Exploration of ADHD Subtype Definitions and Co-Occurring Psychopathology in a Missouri Population-Based Large Sibship Sample

Background: There is some debate regarding the utility of Attention-Deficit/ Hyperactivity Disorder (ADHD) subtypes as currently defined. Differences in co-occurring psychopathology among subtypes would support the validity of subtype definitions.Objective: To explore how ADHD subtype relates to co-occurring psychopathology in a large population-based sample of children and adolescents (n=5744).Method: Parents completed the Strengths and Weaknesses of ADHD-symptoms and Normal behavior (SWAN) questionnaire, the Child Behavior Checklist (CBCL) and the Social Responsiveness Scale (SRS). Methods including discriminant analysis, principal components analysis, and fractional polynomial regression were used to examine the relationship between ADHD diagnostic subtypes and co-occurring psychopathology.Results: Children with different ADHD subtypes show differences on several CBCL subscales. A combination of CBCL subscales and SRS score had good ability to discriminate ADHD subtypes. Conversely, for the same overall number of ADHD symptoms, individuals who present with both inattentive and hyperactive/impulsive symptoms exhibit higher severity of co-occurring psychopathology on a summary measure derived from principal components analysis of the CBCL subscales and SRS. This includes some subjects who fail to meet the DSM-IV-TR ADHD symptom criterion due to having less than 6 inattentive and less than six hyperactive-impulsive symptoms, yet have ADHD symptom severity similar to those with the inattentive or hyperactive-impulsive subtype.Conclusions: Several convergent lines of analysis provide support for the continued use of ADHD subtypes (or current presentation symptom profiles), as evidenced by differences in co-existing psychopathlogy. We also found that current diagnostic criteria may fail to identify a potentially impaired group of individuals who have low-to-moderate levels of both inattention and hyperactivity/impulsivity. Under the upcoming DSM-5, it will be important for clinicians to consider the option of giving an ADHD “not elsewhere classified” diagnosis to such children

Attention-Deficit/Hyperactivity Disorder, autistic traits, and substance use in Missouri adolescents

Background: Although existing literature demonstrates the association of attention-deficit/hyperactivity disorder (ADHD) with both substance use (SU) and autism spectrum disorder (ASD), few studies have examined rates of SU among adolescents with elevated ASD symptoms, with or without comorbid ADHD. Clinic-based studies suggest a possible protective effect of ASD against SU, but this has not been confirmed in population-based studies.Objective: We examined alcohol, tobacco, and drug use in adolescents with either ADHD, elevated autistic traits, or both as compared with controls.Methods: Subjects (N = 2937) who were 13 to 17 years old from a Missouri population-based large sibship sample were assessed for ADHD, autistic traits, and SU with the use of parent-report questionnaires. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD symptom criterion (Criterion A) was applied to the Strengths and Weaknesses of ADHD-symptoms and Normal-behavior (SWAN) questionnaire item responses to determine ADHD diagnosis. The presence of elevated autistic traits was defined as a raw Social Responsiveness Scale (SRS) score of 62 (95th percentile for this sample) or higher. SU was determined with the use of three items from the Child Behavior Checklist (CBCL). Statistical methods used included logistic and fractional polynomial regression.Results: As compared with controls, adolescents with ADHD were at increased risk for alcohol, tobacco, and drug use whether or not they had elevated autistic traits. Adolescents with elevated autistic traits were at significantly increased risk for drug use other than alcohol and tobacco, even if they did not have ADHD. Among those with raw SRS scores in the range of about 20 (normal) to 80 (consistent with mild to moderate ASD), adolescents with ADHD had higher levels of SU than control individuals with similar levels of autistic traits. However, strong conclusions cannot be drawn regarding individuals with very low or very high SRS scores as a result of sparse data.Conclusions: This study confirms previous research showing an increased risk of SU among adolescents with ADHD. It also provides new information indicating that adolescents with high levels of autistic traits are at elevated risk for alcohol and tobacco use if they have comorbid ADHD; in addition, they may be at high risk for other drug use, even if they do not have comorbid ADHD. Therefore, it should not be assumed that adolescents with mild to moderate ASD have a low risk of SU, especially if ADHD is also present

Attention-Deficit/Hyperactivity Disorder, autistic traits, and substance use in Missouri adolescents

Background: Although existing literature demonstrates the association of attention-deficit/hyperactivity disorder (ADHD) with both substance use (SU) and autism spectrum disorder (ASD), few studies have examined rates of SU among adolescents with elevated ASD symptoms, with or without comorbid ADHD. Clinic-based studies suggest a possible protective effect of ASD against SU, but this has not been confirmed in population-based studies.Objective: We examined alcohol, tobacco, and drug use in adolescents with either ADHD, elevated autistic traits, or both as compared with controls.Methods: Subjects (N = 2937) who were 13 to 17 years old from a Missouri population-based large sibship sample were assessed for ADHD, autistic traits, and SU with the use of parent-report questionnaires. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD symptom criterion (Criterion A) was applied to the Strengths and Weaknesses of ADHD-symptoms and Normal-behavior (SWAN) questionnaire item responses to determine ADHD diagnosis. The presence of elevated autistic traits was defined as a raw Social Responsiveness Scale (SRS) score of 62 (95th percentile for this sample) or higher. SU was determined with the use of three items from the Child Behavior Checklist (CBCL). Statistical methods used included logistic and fractional polynomial regression.Results: As compared with controls, adolescents with ADHD were at increased risk for alcohol, tobacco, and drug use whether or not they had elevated autistic traits. Adolescents with elevated autistic traits were at significantly increased risk for drug use other than alcohol and tobacco, even if they did not have ADHD. Among those with raw SRS scores in the range of about 20 (normal) to 80 (consistent with mild to moderate ASD), adolescents with ADHD had higher levels of SU than control individuals with similar levels of autistic traits. However, strong conclusions cannot be drawn regarding individuals with very low or very high SRS scores as a result of sparse data.Conclusions: This study confirms previous research showing an increased risk of SU among adolescents with ADHD. It also provides new information indicating that adolescents with high levels of autistic traits are at elevated risk for alcohol and tobacco use if they have comorbid ADHD; in addition, they may be at high risk for other drug use, even if they do not have comorbid ADHD. Therefore, it should not be assumed that adolescents with mild to moderate ASD have a low risk of SU, especially if ADHD is also present

The effect of smoking during pregnancy on severity and directionality of externalizing and internalizing symptoms: A genetically informed approach

The objective was to examine the association between maternal smoking during pregnancy (SDP) and (I) severity and (II) directionality of externalizing and internalizing symptoms in a sample of sibling pairs while rigorously controlling for familial confounds. The Missouri Mothers and Their Children Study is a family study (N = 173 families) with sibling pairs (aged 7 to 16 years) who are discordant for exposure to SDP. This sibling comparison study is designed to disentangle the effects of SDP from familial confounds. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount). Principal component analysis of externalizing and internalizing behavior, assessed with the Child Behavior Checklist and Teacher Report Form, was used to create symptom severity and directionality scores. The variance in severity and directionality scores was primarily a function of differences between siblings (71% and 85%, respectively) rather than differences across families (29% and 15%, respectively). The severity score that combines externalizing and internalizing symptom severity was not associated with SDP. However, a significant within-family effect of SDP on symptom directionality (b = 0.07

Missouri mothers and their children: A family study of the effects of genetics and the prenatal environment

The Missouri Mothers and Their Children Study was specifically designed to critically investigate prenatal environmental influences on child attention problems and associated learning and cognitive deficits. The project began as a pilot study in 2004 and was formally launched in 2008. Participants in the study were initially identified via the Department of Vital Statistics birth record database. Interview and lab-based data were obtained from (1) mothers of Missouri-born children (born 1998–2005), who smoked during one pregnancy but not during another pregnancy, (2) biological fathers when available, and (3) the children [i.e., full sibling pairs discordant for exposure to maternal smoking during pregnancy (SDP)]. This within-mother, between-pregnancy contrast provides the best possible methodological control for many stable maternal and familial confounding factors (e.g., heritable and socio-demographic characteristics of the mother that predict increased probability of SDP). It also controls for differences between mothers who do and do not smoke during pregnancy, and their partners, that might otherwise artifactually create, or alternatively mask, associations between SDP and child outcomes. Such a design will therefore provide opportunities to determine less biased effect sizes while also allowing us to investigate (on a preliminary basis) the possible contribution of paternal or other second-hand smoke exposure during the pre-, peri- and postnatal periods to offspring outcome. This protocol has developed a cohort that can be followed longitudinally through periods typically associated with increased externalizing symptoms and substance use initiation

Association of SNPs in EGR3 and ARC with schizophrenia supports a biological pathway for schizophrenia risk

We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 x 10(-7); OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes

The variance shared across forms of childhood trauma is strongly associated with liability for psychiatric and substance use disorders

Introduction: Forms of childhood trauma tend to co-occur and are associated with increased risk for psychiatric and substance use disorders. Commonly used binary measures of trauma exposure have substantial limitations. Methods: We performed multigroup confirmatory factor analysis (CFA), separately by sex, using data from the Childhood Trauma (CT) Study's sample of twins and siblings (N = 2594) to derive three first-order factors (childhood physical abuse, childhood sexual abuse, and parental partner abuse) and, as hypothesized, one higher order, childhood trauma factor (CTF) representing a measure of their common variance. Results: CFA produced a good-fitting model in the CT Study; we replicated the model in the Comorbidity and Trauma (CAT) Study's sample (N = 1981) of opioid-dependent cases and controls. In both samples, first-order factors are moderately correlated (indicating they measure largely unique, but related constructs) and their loadings on the CTF suggest it provides a reasonable measure of their common variance. We examined the association of CTF score with risk for psychiatric and substance use disorders in these samples and the OZ-ALC GWAS sample (N = 1538) in which CT Study factor loadings were applied. We found that CTF scores are strongly associated with liability for psychiatric and substance use disorders in all three samples; estimates of risk are extremely consistent across samples. Conclusions: The CTF is a continuous, robust measure that captures the common variance across forms of childhood trauma and provides a means to estimate shared liability while avoiding multicollinearity. Confirmatory factor analysis was used to derive a higher order, childhood trauma factor representing a measure of the common variance across three forms of trauma: childhood physical abuse, childhood sexual abuse, and parental partner abuse. We replicated the model in a second sample. We then examined the association of childhood trauma score with risk for psychiatric and substance use disorders in these samples and a third sample in which the primary sample's factor loadings were applied finding factor scores to be strongly and consistently associated with liability for psychiatric and substance use disorders in all three samples