Childhood correlates and young adult outcomes of trajectories of emotional problems from childhood to adolescence.

BACKGROUND: Emotional problems, especially anxiety, have become increasingly common in recent generations. Few population-based studies have examined trajectories of emotional problems from early childhood to late adolescence or investigated differences in psychiatric and functional outcomes. METHODS: Using the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 8286, 50.4% male), we modeled latent class growth trajectories of emotional problems, using the parent-reported Strength and Difficulties Questionnaire emotional scale (SDQ-E) on seven occasions (4-17 years). Psychiatric outcomes in young adulthood (21-25 years) were major depressive disorder (MDD), generalized anxiety disorder (GAD), and self-harm. Functional outcomes were exam attainment, educational/occupational status, and social relationship quality. RESULTS: We identified four classes of emotional problems: low (67.0%), decreasing (18.4%), increasing (8.9%), and persistent (5.7%) problems. Compared to those in the low class, individuals with decreasing emotional problems were not at elevated risk of any poor adult outcome. Individuals in the increasing and persistent classes had a greater risk of adult MDD (RR: 1.59 95% CI 1.13-2.26 and RR: 2.25 95% CI 1.49-3.41) and self-harm (RR: 2.37 95% CI 1.91-2.94 and RR: 1.87 95% CI 1.41-2.48), and of impairment in functional domains. Childhood sleep difficulties, irritability, conduct and neurodevelopmental problems, and family adversity were associated with a persistent course of emotional problems. CONCLUSIONS: Childhood emotional problems were common, but those whose symptoms improved over time were not at increased risk for adverse adult outcomes. In contrast, individuals with persistent or adolescent-increasing emotional problems had a higher risk of mental ill-health and social impairment in young adulthood which was especially pronounced for those with persistent emotional problems.

Remote assessment of ADHD in children and adolescents: recommendations from the European ADHD Guidelines Group following the clinical experience during the COVID-19 pandemic.

The COVID-19 pandemic led ADHD services to modify the clinical practice to reduce in-person contact as much as possible to minimise viral spread. This had far-reaching effects on day-to-day clinical practice as remote assessments were widely adopted. Despite the attenuation of the acute threat from COVID, many clinical services are retaining some remote practices. The lack of clear evidence-based guidance about the most appropriate way to conduct remote assessments meant that these changes were typically implemented in a localised, ad hoc, and un-coordinated way. Here, the European ADHD Guidelines Group (EAGG) discusses the strengths and weaknesses of remote assessment methods of children and adolescents with ADHD in a narrative review based on available data and expert opinions to highlight key recommendations for future studies and clinical practice. We conclude that going forward, despite remote working in clinical services functioning adequately during the pandemic, all required components of ADHD assessment should still be completed following national/international guidelines; however, the process may need adaptation. Social restrictions, including changes in education provision, can either mask or exacerbate features associated with ADHD and therefore assessment should carefully chart symptom profile and impairment prior to, as well as during an ongoing pandemic. While remote assessments are valuable in allowing clinical services to continue despite restrictions and may have benefits for routine care in the post-pandemic world, particular attention must be paid to those who may be at high risk but not be able to use/access remote technologies and prioritize these groups for conventional face-to-face assessments.

Disentangling nature from nurture in examining the interplay between parent-child relationships, ADHD, and early academic attainment.

BACKGROUND: 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. METHOD: 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. RESULTS: 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). CONCLUSION: 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.

Testosterone therapy for sexual dysfunction in men with Type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

AIM: To evaluate the effectiveness of testosterone therapy on a range of sexual function domains in men with Type 2 diabetes. METHOD: Electronic databases were searched for studies investigating the effect of testosterone therapy on sexual function in men with Type 2 diabetes. All randomized controlled trials were considered for inclusion if they compared the efficacy of testosterone therapy with that of placebo and reported sexual function outcomes. Statistical analysis was performed using a random-effects model, and heterogeneity was expressed using the I2 statistic. RESULTS: A total of 611 articles were screened. Six randomized control trials, in a total of 587 men with Type 2 diabetes, were eligible for inclusion. The pooled data suggested that testosterone therapy improves sexual desire (random-effects pooled effect size 0.314; 95% CI 0.082-0.546) and erectile function (random-effects pooled effect size 0.203; 95% CI 0.007-0.399) when compared with control groups. Testosterone therapy had no significant effect on constitutional symptoms or other sexual domains compared with control groups. No studies have investigated the incidence of prostate cancer, fertility and cardiovascular disease after testosterone therapy in men with Type 2 diabetes. CONCLUSION: Testosterone therapy may moderately improve sexual desire and erectile function in men with Type 2 diabetes; however, available data are limited, and the long-term risks of testosterone therapy are not known in this specific patient group. We conclude that testosterone therapy is a potential treatment for men with Type 2 diabetes non-responsive to phosphodiesterase-5 inhibitors. Testosterone therapy could be considered for men with Type 2 diabetes when potential risks and benefits of therapy are carefully considered and other therapeutic options are unsuitable.

Psychiatric gene discoveries shape evidence on ADHD's biology.

A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10(-4)) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.

Explaining risk for suicidal ideation in adolescent offspring of mothers with depression.

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Systematic Review and Meta-Analysis of Utility of Graduated Compression Stockings in Prevention of Post-Thrombotic Syndrome.

BACKGROUND: Up to 50% of patients develop post-thrombotic syndrome (PTS) following their first proximal deep vein thrombosis (DVT). This meta-analysis aims to evaluate the effectiveness of graduated compression stockings (GCS) in preventing PTS. METHOD: Medline, Embase, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov were electronically searched from inception to January 2015 for studies investigating the effect of GCS in preventing PTS. All randomised control trials were considered for inclusion if they compared the efficacy of GCS (30-40 mmHg at the ankle) with either placebo or no stockings in adults with new proximal lower limb DVT. Methodological assessment, using the Cochrane Risk of Bias Tool, and data extraction was performed by two independent reviewers. The effect of GCS was expressed as the risk difference (RD). RESULTS: A total of 686 articles were screened. Three randomised controlled trials inclusive of 1,177 patients were eligible for inclusion. PTS developed in 49-70% of control patients at 5 years. High statistical heterogeneity was observed between trials (all PTS: I(2) = 0.94; severe PTS: I(2) = 0.79). The risk difference in PTS incidence between control and GCS arms varied from 0% to 39% between trials. In trials with a higher baseline prevalence of PTS, a visual trend towards more benefit with GCS was noted. CONCLUSION: Uncertainty because of sampling variability and heterogeneity was too high to conclude in favour or against an effect of wearing compression stockings in preventing PTS. An effect may be present for higher values of baseline risk. Further evidence is needed. Article history.

Association between obesity and depressive disorder in adolescents at high risk for depression.

OBJECTIVE: To examine the relationship between Body Mass Index (BMI) and depressive disorder in adolescents at high risk for depression. DESIGN: Prospective longitudinal 3-wave study of offspring of parents with recurrent depression. Replication in population-based cohort study. SUBJECTS: Three hundred and thirty-seven families where offspring were aged 9-17 years at baseline and 10-19 years at the final data point. Replication sample of adolescents from population-based cohort study aged 11-13 years at first assessment and 14-17 years at follow-up. MEASUREMENTS: High risk sample used BMI, skin-fold thickness, Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV)-defined major depressive disorder and depression symptoms using the Child and Adolescent Psychiatric Assessment (CAPA). Replication sample used BMI, DSM-IV depressive disorder and depression symptoms using the Development and Well-Being Assessment (DAWBA). RESULTS: Two hundred and eighty-nine adolescents were included in the primary analyses. The mean BMI for each age group in this sample were significantly higher than population norms. There was no significant longitudinal association between categories of weight (or BMI) and new onset depressive disorder or depression symptoms. Similar results were found for skin-fold thickness. The association was also tested in a replication population-based sample and found to be non-significant in the subsample of offspring with mothers who had experienced recurrent depression in the past. BMI at age 12 years was, however, a significant predictor of depression symptoms but not of depressive disorder at age 15 years for the total unselected population. CONCLUSION: BMI does not significantly predict the development of depression in the offspring of parents with recurrent depression.

Impact of risk scoring on decision-making in symptomatic moderate carotid atherosclerosis.

BACKGROUND: Benefit from carotid endarterectomy (CEA) in symptomatic moderate (50-69 per cent) carotid stenosis remains marginal. The Fourth National Clinical Guideline for Stroke recommends use of the risk score from the European Carotid Surgery Trial (ECST) to aid decision-making in symptomatic carotid disease. It is not known whether clinicians are, in fact, influenced by it. METHODS: Using the ECST risk prediction model, three scenarios of patients with a low (less than 10 per cent), moderate (20-25 per cent) and high (40-45 per cent) 5-year risk of stroke were devised and validated. Invitations to complete an online survey were sent by e-mail to vascular surgeons and stroke physicians, with responses gathered. The questionnaire was then repeated with the addition of the ECST risk score. RESULTS: Two hundred and one completed surveys were analysed (21·5 per cent response rate): 107 by stroke physicians and 94 by vascular surgeons. The high-risk scenario after the introduction of the ECST risk score showed an increased use of CEA (66·7 versus 80·1 per cent; P = 0·009). The low-risk scenario after risk score analysis demonstrated a swing towards best medical therapy (23·4 versus 57·2 per cent; P < 0·001). CEA was preferred in the moderate-risk scenario and this was not altered significantly by introduction of the risk score (71·6 versus 75·6 per cent; P = 0·609). Vascular surgeons exhibited a preference towards CEA compared with stroke physicians in both low- and moderate-risk scenarios (P < 0·001 and P = 0·003 respectively). CONCLUSION: The addition of a risk score appeared to influence clinicians in their decision-making towards CEA in high-risk patients and towards best medical therapy in low-risk patients.

Modelling the cost-effectiveness of carotid endarterectomy for asymptomatic stenosis.

BACKGROUND: The aim of this study was to model the cost-effectiveness of carotid endarterectomy for asymptomatic stenosis versus medical therapy based on 10-year data from the Asymptomatic Carotid Surgery Trial (ACST). METHODS: This was a cost-utility analysis based on clinical effectiveness data from the ACST with UK-specific costs and stroke outcomes. A Markov model was used to calculate the incremental cost-effectiveness ratio (ICER, or cost per additional quality-of-life year) for a strategy of early endarterectomy versus medical therapy for the average patient and published subgroups. An exploratory analysis considered contemporary event rates. RESULTS: The ICER was £7584 per additional quality-adjusted life-year (QALY) for the average patient in the ACST. At thresholds of £20,000 and £30,000 there was a 74 and 84 per cent chance respectively of early endarterectomy being cost-effective. The ICER for men below 75 years of age was £3254, and that for men aged 75 years or above was £71,699. For women aged under 75 years endarterectomy was less costly and more effective than medical therapy; for women aged 75 years or more endarterectomy was less effective and more costly than medical therapy. At contemporary perioperative event rates of 2·7 per cent and background any-territory stroke rates of 1·6 per cent, early endarterectomy remained cost-effective. CONCLUSION: In the ACST, early endarterectomy was predicted to be cost-effective in those below 75 years of age, using a threshold of £20,000 per QALY. If background any-territory stroke rates fell below 1 per cent per annum, early endarterectomy would cease to be cost-effective.

'The risks of playing it safe': a prospective longitudinal study of response to reward in the adolescent offspring of depressed parents.

BACKGROUND: 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. Method 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. RESULTS: 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. CONCLUSIONS: 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.

Familial transmission of depression and antisocial behavior symptoms: disentangling the contribution of inherited and environmental factors and testing the mediating role of parenting.

BACKGROUND: Genetic and environmental influences on child psychopathology have been studied extensively through twin and adoption designs. We offer a novel methodology to examine genetic and environmental influences on the intergenerational transmission of psychopathology using a sample of parents and children conceived through in vitro fertilization (IVF). METHOD: The sample included families with children born through IVF methods, who varied as to whether the child was genetically related or unrelated to the rearing mother and father (mother genetically related, n=434; mother genetically unrelated, n=127; father genetically related, n=403; father genetically unrelated, n=156). Using standardized questionnaires, mothers and fathers respectively reported on their own psychopathology (depression, aggression), their parenting behavior toward their child (warmth, hostility) and their child's psychopathology (depression, aggression). A cross-rater approach was used, where opposite parents reported on child symptoms (i.e. fathers reported on symptoms for the mother-child dyad, and vice versa). RESULTS: For mother-child dyads, a direct association between mother depression and child depression was observed among genetically unrelated dyads, whereas a fully mediated path was observed among genetically related dyads through mother-to-child hostility and warmth. For father-child dyads, direct and mediated pathways were observed for genetically related father-child dyads. For aggression, the direct association between parent aggression and child aggression was fully mediated by parent-to-child hostility for both groups, indicating the role of parent-to-child hostility as a risk mechanism for transmission. CONCLUSIONS: A differential pattern of genetic and environmental mediation underlying the intergenerational transmission of psychopathology was observed among genetically related and genetically unrelated father-child and mother-child dyads.

Hypertension and the post-carotid endarterectomy cerebral hyperperfusion syndrome.

OBJECTIVE: Cerebral hyperperfusion syndrome is a preventable cause of stroke after carotid endarterectomy (CEA). It manifests as headache, seizures, hemiparesis or coma due to raised intracranial pressure or intracerebral haemorrhage (ICH). There is currently no consensus on whether to control blood pressure, blood pressure thresholds associated with cerebral hyperperfusion syndrome, choice of anti-hypertensive agent(s) or duration of treatment. METHOD: A systematic review of the PubMed database (1963-2010) was performed using appropriate search terms according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 36 studies were identified as fitting a priori inclusion criteria. Following CEA, the incidence of severe hypertension was 19%, that of cerebral hyperperfusion 1% and ICH 0.5%. The postoperative mean systolic blood pressure of patients, who went on to develop cerebral hyperperfusion syndrome, was 164 mmHg (95% confidence interval (CI) 150-178 mmHg) and the cumulative incidence of cases rose appreciably above a postoperative systolic blood pressure of 150 mmHg. The mean systolic blood pressure of cerebral hyperperfusion cases was 189 mmHg (95% CI 183-196 mmHg) at presentation. The incidence of cerebral hyperperfusion in the first week was 92% with a median time to presentation of 5 days (interquartile range (IQR) 3-6 days). 36% of patients presented with seizures 31% with hemiparesis and 33% with both. The proportion of patients with severe hypertension was significantly higher in cases than in post-CEA controls (p < 0.0001, Odds ratio 19 (95% CI 9-41)). Three large case-control studies identify postoperative hypertension as a risk factor for ICH. CONCLUSION: There is currently level-3 evidence for the prevention of ICH through control of postoperative blood pressure. From the available data, we suggest a definition for cerebral hyperperfusion syndrome, blood pressure thresholds, duration of monitoring and a postoperative blood pressure control strategy for validation in a prospective study. The implications of this are that one in five patients would need intravenous anti-hypertensives and home blood pressure monitoring for 1 week.

The links between prenatal stress and offspring development and psychopathology: disentangling environmental and inherited influences.

BACKGROUND: Exposure to prenatal stress is associated with later adverse health and adjustment outcomes. This is generally presumed to arise through early environmentally mediated programming effects on the foetus. However, associations could arise through factors that influence mothers' characteristics and behaviour during pregnancy which are inherited by offspring. METHOD: A 'prenatal cross-fostering' design where pregnant mothers are related or unrelated to their child as a result of in vitro fertilization (IVF) was used to disentangle maternally inherited and environmental influences. If links between prenatal stress and offspring outcome are environmental, association should be observed in unrelated as well as related mother-child pairs. Offspring birth weight and gestational age as well as mental health were the outcomes assessed. RESULTS: Associations between prenatal stress and offspring birth weight, gestational age and antisocial behaviour were seen in both related and unrelated mother-offspring pairs, consistent with there being environmental links. The association between prenatal stress and offspring anxiety in related and unrelated groups appeared to be due to current maternal anxiety/depression rather than prenatal stress. In contrast, the link between prenatal stress and offspring attention deficit hyperactivity disorder was only present in related mother-offspring pairs and therefore was attributable to inherited factors. CONCLUSIONS: Genetically informative designs can be helpful in testing whether inherited factors contribute to the association between environmental risk factors and health outcomes. These results suggest that associations between prenatal stress and offspring outcomes could arise from inherited factors and post-natal environmental factors in addition to causal prenatal risk effects.

Adolescent and adult differences in major depression symptom profiles.

BACKGROUND: Depression is the leading global cause of disability and often begins in adolescence. The genetic architecture and treatment response profiles for adults and adolescents differ even though identical criteria are used to diagnose depression across different age groups. There is no clear consensus on how these groups differ in their symptom profiles. METHODS: Using data from a two-generation family study, we compared the presentation of DSM-IV depressive symptoms in adolescents and adults with MDD (Major Depressive Disorder). We also compared DSM-IV depressive symptom counts using latent class analysis. RESULTS: Vegetative symptoms (appetite and weight change, loss of energy and insomnia) were more common in adolescent MDD than adult MDD. Anhedonia/loss of interest and concentration problems were more common in adults with MDD. When using latent class analysis to look at depressive symptoms, a vegetative symptom profile was also seen in adolescent depression only. LIMITATIONS: Adults and adolescents were recruited in different ways. Adolescent cases were more likely to be first-onset while adult cases were recurrences. It was not possible to examine how recurrence affected adolescent depression symptom profiles. CONCLUSION: Differences in how depression presents in adolescents and adults may be consistent with different pathophysiological mechanisms. For adolescents, we found that vegetative/physical disturbances were common (loss of energy, changes in weight, appetite and sleep changes). For adults, anhedonia/loss of interest and concentration difficulties were more common.

A risk calculator to predict adult attention-deficit/hyperactivity disorder: generation and external validation in three birth cohorts and one clinical sample.

AIM: 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). METHODS: 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). RESULTS: 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/. CONCLUSIONS: 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.

Testing for gene x environment interaction effects in attention deficit hyperactivity disorder and associated antisocial behavior.

Gene x environment (G x E) interactions are increasingly thought to have substantial influence on the aetiology and clinical manifestations of complex disorders. In ADHD, although main effects of specific genetic variants and pre- or peri-natal variables have been reported and replicated using pooled analyses, few studies have looked at possible interactions. In a clinical sample of 266 children with ADHD, we tested for interaction between gene variants (in DRD4, DAT1, DRD5, and 5HTT) found to be associated with ADHD in pooled analyses and maternal smoking, alcohol use during pregnancy and birth weight. First, G x E effects on a diagnosis of ADHD were tested using conditional logistic regression analyses. Second, possible modifying effects of G x E on symptoms of associated conduct disorder and oppositional defiant disorder (ODD) were investigated using linear regression analysis. The sample size associated with each of the analyses differed as not each variant had been genotyped for each individual. No effects of G x E on ADHD diagnosis were observed. The results suggest that lower birth weight and maternal smoking during pregnancy may interact with DRD5 and DAT1 (birth weight only) in influencing associated antisocial behavior symptoms (ODD and conduct disorder). These preliminary findings showed no evidence of interaction between previously implicated variants in ADHD and specific environmental risk factors, on diagnosis of the disorder. There may be evidence of G x E on associated antisocial behavior in ADHD, but further investigation is needed.

Differential dopamine receptor D4 allele association with ADHD dependent of proband season of birth.

Season of birth (SOB) has been associated with attention deficit hyperactivity disorder (ADHD) in two existing studies. One further study reported an interaction between SOB and genotypes of the dopamine D4 receptor (DRD4) gene. It is important that these findings are further investigated to confirm or refute the findings. In this study, we investigated the SOB association with ADHD in four independent samples collected for molecular genetic studies of ADHD and found a small but significant increase in summer births compared to a large population control dataset. We also observed a significant association with the 7-repeat allele of the DRD4 gene variable number tandem repeat polymorphism in exon three with probands born in the winter season, with no significant differential transmission of this allele between summer and winter seasons. Preferential transmission of the 2-repeat allele to ADHD probands occurred in those who were born during the summer season, but did not surpass significance for association, even though the difference in transmission between the two seasons was nominally significant. However, following adjustment for multiple testing of alleles none of the SOB effects remained significant. We conclude that the DRD4 7-repeat allele is associated with ADHD but there is no association or interaction with SOB for increased risk for ADHD. Our findings suggest that we can refute a possible effect of SOB for ADHD.

Investigating the genetic underpinnings of early-life irritability.

Severe irritability is one of the commonest reasons prompting referral to mental health services. It is frequently seen in neurodevelopmental disorders that manifest early in development, especially attention-deficit/hyperactivity disorder (ADHD). However, irritability can also be conceptualized as a mood problem because of its links with anxiety/depressive disorders; notably DSM-5 currently classifies severe, childhood-onset irritability as a mood disorder. Investigations into the genetic nature of irritability are lacking although twin studies suggest it shares genetic risks with both ADHD and depression. We investigated the genetic underpinnings of irritability using a molecular genetic approach, testing the hypothesis that early irritability (in childhood/adolescence) is associated with genetic risk for ADHD, as indexed by polygenic risk scores (PRS). As a secondary aim we investigated associations between irritability and PRS for major depressive disorder (MDD). Three UK samples were utilized: two longitudinal population-based cohorts with irritability data from childhood (7 years) to adolescence (15-16 years), and one ADHD patient sample (6-18 years). Irritability was defined using parent reports. PRS were derived from large genome-wide association meta-analyses. We observed associations between ADHD PRS and early irritability in our clinical ADHD sample and one of the population samples. This suggests that early irritability traits share genetic risk with ADHD in the general population and are a marker of higher genetic loading in individuals with an ADHD diagnosis. Associations with MDD PRS were not observed. This suggests that early-onset irritability could be conceptualized as a neurodevelopmental difficulty, behaving more like disorders such as ADHD than mood disorders.