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IntroductionGuanfacine extended release (GXR) is a non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD).ObjectiveTo separate efficacy and sedative treatment-emergent adverse events (TEAEs) associated with GXR in four randomized, controlled trials in children (6–12 years) and adolescents (13–17 years) with ADHD.MethodsSPD503-301 (n = 345) and SPD503-304 (n = 324) were 8 and 9 week studies of fixed-dose GXR (≤ 4 mg/day). SPD503-312 (n = 314; adolescents only) and SPD503-316 (n = 338) were 10–13 week studies of dose-optimized GXR (1–7 mg/day).ResultsIn fixed-dose studies, pooled incidences of sedative TEAEs with GXR were highest at week 1 (GXR, 13.9–18.7%; placebo, 8.7%) and decreased to placebo levels at week 8 (0–1.4%; placebo, 0%). In contrast, proportions of responders (≥ 30% reduction from baseline in ADHD Rating Scale IV [ADHD-RS-IV] total score) increased from week 1 (GXR, 29.6–34.8%; placebo, 25.0%) through endpoint (GXR, 66.7–72.2%; placebo, 42.6%). Incidences of sedative TEAEs, but not proportions of responders, increased with GXR dosing. GXR was associated with a statistically significant reduction in ADHD-RS-IV total score from baseline to endpoint in patients without sedative TEAEs in both fixed-dose and dose-optimized studies (GXR versus placebo, effect size = 0.49 and 0.67, respectively; P < 0.001). GXR was associated with statistically significant improvements compared with placebo in both ADHD-RS-IV Hyperactivity/Impulsivity and Inattentiveness subscale scores (P < 0.001).ConclusionThese data from pooled GXR clinical trials indicate that incident sedative TEAEs do not contribute to increased treatment response over time, and that sedation and symptomatic improvement are distinct effects of GXR.Disclosure of interestThe authors have not supplied their declaration of competing interest.

This preliminary study evaluated a method for assessing central noradrenergic function in children via the growth hormone response to a single dose of the alpha-2 adrenergic receptor agonist guanfacine and examined whether this measure distinguishes between attention deficit hyperactivity disorder (ADHD) boys with and without reading disabilities (RD).Plasma growth hormone was assessed before and after the oral administration of guanfacine and placebo in boys with ADHD who were divided into subgroups based on the presence (n = 3) or absence (n = 5) of RD.Guanfacine and placebo conditions did not differ at baseline, but peak growth hormone was significantly higher following guanfacine. The increase in growth hormone following guanfacine was significantly greater in boys without RD as compared to those with RD, with no overlap between the groups.Consistent with findings using peripheral measures of noradrenergic function, these preliminary data suggest that ADHD boys with and without RD may differ in central noradrenergic function.

This study aimed to describe the kinds of stressors and the extent of symptoms of posttraumatic stress disorder (PTSD) that were reported by children and their parents in a pediatric emergency department and to examine the response rate to an emotional trauma questionnaire in this setting.Three self-report questionnaires were given to patients aged eight to 21 years and to their primary caretakers: a brief assessment of service use, the Posttraumatic Stress Reaction Index (PTSRI), and the Impact of Event Scale (IES).Sixty-four of 81 families who were approached agreed to participate (consent rate of 79 percent), and 62 completed the questionnaires. Fifty-six patients reported at least one event that met DSM-IV-TR criteria for emotional trauma. The average number of reported events per child was 3.14 (range, 0 to 7). Eighteen patients met threshold criteria for severity of PTSD symptoms. Twenty-five patients reported that the most distressing traumatic event that they experienced was related to a medical illness. Patients with PTSD reported exposure to more adverse life events than patients without PTSD. IES scores reported by caretakers who identified the same event as their child as the most stressful were as high as those of caretakers who reported a different event as the most stressful.Exposures to emotionally traumatic events and PTSD symptoms are commonly reported in the pediatric emergency department. Asking children and their parents about their history of emotional trauma when they visit the emergency department is possible and can be well received.

Objective To provide preliminary psychometric data on the Children's Aggression Scale–Teacher Version (CAS-T), which was designed to assess severity and frequency of aggressive, as distinct from nonaggressive, disruptive behaviors. Method The CAS-T has 23 items representing five domains: Verbal aggression, Aggression against objects and animals, Provoked physical aggression, Unprovoked physical aggression, and Use of weapons. The CAS-T was completed for 273 nonreferred boys and 67 clinically referred children (60 boys; 7 girls). Coefficient α was assessed separately in clinical and nonreferred groups. Validity was evaluated by comparing CAS-T scores of children with different disruptive behavior disorder diagnoses and by examining the relationship of CAS-T scores to other parent and teacher ratings. Results The scale as a whole had excellent reliability as measured by coefficient α. Children with conduct disorder were rated significantly higher than those with oppositional defiant disorder, attention-deficit/hyperactivity disorder, and no disruptive behavior disorder diagnosis. Further, patterns of correlations with other rating scales provide strong support for the convergent and discriminant validity of the CAS-T. Conclusions The CAS-T may fill a gap in that it distinguishes among various types and severity of aggression, as distinct from oppositional-defiant behaviors.

OBJECTIVE: The authors assessed the efficacy of once-daily atomoxetine administration in the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). METHOD: In a double-blind study, children and adolescents with ADHD (N=171, age range=6–16 years) were randomly assigned to receive 6 weeks of treatment with either atomoxetine (administered once daily) or placebo. RESULTS: Outcomes among atomoxetine-treated patients were superior to those of the placebo treatment group as assessed by investigator, parent, and teacher ratings. The treatment effect size (0.71) was similar to those observed in previous atomoxetine studies that used twice-daily dosing. Parent diary ratings suggested that drug-specific effects were sustained late in the day. Discontinuations due to adverse events were low (less than 3%) for both treatment groups, and no serious safety concerns were observed. CONCLUSIONS: Once-daily administration of atomoxetine is an effective treatment for children and adolesc...

Attention-deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder that affects many domains of life. Studies have shown that adequate treatment of ADHD can affect the course of the disorder in a fundamental manner. While nonpharmacologic treatments such as education and various psycho-social interventions are used in the management of ADHD, pharmacotherapy is the mainstay of treatment for this disorder. Psychostimulants are the only group of agents that have been approved for the ADHD indication and are considered to be first-line treatment for the disorder. Methylphenidate, amphetamines, andpemoline are the most commonly used agents in this group. The stimulants have been successfully used for many years and their efficacy has been confirmed by a large number of clinical studies. Recent pharmacological advances have been made with longer-acting stimulants, new isomers, and more advanced drug delivery systems that enable more convenient dosing schedules with drug effects lasting throughout the day. Other nonstimulant medications have been shown to have anti-ADHD activity as well, although more research is needed on the efficacy and utility of these treatments. Antihypertensive medications and antidepressants, such as tricyclics and bupropion, have been studied and may have applications in the treatment of specific subgroups of patients with comorbid conditions or for patients who do not respond to stimulant treatment.

This study examined seasonal variations in central 5-HT function in a relatively large sample of prepubertal boys with attention-deficit/hyperactivity disorder (ADHD). In addition, seasonal differences in central 5-HT function among aggressive and non-aggressive children in the sample were explored. Ninety-three boys with ADHD were divided into aggressive (n=54) and nonaggressive (n=39) groups based on parental responses to interviews and ratings of behavior. Central 5-HT function was assessed by measuring the prolactin response to a single 1 mg/kg oral dose of d,l-fenfluramine. The prolactin values were derived from different children over the course of eight years, but were collapsed across years and analyzed in terms of day of the year. Cosinor analysis revealed no annual, bi-annual, 3-monthly, 2-monthly, monthly, or bi-monthly rhythms in the prolactin response in the entire sample of boys with ADHD. Moreover, there was no evidence of seasonal differences in the prolactin response between the aggressive and non-aggressive subgroups. These results indicate that seasonality-related variance is not a threat to the validity of the neurochemical procedure and does not account for the inconsistencies in the studies of central 5-HT and aggression in children with ADHD.

Treatment studies in child and adolescent psychiatry are increasingly characterized by long-term, multisite, randomized clinical trials (RCTs). During the course of these RCTs it is common for clinical exigencies to emerge that require rapid, direct intervention. The challenge is to provide clinically appropriate responses that do not contaminate the delivery, distinctness, and interpretation of the treatments under investigation. In multisite studies, the problem is compounded by the need to minimize cross-site differences in the delivery of adjunct treatments. Such minimization requires fully operationalized and manual-based procedures for clinically mandated intervention. The NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (ADHD)--"the MTA"--is a long-term multisite collaborative study in which children with ADHD were randomly assigned to either medication management, behavioral treatment, the combination, or community-comparison assessment and referral. In designing its study, the MTA developed a manual-based set of procedures (the MTA Adjunct Services and Attrition Prevention [ASAP] Manual) for situations not covered by the protocol treatments. The majority of cases requiring adjunct services fell into two major categories: (1) crisis/emergent situations and (2) imminent risk of attrition. This report describes the ASAP guidelines for dealing with cases that required adjunct services that the MTA Steering Committee adopted before initiating the trial. Although the manual-based guidelines are especially applicable to multisite RCTs, many of the procedures in the ASAP Manual can apply to any treatment study in children.

Objectives To provide preliminary psychometric data on the Children's Aggression Scale-Parent Version (CAS-P), which assesses severity, frequency, pervasiveness, and diversity of aggressive, as distinct from nonaggressive, disruptive behaviors. Method The scale has 33 items representing five domains: Verbal Aggression, Aggression Against Objects and Animals, Provoked Physical Aggression, Unprovoked Physical Aggression, and Use of Weapons. The CAS-P was completed for 73 clinically referred children. Validity was evaluated dimensionally by examining the relationship of CAS-P scores to other parent and teacher rating scales, and categorically by comparing scores of children with attention-deficit hyperactivity disorder (ADHD) alone, oppositional defiant disorder, and conduct disorder. Results The scale as a whole had excellent internal consistency (α = .93). Children with conduct disorder were rated significantly higher than those with oppositional defiant disorder, who were rated significantly higher than those with ADHD alone. The CAS-P did not distinguish clinical control children from those with ADHD only. Correlations with other rating scales provide further support for the validity of the CAS-P. Conclusions The CAS-P assesses distinct components of aggressive behavior and may fill a gap in that it distinguishes among various types and severity of aggressive behaviors, and the settings in which they take place.

Examined hypothesized gender and comorbidity differences in the observed classroom behavior of children with attention deficit hyperactivity disorder (ADHD). The behavior of 403 boys and 99 girls with ADHD, ages 7-10, was compared (a) to observed, sex-specific classroom behavior norms, (b) by sex, and (c) by comorbid subgroups. Boys and girls with ADHD deviated significantly from classroom norms on 15/16 and 13/16 categories, respectively. Compared to comparison girls, girls with ADHD had relatively high rates of verbal aggression to children. Boys with ADHD engaged in more rule-breaking and externalizing behaviors than did girls with ADHD, but the sexes did not differ on more "neutral," unobtrusive behaviors. The sex differences are consistent with notions of why girls with ADHD are identified and referred later than boys. Contrary to hypothesis, the presence of comorbid anxiety disorder (ANX) was not associated with behavioral suppression; yet, as hypothesized, children with a comorbid disruptive behavior disorder (DBD) had higher rates of rule-breaking, and impulsive and aggressive behavior, than did children with ADHD alone and those with ADHD+ANX. Elevated rates of ADHD behaviors were also observed in children with comorbid DBD, indicating that these behaviors are truly present and suggesting that reports of higher ADHD ratings in this subgroup are not simply a consequence of negative halo effects and rater biases.

Objective Recent results from the Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder (ADHD; MTA) have demonstrated impairments in several functioning domains in adults with childhood ADHD. The childhood predictors of these adult functional outcomes are not adequately understood. The objective of the present study was to determine the effects of childhood demographic, clinical, and family factors on adult functional outcomes in individuals with and without childhood ADHD from the MTA cohort. Method Regressions were used to determine associations of childhood factors (age range 7–10 years) of family income, IQ, comorbidity (internalizing, externalizing, and total number of non-ADHD diagnoses), parenting styles, parental education, number of household members, parental marital problems, parent–child relationships, and ADHD symptom severity with adult outcomes (mean age 25 years) of occupational functioning, educational attainment, emotional functioning, sexual behavior, and justice involvement in participants with (n = 579) and without (n = 258) ADHD. Results Predictors of adult functional outcomes in ADHD included clinical factors such as baseline ADHD severity, IQ, and comorbidity; demographic factors such as family income, number of household members and parental education; and family factors such as parental monitoring and parental marital problems. Predictors of adult outcomes were generally comparable for children with and without ADHD. Conclusion Childhood ADHD symptoms, IQ, and household income levels are important predictors of adult functional outcomes. Management of these areas early on, through timely treatments for ADHD symptoms, and providing additional support to children with lower IQ and from households with low incomes, could assist in improving adult functioning.

Twenty-five youth with attention-deficit/hyperactivity disorder (ADHD) were scanned with functional magnetic resonance imaging (fMRI) while performing a Go/No-go task before and after 6–8 weeks of randomized once-daily treatment with either the α2A-adrenergic receptor agonist guanfacine or placebo. Clinical improvement was greater for guanfacine than placebo and was differentially associated with reduced activation for guanfacine compared with placebo in the right midcingulate cortex/supplementary motor area and the left posterior cingulate cortex.

Background This study examined the effects of atomoxetine (ATX) and OROS methylphenidate (MPH) on laboratory measures of inhibitory control and attention in youth with attention-deficit/hyperactivity disorder (ADHD). It was hypothesized that performance would be improved by both treatments, but response profiles would differ because the medications work via different mechanisms. Methods One hundred and two youth (77 male; mean age = 10.5 ± 2.7 years) with ADHD received ATX (1.4 ± 0.5 mg/kg) and MPH (52.4 ± 16.6 mg) in a randomized, double-blind, crossover design. Medication was titrated in 4–6-week blocks separated by a 2-week placebo washout. Inhibitory control and attention measures were obtained at baseline, following washout, and at the end of each treatment using Conners' Continuous Performance Test II (CPT-II), which provided age-adjusted T-scores for reaction time (RT), reaction time variability (RT variability), and errors. Repeated-measures analyses of variance were performed, with Time (premedication, postmedication) and Treatment type (ATX, MPH) entered as within-subject factors. Data from the two treatment blocks were checked for order effects and combined if order effects were not present. Clinical trial registration: Clinicaltrials.gov: NCT00183391. Results Main effects for Time on RT (p = .03), RTSD (p = .001), and omission errors (p = .01) were significant. A significant Drug × Time interaction indicated that MPH improved RT, RTSD, and omission errors more than ATX (p

Objectives: This study seeks to determine if variation in the dopamine transporter gene (SLC6A3/DAT1) moderates the dose-response effects of long-acting dexmethylphenidate (D-MPH) and mixed amphetamine salts (MAS) in children with attention-deficit/hyperactivity disorder (ADHD). Methods: Fifty-six children and adolescents (mean age=11.7±2.2) participated in a double-blind, two period crossover, dose-response study with a randomized placebo week in each 4 week drug period. Each period consisted of sequential week-long exposures to three dose levels (10, 20, 25–30 mg, depending upon weight) of D-MPH or MAS. Results: Doses of 10–20 mg of either D-MPH or MAS had little to no effect on hyperactivity-impulsivity and total ADHD symptom scores in subjects with the 9/9 genotype; this was in contrast to the dose-response curves of subjects with either the 10/10 or 10/9 genotype. Conclusions: ADHD youth with the 9/9 genotype may require higher stimulant doses to achieve adequate symptom control.

To examine the association between developmental trajectories of inattention, hyperactivity-impulsivity and delinquency through childhood and adolescence (ages 8-16 years) and subsequent binge drinking and marijuana use in early adulthood (age 21 years).Prospective naturalistic follow-up of children with attention deficit/hyperactivity disorder (ADHD) previously enrolled in a randomized controlled trial (RCT). Treatment-phase assessments occurred at 3, 9 and 14 months after randomization; follow-up assessments occurred at 24 months, 36 months, and 6, 8 and 12 years after randomization.Secondary analysis of data from the Multimodal Treatment Study of ADHD (MTA), a multi-site RCT comparing the effects of careful medication management, intensive behavior therapy, their combination, and referral to usual community care.A total of 579 children with DSM-IV ADHD combined type, aged 7.0 and 9.9 years at baseline (mean = 8.5, SD = 0.80).Ratings of inattention, hyperactivity-impulsivity and delinquency were collected from multiple informants at baseline and through the 8-year follow-up. Self-reports of binge drinking and marijuana use were collected at the 12-year follow-up (mean age 21 years).Trajectories of worsening inattention symptoms and delinquency (and less apparent improvement in hyperactivity-impulsivity) were associated with higher rates of early adult binge drinking and marijuana use, compared with trajectories of stable or improving symptoms and delinquency (of 24 comparisons, all P-values0.05), even when symptom levels in stable trajectories were high.Worsening inattention symptoms and delinquency during adolescence are were associated with higher levels of early adult substance use; this pattern may reflect a developmental course of vulnerability to elevated substance use in early adulthood.

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.

This study was conducted to examine the relationship between whole blood serotonin level and behavioral symptoms in 78 subjects with autism. No significant associations were found between serotonin level and the primary behavioral outcome measures. However, a significant inverse relationship between serotonin level and self-injury was demonstrated.

The present investigation examined factors that predict physical aggression in children with attention-deficit/hyperactivity disorder (ADHD). Stepwise, multiple regression-analyses were used to examine predictors of children's physical aggression as rated by parents at a 1-year follow-up point and by teachers at both 1- and 2-year follow-up points. Early parent and teacher ratings of verbal aggression (ie, cursing, teasing, and threatening) accounted for the greatest proportion of the variance in physical aggression ratings obtained at follow-up. None of the other predictor variable, including early ratings of physical aggression and ADHD behaviors, contributed significant additional variance beyond that accounted for by early verbal aggression ratings. Temporal and cross-informant analyses revealed that the relationship between verbal aggression and later physical aggression was situation-specific for teacher ratings but no parent ratings. Although physical aggression may emerge early in development, these data suggest that verbal aggre sion represents a stable, temperamental characteristic that may be of greater value than early physical aggression for predicting later physically aggressive acts.

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.

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.

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.

While considerable attention has been paid to discriminating attention-deficit/hyperactivity and anxiety disorders, there are as yet no published confirmatory factor analytic studies of any self-report anxiety scale in ADHD youth. The Multidimensional Anxiety Scale for Children (MASC) is a 39-item, 4-point Likert self-report scale that robustly represents the factor structure of anxiety in children aged 8 to 18 years. Using confirmatory factor analytic methods, the present paper reports a replication of the four-factor measurement model for the MASC in a large sample of ADHD youth aged 7 to 10 years. The fit indices proved to be comparable to those obtained in the MASC clinical and non-clinical (normative) samples. Clinically, therefore, this report strengthens confidence that the MASC is a valid measure of anxiety in diverse populations. With respect to research, it provides supporting evidence that results obtained using the MASC in the MTA and other research studies reflect valid estimates of anxiety in those samples. Presumably because pathological anxiety is associated with significant suffering, disruption in normal psychosocial and academic development and family functioning, and increased utilization of medical services, "worry" is among the more common causes of referral to children's mental health care providers (Black, 1995; Simon, Ormel, VonKorff, & Barlow, 1995). Nonetheless, the prevalence of childhood-onset fears in the population, the structure of

The current investigation used laboratory-based measures of inattention, impulsivity, and activity level to identify subgroups of children with attention-deficit/hyperactivity disorder (AD/HD). Data derived from solid state actigraphs and a continuous performance test (CPT) were obtained from a clinically referred sample and submitted to a cluster analysis. These empirically derived groups were then evaluated for clinical relevance and subsequently validated by parent and teacher ratings and tests of intellectual functioning and academic achievement. Four distinct subgroups emerged: Hyperactive-inattentive (HYP-IN), impulsive-inattentive (IMP-IN), inattentive only, and hyperactive only. The HYP-IN group was impaired on measures of intellectual functioning and academic achievement relative to the other three groups. In contrast, the IMP-IN group was generally rated as more aggressive, although this difference was not statistically significant for all measures. The data suggest that the augmentation of clinical descriptors with laboratory-based data may be an effective strategy by which to categorize diagnostic subgroups of AD/HD.

The alpha 2 adrenergic agonists are used to treat a variety of psychiatric disorders and their usage has been increasing. This article presents the rationale and neurochemical basis for treatment of psychiatric disorders with alpha 2 agents, reviews studies examining clinical efficacy, and develops guidelines for usage. Case vignettes are presented to illustrate how the alpha 2 agents can successfully be used in practice.

Data in animals and adults indicate that central serotonergic (5-HT) function may be involved in the development of alcohol abuse. Despite this, studies exploring this mechanism in individuals at risk for alcoholism are scant. This study used a fenfluramine (FEN) challenge procedure to investigate the relationship between risk for alcoholism and 5-HT function in 7- to 11-year-old boys with attention-deficit hyperactivity disorder (ADHD). The prolactin (PRL) and cortisol (CORT) responses to FEN were examined in 10 sons of alcoholic fathers (FA+) and 30 sons of nonalcoholic fathers (FA-). The FA+ group had a significantly greater CORT, but not PRL, response to FEN relative to the FA- group. The discrepancy between the CORT and PRL responses may be due to the different mechanisms that underlie their 5-HT stimulated release. This suggests that, among ADHD boys, those at familial risk for alcohol abuse may differ from those who are not at risk in 5-HT function.

Objective To examine noradrenergic (NA) function in children with attention-deficit hyperactivity disorder (ADHD) by replicating and expanding upon a previous finding that ADHD children with and without reading disabilities (RD) differ in plasma levels of the NA metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG). Method Plasma levels of MHPG were compared in ADHD children who were subdivided on the basis of the presence or absence of RD. Subsequently, this replication sample was combined with a previously studied sample to further explore the relationship between plasma MHPG levels and measures of cognitive function in children with ADHD. Results Plasma levels of MHPG were significantly lower in ADHD children without RD, compared with those with RD, replicating a previously published finding. Analyses in the combined sample indicated that, among children with ADHD, plasma MHPG levels were inversely associated with measures of academic achievement and verbal processing, but not parent or teacher ratings of behavior or continuous performance test measures of attention and impulsivity. Conclusions These data indicate that children with ADHD are not homogeneous with regard to NA function and that neurochemical variation is closely associated with differences in clinical characteristics of the children.

The steering committee of the collaborative six-site Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (the MTA) had to develop a common protocol consistent with public health goals and with scientific and clinical state of the art. With the aid of statistical, educational, and public health consultation, the steering committee balanced the stated objectives of the RFA against budgetary, clinical, ethical, and logistical practicalities. Two primary questions will be addressed: (1) What is the relative long-term effectiveness of excellent medication vs. excellent behavioral treatment vs. the combination? (2) What is the relative long-term effective ness of each of these state-of-the art intense treatments vs. routine community care? In a parallel-group design, 576 children (96 at each site) age 7-9 in grades 1-4 are thoroughly assessed in multiple domains from multiple informants and randomized to 4 treatment conditions: a medication-alone strategy, a psychosocial-treatment-alone strategy, a combination strategy, and community comparison (assessment and referral). The first three groups are treated for 14 months and all are re-assessed periodically for 24 months. Each treatment strategy is multi-component, with compromises between clinical flexibility and cross-site uniformity supported by a multi-tiered supervisory/fidelity structure, including 10 manuals, weekly teleconference panels, site visits, circuit-riding consultants, and feedback loops from therapists and supervisors to the steering committee about clinical realities. The resulting data should not only answer the primary questions above, but also support secondary data analyses about the effect of comorbidity, sex, SES, and other subject characteristics on treatment outcome. The MTA should both provide conclusions useful to the practicing clinician and define questions for the next generation of investigations.

Objective To explore the relationship between central serotonergic (5-HT) function and history of parental aggression in aggressive and nonaggressive boys with attention-deficit hyperactivity disorder (ADHD). Method History of psychiatric symptoms was assessed in the biological parents of 41 boys with ADHD. The relationship between 5-HT function in aggressive and nonaggressive probands, as assessed via the prolactin response to fenfluramine (FEN) challenge, and parental history of aggression was examined. Results Aggressive boys with a parental history of aggressive behavior had a significantly lower prolactin response to FEN challenge than aggressive boys without a parental history of aggression. Nonaggressive boys had a prolactin response midway between those of the two aggressive subgroups, and their prolactin response did not vary as a function of parental aggression. Children subdivided on the basis of parental history of other psychiatric symptoms did not differ in their response to the FEN challenge. Conclusions These data indicate an association between parent aggressive behavior and lower 5-HT function in aggressive boys with ADHD but do not indicate the extent to which this association is environmentally and/or genetically transmitted. There may be different neurochemical mechanisms in familial and nonfamilial aggressive children, which have clinical implications for pharmacological interventions.

Objective To examine the validity of the DSM-IV requirement of an age of onset of impairment due to symptoms before 7 years of age for the diagnosis of attention-deficit/hyperactivity disorder (ADHD). Method The validity of this criterion was examined in a clinic sample of 380 youths aged 4 through 17 years by comparing youths who met symptom criteria for ADHD and either did or did not display impairment before age 7 years. Results Nearly all youths who met symptom criteria for the predominantly hyperactive-impulsive subtype also met the age of onset of impairment criterion, but 18% of youths who met symptom criteria for the combined type, and 43% of youths who met symptom criteria for the predominantly inattentive type, did not manifest impairment before 7 years. For the latter two subtypes, requiring impairment before age 7 years reduced the accuracy of identification of currently impaired cases of ADHD and reduced agreement with clinicians' judgments. Conclusions These findings raise questions about the validity of the DSM-IV definition of age of onset of ADHD. Marked differences in the ages of onset of both symptoms and impairment for the three subtypes of ADHD support the validity of distinguishing among these subtypes in DSM-IV .

Objective The results of several studies suggest an inverse relationship between cortisol secretion and aggressive behavior. This study examined basal plasma cortisol levels in aggressive and nonaggressive boys with attention-deficit hyperactivity disorder (ADHD). Method The subjects were 23 aggressive and 27 nonaggressive boys with ADHD, aged 7 to 11 years. After 3 days of a low monoamine diet and an overnight fast, an indwelling catheter was inserted into a forearm vein. Samples for plasma cortisol levels were obtained 105 and 115 minutes after insertion of the catheter. Results A one-way analysis of covariance (ANCOVA) controlling for body mass revealed no significant difference in plasma cortisol between the aggressive and nonaggressive boys. Furthermore, when the children were alternatively divided on the basis of the presence or absence of a DSM-III-R diagnosis of conduct disorder, a one-way ANCOVA again revealed no significant difference in cortisol levels. Conclusions The hypothesized inverse relationship between cortisol secretion and aggressive behavior in boys with ADHD was not found. These findings are consistent with a large body of literature indicating that the biological substrate of aggression is complex and that the identification of biological laboratory markers of aggressive behavior is not a clinically useful strategy at this time. J. Am. Acad. Child Adolesc. Psychiatry, 1997, 36(5):605–609.

Changes in plasma levels of prolactin (PRL), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) following insertion of an indwelling catheter into a forearm vein were assessed in 11 boys with attention-deficit hyperactivity disorder. Results indicated decreases in plasma PRL and HVA, but not MHPG, from the time of needle stick until 105 min post-insertion. These data indicate a significant increase in plasma PRL and HVA in children following needle stick which gradually decreases over a 1.5-2-h period. These stress-induced changes indicate that values obtained immediately after needle insertion cannot be assumed to accurately reflect baseline levels.

The results of several studies have indicated an inverse relationship between central serotonergic (5-HT) mechanisms and aggression in animals and adults, but studies in children have yielded conflicting results. This study assessed 5-HT function, using a fenfluramine (FEN) challenge procedure, in an attempt to replicate a previously reported enhancement of the prolactin (PRL) response to FEN in aggressive relative to nonaggressive ADHD boys. The study failed to replicate the previous finding. Samples from both studies were then examined to reconcile the discrepant findings. The samples differed significantly in age. The entire group ( n = 50) was then divided into older and younger subgroups and reanalyzed using a two-way (age-group × aggression) analysis of covariance (ANCOVA) controlling for plasma medication level. The ANCOVA generated a significant age-group × aggression interaction. Young aggressive boys had a significantly greater PRL response to FEN than young nonaggressive boys, but no such difference existed in the older age-group. These findings raise the possibility of different developmental trajectories in 5-HT function between aggressive and nonaggressive boys.

As the largest randomized clinical trial conducted by the National Institute of Mental Health, the Multimodal Treatment Study of Children with ADHD (MTA) will yield data on a diverse sample of 576 7.0- to 9.9-year-old children with attention-deficit hyperactivity disorder (ADHD), Combined type, regarding the relative and combined effectiveness of psychosocial and pharmacologic interventions. After delineating key challenges posed by such a multi-site investigation, we describe the MTA's multiple-gating procedures for recruitment, screening, and diagnosis of a diverse sample. We then discuss the cross-domain assessment battery for tracking the sample before, during, and after 14 months of active intervention. Throughout, we emphasize the guiding principles that shaped pertinent decision making. Highlighted are issues of psychometric adequacy; dimensional vs. categorical measurement; multi-method, multi-agent, and multi-domain coverage; plotting of individual trajectories of development and change; respondent bias and burden; appraisal of treatment processes as well as outcomes; and con struction of composite indices.

Attention, impulse control, activity level, and motor decision/response organization were assessed in 70 child psychiatric outpatients, using a continuous performance test (CPT), a solid-state actigraph, and a response incompatibility task. Subjects were divided based on the presence or absence of attention-deficit hyperactivity disorder (ADHD) and/or reading disability (RD). Two-way ANOVAs yielded significant main effects for ADHD, but not RD, on objective measures of impulsivity and overactivity. No significant differences were found on a CPT measure of inattention. The response incompatibility task revealed differential performance between ADHD subgroups with and without comorbid RD. Deficits in motor decision/response organization were observed in the ADHD-only subgroup, but not in the comorbid ADHD+RD subgroup. These findings suggest that children with ADHD, RD and comorbid ADHD+RD have at least partially distinct underlying cognitive and neuropsychological disturbances, and that executive function deficits may be present primarily in ADHD children without RD.

The neural correlates of stimulus-driven processes, such as response preparation, have been posited to be associated with the onset of attention deficit hyperactivity disorder (ADHD) while being distinct from the neural mechanisms associated with recovery. The authors tested this hypothesis in adults with remitted and persistent ADHD.Thirty-eight young adults who were diagnosed with combined-type ADHD in childhood (probands) and 32 carefully matched comparison subjects were followed longitudinally and scanned with functional MRI while performing an event-related cued reaction time task. Probands were characterized as individuals with persistent or remitted ADHD. Differences in thalamo-cortical activation and functional connectivity during response preparation between comparison subjects and probands and between individuals with persistent ADHD and those with remitted ADHD were assessed by contrasting neural activation and functional connectivity during cue or noncue events.Probands exhibited less cue-related activation than comparison subjects in the thalamus, anterior cingulate cortex, supplementary motor area, inferior parietal lobe, and dorsolateral prefrontal cortex despite similar overall patterns of activation. There were no differences in activation between individuals in the remitted ADHD group and those in the persistent ADHD group in any hypothesized regions. However, cue-related functional connectivity between the right thalamus and brainstem was greater in comparison subjects relative to probands, and cue-related connectivity was greater between the right thalamus and prefrontal regions in individuals with remitted ADHD relative to those with persistent ADHD.Decreased thalamo-cortical activation during response preparation was present in adults diagnosed with ADHD in childhood regardless of symptom remission in adulthood, and may be partly driven by less functional coordination between the brainstem and thalamus. Greater functional integration of the thalamo-cortical network might parallel symptom recovery.

Emerging evidence indicates that maternal medical risk during pregnancy, such as gestational diabetes mellitus (GDM), preeclampsia, and obesity, predisposes the offspring to suboptimal development. However, the underlying biological/epigenetic mechanism in utero is still unknown. The current pilot study (N = 50) compared the levels of global methylation in the placenta and umbilical cord blood among women with and without each risk condition (GDM, preeclampsia, and obesity) and explored whether the levels of global methylation were associated with fetal/infant growth. Results show that global methylation levels in the placenta were lower in patients with gestational diabetes (P = .003) and preeclampsia (P = .05) but higher with obesity (P = .01). Suggestive negative associations were found between global methylation level in the placenta and infant body length and head circumference. While preliminary, it is possible that the placenta tissue, but not umbilical cord blood, may be epigenetically programmed by maternal GDM, preeclampsia, and obesity to carry out its own specific functions that influence fetal growth.

Children with attention-deficit/hyperactivity disorder (ADHD) are at heightened risk of antisocial behavior during adolescence/early adulthood. Here, we characterize the antisocial outcomes of a sample of urban, lower-socioeconomic-status, ethnically diverse ADHD youth and investigate the impact of maltreatment history on criminal and substance use disorder (SUD) outcomes. Ninety-eight participants diagnosed with ADHD in childhood were re-assessed 10 years later and compared with controls. Regression analyses investigated the effect of maltreatment on antisocial outcomes among four groups based on ADHD and maltreatment status. ADHD subjects and controls did not differ in rates of arrest, conviction, incarceration, or recidivism. ADHD youth were younger at their first arrest with higher rates of SUDs when compared to controls. Controls and ADHD subjects with maltreatment had significantly higher rates of SUDs compared to the no-ADHD/no-maltreatment group. Only ADHD youth with maltreatment had significantly higher rates of arrest than the reference group. In contrast to prior studies, ADHD youth did not differ from controls on most measures of antisocial behavior. Maltreatment increased the rate of arrest only among ADHD youth, though increased the rate of SUD for ADHD youth and controls. This suggests that ADHD youth, in the absence of maltreatment, are at no greater risk of SUDs or arrest than controls without maltreatment.

We tested the hypothesis that dopamine D1 and D2 receptor gene (DRD1 and DRD2, respectively) polymorphisms and the development of working memory skills can interact to influence symptom change over 10 years in children with attention-deficit/hyperactivity disorder (ADHD). Specifically, we examined whether improvements in working memory maintenance and manipulation from childhood to early adulthood predicted the reduction of ADHD symptoms as a function of allelic variation in DRD1 and DRD2. Participants were 76 7–11-year-old children with ADHD who were genotyped and prospectively followed for almost 10 years. ADHD symptoms were rated using the Attention Problems scale on the Child Behavior Checklist, and verbal working memory maintenance and manipulation, measured by Digit Span forward and backward, respectively, were assessed at baseline and follow-up. After correction for multiple testing, improvements in working memory manipulation, not maintenance, predicted reduction of symptomatology over development and was moderated by major allele homozygosity in two DRD1 polymorphisms (rs4532 and rs265978) previously linked with variation in D1 receptor expression. Depending on genetic background, developmental factors including age-dependent variation in DRD1 penetrance may facilitate the link between improvements in higher-order working memory and the remission of symptoms in individuals with childhood-diagnosed ADHD. Furthermore, the current findings suggest that DRD1 might contribute minimally to the emergence of symptoms and cognitive difficulties associated with ADHD in childhood, but may act as a modifier gene of these clinical features and outcome during later development for those with ADHD.

Objective: Brain dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase dopamine signaling, are therapeutically beneficial. However while the acute increases in dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated. Method: We used positron emission tomography and [ 11 C]cocaine (dopamine transporter radioligand) to measure dopamine transporter availability in the brains of 18 never-medicated adult ADHD subjects prior to and after 12 months of treatment with methylphenidate and in 11 controls who were also scanned twice at 12 months interval but without stimulant medication. Dopamine transporter availability was quantified as non-displaceable binding potential using a kinetic model for reversible ligands. Results: Twelve months of methylphenidate treatment increased striatal dopamine transporter availability in ADHD (caudate, putamen and ventral striatum: +24%, p,0.01); whereas there were no changes in control subjects retested at 12month interval. Comparisons between controls and ADHD participants revealed no significant difference in dopamine transporter availability prior to treatment but showed higher dopamine transporter availability in ADHD participants than control after long-term treatment (caudate: p,0.007; putamen: p,0.005). Conclusion: Upregulation of dopamine transporter availability during long-term treatment with methylphenidate may decrease treatment efficacy and exacerbate symptoms while not under the effects of the medication. Our findings also suggest that the discrepancies in the literature regarding dopamine transporter availability in ADHD participants (some studies reporting increases, other no changes and other decreases) may reflect, in part, differences in treatment histories. Citation: Wang G-J, Volkow ND, Wigal T, Kollins SH, Newcorn JH, et al. (2013) Long-Term Stimulant Treatment Affects Brain Dopamine Transporter Level in

Objective Examine how different dosing schedules and recent stimulant therapy effect incidence, time to onset, and duration of common treatment-emergent adverse events (TEAEs) during atomoxetine treatment. Method Post hoc analyses including safety data (open-ended questions) from 22 pediatric and 3 adult atomoxetine trials (1998-2009) in patients with attention-deficit/hyperactivity disorder. Most common TEAEs were determined by incidence rates and frequency of consumer and clinician inquiries. Onset and duration of TEAEs with slow versus fast titration, once-daily versus twice-daily dosing, and previous stimulant exposure were compared among treatment groups using Kaplan-Meier methods. Results In pediatric patients, the most commonly reported TEAEs were abdominal pain, decreased appetite, fatigue, nausea, somnolence, and vomiting; time to onset of TEAEs was significantly shorter for once-daily versus twice-daily dosing for all TEAEs (P ≤ .007) and for fast versus slow titration for abdominal pain, decreased appetite, and somnolence (all P values ≤ .009); duration of TEAEs with once-daily dosing was significantly longer for decreased appetite (P = .001) and nausea (P = .041); and more common in stimulant-naive patients versus patients with prior stimulant use were abdominal pain, decreased appetite, and fatigue (P ≤ .047). In adult patients, the most commonly reported TEAEs (erectile dysfunction data were excluded) were nausea, insomnia, decreased appetite, urinary hesitation/urinary retention, and fatigue; insomnia had a significantly shorter time to onset and longer duration with twice-daily versus once-daily dosing (P ≤ .032) and fast versus slow titration (P ≤ .007). Conclusions Time to onset and resolution of TEAEs appear dependent on dosing schedule and titration speed. These findings can help to better manage tolerability issues and set appropriate expectations for clinicians and patients during atomoxetine titration, potentially improving treatment adherence and success.