Showing papers by "Stephen V. Faraone published in 2012"

The genetics of attention deficit/hyperactivity disorder in adults, a review

Abstract: The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30–40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Abstract: Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10−6). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ~10% of the cases (P = 4.38 × 10−10) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: A randomized, double-blind, placebo-controlled trial

Abstract: Objective Systemic lupus erythematosus (SLE) patients exhibit T cell dysfunction, which can be regulated through mitochondrial transmembrane potential (Δψm) and mammalian target of rapamycin (mTOR) by glutathione (GSH). This randomized, double-blind, placebo-controlled study was undertaken to examine the safety, tolerance, and efficacy of the GSH precursor N-acetylcysteine (NAC). Methods A total of 36 SLE patients received either daily placebo or 1.2 gm, 2.4 gm, or 4.8 gm of NAC. Disease activity was evaluated monthly by the British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index (SLEDAI), and the Fatigue Assessment Scale (FAS) before, during, and after a 3-month treatment period. Mitochondrial transmembrane potential and mTOR were assessed by flow cytometry. Forty-two healthy subjects matched to patients for age, sex, and ethnicity were studied as controls. Results NAC up to 2.4 gm/day was tolerated by all patients, while 33% of those receiving 4.8 gm/day had reversible nausea. Placebo or NAC 1.2 gm/day did not influence disease activity. Considered together, 2.4 gm and 4.8 gm NAC reduced the SLEDAI score after 1 month (P = 0.0007), 2 months (P = 0.0009), 3 months (P = 0.0030), and 4 months (P = 0.0046); the BILAG score after 1 month (P = 0.029) and 3 months (P = 0.009); and the FAS score after 2 months (P = 0.0006) and 3 months (P = 0.005). NAC increased Δψm (P = 0.0001) in all T cells, profoundly reduced mTOR activity (P = 0.0009), enhanced apoptosis (P = 0.0004), reversed expansion of CD4−CD8− T cells (mean ± SEM 1.35 ± 0.12-fold change; P = 0.008), stimulated FoxP3 expression in CD4+CD25+ T cells (P = 0.045), and reduced anti-DNA production (P = 0.049). Conclusion This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.

What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations

Abstract: Background Robust replication is a sine qua non for the rigorous documentation of proposed associations in the genome-wide association (GWA) setting. Currently, associations of common variants reaching P ≤ 5 × 10(-8) are considered replicated. However, there is some ambiguity about the most suitable threshold for claiming genome-wide significance. Methods We defined as 'borderline' associations those with P > 5 × 10(-8) and P ≤ 1 × 10(-7). The eligible associations were retrieved using the 'Catalog of Published Genome-Wide Association Studies'. For each association we assessed whether it reached P ≤ 5 × 10(-8) with inclusion of additional data from subsequent GWA studies. Results Thirty-four eligible genotype-phenotype associations were evaluated with data and clarifications contributed from diverse investigators. Replication data from subsequent GWA studies could be obtained for 26 of them. Of those, 19 associations (73%) reached P ≤ 5 × 10(-8) for the same or a related trait implicating either the exact same allele or one in very high linkage disequilibrium and 17 reached P 10(-6) [corresponding false-discovery rate 19% (95% CI 7-39%)]. Conclusion A substantial proportion, but not all, of the associations with borderline genome-wide significance represent replicable, possibly genuine associations. Our empirical evaluation suggests a possible relaxation in the current GWS threshold.

Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3

Abstract: OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. METHOD: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. RESULTS: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. CONCLUSIONS: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

Adult Outcome of Attention-Deficit/Hyperactivity Disorder: A Controlled 16-Year Follow-Up Study

Abstract: OBJECTIVE: To estimate the risks for psychopathology and functional impairments in adulthood among a longitudinal sample of youth with and without attention-deficit/hyperactivity disorder (ADHD) diagnosed in childhood. METHOD: This was a case-controlled, 16-year (15-19 years) prospective follow-up study of ADHD. 140 boys with and 120 without DSM-III-R ADHD were recruited from pediatric and psychiatric settings. The main outcome measures were structured diagnostic interviews and measures of psychosocial, educational, and neuropsychological functioning. Data were collected from 1988 to 2006. RESULTS: At the 16-year follow-up, subjects with ADHD continued to significantly differ from controls in lifetime rates of antisocial, mood, anxiety, and addictive disorders, but with the exception of a higher interval prevalence of anxiety disorders (20% vs 8%; z = 2.32, P = .02) and smoking dependence (27% vs 11%; z = 2.30, P = .02), the incidence of individual disorders in the 6-year interval between the current and prior follow-up did not differ significantly from controls. At follow-up, the ADHD subjects compared with controls were significantly (P < .05) more impaired in psychosocial, educational, and neuropsychological functioning, differences that could not be accounted for by other active psychopathology. CONCLUSIONS: These long-term prospective findings provide further evidence for the high morbidity associated with ADHD across the life cycle, stressing the importance of early recognition of this disorder for prevention and early intervention strategies. These findings also indicate that, in adulthood, ADHD confers significant risks for impairment that cannot be accounted for by other psychopathology.

Biomarkers and Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analyses

Abstract: Objective To determine whether peripheral biochemical markers (biomarkers) might differentiate patients with attention-deficit/hyperactivity disorder (ADHD) from non-ADHD individuals. Method We conducted a systematic search and a series of meta-analyses of case-control studies comprising studies from 1969 to 2011. Results We identified 210 studies in the following categories: 71 studies of the main metabolites and metabolism enzymes of monoaminergic neurotransmission pathway; 87 studies of environmental risk factors divided into heavy metals (18 studies), substance/chemical exposures (16 studies), and nutritional factors (trace elements: 29 studies; essential fatty acids: 24 studies); 22 studies of the hypothalamic–pituitary–adrenal axis (HPA) pathway; 31 studies indicated with "other." After screening for the availability for meta-analyses of drug naive/free case-control studies and Bonferroni correction, five comparisons were statistically significant (Norepinephrine [NE], 3-Methoxy-4-hydroxyphenylethylene glycol [MHPG], monoamine oxidase [MAO], Zinc [Zn], cortisol), five of the significant findings found support in studies of response to ADHD medications (NE, MHPG, MAO, b-phenylethylamine [PEA], cortisol), six in studies of symptoms severity (NE, MHPG, MAO, ferritin, Zn, cortisol) and three in studies of neurophysiological or cognitive functioning (lead–ferritin–Zn). No evidence of publication bias was found, whereas significant heterogeneity of effect sizes across studies was found for three of the five biomarkers that differentiated ADHD from control subjects. Suggestive associations were evidenced for neuropeptide Y (NPY), manganese, and dehydroepiandrosterone (DHEA). Conclusions This study provides evidence for several peripheral biomarkers as being associated with ADHD both in diagnosis and in treatment efficacy. Further studies are warranted to replicate these findings, to assess their specificity for ADHD, and to quantify the degree to which they are sufficiently precise to be useful in clinical settings.

The lifetime impact of attention deficit hyperactivity disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)

Abstract: Background To presents nationally representative data on the lifetime independent association between attention deficit hyperactivity disorder (ADHD) and psychiatric comorbidity, correlates, quality of life and treatment-seeking in the United States.

Psychiatric symptoms in systemic lupus erythematosus: a systematic review.

Abstract: Objective Systemic lupus erythematosus (SLE) presents with psychiatric symptoms in most patients that often remain undiagnosed and untreated. This study evaluates the prevalence of psychiatric symptoms in SLE on the basis of clinical trials that fulfilled diagnostic criteria specified by the American College of Rheumatology (ACR). Current hypotheses explaining the pathogenesis of psychiatric symptoms of lupus are reviewed to gain new insights into the neuroimmune pathogenesis of other psychiatric disorders. Data source A MEDLINE search of the literature (English language only) from April 1999 to August 2011 was performed using the search terms lupus and psychiatric to identify studies of neuropsychiatric SLE. Study selection Of 163 publications, 18 clinical studies were selected that focused on psychiatric symptoms, had a sample size of at least 20, and included patients of any age or gender as long as they fulfilled ACR criteria for neuropsychiatric SLE. Data extraction The following data were extracted: author name, year of publication, psychiatric diagnostic method, total number of patients with SLE, and percentage of patients with individual psychiatric diagnoses. The point prevalence of psychiatric symptoms was calculated for neuropsychiatric SLE diagnoses in every study included. Results Psychiatric symptoms are present in the majority of patients with SLE. Depression (in up to 39% of patients) and cognitive dysfunction (up to 80%) are the most common psychiatric manifestations. Genetic and environmental factors (eg, ultraviolet light, retroviruses, and medications) may play a role in the pathogenesis. In addition, the patient's reaction to the illness may result in anxiety (up to 24%) and depression. Currently known biomarkers are nonspecific for neuropsychiatric SLE and indicate inflammation, microglial activation, ischemia, oxidative stress, mitochondrial dysfunction, and blood-brain barrier dysfunction. Conclusions Identification of lupus-specific biomarkers of psychiatric symptoms is a high priority. Our current diagnostic assessment methods need improvement. Development of evidence-based guidelines is needed to improve diagnosis, prevention, and treatment of disabling psychiatric complications in lupus.

Severity of the aggression/anxiety-depression/attention child behavior checklist profile discriminates between different levels of deficits in emotional regulation in youth with attention-deficit hyperactivity disorder.

Abstract: OBJECTIVE:: We examined whether severity scores (1 SD vs 2 SDs) of a unique profile of the Child Behavior Checklist (CBCL) consisting of the Anxiety/Depression, Aggression, and Attention (AAA) scales would help differentiate levels of deficits in children with attention-deficit hyperactivity disorder (ADHD). STUDY DESIGN:: Subjects were 197 children with ADHD and 224 without ADHD. We defined deficient emotional self-regulation (DESR) as an aggregate cutoff score of >180 but Language: en

Neuropsychological correlates of emotional lability in children with ADHD

Abstract: Background: Emotional lability (EL) is commonly seen in patients with attention-deficit/hyperactivity disorder (ADHD). The reasons for this association remain currently unknown. To address this question, we examined the relationship between ADHD and EL symptoms, and performance on a range of neuropsychological tasks to clarify whether EL symptoms are predicted by particular cognitive and/or motivational dysfunctions and whether these associations are mediated by the presence of ADHD symptoms. Methods: A large multi-site sample of 424 carefully diagnosed ADHD cases and 564 unaffected siblings and controls aged 618 years performed a broad neuropsychological test battery, including a Go/No-Go Task, a warned four-choice Reaction Time task, the Maudsley Index of Childhood Delay Aversion and Digit span backwards. Neuropsychological variables were aggregated as indices of processing speed, response variability, executive functions, choice impulsivity and the influence of energetic and/or motivational factors. EL and ADHD symptoms were regressed on each neuropsychological variable in separate analyses controlling for age, gender and IQ, and, in subsequent regression analyses, for ADHD and EL symptoms respectively. Results: Neuropsychological variables significantly predicted ADHD and EL symptoms with moderate-to-low regression coefficients. However, the association between neuropsychological parameters on EL disappeared entirely when the effect of ADHD symptoms was taken into account, revealing that the association between the neuropsychological performance measures and EL is completely mediated statistically by variations in ADHD symptoms. Conversely, neuropsychological effects on ADHD symptoms remained after EL symptom severity was taken into account. Conclusions: The neuropsychological parameters examined, herein, predict ADHD more strongly than EL. They cannot explain EL symptoms beyond what is already accounted for by ADHD symptom severity. The association between EL and ADHD cannot be explained by these cognitive or motivational deficits. Alternative mechanisms, including overlapping genetic influences (pleiotropic effects) and/or alternative neuropsychological processes need to be considered.

Longitudinal Course of Deficient Emotional Self-Regulation CBCL Profile in Youth with ADHD: Prospective Controlled Study

Abstract: BACKGROUND: While symptoms of deficient emotional self-regulation (DESR) have been long associated with attention-deficit/hyperactivity disorder (ADHD), there has been limited investigation of this aspect of the clinical picture of the disorder. The main aim of this study was to examine the predictive utility of DESR in moderating the course of ADHD children into adolescence. METHODS: Subjects comprised 177 children with and 204 children without ADHD followed for an average of 4 years (aged 6-18 years at baseline, 54% male). Subjects were assessed with structured diagnostic interviews and measures of psychosocial functioning. DESR was defined by the presence (n = 79) or absence (n = 98) of Child Behavior Checklist (CBCL)-DESR profile (score ≥ 180 Language: en

Predictors of persistence in girls with attention deficit hyperactivity disorder: results from an 11-year controlled follow-up study.

Abstract: Objective This study sought to examine the age-dependent persistence of attention-deficit/hyperactivity disorder (ADHD) and its predictors in a large sample of girls with and without ADHD followed prospectively for 11 years into young adulthood.

Examining the Comorbidity Between Attention Deficit Hyperactivity Disorder and Bipolar I Disorder: A Meta-Analysis of Family Genetic Studies

Abstract: ObjectiveThe existence of comorbidity between attention deficit hyperactivity disorder (ADHD) and bipolar I disorder has been documented in clinical and epidemiological studies, in studies of children and adults, and in diagnosed ADHD and bipolar I patient samples. Yet questions remain about the validity of diagnosing bipolar I disorder in ADHD youth. The authors aim to clarify these issues by reviewing family genetic studies of ADHD and bipolar I disorder.MethodThe authors applied random-effects meta-analysis to family genetic studies of ADHD and bipolar I disorder. Twenty bipolar proband studies provided 37 estimates of the prevalence of ADHD in 4,301 relatives of bipolar probands and 1,937 relatives of comparison probands. Seven ADHD proband studies provided 12 estimates of the prevalence of bipolar I disorder in 1,877 relatives of ADHD probands and 1,601 relatives of comparison probands.ResultsThese studies found a significantly higher prevalence of ADHD among relatives of bipolar probands and a signi...

Striatal sensitivity during reward processing in attention-deficit/hyperactivity disorder.

Abstract: Objective Attention-deficit/hyperactivity disorder (ADHD) has been linked to deficits in the dopaminergic reward-processing circuitry; yet, existing evidence is limited, and the influence of genetic variation affecting dopamine signaling remains unknown. We investigated striatal responsivity to rewards in ADHD combined type (ADHD-CT) using functional magnetic resonance imaging (fMRI), and whether it is modulated by variation in the dopamine transporter gene ( DAT1) . Method We tested 29 male adolescents with ADHD-CT and 30 age-, handedness-, and gender-matched healthy controls who were selected for DAT1 10/6 haplotype dosage. Based on previous research, we focused our analysis on the ventral striatum and the caudate nucleus. Results Three main findings emerged. First, male adolescents with ADHD-CT did not differ from controls in terms of blood oxygen–level dependent (BOLD) fMRI response to reward-predicting cues (gain or loss-avoidance) in the ventral striatum. Second, male adolescents with ADHD-CT showed a relative increase, compared with controls, in the striatal BOLD response to successful outcomes. Third, DAT1 10/6 dosage differentially modulated neural activation to reward-predicting cues in the caudate nucleus in the ADHD-CT and control groups. Conclusions The findings challenge the idea of a deficit in anticipation-related activation in the ventral striatum in male adolescents with ADHD-CT, while suggesting that the processing of reward outcomes is dysfunctional, consistent with a recent neurobiological model of the disorder. Preliminary evidence suggests that polymorphic variations in genes affecting dopamine signaling need to be taken into consideration when investigating reward-related deficits in ADHD-CT.

Preliminary Examination of the Reliability and Concurrent Validity of the Attention-Deficit/Hyperactivity Disorder Self-Report Scale v1.1 Symptom Checklist to Rate Symptoms of Attention-Deficit/Hyperactivity Disorder in Adolescents

Abstract: Objective: To validate the attention-deficit/hyperactivity disorder (ADHD) Self-Report Scale (ASRS) v1.1 Symptom Checklist versus the clinician-administered ADHD Rating Scale (ADHD-RS) in adolescents with ADHD. Method: A total of 88 adolescents with ADHD aged 13–17 years participated in the study. The study was completed in one or two visits, 1–9 weeks apart. At each visit, participants completed the ASRS v1.1 Symptom Checklist, after which raters administered the ADHD-RS. Internal consistency of the ASRS v1.1 Symptom Checklist was assessed by Cronbach's alpha (Cronbach's α). Concurrent validity between the scales was assessed using Pearson's correlation coefficients. Item-by-item reliability between the scales was assessed by the Kappa coefficient of agreement. Results: The mean age of participants was 14.9±1.5 SD years. 76.1% (n=67) were male. 73.9% (n=65) were currently receiving medication for ADHD. Internal consistency of ASRS v1.1 Symptom Checklist items was high, with Cronbach's α coeffici...

The hierarchical factor model of ADHD: invariant across age and national groupings?

Abstract: Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by problems with attention, impulsivity, and hyperactivity. The diagnosis derives from 18 symptoms indexing these behavioural domains [American Psychiatric Association (APA), DSM-IV-TR, 2000]. There is substantial continuity in maintaining a diagnosis of ADHD from childhood to adolescence (Faraone, Biederman, & Mick, 2006); however the phenotypic expression is highly variable within the diagnosed group and across time (Barkley, 2006; Nigg, 2006). Current diagnostic formulations distinguish between symptoms of inattention and those of hyperactivity-impulsivity. Three ADHD subtypes are recognized in the DSM-IV: the predominantly inattentive type, the predominantly hyperactive-impulsive type, and the combined type (where patients meet criteria on both the inattention and the hyperactive/impulsivity domains). This formulation is currently under review as part of the deliberation of the DSM-5 panel. Indeed, this current characterization remains controversial (Barkley, 2001; Diamond, 2005; Hinshaw, 2001; Lahey, 2001; Milich, Balentine, & Lynam, 2001). Here we focus on factor models of co-occurrence among ADHD symptoms. Two major types of factor models, correlated factor models and hierarchical models, have been used to examine coherence and distinctness among ADHD symptom domains. Hierarchical models provide a way to simultaneously conceptualize both the coherence and separability of symptoms from separate domains. These models include a single general factor accounting for covariation among all symptoms along with separate, specific factors of inattention, hyperactivity, and impulsivity that vary orthogonally from the general factor. These models are also termed as bifactor models in the statistical literature. Hierarchical models are different from correlated factor models that only have factors for the symptom domains of inattention and hyperactivity and/or impulsivity (see Figure 1). Several studies have shown hierarchical models with a general factor as having a better fit than correlated models for reported symptoms of ADHD (e.g., Dumenci, McConaghy, & Achenbach, 2004; Gibbins et al., in press; Martel, Von Eye, & Nigg, 2010; Toplak et al., 2009). These papers span clinical and community samples, and child, adolescent, and adult samples with ADHD. A one-factor model has also been considered, but thus far it has no empirical support (Dumenci et al., 2004). Figure 1 Generic example of a correlated two-factor model for 10 observed symptoms Hierarchical models explicitly acknowledge the common covariation among all ADHD symptoms, which is consistent with the conceptualization of ADHD as a single disorder. There are several lines of evidence suggesting that there is substantial commonality between the domains of inattention and hyperactivity-impulsivity. Inattentive symptoms tend to be more highly correlated with hyperactivity and impulsivity than with other domains of psychopathology (Adams, Kelley, & McCarthy, 1997; Conners, 2008; Strickland et al., 2011), with the exception of oppositional defiant disorder in some studies (Lahey et al., 2008). Current models of ADHD also highlight how the symptom domains of inattention, hyperactivity, and impulsivity likely interact to give rise to the heterogeneous expression of ADHD (Nigg & Casey, 2005; Sagvolden, Johansen, Aase, & Russell, 2005; Sonuga-Barke, 2005; Sonuga-Barke, Sergeant, Nigg, & Willcutt, 2008). To replicate and extend these findings, the current study examined different factor models in a large sample of ADHD patients recruited from a broad age range and from diverse national groupings. We were thus able to test whether a hierarchical model held for the whole sample and whether it also was invariant across different age groups and nationalities. A developmental perspective is important to integrate into models of individual ADHD symptoms, such that a single set of factors could parsimoniously explain the changes that occur over development. Age differences in scores from ADHD measures may reflect true differences in the constructs being measured or may simply reflect measurement differences due to age. Therefore, establishing measurement invariance across age groups is important. The behavioural presentation of ADHD changes considerably from childhood to adolescence. For instance, the expression of hyperactivity seems to decrease from childhood to adolescence and inattention commonly appears later in development than hyperactivity and impulsivity (Biederman et al., 2000; Hart et al., 1995; Larsson et al., 2006; Nigg, 2006). This developmental change introduces complex issues with respect to diagnosis. Subtypes have been used to characterize these different symptom presentations, and the instability of ADHD subtypes in developmental samples has also been well demonstrated (Lahey, Pelham, Loney, Lee, & Willcutt, 2005; Todd et al., 2008). Some of this instability of subtypes may be attributable to measurement variability (Lahey et al., 2005; Valo & Tannock, 2010); however some of this variability would be expected from a developmental perspective, which would presume that children’s symptom presentations change over the course of development. What is needed is a coherent model that can represent these shifts and changes in symptoms. In addition to the question of developmental change and continuity in ADHD symptoms, the current sample also had the unique characteristic of having recruited participants from seven European countries and Israel by 12 different research centers. Most studies examining cross-national samples have been concerned with whether there are comparable rates of prevalence across different countries (Faraone, Sergeant, Gillberg, & Biederman, 2003; Polanczyk, de Lima, Horta, Biederman, & Rohde, 2007) rather than consistency in symptom patterns across countries. In addition to testing the five different factor models in the full sample, invariance analyses were also conducted to examine consistency of the best overall model across countries. Thus, in the current study we first estimated five different factor models to determine which model best accounted for ADHD symptoms pooling all ages and locations using a sample of children and adolescents with ADHD and their siblings. The five factor structures included: a) a one-factor model of inattention/ hyperactivity/impulsivity; b) a non-hierarchical two-factor model with correlated inattention and hyperactivity/impulsivity factors (the correlated 2-factor model); c) a non-hierarchical three-factor model with correlated inattention, hyperactivity, and impulsivity factors (the correlated 3-factor model); d) a hierarchical model of a general ADHD factor with two specific factors of inattention and hyperactivity/impulsivity (the hierarchical 2-factor model); and e) a hierarchical model of a general ADHD factor with three specific factors of inattention, hyperactivity, and impulsivity (the hierarchical 3-factor model). Based on previous research, we expected that a hierarchical model with a general ADHD factor would provide the best fit to observed ADHD symptoms in both the ADHD and sibling samples and across instruments and informants. We then examined whether these modeled relationships among symptoms are equivalent across different groups by formally assessing measurement invariance in the ADHD group. Group differences in observed scores on measurement instruments can be attributed to true differences on the constructs being measured only if measurement invariance or equivalence holds across groups (e.g., Widaman & Reise, 1997). Based on the best fitting model, we conducted invariance analyses to determine whether the measurement parameters relating the constructs implied by the model to the observed symptoms are equivalent across age groups and locations in the ADHD group.

Deficient emotional self-regulation and pediatric attention deficit hyperactivity disorder: a family risk analysis.

Abstract: BACKGROUND: Although deficient emotional self-regulation (DESR) is associated with attention deficit hyperactivity disorder (ADHD), little research investigates this association and little is known about its etiology. Family studies provide a method of clarifying the co-occurrence of clinical features, but no family studies have yet addressed ADHD and DESR in children.MethodSubjects were 242 children with ADHD and 224 children without ADHD. DESR was operationalized using an aggregate score ⩾180 and Language: en

Psychopathology in Adolescent Offspring of Parents With Panic Disorder, Major Depression, or Both: A 10-Year Follow-Up

Abstract: ObjectiveThe authors examined the specificity and course of psychiatric disorders from early childhood through adolescence in offspring of parents with confirmed panic disorder and major depressive disorder.MethodThe authors examined rates of psychiatric disorders at 10-year-follow-up (mean age, 14 years) in four groups: offspring of referred parents with panic and depression (N=137), offspring of referred parents with panic without depression (N=26), offspring of referred parents with depression without panic (N=48), and offspring of nonreferred parents with neither disorder (N=80). Follow-up assessments relied on structured interviews with the adolescents and their mothers; diagnoses were rated present if endorsed by either.ResultsParental panic disorder, independently of parental depression, predicted lifetime rates in offspring of multiple anxiety disorders, panic disorder, agoraphobia, social phobia, and obsessive-compulsive disorder. Parental depression independently predicted offspring bipolar, dru...

Genome-wide association study of motor coordination problems in ADHD identifies genes for brain and muscle function.

Abstract: Objectives. Motor coordination problems are frequent in children with attention deficit/hyperactivity disorder (ADHD). We performed a genome-wide association study to identify genes contributing to motor coordination problems, hypothesizing that the presence of such problems in children with ADHD may identify a sample of reduced genetic heterogeneity. Methods. Children with ADHD from the International Multicentre ADHD Genetic (IMAGE) study were evaluated with the Parental Account of Children's Symptoms. Genetic association testing was performed in PLINK on 890 probands with genome-wide genotyping data. Bioinformatics enrichment-analysis was performed on highly ranked findings. Further characterization of the findings was conducted in 313 Dutch IMAGE children using the Developmental Coordination Disorder Questionnaire (DCD-Q). Results. Although none of the findings reached genome-wide significance, bioinformatics analysis of the top-ranked findings revealed enrichment of genes for motor neuropathy and amyotrophic lateral sclerosis. Genes involved in neurite outgrowth and muscle function were also enriched. Among the highest ranked genes were MAP2K5, involved in restless legs syndrome, and CHD6, causing motor coordination problems in mice. Further characterization of these findings using DCD-Q subscales found nominal association for 15 SNPs. Conclusions. Our findings provide clues about the aetiology of motor coordination problems, but replication studies in independent samples are necessary.

Neuropsychological intra-individual variability explains unique genetic variance of ADHD and shows suggestive linkage to chromosomes 12, 13, and 17.

Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric disorder that is usually accompanied by neuropsychological impairments. The use of heritable, psychometrically robust traits that show association with the disorder of interest can increase the power of gene-finding studies. Due to the robust association of intra-individual variability with ADHD on a phenotypic and genetic level, intra-individual variability is a prime candidate for such an attempt. We aimed to combine intra-individual variability measures across tasks into one more heritable measure, to examine the relatedness to other cognitive factors, and to explore the genetic underpinnings through quantitative trait linkage analysis. Intra-individual variability measures from seven tasks were available for 238 ADHD families (350 ADHD-affected and 195 non-affected children) and 147 control families (271 children). Intra-individual variability measures from seven different tasks shared common variance and could be used to construct an aggregated measure. This aggregated measure was largely independent from other cognitive factors related to ADHD and showed suggestive linkage to chromosomes 12q24.3 (LOD = 2.93), 13q22.2 (LOD = 2.36), and 17p13.3 (LOD = 2.00). A common intra-individual variability construct can be extracted from very diverse neuropsychological tasks; this construct taps into unique genetic aspects of ADHD and may relate to loci conferring risk for ADHD (12q24.3 and 17p13.3) and possibly autism (12q24.3). Given that joining of data across sites boosts the power for genetic analyses, our findings are promising in showing that intra-individual variability measures are viable candidates for across site analyses where different tasks have been used.

A re-review of the association between the NOTCH4 locus and schizophrenia.

Abstract: NOTCH4 has long been identified as a candidate susceptibility gene for schizophrenia, but the collective body of genetic association studies of this gene has been less than conclusive. Recently a variant in NOTCH4 was implicated as one of the most reliably associated polymorphisms observed in a genome-wide association scan of the disorder, and the collective evidence for this polymorphism now surpasses criteria for genome-wide significance. To place these developments in context, we now summarize the initial work identifying NOTCH4 as a candidate gene for schizophrenia. The results of the genome-wide association studies that have confirmed this as a risk gene, and novel bioinformatics analyses that reveal potential functional profiles of the most likely risk-conferring polymorphisms. These analyses suggest that the NOTCH4 polymorphisms most strongly associated with schizophrenia exert their effects on susceptibility by altering the efficiency and/or alternative splicing of Notch4 transcripts. Further experimental evidence should be pursued to clarify the NOTCH4-regulated molecular and cellular phenotypes of relevance to the disorder, and the functional consequences of the implicated polymorphisms in the gene. © 2012 Wiley Periodicals, Inc.

Cognitive Behavioral Treatment Outcomes in Adolescent ADHD

Abstract: Objective: To assess the efficacy of cognitive behavioral therapy (CBT) for managing adolescent ADHD. Method: A total of 68 adolescents with ADHD and associated psychiatric comorbidities completed a manualized CBT treatment protocol. The intervention used in the study was a downward extension of the Safren et al. program for adults with ADHD who have symptoms unresolved by medication. Outcome variables consisted of narrow band (ADHD) and broadband (e.g., mood, anxiety, conduct) symptom measures (Behavior Assessment System for Children–2nd edition and ADHD–Rating Scales) as well as functioning measures (parent/teacher ratings and several ecologically real-world measures). Results: Treatment effects emerged on the medication dosage, parent rating of pharmacotherapy adherence, adolescent self-report of personal adjustment (e.g., self-esteem), parent and teacher ratings of inattentive symptoms, school attendance, school tardiness, parent report of peer, family and academic functioning and teacher report of ad...

Auditory working memory impairments in individuals at familial high risk for schizophrenia.

Abstract: OBJECTIVES The search for predictors of schizophrenia has accelerated with a growing focus on early intervention and prevention of psychotic illness. Studying nonpsychotic relatives of individuals with schizophrenia enables identification of markers of vulnerability for the illness independent of confounds associated with psychosis. The goal of these studies was to develop new auditory continuous performance tests (ACPTs) and evaluate their effects in individuals with schizophrenia and their relatives. METHODS We carried out two studies of auditory vigilance with tasks involving working memory (WM) and interference control with increasing levels of cognitive load to discern the information-processing vulnerabilities in a sample of schizophrenia patients, and two samples of nonpsychotic relatives of individuals with schizophrenia and controls. Study 1 assessed adults (mean age = 41), and Study 2 assessed teenagers and young adults age 13-25 (M = 19). RESULTS Patients with schizophrenia were impaired on all five versions of the ACPTs, whereas relatives were impaired only on WM tasks, particularly the two interference tasks that maximize cognitive load. Across all groups, the interference tasks were more difficult to perform than the other tasks. Schizophrenia patients performed worse than relatives, who performed worse than controls. For patients, the effect sizes were large (Cohen's d = 1.5), whereas for relatives they were moderate (d = ~0.40-0.50). There was no age by group interaction in the relatives-control comparison except for participants <31 years of age. CONCLUSIONS Novel WM tasks that manipulate cognitive load and interference control index an important component of the vulnerability to schizophrenia.

Aetiology for the covariation between combined type ADHD and reading difficulties in a family study: the role of IQ

Abstract: Background: Twin studies using both clinical and population-based samples suggest that the frequent co-occurrence of attention deficit hyperactivity disorder (ADHD) and reading ability/disability (RD) is largely driven by shared genetic influences. While both disorders are associated with lower IQ, recent twin data suggest that the shared genetic variability between reading difficulties and ADHD inattention symptoms is largely independent from genetic influences contributing to general cognitive ability. The current study aimed to extend the previous findings that were based on rating scale measures in a population sample by examining the generalisability of the findings to a clinical population, and by measuring reading difficulties both with a rating scale and with an objective task. This study investigated the familial relationships between ADHD, reading difficulties and IQ in a sample of individuals diagnosed with ADHD combined type, their siblings and control sibling pairs. Methods: Multivariate familial models were run on data from 1,789 individuals at ages 6-19. Reading difficulties were measured with both rating scale and an objective task. IQ was obtained using the Wechsler Intelligence Scales (WISC-III/WAIS-III). Results: Significant phenotypic (.2-.4) and familial (.3-.5) correlations were observed among ADHD, reading difficulties and IQ. Yet, 53%-72% of the overlapping familial influences between ADHD and reading difficulties were not shared with IQ. Conclusions: Our finding that familial influences shared with general cognitive ability, although present, do not account for the majority of the overlapping familial influences on ADHD and reading difficulties extends previous findings from a population-based study to a clinically ascertained sample with combined type ADHD.

Further evidence for robust familiality of pediatric bipolar I disorder: results from a very large controlled family study of pediatric bipolar I disorder and a meta-analysis.

Abstract: Objective To determine the risk for BP-I disorder in first-degree relatives of children with DSM-IV bipolar-I disorder (BP-I) via meta-analysis and expanded controlled study.

Understanding the Effect Size of Lisdexamfetamine Dimesylate for Treating ADHD in Children and Adults

Abstract: Objective: An earlier meta-analysis of pediatric clinical trials indicated that lisdexamfetamine dimesylate (LDX) had a greater effect size than other stimulant medications. This work tested the hypothesis that the apparent increased efficacy was artifactual. Method: The authors assessed two potential artifacts: an unusually high precision of measurement and an unusually low placebo effect. The authors evaluated generalizability from children of adults. Results: The LDX effect sizes for children were significantly larger than the pooled stimulant effect sizes from studies using the same outcome measures. However, although no other individual stimulant study had an effect size greater than LDX, there was overlap between the 95% confidence intervals for some of these studies and the LDX study. The high LDX effect sizes were not due measurement or placebo effect artifacts. LDX effect sizes for adults were not larger than the stimulant effect sizes from other studies. Conclusion: The high LDX effect size for ...

Genome-wide association study of intelligence: additive effects of novel brain expressed genes.

Abstract: Objective: The purpose of the present study was to identify common genetic variants that are associated with human intelligence or general cognitive ability. Method: We performed a genome-wide association analysis with a dense set of 1 million single-nucleotide polymorphisms (SNPs) and quantitative intelligence scores within an ancestrally homogeneous family sample of 656 individuals with at least one child affected by attention-deficit/hyperactivity disorder (ADHD). Results: Haplotype trend regression analysis with sliding four-SNP windows identified haplotypes of genome-wide significance in genes involved in synaptic signaling (KIF16B; p 1.27E-08) and neurodevelopment (PAX5; p 3.58E-08), and highlight findings from a recent genetic study of cognitive ability (RXRA; p 7.7E-08; GYPC; p 2.5E-07). Further interrogation of SNPs within top haplotypes reveals that the minor alleles are associated with higher intelligence, whereas others are associated with relatively lower (but still average range) intelligence. Effects of the eight genes are additive, as a greater number of the associated genotypes in a given individual predict higher intelligence (p 5.36E-08) and account for 8% of variance in intelligence. Conclusions: Analyses that examine additive genetic effects may be useful in identifying regions where the additive effects of SNPs have a significant effect on phenotype. These results describe novel variants and additive effects of genes involved in brain development on variability in intelligence within an ADHD sample. The precise mechanisms of these loci in relation to determining individual differences in general cognitive ability require further investigation. J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(4):432‐440. Key Words: cognitive ability, genetics, SNPs, ADHD, haplotype

Cigarette smoking as a risk factor for other substance misuse: 10-year study of individuals with and without attention-deficit hyperactivity disorder

Abstract: Background We previously documented that cigarette smoking is a risk factor for subsequent alcohol and drug misuse and dependence in adolescent girls with attention-deficit hyperactivity disorder (ADHD). Aims To revisit this hypothesis with a large longitudinal sample of both genders followed up for 10 years into young adulthood. Method We used data from two identically designed, longitudinal, case–control family studies of boys and girls with and without ADHD ascertained from psychiatric and paediatric sources. We studied 165 individuals with ADHD and 374 controls followed up longitudinally and masked for 10 years. We assessed ADHD, smoking and substance use status using structured diagnostic interviews. We tested the association between cigarette smoking and subsequent substance use outcomes using Cox proportional hazard regression models. Results Youth with ADHD who smoked cigarettes ( n = 27) were significantly more likely to subsequently develop drug misuse and dependence compared with youth with ADHD who did not smoke ( n = 138, P <0.05). Conclusions These results confirm that cigarette smoking increases the risk for subsequent drug and alcohol use disorders among individuals with ADHD. These findings have important public health implications, and underscore the already pressing need to prevent smoking in children with ADHD.