ADD/ADHD Online Information

ADD/ADHD Research

A 14-month Randomized Clinical Trial of Treatment Strategies for Attention Deficit Hyperactivity Disorder (ADHD)

The MTA¹ Cooperative Group

Archives of General Psychiatry, in press. Embargoed until publication. Not for distribution, copying, or citation until after publication.

Accepted for publication July 28, 1999.

This study was supported by UO1 MH50461 (Drs. Hinshaw and Elliot), UO1 MH50477 (Drs. Conner, Wells, and March), UO1 MH50440 (Drs. Swanson, Cantwell, and Wigal), UO1 MH50453 (Drs. Abikoff and Hechtman), UO1 MH50454 (Drs. Greenhill and Newcorn), and UO1 MH50467 (Drs. Pelham and Hoza), from the National Institute of Mental Health, Bethesda, MD.

The MTA¹ is a cooperative treatment study performed by six independent research teams in collaboration with the National Institute of Mental Health and the Office of Special Education Programs of the U.S. Department of Education, Washington, D.C.

The National Institute of Mental Health collaborators are Peter S. Jensen, M.D. (Office of the Director), L. Eugene Arnold, M.D., M.Ed. (Department of Psychiatry, Ohio State University), John E. Richters, Ph.D. (Developmental Psychopathology and Prevention Research Branch), Ms. Joanne B. Severe, M.S. (Research Projects and Publications Branch), Donald Vereen, M.D. (Office of Drug Control Policy), Benedetto Vitiello, M.D. (Child & Adolescent Treatment and Preventive Interventions Research Branch). Principal investigators and coinvestigators from the 6 sites are as follows: University of California, Berkeley/San Francisco: Stephen P. Hinshaw, Ph.D. (Department of Psychology, University of California, Berkeley), Glen R. Elliott, M.D., Ph.D. (Department of Psychiatry, University of California, San Francisco); Duke University: C. Keith Conners, Ph.D., Karen C. Wells, Ph.D., John March, M.D., M.P.H. (Department of Psychiatry & Behavioral Sciences); University of California, Irvine/Los Angeles: James Swanson, Ph.D. (Department of Pediatrics and Cognitive Science, University of California, Irvine), Dennis P. Cantwell, M.D., deceased (Department of Psychiatry, Neuropsychiatric Institute, University of California, Los Angeles), Timothy Wigal, Ph.D. (Department of Pediatrics, University of California, Irvine); Long Island Jewish Medical Center/Montreal Children's Hospital: Howard B. Abikoff, Ph.D. (Department of Psychiatry, New York University School of Medicine), Lily Hechtman, M.D. (Department of Psychiatry, McGill University); New York State Psychiatric Institute/Columbia University/Mount Sinai Medical Center: Laurence L. Greenhill, M.D. (Department of Psychiatry, Columbia University), Jeffrey H. Newcorn, M.D. (Department of Psychiatry, Mount Sinai School of Medicine); University of Pittsburgh: William E. Pelham, Ph.D. (Department of Psychology, State University of New York at Buffalo), Betsy Hoza, Ph.D. (Department of Psychological Sciences, Purdue University). Helena C. Kraemer, Ph.D. (Stanford University, Department of Psychiatry & Behavioral Science) is statistical and design consultant. The Office of Special Education Programs/US Department of Education principal collaborator is Ellen Schiller, Ph.D.

Corresponding author: Peter S. Jensen, M.D., Center for the Advancement of Child & Adolescent Mental Health; Department of Child Psychiatry, Unit 78; New York State Psychiatric Institute/Columbia University; 1051 Riverside Drive, New York, NY 10032. E-mail: jensenp@child.cpmc.columbia.edu

Key Words: ADHD, attention deficit, hyperactivity, stimulant medication, behavior therapy

Background: Previous studies have demonstrated the short-term efficacy of pharmacotherapy and behavior therapy for attention-deficit/hyperactivity disorder (ADHD), but no longer-term (i.e., > 4 months) investigations have compared these two treatments or their combination. Methods: A group of 579 children with ADHD-Combined type, aged 7 to 9.9 years, were assigned to 14 months of medication management (titration followed by monthly visits); intensive behavioral treatment (parent, school, and child components, with therapist involvement gradually reduced over time); the two combined; or standard community care (treatments by community providers). Outcomes were assessed in multiple domains before, during, and at treatment endpoint (with combined treatment and medication management groups continuing medication at all assessment points). Data were analyzed through intent-to-treat, random-effects regression. Results: All 4 groups showed sizeable reductions in symptoms over time, with significant differences among them in degrees of change. For most ADHD symptoms, children in the combined and medication management groups showed significantly greater improvement than those given intensive behavioral treatment or community care. Combined and medication management treatments did not differ significantly on any direct comparisons, but in several instances (oppositional/aggressive symptoms, internalizing symptoms, teacher-rated social skills, parent-child relations, and reading achievement) Combined treatment proved superior to intensive behavioral treatment and/or community care while medication management did not. Study medication strategies were superior to community care, despite the fact that 2/3rds of community-treated subjects received medication during the study period. Conclusions: For ADHD symptoms, our carefully crafted medication management was superior to behavioral treatment and to routine community care that included medication. Our combined treatment did not yield significantly greater benefits than medication management for core ADHD symptoms, but may have provided modest additional advantages for non-ADHD-symptom and positive functioning outcomes.

Attention-deficit/hyperactivity disorder (ADHD) occurs in 3-5% of school-aged children, accounts for as many as 30%-50% of child referrals to mental health services^1,2, and results in substantial impairment in peer, family, and academic functioning^2,3. Although benefits of short-term treatments (principally stimulants, behavior therapy, and their combination) have been well documented^4-8 , few controlled studies have examined effectiveness beyond 3 months. Two exceptions^9,10 suggested that stimulant effects persist 1-2 years when taken faithfully. However, the generalizability/usefulness of these 2 studies are constrained by sample sociodemographic homogeneity, exclusion of stimulant non-responders, lack of unimodal comparisons ( medication management vs. behavioral interventions), and inadequate statistical power to examine subject factors predicting treatment response^9,10.

Given public concerns over stimulant treatment^11,12, wide variations in treatment practices¹³, and lack of evidence to guide long-term treatments of this chronic disorder, in 1992 the National Institute of Mental Health and Department of Education co-sponsored a randomized clinical trial, the Multimodal Treatment Study of Children with ADHD (MTA). Its rationale¹⁴ and methods^15-19 have been detailed previously.

The MTA posed three questions: 1) How do long-term medication and behavioral treatments compare? 2) Are there additional benefits when they are used together? 3) What is the effectiveness of systematic, carefully-delivered treatments vs. routine community treatments? This report constitutes the first-ever description of the relative effectiveness of these treatments through 14 months, using an intent-to-treat analytic strategy with random-effects regression techniques^20,21.

Recruitment, screening, and selection procedures aimed to collect a carefully-diagnosed, impaired sample of ADHD children with a wide range of comorbidities and demographic characteristics, representative of patients seen clinically. To minimize site-specific referral biases, sites' referral sources necessarily included mental health settings, pediatricians, advertisements, and school notices. For eligibility, children (of either sex) were between ages 7.0 to 9.9 years, in 1st-4th grades, and in residence with the same primary caretaker(s) > the last 6 months. All met DSM-IV criteria for ADHD, Combined Type (the most common subtype at this age²²), using the Diagnostic Interview Schedule for Children (DISC), parent-report, version 3.0 ²³, supplemented with up to two symptoms identified by children's teachers for cases falling just below DISC diagnostic threshold. Exclusion criteria were limited to situations that would prevent families' full participation in assessments or treatment, or that might require additional treatments incompatible with study treatments^16-18 (Table 1). The presence of comorbidities such as oppositional defiant disorder (ODD), conduct disorder (CD), internalizing disorders, or specific learning disabilities were not exclusions per se; an important aim of the study was to examine their interactions with treatment outcomes.

A four-phase entry procedure (Table 2) screened potential participants, ascertained caseness, and assessed each recruit prior to randomization^17-18. Ninety-five percent of subjects entering the 4^th phase baseline assessment were randomized; they did not differ from initial phone screen subjects on parental education, ethnicity, or gender. Informed consent (parental permission and child assent) was obtained for all participating families, using forms approved by both local Institutional Review Boards and the National Institutes of Health Office for Protection from Research Risks.

In a 4-group parallel design, children were assigned randomly to either medication management (MedMgt), behavioral treatment (Beh), the combination (Comb), or community comparison (CC) for 14 months. Rather than testing fixed, single treatments, we designed each MTA treatment arm as a management strategy, such that each was sufficiently robust and flexible to stand on its own and to respond to individual patients' clinical needs throughout the study.

Power analyses indicated 24 subjects per treatment condition per site (96 families at each of 6 sites) for comparisons of core ADHD symptoms between any two treatment arms (critical effect size 0.4; power 0.81, with a 5% two-tailed test)^17,24,25. Accordingly, 576 subjects were required; 579 were recruited. Sample demographics, mean scores on standardized Conners teacher and parent scales²⁶, comorbidity profile, and impairment ratings (Columbia Impairment Scale) are typical of other ADHD samples this age^26-30 (Table 3).

Randomization was done centrally by the NIMH Data Center, stratified by site, in blocks of 16; four to each group. Sealed, ordered envelopes were sent to sites for successive entries. Treatment assignment was concealed until the family confirmed agreement to accept randomization.

Principal components analyses narrowed the selection of outcome domains from the comprehensive assessment battery²⁸, eliminating redundant measures. Six major outcome domains were identified; within domains, the measures loading highest from each informant were selected, thus: 1) ADHD symptoms -- inattention and hyperactivity-impulsivity subscales of parent- and teacher-completed SNAP ratings (an acronym denoting the names of the instrument's developers)³¹, 2) oppositional/aggressive symptoms -- parent and teacher SNAP ODD subscale; 3) social skills -- parent- and teacher-completed subscale from the Social Skills Rating System (SSRS)³²; 4) internalizing symptoms (anxiety and depression) -- internalizing subscale from parent- and teacher-completed SSRS³², and children's self-ratings on the Multidimensional Anxiety Scale for Children (MASC)³³; 5) parent-child relations, -- 2 composited scales from the Parent-Child Relationship Questionnaire; and 6) academic achievement -- 3 subscales from the Wechsler Individual Achievement Test³⁴ (reading, math, spelling). These measures show acceptable psychometric properties, and are reviewed extensively elsewhere^31-34. Subjects were assessed at baseline, 3, 9, and 14 months (treatment endpoint). Baseline and endpoint values for the outcome domains are presented in Table 4.

The open parent, teacher, and child ratings for domains 1-5 were augmented by blinded ratings of (a) school-based ADHD and oppositional/aggressive symptoms using the Abikoff Classroom Observational System ³⁵, (b) social skills and peer relations, using peer sociometric procedures, and (c) videotaped parent-child interactions during standardized laboratory tasks, done by raters blind to treatment condition. Videotaped interactions, parental characteristics, family functioning, cognitive ability, general impairment, and services use, attitudes, and barriers¹⁸ will be reported in later manuscripts.

The 3 MTA-delivered treatment strategies were chosen for well-established efficacy (at least in the short-term); portability; sufficient intensity to stand alone; and distinction from each other. For all 3 arms subjects had up to 8 additional sessions, provided when needed to address clinical emergencies or instances of possible study attrition.

Behavioral Treatment (Beh) included parent training, a child-focused treatment, and a school-based intervention, organized and integrated with the school year. The parent training, based on work by Barkley³⁶ and Forehand and McMahon³⁷, involved 27 group (6 families per group) and 8 individual sessions per family. It began weekly upon randomization, concurrent with biweekly teacher consultation, with both tapered over time. The same therapist-consultant (TC) conducted parent training and teacher consultation, with each TC having a case load of 12 families.

The child-focused treatment was a summer treatment program (STP) developed by Pelham³⁸ as a therapeutic summer camp. The 8-week, 5-days/week, 9 hours/day STP employed intensive behavioral interventions administered by counselors/aides, supervised by the same TC's who did parent training and teacher consultation . Behavioral interventions were delivered in group-based recreational settings, and included a point system tied to specific rewards, time out, social reinforcement, modeling, group problem-solving, sports skills, and social skills training. STP classrooms provided individualized academic skills practice and reinforcement of appropriate classroom behavior.

The school-based treatment had two components: 1) 10-16 sessions of bi-weekly teacher consultation focused on classroom behavior management strategies⁸ and 2) 12 weeks (60 school days) of a 1/2-time behaviorally-trained paraprofessional aide working directly with the child (methods adapted from Swanson³¹). The aides had been STP counselors and followed the children into the fall classroom, helping generalize STP gains to classrooms. Throughout the school year, a daily report card (DRC) linked home and school. The DRC^8,39 is a one-page teacher-completed checklist of the child's successes on specific preselected behaviors, and is brought home daily by the child to be reinforced by the parent with home-based rewards (e.g., TV time, snacks).

The treatments outlined above constitute the maximum "dose" of Beh children/families could receive, given perfect attendance and compliance. In practice, families (both Beh and Comb) attended an average of 77.8% of parent training sessions, and 36.2 of 40 possible STP days. The school component averaged 10.7 teacher consultation visits and 47.6 days (of 60 possible) of classroom aides. Sites differed significantly in the extent of attendance for two components (parent training and classroom aides), but there were no significant differences between Beh and Comb, either within or across sites, in degree of attendance/implemenation for any behavioral components (tables available upon request). As described in our companion report, a summary measure of attendance/compliance for all Beh components was unrelated to treatment outcomes; likewise, attendance did not mediate any site x treatment interactions on outcomes⁴⁰.

Consistent with the time-limited involvement of providers in clinical practice, the involvement of MTA personnel in the delivery of the behavioral treatments was gradually faded, with the goal that parents would increasingly manage the child's behavioral treatment. In most cases therapist contact with parents had been faded to once monthly or stopped altogether, prior to endpoint assessment.

Medication Management (MedMgt)¹⁵ started with a 28-day double-blind daily-switch titration on methylphenidate using 5 randomly-ordered repeats each of placebo, 5mg, 10 mg, and 15 or 20 mg (higher doses for children > 25 kg). Each of the doses listed was given at breakfast and lunch, with a half-dose (rounded to the nearest 5 mg) in the afternoon. Cross-site teams of experienced clinicians blindly reviewed graphs portraying parent and teacher ratings of responses to each of the 4 doses, and by consensus selected each child's best dose. After agreement on best dose, the blind was broken, and the agreed-upon dose (if not placebo) became the subject's initial maintenance dose. For subjects not obtaining an adequate response to methyphenidate during titration, alternate medications were titrated openly in the following order until a satisfactory one was found: dextroamphetamine, pemoline, imipramine, and, if necessary, others approved by a cross-site panel.

Of 289 total subjects assigned to MedMgt (n=144) and Comb (n=145) for initial titration, 18 had no titration: 17 because they refused the entire medication component and 1 who moved away. An additional 15 subjects started but did not complete titration: 4 because of side effects, 7 because of difficulties tolerating the titration procedures, and 4 who supplied inadequate data. Thus, 256 subjects (88.6%) successfully completed titration, and from these, 198 subjects (68.5% of 289) were assigned to an individually titrated, best dose of methylphenidate, with average initial doses of 30.5 mg/day. The remaining titration completers were either openly titrated to dextroamphetamine (n=26) because of unsatisfactory methylphenidate response or begun initially on no medication (n=32) because of a robust placebo response (two of these placebo responders failed to cooperate further following titration).

During half-hour monthly medication maintenance visits, pharmacotherapists provided support, encouragement, and practical advice (but not behavior therapy). When deemed necessary by the clinician or requested by the parent, readings from an approved list were supplied. After careful review of parent- and teacher-provided information, pharmacotherapists could make algorithm-guided dose adjustments of +/- 10 mg/day of methylphenidate (or an equipotent amount if the subject was taking another drug). Additional adjustments beyond +/-10 mg/day could be authorized by a cross-site panel of experienced pharmacotherapists. In general, dose reductions were allowed only to address dose-related side effects.

By study end, 212 of the 289 MedMgt and Comb subjects (73.4%) were being successfully maintained on methylphenidate, 30 (10.4%) on dextroamphetamine, 4 (1.4%) on pemoline, 3 on imipramine (1.0%), 1 (0.3%) on buproprion, 1 (0.3%) on haloperidol, and 18 on no medication (14 Comb, 4 MedMgt subjects) (3.1%), with 20 persistently unmedicated (18 since study outset, 2 during maintenance). There were no differences between the MedMgt and Comb groups in the proportion of subjects on the various medications.

Side effects were monitored monthly - not present, mild, moderate or severe - using the parent-completed 13-item Pittsburgh Side Effects Rating Scale⁴¹, reviewed by the pharmacotherapist. At end point, 245 Comb/MedMgt families provided information on side effects, with some reporting more than one: 88 (35.9%) reported no side effects, 122 (49.8%) reported mild side effects only, 28 (11.4%) reported moderate side effects, and 7 (2.9%) reported severe side effects. These figures may overestimate side effects, because 6 of 11 reported severe side effects (depression, worrying, or irritability) could have been due to non-medication factors.

Combined Treatment (Comb). Comb provided all treatments outlined above for MedMgt and Beh, namely, titration followed by monthly medication maintenance, parent group and individual sessions, teacher consultation, STP, and the classroom aide. However, to approximate clinical practice we integrated the two treatment modalities -- information was regularly shared between the TC and pharmacotherapist, and used to guide overall decisions. Manualized guidelines determined if and when an adjustment in one treatment should be made, versus intervening first with the other^16,17. Consequently, the multimodal combination was not the simple addition of the two unimodal treatments. Consistent with the literature⁴², by treatment endpoint Comb subjects received lower total daily doses of methylphenidate (31.2 mg) than MedMgt subjects (37.7 mg). Though sites differed significantly in total daily methylphenidate doses (range of mean doses per site: 30.2 - 41.3 mg), there were no site x treatment interactions in total daily doses (treatment group F = 14.6, p < .01; site F = 3.2, p < . 0002; site x treatment group F = 1.2, ns, df = 11, 200).

Community Comparison (CC) Group. CC participants received no MTA treatments, but were provided a report of their initial study assessments, along with a list of community mental health resources. They were subsequently re-assessed in parallel with participants in the 3 MTA treatment arms. At each assessment point, the types of treatments they obtained in the community were documented. Most CC subjects (n = 97, 67.4%) received ADHD medications (principally one of the stimulants) from their own provider during the 14 months: methylphenidate (n=84), pemoline (n=7), amphetamine (n=6), tricyclics (n=6), clonidine/guanfacine (n=4), and/or buproprion (n=1) (10 subjects received more than one medication). In addition, 16 of these 97 children were treated by their physician with another antidepressant (not counting tricyclics or buproprion). For those treated with methylphenidate, the mean total daily dose at study completion was 22.6 mg., averaging 2.3 doses/day (vs. 3.0 doses/day for MTA-treated subjects). Information concerning CC psychotherapeutic treatments have not yet been coded and will not be presented in this paper.

Fidelity and Compliance. The MTA study achieved a high degree of adherence to protocol by cross-arm emphasis on subject rapport, manualization of all treatments, regular supervision of pharmaco- and psychotherapists by skilled clinician investigators, cross-site weekly treatment panels, and audiotaping of all sessions. Good compliance (as reflected by acceptance and attendance at treatment sessions) by patients to protocol was facilitated by monthly pill counts, intermittent saliva levels to monitor taking of methylphenidate, and encouragement of families to make up missed visits. Only 13 of 144 (9.0%) MedMgt subjects and 5 of 145 (3.4%) Comb subjects failed to start medication. More remarkably, none of 144 Beh subjects and only 1 of 145 (0.7%) of Comb subjects refused behavioral treatment. There was no difference between MedMgt or Comb in medication session attendance, nor between Beh and Comb in the degree of behavioral treatment acceptance/attendance. These factors did not affect overall findings⁴⁰.

Subjects/families refusing their respective treatments were encouraged to reconsider their decision throughout the study, as well as continue to complete all assessments. Thus, including all subjects who continued to participate in assessments (despite refusing part of all of their assigned treatments), the absolute attrition rate over the course of the study was 3.5%, with only 20 complete dropouts by 14 months (6 in CC, 3 in Beh, 8 in MedMgt, 3 in Comb).

Given the well-described advantages of random-effects regression (RR) techniques over traditional analyses of variance for clinical trials data^43-46, we used RR whenever possible for our primary intent-to-treat (ITT) analyses^20,21. Rather than define a single outcome, we specified multiple outcome variables, anticipating differential impacts of the treatment modalities on various outcome domains^5-7,14. Based on our data reduction procedures outlined above, the 6 domains were represented by 19 measures (Table 4). For each outcome variable, tests for site, time, time x treatment (the treatment effect over time), and site x treatment x time were conducted within the ITT RR analyses. When omnibus RR analyses comparing all 4 groups were significant, 3 sets of pairwise comparisons were performed, each set addressing one of the 3 principal study questions: (a) MedMgt vs. Beh (2-tailed); (b) Comb vs. MedMgt, Comb vs. Beh (1-tailed, assuming the superiority of Comb); and (c) CC vs. MedMgt, CC vs. Beh; CC vs. Comb (1-tailed, assuming the superiority of MTA treatments).

Bonferonni corrections were applied to all omnibus tests, based upon the number of measures in the respective domain. Thus, for each of 5 measures within the ADHD domain, standard definitions of statistical significance (p < .05) were corrected by dividing by 5, requiring p < .01 for statistical significance. The 6 pairwise contrasts were likewise adjusted by dividing omnibus-corrected significance levels further by 6 (p<.01 , 6 = .0017 in this example). Given our a priori hypotheses about the superiority of multimodal treatment (Comb vs. MedMgt and Beh), as well as the superiority of all 3 MTA-delivered treatments over community care (CC vs. Comb, MedMgt, Beh), we used 1-tailed tests for these specific contrasts. This approach was taken as a means of striking a balance between the dangers of committing Type II errors versus over-interpreting significant findings that occurred simply by chance (Type I errors). Readers are encouraged to exercise caution when interpreting one-tailed findings, and may choose to double one-tailed p values.

Because initial RR analyses revealed both quadratic and linear effects of time on treatment outcomes, we computed the log of the number of days since randomization for each assessment point, and used these log values in all RR analyses.

Despite high compliance, we checked whether compliance with assessments (i.e., missing data) could have changed our findings. RR analyses were completed two ways: once with inclusion of all subjects, and then with only those subjects who provided data over multiple time points during the study. No differences emerged among these two sets of analyses, lending confidence to the overall findings.

In 10 of 19 variables, omnibus tests revealed significant treatment effects over time. For these analyses, we describe the results of the paired comparisons, in order of our original hypotheses. Question 1. Do medication and behavioral treatments result in comparable levels of improvement in pertinent outcomes at the end of treatment? Robust differences were found according to 2 different data sources, indicating the superiority of MedMgt to Beh for ADHD symptoms (Table 5) -- namely, parents' and teachers' ratings of inattention, and teachers' ratings of hyperactivity-impulsivity. MedMgt and Beh did not differ significantly on any other outcomes.

Question 2. Do participants assigned to Comb show higher levels of improvement in overall functioning in pertinent outcome domains than those assigned to either MedMgt or Beh at the end of treatment? (1-tailed hypotheses). These analyses indicate that Comb and MedMgt did not differ significantly across any domain.

Compared to Beh, Comb was superior in benefitting ADHD symptoms according to parents' and teachers' ratings of inattention and parent-rated hyperactivity-impulsivity. Comb also significantly outperformed Beh on parents' SNAP oppositional/aggressive behaviors, parent-rated internalizing symptoms (Table 5), and WIAT reading achievement (Table 4).

Question 3. Do participants assigned to each of the 3 MTA treatments (MedMgt, Beh, Comb) show greater improvement over 14 months than those assigned to CC? (1-tailed). These analyses reveal that Comb and MedMgt were generally superior to CC for parent- and teacher-reported ADHD symptoms, whereas Beh was not (Table 5). In non-ADHD domains, MedMgt and Beh were superior to CC on one domain only (teacher-reported social skills and one measure of parent-child relations, respectively). In contrast, Comb was significantly superior to CC on all 5 non-ADHD domains of functioning (parent-reported oppositional/aggressive behaviors, internalizing symptoms, teacher-reported social skillls, parent-child relations, and WIAT reading achievement scores).

Because our RR intent-to-treat analyses included all subjects' data points through 14 months, it is possible that some treatment groups (especially Beh, where 38 "cross-overs" to medication occurred) may have fared better because of the number who had received additional treatments over the course of the study. To address this issue, we conducted additional RR analyses, censoring any observations obtained after cross-over subjects had received the additional treatments. These analyses yielded no differences from the findings noted in Table 5 (analyses available from the authors upon request).

Graphed in Figure 1 are four RR analyses, selected to highlight findings from different domains, as well as from raters who are likely to witness the target behaviors: one core ADHD symptom -- hyperactivity-impulsivity (teacher report), internalizing symptoms (parent report), social skills (teacher report), and parent-child relations (parent report). The remaining RR graphs are available from the authors upon request.

All 4 groups showed marked reductions in symptoms over time, with significant differences among them in degrees of change. Comb and MedMgt treatments were clinically and statistically superior to Beh and CC in reducing children's ADHD symptoms. Combined behavioral intervention and stimulant medication -- multimodal treatment, the current "gold standard" for ADHD interventions -- yielded no statistically significantly greater benefits than MedMgt for core ADHD symptoms, paralleling findings reported by others^10,42. Also consistent with previous reports, our Comb outcomes were achieved with significantly lower medication doses than used in MedMgt ^42,47.

For other areas of function (oppositional/aggressive behaviors, internalizing symptoms, social skills, parent-child relations and academic achievement) few differences among MTA treatments were noted, and when found, were generally of smaller magnitude. In fact, Comb, MedMgt, and Beh never differed significantly among themselves, with three exceptions (Comb > Beh for parent-reported internalizing problems and oppositional/aggressive symptoms, and WIAT reading achievement).

With respect to comparisons of MTA treatments to CC, Comb and MedMgt fared substantially better than CC on most ADHD outcome measures, while Beh did not. Comb also fared significantly better than CC for all 5 non-ADHD domains according to at least one informant: parent-reported oppositional/aggressive symptoms, parent-reported internalizing problems, teacher-reported social skills, parent-child relations, and reading achievement. In contrast, MedMgt and Beh each fared better than CC in one non-ADHD domain only (teacher-rated social skills and parent-child relations, respectively).

Our finding that MTA treatments (most notably Comb) offered benefits over CC for oppositional/aggressive behaviors, internalizing symptoms, peer interactions, parent-child relations, and reading achievement, has not been previously reported in long-term studies. ^3,5,14 The differential benefits in these non-ADHD domains are consistent with the theoretical aims of multimodal approaches, however.¹⁴ For example, medication is known to reduce negative peer interactions quite dramatically, but increases in positive social behavior are far less robust⁴⁸. Such changes might require intensive and long-term application of the behavioral components of combined treatments, such as those found in our STP and school-based interventions³⁸. Similarly, parent training -- which includes positive parental attention and rewards for the child's appropriate behavior -- when combined with medication, might be expected to decrease oppositionality and enhance parent-child relations more than medication alone. For internalizing symptoms the relatively greater improvements noted for Comb subjects are particularly noteworthy, as none of our treatments were designed to address this domain specifically.

The MTA extends the findings of previous studies demonstrating short-term, robust efficacy of medication management out to a period of 14 months, showing that these effects continue during longer-term treatment. In contrast to frequently expressed concerns, Comb and MedMgt children tolerated medication well, including third doses given in the afternoon. The relative improvements attributed to medication management also parallel findings from other longer-duration stimulant trials^9,10,49. Given the MTA's size and scope, however, we realized effects across diverse settings, patient groups, provider characteristics, and outcome domains -- findings further strengthened by the absence of any site-by-treatment interactions.

Although Comb and MedMgt were generally superior to CC, CC treatments also usually included medication, so it is unclear which components of the two MTA medication treatments may have rendered them more effective than CC care. Further analyses of these findings are presented in our companion report⁴⁰, but review of the apparent differences is instructive. We used a manualized medication titration procedure and "t.i.d." dosing, as well as higher, yet carefully monitored, daily doses to maximize positive effects and minimize side effects¹⁵. We met with parents monthly and obtained systematic feedback both from them and the children's teachers. Parent guidance and selected readings were provided as needed, reported to provide benefits over simple pill dispensing alone⁵⁰. These components, particularly the systematic and regular feedback from teachers, do not appear to be part of routine pediatric ADHD treatment practices¹³, and may have enhanced the effectiveness of our medication management.

The modest benefits for some non-ADHD domains obtained by multimodal treatments have been reported previously^5,51-52 following 3-4 months of treatment. In contrast, the study by Hechtman & Abikoff¹⁰ with 12 months of active treatment failed to demonstrate these effects, perhaps because of their smaller sample (103 subjects distributed across 3 groups). In addition to the MTA's sample size advantages, its behavioral component design required that Beh interventions were delivered across multiple settings and caretakers (home, school, STP), augmented with further strategies to facilitate the generalization of effects across settings and over time^17,19 all enhancements not found in previous studies.⁸

Whether there is greater value for multimodal treatments for ADHD depends upon which intervention is considered as the comparison. If one assumes that a behavioral intervention should always be used as the first line ADHD treatment (often the preference for many parents, and the practice in many European countries), and that the possibly greater benefits of combined treatment should be determined, then Comb appears to offer a great deal of benefit over Beh alone. But if one provides carefully monitored medication treatment similar to that used in the MTA as the first line of treatment, our results suggest that many treated children may not require intensive behavioral interventions⁴⁷.

The significantly lower total daily doses of methylphenidate in the Comb treatment arm is noteworthy, but not unforeseen^42,47. The importance of this finding is unclear, and a rigorous test of this question would likely require a different design. Nonetheless, this issue remains an ongoing source of concern of many parents and clinicians, and should not be dismissed, particularly since side effects are usually dose-related. If equivalent, even sometimes better results can be obtained by a combined treatment that utilizes lower doses, such findings may have public health import.

Concerning the relative benefits of our Beh treatment alone, results must be understood within the context of the limitations of our study design. Most importantly, our design did not include a no-treatment or placebo group (an ethically unacceptable option for an ADHD study of this length), and most CC subjects received medication for most of the study period -- a treatment of known efficacy. Substantial improvement occurred over time across all groups (including CC), regardless of rating source or method. While some of this change could be regression to the mean, this explanation cannot account for the substantial group differences reported here. Over 3/4ths of Beh subjects were successfully maintained without medication throughout the study. Consequently, it should not be concluded that Beh interventions did not work.

One caveat concerns our choice and number of outcome measures. We felt that the treatment effects in different domains and from different respondents might vary, and that these variations were necessary in interpreting the results of the study. Consequently, despite the loss of power due to Bonferonni corrections, we chose 19 primary outcome measures, rather than a single summary outcome score. Power calculations¹⁷ that underlay the setting of sample size were based on setting as the lower limit of clinical significance an effect size of 0.4 ("small to moderate"⁵³), and on the requirement of 80% power (5% level of confidence) to detect effects of that magnitude. Thus, the chance is high of declaring effect sizes lower than 0.4 not statistically significant, even though some clinicians might regard such effects as clinically significant.

Hence, for purposes of assessing clinical significance, the overall pattern of results may be more instructive than any single test statistic or p-value reported in Tables 4-5: The general ordering of treatment groups' benefits is confirmed by simple inspection of the number of times each group placed first compared to all others on the 19 outcome measures: Comb - 12; MedMgt - 4; Beh - 2; and CC -1. While Comb scored numerically "best" on most outcome measures, we did not have statistical power to detect small effects, such as those that might exist between Comb and MedMgt²⁵. Statistical significance, of course, cannot be interpreted as necessarily indicative of clinical or practical significance, and lack of statistical significance is never proof of the equivalency of treatments.

By way of caution, we note that subgroup analyses may yield different treatment effects for specific patient groups than the main "intent-to-treat" analyses presented here. In our companion report⁴⁰ we report analyses indicating that ADHD children with co-occurring disorders, as well as those with fewer family resources, are more likely to benefit specifically from combined and behavioral treatments for some outcome domains. In addition, other post-hoc analyses suggest that alternative approaches to examining specific subgroups (i.e., "excellent responders"), as well as strategies that utilize a single composite outcome measure, yield findings indicative of modest additional advantages of Comb over MedMgt⁴⁷. While such findings should be viewed with caution compared to the primary analyses reported here, response patterns and characteristics of particular subgroups such as "excellent responders" will likely be obscured by large-group analyses. Future articles will report these issues in more detail⁴⁷.

Such considerations highlight the need for caution in interpreting our results, and argue against a "one size fits all" approach to treatment. Moreover, our results cannot necessarily be generalized beyond ADHD-Combined type; other ADHD subtypes (e.g., inattentive subtype) may warrant somewhat different treatments.

Previous research has shown that the medication benefits persist only so long as treatment is continued^6,54. Whenever possible, our Comb and MedMgt subjects were maintained on medication throughout the 14 months, including at all assessment points. By contrast, and consistent with clinical practice, for Beh subjects the frequency of contact with therapists was gradually faded to once-monthly contacts 3 to 6 months prior to post-treatment assessment, and in general, they were assessed one month after their last treatment contact. Procedures for maintenance and generalization were incorporated throughout Beh's implementation, with the goal that benefits would persist as parents and children learned and consolidated their skills. However, our Beh procedures, increasingly non-intensive during fading, were insufficient to produce overall effects comparable or additive to 14-months of ongoing medication management for core ADHD symptoms.

Unanswered in our study are important questions concerning behavioral and combined treatments for ADHD. Are there some children for whom medication management is no longer necessary⁹, and if so, why does this occur? Might the behavioral component of combined treatment allow some children to be successfully tapered off medication? Can and should behavioral and pharmacologic treatments be faded, and how can that be accomplished while maintaining effects? Will findings differ as children age, such that those who have learned increased skills via behavioral interventions eventually function better than those receiving only medication? Follow-up study of MTA subjects past 14 months (currently underway) will address some of these critical questions.

Since ADHD is now regarded by most experts as a chronic disorder¹⁴, ongoing treatment often appears necessary. As with other chronic conditions like diabetes and asthma, however, the need for active treatment may wax and wane. Just as exercise, diet, and pollen load may affect these illnesses, persons' learning or work environments and intercurrent stressors may affect the need for, type, and intensity of ADHD treatments over the life course⁵⁵. Under such conditions, behavioral treatments may help families actively cope with their child's disorder and to make the necessary life accommodations to optimize family functioning, even when such treatments are not as effective as medication in reducing children's ADHD symptoms. Indeed, 14-month endpoint analyses indicated that parent satisfaction ratings differed significantly by treatment group, with pairwise contrasts showing that treatment satisfaction scores for Comb and Beh parents were significantly superior to MedMgt parents' ratings (though not differing between themselves), suggesting that the Beh components benefitted this area of family-relevant outcomes.

The absence of any site x treatment x time interactions suggests that both our pharmacological and behavioral treatments could be delivered with fidelity across 6 very different clinical settings. However, the utility of these treatments will ultimately be determined by the degree to which they are feasible, transportable, and affordable in "real world" settings -- topics for future research. In the interim, however, the MTA study, by virtue of its size, scope and length; parallel groups design; explicit use of manualized, evidence-based treatments; high degree of compliance across arms and over the course of the study; and comprehensive range of outcome assessments, sets an important benchmark for future trials testing new treatments for childhood ADHD.