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Showing papers by "Stephen V. Faraone published in 2013"



Journal ArticleDOI
S. Hong Lee1, Stephan Ripke2, Stephan Ripke3, Benjamin M. Neale3  +402 moreInstitutions (124)
TL;DR: Empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

2,058 citations


Journal ArticleDOI
TL;DR: The genetic architecture of ADHD comprises both common and rare variants, and some common causal variants are likely to be shared between Han Chinese and Caucasians.
Abstract: Attention-deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case-control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM-IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome-wide association analyses were performed using PLINK. SNP-heritability and SNP-genetic correlations with ADHD in Caucasians were estimated with genome-wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein-Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome-wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P = 0.038). SNP-heritability was estimated to be 0.42 (standard error, 0.13, P = 0.0017) and the SNP-genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P = 0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHD's etiology.

173 citations


Journal ArticleDOI
TL;DR: Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression, andPolygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group.
Abstract: OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

139 citations



Journal ArticleDOI
TL;DR: Long-term efficacy and safety of the stimulant drugs methylphenidate and amphetamine, as well as the related compound atomoxetine are reviewed, finding stimulant therapy of ADHD has long-term beneficial effects and is well tolerated.

134 citations


Journal ArticleDOI
TL;DR: The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T cell lineage development; however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear.
Abstract: The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T cell lineage development; however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear. In this study, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBLs relative to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) during 274 visits of 59 patients and 54 matched healthy subjects. Partial least square–discriminant analysis identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (p < 0.0005); increased mitochondrial mass of CD3+/CD4−/CD8− double-negative (DN) T cells (p = 1.1 × 10−22) and FOXP3 depletion in CD4+/CD25+ T cells were top contributors (p = 6.7 × 10−7). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥ 4) relative to 61 visits of remission (SLEDAI decrease ≥ 4). mTOR activation in DN T cells was also noted at preflare visits of SLE patients relative to those with stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25+/CD19+ B cells. Rapamycin treatment in vivo blocked the IL-4 production and necrosis of DN T cells, increased the expression of FOXP3 in CD25+/CD4+ T cells, and expanded CD25+/CD19+ B cells. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells in patients with SLE.

126 citations


Journal ArticleDOI
TL;DR: It is suggested that therapeutic oral doses of stimulants decrease alterations in brain structure and function in subjects with ADHD relative to unmedicated subjects and controls.
Abstract: Objective: To evaluate the impact of therapeutic oral doses of stimulants on the brains of ADHD subjects as measured by magnetic resonance imaging (MRI)-based neuroimaging studies (morphometric, functional, spectroscopy). Data Sources: We searched PubMed and ScienceDirect through the end of calendar year 2011 using the keywords (1) psychostimulants or methylphenidate or amphetamine, and (2) neuroimaging or MRI or fMRI, and (3) ADHD or ADD or attention-deficit/hyperactivity disorder or attention deficit hyperactivity disorder. Study Selection: We included only English language articles with new data from case-control or placebo controlled studies that examined attention-deficit/ hyperactivity disorder (ADHD) subjects on and off psychostimulants (as well as 5 relevant review articles). Data Extraction: We combined details of study design and medication effects in each imaging modality. Results: We found 29 published studies that met our criteria. These included 6 structural MRI, 20 functional MRI studies, and 3 spectroscopy studies. Methods varied widely in terms of design, analytic technique, and regions of the brain investigated. Despite heterogeneity in methods, however, results were consistent. With only a few exceptions, the data on the effect of therapeutic oral doses of stimulant medication suggest attenuation of structural and functional alterations found in unmedicated ADHD subjects relative to findings in controls. Conclusions: Despite the inherent limitations and heterogeneity of the extant MRI literature, our review suggests that therapeutic oral doses of stimulants decrease alterations in brain structure and function in subjects with ADHD relative to unmedicated subjects and controls. These medication-associated brain effects parallel, and may underlie, the well-established clinical benefits.

120 citations


Journal ArticleDOI
TL;DR: There are several important differences between autism spectrum disorder and ADHD, and treatment strategies for the comorbid condition will also be reviewed.
Abstract: ADHD and autism spectrum disorder are common psychiatric comorbidities to each another. In addition, there is behavioral, biological and neuropsychological overlap between the two disorders. There are also several important differences between autism spectrum disorder and ADHD. Treatment strategies for the comorbid condition will also be reviewed. Future areas of research and clinical need will be discussed.

116 citations


Journal ArticleDOI
TL;DR: DESR adversely impacts quality of life in adults with ADHD and was also associated with significant functional impairment as evaluated by the QLES-Q-SF and SAS-SR, and with reduced marital status, as well as higher risk for traffic accidents and arrests.
Abstract: While symptoms of deficient emotional self-regulation (DESR) such as low frustration tolerance, temper outbursts, emotional impulsivity, and mood lability are commonly associated with attention deficit hyperactivity disorder (ADHD), little is known about their nature. The main aim of this post hoc study was to examine the correlates of DESR in a large sample of adults with and without ADHD. Subjects were 206 adults with ADHD and 123 adults without ADHD from a family study of ADHD. Emotional impulsivity was operationalized using items from the Barkley Current Behavior Scale. Subjects were comprehensively assessed for psychiatric comorbidity using structured diagnostic interview methodology. We used the Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form (QLES-Q-SF) and Social Adjustment Scale-Self-report (SAS-SR) to assess quality of life and psychosocial functioning. DESR was more common among ADHD compared with non-ADHD adults, and 55 % of adults with ADHD reported extreme DESR of greater severity than 95 % of control subjects. The association of ADHD and DESR was not entirely accounted for by either current or lifetime comorbid disorders. DESR was also associated with significant functional impairment as evaluated by the QLES-Q-SF and SAS-SR, and with reduced marital status, as well as higher risk for traffic accidents and arrests. DESR adversely impacts quality of life in adults with ADHD. More work is needed to further evaluate DESR in clinical and investigational studies of subjects with ADHD.

113 citations


Journal ArticleDOI
TL;DR: A childhood diagnosis of attention deficit hyperactivity disorder is a risk factor for psychoactive substance use disorder and nicotine dependence in adolescence and comorbid conduct disorder, but not oppositional defiant disorder, further increases the risk of developing psychoactive substances use disorder or nicotine dependence.
Abstract: Aim To examine the relationship between a childhood diagnosis of attention deficit hyperactivity disorder (ADHD) with or without oppositional defiant disorder (ODD)/conduct disorder (CD) and the development of later alcohol/drug use disorder [psychoactive substance use disorder (PSUD)] and nicotine dependence in a large European sample of ADHD probands, their siblings and healthy control subjects. Participants design and settingSubjects (n=1017) were participants in the Belgian, Dutch and German part of the International Multicenter ADHD Genetics (IMAGE) study. IMAGE families were identified through ADHD probands aged 5-17 years attending out-patient clinics, and control subjects from the same geographic areas. After a follow-up period (mean: 4.4 years) this subsample was re-assessed at a mean age of 16.4 years. Measurements PSUD and nicotine dependence were assessed using the Diagnostic Interview Schedule for Children, Alcohol Use Disorders Identification Test, Drug Abuse Screening Test and Fagerstrom test for Nicotine Dependence. Findings The ADHD sample was at higher risk of developing PSUD [hazard ratio (HR)=1.77, 95% confidence interval (CI)=1.05-3.00] and nicotine dependence (HR=8.61, 95% CI=2.44-30.34) than healthy controls. The rates of these disorders were highest for ADHD youth who also had CD, but could not be accounted for by this comorbidity. We did not find an increased risk of developing PSUD (HR=1.18, 95% CI=0.62-2.27) or nicotine dependence (HR=1.89, 95% CI=0.46-7.77) among unaffected siblings of ADHD youth. Conclusions A childhood diagnosis of attention deficit hyperactivity disorder is a risk factor for psychoactive substance use disorder and nicotine dependence in adolescence and comorbid conduct disorder, but not oppositional defiant disorder, further increases the risk of developing psychoactive substance use disorder and nicotine dependence.

Journal ArticleDOI
TL;DR: A substantial minority of ADHD children manifests ATs, and those exhibiting ATs have greater severity of illness and dysfunction than control subjects in psychopathology, interpersonal, school, family, and cognitive domains.
Abstract: OBJECTIVE: To assess the implications of autistic traits (ATs) in youth with attention-deficit/hyperactivity disorder (ADHD) without a diagnosis of autism. METHODS: Participants were youth with ( n = 242) and without ( n = 227) ADHD and controls without ADHD in whom a diagnosis of autism was exclusionary. Assessment included measures of psychiatric, psychosocial, educational, and cognitive functioning. ATs were operationalized by using the withdrawn + social + thought problems T scores from the Child Behavior Checklist. RESULTS: A positive AT profile was significantly overrepresented among ADHD children versus controls (18% vs 0.87%; P CONCLUSIONS: A substantial minority of ADHD children manifests ATs, and those exhibiting ATs have greater severity of illness and dysfunction.

Journal ArticleDOI
TL;DR: It is demonstrated that pathway-based association analyses, using quantitative measurements of ADHD symptom domains, can increase the power of genetic analyses to identify biological risk factors involved in this disorder.
Abstract: Objective Because multiple genes with small effect sizes are assumed to play a role in attention-deficit/hyperactivity disorder (ADHD) etiology, considering multiple variants within the same analysis likely increases the total explained phenotypic variance, thereby boosting the power of genetic studies. This study investigated whether pathway-based analysis could bring scientists closer to unraveling the biology of ADHD. Method The pathway was described as a predefined gene selection based on a well-established database or literature data. Common genetic variants in pathways involved in dopamine/norepinephrine and serotonin neurotransmission and genes involved in neuritic outgrowth were investigated in cases from the International Multicentre ADHD Genetics (IMAGE) study. Multivariable analysis was performed to combine the effects of single genetic variants within the pathway genes. Phenotypes were DSM-IV symptom counts for inattention and hyperactivity/impulsivity (n = 871) and symptom severity measured with the Conners Parent (n = 930) and Teacher (n = 916) Rating Scales. Results Summing genetic effects of common genetic variants within the pathways showed a significant association with hyperactive/impulsive symptoms ( p empirical = .007) but not with inattentive symptoms ( p empirical = .73). Analysis of parent-rated Conners hyperactive/impulsive symptom scores validated this result ( p empirical = .0018). Teacher-rated Conners scores were not associated. Post hoc analyses showed a significant contribution of all pathways to the hyperactive/impulsive symptom domain (dopamine/norepinephrine, p empirical = .0004; serotonin, p empirical = .0149; neuritic outgrowth, p empirical = .0452). Conclusion The present analysis shows an association between common variants in 3 genetic pathways and the hyperactive/impulsive component of ADHD. This study demonstrates that pathway-based association analyses, using quantitative measurements of ADHD symptom domains, can increase the power of genetic analyses to identify biological risk factors involved in this disorder.

Journal ArticleDOI
TL;DR: In patients with SLE, elevated ASRS scores reveal previously unrecognized and clinically significant symptoms of ADHD that respond to N-acetylcysteine treatment.
Abstract: Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that often has debilitating and potentially life-threatening consequences. The cause of SLE is unknown, and current therapies lack specificity and are associated with significant side effects (1). Existing data in the literature provide evidence that a natural antioxidant, glutathione, is depleted in patients with SLE (which may be a key factor underlying abnormal activation of T lymphocytes) and contributes to self-destructive autoimmunity (2). N-acetylcysteine (NAC), which serves as a precursor of glutathione, is widely available, and large doses can be safely administered intravenously to humans. However, NAC is currently unavailable as an oral medication. Therefore, we initiated a double-blind, placebo-controlled, randomized phase I/II study to evaluate the safety and tolerance as well as the metabolic, immunologic, and therapeutic impact of orally formulated NAC in SLE (3). The results of that recently completed pilot study showed NAC to be safe and capable of improving disease activity and fatigue by inhibiting the autoimmune inflammatory process in 36 patients over a 3-month treatment period (3). Neuropsychiatric manifestations are a significant cause of morbidity in SLE. The American College of Rheumatology formulated case definitions for neuropsychiatric SLE syndromes (4) that include cognitive dysfunction in patients who have difficulty with attention, concentration, memory, and word-finding. NAC has been shown in controlled clinical trials to improve memory and cognitive function (5), bipolar disease (6), and schizophrenia (7). Attention deficit and hyperactivity disorder (ADHD) may be an early sign of cognitive impairment and progressive mania or depression (8). In the current study, we documented that ADHD Self-Report Scale (ASRS) scores (9) are elevated in patients with SLE relative to healthy subjects matched for sex, ethnicity, and age within 10 years. Moreover, the cognitive/inattentive components (ASRS part A scores) rather than the hyperactivity/impulsive components (ASRS part B scores) were markedly improved by treatment with NAC. These results suggest that the ASRS can be used to detect cognitive dysfunction, and that early detection of ADHD symptoms may predict and potentially prevent serious neuropsychiatric complications in patients with SLE.

Journal ArticleDOI
TL;DR: The results justify further research on the elucidation of the common genetic background of ADHD and obesity and support the idea that obesity risk alleles may overlap with those relevant for ADHD.
Abstract: Children with attention-deficit/hyperactivity disorder (ADHD) have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. We examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). We screened 32 obesity risk alleles of single nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS) for ADHD based on 495 patients and 1,300 population-based controls and performed in silico analyses of the SNPs in an ADHD meta-analysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X-type motif 3) was associated with ADHD risk (OR: 1.39; P = 3.4 × 10(-4) ; Pcorr = 0.01). In the meta-analysis data we found rs6497416 in the intronic region of the GPRC5B gene (G protein-coupled receptor, family C, group 5, member B; P = 7.2 × 10(-4) ; Pcorr = 0.02) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample rs206936 (NUDT3) and rs10938397 in the glucosamine-6-phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen-activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta-analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/impulsivity. Our results justify further research on the elucidation of the common genetic background of ADHD and obesity.

Journal ArticleDOI
TL;DR: In girls with ADHD, the prevalence of overweight is age dependent and most pronounced in girls aged 10 to 12 years, and they have a 4-fold risk of being obese.
Abstract: OBJECTIVE: Although hyperactivity would seem to increase energy expenditure, attention-deficit hyperactivity disorder (ADHD) appears to increase the risk for being overweight. This study examined the body mass index (BMI) in children with ADHD and its relationship with age, gender, ADHD and comorbid symptom severity, inhibitory control, developmental coordination disorder, sleep duration, and methylphenidate use. METHOD: Participants were 372 Dutch children with ADHD combined type aged 5 to 17 years participating in the International Multicenter ADHD Genetics (IMAGE) study. We categorized BMI according to international age- and gender-specific reference values and calculated BMI-standard deviation scores (BMI-SDS). The control population was matched for age, gender, and ethnicity and originated from the same birth cohort as the ADHD group. Inhibitory control was measured by the computerized Stop-signal task. Prevalence differences of underweight, overweight, and obesity between groups were expressed in odds ratios. We used linear regression analyses with gender, age, parent- and teacher-rated ADHD and comorbid scores, inhibitory control, sleep duration, motor coordination, and methylphenidate use to predict BMI-SDS. RESULTS: Boys with ADHD aged 10 to 17 years and girls aged 10 to 12 years were more likely to be overweight than children in the general Dutch population. Younger girls and female teenagers, however, seemed to be at lower risk for being overweight. Higher oppositional behavior and social communication problems related to higher BMI-SDS scores, whereas more stereotyped behaviors related to lower BMI-SDS scores. We found no effects of the other examined associated risk factors on BMI-SDS. CONCLUSIONS: Attention-deficit hyperactivity disorder in boys is a risk factor for overweight. In girls with ADHD, the prevalence of overweight is age dependent and most pronounced in girls aged 10 to 12 years. They have a 4-fold risk of being obese. Higher oppositional and social communication problems pose an increased risk for overweight, whereas sleep duration, motor coordination problems, and methylphenidate use do not.

Journal ArticleDOI
TL;DR: Stimulant treatment appears to lower the risk of developing substance use disorders and does not have an impact on the development of nicotine dependence in adolescents with ADHD.
Abstract: Background Attention-deficit hyperactivity disorder (ADHD) is linked to increased risk for substance use disorders and nicotine dependence. Aims To examine the effects of stimulant treatment on subsequent risk for substance use disorder and nicotine dependence in a prospective longitudinal ADHD case-control study. Method At baseline we assessed ADHD, conduct disorder and oppositional defiant disorder. Substance use disorders, nicotine dependence and stimulant treatment were assessed retrospectively after a mean follow-up of 4.4 years, at a mean age of 16.4 years. Results Stimulant treatment of ADHD was linked to a reduced risk for substance use disorders compared with no stimulant treatment, even after controlling for conduct disorder and oppositional defiant disorder (hazard ratio (HR) = 1.91, 95% CI 1.10-3.36), but not to nicotine dependence (HR = 1.12, 95% CI 0.45-2.96). Within the stimulant-treated group, a protective effect of age at first stimulant use on substance use disorder development was found, which diminished with age, and seemed to reverse around the age of 18. Conclusions Stimulant treatment appears to lower the risk of developing substance use disorders and does not have an impact on the development of nicotine dependence in adolescents with ADHD.

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TL;DR: Compared to parent and teacher reports of anxiety, child reported comorbid anxiety shows foremost the largest associations with the neurocognitive dysfunctions observed in children with ADHD, stressing the importance of including child self-reported anxiety assessments in clinical and research practice.
Abstract: Previous research established that children with ADHD and comorbid anxiety have a later age of ADHD onset, show less off-task and hyperactive behavior, and have more school problems than children with ADHD alone. Comorbid anxiety appears to ameliorate behavioral inhibition deficits, worsen working memory problems, and lengthen reaction times in ADHD. This study investigated the effect of comorbid anxiety on a broad range of neurocognitive functions and includes child-, parent- and teacher reports of anxiety. The sample consisted of 509 children in the age range 5-19 years, including 238 children with a diagnosis of ADHD combined subtype and 271 normal control children. Children were tested on a broad battery of neurocognitive tasks that proved highly sensitive to ADHD in previous work. Linear Structural Equation Modeling (SEM) was used to estimate the effect of comorbid anxiety on the neurocognitive functions. Child reported anxiety was associated with slower motor speed and response speed and better behavioral inhibition. Teacher reported anxiety was related to worse time production. Parent reported anxiety was not significantly associated with any of the neurocognitive functions. Compared to parent and teacher reports of anxiety, child reported comorbid anxiety shows foremost the largest associations with the neurocognitive dysfunctions observed in children with ADHD. This stresses the importance of including child self-reported anxiety assessments in clinical and research practice.

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TL;DR: This study examined the genetic relationship of 16 commonly used WKY and SHR rat substrains using genome-wide SNP genotyping data and confirmed a large genetic divergence and complex relationships among the SHR and WKY substrains.
Abstract: The spontaneously hypertensive rat (SHR) has been widely used as a model for studies of hypertension and attention deficit/hyperactivity disorder. The inbred Wistar-Kyoto (WKY) rat, derived from the same ancestral outbred Wistar rat as the SHR, are normotensive and have been used as the closest genetic control for the SHR, although the WKY has also been used as a model for depression. Notably, however, substantial behavioral and genetic differences among the WKY substrains, usually from the different vendors and breeders, have been observed. These differences have often been overlooked in prior studies, leading to inconsistent and even contradictory findings. The complicated breeding history of the SHR and WKY rats and the lack of a comprehensive understanding of the genetic background of different commercial substrains make the selection of control rats a daunting task, even for researchers who are mindful of their genetic heterogeneity. In this study, we examined the genetic relationship of 16 commonly used WKY and SHR rat substrains using genome-wide SNP genotyping data. Our results confirmed a large genetic divergence and complex relationships among the SHR and WKY substrains. This understanding, although incomplete without the genome sequence, provides useful guidance in selecting substrains and helps to interpret previous reports when the source of the animals was known. Moreover, we found two closely related, yet distinct WKY substrains that may provide novel opportunities in modeling psychiatric disorders.

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TL;DR: Childhood ADHD symptoms are associated with obesity in women even after comorbid psychiatric disorders are accounted for, and provides a rationale for longitudinal studies assessing the impact of the treatment of childhood ADHD symptoms on Obesity in women.
Abstract: Background A significant association between attention-deficit hyperactivity disorder (ADHD) and obesity has been reported. This study addresses unexplored aspects of this relationship. Aims To evaluate the association between adult obesity and: (a) persistent, remitted or lifetime ADHD; (b) number of childhood ADHD symptoms, controlling for socioeconomic status and mood, anxiety and substance use disorders. Method Face-to-face psychiatric interviews in 34 653 US adults from the National Epidemiologic Study on Alcohol and Related Conditions. Obesity was defined as a body mass index ⩾30. Results Persistent, lifetime or remitted ADHD were not associated with obesity after controlling for confounders. The number of childhood ADHD symptoms was significantly associated with adult obesity, even after adjustment, in women. Conclusions Childhood ADHD symptoms are associated with obesity in women even after comorbid psychiatric disorders are accounted for. This provides a rationale for longitudinal studies assessing the impact of the treatment of childhood ADHD symptoms on obesity in women.

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TL;DR: The International ADHD in Substance Use Disorders Prevalence (IASP) study as discussed by the authors was conducted to determine the prevalence of ADHD in adult treatment seeking patients with SUD in different countries and SUD populations, determine the reliability and validity of the Adult ADHD Self-report Scale V 1.1 (ASRS) as ADHD screening instrument in subjects with substance use disorders (SUDs), investigate the comorbidity profile of SUD patients with and without ADHD, compare risk factors and protective factors, and increase our knowledge about the relationship between ADHD and the onset and course of
Abstract: Attention deficit/hyperactivity disorder (ADHD) is an increasingly recognized comorbid condition in subjects with substance use disorders (SUDs). This paper describes the methods and study population of the International ADHD in Substance Use Disorders Prevalence (IASP) study. Objectives of the IASP are to determine the prevalence of ADHD in adult treatment seeking patients with SUD in different countries and SUD populations, determine the reliability and validity of the Adult ADHD Self-report Scale V 1.1 (ASRS) as ADHD screening instrument in SUD populations, investigate the comorbidity profile of SUD patients with and without ADHD, compare risk factors and protective factors in SUD patients with and without a comorbid diagnosis of ADHD, and increase our knowledge about the relationship between ADHD and the onset and course of SUD. In this cross-sectional, multi-centre two stage study, subjects were screened for ADHD with the ASRS, diagnosed with the Conner's Adult ADHD Diagnostic Interview for DSM-IV (CAADID), and evaluated for SUD, major depression, bipolar disorder, anti social personality disorder and borderline personality disorder. Three thousand five hundred and fifty-eight subjects from 10 countries were included. Of these 40.9% screened positive for ADHD. This is the largest international study on this population evaluating ADHD and comorbid disorders.

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TL;DR: Examining the nature of the comorbidity between pediatric attention deficit/hyperactivity disorder and post‐traumatic stress disorder found to be related to each other finds no clear link between the disorders.
Abstract: Biederman J, Petty CR, Spencer TJ, Woodworth KY, Bhide P, Zhu J, Faraone SV. Examining the nature of the comorbidity between pediatric attention deficit/hyperactivity disorder and post-traumatic stress disorder. Objective: This study sought to address the link between attention deficit/hyperactivity disorder (ADHD) and post-traumatic stress disorder (PTSD) in youth by providing a comprehensive comparison of clinical correlates of ADHD subjects with and without PTSD across multiple non-overlapping domains of functioning and familial patterns of transmission. Method: Participants were 271 youths with ADHD and 230 controls without ADHD of both sexes along with their siblings. Participants completed a large battery of measures designed to assess psychiatric comorbidity, psychosocial, educational, and cognitive parameters. Results: Post-traumatic stress disorder was significantly higher in ADHD probands vs. controls (5.2% vs. 1.7%, χ2(1) = 4.36, P = 0.04). Irrespective of the comorbidity with PTSD, ADHD subjects had similar ages at onset of ADHD, similar type and mean number of ADHD symptoms, and similar ADHD-associated impairments. PTSD in ADHD probands was significantly associated with a higher risk of psychiatric hospitalization, school impairment, poorer social functioning and higher prevalences of mood, conduct disorder, and anxiety disorders. The mean onset of PTSD (12.6 years) was significantly later than that of ADHD and comorbid disorders (all P < 0.05). Siblings of ADHD and ADHD + PTSD probands had higher prevalences of ADHD vs. siblings of controls (35% vs. 18%, z = 4.00, P < 0.001 and 67% vs. 18%, z = 4.02, P < 0.001 respectively) and siblings of ADHD+PTSD probands had a significantly higher prevalence of PTSD compared with the siblings of ADHD and control probands (20% vs. 3% and 3%, z = 2.99, P = 0.003 and z = 2.07, P = 0.04 respectively). Conclusion: Findings indicate that the comorbidity with PTSD in ADHD leads to greater clinical severity as regards psychiatric comorbidity and psychosocial dysfunction. ADHD is equally familial in the presence of PTSD in the proband indicating that their co-occurrence is not owing to diagnostic error.


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TL;DR: Investigations using self-report scales provide evidence that stimulant treatment translates into measurable improvement in daily function for adults with ADHD, and could better characterize the mediators and moderators of individual improvement.

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TL;DR: Examination of NP functioning over one year in a sample of youth at clinical high risk (CHR) for psychosis participating in a treatment study suggests some progressive NP impairments may accompany risk for psychosis and be greatest for those who develop psychotic level symptoms.

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TL;DR: The familial coaggregation of the 2 disorders suggests that these disorders share familial risk factors and that their co-occurrence is not due to diagnostic errors.
Abstract: Objective Attention-deficit/hyperactivity disorder (ADHD) is characterized by clinically significant functional impairment due to symptoms of inattention and/or hyperactivity and impulsivity. Previous research suggests a link, in child samples, between ADHD and posttraumatic stress disorder (PTSD), which is characterized by (1) chronically reexperiencing a traumatic event, (2) hyperarousal, and (3) avoiding stimuli associated with the trauma while exhibiting numbed responsiveness. This study sought to address the link between ADHD and PTSD in adults by providing a comprehensive comparison of ADHD patients with and without PTSD across multiple variables including demographics, patterns of psychiatric comorbidities, functional impairments, quality of life, social adjustment, and familial transmission. Method Participants in our controlled family study conducted between 1998 and 2003 were 190 adults with DSM-IV ADHD who were attending an outpatient mental health clinic in Boston, Massachusetts; 16 adults with DSM-IV ADHD who were recruited by advertisement from the greater Boston area; and 123 adult controls without ADHD who were recruited by advertisement from the greater Boston area. All available first-degree relatives also participated. Subjects completed a large battery of self-report measures (the Quality of Life Enjoyment and Satisfaction Questionnaire, items from the Current Behavior Scale, the Social Adjustment Scale Self-Report, and the Four Factor Index of Social Status) designed to assess various psychiatric and functional parameters. Diagnoses were made using data obtained from structured psychiatric interviews (Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version, and the Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Epidemiologic Version). Results The lifetime prevalence of PTSD was significantly higher among adults with ADHD compared with controls (10.0% vs 1.6%; P = .004). Participants with ADHD and those with ADHD + PTSD did not differ in core symptoms of ADHD nor in age at onset, but those with ADHD + PTSD had higher rates of psychiatric comorbidity than those with ADHD only (including higher lifetime rates of major depressive disorder, oppositional defiant disorder, social phobia, agoraphobia, and generalized anxiety disorder) and worse quality of life ratings for all domains. Familial risk analysis revealed that relatives of ADHD probands without PTSD had elevated rates of both ADHD (51%) and PTSD (12%) that significantly differed from rates among relatives of controls (7% [P ≤ .001] and 0% [P ≤ .05], respectively). A similar pattern of elevated risk for ADHD and PTSD (80% and 40%) was observed in relatives of probands with ADHD + PTSD (P ≤ .001 for both conditions). Conclusions The comorbidity of PTSD and ADHD in adults leads to greater clinical severity in terms of psychiatric comorbidity and psychosocial functioning. The familial coaggregation of the 2 disorders suggests that these disorders share familial risk factors and that their co-occurrence is not due to diagnostic errors.

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TL;DR: The smoking rate at endpoint (mean, 10 months of methylphenidate treatment) was low in the clinical trial subjects and not significantly different from that in the non-ADHD comparators or the ADHD comparators receiving stimulants naturalistically (7.1% vs 8.9% as discussed by the authors ).

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TL;DR: Discovery of this functionally relevant SLC1A1 mutation and its co‐segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders.
Abstract: Growing evidence for genetic overlap between schizophrenia (SCZ) and bipolar disorder (BPD) suggests that causal variants of large effect on disease risk may cross traditional diagnostic boundaries. Extended multigenerational families with both SCZ and BPD cases can be a valuable resource for discovery of shared biological pathways because they can reveal the natural evolution of the underlying genetic disruptions and their phenotypic expression. We investigated a deletion at the SLC1A1 glutamate transporter gene originally identified as a copy number variant exclusively carried by members of a 5-generation Palauan family. Using an expanded sample of 21 family members, quantitative PCR confirmed the deletion in all seven individuals with psychosis, three "obligate-carrier" parents and one unaffected sibling, while four marry-in parents were non-carriers. Linkage analysis under an autosomal dominant model generated a LOD-score of 3.64, confirming co-segregation of the deletion with psychosis. For more precise localization, we determined the approximate deletion end points using alignment of next-generation sequencing data for one affected deletion-carrier and then designed PCR amplicons to span the entire deletion locus. These probes established that the deletion spans 84,298 bp, thus eliminating the entire promoter, the transcription start site, and the first 59 amino acids of the protein, including the first transmembrane Na(2+)/dicarboxylate symporter domain, one of the domains that perform the glutamate transport action. Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders.

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TL;DR: The finding that RTV difference scores measure largely the same etiological process as RTV under baseline condition supports theories emphasizing the malleability of the observed high RTV.
Abstract: Background. Increased reaction time variability (RTV) on cognitive tasks requiring a speeded response is characteristic of several psychiatric disorders. In attention deficit hyperactivity disorder (ADHD), the association with RTV is strong phenotypically and genetically, yet high RTV is not a stable impairment but shows ADHD-sensitive improvement under certain conditions, such as those with rewards. The state regulation theory proposed that the RTV difference score, which captures change from baseline to a rewarded or fast condition, specifically measures 'state regulation'. By contrast, the interpretation of RTV baseline (slow, unrewarded) scores is debated. We aimed to investigate directly the degree of phenotypic and etiological overlap between RTV baseline and RTV difference scores. Method. We conducted genetic model fitting analyses on go/no-go and fast task RTV data, across task conditions manipulating rewards and event rate, from a population-based twin sample (n=1314) and an ADHD and control sibling-pair sample (n=1265). Results. Phenotypic and genetic/familial correlations were consistently high (0.72-0.98) between RTV baseline and difference scores, across tasks, manipulations and samples. By contrast, correlations were low between RTV in the manipulated condition and difference scores. A comparison across two different go/no-go task RTV difference scores (slow-fast/slow-incentive) showed high phenotypic and genetic/familial overlap (r=0.75-0.83). Conclusions. Our finding that RTV difference scores measure largely the same etiological process as RTV under baseline condition supports theories emphasizing the malleability of the observed high RTV. Given the statistical shortcomings of difference scores, we recommend the use of RTV baseline scores for most analyses, including genetic analyses.

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TL;DR: An overview of the epidemiology, neurobiology, genetics, diagnosis and most recent pharmacological approaches for treatment with a focus on safety and efficacy in ADHD is provided and the use of medications used to treat ADHD in special populations are described.
Abstract: Introduction: Attention deficit hyperactivity disorder (ADHD) is an early onset, clinically heterogeneous, complex neurobiological disorder, defined by symptoms of inattention and hyperactivity/imp...