Response inhibition and ADHD traits: correlates and heritability in a community sample.

Endophenotypes or intermediate phenotypes are of great interest in neuropsychiatric genetics because of their potential for facilitating gene discovery. We evaluated response inhibition, latency and variability measures derived from the stop task as endophenotypes of ADHD by testing whether they were related to ADHD traits in the general population, heritable and shared genetic risk with ADHD traits. Participants were 16,099 children and adolescents, ages 6 to 18 years who visited a local science center. We measured ADHD traits using the Strengths and Weaknesses of ADHD-symptoms and Normal-Behavior (SWAN) rating scale and performance on the stop signal task (SST)-response inhibition (SSRT), response latency (GoRT), and response variability (GoRTSD). Regression analysis was used to assess the relationship of cognitive measures and ADHD traits while controlling for family, age, sex, ethnicity, socioeconomic status and treatment status. Heritability of ADHD and cognitive traits was estimated using SOLAR in 7,483 siblings from 3,507 families that included multiple siblings. Bivariate relationships between pairs of variables were examined. Individuals with greater ADHD trait scores had worse response inhibition, slower response latency, and greater variability. Younger participants and girls had inferior performance although the gender effects were minimal and evident in youngest participants. Inhibition, latency, variability, total ADHD traits, inattention and hyperactivity-impulsivity scores were significantly heritable. ADHD traits and inhibition, but not latency or variability were coheritable. In the largest study in the general population, we found support for the validity of response inhibition as an endophenotype of ADHD.

Moderators and mediators of long-term adherence to stimulant treatment in children with ADHD.

OBJECTIVE: To identify moderators and mediators of long-term adherence to stimulant medication in children with attention-deficit hyperactivity disorder (ADHD). METHOD: Seventy-one children with ADHD were prescribed methylphenidate, followed prospectively on an annual basis for 3 years, and evaluated for adherence to stimulant treatment. The study occurred in Toronto between 1993 and 1997. Adherents were those who took methylphenidate, or another psychostimulant, for 5 or more days per week throughout the follow-up period, except for "drug holidays." Children who adhered at consecutive evaluations were compared with those who did not. Severity of ADHD, presence of oppositional defiant disorder/conduct disorder, learning difficulties, anxiety, age, family dysfunction, and socioeconomic adversity at baseline were investigated as moderators of adherence. Response to treatment at school, measured at 12 months, was investigated as a mediator of adherence. RESULTS: Fifty-two percent of children adhered to stimulant treatment for 3 years. Absence of teacher-rated oppositional defiant disorder, more teacher-rated ADHD symptoms, and younger age at baseline predicted adherence. CONCLUSIONS: Adherence to stimulant medications is a significant factor in the long-term treatment of children with ADHD.

Linkage of the dopamine D4 receptor gene and attention-deficit/hyperactivity disorder.

OBJECTIVE: There is considerable evidence supporting a genetic component in the etiology of attention-deficit/hyperactivity disorder (ADHD). Because stimulant medications act primarily on the dopaminergic system, dopamine system genes are prime candidates for genetic susceptibility factors for ADHD. Previous studies by several groups have observed a significant association of ADHD and an allele with 7 copies of the 48 base pair repeat in the third exon of the dopamine D4 receptor. METHOD: The authors sought to replicate these previous findings by collecting an independent sample of families from Toronto, Ontario, Canada, and confirming this finding in an expanded sample of ADHD families collected from Irvine, California. Using the transmission disequilibrium test (TDT), the authors tested for biased transmission of the 7-repeat allele at the exon III polymorphism of the dopamine D4 receptor locus in these samples of ADHD subjects. RESULTS: Biased transmission of the 7-repeat allele from parents to ADHD probands and their affected siblings was observed in the 2 new samples of families collected in Toronto and Irvine (TDT chi2 = 2.711, 1 df, one-sided p value = .050) and for these samples combined with the 52 families previously reported from Irvine (TDT chi2 = 6.426, 1 df, one-sided p value = .006). CONCLUSIONS: The results of this study further support the possibility of a role of the dopamine D4 receptor locus in ADHD.

Reformulating attention-deficit/hyperactivity disorder according to signal detection theory.

OBJECTIVE: The current diagnostic algorithm for attention-deficit/hyperactivity disorder (ADHD) is not highly predictive of impairment and yields low interrater agreement. The objective of this study was to enhance the diagnostic accuracy of ADHD by identifying the symptoms that are associated with impairment. METHOD: Semistructured interviews and impairment rating scales were administered to parents and teachers of 218 children. Combinations of ADHD symptoms were examined according to a receiver operating characteristic (ROC) based procedure to create diagnostic algorithms that predict impairment. RESULTS: In comparison with the DSM-IV, the ROC-based algorithms were 2 to 3 times more efficient in discriminating impaired from nonimpaired children. Parent and teacher agreement was also 3 times higher. CONCLUSIONS: Limiting the diagnosis to symptoms that predict impairment can increase the validity of the ADHD diagnosis. Results also support the use of ROC analyses in developing better diagnostic algorithms.

Beyond words: how do children with ADHD and/or conduct problems process nonverbal information about affect?

OBJECTIVE: To study nonverbal social cue perception in children with attention-deficit/hyperactivity disorder (ADHD; n = 86), conduct problems (CP; n = 24), or both disorders (ADHD + CP; n = 63), as well as normal controls (n = 27). METHOD: Using a standardized test of receptive nonverbal processing abilities, participants were required to interpret emotional cues from pictures of facial expressions and recordings of voices. RESULTS: As predicted, children with CP and ADHD were significantly less accurate at interpreting emotions than normal controls. However, children with CP and ADHD differed in the type of errors made: the ADHD group's errors were generally random in nature, whereas the CP group tended to misinterpret emotions as anger. Contrary to our hypothesis, the ADHD + CP group performed better than the ADHD and CP groups, was as accurate as the control group, and displayed a unique pattern of errors. CONCLUSIONS: These results support the idea that social deficiencies associated with CP arise from a biased perception of emotion, whereas social problems in ADHD originate from a failure to attend to the appropriate cues of affect. The findings also support the theory that comorbid ADHD + CP is a distinct disorder.

Does actigraphy differentiate ADHD subtypes in a clinical research setting?

OBJECTIVE: To compare subtypes of attention-deficit/hyperactivity disorder (ADHD) (predominantly inattentive and combined types) and a comparison group on an objective measure of activity level (actigraphy). METHOD: Actigraphs were worn by 64 children (49 boys, 15 girls) during a full-day clinical diagnostic assessment; 20 subjects had a diagnosis of ADHD predominantly inattentive type, 22 had ADHD combined type, and 22 were non-ADHD controls. Mean actigraph scores were calculated for two 2-hour intervals, comprising, respectively, a psychometric evaluation in the morning and the completion of a speech and language assessment and research measures in the afternoon. RESULTS: There were no significant group differences in activity level in the morning session. During the afternoon session, children with ADHD were significantly more active than controls, but there were no differences between ADHD subtypes. CONCLUSIONS: These data partially support specifications in the DSM-IV regarding hyperactivity in ADHD; however, they also indicate that situational and/or temporal factors may affect the degree to which hyperactivity is expressed. Furthermore, the findings contradict specifications in the DSM-IV that suggest that children with ADHD combined type should be more hyperactive than children with ADHD predominantly inattentive type.

Do typical clinical doses of methylphenidate cause tics in children treated for attention-deficit hyperactivity disorder?

OBJECTIVE: To determine whether typical clinical doses of methylphenidate (MPH) cause tics or exacerbate preexisting mild to moderate tics. METHOD: Ninety-one children with attention-deficit hyperactivity disorder, with and without comorbid tics (excluding severe tics and Tourette's syndrome), were randomly assigned to receive MPH or a placebo in a 1-year prospective study. The target dose was titrated to balance behavior change and side effects. Parents and teachers were the observers. RESULTS: Crossover from the placebo to MPH was common because of poor behavioral response. One MPH-treated subject dropped out; the final MPH group had 72 subjects; the placebo group, 18. The average dose of MPH was 0.5 mg/kg twice daily. Clinically significant tics developed in 19.6% of the subjects without preexisting tics receiving MPH and in 16.7% of those receiving the placebo (Fisher exact test, p = .59, not significant; relative risk = 1.17, confidence interval = 0.31-4.40). Deterioration of tics was observed in 33% of subjects with preexisting tics receiving MPH and in 33% of those receiving the placebo (Fisher exact test, p = .70, not significant; relative risk = 1.0, confidence interval = 0.40-1.85). CONCLUSIONS: Doses of MPH based on the typical clinical titration procedure did not produce significantly more tics than the placebo in children with or without preexisting (mild to moderate) tics.

Response to methylphenidate in children with ADHD and comorbid anxiety.

OBJECTIVE: To determine whether comorbid anxiety alters response to methylphenidate (MPH) in children with attention-deficit hyperactivity disorder (ADHD). METHOD: Ninety-one children with ADHD were assessed for anxiety. Children were randomly assigned to receive MPH or placebo, titrated to a dose of 0.7 mg/kg, while side effects were minimized. Measures of side effects and behavioral response were obtained from parents and teachers before treatment, after titration to optimal dose, and after 4 months of treatment. These measures, dose of drug, and rate of adherence to assigned medication assignment were compared for nonanxious (ADHD- ANX) and anxious ADHD children (ADHD+ ANX). RESULTS: Rates of adherence to original medication assignment did not differ between the groups. ADHD+ ANX on both MPH and placebo titrated to a lower dose at the end of titration, although the dose of drug did not differ among the groups after 4 months of treatment. No differential response to MPH between ADHD+ ANX and ADHD- ANX was noted at end-titration or at 4 months on any side effect or behavioral measures. CONCLUSIONS: Comorbid anxiety does not appear to influence development of side effects or behavioral response to MPH when dose is titrated as in standard clinical practice.

Development of inhibitory control across the life span.

The stop-signal procedure was used to examine the development of inhibitory control. A group of 275 participants, 6 to 81 years of age, performed a visual choice reaction time (go) task and attempted to inhibit their responses to the go task when they heard a stop signal. Reaction times to the stop and go signals were used to assess performance in inhibition and response execution, respectively. Results indicated the speed of stopping becomes faster with increasing age throughout childhood, with limited evidence of slowing across adulthood. By contrast, strong evidence was obtained for age-related speeding of go-signal reaction time throughout childhood, followed by marked slowing throughout adulthood. Hierarchical regression confirmed that the age-related change in inhibitory control could not be explained by general speeding or slowing of responses. Findings are discussed in regard to the contrast between the development of inhibition and response execution and the utility of the stop-signal procedure.

Behavioral, situational, and temporal effects of treatment of ADHD with methylphenidate.

OBJECTIVE: To determine the behavioral, situational, and temporal effects of 4 months of methylphenidate (MPH) treatment for attention-deficit hyperactivity disorder (ADHD). METHOD: Ninety-one children with ADHD were randomly assigned to receive either MPH (titrated to a target dose of 0.7 mg/kg twice a day) or a placebo. Treatment effects were investigated with measures sensitive to various behaviors (core and associated symptoms), situations (home and school), time periods (morning and afternoon, after reaching the target dose, and after 4 months of treatment), and side effects. RESULTS: MPH treatment improved symptoms of ADHD and oppositional behavior at school, both in the morning and afternoon, but not at home. Side effects (increase in physiological and effective symptoms, lack of weight gain) were significantly more frequent with MPH than with placebo treatment. Benefit was evident after titration, but the onset of some side effects was delayed. Side effects were reported by parents but not by teachers. CONCLUSIONS: Positive effects of MPH on behavior are evident in the classroom, but with MPH given twice daily, parents do not report that MPH improves behavior at home. Greater impact on home behavior may require three times daily MPH and combined treatments.

Narrative abilities in children with attention deficit hyperactivity disorder and normal peers.

A story retelling task was used to assess narrative abilities in 30 boys with attention deficit hyperactivity disorder (ADHD) and 30 normally developing boys, matched on age and IQ. Each boy listened to two stories and retold them for another child. Results indicated that the two groups did not differ in their ability to comprehend and extract the main ideas from the stories, but did differ in the production of narratives. Boys with ADHD provided less information overall, and their stories were more poorly organized and less cohesive and contained more inaccuracies. As a result, their stories were often confused and hard to follow. Organization and monitoring of information are functions of executive control. Thus the observed deficits in narrative production in children with ADHD may reflect underlying deficits in executive processes.

Effects of methylphenidate on inhibitory control in hyperactive children.

This study investigated the effects of methylphenidate (MPH) on inhibitory control in hyperactive children. A double-blind, placebo-control, within-subject (crossover) design was used in which 12 children, between 6 and 11 years of age, were each tested four times in each drug condition: 0.3 mg/kg and 1.0 mg/kg of methylphenidate, and placebo. Dependent measures included (a) the probability of inhibiting responses to a primary choice reaction time task given a stop signal, on the Stopping Task, and (b) response latency and errors on the Matching Familiar Figures Test (MFFT). MPH improved the efficiency of the central inhibitory mechanism by speeding the inhibitory process, thereby affording the children greater control over their actions and enabling them to increase the probability with which they inhibited responses given a stop signal. MPH increased response latency but did not reduce errors on the MFFT, and observation of the children's task performance highlighted the interpretive problems associated with this task. Performance on both tasks was better at a dosage of 1.0 mg/kg than at 0.3 mg/kg.

Dose-response effects of methylphenidate on academic performance and overt behavior in hyperactive children.

In the present study, the effects of 0.3 mg/kg and 1.0 mg/kg of methylphenidate on the overt behavior and academic functioning of 12 children with an established diagnosis of attention deficit disorder with hyperactivity were evaluated. A double-blind, placebo-control, within-subject (crossover) design was used, in which each child was tested four times in each drug condition. Drug conditions were alternated on a bidaily basis and each child received two different drug conditions each day. The academic tasks were designed for evaluation of the relationship between task complexity and dose. Whereas overt behavior improved with increasing dose, academic functioning was improved with methylphenidate, but did not vary with either dose or task complexity. Also, investigated were potential carryover effects of a morning dose of methylphenidate on performance in the afternoon. Behavioral and academic improvements produced by a dose of 0.3 mg/kg in the morning were no longer evident in the afternoon, but a morning dose of 1.0 mg/kg produced behavioral improvements that were clinically and statistically discernible in the afternoon, although the academic improvements had dissipated.

Evaluating attitudes of child psychiatry residents to psychotropic medication: implications for training.

The attitudes of child psychiatry residents toward the use of psychotropic medication in child psychiatric practice were studied. Eighteen residents underwent a semistructured interview that covered their experience in child psychiatry, beliefs about etiology of child psychopathology, preferences for treatment, attitude toward and experience with drugs in treating childhood disturbances. The residents favored a psychosocial view of the etiology of child disturbance and preferred family therapy to other forms of treatment. Six had never treated a child with medication and most were uncertain about indications for drug use and felt they had less than average or poor skills in this area. Seven residents, who did not attend department psychopharmacology seminars and had little clinical experience with drugs, had a strong antipathy toward their use. Experience with and attitude toward drug use could not be predicted from the residents' appraisal of their own competence in this field, their experience in child psychiatry, their appreciation of the biological contributions to child psychopathology, or their future practice plans.