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It is unknown why attention deficit hyperactivity disorder (ADHD) is more common in males, whereas anxiety and depression show a female population excess. We tested the hypothesis that anxiety and depression risk alleles manifest as ADHD in males. We also tested whether anxiety and depression in children with ADHD show a different etiology to typical anxiety and depression and whether this differs by sex. The primary clinical ADHD sample consisted of 885 (14% female) children. Psychiatric symptoms were assessed using standardized interviews. Polygenic risk scores (PRS) were derived using large genetic studies. Replication samples included independent clinical ADHD samples (N = 3,794; 25.7% female) and broadly defined population ADHD samples (N = 995; 33.4% female). We did not identify sex differences in anxiety or depression PRS in children with ADHD. In the primary sample, anxiety PRS were associated with social and generalized anxiety in males, with evidence of a sex‐by‐PRS interaction for social anxiety. These results did not replicate in the broadly defined ADHD sample. Depression PRS were not associated with comorbid depression symptoms. The results suggest that anxiety and depression genetic risks are not more likely to lead to ADHD in males. Also, the evidence for shared etiology between anxiety symptoms in those with ADHD and typical anxiety was weak and needs replication.

It is unknown why attention deficit hyperactivity disorder (ADHD) is more common in males, whereas anxiety and depression show a female population excess. We tested the hypothesis that anxiety and depression risk alleles manifest as ADHD in males. We also tested whether anxiety and depression in children with ADHD show a different etiology to typical anxiety and depression and whether this differs by sex. The primary clinical ADHD sample consisted of 885 (14% female) children. Psychiatric symptoms were assessed using standardized interviews. Polygenic risk scores (PRS) were derived using large genetic studies. Replication samples included independent clinical ADHD samples (N = 3,794; 25.7% female) and broadly defined population ADHD samples (N = 995; 33.4% female). We did not identify sex differences in anxiety or depression PRS in children with ADHD. In the primary sample, anxiety PRS were associated with social and generalized anxiety in males, with evidence of a sex-by-PRS interaction for social anxiety. These results did not replicate in the broadly defined ADHD sample. Depression PRS were not associated with comorbid depression symptoms. The results suggest that anxiety and depression genetic risks are not more likely to lead to ADHD in males. Also, the evidence for shared etiology between anxiety symptoms in those with ADHD and typical anxiety was weak and needs replication.

Supplemental material, sj-pdf-1-jad-10.1177_10870547211025612 for Exploring ADHD Symptoms and Associated Impairment across Development by Ayako Niina, Olga Eyre, Robyn Wootton, Evangelia Stergiakouli, Anita Thapar and Lucy Riglin in Journal of Attention Disorders

Background: Children with neurodevelopmental disorders are at increased risk of developing depression. Irritability predicts depression in the general population and is common in children with neurodevelopmental disorders. Thus, it is possible that irritability in children with neurodevelopmental disorders contributes to the link with later depression. This study aimed to (1) examine the association between childhood neurodevelopmental difficulties and adolescent depression and (2) test whether irritability explains this association.Methods: Children with any neurodevelopmental difficulty at age 7-9 (n=1697) and a selected, comparison group without any neurodevelopmental difficulty (n=3177) were identified from a prospective, UK population-based cohort, the Avon Longitudinal Study of Parents and Children. Neurodevelopmental difficulties were defined as a score in the bottom 5% of the sample on at least one measure of cognitive ability, communication, autism spectrum symptoms, attention-deficit/hyperactivity symptoms, reading or motor co-ordination. The Development and Well Being Assessment measured parent-reported child irritability at age 7, parent-reported adolescent depression at ages 10 and 13, and self-reported depression at age 15. Depression measures were combined, deriving an outcome of Major Depressive Disorder (MDD) in adolescence. Logistic regression examined the association between childhood neurodevelopmental difficulties and adolescent MDD, controlling for gender. Path analysis estimated the proportion of this association explained by irritability. Analyses were repeated for individual neurodevelopmental problems.Results: Childhood neurodevelopmental difficulties were associated with adolescent MDD (OR=2.11, 95% CI=1.24,3.60, p=0.006). Childhood irritability statistically accounted for 42% of this association. On examining each neurodevelopmental difficulty separately, autistic, communication and ADHD problems were each associated with depression, with irritability explaining 29%-51% of these links.Conclusions: Childhood irritability appears to be a key contributor to the link between childhood neurodevelopmental difficulties and adolescent MDD. High rates of irritability in children with autistic and ADHD difficulties may explain elevated rates of depression in the neurodevelopmental group.

Attention-deficit/hyperactivity disorder (ADHD) frequently co-occurs with depression, and out-\ud comes are poor when both are present. Little is known about whether depression symptoms present differ-\ud ently in ADHD compared to the general population, or how reliable young people with ADHD are at reporting\ud these symptoms. This study aimed to describe depression symptoms in a clinical ADHD sample compared to a\ud population sample, and compare self-reports of depression symptoms with parent-reports. Methods: Two\ud hundred and forty-nine children with ADHD and their parents completed follow-up questionnaires around\ud 5 years after taking part in a Cardiff University ADHD study. Child depression symptoms were measured using\ud parent- and child-reported Mood and Feelings Questionnaires (MFQ) and compared to a population sample\ud with MFQ data (n = 1460). Within both samples, child- and parent-reported depression symptoms were com-\ud pared. Results: Although the profile of depression symptoms was similar between young people with ADHD\ud and those in the general population, depression symptoms were much more common in the ADHD sample\ud (parent-rated MFQ score = 24.52 vs. 9.39; child-rated = 21.02 vs. 11.86). The most common symptoms in both\ud samples included irritability, restlessness and concentration difficulties, with core depression symptoms such as\ud feeling miserable/unhappy also prominent. Within the ADHD sample, but not the population sample, children\ud reported depression symptoms less frequently than their parents. Conclusions: Young people with ADHD are\ud at high risk of experiencing symptoms of depression but may under-report the severity of their symptoms.\ud Obtaining parent reports of depression symptoms in this group may be important to avoid missing key indica-\ud tors of risk.

Background:\ud \ud Attention deficit hyperactivity disorder (ADHD) is more commonly diagnosed in males than in females. A growing body of research suggests that females with ADHD might be underdiagnosed or receive alternative diagnoses, such as anxiety or depression. Other lines of reasoning suggest that females might be protected from developing ADHD, requiring a higher burden of genetic risk to manifest the disorder.\ud \ud \ud Methods:\ud \ud We tested these two hypotheses, using common variant genetic data from two population-based cohorts. First, we tested whether females and males diagnosed with anxiety or depression differ in terms of their genetic risk for ADHD, assessed as polygenic risk scores (PRS). Second, we tested whether females and males with ADHD differed in ADHD genetic risk burden. We used three different diagnostic definitions: registry-based clinical diagnoses, screening-based research diagnoses and algorithm-based research diagnoses, to investigate possible referral biases.\ud \ud \ud Results:\ud \ud In individuals with a registry-based clinical diagnosis of anxiety or depression, females had higher ADHD PRS than males [OR(CI) = 1.39 (1.12–1.73)] but there was no sex difference for screening-based [OR(CI) = 1.15 (0.94–1.42)] or algorithm-based [OR(CI) = 1.04 (0.89–1.21)] diagnoses. There was also no sex difference in ADHD PRS in individuals with ADHD diagnoses that were registry-based [OR(CI) = 1.04 (0.84–1.30)], screening-based [OR(CI) = 0.96 (0.85–1.08)] or algorithm-based [OR(CI) = 1.15 (0.78–1.68)].\ud \ud \ud Conclusions:\ud \ud This study provides genetic evidence that ADHD risk may be more likely to manifest or be diagnosed as anxiety or depression in females than in males. Contrary to some earlier studies, the results do not support increased ADHD genetic risk in females with ADHD as compared to affected males.

Importance: Early-onset major depressive disorder (MDD) is common in individuals at high familial risk of depression and is associated with poor long-term mental health, social, and educational outcomes.\ud \ud Objectives: To examine the developmental pathways that lead to first-episode adolescent-onset MDD (incident cases) in those at high familial risk and to postulate a theoretically informed model that enables simultaneous testing of different pathways to incident adolescent-onset MDD composed of contributions from familial/genetic and social risk factors, as well as effects via specific clinical antecedents.\ud \ud Design, Setting, and Participants: This investigation was a 4-year longitudinal study (April 2007 to March 2011) among offspring of depressed parents in the general community. Analyses were conducted between September 1, 2015, and May 27, 2016. Participants were 337 families in whom the index parent (315 mothers and 22 fathers) had experienced at least 2 episodes of MDD (recruited through primary care) and among whom there was a biologically related child in the age range of 9 to 17 years living with the index parent (197 girls and 140 boys with a mean [SD] age of 12.4 [2.0] years) at baseline. Offspring with MDD before the study or at baseline (n = 27), offspring with an episode of MDD that had remitted by follow-up (n = 4), and offspring with missing baseline MDD data (n = 2) were excluded. Ninety-two percent (279 of 304) of families completed the follow-up.\ud \ud Main Outcomes and Measures: The primary outcome was new-onset offspring MDD, and the secondary outcome was the total DSM-IV MDD symptom score.\ud \ud Results: On average, children and adolescents had a mean (SD) of 1.85 (1.74) (range, 0-8.5) DSM-IV symptoms of MDD at follow-up. Twenty (6 males and 14 females) had new-onset MDD, with a mean (SD) age at onset of 14.4 (2.0) years (range, 10-18 years). Irritability (β = 0.12, P = .03) and fear and/or anxiety (β = 0.38, P

When embarking on mental health research it is often necessary to apply for approvals from one or more review bodies to ensure that the research is ethical and that the safety and well-being of participants are safeguarded. This can be complicated and time consuming, particularly to those unfamiliar with the process. In this article we describe the approvals commonly required for National Health Service-based research involving patients and endeavour to clearly explain what is involved at each stage. We then highlight some of the main considerations, including ethical aspects, which are particularly pertinent to conducting research in the field of mental health, and finish with general advice and considerations for future developments in the area.

Background: Attention-deficit/hyperactivity disorder (ADHD) and other neurodevelopmental disorders are often associated with depression. Irritability is common in ADHD and other neurodevelopmental disorders, and has been linked to depression in the general population. However, research into the link between irritability and depression in those with neurodevelopmental disorders is lacking. This thesis aimed to examine the association between childhood irritability and depression in young people with ADHD, and in a group with broader neurodevelopmental difficulties.\ud Methods: A clinical ADHD sample, the Study of ADHD Genes and Environment, was used to examine the association between childhood irritability and depression symptoms in young people with ADHD. The same sample was used to examine whether children with ADHD and irritability have an increased genetic liability for depression (indexed by depression polygenic risk scores (PRS)), compared to those with ADHD but no irritability. Finally, a longitudinal population-based cohort, the Avon Longitudinal Study of Parents and Children, was used to examine the role of irritability in the association between childhood neurodevelopmental difficulties and later depression.\ud Results: Childhood irritability was associated with depression symptoms cross-sectionally and longitudinally in the clinical ADHD sample. Persistent irritability across childhood and adolescence was particularly important in the longitudinal association. Childhood irritability was not associated with depression PRS in children with ADHD (although irritability was associated with ADHD PRS). Finally, irritability was important in the association between neurodevelopmental difficulties and later depression in the population-based cohort, specifically in those with ADHD and ASD difficulties.\ud Conclusion: Findings from this thesis suggest that childhood irritability is an important marker of depression risk in children diagnosed with ADHD, as well in children with ADHD and ASD difficulties in the general population. Assessing irritability in children with ADHD and ASD difficulties may allow early identification and treatment of depression, as well as provide an opportunity for prevention.