Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway.

Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [(11)C]raclopride and [(11)C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11±5 vs 14±3, P<0.001) and was significantly correlated with D2/D3 receptors (accumbens: r=0.39, P<0.008; midbrain: r=0.41, P<0.005) and transporters (accumbens: r=0.35, P<0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor-and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.

Comorbidity in adults with attention-deficit/hyperactivity disorder.

This paper describes the clinical manifestations of attention-deficit/hyperactivity disorder (ADHD) in adulthood, with particular emphasis placed on issues relating to comorbidity. Prospective and retrospective studies are reviewed to evaluate the degree to which adults with ADHD exhibit clinical features that mirror their childhood counterparts with analogous comorbid psychiatric (e.g., antisocial, mood, and anxiety) and/or cognitive (i.e., learning) disorders. We also address the question of whether comorbid disorders in adults represent independent diagnostic entities and whether the presence of psychiatric comorbidity varies as a function of ADHD subtype (i.e., inattentive, hyperactive-impulsive, combined, and residual). As is the case for ADHD in childhood, comorbidity is not uncommon among adults with ADHD. However, the reported prevalence of comorbid conditions among adults with ADHD varies considerably depending upon whether the research used a prospective or retrospective design.

Findings from the NIMH Multimodal Treatment Study of ADHD (MTA): implications and applications for primary care providers.

In 1992, the National Institute of Mental Health and 6 teams of investigators began a multisite clinical trial, the Multimodal Treatment of Attention-Deficit Hyperactivity Disorder (MTA) study. Five hundred seventy-nine children were randomly assigned to either routine community care (CC) or one of three study-delivered treatments, all lasting 14 months. The three MTA treatments-monthly medication management (usually methylphenidate) following weekly titration (MedMgt), intensive behavioral treatment (Beh), and the combination (Comb)-were designed to reflect known best practices within each treatment approach. Children were assessed at four time points in multiple outcome. Results indicated that Comb and MedMgt interventions were substantially superior to Beh and CC interventions for attention-deficit hyperactivity disorder symptoms. For other functioning domains (social skills, academics, parent-child relations, oppositional behavior, anxiety/depression), results suggested slight advantages of Comb over single treatments (MedMgt, Beh) and community care. High quality medication treatment characterized by careful yet adequate dosing, three times daily methylphenidate administration, monthly follow-up visits, and communication with schools conveyed substantial benefits to those children that received it. In contrast to the overall study findings that showed the largest benefits for high quality medication management (regardless of whether given in the MedMgt or Comb group), secondary analyses revealed that Comb had a significant incremental effect over MedMgt (with a small effect size for this comparison) when categorical indicators of excellent response and when composite outcome measures were used. In addition, children with parent-defined comorbid anxiety disorders, particularly those with overlapping disruptive disorder comorbidities, showed preferential benefits to the Beh and Comb interventions. Parental attitudes and disciplinary practices appeared to mediate improved response to the Beh and Comb interventions.

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.

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.

Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial.

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

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.

Relationship between central serotonergic function and aggression in prepubertal boys: effect of age and attention-deficit/hyperactivity disorder.

Data indicate that diminished central serotonergic (5-HT) function is related to aggression in adults, but discrepant findings in children suggest that age or the presence of attention-deficit/hyperactivity disorder (ADHD) may influence this relationship. This study examined whether age or ADHD affects the association between 5-HT and aggression in 7-11-year old clinically-referred boys. Forty-six boys were divided into non-aggressive ADHD, aggressive ADHD, and aggressive non-ADHD groups based on responses to interviews and ratings of behavior. Central 5-HT function was assessed by measuring the prolactin response to a 1-mg/kg oral dose of D,L-fenfluramine. There was no significant difference in the prolactin response across the three groups of boys. Furthermore, when examined dimensionally, prolactin response was largely unrelated to ratings of aggression, even after controlling for ADHD. Finally, age was not associated with prolactin response, and had no effect on the relationship between prolactin response and aggression. This study provides further evidence that there is no clear relationship between central 5-HT function and aggression in disruptive boys. Moreover, these data do not confirm the hypothesis that age or the presence of ADHD influence the relationship between 5-HT and childhood aggression.

Anxiety as a predictor and outcome variable in the multimodal treatment study of children with ADHD (MTA).

Initial moderator analyses in the Multimodal Treatment Study of Children with ADHD (MTA) suggested that child anxiety ascertained by parent report on the Diagnostic Interview Schedule for Children 2.3 (DISC Anxiety) differentially moderated the outcome of treatment. Left unanswered were questions regarding the nature of DISC Anxiety, the impact of comorbid conduct problems on the moderating effect of DISC Anxiety, and the clinical significance of DISC Anxiety as a moderator of treatment outcome. Thirty-three percent of MTA subjects met DSM-III-R criteria for an anxiety disorder excluding simple phobias. Of these, two-thirds also met DSM-III-R criteria for comorbid oppositional-defiant or conduct disorder whereas one-third did not, yielding an odds ratio of approximately two for DISC Anxiety, given conduct problems. In this context, exploratory analyses of baseline data suggest that DISC Anxiety may reflect parental attributions regarding child negative affectivity and associated behavior problems (unlike fearfulness), particularly in the area of social interactions, another core component of anxiety that is more typically associated with phobic symptoms. Analyses using hierarchical linear modeling (HLM) indicate that the moderating effect of DISC Anxiety continues to favor the inclusion of psychosocial treatment for anxious ADHD children irrespective of the presence or absence of comorbid conduct problems. This effect, which is clinically meaningful, is confined primarily to parent-reported outcomes involving disruptive behavior, internalizing symptoms, and inattention; and is generally stronger for combined than unimodal treatment. Contravening earlier studies, no adverse effect of anxiety on medication response for core ADHD or other outcomes in anxious or nonanxious ADHD children was demonstrated. When treating ADHD, it is important to search for comorbid anxiety and negative affectivity and to adjust treatment strategies accordingly.

Family processes and treatment outcome in the MTA: negative/ineffective parenting practices in relation to multimodal treatment.

To elucidate processes underlying therapeutic change in a large-scale randomized clinical trial, we examined whether alterations in self-reported parenting practices were associated with the effects of behavioral, medication, or combination treatments on teacher-reported outcomes (disruptive behavior, social skills, internalizing symptoms) in children with attention-deficit hyperactivity disorder (ADHD). Participants were 579 children with Combined-type ADHD, aged 7-9.9 years, in the Multimodal Treatment Study of Children with ADHD (MTA). We uncovered 2 second-order factors of parenting practices, entitled Positive Involvement and Negative/Ineffective Discipline. Although Positive Involvement was not associated with amelioration of the school-based outcome measures, reductions in Negative/Ineffective Discipline mediated improvement in children's social skills at school. For families showing the greatest reductions in Negative/Ineffective Discipline, effects of combined medication plus behavioral treatment were pronounced in relation to regular community care. Furthermore, only in combination treatment (and not in behavioral treatment alone) was decreased Negative/Ineffective Discipline associated with reduction in children's disruptive behavior at school. Here, children in families receiving combination treatment who showed the greatest reductions in Negative/Ineffective Discipline had teacher-reported disruptive behavior that was essentially normalized. Overall, the success of combination treatment for important school-related outcomes appears related to reductions in negative and ineffective parenting practices at home; we discuss problems in interpreting the temporal sequencing of such process-outcome linkages and the means by which multimodal treatment may be mediated by psychosocial processes related to parenting.

Familial aggregation of ADHD characteristics.

Patterns of familial aggregation of ADHD symptoms in parents of ADHD and non-ADHD children were examined. Within the ADHD sample, symptom aggregation was examined as a function of biological relationship, parent and child gender, and children's comorbid diagnoses. Participants consisted of parents of 579 children with ADHD, Combined Type participating in the multimodal treatment study of children with ADHD and parents of 288 normal control participants. Adult symptoms of ADHD were measured by both self-report and report of a significant other. Results indicated that the parents of children with ADHD had higher ratings of inattention/cognitive problems, hyperactivity/restlessness, impulsivity/emotional lability, and lower self-concept than parents of children without ADHD on both self-report and other-report ratings. Within the ADHD sample of children, other-report ratings of inattention/cognitive problems and impulsivity/emotional lability were higher for biological parents compared to nonbiological parents whereas self-ratings were not related to biological status. These findings support previous research documenting familial aggregation of ADHD and appear to strengthen the hypothesis that there is a genetic contribution to ADHD.

Serotonin and aggression in children.

Research consistently indicates that in animals and adults, reduced central serotonergic (5-HT) function is associated with increased aggression. This relationship has been elucidated via cerebrospinal fluid monoamine metabolite levels, hormonal responses to pharmacologic challenge using serotonergic probes, platelet receptor binding studies, and, more recently, through molecular genetic approaches. In contrast, studies examining the relationship of 5-HT to aggression in children have been characterized by inconsistent findings. The literature examining the relationship between central 5-HT function and aggression is reviewed. Several hypotheses that might account for the discrepancies in the child literature are examined.

The neurobiology of attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder is a childhood psychiatric disorder characterized by inattention, impulsivity, and overactivity. Considerable research has focused on the neurobiological substrates of this disorder. Although the specific nature of the brain dysfunction remains elusive, progress has been made and several models of the underlying pathophysiology have been suggested. Research in the fields of neuropsychology, neuroimaging, neurochemistry, and molecular genetics, which points to a multifactorial etiology for the disorder, is reviewed. While several inconsistencies exist across studies, evidence supports dysfunction of fronto-striatal dopaminergic and noradrenergic circuits with resultant executive deficits in cognitive functioning.

Parent-teacher concordance for DSM-IV attention-deficit/hyperactivity disorder in a clinic-referred sample.

OBJECTIVE: To examine concordance between parent and teacher reports of DSM-IV attention-deficit/hyperactivity disorder (ADHD) and its symptoms. METHOD: Parents and teachers of 74 clinically referred children were interviewed using the ADHD module of the Diagnostic Interview Schedule for Children. Parent-teacher agreement for the diagnosis of ADHD and its subtypes, as defined in DSM-IV, as well as parent-teacher concordance of in-school ADHD symptoms, was examined. RESULTS: Agreement between parents and teachers was found to be relatively poor, with virtually no agreement for individual ADHD subtypes. Diagnoses based on either parent or teacher report frequently yielded a diagnosis of either inattentive or hyperactive-impulsive subtype of ADHD. However, when cross-informant data were used to form diagnoses, these subtypes became relatively rare, with most cases meeting criteria for ADHD combined type. In addition, parent reports of in-school behavior were more highly correlated with their own reports of their child's behavior at home than with teacher reports of their child's behavior in school. CONCLUSIONS: These data suggest that the diagnosis of ADHD inattentive or hyperactive-impulsive subtype based on data from a single informant may be of questionable validity, and they point to the importance of using multiple informants when diagnosing this disorder in clinically referred samples.

ADHD and reading disabilities: a cluster analytic approach for distinguishing subgroups.

Data suggest that children with reading disability (RD) and non-RD children with attention-deficit/hyperactivity disorder (ADHD) may comprise distinct subgroups. Research has been hampered by variance in definitional criteria, which results in the study of different subgroups of children. Using cluster analysis, this study empirically divided children with ADHD (N = 54), based on their Full Scale IQ (FSIQ) and reading ability. Four distinct subgroups emerged in which cognitive, behavioral, and neurochemical function was compared. Cluster 1 was of average FSIQ and reading scores; Cluster 2 was of average FSIQ but showed impairment in reading; Cluster 3 had high FSIQ and reading scores; and Cluster 4 had low scores in both domains. The groups had different patterns of cognitive, behavioral, and neurochemical function, as determined by discrepancies in Verbal-Performance IQ, academic achievement scores, parent aggression ratings, and a measure of noradrenergic function. These distinctions are discussed with regard to etiology, treatment, and long-term outcome.