Long-term but not short-term p38 mitogen-activated protein kinase inhibition improves cardiac function and reduces cardiac remodeling post-myocardial infarction.

p38 mitogen-activated protein kinase (p38 MAPK) inhibition exerts beneficial effects on left ventricular (LV) remodeling and dysfunction. p38 MAPK activity is transiently increased soon after myocardial infarction (MI), suggesting brief inhibition may afford the same benefit as long-term inhibition. We examined chronic 12-week p38 MAPK inhibition compared with short-term (7-day) inhibition, and then we discontinued inhibition after MI. Post-MI rats at day 7 received either vehicle, 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1-ol (RWJ67657; RWJ) for 12 weeks (long term; LT-RWJ), RWJ for 1 week and discontinued for 11 weeks (1-week RWJ), or continuous ramipril for 12 weeks. In separate groups of animals, 24 h after MI, vehicle or RWJ was administered for 7 days. Cardiac function was assessed by echocardiography and hemodynamic measurements. Percentage of fractional shortening improved after LT-RWJ and ramipril, but not after 1-week RWJ treatment. Likewise, LV contractility and maximal first derivative of left ventricular pressure (dP/dt(max)) was improved (12.5 and 14.4%) and LV end diastolic pressure (LVEDP) was reduced (49.4 and 54.6%) with both treatments. Functional outcomes were accompanied by regression of interstitial collagen I and alpha-smooth muscle actin expression in LV noninfarct, border, and infarct regions with LT-RWJ and ramipril treatment. Hypertrophy was reduced in noninfarct (18.3 and 12.2%) and border regions (16.3 and 12.0%) with both treatments, respectively. Animals receiving RWJ 24 h after MI for 7 days showed similar improvements in fractional shortening, dP/dt(max), LVEDP, including reduced fibrosis and hypertrophy. In vitro experiments confirmed a dose-dependent reduction in hypertrophy, with RWJ following tumor necrosis factor-alpha stimulation. Continuous but not short-term p38 MAPK blockade attenuates post-MI remodeling, which is associated with functional benefits on the myocardium.

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.

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.

Is expressed emotion a specific risk factor for depression or a nonspecific correlate of psychopathology?

Five Minute Speech Sample Expressed Emotion (FMSS-EE) was examined in families of youth with depressive disorders, nondepressed youth with attention deficit/hyperactivity disorder (ADHD), and community controls screened for the absence of depression and ADHD. Consistent with the hypothesis that FMSS-EE shows some specificity as a risk factor for depression, rates of critical EE were significantly higher among mothers of youth with depression as compared to mothers of nondepressed youth with ADHD, or mothers of controls. When both mothers' and fathers' scores were used to generate family EE ratings, rates of overall EE and critical EE were significantly higher for the depressed group than the control group, but the nondepressed ADHD group did not differ significantly from the other groups. Results support the hypothesis that critical EE in mothers shows some specificity as a risk factor or correlate of depression in youth.

Psychosocial treatment strategies in the MTA study: rationale, methods, and critical issues in design and implementation.

The Collaborative Multimodal Treatment Study of Children with Attention Deficit Hyperactivity Disorder (ADHD), the MTA, is the first multisite, cooperative agreement treatment study of children, and the largest psychiatric/psychological treatment trial ever conducted by the National Institute of Mental Health. It examines the effectiveness of Medication vs. Psychosocial treatment vs. their combination for treatment of ADHD and compares these experimental arms to each other and to routine community care. In a parallel group design, 579 (male and female) ADHD children, aged 7-9 years, 11 months, were randomly assigned to one of the four experimental arms, and then received 14 months of prescribed treatment (or community care) with periodic reassessments. After delineating the theoretical and empirical rationales for Psychosocial treatment of ADHD, we describe the MTA's Psychosocial Treatment strategy applied to all children in two of the four experimental arms (Psychosocial treatment alone; Combined treatment). Psychosocial treatment consisted of three major components: a Parent Training component, a two-part School Intervention component, and a child treatment component anchored in an intensive Summer Treatment Program. Components were selected based on evidence of treatment efficacy and because they address comprehensive symptom targets, settings, comorbidities, and functional domains. We delineate key conceptual and logistical issues faced by clinical researchers in design and implementation of Psychosocial research with examples of how these issues were addressed in the MTA study.

Do stimulants improve self-esteem in children with ADHD and peer problems?

The self-esteem of children with Attention Deficit Hyperactivity Disorder (ADHD) has been shown to be low. The effects of stimulant medication upon their self-esteem have not been systematically studied. The present study employed a reliable self-report instrument to measure the self-esteem of children with ADHD medicated with stimulants vs. those who were unmedicated. Results showed that stimulants were associated with significantly higher self-esteem. Children with ADHD prescribed stimulants reported feeling more intelligent and more popular than unmedicated children with ADHD. Children with ADHD and Oppositional Defiant Disorder (ODD) prescribed stimulants reported feeling better behaved. Significant correlations indicated that higher doses were associated with higher self-esteem. The present results suggest a need for a well-controlled study to determine if stimulants were responsible for the observed differences in self-esteem.

When the earth stops shaking: earthquake sequelae among children diagnosed for pre-earthquake psychopathology.

OBJECTIVE: To examine risk and protective processes for posttraumatic stress reactions and negative sequelae following the Northridge earthquake (EQ) among youths diagnosed for pre-EQ psychopathology. METHOD: Symptoms of posttraumatic stress disorder (PTSD), depression, general anxiety, and social impairment were evaluated using telephone interviews among 66 children participating in a family-genetic study of childhood-onset depression at the time of the EQ. RESULTS: Significant predictors of PTSD symptoms 1 year after the EQ included perceived stress and resource loss associated with the EQ, a pre-EQ anxiety disorder, and more frequent use of cognitive and avoidance coping strategies. PTSD symptoms were associated with high rates of concurrent general anxiety symptoms, depressive symptoms, and social adjustment problems with friends. The only significant correlation between sibling scores was on measures of sibling reports of objective exposure. CONCLUSIONS: Preexisting anxiety disorders represent a risk factor for postdisaster PTSD reactions. Postdisaster services need to attend to the needs of these youths as well as those of youths experiencing high levels of subjective stress, resource loss, and/or high exposure. That children within families show significant variation in postdisaster reactions underscores the need for attention to individual child characteristics and unshared environmental attributes.

Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral problem afflicting 5-10% of children and adolescents and persisting into adulthood in 30-50% or more of cases. Family, twin, and adoption studies suggest genetic factors contribute to ADHD and symptoms of inattention, impulsivity, and hyperactivity. Because stimulant intervention is effective in reducing ADHD symptoms in about 70-80% of cases, molecular genetic investigations of genes involved in dopamine regulation are currently underway by many groups. In a case control study of the dopamine D4 receptor gene (DRD4) and ADHD, La Hoste and colleagues found an increase of a 7-repeat variant of a 48-bp VNTR in exon 3 among ADHD subjects compared to controls. Swanson and colleagues replicated this finding in a sample of 52 ADHD probands and their biological parents using a haplotype relative risk analysis. Here, we describe linkage investigations of the VNTR and ADHD in affected sibling pair (ASP) families and singleton families using both the transmission disequilibrium test (TDT) and a mean test of identity-by-descent (IBD) sharing. Using the TDT in the total sample, the 7 allele is differentially transmitted to ADHD children (P = 0.03) while the mean test revealed no evidence of increased IBD sharing among ASPs. In the current sample, the 7 allele attributes a 1.5-fold risk for developing ADHD over non-carriers of the allele estimated under a model described by Risch and Merikangas.

Objective and subjective measures of the pharmacodynamic effects of Adderall in the treatment of children with ADHD in a controlled laboratory classroom setting.

In a randomized double-blind crossover study of children with attention deficit hyperactivity disorder (ADHD), the time course effects of four doses of Adderall (5, 10, 15, and 20 mg) and an inactive (placebo) control, and an active (Ritalin) control were evaluated. A laboratory classroom setting was established in which subjective (teacher ratings of deportment and attention) and objective (scores on math tests) measurements were taken every 1.5 hours across the day. In addition to significant time and dose effects of Adderall, significant time-of-day effects were documented in the placebo condition for the subjective measure of deportment and objective measures of performance. Regression analyses were used to estimate the magnitude of these baseline effects. Correlations across time were used to evaluate the test-retest reliability of each measure in the face of these time-dependent placebo effects. After placebo/time adjustments, within-subject correlations between pairs of measures were used to evaluate the validity of the math test as a measure of response to stimulant medication.

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.

ADHD through the life span: the role of bupropion in treatment.

Attention-deficit/hyperactivity disorder (ADHD) is a common problem that begins early in life and in many cases persists through the life span. Psychostimulants have been the psychopharmacologic treatment of choice. Not all patients respond to psychostimulants, and some patients have significant side effects. This paper reviews the use of a nonstimulant psychopharmacologic agent, bupropion, to treat ADHD in both children and adults.

Evaluation of individual subjects in the analog classroom setting: II. Effects of dose of amphetamine (Adderall).

Multiple dependent variables were graphed for 29 subjects who participated in a double-blind evaluation of 4 doses of Adderall, plus positive (methylphenidate) and placebo control conditions. Five judges ranked the conditions for each subject, and analyses of individual subjects indicated that these rankings were concordant (reliable) across judges. Consensus rankings were assigned to each subject, and an analysis of these ranks showed that the conditions differed significantly. The choice of best conditions were judged to be across 3 doses of Adderall (10, 15, and 20 mg). This confirms the clinical impression of individual differences in optimal dose of stimulant medication. The methodological, graphical, and statistical methods presented in this article provide a systematic, reliable procedure for evaluating relative response of individuals to different doses of stimulant medication.

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.

Parent-assisted transfer of children's social skills training: effects on children with and without attention-deficit hyperactivity disorder.

OBJECTIVE: Previous research has demonstrated that peer rejection is a significant part of the clinical presentation of many children with attention-deficit hyperactivity disorder (ADHD). Outcome studies of treatment interventions have typically failed to show generalization of treatment gains to the home and classroom. This has been especially true for children who have comorbid oppositional defiant disorder (ODD). The present study was intended to demonstrate generalization of an outpatient social skills training program when parents were trained in skills relevant to their child's social adjustment. METHOD: Thirty-five children with ADHD and 14 children without ADHD were given 12 sessions of treatment (treatment group). Outcome was compared with 12 children with ADHD and 12 children without ADHD who were on a waitlist for treatment (waitlist group). Nineteen children with ODD were in the treatment group and five in the waitlist. Stimulant medication was prescribed for all children with ADHD. RESULTS: Subjects with ADHD showed improvement comparable with that of subjects without ADHD on all teacher- and parent-reported measures of peer adjustment and social skills, except teacher-reported withdrawal. Children with ODD had outcome comparable with that of children without ODD. Effect sized ranged from 0.93 to 1.34 indicating that the average treatment group subject was better off than 83.4% of waitlist subjects on outcome measures. CONCLUSIONS: The present results suggest that children with ADHD are best heiped by a combination of social skills training for themselves, collateral training for their parents and stimulant medication.

Comorbidity in ADHD: implications for research, practice, and DSM-V.

OBJECTIVE: Since the introduction of DSM-III/III-R, clinicians and investigators have shown increasing interest in the study of conditions comorbid with attention-deficit hyperactivity disorder (ADHD). Better understanding ADHD comorbidity patterns is needed to guide treatment, research and future classification approaches. METHOD: The ADHD literature from the past 15 years was reviewed to (1) explore the most prevalent patterns of ADHD comorbidity; (2) examine the correlates and longitudinal predictors of comorbidity; and (3) determine the extent to which comorbid patterns convey unique information concerning ADHD etiology, treatment and outcomes. To identify potential new syndromes, the authors examined comorbid patterns based on eight validational criteria. RESULTS: The largest available body of literature concerned the comorbidity with ADHD and conduct disorder/aggression, with a substantially smaller amount of data concerning other comorbid conditions. In many areas the literature was sparse, and pertinent questions concerning comorbidity patterns remain unexplored. Nonetheless available data warrant the delineation of two new subclassifications of ADHD: (1) ADHD aggressive subtype, and (2) ADHD, anxious subtype. CONCLUSIONS: Additional studies of the frequency of comorbidity and associated factors are greatly needed to include studies of differential effects of treatment of children with various comorbid ADHD disorders, as well as of ADHD children who differ on etiological factors.

Use of the Child Behavior Checklist and DSM-III-R diagnosis in predicting outcome of children's social skills training.

A standardized 12-week cognitive-behavioral social skills package in which parents assisted children with socialization homework assignments, was presented to 52 nonpsychotic outpatient boys, many of whom were diagnosed with DSM-III-R Attention Deficit-Hyperactivity Disorder and Oppositional Defiant Disorder. Results demonstrated that the Thought Problems factor of the mother-completed Child Behavior Checklist aided in predicting changes in teacher-rated aggression. DSM-III-R diagnosis of Oppositional Defiant Disorder predicted changes in teacher-rated withdrawal subsequent to treatment. The need for research to determine which children benefit from which treatment was discussed.