance was accounted for by sensitivity to environmental stressors. Results suggest that this moderating effect of cognitive ability in girls is largely attributable to greater available resources for cognitive operations that offer protection against stress-induced reductions in cognitive processing and cognitive control which in turn reduces the likelihood of depressive symptomatology.
Past research has identified maternal depression and family of origin maltreatment as precursors to adolescent depression and antisocial behavior. Caregiving experiences have been identified as a factor that may ameliorate or accentuate adolescent psychopathology trajectories. Using a multilevel approach that pools the unique attributes of two geographically diverse, yet complementary, longitudinal research designs, the present study examined the role of maternal caregiver involvement as a factor that promotes resilience-based trajectories related to depressive symptoms and antisocial behaviors among adolescent girls. The first sample comprises a group of US-based adolescent girls in foster care (n = 100; mean age = 11.50 years), each of whom had a history of childhood maltreatment and removal from their biological parent(s). The second sample comprises a group of UK-based adolescent girls at high familial risk for depression (n = 145; mean age = 11.70 years), with all girls having biological mothers who experienced recurrent depression. Analyses examined the role of maternal caregiving on girls' trajectories of depression and antisocial behavior, while controlling for levels of co-occurring psychopathology at each time point. Results suggest increasing levels of depressive symptoms for girls at familial risk for depression but decreasing levels of depression for girls in foster care. Foster girls' antisocial behavior also decreased over time. Maternal caregiver involvement was differentially related to intercept and slope parameters in both samples. Results are discussed with respect to the benefits of applying multilevel (multisample, multiple outcome) approaches to identifying family-level factors that can reduce negative developmental outcomes in high-risk youth.
To determine rates of parent-reported child awareness of parental depression, examine characteristics of parents, children and families according to child awareness, and explore whether child awareness is associated with child psychopathology. Data were available from 271 families participating in the Early Prediction of Adolescent Depression (EPAD) study, a longitudinal study of offspring of parents with recurrent depression.
Seventy-three per cent of participating children were perceived as being aware of their parent's depression. Older children, and children of parents who experienced more severe depression, were more likely to be aware. Awareness was not associated with child psychopathology.
Considering children in the context of parental depression is important. Child awareness may influence their access to early intervention and prevention programmes. Further research is needed to understand the impact of awareness on the child.
Children with 22q11.2 deletion syndrome (22q11.2DS) have been reported to have high rates of cognitive and psychiatric problems.
To establish the nature and prevalence of psychiatric disorder and neurocognitive impairment in children with 22q11.2DS and test whether risk of psychopathology is mediated by the children's intellectual impairment.
Neurocognition and psychopathology were assessed in 80 children with 22q11.2DS (mean age 10.2 years, s.d. = 2.1) and 39 sibling controls (mean age 10.9 years, s.d. = 2.0).
More than half (54%) of children with 22q11.2DS met diagnostic criteria for one or more DSM-IV-TR psychiatric disorder. These children had lower IQ (mean 76.8, s.d. = 13.0) than controls (mean 108.6, s.d. = 15.2) (P<0.001) and showed a range of neurocognitive impairments. Increased risk of psychopathology was not mediated by intellectual impairment.
22q11.2DS is not related to a specific psychiatric phenotype in children. Moreover, the deletion has largely independent effects on IQ and risk of psychopathology, indicating that psychopathology in 22q11.2DS is not a non-specific consequence of generalised cognitive impairment.
There is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants.
To determine whether there is overlap between common alleles conferring risk of schizophrenia in adults with those that do so for ADHD in children.
We used recently published Psychiatric Genome-wide Association Study (GWAS) Consortium (PGC) adult schizophrenia data to define alleles over-represented in people with schizophrenia and tested whether those alleles were more common in 727 children with ADHD than in 2067 controls.
Schizophrenia risk alleles discriminated ADHD cases from controls (P = 1.04 × 104, R2 = 0.45%); stronger discrimination was given by alleles that were risk alleles for both adult schizophrenia and adult bipolar disorder (also derived from a PGC data-set) (P = 9.98 ×10−6, R2 × 0.59%).
This increasing evidence for a small, but significant, shared genetic susceptibility between adult schizophrenia and childhood ADHD highlights the importance of research work across traditional diagnostic boundaries.
Parental depression is associated with disruptions in the parent–child relationship, exposure to stressful family life events, and offspring depressive symptoms. Evidence suggests that intergenerational transmission of depression involves environmental and inherited contributions. We sought to evaluate the role of passive gene–environment correlation (rGE) in relation to depression, family life events that were due to parental behavior, and parental positivity in a sample where children varied in genetic relatedness to their rearing parents. Our study included 865 families with children born through assisted conception (444 related to both parents, 210 related to the mother only, 175 related to the father only, and 36 related to neither parent). Consistent with previous studies, the intergenerational transmission of depressive symptoms was largely due to environmental factors, although parent and child gender influenced results. Maternal and paternal depressive symptoms were associated with reduced positivity and increased parentally imposed life events regardless of parent–child relatedness. Results of path analysis were consistent with passive rGE for both maternal and paternal positivity in that positivity partially mediated the link between maternal/paternal depression and child depression only in genetically related parent–child pairs. Results also suggested passive rGE involving parentally imposed life events for mothers and fathers although passive rGE effects were smaller than for positivity.
Offspring of mothers with depression are at heightened risk of psychiatric disorder. Many mothers with depression have comorbid psychopathology. How these co-occurring problems affect child outcomes has rarely been considered.
To consider whether the overall burden of co-occurring psychopathology in mothers with recurrent depression predicts new-onset psychopathology in offspring.
Mothers with recurrent depression and their adolescent offspring (9–17 years at baseline) were assessed in 2007 and on two further occasions up to 2011. Mothers completed questionnaires assessing depression severity, anxiety, alcohol problems and antisocial behaviour. Psychiatric disorder in offspring was assessed using the Child and Adolescent Psychiatric Assessment.
The number of co-occurring problems in mothers (0, 1 or 2+) predicted new-onset offspring disorder (odds ratio (OR) = 1.80, 95% CI 1.17–2.77, P = 0.007). Rates varied from 15.7 to 34.8% depending on the number of co-occurring clinical problems. This remained significant after controlling for maternal depression severity (OR = 1.73, 95% CI 1.03–2.89, P = 0.040).
The burden of co-occurring psychopathology among mothers with recurrent depression indexes increased risk of future onset of psychiatric disorder for offspring. This knowledge can be used in targeting preventive measures in children at high risk of psychiatric disorder.
Past research has linked interparental conflict, parent psychopathology, hostile parenting, and externalizing behavior problems in childhood. However, few studies have examined these relationships while simultaneously allowing the contribution of common genetic factors underlying associations between family- and parent-level variables on child psychopathology to be controlled. Using the attributes of a genetically sensitive in vitro fertilization research design, the present study examined associations among interparental conflict, parents' antisocial behavior problems, parents' anxiety symptoms, and hostile parenting on children's antisocial behavior problems among genetically related and genetically unrelated mother–child and father–child groupings. Path analyses revealed that for genetically related mothers, interparental conflict and maternal antisocial behavior indirectly influenced child antisocial behavior through mother-to-child hostility. For genetically unrelated mothers, effects were apparent only for maternal antisocial behavior on child antisocial behavior through mother-to-child hostility. For both genetically related and genetically unrelated fathers and children, interparental conflict and paternal antisocial behavior influenced child antisocial behavior through father-to-child hostility. Effects of parental anxiety symptoms on child antisocial behavior were apparent only for genetically related mothers and children. Results are discussed with respect to the relative role of passive genotype–environment correlation as a possible confounding factor underlying family process influences on childhood psychopathology.
Alterations in reward processing may represent an early vulnerability factor for the development of depressive disorder. Depression in adults is associated with reward hyposensitivity and diminished reward seeking may also be a feature of depression in children and adolescents. We examined the role of reward responding in predicting depressive symptoms, functional impairment and new-onset depressive disorder over time in the adolescent offspring of depressed parents. In addition, we examined group differences in reward responding between currently depressed adolescents, psychiatric and healthy controls, and also cross-sectional associations between reward responding and measures of positive social/environmental functioning.
We conducted a 1-year longitudinal study of adolescents at familial risk for depression (n = 197; age range 10–18 years). Reward responding and self-reported social/environmental functioning were assessed at baseline. Clinical interviews determined diagnostic status at baseline and at follow-up. Reports of depressive symptoms and functional impairment were also obtained.
Low reward seeking predicted depressive symptoms and new-onset depressive disorder at the 1-year follow-up in individuals free from depressive disorder at baseline, independently of baseline depressive symptoms. Reduced reward seeking also predicted functional impairment. Adolescents with current depressive disorder were less reward seeking (i.e. bet less at favourable odds) than adolescents free from psychopathology and those with externalizing disorders. Reward seeking showed positive associations with social and environmental functioning (extra-curricular activities, humour, friendships) and was negatively associated with anhedonia. There were no group differences in impulsivity, decision making or psychomotor slowing.
Reward seeking predicts depression severity and onset in adolescents at elevated risk of depression. Adaptive reward responses may be amenable to change through modification of existing preventive psychological interventions.