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.

Diagnosing attention-deficit/hyperactivity disorder in children.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous behavioral disorder of uncertain etiology that is always evident first in childhood. The correct diagnosis of the ADHD patient thus requires familiarity with how the diagnosis should be established across the life span. This article provides a description of the DSM-IV syndrome of ADHD, information on prevalence, and an overview of standard methods used in office practice to diagnose ADHD in children. These practice parameters will be examined in the light of the practitioner's current concerns about the validity of the diagnosis.

Molindone hydrochloride treatment of hospitalized children with conduct disorder.

Treatment-emergent symptoms and behavioral changes were assessed during an 8-week double-blind study comparing molindone and thioridazine in 31 aggressive hospitalized children (ages 6-11). Molindone was found to be as effective as thioridazine in this sample. Adverse effects differed (nonsignificantly) for the two groups, with more sedation in the thioridazine-treated children. Clinical records from 6 adolescent inpatients treated with molindone were reviewed as a comparison group. Molindone is a relatively safe neuroleptic for child and adolescent inpatients because of its short half-life and minimal prolonged tissue accumulation. Additional studies on different child populations are necessary before the proper indications for molindone usage in the pediatric group can be established.

Estimation of the association between desipramine and the risk for sudden death in 5- to 14-year-old children.

BACKGROUND: Four cases of sudden death in children 12 years or younger during desipramine treatment were identified between 1986 and 1992. We evaluated whether these events support the hypothesis that exposure to therapeutic doses of desipramine contributes to the risk for sudden death in otherwise healthy children. METHOD: The National Center for Health Statistics provided the baseline number of sudden unexplained deaths in children 5 to 14 years old. Data from the National Disease and Therapeutic Index were used to estimate the exposure to desipramine in children in the same age group. Since two of the four deaths were identified by 1987, we used the post-1987 experience as if it were a prospective period in which a causal association could be examined. RESULTS: The number of sudden deaths in desipramine-exposed children did not increase from 1986 to 1992 despite a marked increase in exposure. By using 4 to 6 months as the average lifetime of a desipramine prescription and a baseline rate of sudden death of 4.2 deaths/million/year in this population, the post-1987 period would account for 162,000 to 242,000 person-years of desipramine exposure. Although not statistically significant, this level of exposure corresponds to a relative risk of 2.1 (95% CI = 0.5 to 15) to 3.1 (95% CI = 0.8 to 22). CONCLUSION: Although, based on our estimates, the evidence for an association between desipramine and sudden death in children aged 5 to 14 years appears weak, replication of our findings is needed with a more precise numerator (total number of deaths) and denominator (the appropriate conversion from drug appearance to actual exposure) before a firm conclusion on this subject can be drawn. Until then, even if remote, the possibility of an association between desipramine and sudden death in children stresses the importance of assessing risks and benefits when desipramine is used in pediatric patients.

Stimulant medications.

OBJECTIVE: To review the short- and long-term safety and efficacy of stimulants for the treatment of children with attention-deficit/hyperactivity disorder (ADHD). METHOD: A Medline search was conducted for both randomized controlled trials and reviews to determine the efficacy and safety of stimulant drugs for treating children with ADHD. Information was obtained on adverse events associated with their use, including their impact on height and weight gain during childhood. Animal data were reviewed for information on tolerance, sensitization, and the impact of high-dose stimulant effects on neurons and on the development of hepatic tumors. Human data on dopamine transporter occupancy by stimulants were also included. RESULTS: Stimulant treatment studies show robust short-term efficacy and a good safety profile. Longer-term studies are few in number but have produced no conclusive evidence that careful therapeutic use of these medications is harmful. CONCLUSION: Current evidence indicates that stimulants show efficacy and safety in studies lasting up to 24 months.

Childhood schizophrenia: theoretical and treatment issues.

Michael is an 8.5-year-old Caucasian male inpatient who presented at admission with severe agitation, suicidal impulses, and aggression toward his 18-month-old sister. He had been treated with stimulant medications before admission. Past history revealed bilateral genetic loading with two primary family members having a history of hallucinations and hospitalization, and two paternal aunts who were hospitalized since early childhood. Michael was raised in a chaotic, violent family environment where there was emotional, physical, and perhaps sexual abuse. Medical history included frequent staring spells. During residential treatment, more extensive interviews revealed a year's history of auditory hallucinations, inappropriate and labile affect, and a fixed delusional system. The patient was switched to neuroleptics and showed a slow response despite high doses.

Sustained release methylphenidate: pharmacokinetic studies in ADDH males.

Methylphenidate is widely used in the treatment of school-age children with attention deficit disorder with hyperactivity (ADDH). It is available in a short-acting (MPH) and a long-acting (MPH-SR) preparation. Nine males with ADDH participated in a 1-day pharmacokinetic study following a single morning dose of 20 mg. MPH-SR. Data are presented on MPH-SR's half-life (T 1/2), peak concentrations achieved (Cmax) and the time to the peak plasma concentrations (Tmax). Similar data were gathered from a second group of eight ADDH males treated with a higher, single morning dose of standard, short-acting MPH. After adjusting for dose differences, comparisons of the two sets of plasma concentration curves suggest that MPH-SR has a longer Tmax, but that it does not reach the same Cmax as an identical dose of standard MPH.

Effects of desipramine on autonomic input to the heart.

OBJECTIVE: To examine the impact of age on the effects of desipramine (DMI) on autonomic input to the heart. METHOD: Twenty-four-hour electrocardiograms were obtained from 42 subjects, aged 7 to 66 years, while off and on DMI. To obtain measures of autonomic input to the heart, heart rate variability was assessed via spectral analysis of RR interval variability. RESULTS: DMI treatment was associated with a significant increase in 24-hour mean heart rate and significant decreases in RR interval variability in all spectral bands, including in the high-frequency band, which provides a measure of parasympathetic input to the heart. RR interval variability was greater in younger individuals both off and on DMI. CONCLUSIONS: DMI treatment was associated with a marked decline in RR interval variability, indicating that DMI affects autonomic input to the heart. Specifically, DMI reduced parasympathetic input, which, in theory, may increase vulnerability to arrhythmias. However, the magnitude of DMI's impact on RR interval variability did not vary with age.

Cardiovascular effects of desipramine in children and adults during exercise testing.

OBJECTIVE: In light of recent reports of sudden death in children being treated with desipramine (DMI), 3 of which were associated with physical exercise, the authors examined the effects of DMI on exercise in children and adults before and during DMI treatment. METHOD: Before treatment, 22 subjects (9 children, 13 adults) participated in a graded treadmill exercise test. Outcome measures included exercise tolerance, cardiovascular, and electrocardiographic parameters at progressive intensity levels and serum norepinephrine (NE) levels before and after exercise testing. Subjects were then treated with DMI, titrated to an average DMI dosage of 3 mg/kg, and underwent repeated exercise testing. RESULTS: DMI treatment was associated with a significant elevation of circulating NE levels in the pre-exercise assessment. Exercise tolerance was not affected by DMI, and blood pressure and heart rate effects were modest. The cardiovascular impact of DMI treatment was similar in children and adults. One 31-year-old subject exhibited a brief episode of ventricular tachycardia associated with exercise during DMI treatment. CONCLUSIONS: DMI has only minor effects on the cardiovascular response to exercise, and these effects do not appear age-related. However, DMI may increase the risk of exercise-associated arrhythmias in rare individuals.

Summary of the practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults.

This practice parameter describes treatment with stimulant medication. It uses an evidence-based medicine approach derived from a detailed literature review and expert consultation. Stimulant medications in clinical use include methylphenidate, dextroamphetamine, mixed salts of amphetamine, and pemoline. They carry U.S. Food and Drug Administration indications for the treatment of attention-deficit hyperactivity disorder.

The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part I. Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: Expert consensus methodology was used to develop evidence-based, consensually agreed-upon medication treatment algorithms for attention-deficit/hyperactivity disorder (ADHD) in the public mental health sector. Although treatment algorithms for adult mental disorders have been developed, this represents one of the first attempts to develop similar algorithms for childhood mental disorders. Although these algorithms were developed initially for the public sector, the goals of this approach are to increase the uniformity of treatment and improve the clinical outcomes of children and adolescents with ADHD in a variety of treatment settings. METHOD: A consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families was convened to develop evidence-based consensus algorithms for the pharmacotherapy of childhood ADHD. After a series of presentations of current research evidence and panel discussion, the consensus panel met and drafted the algorithms along with guidelines for implementation. RESULTS: The panel developed consensually agreed-upon algorithms for ADHD with and without specific comorbid disorders. The algorithms consist of systematic strategies for psychopharmacological interventions and tactics to ensure successful implementation of the strategies. While the algorithms focused on the medication management of ADHD, the conference emphasized that psychosocial treatments are often a critical component of the overall management of ADHD. CONCLUSIONS: Medication algorithms for ADHD can be developed with consensus. A companion article will discuss the implementation of these algorithms.

The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part II: Tactics. Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: Expert consensus methodology was used to develop a medication treatment algorithm for attention-deficit/hyperactivity disorder (ADHD). The algorithm broadly outlined the choice of medication for ADHD and some of its most common comorbid conditions. Specific tactical recommendations were developed with regard to medication dosage, assessment of drug response, management of side effects, and long-term medication management. METHOD: The consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families developed evidence-based tactics for the pharmacotherapy of childhood ADHD and its common comorbid disorders. The panel discussed specifics of treatment of ADHD and its comorbid conditions with stimulants, antidepressants, mood stabilizers, alpha-agonists, and (when appropriate) antipsychotics. RESULTS: Specific tactics for the use of each of the above agents are outlined. The tactics are designed to be practical for implementation in the public mental health sector, but they may have utility in many practice settings, including the private practice environment. CONCLUSIONS: Tactics for psychopharmacological management of ADHD can be developed with consensus.

Analog classroom assessment of Adderall in children with ADHD.

OBJECTIVE: This was a randomized, double-blind, crossover study of 30 children with attention-deficit/hyperactivity disorder (ADHD) that evaluated the time course effects of four doses of Adderall (5, 10, 15, and 20 mg), an inactive control (placebo), and a positive control (clinical dose of methylphenidate). METHOD: For each treatment condition, a capsule was administered in the morning and assessments were performed in an analog classroom setting every 1.5 hours across the day. Subjective (teacher ratings of deportment and attention) and objective (scores on math tests) measures were obtained for each classroom session, and these measures were used to evaluate time-response and dose response effects of Adderall. RESULTS: For doses of Adderall greater than 5 mg, significant time course effects were observed. Rapid improvements on teacher ratings and math performance were observed by 1.5 hours after administration, and these effects dissipated by the end of the day. The specific pattern of time course effects depended on dose: the time of peak effects and the duration of action increased with dose of Adderall. CONCLUSIONS: This documentation of efficacy in a controlled study supports the addition of Adderall to the armamentarium of psychotropic medications for the treatment of ADHD. The differences in time-response patterns of Adderall and methylphenidate may help tailor treatment to meet specific clinical needs of different children with ADHD.

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.

Methylphenidate dosage for children with ADHD over time under controlled conditions: lessons from the MTA.

OBJECTIVES: 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). METHOD: 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. RESULTS: 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). CONCLUSIONS: 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.

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.

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.