NIMH Collaborative Multisite Multimodal Treatment Research Articles

Variation in latent social profiles of adolescent ADHD and related clinical features

Social impairment is a hallmark of Attention-deficit/hyperactivity disorder (ADHD), but the extent of variation in adolescent social strengths and weaknesses is unclear. We compared teacher-reported characteristics of social functioning in adolescents with a history of ADHD (N = 340), and without ADHD (N = 182) from the NIMH Collaborative Multisite Multimodal Treatment Study of Children with ADHD (MTA) at 72-month follow-up (13 – 15.9 years-old). Latent profile analysis of teacher-reported cooperation, assertion and self-control on the Social Skills Rating System (SSRS), was used to identify “social profiles”. Their associations with clinical features were explored. Significant differences in social functioning were identified between adolescents with a history of ADHD, and without ADHD (ES = 0.54 – 0.77). Four distinct social profiles were identified in adolescents with a history of ADHD: unskilled (N = 24, 7%), low average (N = 144, 42%), average (N = 141, 41%), and skilled (N = 31, 9%). Profiles with worse social functioning (low average, unskilled) displayed more symptoms of inattention, hyperactivity/impulsivity, oppositionality, depression, global impairment, and were less liked, more rejected and ignored by peers than average and skilled. Social profile membership was not associated with sex, anxiety symptoms, or remittance / persistence of ADHD. Social functioning in adolescents with a history of ADHD is variable, and associated with worse symptomology, global functioning, and peer relationships, irrespective of persistence or remittance of ADHD. Group level summaries of social difficulties in ADHD may be inadequate given nearly half of adolescents with a history of ADHD presented with average or skilled social profiles.

Attention deficit hyperactivity disorder and intellectual giftedness: a study of symptom frequency and minor physical anomalies.

To evaluate the presence of symptoms of attention deficit and hyperactivity disorder (ADHD) in intellectually gifted adults and children. Two cross-sectional studies were performed in children and adults whose intelligence quotient (IQ) had been previously evaluated using Raven's Progressive Matrices (RPM) test. Seventy-seven adults displaying IQ scores above the 98th percentile were assessed using the Adult Self-Report Scale (ASRS-18) for signs of ADHD and a modified Waldrop scale for minor physical anomalies (MPAs). Thirty-nine children (grades 1-5) exhibiting IQ scores above the 99th percentile, as well as an equally matched control group, were assessed for ADHD by teachers using the Swanson, Nolan and Pelham IV Rating Scale (SNAP-IV) as used in the NIMH Collaborative Multisite Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA-SNAP-IV). In gifted adults, the frequency of ADHD-positive cases was 37.8%, and the total MPA score was significantly associated with ADHD (p < 0.001). In children, the ADHD-positive case frequency was 15.38% in the gifted group and 7.69% in the control group (odds ratio [OR] = 2.18, p = 0.288). The high frequency of ADHD symptoms observed, both in gifted adults and in gifted (and non-gifted) children, further supports the validity of this diagnosis in this population. Furthermore, the significant association between MPAs and ADHD suggests that a neurodevelopmental condition underlies these symptoms.

주의력결핍 과잉행동장애 치료에서 MTA의 주요 교훈

Objectives ： The current review aimed to describe the major findings of the NIMH Collaborative Multisite Multimodal Treatment Study of Children with Attention-Deficit Hyperactivity Disorder (MTA) with regard to the treatment of children with attention-deficit hyperactivity disorder (ADHD). Methods ： We performed a general review of the literature regarding the efficacy of the MTA's proposed treatments. Results ： There is a large and still increasing body of evidence regarding the MTA's treatment outcomes. We present and discuss details of the findings at each follow-up point. Conclusion ： Currently, findings regarding the MTA's treatments suggest children with combined-type ADHD exhibit significant impairment in adolescence, despite their initial symptom improvement. Further studies, using innovative treatment approaches and targeting specific areas of adolescent impairment, are needed in order to enhance ADHD treatment outcomes.

Medication Adherence in the MTA: Saliva Methylphenidate Samples Versus Parent Report and Mediating Effect of Concomitant Behavioral Treatment

ObjectivesAlthough 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. MethodDrawing 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. ResultsOverall, 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. ConclusionsSame-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.

In This Issue/Abstract Thinking: The Costs of Mental Illness

Several articles in this month's issue of the Journal advance what is known about attention-deficit/hyperactivity disorder (ADHD). Articles by Molina et al. ( p. 484 ) and Jensen et al. ( p. 501 ) provide new analyses of the landmark NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA). In the original MTA study, 579 children between 7 and 9.9 years old were randomized to 14 months of either systematic medication management with methylphenidate, multicomponent behavior therapy, combined medication plus behavior therapy, or community care.

The MTA at 8 Years: Prospective Follow-up of Children Treated for Combined-Type ADHD in a Multisite Study

ObjectivesTo determine any long-term effects, 6 and 8 years after childhood enrollment, of the randomly assigned 14-month treatments in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA; N = 436); to test whether attention-deficit/hyperactivity disorder (ADHD) symptom trajectory through 3 years predicts outcome in subsequent years; and to examine functioning level of the MTA adolescents relative to their non-ADHD peers (local normative comparison group; N = 261). MethodMixed-effects regression models with planned contrasts at 6 and 8 years tested a wide range of symptom and impairment variables assessed by parent, teacher, and youth report. ResultsIn nearly every analysis, the originally randomized treatment groups did not differ significantly on repeated measures or newly analyzed variables (e.g., grades earned in school, arrests, psychiatric hospitalizations, other clinically relevant outcomes). Medication use decreased by 62% after the 14-month controlled trial, but adjusting for this did not change the results. ADHD symptom trajectory in the first 3 years predicted 55% of the outcomes. The MTA participants fared worse than the local normative comparison group on 91% of the variables tested. ConclusionsType or intensity of 14 months of treatment for ADHD in childhood (at age 7.0–9.9 years) does not predict functioning 6 to 8 years later. Rather, early ADHD symptom trajectory regardless of treatment type is prognostic. This finding implies that children with behavioral and sociodemographic advantage, with the best response to any treatment, will have the best long-term prognosis. As a group, however, despite initial symptom improvement during treatment that is largely maintained after treatment, children with combined-type ADHD exhibit significant impairment in adolescence. Innovative treatment approaches targeting specific areas of adolescent impairment are needed.

Review of ADHD Pharmacotherapies: Advantages, Disadvantages, and Clinical Pearls

Pharmacotherapy for the treatment of attention-deficit/hyperactivity disorder (ADHD) originally consisted primarily of stimulant medications in immediate-release preparations dosed multiple times per day. Data demonstrating the efficacy of these stimulant medications for the treatment of ADHD and their role in treating children was well established by the 1970s. Multiple formulations of the stimulant medications have subsequently been developed during the past 40 years. Recent studies, including the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder and the Preschool ADHD Treatment Study, have helped to clarify the role of stimulant medications in the treatment of ADHD.

Emergency/Adjunct Services and Attrition Prevention for Randomized Clinical Trials in Children: The MTA Manual-Based Solution

Treatment studies in child and adolescent psychiatry are increasingly characterized by long-term, multisite, randomized clinical trials (RCTs). During the course of these RCTs it is common for clinical exigencies to emerge that require rapid, direct intervention. The challenge is to provide clinically appropriate responses that do not contaminate the delivery, distinctness, and interpretation of the treatments under investigation. In multisite studies, the problem is compounded by the need to minimize cross-site differences in the delivery of adjunct treatments. Such minimization requires fully operationalized and manual-based procedures for clinically mandated intervention. The NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (ADHD)--"the MTA"--is a long-term multisite collaborative study in which children with ADHD were randomly assigned to either medication management, behavioral treatment, the combination, or community-comparison assessment and referral. In designing its study, the MTA developed a manual-based set of procedures (the MTA Adjunct Services and Attrition Prevention [ASAP] Manual) for situations not covered by the protocol treatments. The majority of cases requiring adjunct services fell into two major categories: (1) crisis/emergent situations and (2) imminent risk of attrition. This report describes the ASAP guidelines for dealing with cases that required adjunct services that the MTA Steering Committee adopted before initiating the trial. Although the manual-based guidelines are especially applicable to multisite RCTs, many of the procedures in the ASAP Manual can apply to any treatment study in children.

Symptom Profiles in Children With ADHD: Effects of Comorbidity and Gender

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. 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. 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. 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.

Methylphenidate Dosage for Children With ADHD Over Time Under Controlled Conditions: Lessons From the MTA

To examine the trajectory of methylphenidate (MPH) dosage over time, following a controlled titration, and to ascertain how accurately the titration was able to predict effective long-term treatment in children with attention-deficit/hyperactivity disorder (ADHD). Using the 14-month-treatment database of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), the outcome of the initial placebo-controlled, double-blind, randomized daily switch titration of MPH was compared with the subsequent maintenance pharmacotherapy. Children received monthly monitoring visits and, when needed, medication adjustments. Of the 198 children for whom MPH was the optimal treatment at titration (mean +/- SD dose: 30.5 +/- 14.2 mg/day), 88% were still taking MPH at the end of maintenance (mean dose 34.4 +/- 13.3 mg/day). Titration-determined dose and end-of-maintenance dose were significantly correlated (r = 0.52-0.68). Children receiving combined pharmacotherapy and behavioral treatment ended maintenance on a lower dose (31.1 +/- 11.7 mg/day) than did children receiving pharmacotherapy only (38.1 +/- 14.2 mg/day). Of the 230 children for whom titration identified an optimal treatment, 17% continued both the assigned medication and dosage throughout maintenance. The mean number of pharmacological changes per child was 2.8 +/- 1.8 (SD), and time to first change was 4.7 months +/- 0.3 (SE). For most children, initial titration found a dose of MPH in the general range of the effective maintenance dose, but did not prevent the need for subsequent maintenance adjustments. For optimal pharmacological treatment of ADHD, both careful initial titration and ongoing medication management are needed.

Multimodal Treatment of ADHD in the MTA: An Alternative Outcome Analysis

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. 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. 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. 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. 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.

—Introduction—: ADHD Comorbidity and Treatment Outcomes in the MTA

This Special Section constitutes an important expansion of the first reports of the results of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) (MTA Cooperative Group, 1999a). In the MTA, 579 children with ADHD-combined type were assigned to 14 months of medication management (titration followed by monthly visits); intensive behavioral treatment (parent, school, and child components, with therapist involvement reduced over time); an optimal combination of both approaches; or “usual care” (whatever treatments families chose to obtain through their local community providers).

Impairment and Deportment Responses to Different Methylphenidate Doses in Children With ADHD: The MTA Titration Trial

Results of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were analyzed to determine whether a double-blind, placebo-controlled methylphenidate (MPH) titration trial identified the best MPH dose for each child with attention-deficit/hyperactivity disorder (ADHD). Children with ADHD assigned to MTA medication treatment groups (n = 289) underwent a controlled 28-day titration protocol that administered different MPH doses (placebo, low, middle, and high) on successive days. A repeated-measures analysis of variance revealed main effects for MPH dose with greater effects on teacher ratings of impairment and deportment (F3 = 100.6, n = 223, p = .0001; effect sizes 0.8-1.3) than on parent ratings of similar endpoints (F3 = 55.61, n = 253, p = .00001; effect sizes 0.4-0.6). Dose did not interact with period, dose order, comorbid diagnosis, site, or treatment group. The MTA titration protocol validated the efficacy of weekend MPH dosing and established a total daily dose limit of 35 mg of MPH for children weighing less than 25 kg. It replicated previously reported MPH response rates (77%), distribution of best doses (10-50 mg/day) across subjects, effect sizes on impairment and deportment, as well as dose-related adverse events.

ADHD Comorbidity, Gender, and Symptom Profiles

The results of the NIMH Collaborative Multisite Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA) have been reexamined from several standpoints.

Clinical Relevance of the Primary Findings of the MTA: Success Rates Based on Severity of ADHD and ODD Symptoms at the End of Treatment

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). 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"). 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. These secondary analyses confirm the primary findings and clarify clinical decisions about the choice between multimodal and unimodal treatment with medication.

ADHD Comorbidity Findings From the MTA Study: Comparing Comorbid Subgroups

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. 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. 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. 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.

Medication Treatment Strategies in the MTA Study: Relevance to Clinicians and Researchers

Clinicians have difficulty applying drug research findings to clinical practice, because research protocols use methods different from those used in daily office practice settings. 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. 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.

NIMH Collaborative Multisite Multimodal Treatment Study of Children with ADHD: I. Background and Rationale

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. 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. 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)? The important scientific, clinical, and public health issues nested within this manifold question provide both the impetus and scaffolding for the MTA.