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Attention-deficit/hyperactivity disorder (ADHD) is often comorbid with other psychiatric conditions in adults. Yet, less is known about its relationship with common metabolic disorders and how sex and ageing affect the overall comorbidity patterns of adult ADHD. We aimed to examine associations of adult ADHD with several common psychiatric and metabolic conditions. Through the linkage of multiple Swedish national registers, 5,551,807 adults aged 18 to 64 years and living in Sweden on December 31, 2013 were identified and assessed for clinical diagnoses of adult ADHD, substance use disorder (SUD), depression, bipolar disorder, anxiety, type 2 diabetes mellitus (T2DM), and hypertension. Logistic regression models and regression standardization method were employed to obtain estimates of prevalence, prevalence difference (PD), and prevalence ratio (PR). All comorbid conditions of interest were more prevalent in adults with ADHD (3.90% to 44.65%) than in those without (0.72% to 4.89%), with the estimated PRs being over nine for psychiatric conditions (p < 0.001) and around two for metabolic conditions (p < 0.001). Sex differences in the prevalence of comorbidities were observed among adults with ADHD. Effect modification by sex was detected on the additive scale and/or multiplicative scale for the associations of adult ADHD with all comorbidities. ADHD remained associated with all comorbidities in older adults aged 50 to 64 when all conditions were assessed from age 50 onwards. The comorbidity patterns of adult ADHD underscore the severity and clinical complexity of the disorder. Clinicians should remain vigilant for a wide range of psychiatric and metabolic problems in ADHD affected adults of all ages and both sexes.

It is unclear whether and to what extent stress-related exposures moderate the effects of polygenic risk scores (PRSs) on depression and anxiety. We aimed to examine such moderation effects for a variety of stress-related exposures on depression and anxiety. We included 41,810 participants with both genome-wide genetic data and measurements of depression and anxiety in the Lifelines Cohort Study. Current depression and anxiety were measured by the MINI International Neuropsychiatric Interview. Stress-related exposures included long-term difficulties, stressful life events, reduced social support, childhood trauma, and loneliness, which were measured by self-report questionnaires. PRSs were calculated based on recent large genome-wide association studies for depression and anxiety. We used linear mixed models adjusting for family relationships to estimate the interactions between PRSs and stress-related exposures. Nine of the ten investigated interactions between the five stress-related exposures and the two PRSs for depression and anxiety were significant (Ps < 0.001). Reduced social support, and higher exposure to long-term difficulties, stressful life events, and loneliness amplified the genetic effects on both depression and anxiety. As for childhood trauma exposure, its interaction with the PRS was significant for depression (P = 1.78 × 10–05) but not for anxiety (P = 0.32). Higher levels of stress-related exposures significantly amplify the effects of genetic susceptibility on depression and anxiety. With a large sample size and a comprehensive set of stress-related exposures, our study provides powerful evidence on the presence of polygenic risk-by-environment interactions in relation to depression and anxiety.

Depression, anxiety, obesity and substance use are heritable and often co-occur. However, the mechanisms underlying this co-occurrence are not fully understood. We estimated their familial aggregation and co-aggregation as well as heritabilities and genetic correlations to improve etiological understanding. Data came from the multi-generational population-based Lifelines Cohort Study ( n  = 162,439). Current depression and anxiety were determined using the MINI International Neuropsychiatric Interview. Smoking, alcohol and drug use were assessed by self-report questionnaires. Body mass index (BMI) and obesity were calculated by measured height and weight. Modified Cox proportional hazards models estimated recurrence risk ratios (λ R ), and restricted maximum likelihood variance decomposition methods estimated heritabilities (h 2 ) and genetic correlations (r G ). All analyses were adjusted for age, age 2 , and sex. Depression, anxiety, obesity and substance use aggregated within families (λ R first-degree relative  = 1.08–2.74) as well as between spouses (λ R  = 1.11–6.60). All phenotypes were moderately heritable (from h 2 depression  = 0.25 to h 2 BMI  = 0.53). Depression, anxiety, obesity and smoking showed positive familial co-aggregation. That is, each of these traits confers increased risk on the other ones within families, consistent with the positive genetic correlations between these phenotypes (r G  = 0.16–0.94). The exception was obesity, which showed a negative co-aggregation with alcohol and drug use and vice versa, consistent with the negative genetic correlations of BMI with alcohol (r G  = −0.14) and soft drug use (r G  = −0.10). Patterns of cross-phenotype recurrence risk highlight the co-occurrence among depression, anxiety, obesity and substance use within families. Patterns of genetic overlap between these phenotypes provide clues to uncovering the mechanisms underlying familial co-aggregation.

The recent successful genome-wide association studies (GWASs) for depression have yielded more than 80 replicated loci and brought back the excitement that had evaporated during the years of negative GWAS findings. The identified loci provide anchors to explore their relevance for depression, but this comes with new challenges. Using the watershed model of genotype–phenotype relationships as a conceptual aid and recent genetic findings on other complex phenotypes, we discuss why it took so long and identify seven future challenges. The biggest challenge involves the identification of causal mechanisms since GWAS associations merely flag genomic regions without a direct link to underlying biological function. Furthermore, the genetic association with the index phenotype may also be part of a more extensive causal pathway (e.g., from variant to comorbid condition) or be due to indirect influences via intermediate traits located in the causal pathways to the final outcome. This challenge is highly relevant for depression because even its narrow definition of major depressive disorder captures a heterogeneous set of phenotypes which are often measured by even more broadly defined operational definitions consisting of a few questions (minimal phenotyping). Here, Mendelian randomization and future discovery of additional genetic variants for depression and related phenotypes will be of great help. In addition, reduction of phenotypic heterogeneity may also be worthwhile. Other challenges include detecting rare variants, determining the genetic architecture of depression, closing the “heritability gap”, and realizing the potential for personalized treatment. Along the way, we identify pertinent open questions that, when addressed, will advance the field.

Mental health problems during adolescence may create a problematic start into adulthood for affected individuals. Usually, categorical indicators of adolescent mental health issues (yes/no psychiatric disorder) are used in studies into long-term functional outcomes. This however does not take into account the full spectrum of mental health, nor does it consider the trajectory of mental health problem development over time. The aim of this study was twofold: (1) to identify distinct developmental trajectories of (co-occurring) internalizing and externalizing mental health symptoms over the course of adolescence (ages 11-19), and (2) to document the associations between these adolescent trajectories and economic, social, and health outcomes in young adulthood (age 22), unadjusted and adjusted for childhood functioning, putative confounders and current mental health. Data were used from the Dutch TRAILS cohort study (subsample n = 1524, 47.3% males). Self-reported INT and EXT symptoms using the Youth/Adult Self Report were assessed four times (ages 11y, 13y, 16y, 19y). Adolescent mental health trajectories were estimated using Parallel-Processes Latent Class Growth Analyses. Self-reported economic, social, and health outcomes and parent-reported current mental health (using Adult Behaviour Checklist) were assessed at age 22. Multiple logistic regression analyses were performed to test associations between trajectories and outcomes. Four distinct trajectory classes were identified: (1) a normative class with decreasing-low INT+EXT symptoms (n = 460), (2) continuous moderately-high INT+EXT (n = 298), (3) continuous moderate, INT>EXT (n = 414), and (4) decreasing moderate, EXT>INT (n = 352). Compared to the normative class, the other three trajectories generally predicted less optimal early-adult outcomes, with the strongest effects observed for individuals with continuous moderate-high levels of both INT and EXT symptoms throughout adolescence. The associations largely remained after adjustment for pre-adolescent functioning, selected confounders and current mental health. Both adolescent trajectories and current mental health had substantial independent effects on early-adult functioning.

Background Comorbidity between depressive and anxiety disorders is common. A hypothesis of the network perspective on psychopathology is that comorbidity arises due to the interplay of symptoms shared by both disorders, with overlapping symptoms acting as so-called bridges , funneling symptom activation between symptom clusters of each disorder. This study investigated this hypothesis by testing whether (i) two overlapping mental states “worrying” and “feeling irritated” functioned as bridges in dynamic mental state networks of individuals with both depression and anxiety as compared to individuals with either disorder alone, and (ii) overlapping or non-overlapping mental states functioned as stronger bridges. Methods Data come from the Netherlands Study of Depression and Anxiety (NESDA). A total of 143 participants met criteria for comorbid depression and anxiety (65%), 40 participants for depression-only (18.2%), and 37 for anxiety-only (16.8%) during any NESDA wave. Participants completed momentary assessments of symptoms (i.e., mental states) of depression and anxiety, five times a day, for 2 weeks (14,185 assessments). First, dynamics between mental states were modeled with a multilevel vector autoregressive model, using Bayesian estimation. Summed average lagged indirect effects through the hypothesized bridge mental states were compared between groups. Second, we evaluated the role of all mental states as potential bridge mental states. Results While the summed indirect effect for the bridge mental state “worrying” was larger in the comorbid group compared to the single disorder groups, differences between groups were not statistically significant. The difference between groups became more pronounced when only examining individuals with recent diagnoses (< 6 months). However, the credible intervals of the difference scores remained wide. In the second analysis, a non-overlapping item (“feeling down”) acted as the strongest bridge mental state in both the comorbid and anxiety-only groups. Conclusions This study empirically examined a prominent network-approach hypothesis for the first time using longitudinal data. No support was found for overlapping mental states “worrying” and “feeling irritable” functioning as bridge mental states in individuals vulnerable for comorbid depression and anxiety. Potentially, bridge mental state activity can only be observed during acute symptomatology. If so, these may present as interesting targets in treatment, but not prevention. This requires further investigation.

During conversation, speakers constantly make choices about how specific they wish to be in their use of referring expressions. In the present study we investigate whether speakers take the listener into account or whether they base their referential choices solely on their own representation of the discourse. We do this by examining the cognitive mechanisms that underlie the choice of referring expression at different discourse moments. Furthermore, we provide insights into how children with Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) use referring expressions and whether their use differs from that of typically developing (TD) children. Children between 6 and 12 years old (ASD: n=46; ADHD: n=37; TD: n=38) were tested on their production of referring expressions and on Theory of Mind, response inhibition and working memory. We found support for the view that speakers take the listener into account when choosing a referring expression: Theory of Mind was related to referential choice only at those moments when speakers could not solely base their choice on their own discourse representation to be understood. Working memory appeared to be involved in keeping track of the different referents in the discourse. Furthermore, we found that TD children as well as children with ASD and children with ADHD took the listener into account in their choice of referring expression. In addition, children with ADHD were less specific than TD children in contexts with more than one referent. The previously observed problems with referential choice in children with ASD may lie in difficulties in keeping track of longer and more complex discourses, rather than in problems with taking into account the listener.

Autism spectrum disorder (ASD) and Attention-deficit/hyperactivity disorder (ADHD) are often comorbid. The purpose of this study is to explore the relationships between ASD and ADHD symptoms by applying causal modeling. We used a large phenotypic data set of 417 children with ASD and/or ADHD, 562 affected and unaffected siblings, and 414 controls, to infer a structural equation model using a causal discovery algorithm. Three distinct pathways between ASD and ADHD were identified: (1) from impulsivity to difficulties with understanding social information, (2) from hyperactivity to stereotypic, repetitive behavior, (3) a pairwise pathway between inattention, difficulties with understanding social information, and verbal IQ. These findings may inform future studies on understanding the pathophysiological mechanisms behind the overlap between ASD and ADHD.

Attention-deficit/hyperactivity disorder (ADHD; also known as hyperkinetic disorder) is a common neurodevelopmental condition that affects children and adults worldwide. ADHD has a predominantly genetic aetiology that involves common and rare genetic variants. Some environmental correlates of the disorder have been discovered but causation has been difficult to establish. The heterogeneity of the condition is evident in the diverse presentation of symptoms and levels of impairment, the numerous co-occurring mental and physical conditions, the various domains of neurocognitive impairment, and extensive minor structural and functional brain differences. The diagnosis of ADHD is reliable and valid when evaluated with standard diagnostic criteria. Curative treatments for ADHD do not exist but evidence-based treatments substantially reduce symptoms and/or functional impairment. Medications are effective for core symptoms and are usually well tolerated. Some non-pharmacological treatments are valuable, especially for improving adaptive functioning. Clinical and neurobiological research is ongoing and could lead to the creation of personalized diagnostic and therapeutic approaches for this disorder. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that typically starts in childhood. This Primer summarizes the epidemiology, mechanisms, diagnosis and treatment of ADHD.

A subsample of children and young people (CYP) with anxiety disorders presents with comorbid behavioral problems. These CYP have greater impairment in daily life, profit less from current treatments, and have an increased risk for continued mental problems. We investigated two potential explanations for these comorbid behavioral problems. First, high punishment sensitivity (PS) may lead to a strong inclination to experience threat, which may not only elicit anxiety but also defensive behavioral problems. Second, behavioral problems may arise from high reward sensitivity (RS), when rewards are not obtained. Behavioral problems may subsequently elicit parental rejection, thereby fueling anxiety. We used a cross-sectional (age = 16.1, N = 61) and prospective (age = 22.2, N = 91) approach to test the relationship between PS/RS and comorbid behavioral problems. Participants were a subsample of highly anxious CYP from a large prospective cohort study. PS/RS were indexed by a spatial orientation task. We also investigated the prospective association between behavioral problems and anxiety at 6-year follow-up, and the proposed mediation by parental rejection. PS and RS showed no cross-sectional or prospective relationships with comorbid behavioral problems in highly anxious CYP. Yet, behavioral problems in adolescence showed a small prospective relationship with anxiety in young adulthood, but this was not mediated nor moderated by parental rejection. No evidence was found for PS/RS being involved in comorbid behavioral problems in anxious CYP. Findings point to comorbid behavioral problems as potential factor contributing to the further increase of anxiety.