Showing papers by "Stephen V. Faraone published in 2010"
TL;DR: Although twin studies demonstrate that ADHD is a highly heritable condition, molecular genetic studies suggest that the genetic architecture of ADHD is complex as discussed by the authors, and the handful of genomewide linkage and association scans that have been conducted thus far show divergent findings and are therefore not conclusive.
973 citations
TL;DR: Though the level of risk is less than that with the APOE4 allele, the high prevalence of these disorders may result in substantial increases in future incidence of AD.
590 citations
Broad Institute1, Harvard University2, QIMR Berghofer Medical Research Institute3, King's College London4, Radboud University Nijmegen Medical Centre5, University of Würzburg6, State University of New York Upstate Medical University7, University of Marburg8, Cardiff University9, University of Zurich10, University of Basel11, Aarhus University Hospital12, Goethe University Frankfurt13, University of Trier14, Trinity College, Dublin15, University of St Andrews16, VU University Amsterdam17, Ghent University18, Semel Institute for Neuroscience and Human Behavior19, University of Pennsylvania20, Children's Hospital of Philadelphia21, Washington University in St. Louis22, University of Valencia23, Hebrew University of Jerusalem24, University of Göttingen25, University of Duisburg-Essen26, New York University27, University of Southampton28, Eli Lilly and Company29, Pfizer30, University of California, Los Angeles31
TL;DR: This paper conducted a meta-analysis of existing studies to boost statistical power and found no genome-wide significant associations, although an analysis of candidate genes suggests that they may be involved in the disorder.
Abstract: Objective Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.
467 citations
TL;DR: In this paper, the authors examined the age-dependent persistence of attention-deficit hyperactivity disorder (ADHD) in boys transitioning from adolescence into early adulthood attending to different definitions of persistence.
Abstract: The main aim of this study was to examine the age-dependent persistence of attention-deficit hyperactivity disorder (ADHD) in boys transitioning from adolescence into early adulthood attending to different definitions of persistence. We conducted a 10-year follow-up study (mean follow-up time=11 years) of 110 boys with ADHD and 105 non-ADHD controls. Both groups were 6-17 years of age at ascertainment. ADHD was considered persistent at follow-up if subjects met full or subthreshold (more than half of the symptoms required for a full diagnosis) Diagnostic and Statistical Manual of Mental Disorders, fourth edition, (DSM-IV) diagnostic criteria, failed to attain functional remission (Global Assessment of Functioning, GAF score < or =60) or were receiving treatment for ADHD. While 65% of children with ADHD no longer met full DSM-IV criteria for ADHD at the 10-year follow-up, 78% of subjects met at least one of our definitions of persistence. Persistence as described above was associated with more psychiatric co-morbidity, more familiality with mood disorders and higher levels of educational and interpersonal impairments than controls. This 10-year longitudinal follow-up study shows that the majority of ADHD boys experience persistent symptoms and functional impairments into early adulthood. Persistence of ADHD is associated with greater psychiatric comorbidity, familiality and functional impairments.
435 citations
TL;DR: Amfetamine products may be moderately more efficacious than methylphenidate products, even after controlling for potentially confounding study design features, and this difference in effect size may be due to differences between amfetamine and methyl phenidate in the molecular mechanisms involved in facilitating the dopaminergic neurotransmission.
Abstract: Stimulants used to treat attention-deficit/hyperactivity disorder (ADHD) have been well researched, but comparisons among stimulants are hindered by the absence of direct comparative trials. The goal of this work was to compare the efficacy of methylphenidate and amfetamine formulations through a meta-analysis of double-blind placebo-controlled trials. We analyzed recent published literature on the stimulant therapy of ADHD to describe the variability of drug-placebo effect sizes. A literature search was conducted to identify double-blind, placebo-controlled studies of ADHD in children and adolescents published after 1979. Meta-analysis regression assessed the influence of medication type and study design features on medication effects. Twenty-three trials met criteria and were included in this meta-analysis. These trials studied 11 drugs using 19 different outcome measures of hyperactive, inattentive, or impulsive behavior. We found significant differences between amfetamine and methylphenidate products, even after correcting for study design features that might have confounded the results. Our analyses indicate that effect sizes for amfetamine products are significantly, albeit moderately, greater than those for methylphenidate. We found that most measures of effect from all studies were statistically significant. Our findings suggest that amfetamine products may be moderately more efficacious than methylphenidate products, even after controlling for potentially confounding study design features. This difference in effect size may be due to differences between amfetamine and methylphenidate in the molecular mechanisms involved in facilitating the dopaminergic neurotransmission.
418 citations
TL;DR: Although both stimulant and nonstimulant medications are effective for treating ADHD in adults, stimulant medications show greater efficacy for the short durations of treatment characteristic of placebo-controlled studies.
Abstract: OBJECTIVES Medications used to treat attention-deficit/hyperactivity disorder (ADHD) in adults have been well researched, but comparisons among drugs are hindered by the absence of direct comparative trials. Our objectives were to (1) estimate the effect size of the medications used to treat adult ADHD, (2) determine if differences in the designs of studies confound comparisons of medication efficacy, (3) quantify the evidence for differences in effect sizes among medications, and (4) see if features of study design influence estimates of efficacy. DATA SOURCES The following search engines were used: PubMed, Ovid, ERIC, CINAHL, MEDLINE, PREMEDLINE, the Cochrane database, e-psyche, and Social Sciences Abstracts. Presentations from the American Psychiatric Association and American Academy of Child and Adolescent Psychiatry meetings were reviewed. STUDY SELECTION A literature search was conducted to identify double-blind, placebo-controlled studies of ADHD in adults published in English after 1979. Only trials that used DSM-III, -III-R, or -IV ADHD criteria and followed subjects for > or = 2 weeks were selected. DATA EXTRACTION Meta-analysis regression assessed the influence of medication type and study design features on medication effects. RESULTS Nineteen trials met criteria and were included in this meta-analysis. These trials studied 13 drugs using 18 different outcome measures of hyperactive, inattentive, or impulsive behavior. After trials were stratified on the class of drug studied (short-acting stimulant vs long-acting stimulant vs nonstimulant), significant differences in effect size were observed between stimulant and nonstimulant medications (P = .006 and P = .0001, respectively, for short- and long-acting stimulants vs nonstimulants), but the effect for short-acting stimulants was not significant after correcting for study design features. The effect sizes for each drug class were similar in magnitude to what we previously reported for medication treatment studies of children with ADHD. We found significant heterogeneity of effect sizes for short-acting stimulants (P < .001) but not for other medication groups. CONCLUSIONS Although both stimulant and nonstimulant medications are effective for treating ADHD in adults, stimulant medications show greater efficacy for the short durations of treatment characteristic of placebo-controlled studies. We found no significant differences between short- and long-acting stimulant medications. Study design features vary widely among studies and can confound indirect comparisons unless addressed statistically as we have done in this study.
345 citations
University of Göttingen1, Radboud University Nijmegen2, University of Southampton3, VU University Amsterdam4, Trinity College, Dublin5, Memorial Hospital of South Bend6, University of Valencia7, Ghent University8, Aarhus University Hospital9, University of Zurich10, State University of New York Upstate Medical University11
TL;DR: In this article, the occurrence, severity and clinical correlates of emotional lability in children with attention deficit/hyperactivity disorder (ADHD), and examine factors contributing to EL and familiality of EL in youth with ADHD.
Abstract: Background: The goal of this study was to investigate the occurrence, severity and clinical correlates of emotional lability (EL) in children with attention deficit/hyperactivity disorder (ADHD), and to examine factors contributing to EL and familiality of EL in youth with ADHD. Methods: One thousand, one hundred and eighty-six children with ADHD combined type and 1827 siblings (aged 6–18 years) were assessed for symptoms of EL, ADHD, associated psychopathology and comorbid psychiatric disorders with a structured diagnostic interview (PACS) as well as parent and teacher ratings of psychopathology (SDQ; CPRS-R:L; CTRS-R:L). Analyses of variance, regression analyses, ?2-tests or loglinear models were applied. Results: Mean age and gender-standardized ratings of EL in children with ADHD were >1.5 SD above the mean in normative samples. Severe EL (>75th percentile) was associated with more severe ADHD core symptoms, primarily hyperactive-impulsive symptoms, and more comorbid oppositional defiant, affective and substance use disorders. Age, hyperactive-impulsive, oppositional, and emotional symptoms accounted for 30% of EL variance; hyperactive-impulsive symptoms did not account for EL variance when coexisting oppositional and emotional problems were taken into account, but oppositional symptoms explained 12% of EL variance specifically. Severity of EL in probands increased the severity of EL in siblings, but not the prevalence rates of ADHD or ODD. EL and ADHD does not co-segregate within families. Conclusion: EL is a frequent clinical problem in children with ADHD. It is associated with increased severity of ADHD core symptoms, particularly hyperactivity-impulsivity, and more symptoms of comorbid psychopathology, primarily symptoms of oppositional defiant disorder (ODD), but also affective symptoms, and substance abuse. EL in ADHD seems to be more closely related to ODD than to ADHD core symptoms, and is only partly explainable by the severity of ADHD core symptoms and associated psychopathology. Although EL symptoms are transmitted within families, EL in children with ADHD does not increase the risk of ADHD and ODD in their siblings.
310 citations
TL;DR: Findings document the greater persistence of inattentive than of hyperactive/impulsive childhood symptoms of ADHD in adulthood but also show that inattention is not specific to ADHD because it is strongly associated with other adult mental disorders.
Abstract: Context Controversy exists about the appropriate criteria for a diagnosis of adult attention-deficit/hyperactivity disorder (ADHD). Objective To examine the structure and symptoms most predictive of DSM-IV adult ADHD. Design The data are from clinical interviews in enriched subsamples of the National Comorbidity Survey Replication (n = 131) and a survey of a large managed health care plan (n = 214). The physician-administered Adult ADHD Clinical Diagnostic Scale (ACDS) was used to assess childhood ADHD and expanded symptoms of current adult ADHD. Analyses examined the stability of symptoms from childhood to adulthood, the structure of adult ADHD, and the adult symptoms most predictive of current clinical diagnoses. Setting The ACDS was administered telephonically by clinical research interviewers with extensive experience in the diagnosis and treatment of adult ADHD. Participants An enriched sample of community respondents. Main Outcome Measure Diagnoses of DSM-IV /ACDS adult ADHD. Results Almost half of the respondents (45.7%) who had childhood ADHD continued to meet the full DSM-IV criteria for current adult ADHD, with 94.9% of these patients having current attention-deficit disorder and 34.6% having current hyperactivity disorder. Adult persistence was much greater for inattention than for hyperactivity/impulsivity. Additional respondents met the full criteria for current adult ADHD despite not having met the full childhood criteria. A 3-factor structure of adult symptoms included executive functioning (EF), inattention/hyperactivity, and impulsivity. Stepwise logistic regression found EF problems to be the most consistent and discriminating predictors of adult DSM-IV /ACDS ADHD. Conclusions These findings document the greater persistence of inattentive than of hyperactive/impulsive childhood symptoms of ADHD in adulthood but also show that inattention is not specific to ADHD because it is strongly associated with other adult mental disorders. In comparison, EF problems are more specific and consistently important predictors of DSM-IV adult ADHD despite not being in the DSM-IV , suggesting that the number of EF symptoms should be increased in the DSM-V/ICD-11 .
291 citations
National Institutes of Health1, University of Antioquia2, Children's Hospital of Philadelphia3, University of Bergen4, University of Barcelona5, Autonomous University of Barcelona6, Virginia Commonwealth University7, State University of New York Upstate Medical University8, Saarland University9, University of Trier10, University of Würzburg11, University of California, Irvine12, New York University13
TL;DR: Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication.
Abstract: Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.
255 citations
TL;DR: By young adulthood, girls with ADHD were at high risk for antisocial, addictive, mood, anxiety, and eating disorders, and further evidence for the high morbidity associated with ADHD across the life cycle is provided.
Abstract: ObjectiveFew follow-up studies have been conducted of girls with ADHD, and none have followed girls into adulthood. The authors sought to estimate the prevalence of psychopathology in girls with and without ADHD followed into young adulthood. MethodThe authors conducted a longitudinal case-control study of 6- to 18-year-old girls with (N=140) and without (N=122) ADHD ascertained from psychiatric and pediatric sources. At the 11-year follow-up, 96 (69%) of the girls with ADHD and 91 (75%) of the comparison girls were reassessed (mean age=22 years). Participants were blindly assessed by structured diagnostic interviews. ResultsLifetime and 1-year risks for all composite categories of psychopathology were significantly greater in girls with ADHD grown up relative to comparison girls; lifetime hazard ratios were 7.2 (95% CI=4.0–12.7) for antisocial disorders, 6.8 (95% CI=3.7–12.6) for mood disorders, 2.1 (95% CI=1.6–2.9) for anxiety disorders, 3.2 (95% CI=2.0–5.3) for developmental disorders, 2.7 (95% CI=1.6–...
247 citations
TL;DR: This article provided a meta-analysis of neurocognitive findings from 47 studies of first-episode (FE) schizophrenia published through October 2007, using 43 separate samples of 2,204 FE patients with a mean age of 25.5 and 2,775 largely age and gender-matched control participants.
TL;DR: The first results of the International Multicentre Persistent ADHD Genetics CollaboraTion (IMpACT) are presented, finding a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier associations.
Harvard University1, Massachusetts Institute of Technology2, QIMR Berghofer Medical Research Institute3, Trinity College, Dublin4, Medical Research Council5, Radboud University Nijmegen Medical Centre6, University of St Andrews7, State University of New York Upstate Medical University8, Cardiff University9, University of Würzburg10, University of Marburg11, University of Zurich12, Goethe University Frankfurt13, University of Trier14, University of Göttingen15, VU University Amsterdam16, Ghent University17
TL;DR: The candidate gene findings are consistent with a prior meta-analysis in suggesting that the effects of ADHD risk variants must, individually, be very small and/or include multiple rare alleles.
Abstract: Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genomewide significant level have yet to be identified. Thus additional genomewide association studies (GWAS) are needed. Method: We used case-control analyses of 896 cases with DSM-IV ADHD genotyped using the Affymetrix 5.0 array and 2,455 repository controls screened for psychotic and bipolar symptoms genotyped using Affymetrix 6.0 arrays. A consensus SNP set was imputed using BEAGLE 3.0, resulting in an analysis dataset of 1,033,244 SNPs. Data were analyzed using a generalized linear model. Results: No genomewide significant associations were found. The most significant results implicated the following genes: PRKG1, FLNC, TCERG1L, PPM1H, NXPH1, PPM1H, CDH13, HK1, and HKDC1. Conclusions: The current analyses are a useful addition to the present literature and will make a valuable contribution to future meta-analyses. The candidate gene findings are consistent with a prior meta-analysis in suggesting that the effects of ADHD risk variants must, individually, be very small and/or include multiple rare alleles. J. Am. Acad. Child Adolesc. Psychiatry, 2010;49(9):906‐920. Key Words: ADHD, genetics, genome-wide association, imputation
University of London1, University of Alabama at Birmingham2, Queen's University Belfast3, Trinity College, Dublin4, University of Göttingen5, Radboud University Nijmegen6, VU University Amsterdam7, Ghent University8, University of Southampton9, Heidelberg University10, University of Valencia11, University of Duisburg-Essen12, Aarhus University13, University of Basel14, University of Zurich15, State University of New York System16
TL;DR: The findings suggest the existence of 2 familial pathways to cognitive impairments in ADHD and indicate promising cognitive targets for future molecular genetic investigations.
Abstract: CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is associated with widespread cognitive impairments, but it is not known whether the apparent multiple impairments share etiological roots or separate etiological pathways exist A better understanding of the etiological pathways is important for the development of targeted interventions and for identification of suitable intermediate phenotypes for molecular genetic investigations OBJECTIVES: To determine, by using a multivariate familial factor analysis approach, whether 1 or more familial factors underlie the slow and variable reaction times, impaired response inhibition, and choice impulsivity associated with ADHD DESIGN: An ADHD and control sibling-pair design SETTING: Belgium, Germany, Ireland, Israel, Spain, Switzerland, and the United Kingdom PARTICIPANTS: A total of 1265 participants, aged 6 to 18 years: 464 probands with ADHD and 456 of their siblings (524 with combined-subtype ADHD), and 345 control participants MAIN OUTCOME MEASURES: Performance on a 4-choice reaction time task, a go/no-go inhibition task, and a choice-delay task RESULTS: The final model consisted of 2 familial factors The larger factor, reflecting 85% of the familial variance of ADHD, captured 98% to 100% of the familial influences on mean reaction time and reaction time variability The second, smaller factor, reflecting 13% of the familial variance of ADHD, captured 62% to 82% of the familial influences on commission and omission errors on the go/no-go task Choice impulsivity was excluded in the final model because of poor fit CONCLUSIONS: The findings suggest the existence of 2 familial pathways to cognitive impairments in ADHD and indicate promising cognitive targets for future molecular genetic investigations The familial distinction between the 2 cognitive impairments is consistent with recent theoretical models--a developmental model and an arousal-attention model--of 2 separable underlying processes in ADHD Future research that tests the familial model within a developmental framework may inform developmentally sensitive interventions
TL;DR: Variation in genes putatively influencing dopamine signaling in the prefrontal cortex and the striatum are linked with discounting rates in a hypothetical task (but not a real-time task) and self-ratings of trait impulsivity in ADHD-CT and healthy controls.
TL;DR: Reaction-time variability and accuracy parameters could be useful neuropsychological endophenotypes for ADHD and performance-modulating effects of incentives suggested a familially driven motivational dysfunction which may play an important role on etiologic pathways and treatment approaches for ADHD.
Abstract: Background: Attention-deficit hyperactivity disorder (ADHD) is one of the most common and highly heritable child psychiatric disorders. There is strong evidence that children with ADHD show slower and more variable responses in tasks such as Go/Nogo tapping aspects of executive functions like sustained attention and response control which may be modulated by motivational factors and/or state-regulation processes. The aim of this study was (1) to determine if these executive functions may constitute an endophenotype for ADHD; (2) to investigate for the first time whether known modulators of these executive functions may also be familial; and (3) to explore whether gender has an impact on these measures. Methods: Two hundred and five children with ADHD combined type, 173 nonaffected biological siblings and 53 controls with no known family history of ADHD were examined using a Go/Nogo task in the framework of a multi-centre study. Performance-measures and modulating effects of event-rate and incentives were examined. Shared familial effects on these measures were assessed, and the influence of gender was tested. Results: Children with ADHD responded more slowly and variably than nonaffected siblings or controls. Nonaffected siblings showed intermediate scores for reaction-time variability, false alarms and omission errors under fast and slow event-rates. A slower event-rate did not lead to reduced performance specific to ADHD. In the incentive condition, mean reaction-times speeded up and became less variable only in children with ADHD and their nonaffected siblings, while accuracy was improved in all groups. Males responded faster, but also committed more false alarms. There were no interactions of group by gender. Conclusions: Reaction-time variability and accuracy parameters could be useful neuropsychological endophenotypes for ADHD. Performance-modulating effects of incentives suggested a familially driven motivational dysfunction which may play an important role on etiologic pathways and treatment approaches for ADHD. The effects of gender were independent of familial effects or ADHD-status, which in turn suggests that the proposed endophenotypes are independent of gender.
TL;DR: A third, independent, multisite GWAS of DSM-IV-TR ADHD found additional evidence of association with SLC9A9, a candidate gene of interest for ADHD, and is working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders.
Abstract: Objective Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD. Method Families were ascertained at Massachusetts General Hospital (MGH; N=309 trios), Washington University at St. Louis (WASH-U; N=272 trios), and University of California at Los Angeles (UCLA; N=156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families. Results Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p=6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9. Conclusions We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders.
TL;DR: Male but not female adults with ADHD showed significantly altered patterns of neural activity during a verbal working memory task, and men and women showed different associations between neural activity and ADHD symptoms.
Abstract: ObjectiveAlthough attention deficit hyperactivity disorder (ADHD) in adults is associated with significant morbidity and dysfunction and afflicts both sexes, relatively few imaging studies have examined female subjects and none have had sufficient power to adequately examine sex differences. The authors examined sex differences in the neural functioning of adults with ADHD during performance of a verbal working memory task. MethodThe participants were 44 adults with ADHD matched on age, sex, and estimated IQ to 49 comparison subjects. Accuracy and reaction time on an N-back task were measured to assess working memory. The blood-oxygen-level-dependent functional MRI response was used as a measure of neural activity. ResultsA group-by-sex analysis of variance showed no between-group differences in either reaction time or percent correct for the working memory task. For both sexes combined, the adults with ADHD showed less activity than comparison subjects in prefrontal regions. However, sex-by-group analyse...
TL;DR: In this paper, the best predictor of adolescent prodromal psychotic symptoms was parent ratings of childhood odd/eccentric symptoms and child performance on a measure of executive functioning, the Wisconsin Card Sorting Test.
Abstract: Objective To predict prodromal psychosis in adolescents with velocardiofacial syndrome (VCFS). Method A total of 70 youth with VCFS, 27 siblings of youth with VCFS, and 25 community controls were followed from childhood (mean age=11.8 years) into mid-adolescence (mean age=15.0 years). Psychological tests measuring intelligence, academic achievement, learning/memory, attention, and executive functioning as well as measures of parent and clinician ratings of child psychiatric functioning were completed at both time points. Results Major depressive disorder, oppositional defiant disorder, and generalized anxiety disorder diagnoses increased in the VCFS sample. With very low false positive rates, the best predictor of adolescent prodromal psychotic symptoms was parent ratings of childhood odd/eccentric symptoms and child performance on a measure of executive functioning, the Wisconsin Card Sorting Test. Conclusions Similar to the non-VCFS prodromal psychosis literature, a combination of cognitive and psychiatric variables appears to predict psychosis in adolescence. A child with VCFS who screens positive is noteworthy and demands clinical attention.
TL;DR: The results do not support an association between deficits in growth outcomes and either ADHD or psychostimulant treatment for ADHD, and should assist clinicians and parents in formulating treatment plans for children with ADHD.
TL;DR: Using the largest international familial schizophrenia cohort to date, it is shown that a substantial portion of the phenotypic correlation between schizophrenia and cognition is caused by shared genetic effects.
Abstract: Content The DSM-IV concept of schizophrenia offers diagnostic reliability but etiologic and pathologic heterogeneity, which probably contributes to the inconsistencies in genetic studies. One solution is to identify intermediate phenotypes, “narrower” constructs of liability, that hypothetically share genetic risk with the disorder. Although a variety of candidate intermediate phenotypes have emerged, few have explicitly quantified the extent of their genetic overlap with schizophrenia. Objective To quantify the net-shared genetic effects between schizophrenia and specific cognitive candidate intermediate phenotypes. Design Twin and family design. Setting Adult psychiatric research centers in the United States and the United Kingdom. Participants A total of 2056 participants: 657 patients with schizophrenia, 674 first-degree relatives (including co-twins), and 725 controls. Main Outcome Measures (1) Latent factors capturing the common variance between cognitive tasks, (2) separation of the latent factors into their genetic and environmental components, and (3) estimation of the net-shared genetic variance between the latent cognitive factors or intelligence and schizophrenia. Results Genetic factors contributed substantially to the total variance in cognition (immediate recall latent factor: 0.66; 95% confidence interval [CI], 0.62 to 0.85; delayed recall latent factor: 0.48; 0.42 to 0.55; and intelligence: 0.66; 0.62 to 0.71). The latent common factors for modality-specific immediate and delayed recall and intelligence showed similar levels of phenotypic covariance with schizophrenia (immediate recall: −0.35; delayed recall: −0.37; and intelligence: −0.38), with 72%, 86%, and 89%, respectively, due to shared genetic effects with schizophrenia. Environmental effects accounted for little phenotypic correlation between cognition and schizophrenia. Conclusions Using the largest international familial schizophrenia cohort to date, we showed that a substantial portion of the phenotypic correlation between schizophrenia and cognition is caused by shared genetic effects. However, because the phenotypic and genetic correlations are far from unity, the genetics of schizophrenia are clearly not merely the genetics of cognition.
TL;DR: The findings show that subsecond timing abnormalities in ADHD youth persist into adulthood and suggest that abnormalities in the temporal structure of behavior observed in ADHD adults result from atypical function of corticocerebellar and corticostriatal timing systems.
TL;DR: Differences in the pathophysiology of the combined versus the predominantly inattentive animal model of ADHD are suggested and treatment with methylphenidate might reduce elevated DAT levels more effectively in the combined subtype especially when applied before puberty.
TL;DR: High-IQ adults with ADHD perform less well on tests of executive functioning relative to high-IQ control participants and performance on several tests ofexecutive functioning was a significant predictor of functioning.
Abstract: BackgroundTo examine the association between psychological tests of executive functioning and functional outcomes among high-IQ adults with attention deficit hyperactivity disorder (ADHD).MethodSubjects were high-IQ adults with (n=64) and without ADHD (n=53). Subjects were administered a battery of neuropsychological tests assessing executive functioning.ResultsHigh-IQ adults with ADHD performed less well than those without ADHD on several psychological tests of executive functioning, including the Wisconsin Card Sorting Test (WCST), Stroop Color and Word Test, Rey–Osterrieth Complex Figure Test (ROCF), California Verbal Learning Test (CVLT) and an auditory continuous performance test (CPT). Test performance in the high-IQ adult ADHD group, however, was average. In the entire sample, performance on several tests of executive functioning including the ROCF and the CVLT were significant predictors of real-world functioning.ConclusionsHigh-IQ adults with ADHD perform less well on tests of executive functioning relative to high-IQ control participants. Performance on several tests of executive functioning was a significant predictor of functioning.
TL;DR: A new Child Behavior checklist-ASD profile consisting of the Child Behavior Checklist-Withdrawn, Social, and Thought Problems scales could serve as a rapid and cost-effective screening instrument to help identify cases likely to meet clinical criteria for ASDs in the clinical setting.
Abstract: Objective To evaluate the properties of clinical scales of the Child Behavior Checklist in discriminating referred children with autism spectrum disorders (ASDs) (autistic disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified) from psychiatrically referred children without ASDs. Method Comparisons were made between children with ASDs (n = 65) with intelligence quotient >70 and children without ASDs (N = 83) on the clinical scales of the Child Behavior Checklist. Stepwise logistic regression was used to identify those scales that best predicted ASDs when compared with the non-ASD comparison group. Receiver operating characteristic curves examined the ability of the significant predictor T-scores to identify ASDs versus the non-ASD subjects. Results Withdrawn, Social Problems, and Thought Problems T-scores were the best independent predictors of ASD status. The Withdrawn + Social + Thought Problems T-scores yielded an area under the curve of 0.86, indicating an 86% chance that a randomly selected sample of ASD subject will have abnormal scores on these scales than a randomly selected sample of non-ASD subjects. Conclusion These findings suggest that a new Child Behavior Checklist-ASD profile consisting of the Child Behavior Checklist-Withdrawn, Social, and Thought Problems scales could serve as a rapid and cost-effective screening instrument to help identify cases likely to meet clinical criteria for ASDs in the clinical setting.
TL;DR: A meta‐analysis of published as well as unpublished data from four different centers that are part of the International Multicentre Persistent ADHD CollaboraTion showed that the involvement of p.Val66Met in the pathogenesis of this neuropsychiatric disorder is not supported.
Abstract: Attention-deficit hyperactivity disorder (ADHD) is a multifactorial, neurodevelopmental disorder that often persists into adolescence and adulthood and is characterized by inattention, hyperactivity and impulsiveness. Before the advent of the first genome-wide association studies in ADHD, genetic research had mainly focused on candidate genes related to the dopaminergic and serotoninergic systems, although several other genes had also been assessed. Pharmacological data, analysis of animal models and association studies suggest that Brain-Derived Neurotrophic Factor (BDNF) is also a strong candidate gene for ADHD. Several polymorphisms in BDNF have been reported and studied in psychiatric disorders but the most frequent is the p.Val66Met (rs6265G > A) single nucleotide polymorphism (SNP), with functional effects on the intracellular trafficking and secretion of the protein. To deal with the inconsistency raised among different case-control and family-based association studies regarding the p.Val66Met contribution to ADHD, we performed a meta-analysis of published as well as unpublished data from four different centers that are part of the International Multicentre Persistent ADHD CollaboraTion (IMpACT). A total of 1,445 adulthood ADHD patients and 2,247 sex-matched controls were available for the study. No association between the p.Val66Met polymorphism and ADHD was found in any of the four populations or in the pooled sample. The meta-analysis also showed that the overall gene effect for ADHD was not statistically significant when gender or comorbidity with mood disorders were considered. Despite the potential role of BDNF in ADHD, our data do not support the involvement of p.Val66Met in the pathogenesis of this neuropsychiatric disorder.
TL;DR: Treated children had more severe motor problems, and less frequently presented with comorbid anxiety and conduct disorder, and Behavioural factors play a role in referral and intervention.
Abstract: BACKGROUND: Motor problems occur in 30% to 50% of children with ADHD, and have a severe impact on daily life. In clinical practice there seems to be little attention for this comorbidity with the possible consequence that these motor problems go undertreated. METHOD: Clinical interview and questionnaire survey of treatment by physiotherapy and factors predicting treatment of motor problems in 235 children with ADHD and 108 controls. RESULTS: Half of motor-affected children had received physiotherapy. Treated children had more severe motor problems, and less frequently presented with comorbid anxiety and conduct disorder. Treated and untreated children were similar in age, and rated similarly on ADHD inattentive and hyperactive-impulsive scales and parental socio-economic status. CONCLUSION: Currently, undertreatment of motor problems in ADHD occurs. Behavioural factors play a role in referral and intervention.
TL;DR: A larger study to assess the effect of OROS-MPH on seizure risk is needed, and a crossover design including subjects with frequent seizures could maximize power and address high patient heterogeneity and recruitment difficulties.
TL;DR: If symptoms and quality of life improve simultaneously, improvement inquality of life can be understood as more than just a downstream, secondary effect of symptom remission.
Abstract: Objective The Quality of Life, Effectiveness, Safety, and Tolerability (QU.E.S.T.) study was designed to evaluate effectiveness of long-acting amphetamines in adults with attention-deficit/hyperactivity disorder (ADHD) in community practice settings. This article reports moderators and mediators of symptoms and quality of life outcomes. Method This was an open-label study of 725 adults with DSM-IV-diagnosed ADHD, treated with mixed amphetamine salts extended release and followed for up to 8 months. Multiple regressions were used to determine if patient moderators impact response in ADHD symptoms and how ADHD symptoms and medication satisfaction mediate quality of life. The study was conducted from December 2003 to December 2004. Results Amphetamine treatment of ADHD resulted in a robust and enduring symptom response. Patient characteristics such as age, female gender, severity of illness, and treatment-naive status moderate improved symptom outcome. Symptom change and satisfaction with medication independently mediate change in mental but not physical quality of life outcomes. There is no time lag between changes in symptoms and improved quality of life. Attention is a stronger mediator of ADHD-specific quality of life outcomes than disruptive behavior. Conclusions If symptoms and quality of life improve simultaneously, improvement in quality of life can be understood as more than just a downstream, secondary effect of symptom remission. Satisfaction with medication is a direct measure of the complex interplay of symptom change, tolerability, and patient perception of treatment that predicts self-report of quality of life benefits. Although the disruptive symptoms of ADHD are more obvious, adults self-report that attention has greater impact.
TL;DR: The results raise the possibility that in ADHD there are volumetric deficits persistent into adulthood, that are independent of medical treatment.
Abstract: Objective: We sought to examine preliminary results of brain alterations in anterior cingulate cortex (ACC) in treatment-naive adults with ADHD. The ACC is a central brain node for the integration of cognitive control and allocation of attention, affect and drive. Thus its anatomical alteration may give rise to impulsivity, hyperactivity and inattention, which are cardinal behavioral manifestations of ADHD. Method: Segmentation and parcellation of the ACC was performed on controls (n = 22), treated (n = 13) and treatment-naive adults with ADHD (n = 13). Results: There was a 21% volume reduction in the left ACC of the treatment-naive group relative to the control group. Also, there was a 23% volume reduction in the right ACC of the treated group relative to the control group. Conclusion: These results raise the possibility that in ADHD there are volumetric deficits persistent into adulthood, that are independent of medical treatment. (J. of Att. Dis. 2010; 13(4) 407-413)