MAOA methylation is associated with impulsive and antisocial behaviour: dependence on allelic variation, family environment and diet.

Congenital absence of monoamine oxidase A (MAO-A) activity predisposes to antisocial impulsive behaviour, and the MAOA uVNTR low-expressing genotype (MAOA-L) together with childhood maltreatment is associated with similar phenotypes in males. A possible explanation of how family environment may lead to such behaviour involves DNA methylation. We have assessed MAOA methylation and impulsive/antisocial behaviour in 121 males from the Estonian Children Personality Behaviour and Health Study. Of the 12 CpG sites measured, methylation levels at the locus designated CpG3 were significantly lower in subjects with antisocial behaviour involving police contact. CpG3 methylation was lower in subjects with alcohol use disorder by age 25, but only in MAOA-H genotype. No correlation between MAOA CpG3 methylation levels and adaptive impulsivity was found at age 15, but in MAOA-L genotype a positive correlation appeared by age 18. By age 25, this positive correlation was no longer observed in subjects with better family relationships but had increased further with experience of adversity within the family. MAOA CpG3 methylation had different developmental dynamics in relation to maladaptive impulsivity. At age 18, a positive correlation was observed in MAOA-L genotype with inferior family relationships and a negative correlation was found in MAOA-H with superior home environment; both of these associations had disappeared by age 25. CpG3 methylation was associated with dietary intake of several micronutrients, most notable was a negative correlation with the intake of zinc, but also with calcium, potassium and vitamin E; a positive correlation was found with intake of phosphorus. In conclusion, MAOA CpG3 methylation is related to both maladaptive and adaptive impulsivity in adolescence in MAOA-L males from adverse home environment. By young adulthood, this relationship with maladaptive impulsivity had disappeared but with adaptive impulsivity strengthened. Thus, MAOA CpG3 methylation may serve as a marker for adaptive developmental neuroplasticity in MAOA-L genotype. The mechanisms involved may include dietary factors.

Arg4810Lys mutation in RNF213 among Eastern Indian non-MMD ischemic stroke patients: a genotype-phenotype correlation.

INTRODUCTION: RNF213 mutations have been reported mostly in moyamoya disease (MMD) with varying frequencies across different ethnicities. However, its prevalence in non-MMD adult-onset ischemic stroke is still not well explored. AIMS AND OBJECTIVES: This present study thus aims to screen the most common RNF213 variant (Arg4810Lys, among East Asians) in the Eastern Indian non-MMD ischemic stroke patients and correlate it with long-term progression and prognosis of the patients. The subjects were analyzed for this variant using PCR-RFLP and confirmed using Sanger sequencing method. RESULT AND CONCLUSION: We have identified Arg4810Lys variant among eleven young-onset familial ischemic stroke patients in heterozygous manner. A positive correlation of the variant with positive family history (P = 0.001), earlier age at onset (P = 0.002), and history of recurrent stroke (P = 0.015) was observed. However, the carriers showed better cognitive performances in memory (P = 0.042) and executive function (P = 0.004). Therefore, we can conclude that Arg4810Lys/RNF213 - a pathogenic variant for young-onset familial ischemic stroke with higher incidence of recurrent events unlike in MMD cases, have no additional impact on cognition among Eastern Indians.

Genome-wide DNA methylation analysis of aggressive behaviour: a longitudinal population-based study.

BACKGROUND: Human aggression is influenced by an interplay between genetic predisposition and experience across the life span. This interaction is thought to occur through epigenetic mechanisms, inducing differential gene expression, thereby moderating neuronal cell and circuit function, and thus shaping aggressive behaviour. METHODS: Genome-wide DNA methylation (DNAm) levels were measured in peripheral blood obtained from 95 individuals participating in the Estonian Children Personality Behaviours and Health Study (ECPBHS) at 15 and 25 years of age. We examined the association between aggressive behaviour, as measured by Life History of Aggression (LHA) total score and DNAm levels both assessed at age 25. We further examined the pleiotropic effect of genetic variants regulating LHA-associated differentially methylated positions (DMPs) and multiple traits related to aggressive behaviours. Lastly, we tested whether the DNA methylomic loci identified in association with LHA at age 25 were also present at age 15. RESULTS: We found one differentially methylated position (DMP) (cg17815886; p = 1.12 × 10-8 ) and five differentially methylated regions (DMRs) associated with LHA after multiple testing adjustments. The DMP annotated to the PDLIM5 gene, and DMRs resided in the vicinity of four protein-encoding genes (TRIM10, GTF2H4, SLC45A4, B3GALT4) and a long intergenic non-coding RNA (LINC02068). We observed evidence for the colocalization of genetic variants associated with top DMPs and general cognitive function, educational attainment and cholesterol levels. Notably, a subset of the DMPs associated with LHA at age 25 also displayed altered DNAm patterns at age 15 with high accuracy in predicting aggression. CONCLUSIONS: Our findings highlight the potential role of DNAm in the development of aggressive behaviours. We observed pleiotropic genetic variants associated with identified DMPs, and various traits previously established to be relevant in shaping aggression in humans. The concordance of DNAm signatures in adolescents and young adults may have predictive value for inappropriate and maladaptive aggression later in life.

Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation.

Alcohol use disorder (AUD) is a chronic debilitating disorder with limited treatment options and poorly defined pathophysiology. There are substantial genetic and epigenetic components; however, the underlying mechanisms contributing to AUD remain largely unknown. We conducted the largest DNA methylation epigenome-wide association study (EWAS) analyses currently available for AUD (total N = 625) and employed a top hit replication (N = 4798) using a cross-tissue/cross-phenotypic approach with the goal of identifying novel epigenetic targets relevant to AUD. Results show that a network of differentially methylated regions in glucocorticoid signaling and inflammation-related genes were associated with alcohol use behaviors. A top probe consistently associated across all cohorts was located in the long non-coding RNA growth arrest specific five gene (GAS5) (p < 10-24). GAS5 has been implicated in regulating transcriptional activity of the glucocorticoid receptor and has multiple functions related to apoptosis, immune function and various cancers. Endophenotypic analyses using peripheral cortisol levels and neuroimaging paradigms showed that methylomic variation in GAS5 network-related probes were associated with stress phenotypes. Postmortem brain analyses documented increased GAS5 expression in the amygdala of individuals with AUD. Our data suggest that alcohol use is associated with differential methylation in the glucocorticoid system that might influence stress and inflammatory reactivity and subsequently risk for AUD.

Predictive utility of childhood diagnosis of ICD-10 hyperkinetic disorder: adult outcomes in the MTA and effect of comorbidity.

Diagnostic guidelines differ between DSM attention-deficit/hyperactivity disorder (ADHD) and ICD hyperkinetic disorder (HKD). Only 145 of 579 children age 7-9 in the Multimodal Treatment Study of ADHD (the MTA) with combined-type DSM-IV ADHD met criteria for ICD-10 HKD, because major internalizing comorbidities and more stringent symptom count/pervasiveness requirements excluded most. The 145 HKD had significantly better 14-month medication response than the rest. We explored whether HKD had greater adult symptom persistence and/or impairment than other ADHD. Multi-informant assessments were done for 16 years. We used the 12/14/16-year assessments, in young adulthood. The post-attrition 109 with baseline HKD had no greater adult persistence of ADHD symptoms/impairment than 367 without HKD, but had more cumulative stimulant use, more job losses, lower emotional lability, and fewer car crashes. However, those excluded for internalizing comorbidity but otherwise meeting HKD criteria had significantly more persistence. Only 6 of the 109 (5.5%) with baseline HKD met ICD-10 criteria for HKD in adulthood, compared to 25 of 367 (6.8%) without a childhood HKD diagnosis. Despite greater initial symptom severity, HKD had no worse 16-year young adult outcome than others, except for job losses, balanced by less emotional lability and fewer crashes. Comorbid internalizing disorder seems to have worse prognosis than initial severity/pervasiveness of ADHD symptoms.

Peer dislike and victimisation in pathways from ADHD symptoms to depression.

The following hypotheses were tested in a longitudinal, population-based study: (1) Attention deficit hyperactivity disorder (ADHD) symptoms are associated with peer dislike and victimisation; (2) Peer dislike and victimisation increase the risk for subsequent depression; and (3) The effect of ADHD symptoms on depression is partly mediated through peer dislike and victimisation. Gender differences in mediating pathways through peer dislike and victimisation to depression were additionally explored. The Child Behaviour Checklist (CBCL), Youth Self Report (YSR) and Teacher's Checklist of Pathology (TCP) assessed ADHD symptoms in 728 adolescents. Peer nominations were used to assess peer dislike and victimisation. The Composite International Diagnostic Interview (CIDI) was used to assess depression. Effects of peer dislike, victimisation, and ADHD symptoms on depression were modelled using Cox regression. ADHD symptoms were associated with peer dislike (rs = 0.17, p < 0.001) and victimisation (rs = 0.11, p = 0.001). Dislike, victimisation, and ADHD symptoms increased risk for depression. Risk for depression associated with victimisation and ADHD symptoms reduced with time. Dislike and victimisation mediated 7 % of the effect of ADHD symptoms on depression. Pathways through dislike and victimisation were present in girls but not in boys. Peer dislike and victimisation explain, to a limited extent, the prospective association between ADHD and depression, particularly in girls.

Review: Adult Outcome as Seen Through Controlled Prospective Follow-up Studies of Children With Attention-Deficit/Hyperactivity Disorder Followed Into Adulthood.

OBJECTIVE: To describe adult outcome of people with attention-deficit/hyperactivity disorder (ADHD) diagnosed in childhood and its several key predictors via a review of 7 North American controlled prospective follow-up studies: Montreal, New York, Milwaukee, Pittsburgh, Massachusetts General Hospital (MGH), Berkeley, and 7-site Multimodal Treatment Study of Children With ADHD (MTA). METHOD: All studies were prospective and followed children with a diagnosis of ADHD and an age- and gender-matched control group at regular intervals from childhood (6-12 years of age) through adolescence into adulthood (20-40 years of age), evaluating symptom and syndrome persistence, functional outcomes, and predictors of these outcomes. RESULTS: The rates of ADHD syndrome persistence ranged from 5.7% to 77%, likely owing to varying diagnostic criteria and the source of information (self-report vs informant report) across the studies. However, all studies observed high rates of symptomatic persistence ranging from 60% to 86%. The 7 studies were largely consistent in finding that relative to control groups, research participants with childhood-diagnosed ADHD had significant impairments in the areas of educational functioning, occupational functioning, mental health, and physical health as well as higher rates of substance misuse, antisocial behavior, and unsafe driving. The most consistently observed predictors of functional outcomes included ADHD persistence and comorbidity, especially with disruptive behavior disorders. CONCLUSION: Childhood ADHD has high rates of symptomatic persistence, which is associated with negative functional outcomes. Characteristics that predict these negative outcomes, such as comorbid disruptive behavior disorders, may be important targets for intervention.

Variable Patterns of Remission From ADHD in the Multimodal Treatment Study of ADHD.

OBJECTIVE: It is estimated that childhood attention deficit hyperactivity disorder (ADHD) remits by adulthood in approximately 50% of cases; however, this conclusion is typically based on single endpoints, failing to consider longitudinal patterns of ADHD expression. The authors investigated the extent to which children with ADHD experience recovery and variable patterns of remission by adulthood. METHODS: Children with ADHD (N=558) in the Multimodal Treatment Study of ADHD (MTA) underwent eight assessments over follow-ups ranging from 2 years (mean age, 10.44 years) to 16 years (mean age, 25.12 years) after baseline. The authors identified participants with fully remitted, partially remitted, and persistent ADHD at each time point on the basis of parent, teacher, and self-reports of ADHD symptoms and impairment, treatment utilization, and substance use and mental disorders. Longitudinal patterns of remission and persistence were identified that considered context and timing. RESULTS: Approximately 30% of children with ADHD experienced full remission at some point during the follow-up period; however, a majority of them (60%) experienced recurrence of ADHD after the initial period of remission. Only 9.1% of the sample demonstrated recovery (sustained remission) by study endpoint, and only 10.8% demonstrated stable ADHD persistence across study time points. Most participants with ADHD (63.8%) had fluctuating periods of remission and recurrence over time. CONCLUSIONS: The MTA findings challenge the notion that approximately 50% of children with ADHD outgrow the disorder by adulthood. Most cases demonstrated fluctuating symptoms between childhood and young adulthood. Although intermittent periods of remission can be expected in most cases, 90% of children with ADHD in MTA continued to experience residual symptoms into young adulthood.

Developing a biomarker for restless leg syndrome using genome wide DNA methylation data.

This study reports on an epigenetic biomarker for restless leg syndrome (RLS) developed using whole genome DNA methylation data. Lymphocyte-derived DNA methylation was examined in 15 subjects with and without RLS (discovery cohort). T-tests and linear regressions were used followed by a principal component analysis (PCA). The principal component model from the discovery cohort was used to predict RLS status in a peripheral blood (N = 24; including 12 cases and 12 controls) and a post-mortem neural tissue (N = 71; including 36 cases and 35 controls) replication cohort as well as iron deficiency anemia status in a publicly available dataset (N = 71, 59 cases with iron deficiency anemia, 12 controls). Using receiver-operating characteristic analysis the optimum biomarker model - that included 49 probes - predicted RLS status in the blood-based replication cohort with an area under the curve (AUC) of 87.5% (confidence interval = 71.9%-100%). In the neural tissue samples, the model predicted RLS status with an AUC of 73.4% (confidence interval = 61.5%-85.3%). An AUC of 83% was found for predictions of iron deficiency anemia. Thus, the blood-based biomarker model reported here and built with epigenome-wide data showed reasonable replicability in lymphocytes and neural tissue samples. A limitation of this study is that we could not determine the metabolic or neurobiological pathways linking epigenetic changes with RLS. Further research is needed to fine-tune this model for prospective predictions of RLS and to enable translation for clinical use.

REVERSE phenotyping-Can the phenotype following constitutive Tph2 gene inactivation in mice be transferred to children and adolescents with and without adhd?

INTRODUCTION: Experimental models of neuropsychiatric disorders, for example, ADHD, are used to mimic specific phenotypic traits of a complex human disorder. However, it remains unresolved to what extent the animal phenotype reflects the specific human trait. The null mutant mouse of the serotonin-synthesizing tryptophan hydroxylase-2 (Tph2-/- ) gene has been proposed as experimental model for ADHD with high face validity for impulsive, aggressive, and anxious behaviors. To validate this ADHD-like model, we examined the Tph2-/- phenotype in humans when considering allelic variation of TPH2 function ("reverse phenotyping"). METHODS: 58 participants (6 females, 8-18 years) were examined, of whom 32 were diagnosed with ADHD. All participants were phenotyped for impulsivity, aggression, and anxiety using questionnaires, behavioral tests, and MRI scanning while performing the 4-choice serial reaction time task. Additionally, participants were genotyped for the TPH2 G-703T (rs4570625) polymorphism. To analyze the relation between TPH2 G-703T variants and the impulsive/aggressive/anxious phenotype, mediation analyses were performed using behavioral and MRI data as potential mediators. RESULTS: We found that the relation between TPH2 G-703T and aggression as part of the reverse Tph2- /- phenotype was mediated by structure and function of the right middle and inferior frontal gyrus. CONCLUSION: At the example of trait aggression, our results support the assumption that the Tph2 null mutant mouse reflects the TPH2 G-703T-dependent phenotype in humans. Additionally, we conclude that "reverse phenotyping" is a promising method to validate experimental models and human findings for refined analysis of disease mechanisms.

A Qualitative Analysis of Contextual Factors Relevant to Suspected Late-Onset ADHD.

Objective: Recent studies suggest attention-deficit/hyperactivity disorder (ADHD) may emerge post-childhood. We integrate qualitative methods to systematically characterize contextual factors that may (a) delay identification of ADHD in childhood and (b) inform why ADHD symptoms emerge post-childhood. Method: Suspected late-onset ADHD cases from the local normative comparison group of the Multimodal Treatment Study of ADHD completed a qualitative interview (14 young adults and 7 caregivers). Interviews were qualitatively analyzed. Results: We identified five themes. Three themes may attenuate or delay identification of childhood ADHD: external factors (e.g., supportive adults), internal factors (e.g., strong intellectual functioning), and other factors (e.g., dismissive attitudes toward ADHD). Two themes may accompany an increase in ADHD symptoms post-childhood: external factors (e.g., increased external demands) and internal factors (e.g., perceived stress). Conclusion: Clinicians should probe these factors in suspected late-onset cases to address (a) whether, how, and to what extent ADHD was attenuated in childhood and (b) why symptoms emerge post-childhood.

A machine learning approach predicts future risk to suicidal ideation from social media data.

Machine learning analysis of social media data represents a promising way to capture longitudinal environmental influences contributing to individual risk for suicidal thoughts and behaviors. Our objective was to generate an algorithm termed "Suicide Artificial Intelligence Prediction Heuristic (SAIPH)" capable of predicting future risk to suicidal thought by analyzing publicly available Twitter data. We trained a series of neural networks on Twitter data queried against suicide associated psychological constructs including burden, stress, loneliness, hopelessness, insomnia, depression, and anxiety. Using 512,526 tweets from N = 283 suicidal ideation (SI) cases and 3,518,494 tweets from 2655 controls, we then trained a random forest model using neural network outputs to predict binary SI status. The model predicted N = 830 SI events derived from an independent set of 277 suicidal ideators relative to N = 3159 control events in all non-SI individuals with an AUC of 0.88 (95% CI 0.86-0.90). Using an alternative approach, our model generates temporal prediction of risk such that peak occurrences above an individual specific threshold denote a ~7 fold increased risk for SI within the following 10 days (OR = 6.7 ± 1.1, P = 9 × 10-71). We validated our model using regionally obtained Twitter data and observed significant associations of algorithm SI scores with county-wide suicide death rates across 16 days in August and in October, 2019, most significantly in younger individuals. Algorithmic approaches like SAIPH have the potential to identify individual future SI risk and could be easily adapted as clinical decision tools aiding suicide screening and risk monitoring using available technologies.

Early substance use in the pathway from childhood attention-deficit/hyperactivity disorder (ADHD) to young adult substance use: Evidence of statistical mediation and substance specificity.

This study tested whether early and developmentally atypical substance use mediates risk for adult substance use among children with attention-deficit/hyperactivity disorder (ADHD), and whether that risk is substance-specific. Participants were children with ADHD previously enrolled in a randomized controlled trial (RCT), and a demographically similar non-ADHD group, assessed at 2 through 16 years after the original RCT baseline. Self-reports of heavy drinking, marijuana use, daily smoking, and other illicit drug use were collected at follow-ups to establish atypically early and frequent use. Models estimated statistically mediated effects of childhood ADHD on adult substance use via early substance involvement, with planned comparisons to evaluate substance specificity. Results supported the mediation hypothesis, showing that childhood ADHD was associated with more frequent adult substance use via early substance involvement for marijuana, cigarettes, illicit drugs, and to a lesser extent, alcohol. Mediation was not escalated by comorbid childhood conduct disorder or oppositional defiant disorder except for early use of nonmarijuana illicit drugs. Substance-specificity in the mediational pathway was largely absent except for cigarette use, where ADHD-related early smoking most strongly predicted adult daily smoking. Findings from this study provide new evidence that atypically early substance use associated with childhood ADHD signals important cross-drug vulnerability by early adulthood, but cigarette use at a young age is especially associated with increased risk for habitual (daily) smoking specifically. Efforts to prevent, delay, or reduce substance experimentation should occur early and focus on factors relevant to multiple drugs of abuse in this at-risk population. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Effects of Childhood and Adult Persistent Attention-Deficit/Hyperactivity Disorder on Risk of Motor Vehicle Crashes: Results From the Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: To determine motor vehicle crash (MVC) risk in adults with a history of childhood attention-deficit/hyperactivity disorder (ADHD) and persistent ADHD symptoms. METHOD: Participants with (n = 441) and without (n = 239; local normative comparison group) childhood ADHD from the Multimodal Treatment of Attention-Deficit/Hyperactivity Disorder (MTA) Study were included. Participants provided self-reports on total number of MVCs they had been involved in and the time of licensure. Driving experience was estimated as the number of months since licensure. Total number of MVCs by adulthood was regressed on baseline ADHD status adjusting for sex, age at follow-up, driving experience, baseline oppositional defiant disorder/conduct disorder comorbidity, baseline household income level, adult oppositional defiant disorder/conduct disorder symptoms, adolescent and adult substance use, and adult antisocial personality disorder symptoms. We repeated the analysis using adult ADHD status (persistent versus desistant versus local normative comparison group) and symptom level as the predictor variables. Results are presented as incidence rate ratio (IRR) and CI. RESULTS: Childhood ADHD was associated with a higher number of MVCs (IRR = 1.45, CI = 1.15-1.82), and adult ADHD symptom persistence was associated with more MVCs than desistance (IRR = 1.46, CI = 1.14-1.86). ADHD desistance was not associated with a significantly increased risk for MVCs compared with the local normative comparison group (IRR = 1.24, CI = 0.96-1.61). Concurrent symptoms of inattention and hyperactivity/impulsivity predicted MVC risk. CONCLUSION: Persistence of ADHD into adulthood is a stronger predictor of MVC risk than childhood-limited ADHD. CLINICAL TRIAL REGISTRATION INFORMATION: Multimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) Study; https://clinicaltrials.gov; NCT00000388.

Depression and ADHD-Related Risk for Substance Use in Adolescence and Early Adulthood: Concurrent and Prospective Associations in the MTA.

Childhood attention-deficit/hyperactivity disorder (ADHD) is prospectively linked to substance use and disorder. Depression emerging in adolescence is an understudied risk factor that may explain some of this risk. In the present study, we considered mediating and moderating roles of adolescent depression in explaining this association by using longitudinal data from the prospective 16-year follow-up of the Multimodal Treatment Study of ADHD (MTA). Participants were 547 children diagnosed with DSM-IV ADHD Combined Type, and 258 age- and sex-matched comparison children. In adolescence, depressive symptoms did not exacerbate effects of childhood ADHD on any substance use. For both groups, time-varying and average depressive symptoms were associated with more frequent use of all substances. Prospectively, we found no evidence of depression mediation to adult substance use. However, adolescent depression moderated the association between childhood ADHD and adult marijuana use. Although adults without ADHD histories used marijuana more frequently if they had elevated depressive symptoms in adolescence, marijuana use by adults with ADHD histories was independent of their adolescent depression. In adulthood, depression diagnoses and ADHD persistence continued to operate as independent, additive correlates of substance use risk. Our findings suggest a circumscribed role for depression in substance use risk that adds to, but does not alter or explain, ADHD-related risk.

Family environment interacts with CRHR1 rs17689918 to predict mental health and behavioral outcomes.

BACKGROUND: Corticotrophin-releasing hormone receptor-1 gene (CRHR1) variants have been implicated in mental health. However, little is known of the effects of CRHR1 on long-term mental health and behavior in presence of environmental stressors. We assess the effects of CRHR1 variant (rs17689918)-by-environment interactions on emotionality and behavioral traits, including anxiety, depression, aggression and antisocial behaviors. We also determine effects of rs17689918-by-environment-by-sex interactions on the above-mentioned outcomes. METHODS: Genotypic assessments were carried out in 564 children (mean age 10 years, 52.5% females) from the ongoing longitudinal Estonian Children Personality Behaviour and Health Study (ECPBHS). Information on stressful life events and family relationships were available at baseline and information on behavioral and mental health outcomes (self- and parent-reports) were available at follow-up ages of 18 and 25 years. ANOVAs were used to determine associations of two-way CRHR1-by-environment and three-way CRHR1-by-sex-by-environment interactions on behavioral and mental health outcomes. RESULTS: Two-way CRHR1 interaction effects showed associations between low familial warmth and hostility in individuals with the GG genotype. Associations of low familial warmth with aggression, of higher number of stressful life events with aggression, and of stressful live events with anxious-depressive symptoms were noted in male A-allele carriers and female GG homozygotes. CONCLUSION: CRHR1-by-familial environment interactions influence both outwardly-directed aggression as well as mood and anxiety disorder symptoms in a sex-specific manner. The type of environmental stressor can also influence effects of CRHR1 on behavioral and mental health outcomes.

Late-Onset ADHD Reconsidered With Comprehensive Repeated Assessments Between Ages 10 and 25.

OBJECTIVE: Adolescents and young adults without childhood attention deficit hyperactivity disorder (ADHD) often present to clinics seeking stimulant medication for late-onset ADHD symptoms. Recent birth-cohort studies support the notion of late-onset ADHD, but these investigations are limited by relying on screening instruments to assess ADHD, not considering alternative causes of symptoms, or failing to obtain complete psychiatric histories. The authors address these limitations by examining psychiatric assessments administered longitudinally to the local normative comparison group of the Multimodal Treatment Study of ADHD. METHOD: Individuals without childhood ADHD (N=239) were administered eight assessments from comparison baseline (mean age=9.89 years) to young adulthood (mean age=24.40 years). Diagnostic procedures utilized parent, teacher, and self-reports of ADHD symptoms, impairment, substance use, and other mental disorders, with consideration of symptom context and timing. RESULTS: Approximately 95% of individuals who initially screened positive on symptom checklists were excluded from late-onset ADHD diagnosis. Among individuals with impairing late-onset ADHD symptoms, the most common reason for diagnostic exclusion was symptoms or impairment occurring exclusively in the context of heavy substance use. Most late-onset cases displayed onset in adolescence and an adolescence-limited presentation. There was no evidence for adult-onset ADHD independent of a complex psychiatric history. CONCLUSIONS: Individuals seeking treatment for late-onset ADHD may be valid cases; however, more commonly, symptoms represent nonimpairing cognitive fluctuations, a comorbid disorder, or the cognitive effects of substance use. False positive late-onset ADHD cases are common without careful assessment. Clinicians should carefully assess impairment, psychiatric history, and substance use before treating potential late-onset cases.

Cognitive Functioning in Adolescents with Self-Reported ADHD and Depression: Results from a Population-Based Study.

This study aims to assess cognitive functioning differences among adolescents with retrospectively self-reported: ADHD and an onset of depression, only ADHD, only depression, and neither ADHD nor depression. Data from the Tracking Adolescents' Individual Lives Survey (TRAILS) cohort was used in this study. Neuropsychological functioning was assessed in 1549 adolescents, at baseline and follow-up (mean ages 11 and 19 years). The Composite International Diagnostic Interview was used to classify adolescents into 4 groups: ADHD with onset of depression, only ADHD, only depression, and neither ADHD nor depression. Linear mixed effects models were used to analyse group differences in cognitive functioning at baseline and follow-up, and the change in cognitive functioning between these 2 time-points. Results showed a significant main effect of group on response time variability at baseline, working memory maintenance at follow up, and change in response time variability scores between baseline and follow-up. As compared to the healthy and depressed-only groups, adolescents with only ADHD showed longer response time variability at baseline and, which declined between baseline and follow-up. Adolescents with ADHD plus depression showed higher reaction time for working memory maintenance than the depressed only and healthy groups at follow-up. In conclusion, adolescents with self-reported ADHD show poorer cognitive functioning than healthy adolescents and those with only depression. Amongst adolescents with ADHD, specific cognitive domains show poor functioning depending on the presence or absence of comorbid depression. While adolescents with only ADHD have lower reaction time variability, those with comorbid depression have poorer working memory maintenance.

Childhood Predictors of Adult Functional Outcomes in the Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder (MTA).

OBJECTIVE: Recent results from the Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder (ADHD; MTA) have demonstrated impairments in several functioning domains in adults with childhood ADHD. The childhood predictors of these adult functional outcomes are not adequately understood. The objective of the present study was to determine the effects of childhood demographic, clinical, and family factors on adult functional outcomes in individuals with and without childhood ADHD from the MTA cohort. METHOD: Regressions were used to determine associations of childhood factors (age range 7-10 years) of family income, IQ, comorbidity (internalizing, externalizing, and total number of non-ADHD diagnoses), parenting styles, parental education, number of household members, parental marital problems, parent-child relationships, and ADHD symptom severity with adult outcomes (mean age 25 years) of occupational functioning, educational attainment, emotional functioning, sexual behavior, and justice involvement in participants with (n = 579) and without (n = 258) ADHD. RESULTS: Predictors of adult functional outcomes in ADHD included clinical factors such as baseline ADHD severity, IQ, and comorbidity; demographic factors such as family income, number of household members and parental education; and family factors such as parental monitoring and parental marital problems. Predictors of adult outcomes were generally comparable for children with and without ADHD. CONCLUSION: Childhood ADHD symptoms, IQ, and household income levels are important predictors of adult functional outcomes. Management of these areas early on, through timely treatments for ADHD symptoms, and providing additional support to children with lower IQ and from households with low incomes, could assist in improving adult functioning.

Childhood Factors Affecting Persistence and Desistence of Attention-Deficit/Hyperactivity Disorder Symptoms in Adulthood: Results From the MTA.

OBJECTIVE: To determine childhood factors that predict attention-deficit/hyperactivity disorder (ADHD) persistence and desistence in adulthood. METHOD: Regression analyses were used to determine associations between childhood factors and adult ADHD symptom persistence in 453 participants (mean age, 25 years) from the Multimodal Treatment Study of Children with ADHD (MTA). Childhood IQ, total number of comorbidities, child-perceived parenting practices, child-perceived parent-child relationships, parental mental health problems, marital problems of parents, household income levels, and parental education were assessed at a mean age of 8 years in all participants. Adult ADHD persistence was defined using DSM-5 symptom counts either with or without impairment, as well as mean ADHD symptom scores on the Conners' Adult ADHD Rating Scale (CAARS). Age, sex, MTA site, and childhood ADHD symptoms were covaried. RESULTS: The most important childhood predictors of adult ADHD symptom persistence were initial ADHD symptom severity (odds ratio [OR] = 1.89, standard error [SE] = 0.28, p = .025), comorbidities (OR = 1.19, SE = 0.07, p = .018), and parental mental health problems (OR = 1.30, SE = 0.09, p = .003). Childhood IQ, socioeconomic status, parental education, and parent-child relationships showed no associations with adult ADHD symptom persistence. CONCLUSION: Initial ADHD symptom severity, parental mental health, and childhood comorbidity affect persistence of ADHD symptoms into adulthood. Addressing these areas early may assist in reducing adult ADHD persistence and functioning problems.