White matter abnormalities associated with ADHD outcomes in adulthood.

It remains unclear if previously reported structural abnormalities in children with ADHD are present in adulthood regardless of clinical outcome. In this study, we examined the extent to which focal-rather than diffuse-abnormalities in fiber collinearity of 18 major white matter tracts could distinguish 126 adults with rigorously diagnosed childhood ADHD (ADHD; mean age [SD] = 34.3 [3.6] years; F/M = 12/114) from 58 adults without ADHD histories (non-ADHD; mean age [SD] = 33.9 [4.1] years; F/M = 5/53) and if any of these abnormalities were greater for those with persisting ADHD symptomatology. To this end, a tract profile approach was used. After accounting for age, sex, handedness, and comorbidities, a MANCOVA revealed a main effect of group (ADHD < non-ADHD; F[18,155] = 2.1; p = 0.007) on fractional anisotropy (FA, a measure of fiber collinearity and/or integrity), in focal portions of white matter tracts involved in visuospatial processing and memory (i.e., anterior portion of the left inferior longitudinal fasciculus, and middle portion of the left and right cingulum angular bundle). Only abnormalities in the anterior portion of the left inferior longitudinal fasciculus distinguished probands with persisting versus desisting ADHD symptomatology, suggesting that abnormalities in the cingulum angular bundle might reflect "scarring" effects of childhood ADHD. To our knowledge, this is the first study using a tract profile approach to identify focal or widespread structural abnormalities in adults with ADHD rigorously diagnosed in childhood.

Association of maternal dopamine transporter genotype with negative parenting: evidence for gene x environment interaction with child disruptive behavior.

Although maternal parenting is central to child development, little is known about the interplay between molecular genetic and environmental factors that influence parenting. We tested the association of the 40-bp variable number tandem repeat polymorphism of the dopamine transporter (DAT1; SLC6A3) gene with three dimensions of observed maternal parenting behavior (positive parenting, negative parenting and total maternal commands). A significant nonadditive association was found between maternal DAT1 genotype and both negative parenting and total commands during a structured mother-child interaction task, even after controlling demographic factors, maternal psychopathology and disruptive child behavior during the task. Furthermore, the association between maternal DAT1 genotype and negative parenting was significantly stronger among mothers whose children were highly disruptive during the mother-child interaction task, suggesting a gene-environment interaction.

Methylphenidate and children with attention deficit disorder. Dose effects on classroom academic and social behavior.

The short-term, dose-response effects of methylphenidate hydrochloride were evaluated on academic and social classroom measures in 29 children with attention deficit disorder. In a double-blind, cross-over design with order randomized, children received a placebo for two weeks and three doses of methylphenidate hydrochloride (0.15 mg/kg, 0.3 mg/kg, and 0.6 mg/kg) for one week each. Dependent measures included the output and accuracy of performance in grade-appropriate reading comprehension workbooks and arithmetic problems, spelling word acquisition, and observations of disruptive and on-task behavior. Beneficial drug effects and linear dose-response curves on all dependent measures were found. The results suggest that beneficial methylphenidate effects on classroom behavior may be accompanied by enhanced academic achievement in some hyperactive children.

National Institute of Mental Health Collaborative Multimodal Treatment Study of Children with ADHD (the MTA). Design challenges and choices.

The Collaborative Multimodal Treatment Study of Children with Attention Deficit Hyperactivity Disorder (ADHD), the MTA, is the first child multisite cooperative agreement treatment study of children conducted by the National Institute of Mental Health, Rockville, Md. It examines the long-term effectiveness of medication vs behavioral treatment vs both for treatment of ADHD and compares state-of-the-art treatment with routine community care. In a parallel-groups design, 576 children (age, 7-9 years) with ADHD (96 at each site) are thoroughly assessed and randomized to 4 conditions: (1) medication alone, (2) psychosocial treatment alone, (3) the combination of both, (4) or community comparison. The first 3 groups are treated for 14 months and all are reassessed periodically for 24 months. Designers met the following challenges: framing clinically relevant primary questions; defining the target population; choice, intensity, and integration and combination of treatments for fair comparisons; combining scientific controls and standardization with clinical flexibility; and implementing a controlled clinical trial in a nonclinical setting (school) controlled by others. Innovative solutions included extensive decision algorithms and manualized adaptations of treatments to specific needs.

Sustained release and standard methylphenidate effects on cognitive and social behavior in children with attention deficit disorder.

Two studies were conducted to investigate the relative effects of sustained release methylphenidate (Ritalin [SR-20]) and standard methylphenidate (Ritalin, 10 mg, administered twice daily). In the first study, 13 boys with attention deficit disorder participating in a summer treatment program went through a double-blind, within-subject trial of each form of methylphenidate and placebo. Measures of social and cognitive behavior were gathered in classroom and play settings. Although group analyses of the data showed that both drugs were effective and there were few differences between them, standard methylphenidate was superior to SR-20 on several important measures of disruptive behavior. Furthermore, analyses of individual responsivity showed clearly that most boys responded more positively to standard methylphenidate than to SR-20. The second study involved a partially overlapping group of nine boys with attention deficit disorder participating in the same summer treatment program. Also double-blind, within-subject, and placebo controlled, this study tracked the time courses of the two forms of methylphenidate. Both were shown to have similar time courses on the Abbreviated Conners Rating Scale and other measures, but SR-20 had a slower onset than did the standard drug form on a continuous performance task. Effects of SR-20 were still evident eight hours after ingestion.

Relative efficacy of long-acting stimulants on children with attention deficit-hyperactivity disorder: a comparison of standard methylphenidate, sustained-release methylphenidate, sustained-release dextroamphetamine, and pemoline.

Twenty-two children with attention deficit-hyperactivity disorder underwent a double-blind, placebo-controlled, crossover evaluation of the efficacy of standard methylphenidate twice a day and comparable doses every morning of a sustained-release preparation of methylphenidate (SR-20 Ritalin), a sustained-release form of dextroamphetamine (Dexedrine Spansule), and pemoline. The children were participating in a summer treatment program in which they engaged in recreational and classroom activities. Dependent measures include evaluations of social behavior during group recreational activities, classroom performance, and performance on a continuous performance task. Results revealed generally equivalent and beneficial effects of all four medications. Dexedrine Spansule and pemoline tended to produce the most consistent effects and were recommended for 10 of the 15 children who were responders to medication. The continuous performance task results showed that all four medications had an effect within 2 hours of ingestion, and the effects lasted for 9 hours. The implications of these results for the use of long-acting stimulant medication in children with attention deficit-hyperactivity disorder are discussed.

Teacher ratings of DSM-III-R symptoms for the disruptive behavior disorders.

Ratings were collected on a rating scale comprised of the DSM-III-R diagnostic criteria for disruptive behavior disorders. Teacher ratings were obtained for 931 boys in regular classrooms in grades K through 8 from around North America. Means and standard deviations for attention-deficit hyperactivity disorder (ADHD), oppositional-defiant disorder (ODD), and conduct disorder (CD) scales are reported by age. Frequencies of DSM-III-R symptoms are reported by age, and suggested diagnostic cutoffs are discussed. A factor analysis revealed three factors: one reflecting ODD and several CD symptoms, one on which ADHD symptoms of inattention loaded, and one comprised of ADHD impulsivity/overactivity symptoms. Conditional probability analyses revealed that several hallmark symptoms of ADHD had very poor predictive power, whereas combinations of symptoms from the two ADHD factors had good predictive power. Combinations of ODD symptoms also had very high predictive power. The limited utility of teacher ratings in assessing symptoms of conduct disorder in this age range is discussed.

Pemoline effects on children with ADHD: a time-response by dose-response analysis on classroom measures.

OBJECTIVE: To evaluate the dose-response by time-response characteristics of pemoline (Cylert) on dependent measures of behavior and academic performance in a laboratory classroom. METHOD: After a 2-week baseline, a double-blind crossover design was used to compare placebo, 18.75 mg, 37.5 mg, 75 mg, and 112.5 mg of pemoline, q.a.m., with each dose administered for 1 week. Medication was given at 9:00 A.M., and performance was measured beginning immediately and beginning 2, 4, and 6 hours after ingestion. The dependent measures included number of math problems completed correctly, teacher-recorded rates of on-task behavior and noncompliance, and teacher ratings on an Abbreviated Conners Teacher Rating Scale. RESULTS: There were linear effects of medication, with pemoline doses greater than 18.75 mg having an effect beginning 2 hours after ingestion and lasting through the seventh hour after ingestion. CONCLUSIONS: Results are contrasted with widespread misbeliefs regarding pemoline's time course and efficacy.

Equivalent effects of stimulant treatment for attention-deficit hyperactivity disorder during childhood and adolescence.

OBJECTIVE: To compare the therapeutic effect size of methylphenidate on attention-deficit hyperactivity disorder (ADHD) during childhood versus adolescence. METHOD: A retrospective follow-up study of 16 individuals with diagnosed ADHD who completed double-blind, placebo-controlled, crossover studies of methylphenidate 0.3 mg/kg during two separate summer treatment programs. The programs were completed when the subjects were children (aged 8 to 11 years) and adolescents (aged 12 to 14.5 years). Dependent variables include objective measures of academic performance and social behavior and ratings completed by counselors and teachers. RESULTS: Effect sizes ranged from very large to small, with most effects in the moderate to large range. Across the 12 dependent variables, t tests found that only 3 showed statistically significant changes in effect size from childhood to adolescence. Putative changes in effect sizes can be dismissed for methodological reasons. CONCLUSION: Stimulant medication is equally effective with children and adolescents with ADHD if they are engaged in similar activities. Treatment providers should rigorously examine environmental causes to problems before prescribing higher doses of stimulants to adolescents with ADHD who exhibit a worsening in functioning.

Attention-deficit hyperactivity disorder and problems in peer relations: predictions from childhood to adolescence.

OBJECTIVE: To determine whether childhood attention-deficit hyperactivity disorder (ADHD) and persistence of the disorder are associated with later difficulty in adolescent peer relations. METHOD: One hundred eleven children with ADHD were interviewed as adolescents and compared with 100 adolescents without an ADHD history (aged 13-18 years). The multi-informant assessment strategy included parents, teachers, and adolescents. RESULTS: Parents of probands reported fewer close friendships and greater peer rejection compared with the non-ADHD group. Probands reported that their friends were less involved in conventional activities compared with the non-ADHD group. Childhood aggression predicted less self-perceived social competence for probands. The long-term effects of ADHD on social functioning were more pronounced for probands with persistent ADHD or conduct disorder in adolescence. CONCLUSIONS: Impairments in peer relations for ADHD youths, known to be common in childhood, also exist in adolescence. Given the developmental significance of peer relations, further research into the causes and treatment of poor social functioning in youths with ADHD is recommended.

Comparative effects of methylphenidate on ADD girls and ADD boys.

The effects of 0.3 mg/kg methylphenidate were compared for 12 ADD boys and 12 ADD girls participating in a summer treatment program for children with behavior and/or learning problems. Previous investigations have suggested that ADD girls may differ from ADD boys in some important respects. No information exists regarding whether the effects of the most common treatment for these children, methylphenidate, has comparable effects on boys and girls. The boys and girls were matched for age and IQ. The results revealed equivalent and beneficial effects of methylphenidate for both boys and girls. Methylphenidate therefore would appear to be as useful a treatment for ADD girls as for ADD boys.

NIMH collaborative multisite multimodal treatment study of children with ADHD: I. Background and rationale.

OBJECTIVE: The National Institute of Mental Health's recently initiated 5-year, multisite, multimodal treatment study of children with attention-deficit hyperactivity disorder (MTA) is the first major clinical trial in its history focused on a childhood mental disorder. This article reviews the major scientific and clinical bases for initiating the MTA. METHOD: A selective review of the literature is presented in the service of describing the estimated prevalence of ADHD among children and adolescents, its core clinical features, evidence concerning psychopharmacological and psychosocial treatment effects, and related research issues and trends leading to the development of the MTA. RESULTS: Despite decades of treatment research and clinical practice, there is an insufficient basis for answering the following manifold question: under what circumstances and with what child characteristics (comorbid conditions, gender, family history, home environment, age, nutritional/metabolic status, etc.) do which treatments or combinations of treatment (stimulants, behavior therapy, parent training, school-based intervention) have what impacts (improvement, stasis, deterioration) on what domains of child functioning (cognitive, academic, behavioral, neurophysiological, neuropsychological, peer relations, family relations), for how long (short versus long term), to what extent (effect sizes, normal versus pathological range), and why (processes underlying change)? CONCLUSIONS: The important scientific, clinical, and public health issues nested within this manifold question provide both the impetus and scaffolding for the MTA.

Validity of DSM-IV attention-deficit/hyperactivity disorder for younger children.

OBJECTIVE: Little is known about the validity of the diagnosis of attention-deficit/hyperactivity disorder (ADHD) in young children. Moreover, the results of the DSM-IV field trials raised concerns that inclusion of the new predominantly hyperactive-impulsive type of ADHD in DSM-IV might increase the likelihood of the diagnosis being given to active but unimpaired preschool and primary school children. METHOD: The validity of DSM-IV criteria for each subtype of ADHD was evaluated in 126 children, aged 4 through 6 years, and 126 matched comparison children. Probands and controls were classified by using structured diagnostic interviews of the parent and a DSM-IV checklist completed by the teacher. RESULTS: Children who met DSM-IV criteria for each subtype of ADHD according to parent and teacher reports differed consistently from controls on a wide range of measures of social and academic impairment, even when other types of psychopathology and other potential confounds were controlled. CONCLUSIONS: When diagnosed by means of a structured diagnostic protocol, all three DSM-IV subtypes of ADHD are valid for 4- through 6-year-old children in the sense of identifying children with lower mean scores on measures of adaptive functioning that are independently associated with ADHD.

Medication treatment strategies in the MTA Study: relevance to clinicians and researchers.

OBJECTIVE: Clinicians have difficulty applying drug research findings to clinical practice, because research protocols use methods different from those used in daily office practice settings. METHOD: To design a medication protocol for a multisite clinical trial involving 576 children with attention-deficit hyperactivity disorder (ADHD) while maintaining relevance to clinical practice, investigators from the NIMH Collaborative Multisite Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA study) developed novel medication strategies. These were designed to work either in a monomodal or multimodal format and to ensure standard approaches are used across diverse sites. Each child randomized to medication (projected N = 288) is individually titrated to his or her "best" methylphenidate dose and has individual ADHD symptoms monitored. Decision rules were developed to guide "best dose" selection, dose changes, medication changes, the management of side effects, and integration with psychosocial treatments. CONCLUSIONS: The MTA study uses a controlled method to standardize the identification of each child's "best" methylphenidate dose in a national, multisite cooperative treatment program. Although the titration protocol is complex, the study's individual dosing approach and algorithms for openly managing ADHD children's medication over time will be of interest to clinicians in office practice.

Symptom profiles in children with ADHD: effects of comorbidity and gender.

OBJECTIVE: To examine ratings and objective measures of attention-deficit/hyperactivity disorder (ADHD) symptoms to assess whether ADHD children with and without comorbid conditions have equally high levels of core symptoms and whether symptom profiles differ as a function of comorbidity and gender. METHOD: Four hundred ninety-eight children from the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were divided into comorbid groups based on the parent Diagnostic Interview Schedule for Children and assessed via parents' and teachers' Swanson, Nolan, and Pelham (SNAP) ratings and a continuous performance test (CPT). Comorbidity and gender effects were examined using analyses of covariance controlled for age and site. RESULTS: CPT inattention, impulsivity, and dyscontrol errors were high in all ADHD groups. Children with ADHD + oppositional defiant or conduct disorder were rated as more impulsive than inattentive, while children with ADHD + anxiety disorders (ANX) were relatively more inattentive than impulsive. Girls were less impaired than boys on most ratings and several CPT indices, particularly impulsivity, and girls with ADHD + ANX made fewer CPT impulsivity errors than girls with ADHD-only. CONCLUSIONS: Children with ADHD have high levels of core symptoms as measured by rating scales and CPT, irrespective of comorbidity. However, there are important differences in symptomatology as a function of comorbidity and gender.

ADHD comorbidity findings from the MTA study: comparing comorbid subgroups.

OBJECTIVES: Previous research has been inconclusive whether attention-deficit/hyperactivity disorder (ADHD), when comorbid with disruptive disorders (oppositional defiant disorder [ODD] or conduct disorder [CD]), with the internalizing disorders (anxiety and/or depression), or with both, should constitute separate clinical entities. Determination of the clinical significance of potential ADHD + internalizing disorder or ADHD + ODD/CD syndromes could yield better diagnostic decision-making, treatment planning, and treatment outcomes. METHOD: Drawing upon cross-sectional and longitudinal information from 579 children (aged 7-9.9 years) with ADHD participating in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), investigators applied validational criteria to compare ADHD subjects with and without comorbid internalizing disorders and ODD/CD. RESULTS: Substantial evidence of main effects of internalizing and externalizing comorbid disorders was found. Moderate evidence of interactions of parent-reported anxiety and ODD/CD status were noted on response to treatment, indicating that children with ADHD and anxiety disorders (but no ODD/CD) were likely to respond equally well to the MTA behavioral and medication treatments. Children with ADHD-only or ADHD with ODD/CD (but without anxiety disorders) responded best to MTA medication treatments (with or without behavioral treatments), while children with multiple comorbid disorders (anxiety and ODD/CD) responded optimally to combined (medication and behavioral) treatments. CONCLUSIONS: Findings indicate that three clinical profiles, ADHD co-occurring with internalizing disorders (principally parent-reported anxiety disorders) absent any concurrent disruptive disorder (ADHD + ANX), ADHD co-occurring with ODD/CD but no anxiety (ADHD + ODD/CD), and ADHD with both anxiety and ODD/CD (ADHD + ANX + ODD/CD) may be sufficiently distinct to warrant classification as ADHD subtypes different from "pure" ADHD with neither comorbidity. Future clinical, etiological, and genetics research should explore the merits of these three ADHD classification options.

Multimodal treatment of ADHD in the MTA: an alternative outcome analysis.

OBJECTIVE: To conduct a post hoc investigation of the utility of a single composite measure of treatment outcome for the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) at 14 months postbaseline. BACKGROUND: Examination of multiple measures one at a time in the main MTA intent-to-treat outcome analyses failed to detect a statistically significant advantage of combined treatment (Comb) over medication management (MedMgt). A measure that increases power and precision using a single outcome score may be a useful alternative to multiple outcome measures. METHOD: Factor analysis of baseline scores yielded two "source factors" (parent and teacher) and one "instrument factor" (parent-child interactions). A composite score was created from the average of standardized parent and teacher measures. RESULTS: The composite was internally consistent (alpha = .83), reliable (test-retest over 3 months = 0.86), and correlated 0.61 with clinician global judgments. In an intent-to-treat analysis, Comb was statistically significantly better than all other treatments, with effect sizes ranging from small (0.28) versus MedMgt, to moderately large (0.70) versus a community comparison group. CONCLUSIONS: A composite of ADHD variables may be an important tool in future treatment trials with ADHD and may avoid some of the statistical limitations of multiple measures.

Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment.

OBJECTIVES: To develop a categorical outcome measure related to clinical decisions and to perform secondary analyses to supplement the primary analyses of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA). METHOD: End-of-treatment status was summarized by averaging the parent and teacher ratings of attention-deficit/hyperactivity disorder and oppositional defiant disorder symptoms on the Swanson, Nolan, and Pelham, version IV (SNAP-IV) scale, and low symptom-severity ("Just a Little") on this continuous measure was set as a clinical cutoff to form a categorical outcome measure reflecting successful treatment. Three orthogonal comparisons of the treatment groups (combined treatment [Comb], medication management [MedMgt], behavioral treatment [Beh], and community comparison [CC]) evaluated hypotheses about the MTA medication algorithm ("Comb + MedMgt versus Beh + CC"), multimodality superiority ("Comb versus MedMgt"), and psychosocial substitution ("Beh versus CC"). RESULTS: The summary of SNAP-IV ratings across sources and domains increased the precision of measurement by 30%. The secondary analyses of group differences in success rates (Comb = 68%; MedMgt = 56%; Beh = 34%; CC = 25%) confirmed the large effect of the MTA medication algorithm and a smaller effect of multimodality superiority, which was now statistically significant (p < .05). The psychosocial substitution effect remained negligible and nonsignificant. CONCLUSION: These secondary analyses confirm the primary findings and clarify clinical decisions about the choice between multimodal and unimodal treatment with medication.

Academic task persistence of normally achieving ADHD and control boys: performance, self-evaluations, and attributions.

The authors examined academic task persistence, pretask expectancies, self-evaluations, and attributions of boys with attention-deficit/hyperactivity disorder (ADHD) as compared with control boys. Participants were 83 ADHD boys and 66 control boys, all normally achieving. Prior to the task, performance expectancies were assessed. After a success-failure manipulation with find-a-word puzzles, performance on subsequent trials, self-evaluations, and attributions were evaluated. Compared with controls, ADHD boys solved fewer test puzzles, quit working more often, and found fewer words on a generalization task. Consistent with these behavioral findings, research assistants rated ADHD boys as less effortful and less cooperative than control boys. Although ADHD boys did not differ significantly from controls in their posttask self-evaluations, they did differ significantly from controls in some aspects of their attributions. Attributional data indicated that ADHD boys endorsed luck as a reason for success more strongly and lack of effort as a reason for failure less strongly than controls.

Attention-deficit hyperactivity disordered boys' evaluations of and attributions for task performance on medication versus placebo.

The present study examined the effects of stimulant medication on the self-evaluations of and attributions for task performance of 26 attention-deficit hyperactivity disordered boys. Each boy performed a continuous performance task twice, once while on medication and once while on placebo. Immediately following the completion of the task, the boys were asked a series of questions concerning their self-evaluations of, and attributions for, their performance. Two findings of note were obtained. First, medication, compared with placebo, increased the correspondence between the boys' self-evaluations and their performance. Second, the boys did not use medication as a frequent explanation for their performance, as others have predicted. In fact, the boys picked medication as an explanation for their successes significantly less often than either effort or ability.