Ann Abramowitz

Association and Linkage of the Dopamine Transporter Gene and Attention-Deficit Hyperactivity Disorder in Children: Heterogeneity owing to Diagnostic Subtype and Severity

Attention-deficit hyperactivity disorder (ADHD) affects approximately 3%-5% of children in the United States. In the current psychiatric nomenclature, ADHD comprises three subtypes: inattentive, hyperactive-impulsive, and combined. In this study, we used four analytic strategies to examine the association and linkage of the dopamine transporter gene (DAT1) and ADHD. Our sample included 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD, as well as their parents and siblings. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Siblings discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibling with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1 and that this relation was especially strong with the combined but not the inattentive subtype. The relation of DAT1 to ADHD increased monotonically, from low to medium to high levels of symptom severity. Our results replicate and extend previous findings of the association between the DAT1 gene and childhood ADHD. This represents one of the first replicated relations of a candidate gene and a psychiatric disorder in children.

Parenting and family stress treatment outcomes in Attention Deficit Hyperactivity Disorder (ADHD): An empirical analysis in the MTA study

Parenting and family stress treatment outcomes in the MTA study were examined. Male and female (579), 7–9-year-old children with combined type Attention Deficit Hyperactivity Disorder (ADHD), were recruited at six sites around the United States and Canada, and randomly assigned to one of four groups: intensive, multi-faceted behavior therapy program alone (Beh); carefully titrated and monitored medication management strategy alone (MedMgt); a well-integrated combination of the two (Comb); or a community comparison group (CC). Treatment occurred over 14 months, and assessments were taken at baseline, 3, 9, and 14 months. Parenting behavior and family stress were assessed using parent-report and child-report inventories. Results showed that Beh alone, MedMgt alone, and Comb produced significantly greater decreases in a parent-rated measure of negative parenting, Negative/Ineffective Discipline, than did standard community treatment. The three MTA treatments did not differ significantly from each other on this domain. No differences were noted among the four groups on positive parenting or on family stress variables. Results are discussed in terms of the theoretical and empirically documented importance of negative parenting in the symptoms, comorbidities and long-term outcomes of ADHD.

Psychosocial treatment strategies in the MTA study: rationale, methods, and critical issues in design and implementation.

The Collaborative Multimodal Treatment Study of Children with Attention Deficit Hyperactivity Disorder (ADHD), the MTA, is the first multisite, cooperative agreement treatment study of children, and the largest psychiatric/psychological treatment trial ever conducted by the National Institute of Mental Health. It examines the effectiveness of Medication vs. Psychosocial treatment vs. their combination for treatment of ADHD and compares these experimental arms to each other and to routine community care. In a parallel group design, 579 (male and female) ADHD children, aged 7–9 years, 11 months, were randomly assigned to one of the four experimental arms, and then received 14 months of prescribed treatment (or community care) with periodic reassessments. After delineating the theoretical and empirical rationales for Psychosocial treatment of ADHD, we describe the MTAs Psychosocial Treatment strategy applied to all children in two of the four experimental arms (Psychosocial treatment alone; Combined treatment). Psychosocial treatment consisted of three major components: a Parent Training component, a two-part School Intervention component, and a child treatment component anchored in an intensive Summer Treatment Program. Components were selected based on evidence of treatment efficacy and because they address comprehensive symptom targets, settings, comorbidities, and functional domains. We delineate key conceptual and logistical issues faced by clinical researchers in design and implementation of Psychosocial research with examples of how these issues were addressed in the MTA study.

THE RELATION OF THE DOPAMINE TRANSPORTER GENE (DAT1) TO SYMPTOMS OF INTERNALIZING DISORDERS IN CHILDREN

The relation of the dopamine transporter gene (DAT1) to symptoms of internalizing disorders, Tourettes disorder, and obsessive-compulsive disorder was examined using both within- and between-family tests of association. The sample consisted of clinic-referred children and their siblings and controls and their siblings. Between-family association was examined via the association of DAT1 genotypes with disorder symptoms in the population. Symptoms of all eight disorders increased with a greater number of 10-repeat DAT1 alleles. Using a quantitative transmission disequilibrium test (QTDT), linkage and within-family association was indicated by increased symptoms in children who received 10 repeat alleles from heterozygous parents relative to children who received 9 repeat alleles. Four disorders were associated with DAT1 using the QTDT: generalized anxiety, social phobia, obsessive-compulsive, and Tourettes. The effects of comorbidity were investigated by repeating the same between- and within-family analyses on residual scores, with any effects of attention deficit hyperactivity disorder symptoms removed. Although the residuals were associated less strongly with DAT1 than were the original scores, three disorders continued to show association both between and within families: generalized anxiety, Tourettes, and social phobia.

The Prevalence of ADHD: Its Diagnosis and Treatment in Four School Districts Across Two States

Objective: To describe the epidemiology of ADHD in communities using a DSM-IVTR case definition. Method: This community-based study used multiple informants to develop and apply a DSM -IVTR-based case definition of ADHD to screening and diagnostic interview data collected for children 5-13 years of age. Teachers screened 10,427 children (66.4%) in four school districts across two states (SC and OK). ADHD ratings by teachers and parent reports of diagnosis and medication treatment were used to stratify children into high and low risk for ADHD. Parents (n = 855) of high risk and gender frequency-matched low risk children completed structured diagnostic interviews. The case definition was applied to generate community prevalence estimates, weighted to reflect the complex sampling design. Results: ADHD prevalence was 8.7% in SC and 10.6% in OK. The prevalence of ADHD medication use was 10.1% (SC) and 7.4% (OK). Of those medicated, 39.5% (SC) and 28.3% (OK) met the case definition. Comparison children taking medication had higher mean symptom counts than other comparison children. Conclusions: Our ADHD estimates are at the upper end of those from previous studies. The identification of a large proportion of comparison children taking ADHD medication suggests that our estimates may be conservative; these children were not included as cases in the case definition, although some might be effectively treated.

Investigation of Phenotypes Associated with Mood and Anxiety Among Male and Female Fragile X Premutation Carriers

The fragile X disorder spectrum, due to a CGG expansion in FMR1, includes fragile X syndrome (>200 repeats) and the premutation-associated disorders of ovarian insufficiency and tremor/ataxia syndrome (~55–199 repeats). Altered neurobehavioral profiles including variation of phenotypes associated with mood and anxiety may be expected among younger premutation carriers given this spectrum of disorders. However, previous studies have produced conflicting findings, providing the motivation to examine these phenotypes further. We investigated measures of mood and anxiety in 119 males and 446 females age 18–50 ascertained from families with a history of fragile X syndrome and from the general population. Scores were analyzed using a linear model with repeat length as the main predictor, adjusting for potential confounders. Repeat length was not associated with anxiety, but was marginally associated with depression and negative affect in males and negative affect only in females. These results suggest that premutation carriers may be at risk for emotional morbidity; however, phenotypic differences were subtle and of small effect size.

Effects of methylphenidate on attention and nonverbal learning in children with attention-deficit hyperactivity disorder.

OBJECTIVE To examine effects of methylphenidate (MPH) doses on attention and learning tasks requiring varying levels of processing in 23 children with attention-deficit hyperactivity disorder. METHOD Performance on a continuous performance task (CPT) and two difficulty levels of a nonverbal learning task was evaluated on two doses of MPH (0.3 mg/kg and 0.8 mg/kg) and placebo. RESULTS CPT commission errors were significantly reduced with low-dose MPH compared with placebo while omission errors were not medication-sensitive. Performance on nonverbal learning tasks was significantly improved with MPH. On the easy level of the nonverbal learning task performance improved equally well with either dose. On the hard level, performance was significantly better at the high dose compared with placebo; no between-dose differences emerged across learning trials. However, the high dose was superior to low and placebo doses in memory recall trials. CONCLUSIONS Impulsivity may be reduced on an attentional task with a low dose of MPH, and a high dose of MPH may optimize retention and recall of complex nonverbal information.

The relative impact of long and short reprimands on children's off-task behavior in the classroom *

This study compared the relative impact of long and short reprimands on childrens off-task behavior in a classroom. Subjects were seven hyperactive second and third graders. An alternating treatments design was employed. Short reprimands resulted in significantly lower rates of off-task behavior than did long reprimands when frequencies of praise and reprimands were controlled. A trend for a similar effect on academic performance was found. Possible explanations for these findings are discussed.

Reducing off-task behavior in the classroom: A comparison of encouragement and reprimands

Teachers report using both reprimands and encouragement as strategies to reduce offtask behavior in the classroom. Although numerous studies have demonstrated the effectiveness of reprimands, none has examined the efficacy of encouragement. In order to answer this question, two experiments were performed. Subjects were 16 children with academic and/or behavioral problems who were assigned to one of two classes in a remedial summer program. Experiment I employed a reversal design in each class to compare either reprimands or encouragement with No-Feedback conditions. Reprimands proved superior to No Feedback in reducing offtask behavior, but Encouragement did not. In Experiment II Reprimands and Encouragement were directly compared to one another, with each class exposed to both conditions. Reprimands resulted in lower rates of offtask behavior and higher academic productivity than Encouragement.

Is there evidence for neuropsychological and neurobehavioral phenotypes among adults without FXTAS who carry the FMR1 premutation? A review of current literature

Abstract: Carriers of expanded, but unmethylated, premutation alleles of the fragile X mental retardation gene are at risk for a late-onset tremor/ataxia syndrome, mostly affecting men over age 50. However, the general neuropsychological and neurobehavioral impact of carrying a premutation allele in younger adults not affected by the tremor/ataxia syndrome remains unclear. Past studies have utilized varying study designs resulting in inconsistent conclusions. To better understand the current evidence of the influence of the premutation on such traits in adult carriers, we reviewed the literature and identified 16 studies that met conservative inclusion criteria, including molecular measures of the fragile X mental retardation gene CGG triplet repeat length and standard measures of neurobehavioral and neurocognitive phenotypes. A review of these studies is presented to assess the evidence for possible premutation-associated neuropsychological deficits among adult men and women who do not meet diagnostic criteria of the tremor/ataxia syndrome. Results of these studies, and possible reasons for inconsistent conclusions, are discussed. The primary conclusion from this review is the need for further research using a standard protocol in a large multisite project to ensure the necessary sample size.