Pemoline, methylphenidate, and placebo in children with minimal brain dysfunction.

An eight-week double-blind comparison between pemoline (Cylert), methylphenidate (Ritalin) hydrochloride, and placebo was carried out on 60 hyperactive children. Measurements of home, school, achievement, cognitive function, and global clinical status were made at baseline, midtreatment, end of treatment, and posttreatment. Both drugs produced improvement in all areas except the achievement measures. One major difference between drugs was the apparently longer action of pemoline, since its effects at home and school tended to persist when the drug was withdrawn, whereas the patients receiving methylphenidate tended to regress to their baseline levels.

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.

Food additives and hyperkinesis: a controlled double-blind experiment.

A double-blind crossover trial involving a control diet and a diet eliminating artificial flavors, colors, and natural salicylates as recommended by Feingold was conducted on 15 hyperkinetic children. Teachers and parents observed the children for one month prior to treatment, using standardized rating scales. Both parents and teachers reported fewer hyperkinetic symptoms on the K-P diet as compared to the pretreatment baseline. The teachers noted a highly significant reduction of symptoms on the K-P diet as compared to the control diet but the parents did not. The control diet ratings did not differ from the baseline period ratings for either parents or teachers. It is concluded that the K-P diet may reduce hyperkinetic symptoms, though this result is put forth with caution in view of several features inherent in the present study which need further evaluation, including objective measures of change, manipulation of the independent variable, and reducing the independent variable to more specific components.

Neurological sequelae of the operation "baby lift" airplane disaster.

The aircraft disaster of the first flight of Operation "Baby Lift", which departed from Saigon, Vietnam, April 4, 1975, was survived by 149 orphaned children on their way to adoptive homes in the West. It had 157 passenger fatalities. The aircraft disaster exposed the surviving children to a complex disaster environment in which subatmospheric decompression, hypoxia, and deceleration were experienced, many children suffered a transient unconsciousness. We examined 135 surviving children between 1978 and 1985. The U.S. resident children were examined in the years 1979 to 1982 at an average age of 8 years and 6 months. They displayed the following symptomatology: attention deficit (> 75%), hyperactivity (> 65%), impulse disorder (> 55%), learning disabilities (> 35%), speech and language pathology (> 70%), and soft neurological signs (> 75%). The European children were examined in the years 1983 to 1985. On arrival at the adoptive home, 2 weeks after the accident they displayed the following symptomatology: muscle hypotonia (26%), seizures (2.5%), and regressed developmental milestones (33%). At the time of the diagnostic evaluations (1983 to 1985) the average age was 11 years and 8 months. They displayed the following symptomatology: attention deficit (59%), hyperactivity (52%), impulse disorder (48%), learning disabilities (43%), soft neurological signs (43%), epilepsy (16%), and speech and language pathology (34%). We conclude that a complex disaster environment can cause brain damage in children without prolonged unconsciousness, and that victims of disasters require a thorough evaluation from a multidisciplinary team.

Rating scales in attention-deficit/hyperactivity disorder: use in assessment and treatment monitoring.

Rating scales are valuable tools in both assessment and treatment monitoring. However, caution in their use is indicated because of several types of rater errors. Recent large-scale normative studies provide a set of instruments that cover child, adolescent, and adult ages, with separate gender norms and large representative samples. By including DSM-IV symptoms for ADHD in a proposed nationwide standardization of parent, teacher, and self-report scales, it is apparent that the proposed subtypes of ADHD are reasonable; however, item content in this standardization is somewhat broader than that proposed by DSM-IV. Empirical indexes were created and cross-validated, providing powerful discrimination between ADHD and non-ADHD samples. Separate scoring for the traditional DSM subtypes of ADHD allows both categorical and dimensional measures to be used in assessment and treatment monitoring.

Imipramine and EEG sleep in children with depressive symptoms.

Depression in children is currently an area of considerable controversy, as is the use of potent psychopharmacologic agents in children. Since EEG sleep techniques have proven to be useful in understanding the mechanisms of depression in adults and in predicting their response to antidepressants, a pilot study employing these techniques was undertaken in a population of hospitalized children. The EEG sleep of 12 children with significant depressive symptomatology was first examined after a two-week drug-free period and again approximately three weeks later when an optimum dose of imipramine had been maintained for at least 7 -- 10 days. Changes in sleep continuity, as reflected in increased wakefulness and a decreased sleep efficiency, as well as an increase in Stage 2 and a decrease in Stage 4 sleep, were observed throughout the entire sample. REM suppression was also noted, but tended to be most pronounced in those children who improved on imipramine.

Nicotine effects on adults with attention-deficit/hyperactivity disorder.

Several lines of evidence suggest that nicotine may be useful in treating the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). The current study was an acute, placebo-controlled double-blind experiment to determine whether nicotine might be useful as an alternative treatment of adults with ADHD symptomatology. Six smokers and 11 nonsmokers who were outpatient referrals for ADHD were diagnosed by DSM-IV criteria. Measures of treatment effect included the Clinical Global Impressions (CGI) scale, Hopkins' symptom check list (SCL-90-R), the Profile of Mood States (POMS), Conners' computerized Continuous Performance Test (CPT), the Stroop test, and an interval-timing task. The smokers underwent overnight deprivation from smoking and were given a 21 mg/day nicotine skin patch for 4.5 h during a morning session. The nonsmokers were given a 7 mg/day nicotine skin patch for 4.5 h during a morning session. Active and placebo patches were given in a counter-balanced order approximately 1 week apart. Nicotine caused a significant overall nicotine-induced improvement on the CGI. This effect was significant when only the nonsmokers were considered, which indicated that it was not due merely to withdrawal relief. Nicotine caused significantly increased vigor as measured by the POMS test. Nicotine caused an overall significant reduction in reaction time (RT) on the CPT, as well as, with the smokers, a significant reduction in another index of inattention, variability in reaction time over trial blocks. Nicotine improved accuracy of time estimation and lowered variability of time-estimation response curves. Because improvements occurred among nonsmokers, the nicotine effect appears not to be merely a relief of withdrawal symptoms. It is concluded that nicotine deserves further clinical trials with ADHD.

Transdermal nicotine effects on attention.

Nicotine has been shown to improve attentiveness in smokers and attenuate attentional deficits in Alzheimer's disease patients, schizophrenics and adults with attention-deficit/hyperactivity disorder (ADHD). The current study was conducted to determine whether nicotine administered via transdermal patches would improve attentiveness in non-smoking adults without attentional deficits. The subjects underwent the nicotine and placebo exposure in a counterbalanced double-blind manner. Measures of treatment effect included the Profile of Mood States (POMS), Conners' computerized Continuous Performance Test (CPT) of attentiveness and a computerized interval-timing task. The subjects were administered a 7 mg/day nicotine transdermal patch for 4.5 h during a morning session. Nicotine significantly increased self-perceived vigor as measured by the POMS test. On the CPT, nicotine significantly decreased the number of errors of omission without causing increases in either errors of commission or correct hit reaction time. Nicotine also significantly decreased the variance of hit reaction time and the composite measure of attentiveness. This study shows that, in addition to reducing attentional impairment, nicotine administered via transdermal patches can improve attentiveness in normal adult non-smokers.

Nutritional effects on behavior of children.

Studies of nutritional effects on behavior of children present many of the same methodological problems as studies of drugs on behavior of children. Dependent measures must be made across several classes of response at different time scales and levels of precision. A schema is presented for an integrated series of nutritional studies. The effects of missing breakfast and of simple sugars are used to illustrate several applications from this schema, including autonomic (evoked cardiac response), central (event-related potentials), and behavioral measures. Each class of measures is found to be sensitive to these nutritional manipulations. Attention and motor behavior appear to be quite sensitive to subtle nutritional effects.

The Multidimensional Anxiety Scale for Children (MASC): factor structure, reliability, and validity.

OBJECTIVE: To describe the history, factor structure, reliability, and validity of the Multidimensional Anxiety Scale for Children (MASC). METHOD: In two separate school-based population studies, principal-components factor analysis was used, first, to test a theory-driven factor structure, and second, to develop an empirically derived factor structure for the MASC. In a separate study using a clinical population, test-retest reliability at 3 weeks and 3 months, interrater concordance, and convergent and divergent validity were examined. RESULTS: The final version of the MASC consists of 39 items distributed across four major factors, three of which can be parsed into two subfactors each. Main and subfactors include (1) physical symptoms (tense/restless and somatic/autonomic), (2) social anxiety (humiliation/rejection and public performance fears), (3) harm avoidance (perfectionism and anxious coping), and (4) separation anxiety. The MASC factor structure, which presumably reflects the in the vivo structure of pediatric anxiety symptoms, is invariant across gender and age and shows excellent internal reliability. As expected, females show greater anxiety on all factors and subfactors than males. Three-week and 3-month test-retest reliability was satisfactory to excellent. Parent-child agreement was poor to fair. Concordance was greatest for easily observable symptom clusters and for mother-child over father-child or father-mother pairs. Shared variance with scales sampling symptom domains of interest was highest for anxiety, intermediate for depression, and lowest for externalizing symptoms, indicating adequate convergent and divergent validity. CONCLUSION: The MASC is a promising self-report scale for assessing anxiety in children and adolescents.

The Diagnostic Interview Schedule for Children-Revised Version (DISC-R): I. Preparation, field testing, interrater reliability, and acceptability.

OBJECTIVE: To describe the history and assessment strategies used to investigate and revise the Diagnostic Interview Schedule for Children (DISC), a highly structured interview form used by lay interviewers to elicit diagnostic criteria for the common psychiatric disorders of childhood and adolescence. METHOD: Revision was based on clinical and community data that identified unreliable and undiscriminating items in an earlier version of the instrument (DISC-1). A field study was carried out with 74 parent-child pairs. Interrater reliability and acceptability to patients was high. Accompanying papers describe the test-retest and construct validity of the instrument. CONCLUSIONS: Taken together, the findings suggest that the DISC is an acceptable, brief, inexpensive, and convenient instrument for ascertaining a comprehensive range of child and adolescent diagnoses whose methodological properties are comparable with other child diagnostic instruments.

Bupropion hydrochloride in attention deficit disorder with hyperactivity.

OBJECTIVE: This is a multisite, double-blind, placebo-controlled trial to determine the safety and efficacy of bupropion in the treatment of children with attention deficit disorder with hyperactivity (ADDH). METHOD: In a four-center, double-blind comparison of bupropion (n = 72) and placebo (n = 37), children aged 6 to 12 years meeting DSM-III criteria for ADDH were randomized to receive bupropion 3 to 6 mg/kg per day or placebo, administered twice daily, at 7 A.M. and 7 P.M. Measures of efficacy included the Conners Parent and Teacher Questionnaires (93-item, 39-item, and 10 item), Clinical Global Impressions Scales of Severity and Improvement, the Sternberg Short-Term Memory Task, and the Continuous Performance Test. Screen and posttreatment physical examinations, electrocardiograms, electroencephalograms, and clinical laboratory evaluations were performed. Height, weight, and vital signs were measured and adverse experiences were assessed weekly. RESULTS: A significant treatment effect, apparent as early as day 3, was present for both conduct problems and hyperactivity on the Conners 10-item and 39-item teacher's checklist, and at day 28 for conduct problems and restless-impulsive behavior on the 93-item parent questionnaire. Findings were of smaller magnitude for parent ratings than teacher ratings. Significant treatment effects were present on both the Continuous Performance Test and memory retrieval test. Effect sizes of bupropion/placebo differences for teacher and parent ratings in this study were somewhat smaller than for standard stimulant drugs used to treat ADDH. Bupropion appeared to be well tolerated in most children. Dermatological reactions were twice as frequent in the drug group as the placebo group, with four reactions involving rash and urticaria that were serious enough to require discontinuation of medication. CONCLUSIONS: Bupropion may be a useful addition to available treatments for ADDH. Comparative trials with such standard drugs as methylphenidate are warranted to determine the relative clinical merits of bupropion.

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.

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.

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

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

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

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

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

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

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

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

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

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