Showing papers by "Stephen V. Faraone published in 2008"

Whole-genome association study of bipolar disorder

Abstract: We performed a genome-wide association scan in 1461 patients with bipolar (BP) 1 disorder, 2008 controls drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder and the University College London sample collections with successful genotyping for 372,193 single nucleotide polymorphisms (SNPs). Our strongest single SNP results are found in myosin5B (MYO5B; P=1.66 x 10(-7)) and tetraspanin-8 (TSPAN8; P=6.11 x 10(-7)). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P=2.04 x 10(-8), TSPAN8; P=7.57 x 10(-7) and EGFR; P=8.36 x 10(-8)). For replication, we genotyped 304 SNPs in family-based NIMH samples (n=409 trios) and University of Edinburgh case-control samples (n=365 cases, 351 controls) that did not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case-Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene. Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.

Interpreting Estimates of Treatment Effects Implications for Managed Care

Abstract: How should health care professionals choose among the many therapies claimed to be efficacious for treating specific disorders? The practice of evidence-based medicine provides an answer. Advocates of this approach urge health care professionals to base treatment choices on the best evidence from systematic research on both the efficacy and adverse effects of various therapeutic alternatives. Ideally, health care professionals would compare different treatments by referring to randomized, double-blind, head-to-head trials that compared the treatment options. Although individual medications are typically well researched when these placebo-controlled studies are performed, studies that directly compare treatments are rare. In the absence of direct head-to-head trials, other evidence comes from indirect comparisons of two or more therapies by examining individual studies involving each treatment. This article provides an introductory review of methods of such indirect comparisons of therapies across studies, provides examples of how these methods can be used to make treatment decisions, and presents a general overview of relevant issues and statistics for readers interested in understanding these methods more thoroughly.

Genome-wide association scan of quantitative traits for Attention Deficit Hyperactivity Disorder identifies novel associations and confirms candidate gene associations

Abstract: Attention deficit hyperactivity disorder (ADHD) is a complex condition with environmental and genetic etiologies. Up to this point, research has identified genetic associations with candidate genes from known biological pathways. In order to identify novel ADHD susceptibility genes, 600,000 SNPs were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. We generated six quantitative phenotypes from 18 ADHD symptoms to be used in genome-wide association analyses. With the PBAT screening algorithm, we identified 2 SNPs, rs6565113 and rs552655 that met the criteria for significance within a specified phenotype. These SNPs are located in intronic regions of genes CDH13 and GFOD1, respectively. CDH13 has been implicated previously in substance use disorders. We also evaluated the association of SNPs from a list of 37 ADHD candidate genes that was specified a priori. These findings, along with association P-values with a magnitude less than 10(-5), are discussed in this manuscript. Seventeen of these candidate genes had association P-values lower then 0.01: SLC6A1, SLC9A9, HES1, ADRB2, HTR1E, DDC, ADRA1A, DBH, DRD2, BDNF, TPH2, HTR2A, SLC6A2, PER1, CHRNA4, SNAP25, and COMT. Among the candidate genes, SLC9A9 had the strongest overall associations with 58 association test P-values lower than 0.01 and multiple association P-values at a magnitude of 10(-5) in this gene. In sum, these findings identify novel genetic associations at viable ADHD candidate genes and provide confirmatory evidence for associations at previous candidate genes. Replication of these results is necessary in order to confirm the proposed genetic variants for ADHD.

New insights into the comorbidity between ADHD and major depression in adolescent and young adult females.

Abstract: Objective The main aim of this study was to evaluate the association between attention-deficit/hyperactivity disorder (ADHD) and major depression (MD) in adolescent and young adult females. Method Subjects were females with ( n = 140) and without ( n = 122) ADHD ascertained from pediatric and psychiatric settings. Subjects were followed prospectively for 5 years into adolescence and young adulthood and reassessed in multiple nonoverlapping domains including psychiatric, cognitive, interpersonal, family, and educational functioning. Results Females with ADHD had a 2.5 times higher risk for MD at adolescent follow-up compared with control females, adjusting for psychiatric comorbidity. MD in females with ADHD was associated with an earlier age at onset, greater than twice the duration, more severe depression-associated impairment, a higher rate of suicidality, and a greater likelihood of requiring psychiatric hospitalization than MD in control girls. Parental MD and proband mania were significant predictors of MD among females with ADHD, independently of other predictors. Conclusions MD emerging in the context of ADHD in females is an impairing and severe comorbidity worthy of further clinical and scientific considerations.

Genome-wide association scan of attention deficit hyperactivity disorder

Abstract: Results of behavioral genetic and molecular genetic studies have converged to suggest that genes substantially contribute to the development of attention deficit/hyperactivity disorder (ADHD), a common disorder with an onset in childhood. Yet, despite numerous linkage and candidate gene studies, strongly consistent and replicable association has eluded detection. To search for ADHD susceptibility genes, we genotyped approximately 600,000 SNPs in 958 ADHD affected family trios. After cleaning the data, we analyzed 438,784 SNPs in 2,803 individuals comprising 909 complete trios using ADHD diagnosis as phenotype. We present the initial TDT findings as well as considerations for cleaning family-based TDT data. None of the SNP association tests achieved genome-wide significance, indicating that larger samples may be required to identify risk loci for ADHD. We additionally identify a systemic bias in family-based association, and suggest that variable missing genotype rates may be the source of this bias.

Effect of Stimulants on Height and Weight: A Review of the Literature

Abstract: Objective Stimulant medications are effective treatments for attention-deficit/hyperactivity disorder, but concerns remain about their effects on growth. Method We provide a quantitative analysis of longitudinal studies about deficits in expected growth among children with attention-deficit/hyperactivity disorder treated with stimulant medication. Study selection criteria were use of DSM criteria or clear operational definitions for hyperactivity or minimal brain dysfunction; outcome measures including raw, standardized, or percentile measurement of change in height and/or weight; first assessment of effects on growth occurred during childhood; and follow-up for at least 1 year. For issues not suitable for quantitative analyses, we provide a systematic, qualitative review. Results The quantitative analyses showed that treatment with stimulant medication led to statistically significant delays in height and weight. This review found statistically significant evidence of attenuation of these deficits over time. The qualitative review suggested that growth deficits may be dose dependent, deficits may not differ between methylphenidate and amphetamine, treatment cessation may lead to normalization of growth, and further research should assess the idea that attention-deficit/hyperactivity disorder itself may be associated with dysregulated growth. Conclusions Treatment with stimulants in childhood modestly reduced expected height and weight. Although these effects attenuate over time and some data suggest that ultimate adult growth parameters are not affected, more work is needed to clarify the effects of continuous treatment from childhood to adulthood. Although physicians should monitor height, deficits in height and weight do not appear to be a clinical concern for most children treated with stimulants. J. Am. Acad. Child Adolesc. Psychiatry , 2008; 47(9):000–000.

The long-term longitudinal course of oppositional defiant disorder and conduct disorder in ADHD boys: findings from a controlled 10-year prospective longitudinal follow-up study

Abstract: BackgroundA better understanding of the long-term scope and impact of the co-morbidity with oppositional defiant disorder (ODD) and conduct disorder (CD) in attention deficit hyperactivity disorder (ADHD) youth has important clinical and public health implications.MethodSubjects were assessed blindly at baseline (mean age=10.7 years), 1-year (mean age=11.9 years), 4-year (mean age=14.7 years) and 10-year follow-up (mean age=21.7 years). The subjects' lifetime diagnostic status of ADHD, ODD and CD by the 4-year follow-up were used to define four groups (Controls, ADHD, ADHD plus ODD, and ADHD plus ODD and CD). Diagnostic outcomes at the 10-year follow-up were considered positive if full criteria were met any time after the 4-year assessment (interval diagnosis). Outcomes were examined using a Kaplan–Meier survival function (persistence of ODD), logistic regression (for binary outcomes) and negative binomial regression (for count outcomes) controlling for age.ResultsODD persisted in a substantial minority of subjects at the 10-year follow-up. Independent of co-morbid CD, ODD was associated with major depression in the interval between the 4-year and the 10-year follow-up. Although ODD significantly increased the risk for CD and antisocial personality disorder, CD conferred a much larger risk for these outcomes. Furthermore, only CD was associated with significantly increased risk for psychoactive substance use disorders, smoking, and bipolar disorder.ConclusionsThese longitudinal findings support and extend previously reported findings from this sample at the 4-year follow-up indicating that ODD and CD follow a divergent course. They also support previous findings that ODD heralds a compromised outcome for ADHD youth grown up independently of the co-morbidity with CD.

Stimulant Therapy and Risk for Subsequent Substance Use Disorders in Male Adults With ADHD: A Naturalistic Controlled 10-Year Follow-Up Study

Abstract: Objective: The extant literature does not provide definite answers pertaining to whether stimulant treatment increases, decreases, or does not affect the risk for subsequent substance use disorders in youths with attention deficit hyperactivity disorder (ADHD). The authors examined the association between stimulant treatment in childhood and adolescence and subsequent substance use disorders (alcohol, drug, and nicotine) into the young adult years. Method: The authors conducted a 10year prospective follow-up study. One hundred forty male Caucasian children with ADHD, ages 6 to 17, were examined at baseline. Of these, 112 (80%) were reassessed at the 10-year follow-up (mean age at follow-up=22 years). Assessments were made using Cox proportional hazards survival models. All models were adjusted for conduct disorder, since conduct disorder is a potent predictor of subsequent substance use disorders. Results: Of the 112 ADHD subjects who were reassessed at the 10-year follow-up, 82 (73%) had been treated previously with stimulants and 25 (22%) were undergoing stimulant treatment at the time of the follow-up assessment. There were no statistically significant associations between stimulant treatment and alcohol, drug, or nicotine use disorders. Conclusions: The findings revealed no evidence that stimulant treatment increases or decreases the risk for subsequent substance use disorders in children and adolescents with ADHD when they reach young adulthood.

Motor coordination problems in children and adolescents with ADHD rated by parents and teachers: effects of age and gender

Abstract: Objective. ADHD is frequently accompanied by motor coordination problems. However, the co-occurrence of poor motor performance has received less attention in research than other coexisting problems in ADHD. The underlying mechanisms of this association remain unclear. Therefore, we investigated the prevalence of motor coordination problems in a large sample of children with ADHD, and the relationship between motor coordination problems and inattentive and hyperactive/impulsive symptoms. Furthermore, we assessed whether the association between ADHD and motor coordination problems was comparable across ages and was similar for both genders. Method. We investigated 486 children with ADHD and 269 normal controls. Motor coordination problems were rated by parents (Developmental Coordination Disorder Questionnaire) and teachers (Groningen Motor Observation Scale). Results. Parents and teachers reported motor coordination problems in about one third of children with ADHD. Problems of fine and gross motor skills, coordination skills and motor control were all related to inattentive rather than hyperactive/impulsive symptoms. Relative to controls, motor coordination problems in ADHD were still present in teenagers according to parents; the prevalence diminished somewhat according to teachers. Boys and girls with ADHD were comparably affected, but motor performance in controls was better in girls than in boys. Conclusions. Motor coordination problems were reported in one third of children with ADHD and affected both boys and girls. These problems were also apparent in adolescents with ADHD. Clinicians treating children with ADHD should pay attention to co-occurring motor coordination problems because of the high prevalence and the negative impact of motor coordination problems on daily life.

Meta-Analysis of Genome-Wide Linkage Scans of Attention Deficit Hyperactivity Disorder

Abstract: Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome-wide significant linkage (P(SR) = 0.00034, P(OR) = 0.04) was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes.

The influence of serotonin- and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis

Abstract: Background Low serotonergic (5-HT) activity correlates with increased impulsive-aggressive behavior, while the opposite association may apply to cognitive impulsiveness. Both types of impulsivity are associated with attention-deficit/hyperactivity disorder (ADHD), and genes of functional significance for the 5-HT system are implicated in this disorder. Here we demonstrate the separation of aggressive and cognitive components of impulsivity from symptom ratings and test their association with 5-HT and functionally related genes using a family-based association test (FBAT-PC).

DSM-IV combined type ADHD shows familial association with sibling trait scores: a sampling strategy for QTL linkage.

Abstract: Attention deficit hyperactivity disorder (ADHD) is a discrete clinical syndrome characterized by the triad of inattention, hyperactivity, and impulsivity in the context of marked impairments. Molecular genetic studies have been successful in identifying genetic variants associated with ADHD, particularly with DSM-IV inattentive and combined subtypes. Quantitative trait locus (QTL) approaches to linkage and association mapping have yet to be widely used in ADHD research, although twin studies investigating individual differences suggest that genetic liability for ADHD is continuously distributed throughout the population, underscoring the applicability of quantitative dimensional approaches. To investigate the appropriateness of QTL approaches, we tested the familial association between 894 probands with a research diagnosis of DSM-IV ADHD combined type and continuous trait measures among 1,135 of their siblings unselected for phenotype. The sibling recurrence rate for ADHD combined subtype was 12.7%, yielding a sibling recurrence risk ratio (lambda(sib)) of 9.0. Estimated sibling correlations around 0.2-0.3 are similar to those estimated from the analysis of fraternal twins in population twin samples. We further show that there are no threshold effects on the sibling risk for ADHD among the ADHD probands; and that both affected and unaffected siblings contributed to the association with ADHD trait scores. In conclusion, these data confirm the main requirement for QTL mapping of ADHD by demonstrating that narrowly defined DSM-IV combined type probands show familial association with dimensional ADHD symptom scores amongst their siblings.

Educational and occupational underattainment in adults with attention-deficit/hyperactivity disorder: A controlled study.

Abstract: Objective Attention-deficit/hyperactivity disorder (ADHD) has been consistently associated with intellectual, educational, and employment deficits. This study evaluated subjects to determine whether the educational and occupational deficits associated with ADHD are what would be expected given their intellectual abilities or lower than expected given their intellectual abilities. Method Participants derived from a case-control study of adults with (N = 224) and without (N = 146) DSM-IV ADHD. Subjects were comprehensively assessed with structured diagnostic interviews and neuropsychological assessments. Educational and occupational attainments were based on Hollingshead socioeconomic status scale. The expected educational and occupational levels of participants with ADHD were computed using ordered logistic regression models as a function of age, sex, and full scale IQ of controls. The study was conducted from 1998 to 2003. Results Based on their IQ, subjects with ADHD were predicted to have significantly more education than they actually attained. Additionally, based on their observed education, participants with ADHD were predicted to have significantly higher occupational levels than actually observed. Conclusion These findings indicate that ADHD is associated with significant educational and occupational underattainments relative to what would have been expected on the basis of intellectual potential.

Effect of prior stimulant treatment for attention-deficit/hyperactivity disorder on subsequent risk for cigarette smoking and alcohol and drug use disorders in adolescents.

Abstract: Objective To examine the effects of early stimulant treatment on subsequent risk for cigarette smoking and substance use disorders (SUDs) in adolescents with attention-deficit/hyperactivity disorder (ADHD). Design Case-controlled, prospective, 5-year follow-up study. Setting Massachusetts General Hospital, Boston. Participants Adolescents with and without ADHD from psychiatric and pediatric sources. Blinded interviewers determined all diagnoses using structured interviews. Intervention Naturalistic treatment exposure with psychostimulants for ADHD. Main Outcome Measures We modeled time to onset of SUDs and smoking as a function of stimulant treatment. Results We ascertained 114 subjects with ADHD (mean age at follow-up, 16.2 years) having complete medication and SUD data; 94 of the subjects were treated with stimulants. There were no differences in SUD risk factors between naturalistically treated and untreated groups other than family history of ADHD. We found no increased risks for cigarette smoking or SUDs associated with stimulant therapy. We found significant protective effects of stimulant treatment on the development of any SUD (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.13-0.60; χ 2 113 = 10.57, P = .001) and cigarette smoking (HR, 0.28; 95% CI, 0.14-0.60; χ 2 111 = 10.05, P = .001) that were maintained when controlling for conduct disorder. We found no effects of time to onset or duration of stimulant therapy on subsequent SUDs or cigarette smoking in subjects with ADHD. Conclusion Stimulant therapy does not increase but rather reduces the risk for cigarette smoking and SUDs in adolescents with ADHD.

Conduct disorder and ADHD: evaluation of conduct problems as a categorical and quantitative trait in the international multicentre ADHD genetics study.

Abstract: Attention-deficit/hyperactivity disorder (ADHD) is typically characterized by inattention, excessive motor activity, impulsivity, and distractibility. Individuals with ADHD have significant impairment in family and peer relations, academic functioning, and show high co-morbidity with a wide range of psychiatric disorders including oppositional defiant disorder (ODD), conduct disorder (CD), anxiety disorder, depression, substance abuse, and pervasive developmental disorder (PDD). Family studies suggest that ADHD + CD represents a specific subtype of the ADHD disorder with familial risk factors only partly overlapping with those of ADHD alone. We performed a hypothesis-free analysis of the GAIN–ADHD sample to identify markers and genes important in the development of conduct problems in a European cohort of individuals with ADHD. Using the Family-Based Association Test (FBAT) package we examined three measures of conduct problems in 1,043,963 autosomal markers. This study is part of a series of exploratory analyses to identify candidate genes that may be important in ADHD and ADHD-related traits, such as conduct problems. We did not find genome-wide statistical significance (P < 5 × 10−7) for any of the tested markers and the three conduct problem traits. Fifty-four markers reached strong GWA signals (P < 10−5). We discuss these findings in the context of putative candidate genes and the implications of these findings in the understanding of the etiology of ADHD + CD. We aimed to achieve insight into the genetic etiology of a trait using a hypothesis-free study design and were able to identify a number of biologically interesting markers and genes for follow-up studies.

Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder.

Abstract: A time-to-onset analysis for family-based samples was performed on the genomewide association (GWAS) data for attention deficit hyperactivity disorder (ADHD) to determine if associations exist with the age at onset of ADHD. The initial dataset consisted of 958 parent-offspring trios that were genotyped on the Perlegen 600,000 SNP array. After data cleaning procedures, 429,981 autosomal SNPs and 930 parent-offspring trios were used found suitable for use and a family-based logrank analysis was performed using that age at first ADHD symptoms as the quantitative trait of interest. No SNP achieved genome-wide significance, and the lowest P-values had a magnitude of 10(-7). Several SNPs among a pre-specified list of candidate genes had nominal associations including SLC9A9, DRD1, ADRB2, SLC6A3, NFIL3, ADRB1, SYT1, HTR2A, ARRB2, and CHRNA4. Of these findings SLC9A9 stood out as a promising candidate, with nominally significant SNPs in six distinct regions of the gene.

Discordance between Psychometric Testing and Questionnaire-Based Definitions of Executive Function Deficits in Individuals with ADHD.

Abstract: Objective: One suspected source of negative outcomes associated with ADHD has been deficits in executive functions. Although both psychometrically defined and self-reported executive function deficits (EFDs) have been shown to be associated with poor academic and occupational outcomes, whether these two approaches define the same individuals remains unknown. Method: Participants were 194 adults with ADHD from a case-control study of ADHD. Empirically based cutoffs were ascertained for an EFD diagnosis on both psychometric tests and scores on the Current Behavior Scale. Results: Results showed a modest overlap between the psychometric and self-reported definitions of EFDs. Whereas neuropsychological testing largely identified individuals with lower IQ and achievement testing, the behavioral questionnaire largely identified individuals with higher levels of ADHD symptoms, psychiatric comorbidity, and interpersonal deficits. Conclusion: Results indicate that behavioral questionnaires cannot be used interchan...

Familial risk analyses of attention deficit hyperactivity disorder and substance use disorders.

Abstract: Objective: A robust and bidirectional comorbidity between attention deficit hyperactivity disorder (ADHD) and psychoactive substance use disorder (alcohol or drug abuse or dependence) has been consistently reported in the extant literature. Method: First-degree relatives from a large group of pediatrically and psychiatrically referred boys with (112 probands, 385 relatives) and without (105 probands, 358 relatives) ADHD were comprehensively assessed by blind raters with structured diagnostic interviews. Familial risk analysis examined the risks in first-degree relatives for ADHD, psychoactive substance use disorder, alcohol dependence, and drug dependence after stratifying probands by the presence and absence of these disorders. Results: ADHD in the proband was consistently associated with a significant risk for ADHD in relatives. Drug dependence in probands increased the risk for drug dependence in relatives irrespective of ADHD status, whereas alcohol dependence in relatives was predicted only by ADHD p...

Phenomic, convergent functional genomic, and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism.

Abstract: We had previously identified the clock gene D-box binding protein (Dbp) as a potential candidate gene for bipolar disorder and for alcoholism, using a Convergent Functional Genomics (CFG) approach Here we report that mice with a homozygous deletion of DBP have lower locomotor activity, blunted responses to stimulants, and gain less weight over time In response to a chronic stress paradigm, these mice exhibit a diametric switch in these phenotypes DBP knockout mice are also activated by sleep deprivation, similar to bipolar patients, and that activation is prevented by treatment with the mood stabilizer drug valproate Moreover, these mice show increased alcohol intake following exposure to stress Microarray studies of brain and blood reveal a pattern of gene expression changes that may explain the observed phenotypes CFG analysis of the gene expression changes identified a series of novel candidate genes and blood biomarkers for bipolar disorder, alcoholism, and stress reactivity

Genome-wide association study of response to methylphenidate in 187 children with attention-deficit/hyperactivity disorder.

Abstract: We conducted a genome-wide association study of symptom response in an open-label study of a methylphenidate transdermal system (MTS). All DNA extraction and genotyping was conducted at SUNY Upstate Medical University using the Affymetrix Genome-Wide Human SNP Array 6.0. All quality control and association analyses were conducted using the software package PLINK. After data cleaning and quality control, there were 187 subjects (72% (N = 135) male) with mean age 9.2 +/- 2.0 years and 319,722 SNPs available for analysis. The most statistically significant association (rs9627183 and rs11134178; P = 3 x 10(-6)) fell short of the threshold for a genome-wide significant association. The most intriguing association among suggestive findings (rs3792452; P = 2.6 x 10(-5)) was with the metabotropic glutamate receptor 7 gene (GRM7) as it is expressed in brain structures also previously associated with ADHD. Among the 102 available SNPs covering previously studied candidate genes, two SNPs within the norepinephrine transporter gene (NET, SLC6A2) were significant at P < or = 1 x 10(-2). These results should be considered preliminary until replicated in larger adequately powered, controlled samples but do suggest that noradrenergic and possibly glutaminergic genes may be involved with response to methylphenidate.

The Reliability and Validity of Self- and Investigator Ratings of ADHD in Adults

Abstract: Objective: Little information is available comparing self- versus investigator ratings of symptoms in adult ADHD. The authors compared the reliability, validity, and utility in a sample of adults with ADHD and also as an index of clinical improvement during treatment of self- and investigator ratings of ADHD symptoms via the Conners Adult ADHD Rating Scale (CAARS). Method: We analyzed data from two double-blind, parallel-design studies of 536 adult ADHD patients, randomized to 10-week treatment with atomoxetine or placebo. Outcome variables included ADHD symptom severity (CAARS self- and investigator ratings), psychiatric symptom comorbidity, and functioning. Results: All five CAARS subscales showed good internal consistency at each time point. Similarly, interrater reliability was acceptable for each subscale. Following treatment, CAARS total scores and subscale scores improved significantly from baseline. CAARS subscales also predicted changes in other psychiatric symptoms and functioning. Overall, base...

Sexually dimorphic effects of four genes (COMT, SLC6A2, MAOA, SLC6A4) in genetic associations of ADHD: a preliminary study.

Abstract: A growing body of literature finds gender differences in ADHD. However, little is known about the causes of these differences. One possibility is that ADHD risk genes have sexually dimorphic effects. We have investigated four ADHD candidate genes (COMT, SLC6A2, MAOA, SLC6A4) for which there is evidence of sexually dimorphic effects. Past neurobiological and genetic studies suggest that COMT, and SLC6A4 variants may have a greater influence on males and that SLC6A2, and MAOA variants may have a greater influence on females. Our results indicate that genetic associations are stronger when stratified by sex and in the same direction as the previous neurobiological studies indicate: associations were stronger in males for COMT, SLC6A4 and stronger in females for SLC6A2, MAOA. Moreover, we found a statistically significant gender effect in the case of COMT (P = 0.007) when we pooled our work with a prior study. In conclusion, we have found some evidence suggesting that the genetic association for these genes with ADHD may be influenced by the sex of the affected individual. Although our results are not fully validated yet, they should motivate further investigation of gender effects in ADHD genetic association studies.

Does parental expressed emotion moderate genetic effects in ADHD? An exploration using a genome wide association scan.

Abstract: Studies of gene × environment (G × E) interaction in ADHD have previously focused on known risk genes for ADHD and environmentally mediated biological risk. Here we use G × E analysis in the context of a genome-wide association scan to identify novel genes whose effects on ADHD symptoms and comorbid conduct disorder are moderated by high maternal expressed emotion (EE). SNPs (600,000) were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. ADHD symptom severity and comorbid conduct disorder was measured using the Parental Account of Childhood Symptoms interview. Maternal criticism and warmth (i.e., EE) were coded by independent observers on comments made during the interview. No G × E interactions reached genome-wide significance. Nominal effects were found both with and without genetic main effects. For those with genetic main effects 36 uncorrected interaction P-values were <10−5 implicating both novel genes as well as some previously supported candidates. These were found equally often for all of the interactions being investigated. The observed interactions in SLC1A1 and NRG3 SNPs represent reasonable candidate genes for further investigation given their previous association with several psychiatric illnesses. We find evidence for the role of EE in moderating the effects of genes on ADHD severity and comorbid conduct disorder, implicating both novel and established candidates. These findings need replicating in larger independent samples.

Assessing the validity of the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form in adults with ADHD.

Abstract: Objective: The authors assessed the psychometric properties of the Quality of Life Enjoyment and Satisfaction Questionnaire—Short Form (Q-LES-QSF) in adults with ADHD. Method: One hundred fifty ADHD and 134 non-ADHD adults from a case-control study and 173 adults randomized to placebo or methylphenidate were assessed with the Q-LES-QSF and the Social Adjustment Scale (SAS). Response to change was estimated by comparing change in Q-LES-QSF scores in responders and nonresponders in our randomized clinical trial. Results: Internal consistency of the Q-LES-QSF items was .88, and the correlation between the Q-LES-QSF total score and the SAS total T score was .72 in adults with ADHD. ADHD cases had statistically significantly poorer scores on the Q-LES-QSF than controls (76.5 ± 10.9 vs. 59.2 ± 17.3, p < .001), whereas ADHD responders showed Q-LES-QSF improvement compared to nonresponders (76.1 ± 12.0 versus 67.9 ± 14.5, p < .001). Conclusion: These results support the validity of the Q-LES-QSF as a measure of q...

Gender differences in 2 clinical trials of adults with attention-deficit/hyperactivity disorder: a retrospective data analysis.

Abstract: Introduction Studies show that, in childhood attention-deficit/hyperactivity disorder (ADHD), boys have the combined type with externalizing behaviors more frequently, and girls have the inattentive type with increased internalizing disorders more frequently. Method This study explored gender differences in adults with ADHD in 2 large, placebo-controlled, multicenter studies conducted from 2000 to 2001. Information collected included 2 measures of ADHD, multiple psychological measures, general physical symptoms, and treatment response. Results Thirty-four percent of the subjects were female. Women were rated as more impaired on every measure of ADHD symptoms including total Conners' Adult ADHD Rating Scale-Investigator Format (CAARS-INV), total Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS), and most subscales of both measures. More women (75%) had combined type compared with men (62%). Women showed a more complex presentation, with higher scores on the Hamilton Rating Scale for Anxiety (HAM-A) and the Hamilton Rating Scale for Depression, 17-item version (HAM-D(17)), more sleep problems, and more past DSM-IV Axis I diagnoses. Both sexes displayed substantial impairment on 3 Psychological General Well-Being Schedule factors: tension-anxiety, life satisfaction, and vitality-drive. Women experienced significantly (p = .003) greater rates of emotional dysregulation (37%) versus men (29%) as defined by a cluster of symptoms on the WRAADDS. The emotional dysregulation factor is derived by combining 3 symptoms--temper control, mood lability, and emotional overreactivity--from the Utah Criteria for ADHD in adults. These symptoms are considered associated symptoms in the DSM-IV description of ADHD. Women also experienced greater improvement (p = .011) on this symptom factor. Conclusion In contrast to the results from childhood studies, women were more impaired than men on ADHD scales in our study. The higher level of emotional symptoms and more complicated presentation in women may obscure the diagnosis of ADHD. Thus, the assessments of adults with ADHD should include an exploration of the emotional dimensions of the illness.

Towards further understanding of the co-morbidity between attention deficit hyperactivity disorder and bipolar disorder: a MRI study of brain volumes.

Abstract: Background. Although attention deficit hyperactivity disorder (ADHD) and bipolar disorder (BPD) co-occur frequently and represent a particularly morbid clinical form of both disorders, neuroimaging research addressing this co-morbidity is scarce. Our aim was to evaluate the morphometric magnetic resonance imaging (MRI) underpinnings of the co-morbidity of ADHD with BPD, testing the hypothesis that subjects with this co-morbidity would have neuroanatomical correlates of both disorders. Method. Morphometric MRI findings were compared between 31 adults with ADHD and BPD and with those of 18 with BPD, 26 with ADHD, and 23 healthy controls. The volumes (cm 3 ) of our regions of interest (ROIs) were estimated as a function of ADHD status, BPD status, age, sex, and omnibus brain volume using linear regression models. Results. When BPD was associated with a significantly smaller orbital prefrontal cortex and larger right thalamus, this pattern was found in co-morbid subjects with ADHD plus BPD. Likewise, when ADHD was associated with significantly less neocortical gray matter, less overall frontal lobe and superior prefrontal cortex volumes, a smaller right anterior cingulate cortex and less cerebellar gray matter, so did co-morbid ADHD plus BPD subjects. Conclusions. Our results support the hypothesis that ADHD and BPD independently contribute to volumetric alterations of selective and distinct brain structures. In the co-morbid state of ADHD plus BPD, the profile of brain volumetric abnormalities consists of structures that are altered in both disorders individually. Attention to co-morbidity is necessary to help clarify the heterogeneous neuroanatomy of both BPD and ADHD.

Neuropsychological Endophenotype Approach to Genome-wide Linkage Analysis Identifies Susceptibility Loci for ADHD on 2q21.1 and 13q12.11

Abstract: ADHD linkage findings have not all been consistently replicated, suggesting that other approaches to linkage analysis in ADHD might be necessary, such as the use of (quantitative) endophenotypes (heritable traits associated with an increased risk for ADHD). Genome-wide linkage analyses were performed in the Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study comprising 238 DSM-IV combined-type ADHD probands and their 112 affected and 195 nonaffected siblings. Eight candidate neuropsychological ADHD endophenotypes with heritabilities > 0.2 were used as quantitative traits. In addition, an overall component score of neuropsychological functioning was used. A total of 5407 autosomal single-nucleotide polymorphisms (SNPs) were used to run multipoint regression-based linkage analyses. Two significant genome-wide linkage signals were found, one for Motor Timing on chromosome 2q21.1 (LOD score: 3.944) and one for Digit Span on 13q12.11 (LOD score: 3.959). Ten suggestive linkage signals were found (LOD scores ≥ 2) on chromosomes 2p, 2q, 3p, 4q, 8q, 12p, 12q, 14q, and 17q. The suggestive linkage signal for the component score that was found at 2q14.3 (LOD score: 2.878) overlapped with the region significantly linked to Motor Timing. Endophenotype approaches may increase power to detect susceptibility loci in ADHD and possibly in other complex disorders.

Co-transmission of conduct problems with attention-deficit= hyperactivity disorder: familial evidence for a distinct disorder

Abstract: Common disorders of childhood and adolescence are attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD). For one to two cases in three diagnosed with ADHD the disorders may be comorbid. However, whether comorbid conduct problems (CP) represents a separate disorder or a severe form of ADHD remains controversial. We investigated familial recurrence patterns of the pure or comorbid condition in families with at least two children and one definite case of DSM-IV ADHDct (combined-type) as part of the International Multicentre ADHD Genetics Study (IMAGE). Using case diagnoses (PACS, parental account) and symptom ratings (Parent/Teacher Strengths and Difficulties [SDQ], and Conners Questionnaires [CPTRS]) we studied 1009 cases (241 with ADHDonly and 768 with ADHD + CP), and their 1591 siblings. CP was defined as ≥4 on the SDQ conduct-subscale, and T ≥ 65, on Conners’ oppositional-score. Multinomial logistic regression was used to ascertain recurrence risks of the pure and comorbid conditions in the siblings as predicted by the status of the cases. There was a higher relative risk to develop ADHD + CP for siblings of cases with ADHD + CP (RRR = 4.9; 95%CI: 2.59–9.41); p < 0.001) than with ADHDonly. Rates of ADHDonly in siblings of cases with ADHD + CP were lower but significant (RRR = 2.9; 95%CI: 1.6–5.3, p < 0.001). Children with ADHD + CP scored higher on the Conners ADHDct symptom-scales than those with ADHDonly. Our finding that ADHD + CP can represent a familial distinct subtype possibly with a distinct genetic etiology is consistent with a high risk for cosegregation. Further, ADHD + CP can be a more severe disorder than ADHDonly with symptoms stable from childhood through adolescence. The findings provide partial support for the ICD-10 distinction between hyperkinetic disorder (F90.0) and hyperkinetic conduct disorder (F90.1).

A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16.

Abstract: As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, approximately 95 cM) and Dutch (LOD>1, approximately 100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.