Showing papers by "Stephen V. Faraone published in 2019"
Aarhus University1, Lundbeck2, Broad Institute3, Harvard University4, Cardiff University5, Karolinska Institutet6, Statens Serum Institut7, QIMR Berghofer Medical Research Institute8, deCODE genetics9, University of Iceland10, Mental Health Services11, Charité12, University of California, Los Angeles13, Semel Institute for Neuroscience and Human Behavior14, University of Queensland15, Oslo University Hospital16, King's College London17, University of Toronto18, VU University Amsterdam19, Radboud University Nijmegen20, Yale University21, Veterans Health Administration22, Children's Hospital of Philadelphia23, University of Bergen24, Haukeland University Hospital25, University of Pennsylvania26, I.M. Sechenov First Moscow State Medical University27, Maastricht University28, University of Würzburg29, Goethe University Frankfurt30, Universidade Federal do Rio Grande do Sul31, Icahn School of Medicine at Mount Sinai32, University of North Carolina at Chapel Hill33, Emory University34, University of Copenhagen35, Aarhus University Hospital36, State University of New York Upstate Medical University37
TL;DR: A genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls identifies variants surpassing genome- wide significance in 12 independent loci and implicates neurodevelopmental pathways and conserved regions of the genome as being involved in underlying ADHD biology.
Abstract: Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
1,436 citations
TL;DR: Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes.
781 citations
TL;DR: From studies of copy number variants, it is learned that the rare insertions or deletions account for part of ADHD’s heritability, which has implicated new biological pathways that may eventually have implications for treatment development.
Abstract: Decades of research show that genes play an vital role in the etiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. Family, twin, and adoption studies show that ADHD runs in families. ADHD’s high heritability of 74% motivated the search for ADHD susceptibility genes. Genetic linkage studies show that the effects of DNA risk variants on ADHD must, individually, be very small. Genome-wide association studies (GWAS) have implicated several genetic loci at the genome-wide level of statistical significance. These studies also show that about a third of ADHD’s heritability is due to a polygenic component comprising many common variants each having small effects. From studies of copy number variants we have also learned that the rare insertions or deletions account for part of ADHD’s heritability. These findings have implicated new biological pathways that may eventually have implications for treatment development.
612 citations
Shanghai Jiao Tong University1, Harvard University2, Broad Institute3, Karolinska Institutet4, CAS-MPG Partner Institute for Computational Biology5, King's College London6, Fujita Health University7, University of Queensland8, University of South Australia9, Columbia University10, Peking University11, University of Tokyo12, Chonnam National University13, University of Indonesia14, National Taiwan University15, Utrecht University16, Xi'an Jiaotong University17, State University of New York System18, State University of New York Upstate Medical University19, Jinan University20, Icahn School of Medicine at Mount Sinai21, University of Western Australia22, Cardiff University23, University of North Carolina at Chapel Hill24, Charité25, Jining Medical University26, Li Ka Shing Faculty of Medicine, University of Hong Kong27, University of Hong Kong28, Samsung Medical Center29, Illawarra Health & Medical Research Institute30, University of Wollongong31, University of California, San Diego32, Genome Institute of Singapore33, National University of Singapore34
TL;DR: The largest study to date of East Asian participants is reported, identifying 21 genome-wide-significant associations in 19 genetic loci associated with schizophrenia and highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.
Abstract: Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.
362 citations
TL;DR: A recent review as mentioned in this paper provides an overview of conceptual issues and genetic findings that bear on the relationships among and boundaries between psychiatric disorders and other conditions, highlighting implications for the evolving classification of psychopathology and the challenges for clinical translation.
Abstract: For over a century, psychiatric disorders have been defined by expert opinion and clinical observation. The modern DSM has relied on a consensus of experts to define categorical syndromes based on clusters of symptoms and signs, and, to some extent, external validators, such as longitudinal course and response to treatment. In the absence of an established etiology, psychiatry has struggled to validate these descriptive syndromes, and to define the boundaries between disorders and between normal and pathologic variation. Recent advances in genomic research, coupled with large-scale collaborative efforts like the Psychiatric Genomics Consortium, have identified hundreds of common and rare genetic variations that contribute to a range of neuropsychiatric disorders. At the same time, they have begun to address deeper questions about the structure and classification of mental disorders: To what extent do genetic findings support or challenge our clinical nosology? Are there genetic boundaries between psychiatric and neurologic illness? Do the data support a boundary between disorder and normal variation? Is it possible to envision a nosology based on genetically informed disease mechanisms? This review provides an overview of conceptual issues and genetic findings that bear on the relationships among and boundaries between psychiatric disorders and other conditions. We highlight implications for the evolving classification of psychopathology and the challenges for clinical translation.
241 citations
Radboud University Nijmegen1, Erasmus University Medical Center2, University of Southern California3, National Institutes of Health4, Oregon Health & Science University5, Autonomous University of Barcelona6, Polytechnic University of Valencia7, Hartford Hospital8, University of Groningen9, VU University Amsterdam10, University of São Paulo11, University of Melbourne12, RWTH Aachen University13, Harvard University14, VA Boston Healthcare System15, University of California, San Diego16, University of California, Irvine17, University of Cincinnati18, University of Würzburg19, University of Amsterdam20, Haukeland University Hospital21, University of Bergen22, New York University23, Trinity College, Dublin24, Norwegian University of Science and Technology25, University of Zurich26, University of Barcelona27, University of London28, University of Reading29, University of Brighton30, Heidelberg University31, Federal University of Rio de Janeiro32, University of Tübingen33, Erasmus University Rotterdam34, Russian National Research Medical University35, University Hospital of Lausanne36, University of Sussex37, Brighton and Sussex University Hospitals NHS Trust38, Monash University39, Deakin University40, ETH Zurich41, German Center for Neurodegenerative Diseases42, University of Regensburg43, Nathan Kline Institute for Psychiatric Research44, Goethe University Frankfurt45, VU University Medical Center46, Yale University47, Pompeu Fabra University48, State University of New York System49
TL;DR: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention.
Abstract: OBJECTIVE: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.
231 citations
TL;DR: The various terms used to define emotional symptoms in ADHD are reviewed, how these symptoms are demarcated from mood disorders are clarified, and the possibility that symptoms of emotional impulsivity and deficient emotional self-regulation should be considered as core symptoms of ADHD are assessed.
Abstract: BACKGROUND Because emotional symptoms are common in attention-deficit/hyperactivity disorder (ADHD) patients and associate with much morbidity, some consider it to be a core feature rather than an associated trait. Others argue that emotional symptoms are too nonspecific for use as diagnostic criteria. This debate has been difficult to resolve due, in part, to the many terms used to describe emotional symptoms in ADHD and to concerns about overlap with mood disorders. METHODS We sought to clarify the nature of emotional symptoms in ADHD by reviewing conceptual and measurement issues and by examining the evidence base regarding specificity of such symptoms for ADHD. We reviewed the various terms used to define emotional symptoms in ADHD, clarify how these symptoms are demarcated from mood disorders, and assess the possibility that symptoms of emotional impulsivity and deficient emotional self-regulation should be considered as core symptoms. We addressed psychiatric comorbidities, the effects of ADHD treatments on associated emotional dysregulation, and the utility of current rating scales to assess emotional symptoms associated with ADHD. RESULTS Emotional symptoms are common and persistent in youth and adults with ADHD. Although emotional symptoms are common in other psychiatric disorders, emotional impulsivity (EI), and deficient emotional self-regulation (DESR) may be sufficiently specific for ADHD to function as diagnostic criteria. CONCLUSIONS Emotional symptoms in ADHD cause clinically significant impairments. Although there is a solid theoretical rationale for considering EI and DESR to be core symptoms of ADHD, there is no consensus about how to define these constructs sin a manner that would be specific to the disorder. An instrument to measure EI and DESR which demarcates them from irritability and other emotional symptoms could improve the accuracy of diagnostic criteria for ADHD.
190 citations
165 citations
Radboud University Nijmegen1, Utrecht University2, Harvard University3, Broad Institute4, Aarhus University5, Lundbeck6, University of North Carolina at Chapel Hill7, University of Southern California8, Erasmus University Rotterdam9, University of Toronto10, King's College London11, University of Würzburg12, Karolinska Institutet13, Stockholm County Council14, QIMR Berghofer Medical Research Institute15, State University of New York Upstate Medical University16, University of Bergen17
TL;DR: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level.
Abstract: Objective:Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the n...
71 citations
TL;DR: Psychiatric comorbidity appears to play an important role in all-cause and cause-specific mortality risks in ADHD in adulthood, which contributed primarily to the association with death due to natural causes, whereas later-onset psychiatric comorbbidity mainly influenced deathDue to unnatural causes, including suicide and unintentional injury.
Abstract: Importance A previous register-based study reported elevated all-cause mortality in attention-deficit/hyperactivity disorder (ADHD), but cause-specific risks and the potential associations of psychiatric comorbidities remain unknown. Objectives To investigate the all-cause and cause-specific mortality risks in ADHD and to explore the potential role of psychiatric comorbidities. Design, Setting, and Participants This prospective cohort study used Swedish national registers to identify 2 675 615 individuals born in Sweden from January 1, 1983, through December 31, 2009, as the study population, among whom 86 670 individuals (3.2%) received a diagnosis of ADHD during follow-up. Follow-up was completed December 31, 2013, and data were analyzed from October 2018 through March 2019. Exposures Attention-deficit/hyperactivity disorder identified by first clinical diagnosis or first prescription of ADHD medications as recorded in Swedish registers. Clinical diagnosis of psychiatric comorbidity was available in the National Patient Register. Main Outcomes and Measures All-cause and cause-specific mortalities and hazard ratios (HRs) using Cox proportional hazards regression models. Results In the overall cohort of 2 675 615 individuals, 1 374 790 (51.4%) were male (57 919 with an ADHD diagnosis) and 1 300 825 (48.6%) were female (28 751 with an ADHD diagnosis). Mean (SD) age at study entry was 6.4 (5.6) years. During follow-up, 424 individuals with ADHD and 6231 without ADHD died, resulting in mortality rates of 11.57 and 2.16 per 10 000 person-years, respectively. The association was stronger in adulthood (HR, 4.64; 95% CI, 4.11-5.25) compared with childhood (HR, 1.41; 95% CI, 0.97-2.04) and increased substantially with the number of psychiatric comorbidities with ADHD (HR for individuals with only ADHD, 1.41 [95% CI, 1.01-1.97]; HR for those with ≥4 comorbidities, 25.22 [95% CI, 19.60-32.46]). In adulthood, when adjusting for early-onset psychiatric comorbidity, the association between ADHD and risk of death due to natural causes was attenuated substantially and was no longer statistically significant (HR, 1.32; 95% CI, 0.94-1.85). When adjusting for later-onset psychiatric disorders, the association was attenuated to statistical nonsignificance for death due to suicide (HR, 1.13; 95% CI, 0.88-1.45) but remained statistically significant for death caused by unintentional injury (HR, 2.14; 95% CI, 1.71-2.68) or other external causes (HR, 1.75; 95% CI, 1.23-2.48). Conclusions and Relevance Psychiatric comorbidity appears to play an important role in all-cause and cause-specific mortality risks in ADHD. In adulthood, early-onset psychiatric comorbidity contributed primarily to the association with death due to natural causes, whereas later-onset psychiatric comorbidity mainly influenced death due to unnatural causes, including suicide and unintentional injury. These findings suggest that health care professionals should closely monitor specific psychiatric comorbidities in individuals with ADHD to identify high-risk groups for prevention efforts.
67 citations
TL;DR: The cross-species and integrated approach to generate a more confident and comprehensive view of the complex genetics underlying aggression provides insights into the genetic etiology of aggression.
Abstract: Human genome-wide association studies (GWAS), transcriptome analyses of animal models, and candidate gene studies have advanced our understanding of the genetic architecture of aggressive behaviors. However, each of these methods presents unique limitations. To generate a more confident and comprehensive view of the complex genetics underlying aggression, we undertook an integrated, cross-species approach. We focused on human and rodent models to derive eight gene lists from three main categories of genetic evidence: two sets of genes identified in GWAS studies, four sets implicated by transcriptome-wide studies of rodent models, and two sets of genes with causal evidence from online Mendelian inheritance in man (OMIM) and knockout (KO) mice reports. These gene sets were evaluated for overlap and pathway enrichment to extract their similarities and differences. We identified enriched common pathways such as the G-protein coupled receptor (GPCR) signaling pathway, axon guidance, reelin signaling in neurons, and ERK/MAPK signaling. Also, individual genes were ranked based on their cumulative weights to quantify their importance as risk factors for aggressive behavior, which resulted in 40 top-ranked and highly interconnected genes. The results of our cross-species and integrated approach provide insights into the genetic etiology of aggression.
TL;DR: This study indicates that the association between ADHD and several comorbid disorders is stronger in female than in male individuals and suggests that female individuals diagnosed with ADHD are a more vulnerable group of patients.
Abstract: Objective To investigate sex differences in associations between attention-deficit/hyperactivity disorder (ADHD) and a spectrum of comorbid disorders. Method The study population included all children born in Denmark from 1981 through 2013 (N = 1,665,729). Data were merged from Danish registers and information was obtained on birth characteristics, socioeconomic status, familial psychiatric history, and diagnoses of ADHD (n = 32,308) and comorbid disorders. To estimate absolute and relative risks of comorbid disorders, incidence rates and adjusted hazard ratios (HRs) with 95% CIs were calculated for female and male individuals. In addition, interactions between ADHD and sex in association with comorbid disorders were estimated as HR ratios (HRRs) in female and male individuals (95% CIs). Results Individuals diagnosed with ADHD had significantly increased absolute and relative risks of all 12 comorbid psychiatric disorders investigated. ADHD-sex interactions were found for some comorbid disorders. Compared with male individuals, ADHD in female individuals showed a stronger association with autism spectrum disorder (HRR 1.86, 95% CI 1.62–2.14), oppositional defiant/conduct disorder (HRR 1.97, 95% CI 1.68–2.30), intellectual disability (HRR 1.79, 95% CI 1.54–2.09), personality disorders (HRR 1.23, 95% CI 1.06–1.43), schizophrenia (HRR 1.21, 95% CI 1.02–1.43), substance use disorders (HRR 1.21, 95% CI 1.07–1.38), and suicidal behavior (1.28, 95% CI 1.12–1.47). The remaining disorders showed no significant sex differences in association with ADHD. Conclusion This study indicates that the association between ADHD and several comorbid disorders is stronger in female than in male individuals. These important findings add to the literature on sex differences in ADHD and suggest that female individuals diagnosed with ADHD are a more vulnerable group of patients.
TL;DR: Findings indicate that children with subthreshold ADHD symptoms are at significantly greater risk for negative outcomes in a wide range of non-overlapping functional domains worthy of further clinical and scientific consideration.
Abstract: We conducted a qualitative review (n = 15 manuscripts) and meta-analysis (n = 9 manuscripts) of the extant literature to evaluate the prevalence and morbidity of subthreshold Attention Deficit Hyperactivity Disorder (ADHD). Our qualitative review showed that a sizable minority (mean: 17.7%) of clinically referred and non-referred children met a priori definitions of subthreshold ADHD. Those affected exhibited significantly higher rates of family dysfunction, cognitive impairment, executive dysfunction, interpersonal and school deficits, temperament problems, psychiatric comorbidity, and juvenile delinquency compared to children with no ADHD symptoms. These deficits were highly consistent with those observed in children with full threshold ADHD. These findings indicate that children with subthreshold ADHD symptoms are at significantly greater risk for negative outcomes in a wide range of non-overlapping functional domains worthy of further clinical and scientific consideration.
University of New South Wales1, Autonomous University of Barcelona2, University of Amsterdam3, Columbia University4, State University of New York Upstate Medical University5, Curtin University6, University of Fribourg7, Semmelweis University8, Karolinska Institutet9, Eötvös Loránd University10, University of Antwerp11, University of Western Australia12, University of Sydney13, University of Bordeaux14, Deakin University15, University of Haifa16
TL;DR: In this paper, the authors examined ADHD symptom persistence and subtype stability among substance use disorder (SUD) treatment seekers, and found that ADHD is highly prevalent and persistent among SUD treatment seekers and is associated with the more severe phenotype.
Abstract: Objective: To examine ADHD symptom persistence and subtype stability among substance use disorder (SUD) treatment seekers. Method: In all, 1,276 adult SUD treatment seekers were assessed for childhood and adult ADHD using Conners' Adult ADHD Diagnostic Interview for Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; CAADID). A total of 290 (22.7%) participants met CAADID criteria for childhood ADHD and comprise the current study sample. Results: Childhood ADHD persisted into adulthood in 72.8% (n = 211) of cases. ADHD persistence was significantly associated with a family history of ADHD, and the presence of conduct disorder and antisocial personality disorder. The combined subtype was the most stable into adulthood (78.6%) and this stability was significantly associated with conduct disorder and past treatment of ADHD. Conclusion: ADHD is highly prevalent and persistent among SUD treatment seekers and is associated with the more severe phenotype that is also less likely to remit. Routine screening and follow-up assessment for ADHD is indicated to enhance treatment management and outcomes.
State University of New York Upstate Medical University1, Autonomous University of Barcelona2, Oslo University Hospital3, Radboud University Nijmegen4, University of Southern California5, University of California, Berkeley6, University of Melbourne7, Epilepsy Society8, UCL Institute of Neurology9, University of Cape Town10, University of Amsterdam11, University of California, Irvine12, Vanderbilt University Medical Center13
TL;DR: In this article, the authors show substantial similarities in sMRI phenotypes among neuropsychiatric disorders and suggest that these similarities are accounted for, in part, by corresponding similarities in common genetic variant architectures.
Abstract: Background Genomewide association studies have found significant genetic correlations among many neuropsychiatric disorders. In contrast, we know much less about the degree to which structural brain alterations are similar among disorders and, if so, the degree to which such similarities have a genetic etiology. Methods From the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium, we acquired standardized mean differences (SMDs) in regional brain volume and cortical thickness between cases and controls. We had data on 41 brain regions for: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), epilepsy, major depressive disorder (MDD), obsessive compulsive disorder (OCD) and schizophrenia (SCZ). These data had been derived from 24,360 patients and 37,425 controls. Results The SMDs were significantly correlated between SCZ and BD, OCD, MDD, and ASD. MDD was positively correlated with BD and OCD. BD was positively correlated with OCD and negatively correlated with ADHD. These pairwise correlations among disorders were significantly correlated with the corresponding pairwise correlations among disorders derived from genomewide association studies (r = 0.494; p = 0.025). Conclusions Our results show substantial similarities in sMRI phenotypes among neuropsychiatric disorders and suggest that these similarities are accounted for, in part, by corresponding similarities in common genetic variant architectures.
TL;DR: In combination with an attention task, vergence responses can be used as an objective marker to detect ADHD in children.
Abstract: Objective: ADHD youth show poor oculomotor control. Recent research shows that attention-related eye vergence is weak in ADHD children. Method: To validate vergence as a marker to classify ADHD, we...
TL;DR: The findings show that in stimulant-treated adolescents with ADHD, long-term outcomes are associated with treatment characteristics, something that is often ignored when treated individuals are compared to untreated individuals.
Abstract: Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence (ND). It remains unclear whether and how stimulant treatment may affect this risk. We aimed to investigate how stimulant use profiles influence the risk of SUDs and ND, using a novel data-driven community detection analysis to construct different stimulant use profiles. Comprehensive lifetime stimulant prescription data and data on SUDs and ND were available for 303 subjects with ADHD and 219 controls, with a mean age 16.3 years. Community detection was used to define subgroups based on multiple indicators of treatment history, start age, treatment duration, total dose, maximum dose, variability, stop age. In stimulant-treated participants, three subgroups with distinct medication trajectories were distinguished (late-and-moderately dosed, n = 91; early-and-moderately dosed, n = 51; early-and-intensely dosed, n = 103). Compared to stimulant-naive participants (n = 58), the early-and-intense treatment group had a significantly lower risk of SUDs and ND (HR = 0.28, and HR = 0.29, respectively), while the early-and-moderate group had a significantly lower risk of ND only (HR = 0.30). The late-and-moderate group was at a significantly higher risk of ND compared to the other two treatment groups (HR = 2.66 for early-and-moderate, HR = 2.78 for early-and-intense). Our findings show that in stimulant-treated adolescents with ADHD, long-term outcomes are associated with treatment characteristics, something that is often ignored when treated individuals are compared to untreated individuals.
TL;DR: High-level mind wandering is prevalent in adults with ADHD and is associated with more severe ADHD symptoms, more executive function deficits, more emotional dysregulation, higher levels of associated psychopathology, and more impaired quality of life.
TL;DR: Findings, which show low rates of medication adherence among children and adolescents with ADHD, suggest the need for efforts to improve these rates and rely on a novel definition of medications adherence as a timely renewal of an index prescription determined using the electronically recorded issuance of a stimulant prescription in the EMR.
Abstract: Objective:The objective of this study was to evaluate rates and correlates of stimulant medication adherence in a sample of pediatric patients using data derived from electronic medical records (EM...
TL;DR: ASRS- and AISRS-expanded versions have high validity in assessment of core 18 adult ADHD Diagnostic and Statistical Manual of Mental Disorders (DSM) symptoms and EFD and EC symptoms.
Abstract: Objective: The aim of this study is to validate the Adult ADHD Self-Report Scale (ASRS) and Adult ADHD Investigator Symptom Rating Scale (AISRS) expanded versions, including executive function deficits (EFDs) and emotional dyscontrol (EC) items, and to present ASRS and AISRS pilot normative data. Method: Two patient samples (referred and primary care physician [PCP] controls) were pooled together for these analyses. Results: Final analysis included 297 respondents, 171 with adult ADHD. Cronbach's alphas were high for all sections of the scales. Examining histograms of ASRS 31-item and AISRS 18-item total scores for ADHD controls, 95% cutoff scores were 70 and 23, respectively; histograms for pilot normative sample suggest cutoffs of 82 and 26, respectively. Conclusion: (a) ASRS- and AISRS-expanded versions have high validity in assessment of core 18 adult ADHD Diagnostic and Statistical Manual of Mental Disorders (DSM) symptoms and EFD and EC symptoms. (b) ASRS (31-item) scores 70 to 82 and AISRS (18-item) scores from 23 to 26 suggest a high likelihood of adult ADHD.
Max Planck Society1, Aarhus University2, Lundbeck3, University of Cambridge4, University of New Mexico5, Erasmus University Rotterdam6, VU University Amsterdam7, Broad Institute8, Harvard University9, State University of New York Upstate Medical University10, University of Bristol11, Radboud University Nijmegen12
TL;DR: Investigating genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children, shows that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading- related abilities, and explained ≤1.6% phenotypic variation.
Abstract: Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is
challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate
genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as
assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide
summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our
findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most
consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then
dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR).
Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic
awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative
ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading
performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold <
0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the
predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least
equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold
instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA,
although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacyrelated impairments
TL;DR: By showing that the rate of placebo AEs impacts the RR, this study provides the field with a useful covariate for adjusting RR statistics and shows that the RR and its interpretation are constrained by the placebo AE rate.
Abstract: OBJECTIVE Sleep disturbances are a feature of attention-deficit/hyperactivity disorder (ADHD) and an adverse event (AE) of methylphenidate treatment. The authors sought to clarify methylphenidate-associated sleep problems and how studies are affected by confounding factors. DATA SOURCES Published studies in English collected via online databases and unpublished data from www.clinicaltrials.gov and US Food and Drug Administration websites. Sources were searched from inception to August 2017. STUDY SELECTION Included were blinded placebo-controlled studies of youth with ADHD conducted in naturalistic settings, leading to 35 studies yielding 75 observations of sleep-related AEs. These studies comprised 3,079 drug-exposed and 2,606 placebo-treated patients. DATA EXTRACTION Two PhD-level reviewers reviewed each study for inclusion. Four PhD/PharmD-level reviewers extracted data in duplicate. Discrepancies were resolved by discussion or, if needed, by the senior author. RESULTS Increased pooled relative risks (RRs) were found for methylphenidate-associated sleep-related AEs for insomnia (general), initial insomnia, middle insomnia, combined insomnia, and sleep disorder. Several sample or study design features were significantly associated with the RR for sleep-related AEs and the methylphenidate formulation studied (P < .05). After correction for confounding variables, significant differences among drugs were found for initial insomnia, insomnia (general), and sleep disorder (P < .0001) as the other categories could not be tested due to insufficient studies. The findings also show that the RR and its interpretation are constrained by the placebo AE rate. CONCLUSIONS Several types of insomnia and sleep problems are associated with methylphenidate treatment. Study design and sample features influence the RR statistic. By showing that the rate of placebo AEs impacts the RR, this study provides the field with a useful covariate for adjusting RR statistics.
TL;DR: Oral and nonoral NMU of AMP are associated with significant risks of morbidity and mortality, and Oral NMU conferred a significantly greater risk of suicide attempts.
Abstract: Objective: To describe consequences of the nonmedical use (NMU) of prescription amphetamines (AMPs). Method: Data from the U.S. National Poison Data System yielded four groups: intravenous NMU (IV NMU) intentionally injected AMP, Nasal NMU intentionally inhaled AMP but did not inject, Oral NMU intentionally ingested AMP, and controls reported unintentional oral exposure to AMP. Results: The Nasal NMU group was at greater risk of admission to a health care facility. All NMU groups were at greater risk for adverse clinical effects. IV NMU had the greatest number of adverse effects, followed by Nasal and Oral NMU. Nasal NMU had a greater risk for major medical outcomes versus Oral NMU. The IV NMU group was 21.9 times more likely to die from AMP NMU than controls. Oral NMU conferred a significantly greater risk of suicide attempts. Conclusion: Oral and nonoral NMU of AMP are associated with significant risks of morbidity and mortality.
TL;DR: This proof-of-concept study identified ADHD-related neural correlates across multiple functional networks, showing distinct categorical and dimensional mechanisms and their links to neurocognitive functioning.
TL;DR: The association between ADHD and clinical obesity in adolescence and young adulthood can be entirely attributed to genetic underpinnings shared by the two conditions.
Abstract: BACKGROUND: A recent family study of young adult males suggests a shared familial liability between attention-deficit/hyperactivity disorder (ADHD) and high body mass index (BMI), and a genome-wide meta-analysis reported a genetic correlation of 0.26 between ADHD and BMI. To date, it is unclear whether these findings generalize to the relationship between ADHD and clinically diagnosed obesity. METHOD: By linking the Swedish national registers, we identified 25 38 127 individuals born between 1973 and 2000, together with their siblings and cousins. The risk of clinical obesity in individuals with ADHD was compared with the risk in those without ADHD. The relative contributions of genetic and environmental factors to the association between ADHD and clinical obesity were examined via assessment of the familial co-aggregation of the two conditions and quantitative genetic analysis. RESULTS: Individuals with ADHD were at an increased risk of clinical obesity compared with those without (risk difference 3.73%, 95% confidence interval (CI) 3.55-3.90%; risk ratio 3.05, 95% CI 2.95-3.15). Familial co-aggregation of ADHD and clinical obesity was detected and the strength of the co-aggregation decreased by decreasing genetic relatedness. The correlation between the liabilities to ADHD and clinical obesity can be entirely attributed to their genetic correlation (rg 0.30, 95% CI 0.17-0.44). CONCLUSION: The association between ADHD and clinical obesity in adolescence and young adulthood can be entirely attributed to genetic underpinnings shared by the two conditions. Children with ADHD should be monitored for weight gain so that preventive measures can be taken for those on a suboptimal trajectory.
TL;DR: To estimate Adult ADHD Self‐Report Scale (ASRS‐v1.1) Symptom Checklist normative total scores among the US adult general population and to evaluate overall attention‐deficit hyperactivity disorder (ADHD) symptom burden among US adults with ADHD is evaluated.
Abstract: AIMS To estimate Adult ADHD Self-Report Scale (ASRS-v1.1) Symptom Checklist normative total scores among the US adult general population and to evaluate overall attention-deficit hyperactivity disorder (ADHD) symptom burden among US adults with ADHD. METHODS Prior 2012 and 2013 US National Health and Wellness Survey respondents were re-contacted. Demographics, comorbidities, and ASRS-v1.1 data were collected. ASRS-v1.1 scores were compared by sex, age, ADHD diagnosis, and ADHD medication use. Group differences were evaluated using chi-square tests and independent samples t-tests for categorical and continuous variables, respectively. RESULTS Of 22 397 respondents, 465 self-reported being diagnosed with ADHD by a physician; of these, 174 self-reported using ADHD medication. The mean ASRS-v1.1 total score was 2.0 (SD = 3.2); scores differed by age and sex (all, P < 0.001). ADHD (vs no ADHD) was associated with depression (58.1% vs 18.0%), anxiety (53.1% vs 16.0%), and sleep difficulties (37.0% vs 14.0%) (all, P < 0.001). ADHD medication use (vs no use) was associated with depression (68.4% vs 51.9%), anxiety (67.2% vs 44.7%), panic disorder (25.9% vs 17.2%), and insomnia (27.6% vs 19.6%) (all, P < 0.05). ADHD (vs no ADHD) respondents scored higher on all 18 ASRS-v1.1 items (all, P < 0.05). Medication users (vs non-users) scored higher on six items (all, P < 0.05). DISCUSSION Adult ADHD may be undertreated or sub-optimally treated, despite a high symptom burden. Normative data will allow comparisons with individuals' scores to support the assessment of ADHD symptom burden among adults. CONCLUSION Findings highlight the importance of assessing ADHD symptom burden, especially among adults presenting with comorbidities.
TL;DR: This work followed a systematic approach to identify risk variants for ADHD that correlated with differential cis-methylation, identifying three novel genes contributing to the disorder.
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder caused by an interplay of genetic and environmental factors. Epigenetics is crucial to lasting changes in gene expression in the brain. Recent studies suggest a role for DNA methylation in ADHD. We explored the contribution to ADHD of allele-specific methylation (ASM), an epigenetic mechanism that involves SNPs correlating with differential levels of DNA methylation at CpG sites. We selected 3896 tagSNPs reported to influence methylation in human brain regions and performed a case-control association study using the summary statistics from the largest GWAS meta-analysis of ADHD, comprising 20,183 cases and 35,191 controls. We observed that genetic risk variants for ADHD are enriched in ASM SNPs and identified associations with eight tagSNPs that were significant at a 5% false discovery rate (FDR). These SNPs correlated with methylation of CpG sites lying in the promoter regions of six genes. Since methylation may affect gene expression, we inspected these ASM SNPs together with 52 ASM SNPs in high LD with them for eQTLs in brain tissues and observed that the expression of three of those genes was affected by them. ADHD risk alleles correlated with increased expression (and decreased methylation) of ARTN and PIDD1 and with a decreased expression (and increased methylation) of C2orf82. Furthermore, these three genes were predicted to have altered expression in ADHD, and genetic variants in C2orf82 correlated with brain volumes. In summary, we followed a systematic approach to identify risk variants for ADHD that correlated with differential cis-methylation, identifying three novel genes contributing to the disorder.
TL;DR: The objective of this study was to evaluate the morbidity of subthreshold pediatric bipolar (BP) disorder.
Abstract: Objective The objective of this study was to evaluate the morbidity of subthreshold pediatric bipolar (BP) disorder. Methods We performed a systematic literature search in November 2017 and included studies examining the morbidity of pediatric subthreshold BP. Extracted outcomes included functional impairment, severity of mood symptoms, psychiatric comorbidities, suicidal ideation and behaviors, and mental health treatment. We used meta-analysis to compute the pooled standardized mean difference (SMD) for continuous measures and the pooled risk ratio (RR) for binary measures between two paired groups: subthreshold pediatric BP vs controls and subthreshold pediatric BP vs pediatric BP-I. Results Eleven papers, consisting of seven datasets, were included. We compared subthreshold pediatric BP (N = 244) to non-BP controls (N = 1125) and subthreshold pediatric BP (N = 643) to pediatric BP-I (N = 942). Subthreshold pediatric BP was associated with greater functional impairment (SMD = 0.61, CI 0.25-0.97), greater severity of mood symptomatology (mania: SMD = 1.88, CI 1.38-2.38; depression: SMD = 0.66, CI 0.52-0.80), higher rates of disruptive behavior (RR = 1.75, CI 1.17-2.62), mood (RR = 1.78, CI 1.29-2.79) and substance use (RR = 2.27, CI 1.23-4.21) disorders, and higher rates of suicidal ideation and attempts (RR = 7.66, CI 1.71-34.33) compared to controls. Pediatric BP-I was associated with greater functional impairment, greater severity of manic symptoms, higher rates of suicidal ideation and attempts, and higher rates of mental health treatment compared to subthreshold pediatric BP. There were no differences between full and subthreshold cases in the severity of depressive symptoms or rates of comorbid disorders. Conclusions Subthreshold pediatric BP disorder is an identifiable morbid condition associated with significant functional impairment including psychiatric comorbidities and high rates of suicidality.
TL;DR: Findings provide strong support for the use of a readily accessible, inexpensive, and widely available technology to improve the poor rate of adherence to stimulant treatment in adults with ADHD.
Abstract: BACKGROUND Attention deficit/hyperactivity disorder (ADHD) is a prevalent neurobiological disorder associated with a wide range of adverse outcomes. Although large data sets document that stimulants decrease the risks for many ADHD-associated adverse outcomes, compliance with stimulants remains very poor. The main aim of this study was to assess the effectiveness of a novel text messaging-based intervention aimed at improving the poor rate of adherence to stimulant medications in adults with ADHD. METHODS Subjects were adults with ages 18 to 55, prescribed a stimulant medication for ADHD treatment. For comparators, we identified at a 5-to-1 ratio (age and sex matched) adult patients from the Partners HealthCare electronic medical record who had been prescribed stimulant medications over a 1-year period. We determined whether patients had timely prescription refills, defined as refilled within 37 days, using prescriptions documented in their electronic medical record. RESULTS Our results showed that 68% of the SMS intervention group refilled their prescriptions in a timely manner. In contrast, only 34% of patients receiving treatment as usual refilled their prescriptions in a timely fashion (odds ratio, 4.04; 95% confidence interval, 2.49-6.56; P < 0.001). CONCLUSIONS These data indicate that an innovative ADHD-centric text messaging intervention significantly improved patient engagement to treatment with stimulants in adults with ADHD. Findings provide strong support for the use of a readily accessible, inexpensive, and widely available technology to improve the poor rate of adherence to stimulant treatment in adults with ADHD. To the best of our knowledge, this study is the first digital health intervention aimed at improving adherence to stimulant medication for adults with ADHD.
TL;DR: This work finds ADHD-related sMRI differences in adults and shows that the brain differences between cases and controls seen in youth can be useful in discriminating adults with and without ADHD.
Abstract: Background Clinical symptoms-based ADHD diagnosis is considered “subjective”. Machine learning (ML) classifiers have been explored to develop objective diagnosis of ADHD using magnetic resonance imaging (MRI) biomarkers. Methods We reviewed previous literature and developed ensemble classifiers using the ENIGMA-ADHD dataset, with the implementation of data balancing to control for age, sex, diagnostic groups, and sample sites and a held-out test set for independent evaluation. Results Our review showed that classification accuracies reported previously using cross-validation (CV) samples were inflated and did not generalize well to independent test samples. Our results showed a significant discrimination between ADHD and control samples for both adult and children, but the accuracies were modest (the area under the receiver operating characteristic curve (AUC): 66% and 67% respectively). We found that child samples were informative for predicting adult ADHD, and vice versa. The most important brain MRI structures for prediction were intracranial volume (ICV), followed by surface area and some subcortical volumes. The cortical thickness measurements were the least useful. Conclusions Although previous ML classification studies reported overly optimistic accuracies and suffered methodological limitations, our results suggest that clinically useful classification of ADHD may be possible with larger samples. In contrast to prior reports of ENIGMA-ADHD studies, our work finds ADHD-related sMRI differences in adults and shows that the brain differences between cases and controls seen in youth can be useful in discriminating adults with and without ADHD. This provides additional evidence for the continuity of ADHD’s pathophysiology from childhood to adulthood.