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Objective: Although research supports the use of appropriately administered stimulant medication to treat children with ADHD, poor adherence and early termination undermine the efficacy of this treatment in real-world settings. Moreover, adherence measures often rely on parent report of medication use, and their validity and reliability are unknown., Method: Drawing on data from 254 participants in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder, we examine the discrepancy between parents' verbal reports of medication adherence and physiological adherence measures determined via methylphenidate saliva assays collected at four time points during the 14-month treatment period. In addition, we examine the impact of physiologically documented medication adherence on parent- and teacher-reported outcomes through 14 months., Results: Overall, nearly one fourth (24.5%) of the saliva samples indicated nonadherence. Among subjects, 63 (24.8%) of the 254 participants were nonadherent on 50% or more of their repeated saliva assays. Only 136 (53.5%) of the subjects were adherent at every time point at which saliva assays were taken, indicating that some degree of nonadherence characterized nearly half of all other NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder-treated children. Findings also indicated that nonadherence produced greater deleterious effects in children in the medication-only condition compared with those receiving both medication and behavioral treatment., Conclusions: Same-day saliva methylphenidate assays suggest that nearly half of the parents are inaccurate informants of their child's ADHD medication adherence and that parents may overestimate actual (physiological) adherence. This finding suggests the need for interventions to improve accuracy of parental report. Clinicians need to focus on adherence enhancement strategies to improve outcomes of children being treated with medication, particularly when benefits are suboptimal.

Objective: Few treatment studies of attention-deficit/hyperactivity disorder (ADHD) extend beyond a few months. This article reports an interim analysis of a 24-month study evaluating the 12-month tolerability and effectiveness of a once-daily OROS formulation of methylphenidate (OROS MPH) in children with ADHD., Method: Children, aged 6-13 years, with ADHD who participated in previous controlled studies and were MPH responders, received once-daily OROS MPH in this multicenter, open-label, nonrandomized study. Effectiveness was evaluated monthly by parents/caregivers and schoolteachers using validated rating scales (e.g., IOWA Conners). Safety and adverse events assessments involved objective (e.g., vital signs, growth) and subjective (sleep quality, tics) reporting., Results: Seventy-one percent of subjects (289/407) completed 12 months' treatment. Effectiveness was maintained throughout 12 months as demonstrated by stable IOWA Conners ratings and sustained improvements in peer interaction and Global Assessment Scale scores. OROS MPH was well tolerated, with adverse events similar to those expected with short-acting stimulant medication. OROS MPH had minimal impact on sleep quality and tics. There were no clinically meaningful changes in blood pressure, pulse, or height. The apparent absence of meaningful changes is tempered by the fact that children were MPH responders and were medicated at baseline, most for extended periods prior to enrollment., Conclusion: In this open-label study, once-daily OROS MPH treatment appears to be well tolerated and effectiveness was maintained for up to 12 months in these children with ADHD.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.