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Genome-wide studies are yielding a growing catalog of common and rare variants that confer risk for psychopathology. However, despite representing unprecedented progress, emerging data also indicate that the full promise of psychiatric genetics—including understanding pathophysiology and improving personalized care—will not be fully realized by targeting traditional dichotomous diagnostic categories. The current article provides reflections on themes that emerged from a 2021 National Institute of Mental Health–sponsored conference convened to address strategies for the evolving field of psychiatric genetics. As anticipated by the National Institute of Mental Health's Research Domain Criteria framework, multilevel investigations of dimensional and transdiagnostic phenotypes, particularly when integrated with biobanks and big data, will be critical to advancing knowledge. The path forward will also require more diverse representation in source studies. Additionally, progress will be catalyzed by a range of converging approaches, including capitalizing on computational methods, pursuing biological insights, working within a developmental framework, and engaging health care systems and patient communities. [ABSTRACT FROM AUTHOR]

It is well established that mental health conditions, including substance use disorders, are associated with premature mortality. A meta-analysis1 has demonstrated that this association holds across a range of diagnoses. Although the effect is stronger for schizophrenia, depression and anxiety contribute to more deaths overall because of their high prevalence rates. Moreover, more than two-thirds of associated deaths were explained by natural causes.1 The next logical questions, then, are as follows: which mechanisms underlie this association, and can they can be mitigated? In the current issue of JAACAP , Clark et al. 2 aim to tie mental health symptoms and substance use to the acceleration of biological aging. [ABSTRACT FROM AUTHOR]

Suicide is among the leading causes of death in children and adolescents. There are well-known risk factors of suicide, including childhood abuse, family conflicts, social adversity, and psychopathology. While suicide risk is also known to be heritable, few studies have investigated genetic risk in younger individuals. Using polygenic risk score analysis, we examined whether genetic susceptibility to major psychiatric disorders is associated with suicidal behaviors among 11,878 children enrolled in the ABCD (Adolescent Brain Cognitive Development) Study. Suicidal ideation and suicide attempt data were assessed using the youth report of the Kiddie Schedule for Affective Disorders and Schizophrenia for DSM-5. After performing robust quality control of genotype data, unrelated individuals of European descent were included in analyses (n = 4344). Among 8 psychiatric disorders we examined, depression polygenic risk scores were associated with lifetime suicide attempts both in the baseline (odds ratio = 1.55, 95% CI = 1.10–2.18, p = 1.27 × 10−2) and in the follow-up year (odds ratio = 1.38, 95% CI = 1.08–1.77, p = 1.05 × 10−2), after adjusting for children's age, sex, socioeconomic backgrounds, family history of suicide, and psychopathology. In contrast, attention-deficit/hyperactivity disorder polygenic risk scores were associated with lifetime suicidal ideation (odds ratio = 1.15, 95% CI = 1.05–1.26, p = 3.71 × 10−3), suggesting a distinct contribution of the genetic risk underlying attention-deficit/hyperactivity disorder and depression on suicidal behaviors of children. The largest genetic sample of suicide risk data in U.S. children suggests a significant genetic basis of suicide risk related to attention-deficit/hyperactivity disorder and depression. Further research is warranted to examine whether incorporation of genomic risk may facilitate more targeted screening and intervention efforts. [ABSTRACT FROM AUTHOR]

Background: Studies are documenting the impact of the COVID-19 pandemic on youth mental health. We extended this literature by characterizing a child psychiatric outpatient sample in the United States during the middle of the 2020–2021 school year. We also used a computational strategy to identify distinct patterns of psychopathology symptom change and examined correlates and predictors of such change. Among potential predictors were cognition and clinical diagnoses, which have not been studied in this context previously. Methods: Participants were 171 youth (aged 10.6 ± 3.1) referred for neuropsychiatric evaluation who enrolled in research and whose parents filled out a survey on COVID-19. The questionnaire included eight psychiatric and six psychosocial domains rated retrospectively prior to the pandemic and currently at the time of evaluation. We examined change in severity of individual domains with Wilcoxon signed-rank tests. We used a latent profile analysis (LPA) to identify groups with distinct symptom change profiles. Using multinomial logistic regression, we examined potential predictors and correlates of LPA-derived groups. Models controlled for age, sex, and assessment date and corrected for multiple testing. Results: Although the majority of individual psychopathology domains were worse on average during the 2020–2021 school year, youth showed distincive patterns of symptom change. In addition to a large group (72.2%) with relatively stable symptoms and a small group (6.4%) that improved on most symptoms, there were two groups with different constellations of worsening symptoms. These latter groups both showed increased sadness, anxiety and oppositionality; however, one had increased hyperactivity/impulsivity and no change in hopelessness while the other showed greater hopelessness and no change in hyperactivity. Symptoms related to the distinguishable domains of these groups predicted group membership, and changes in screen time, conflict with parents and social isolation were correlates of worsening. Cognition and lifetime clinical diagnoses failed to predict group membership. Conclusions: In youth outpatients, psychiatric and psychosocial difficulties were worse on average during the school year following the spring 2020 COVID-19 lockdown; yet, some youth experienced greater and distinctive symptom change. A personalized approach to support may be needed as youth emerge from this period. [ABSTRACT FROM AUTHOR]

Objectives: Studies suggest that impairments in some of the same domains of cognition occur in different neuropsychiatric conditions, including those known to share genetic liability. Yet, direct, multi-disorder cognitive comparisons are limited, and it remains unclear whether overlapping deficits are due to comorbidity. We aimed to extend the literature by examining cognition across different neuropsychiatric conditions and addressing comorbidity. Methods: Subjects were 486 youth consecutively referred for neuropsychiatric evaluation and enrolled in the Longitudinal Study of Genetic Influences on Cognition. First, we assessed general ability, reaction time variability (RTV), and aspects of executive functions (EFs) in youth with non-comorbid forms of attention-deficit/hyperactivity disorder (ADHD), mood disorders and autism spectrum disorder (ASD), as well as in youth with psychosis. Second, we determined the impact of comorbid ADHD on cognition in youth with ASD and mood disorders. Results: For EFs (working memory, inhibition, and shifting/flexibility), we observed weaknesses in all diagnostic groups when participants' own ability was the referent. Decrements were subtle in relation to published normative data. For RTV, weaknesses emerged in youth with ADHD and mood disorders, but trend-level results could not rule out decrements in other conditions. Comorbidity with ADHD did not impact the pattern of weaknesses for youth with ASD or mood disorders but increased the magnitude of the decrement in those with mood disorders. Conclusions: Youth with ADHD, mood disorders, ASD, and psychosis show EF weaknesses that are not due to comorbidity. Whether such cognitive difficulties reflect genetic liability shared among these conditions requires further study. [ABSTRACT FROM AUTHOR]

Unbiased genomewide association studies of tens of thousands of individuals are transforming our understanding of the origins and structure of psychopathology across the lifespan. Together with findings from epidemiology and cognitive neuroscience, these recent molecular genetic studies underscore the importance of studying phenotypes across as well as within conventional psychiatric diagnoses in order to construct a more pathophysiologically grounded taxonomy from the bottom up. Such efforts, promoted by NIMH's Research Domain Criteria ( RDoC) framework, are critical to developing more accurate models of the risk mechanisms that are shared and distinct across various psychopathologic outcomes. In turn, these models could reveal new treatment targets and early intervention opportunities. In their article in the 2015 JCPP Annual Research Review, Scerif and Baker remind us that bottom-up insights into psychiatric illness might also be gained by examining specific genetic disorders that often fall within the purview of pediatrics and neurology. These authors note high rates of symptoms of attention-deficit hyperactivity disorder ( ADHD) in syndromes with known and often monogenic genetic causes (e.g. Fragile X) and suggest that studying the ADHD-like phenomena in these conditions may provide insight into ADHD itself. This commentary highlights themes from Scerif and Baker's review that overlap with the core tenets of RDoC and notes their significance for advancing our understanding of ADHD in the coming years. It concludes by suggesting ways in which further attention to the RDoC framework could also enhance Scerif and Baker's agenda. [ABSTRACT FROM AUTHOR]

The article presents a study which aims to identify quantitative trait loci that influence the Child Behavior Checklist Juvenile Bipolar Disorder (CBCL-JBD) phenotype by using a powerful set of single-nucleotide polymorphism markers. The study completed a linkage analysis on individuals and families with CBCL. The study shows a possibility that genes in the region influence variation on the CBCL-JBD scale and the emotional and behavioral dysregulation associated with severe psychopathology.

Background: Little is known about the neuropsychological status of youth with bipolar disorder (BPD) or whether cognitive deficits in this population are accounted for by comorbidity with attention deficit/hyperactivity disorder (ADHD). We compared neuropsychological and academic functioning of youth with and without DSM-IV BPD, controlling for effects of comorbid ADHD. Methods: Fifty-seven youth with BPD and 46 healthy control subjects were assessed on a battery of clinical neuropsychological measures including subtests from the Wechsler Intelligence Scales for Children and Adults (Third Editions), the Stroop, the Wisconsin Card Sorting Test, the Rey–Osterreith Complex Figure, an auditory working memory Continuous Performance Test, a measure of verbal learning, and the Wide Range Achievement Test-Third Edition. Results: Bipolar disorder was associated with impairments on subtests reflecting sustained attention, working memory, and processing speed after controlling for ADHD. Additionally, decrements of moderate effect sizes were found for measures of interference control, abstract problem solving, and verbal learning but did not meet criteria for statistical significance. Conclusions: After controlling for ADHD, youth with BPD show neuropsychological deficits similar to impairments found in adults with the disorder. Further studies are needed to understand the clinical implications of these impairments as well as their role in the underlying risk for pediatric BPD. [Copyright &y& Elsevier]

Behavioral genetic studies provide strong evidence that attention-deficit/hyperactivity disorder (ADHD) has a substantial genetic component. Yet, due to the complexity of the ADHD phenotype, questions remain as to the specific genes that contribute to this condition as well as the pathways from genes to behavior. Endophenotypes, or phenotypes that are more closely linked to the neurobiological substrate of a disorder, offer the potential to address these two issues simultaneously (Freedman, Adler, & Leonard, 1999). Thus far, potential endophenotypes for ADHD have not been systematically studied. The current paper reviews evidence supporting the use of deficits on neurocognitive measures of executive functions for this purpose. Such deficits are a correlate of ADHD and show preliminary evidence of heritability and association with relevant candidate genes. Nonetheless, studies that have assessed the familial and genetic overlap of neurocognitive impairments with ADHD have yielded inconsistent results. In order for executive function deficits to be used as an endophenotype for ADHD, we recommend greater attention to the neurocognitive heterogeneity of this disorder and to the precision of measurement of the neuropsychological tests employed. We also discuss empirical strategies that may be necessary to allow such research to progress prior to full resolution of the pathophysiological basis of ADHD. [ABSTRACT FROM AUTHOR]

One of the most prominent neuropsychologic theories of attention-deficit/hyperactivity disorder (ADHD) suggests that its symptoms arise from a primary deficit in executive functions (EF), defined as neurocognitive processes that maintain an appropriate problem-solving set to attain a later goal. To examine the validity of the EF theory, we conducted a meta-analysis of 83 studies that administered EF measures to groups with ADHD (total N = 3734) and without ADHD (N = 2969). Groups with ADHD exhibited significant impairment on all EF tasks. Effect sizes for all measures fell in the medium range (.46–.69), but the strongest and most consistent effects were obtained on measures of response inhibition, vigilance, working memory, and planning. Weaknesses in EF were significant in both clinic-referred and community samples and were not explained by group differences in intelligence, academic achievement, or symptoms of other disorders. ADHD is associated with significant weaknesses in several key EF domains. However, moderate effect sizes and lack of universality of EF deficits among individuals with ADHD suggest that EF weaknesses are neither necessary nor sufficient to cause all cases of ADHD. Difficulties with EF appear to be one important component of the complex neuropsychology of ADHD. [Copyright &y& Elsevier]

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder with a multifactorial pattern of inheritance. For complex conditions such as this, biologically based phenotypes that lie in the pathway from genes to behavior may provide a more powerful target for molecular genetic studies than the disorder as a whole. Although their use in ADHD is relatively new, such “endophenotypes” have aided the clarification of the etiology and pathophysiology of several other conditions in medicine and psychiatry. In this article, we review existing data on potential endophenotypes for ADHD, emphasizing neuropsychological deficits because assessment tools are cost effective and relatively easy to implement. Neuropsychological impairments, as well as measures from neuroimaging and electrophysiological paradigms, show correlations with ADHD and evidence of heritability, but the familial or genetic overlap between these constructs and ADHD remains unclear. We conclude that these endophenotypes will not be a quick fix for the field but offer potential if careful consideration is given to issues of heterogeneity, measurement and statistical power. [Copyright &y& Elsevier]

Reports on the use of familial risk analysis to clarify the relationship in girls between attention deficit hyperactivity disorder (ADHD) and learning disabilities in either mathematics or reading. Comparison of the actual aggregation of ADHD and learning disabilities in relatives to patterns predicted by different models of transmission; Emphasis on the importance of direct assessments of ADHD and related conditions in girls.

Analyzes the association between the seven-repeat allele of dopamine D[sub 4] receptor gene and attention deficit hyperactivity disorder (ADHD). Definition of ADHD; Role of meta-analysis in the linkage studies of complex traits; Etiology of ADHD.

Examines the efficiency of test-based diagnostic discriminations in a sample of referred boys with and without attention deficit hyperactivity disorder. Participant characteristics; Neuropsychological tests used; Group differences in neuropsychological tests; Diagnostic efficiency of neuropsychological test scores.

There is, in the content of the Journal , an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, modifying version after version into shape. Acknowledging these biases, here are the 2024 articles that we think deserve your attention or at least a second read. [ABSTRACT FROM AUTHOR]

The conceptualization and treatment of oppositional defiant disorder (ODD) has been characterized by surprising homogeneity. In this paper evidence is presented to underscore the heterogeneity within ODD, including research demonstrating (a) the distinction between reactive and proactive forms of aggression; (b) the importance of affective modulation and self-regulation, and associated cognitive skills, in the development of the skill of compliance; and (c) high levels of comorbidity between ODD and other disorders. The disparate pathways that give rise to oppositional behavior suggest that different children with ODD may require different forms of intervention. The necessity of a transactional conceptualization, of achieving a comprehensive understanding of the factors underlying the difficulties of individual children with ODD, and of matching intervention ingredients to the specific needs of different children and families is discussed. [ABSTRACT FROM AUTHOR]

Examines aspects of the validity of the Behavior Assessment System for Children Parent Rating Scale (BASC-PRS) in 156 children with cross-setting disruptive behavior. Information on the BASC-PRS measure; Details on the assessment of convergent validity; Methods used within in this study.

A recent genome-wide association analysis has identified specific susceptibility variants and a substantial polygenic component for Attention-Deficit/Hyperactivity Disorder (ADHD). Given that emerging risk variants are unlikely to track precisely with conventional diagnoses, whether these discoveries will have utility in clinical settings for improved diagnostics and risk stratification requires further study. Our overall goal is to establish the relevance of emerging psychiatric genetics findings to youth clinical samples. In the current study, we aimed to 1) confirm the convergent validity of ADHD polygenic risk with ADHD-related phenotypes in youth presenting for neuropsychiatric evaluation; and 2) determine the extent to which ADHD polygenic risk associates with phenotypes beyond ADHD that putatively share its underlying liability and have implications for functional outcome. Participants were 470 youth, ages 7 to 18, consecutively referred for neuropsychiatric evaluation and genotyped on the Illumina Infinium PsychArray Beadchip. Diagnoses made subsequent to study enrollment reflected a range of psychopathology and comorbidity. We determined the burden of ADHD-related common variants in these patients at different significance thresholds from the ADHD PGC-iPSYCH meta-analysis. We then associated this polygenic risk with clinical phenotypes. First, we conducted univariate analyses relating ADHD polygenic risks scores (PRSs) to ADHD diagnoses (none/borderline/full) and symptoms, cognition, and dimensional ratings of aggression and mania. Second, we stratified youth by low, medium, and high ADHD polygenic burden and used a mixed modeling approach to determine whether risk strata associated with distinct multivariate clinical profiles. Third, we determined phenotypically distinct latent classes in these and other youth (N~900) based on eight dimensional measures of psychopathology and examined whether the ADHD-PRS discriminated among them. The ADHD-PRS predicted the ADHD diagnosis at seven discovery sample thresholds after correction for potential confounds and multiple testing. The strongest association occurred at discovery sample p <.000001 [Wald ×2(2) = 13.34, p=.0013], where an ADHD PRS score increase of 1.0 SD increased the relative risk of having ADHD versus not having ADHD 1.5-fold among youth with a range of diagnoses. Variation in ADHD risk also predicted cross-diagnostic variation in ADHD symptoms, aggression and working memory at multiple discovery sample thresholds. Here, the strongest associations explained 2.3 -3.0% of the trait variation. Youth with high ADHD polygenic burden also showed a distinct clinical profile [Wald ×2 (2) = 8.15, p=.017], driven by greater severity on measures of inattention, hyperactivity, inhibition, aggression and anxiety. Finally, among the four latent classes of youth, the ADHD PRS distinguished the two classes with the greatest and least psychopathology severity (F(1,421) = 10.73, p=.0011). These groups exhibited significant differences on ADHD symptoms as well as other dimensions of emotional and behavioral dysregulation. In a multi-diagnostic clinical sample, ADHD polygenic risk showed convergent validity with ADHD phenotypes. Genotype- and phenotype-first analyses also indicated that ADHD polygenic burden associates with traits reflecting cognition and behavioral and emotional dysregulation that extend beyond ADHD and that have implications for functional outcome. [ABSTRACT FROM AUTHOR]

In 2020, we wrote to you about our dedication and vision for JAACAP "to be antiracist at every level."1 Over the last 4 years we have pursued initiatives "to reshape the Journal to pursue this vision."2-4 In this article, we provide an update on these goals and initiatives (Figure 1). These initiatives include both scientific journals in the JAACAP family, JAACAP and JAACAP Open. Through this work we aspire to be a leader among mental health journals in our intentional pursuit of antiracist policies and practices. [ABSTRACT FROM AUTHOR]

AbstractObjective: Research establishing the validity of neuropsychological assessment using telehealth (teleNP) is much needed in pediatric populations. Method: Current analyses compared performances on twelve common neuropsychological measures completed at home via teleNP or in-person during the COVID-19 pandemic in 476 youth (ages 6 to 17, Mage 11.4 ± 3.0). Results: No differences were found on nine measures. In-person performances on three verbal tests were ∼1 scaled score point lower (all padjusted <.05). Post-hoc analyses showed that the in-person pandemic performances were comparable to an in-person pre-pandemic cohort (unmasked). Conclusions: Overall, teleNP was comparable to in-person assessment. Results indicate that teleNP administration does not result in substantially different performance in pediatric patients undergoing clinical evaluations. [ABSTRACT FROM AUTHOR]

To determine the degree to which dimensional psychopathology predicts length of stay in an emergency department (ED) and need for hospital admission among children with psychiatric complaints. Electronic health records of children age 4–17 years who presented to the ED of a large academic medical center were analyzed using a natural language processing tool to estimate Research Domain Criteria (RDoC) symptom scores. These scores' association with length of stay and probability of admission versus discharge to home were evaluated. We identified 3061 children and adolescents who presented to the ED and were evaluated by the psychiatry service between November 2008 and March 2015. Median length of stay was 7.8 h (interquartile range 5.2–14.3 h) and 1696 (55.4%) were admitted to the hospital. Higher estimated RDoC arousal, cognitive, positive, and social domain scores were associated with increased length of stay in multiple regression models, adjusted for age, sex, race, private insurance, voluntary admission, and diagnostic categories. In similarly adjusted models, odds of hospital admission were increased by higher RDoC arousal and cognitive domain scores and decreased by higher negative domain scores. A natural language processing tool to characterize dimensional psychopathology identified features associated with differential outcomes in children in the psychiatric ED, most notably symptoms reflecting arousal and cognitive function. Methodologically, this in silico approach to risk stratification should facilitate precision psychiatry in children within the emergency setting. [ABSTRACT FROM AUTHOR]

An abstract of the article "Schizophrenia Polygenic Risk Associates With Working Memory in a Child and Adolescent Clinical Sample" by Alysa Doyle is presented.

There is, in the content of the Journal , an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, modifying version after version into shape. Acknowledging these biases, here are the 2023 articles that we think deserve your attention or at least a second read. [ABSTRACT FROM AUTHOR]

In 2020, we wrote to you of our dedication and vision for JAACAP "to be antiracist at every level."1 Over the last 3 years, we have pursued initiatives "to reshape the Journal to pursue this vision."2,3 In this article, we provide an update on these goals and initiatives (Figure 1). With the launching of our new open access journal, JAACAP Open ,4 in late 2022, we now extend these initiatives to both scientific journals in the JAACAP family and aspire to be a leader among mental health journals in our intentional pursuit of antiracist policies and practices. [ABSTRACT FROM AUTHOR]

This study examined the impact of the COVID-19 pandemic on cognitive and academic functioning in 574 youth presenting for outpatient clinical neuropsychiatric evaluations. We extended the prior literature by (a) determining the extent to which academic difficulties documented in population and community samples also occurred in child psychiatric outpatients; (b) evaluating the impact of the pandemic on neuropsychological functions relevant to academic performance (overall cognition, executive functions, and graphomotor skill); and (c) investigating the moderating impact of attention deficit hyperactivity disorder (ADHD) diagnosis. We compared cross-sectional scores on standardized measures for groups of youth evaluated at three time periods related to the COVID-19 pandemic: (a) prior to onset (PRIOR; N = 198), (b) during Year 1 (Y1; N = 149), and (c) during Year 2 (Y2; N = 227). Relative to overall cognitive ability, math scores were lower in Y1 and Y2 and reading scores were lower in Y2. Additionally, relative to overall cognitive ability, youth showed lower working memory in Y1 and lower processing speed in Y1 and Y2. Graphomotor skill and parent-rated executive functions (EF) did not vary significantly across the three time periods. ADHD status did not moderate psychometric test scores but did moderate parent-rated EF. These data suggest that the COVID-19 pandemic has negatively impacted academic and executive functions in child psychiatry outpatients. More research is needed to understand the long-term implications for development. Public Significance Statement: Current findings extend evidence for the negative impact of the COVID-19 pandemic by showing reduced postpandemic math and reading skills in child psychiatry outpatients who are known to be at-risk for learning difficulties. We also found differences in executive functions, which has implications for assessment and interventions. [ABSTRACT FROM AUTHOR]

There is, in the content of the Journal , an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, hammering version after version into shape. Acknowledging these biases, here are the 2022 articles that we think deserve your attention or at least a second read. [ABSTRACT FROM AUTHOR]

The article looks at common genetic variants associated with human intelligence (IQ) and cognitive abilities. Particular attention in the study is given to the role of single nucleotide polymorphisms (SNPs) and whether they carry information to describe genetic variants. The study also considers genes contributing to IQ and cases of children with attention-deficit hyperactivity disorder (ADHD). Included are the effects of genes on brain development, integrity, and efficiency on intelligence.

The article investigates the role of the Catechol-O-methyl transferase (COMT) and serotonin transporter (SLC6A4) genes in the risk for conduct disorder (CD) and its symptomatic subtypes in the context of attention-deficit/hyperactivity disorder (ADHD). It shows that findings contribute to understanding of the genetic basis of antisocial behavior in the ADHD population. It offers additional support for the notion that aggressive and covert CD symptom subtypes are etiologically distinct.

Background: Diagnosing attention-deficit/hyperactivity disorder (ADHD) in adults is difficult when the diagnostician cannot establish an onset prior to the DSM-IV criterion of age 7 or if the number of symptoms recalled does not achieve the DSM-IV threshold for diagnosis. Because neuropsychological deficits are associated with ADHD, we addressed the validity of the DSM-IV age at onset and symptom threshold criteria by using neuropsychological test scores as external validators. Methods: We compared four groups of adults: 1) full ADHD subjects met all DSM-IV criteria for childhood-onset ADHD; 2) late-onset ADHD subjects met all criteria except the age at onset criterion; 3) subthreshold ADHD subjects did not meet full symptom criteria; and 4) non-ADHD subjects did not meet any of the above criteria. Results: Late-onset and full ADHD subjects had similar patterns of neuropsychological dysfunction. By comparison, subthreshold ADHD subjects showed few neuropsychological differences with non-ADHD subjects. Conclusions: Our results showing similar neuropsychological underpinning in subjects with late-onset ADHD suggest that the DSM-IV age at onset criterion may be too stringent. Our data also suggest that ADHD subjects who failed to ever meet the DSM-IV threshold for diagnosis have a milder form of the disorder. [Copyright &y& Elsevier]

Abstract: Objective: To determine whether SNPs within the dopamine transporter gene (DAT) are associated with quantitative phenotypes generated from drug frequency variables in an ADHD sample. Method: 35 SNPs were genotyped in and around DAT. We developed a quantitative phenotype at each SNP by weighting the drug frequency variables. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, a screening procedure was used to select and test the SNPs with the greatest power to detect an association in DAT. Results: No SNPs in DAT were associated with the quantitative phenotypes generated from the drug frequency variables after the multiple comparisons adjustment; however, some SNPs achieved nominal significance. A sliding window of analysis of 3 SNPs also resulted in only nominal associations. Conclusions: SNPs in DAT do not appear to be associated with the phenotypes generated from drug frequency variables among individuals with ADHD. [Copyright &y& Elsevier]

Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25. [Copyright &y& Elsevier]

Before assigning full etiologic validity to a psycopathologic disorder, disease theory suggests that a causal dysfunction in a mechanism within the affect individuals must be identified. Existing theories on attention-deficit/hyperactivity disorder (ADHD) suggest such dysfunctions in cognitive, neuropsychological, or motivational processes in the child. To date, researchers have tested these theories by comparing groups with DSM-defined ADHD to children without ADHD. Using executive functioning as an illustration of an issue that exists across all such theories, this article describes substantial overlaps in the group performance data. Thus only a subgroup may have executive deficits. Noted are other supportive data suggesting multiple pathways to ADHD. The article explores implications and recommends that future theory and research give more consideration to the probability that only a subset of behaviorally defined children will have a deficit in a given neurocognitive mechanism believed to contribute to the disorder. Creation of a provisional set of criteria in DSM-V for defining an “executive deficit type” could stimulate research to validate the first etiologic subtype of ADHD and spur the development of more sophisticated causal models, which in the longer term may give clinicians ways to target and tailor treatments. [Copyright &y& Elsevier]

The association between executive function deficits (EFDs) and functional outcomes were examined among children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Participants were children and adolescents with (n = 259) and without (n = 222) ADHD, as ascertained from pediatric and psychiatric clinics. The authors defined EFD as at least 2 executive function measures impaired. Significantly more children and adolescents with ADHD had EFDs than did control participants. ADHD with EFDs was associated with an increased risk for grade retention and a decrease in academic achievement relative to (a) ADHD alone, (b) controlled socioeconomic status, (c) learning disabilities, and (d) IQ. No differences were noted in social functioning or psychiatric comorbidity. Children and adolescents with ADHD and EFDs were found to be at high risk for significant impairments in academic functioning. These results support screening children with ADHD for EFDs to prevent academic failure. [ABSTRACT FROM AUTHOR]

- We evaluated the convergence of CBCL scales with the diagnosis of ADHD and comorbid disorders in 133 ADHD and 118 normal control boys, aged 6-17 years old. We evaluated the strength of association between each CBCL scale and structured-interview derived diagnoses with Total Predictive Value (TPV) and the odds-ratio (OR). Excellent convergence was found between the GBGL Attention Problems scale with the diagnosis of ADHD, between the Delinquent Behaviour scale and the diagnosis of CD, and between die Anxiety/Depression scale and the diagnoses of Anxiety Disorders. These findings indicate that the CBCL could serve as a rapid and useful screening instrument to identity comoribid and non-comorbid cases of ADHD. [ABSTRACT FROM AUTHOR]

Objective: Numerous adverse prenatal exposures have been individually associated with risk for psychiatric illness in the offspring. However, such exposures frequently co-occur, raising questions about their cumulative impact. We evaluated effects of cumulative adverse prenatal exposure burden on psychopathology risk in school-aged children. Methods: Using baseline surveys from the U.S.-based Adolescent Brain and Cognitive Development (ABCD) Study (7,898 non-adopted, unrelated children from 21 sites, age 9–10, and their primary caregivers), we examined 8 retrospectively-reported adverse prenatal exposures in relation to caregiver-reported total and subscale Child Behavior Checklist (CBCL) scores. We also assessed cumulative effects of these factors on CBCL total as a continuous measure, as well as on odds of clinically significant psychopathology (CBCL total ≥60), in both the initial set and a separate ABCD sample comprising an additional 696 sibling pairs. Analyses were conducted before and after adjustment for 14 demographic and environmental covariates. Results: In minimally and fully adjusted models, 6 exposures (unplanned pregnancy; maternal alcohol, marijuana, and tobacco use early in pregnancy; pregnancy complications; and birth complications) independently associated with significant but small increases in CBCL total score. Among these 6, none increased the odds of crossing the threshold for clinically significant symptoms by itself. However, odds of exceeding this threshold became significant with 2 exposures (OR = 1.86, 95% CI 1.47–2.36), and increased linearly with each level of exposure (OR = 1.39, 95% CI 1.31–1.47), up to 3.53-fold for ≥4 exposures versus none. Similar effects were observed in confirmatory analysis among siblings. Within sibling pairs, greater discordance for exposure load associated with greater CBCL total differences, suggesting that results were not confounded by unmeasured family-level effects. Conclusion: Children exposed to multiple common, adverse prenatal events showed dose-dependent increases in broad, clinically significant psychopathology at age 9–10. Fully prospective studies are needed to confirm and elaborate upon this pattern. [ABSTRACT FROM AUTHOR]

Background: The adoption of neuropsychological tests as endophenotypic measures can provide an increased sensitivity to specific dimensions of attention-deficit/hyperactivity disorder (ADHD). Methods: The association between a variable number of tandem repeats polymorphism at the dopamine D4 receptor gene (DRD4) and the performance of children and adolescents with ADHD in a continuous performance test (CPT) was evaluated. The sample comprised 90 clinically referred children and adolescents with ADHD. Errors of omission and commission in the CPT were computed and the number of 48-base pairs tandem repeats in the exon III of DRD4 was assessed. Results: The presence of a 7-repeat allele was associated with more errors of commission and the homozygosity of the 4-repeat allele was related to fewer errors of commission and omission even after adjusting for age. Conclusions: These findings bring further evidence on the role of DRD4 polymorphisms on the performance in sustained attention tasks among children and adolescents with ADHD diagnosis. [Copyright &y& Elsevier]

While slow processing speed (PS) is well documented in youth with ADHD, growing evidence suggests that this difficulty affects children with other neuropsychiatric conditions. Clarifying the relationship between slow PS and different forms of psychopathology is important clinically, given the potential impact of PS on academic functioning, and conceptually. In 751 youth, ages 6–21, consecutively referred for neuropsychiatric evaluation, we examined the association between slow PS (i.e., Wechsler PS Index < 85) and seven neuropsychiatric diagnostic groups. In 492 of these youth, we also related slow PS to eight psychopathology symptom dimensions. Finally, we modeled the relationship between PS, other cognitive functions and academic achievement. Data are from the Longitudinal Study of Genetic Influences on Cognition. Analyses included one-sample t tests, ANOVA, logistic regression, mixed modeling, and structural equation modeling (SEM), controlling for age, sex, and medication. Compared to normative data, all clinical groups showed PS decrements. Compared to referred youth without full diagnoses and accounting for other psychopathology, risk for slow PS was elevated in youth with autism spectrum disorder (OR = 1.8), psychotic disorders (OR = 3.4) and ADHD-inattentive type (OR = 1.6). Having multiple comorbidities also increased risk for slow PS. Among dimensions, inattention (OR = 1.5) associated with slow PS but did not fully explain the association with autism or psychosis. In SEM, PS had direct effects on academic achievement and indirect effects through working memory. Findings extend evidence that PS relates to multiple aspects of child psychopathology and associates with academic achievement in child psychiatric outpatients. [ABSTRACT FROM AUTHOR]

Objective: Genomic discoveries should be investigated in generalizable child psychiatric samples in order to justify and inform studies that will evaluate their use for specific clinical purposes. In youth consecutively referred for neuropsychiatric evaluation, we examined 1) the convergent and discriminant validity of attention-deficit/hyperactivity disorder (ADHD) polygenic risk scores (PRSs) in relation to DSM-based ADHD phenotypes; 2) the association of ADHD PRSs with phenotypes beyond ADHD that share its liability and have implications for outcome; and 3) the extent to which youth with high ADHD PRSs manifest a distinctive clinical profile.Method: Participants were 433 youth, ages 7-18 years, from the Longitudinal Study of Genetic Influences on Cognition. We used logistic/linear regression and mixed effects models to examine associations with ADHD-related polygenic variation from the largest ADHD genome-wide association study to date. We replicated key findings in 5,140 adult patients from a local health system biobank.Results: Among referred youth, ADHD PRSs were associated with ADHD diagnoses, cross-diagnostic ADHD symptoms and academic impairment (odds ratios ∼1.4; R2 values ∼2%-3%), as well as cross-diagnostic variation in aggression and working memory. In adults, ADHD PRSs were associated with ADHD and phenotypes beyond the condition that have public health implications. Finally, youth with a high ADHD polygenic burden showed a more severe clinical profile than youth with a low burden (β coefficients ∼.2).Conclusion: Among child and adolescent outpatients, ADHD polygenic risk was associated with ADHD and related phenotypes as well as clinical severity. These results extend the scientific foundation for studies of ADHD polygenic risk in the clinical setting and highlight directions for further research. [ABSTRACT FROM AUTHOR]

Background: Recent initiatives in psychiatry emphasize the utility of characterizing psychiatric symptoms in a multidimensional manner. However, strategies for applying standard self-report scales for multiaxial assessment have not been well-studied, particularly where the aim is to support both categorical and dimensional phenotypes. Methods: We propose a method for applying natural language processing to derive dimensional measures of psychiatric symptoms from questionnaire data. We utilized nine self-report symptom measures drawn from a large cellular biobanking study that enrolled individuals with mood and psychotic disorders, as well as healthy controls. To summarize questionnaire results we used word embeddings, a technique to represent words as numeric vectors preserving semantic and syntactic meaning. A low-dimensional approximation to the embedding space was used to derive the proposed succinct summary of symptom profiles. To validate our embedding-based disease profiles, these were compared to presence or absence of axis I diagnoses derived from structured clinical interview, and to objective neurocognitive testing. Results: Unsupervised and supervised classification to distinguish presence/absence of axis I disorders using survey-level embeddings remained discriminative, with area under the receiver operating characteristic curve up to 0.85, 95% confidence interval (CI) (0.74,0.91) using Gaussian mixture modeling, and cross-validated area under the receiver operating characteristic curve 0.91, 95% CI (0.88,0.94) using logistic regression. Derived symptom measures and estimated Research Domain Criteria scores also associated significantly with performance on neurocognitive tests. Conclusions: Our results support the potential utility of deriving dimensional phenotypic measures in psychiatric illness through the use of word embeddings, while illustrating the challenges in identifying truly orthogonal dimensions. [ABSTRACT FROM AUTHOR]

The association between slow processing speed and sluggish cognitive tempo (SCT), a phenotype described within attention-deficit/hyperactivity disorder (ADHD) samples over the past decade, remains unclear. We examined whether SCT and processing speed predict different functional correlates within children and adolescents with ADHD. Participants were 193 clinically-referred youth meeting DSM ADHD criteria without comorbid conditions (mean age = 9.9 years, SD = 2.5; age range 6-16). The incremental utility of SCT and processing speed to predict (1) adaptive functioning and (2) academic achievement, after controlling for age, sex, medication status, and ADHD symptom burden, was assessed using hierarchical multiple regressions. SCT symptoms significantly predicted adaptive functioning, accounting for 6% of the variance, but did not predict academic achievement. Processing speed did not add incrementally to the prediction of adaptive functioning, but did predict academic achievement, accounting for 4% of the variance. Results suggest that SCT and processing speed differentially predict functional abilities not accounted for by ADHD symptom burden. [ABSTRACT FROM AUTHOR]

On average, compared to non-referred youth, child psychiatric outpatients show elevated rates of suicidal thoughts and behaviors (STBs), which are predictors of completed suicide. Determining the psychopathology features that associate with highest risk for STBs among youth outpatients may yield opportunities for targeted prevention/intervention. Yet, outpatient studies are limited and have not systematically examined comorbidity and dimensional psychopathology. In 758 youth, aged 6-18, consecutively referred for neuropsychiatric evaluation, we examined the extent to which diagnostic groups, comorbid subgroups and dimensional symptoms associated with STBs. After controlling for comorbidity, mood, anxiety and conduct disorders associated with elevated STB risk. Regarding dimensions, symptoms of depression, aggression and psychosis all contributed to higher STB risk. Although ADHD (as a diagnosis or dimension) did not associate with elevated STB risk independently, ADHD that was comorbid with other conditions did. Suicide prevention/intervention efforts should be investigated in youth outpatients with the highest risk for STBs. [ABSTRACT FROM AUTHOR]