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OBJECTIVE: To estimate long-term stimulant treatment associations on standardized height, weight and BMI trajectories from childhood to adulthood in the Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder (MTA). METHOD: Of 579 children with DSM-IV ADHD-Combined Type at baseline (ages 7.0–9.9 years) and 289 classmates (local normative comparison group, LNCG), 568 and 258 respectively, were assessed 8 times over 16 years (final mean age = 24.7). Parent interview data established subgroups with self-selected Consistent (N=53, 9%), Inconsistent (N=374, 66%), and Negligible (N=141, 25%) stimulant medication use, as well as cases starting stimulants prior to MTA entry (N=211, 39%). Height and weight growth trajectories were calculated for each subgroup. RESULTS: Height z-scores trajectories differed among subgroups (F=2.22, P

Although the phenomenon that we know as parental alienation (PA) had been described in the mental health and legal literature for many years, it was given its name-parental alienation syndrome-by Richard Gardner in 1985. As time went on, most writers abandoned the use of the word syndrome and simply referred to this mental condition as parental alienation. The definition of PA is a mental state in which a child-usually one whose parents are engaged in a high-conflict separation or divorce-allies strongly with one parent (the favored parent) and rejects a relationship with the other parent (the alienated parent) without a good reason. Of course, it is a major loss for a child to experience the removal of a parent from their life in that manner. The purposes of this commentary are to explain definitions and distinctions related to PA; describe the Five-Factor Model (FFM) for the identification of PA; and offer clinical, legal, and training implications stemming from an understanding of PA.

We identified relapse/maintenance-of-response (MOR) predictors following discontinuation of long-term atomoxetine treatment in pediatric and adult patients with attention-deficit/hyperactivity disorder (ADHD) and assessed correlations between ADHD symptoms and quality of life (QoL). Post hoc analyses of data from two randomized, double-blind, placebo-controlled, phase 3 withdrawal studies in patients with ADHD meeting predefined response criteria before randomization. Study 1: patients (N = 163; 6-15 years) received atomoxetine (1.2-1.8 mg/kg/day) for 1 year, followed by randomization to atomoxetine (n = 81) or placebo (n = 82) for 6 months. Study 2: patients (N = 524; 18-50 years) received atomoxetine (80-100 mg/day) for ~6 months, followed by randomization to atomoxetine (n = 266) or placebo (n = 258) for ~6 months. Placebo patients were used for the analyses. Relapse: ≥50% worsening of prerandomization improvement in ADHD symptoms and ≥2 level severity increase on the Clinical Global Impression-Severity (CGI-S) scale at 2 consecutive visits; MOR: retaining ≥75% of prerandomization symptom improvement and CGI-S ≤ 2 at all visits (study 1); retaining ≥70% of prerandomization symptom improvement and CGI-S ≤ 3 at all visits (study 2). In adults, statistically significantly (P ≤ .05) increased likelihood of relapse was associated with prerandomization presence of Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Investigator-Rated:Screening Version (CAARS-Inv:SV) items "difficulty awaiting turn" and "careless mistakes." In pediatric patients, less MOR was associated with prerandomization presence of ADHD Rating Scale-IV-Parent Version Investigator-Rated item "does not listen"; in adults, less MOR was associated with prerandomization presence of CAARS-Inv:SV items "loses things" and "difficulty awaiting turn." Changes in patients' QoL after withdrawal from atomoxetine moderately correlated with changes in ADHD symptoms in pediatric patients and mildly in adults.

Objective: To evaluate measures of sleep (exploratory endpoints) in two pivotal studies of a multilayer bead extended-release methylphenidate (MPH-MLR) treatment of attention-deficit/hyperactivity disorder in children. Methods: Study 1 evaluated the time course of response to MPH-MLR (n = 26) patients in an analog classroom setting through four phases: screening (≤28 days), open label (OL) dose optimization (4 weeks), double-blind (DB) crossover (2 weeks; placebo vs. optimized dose), and follow-up call. Study 2 was a forced-dose parallel evaluation of MPH-MLR (n = 230) in four phases: screening (≤28 days), DB (1 week; placebo or MPH-MLR 10, 15, 20, or 40 mg/day), OL dose optimization (11 weeks), and follow-up call. Sleep was evaluated by parents using the Children's or Adolescent Sleep Habits Questionnaire (CSHQ or ASHQ) during the DB and OL phases. DB analysis: Study 1 (crossover), analysis of variance; Study 2, analysis of covariance. OL analysis: paired t-test. Results: DB: treatments were significantly different in Study 1 only for CSHQ Sleep Onset Delay (MPH-MLR, 1.90 vs. placebo, 1.34; p = 0.0046, placebo was better), and Study 2 for CSHQ Parasomnias (treatment, p = 0.0295), but no MPH-MLR treatment was different from placebo (pairwise MPH-MLR treatment to placebo, all p ≥ 0.170). OL: CSHQ total and Bedtime Resistance, Sleep Duration, Sleep Anxiety, Night Wakings, Parasomnias, and Sleep-disordered Breathing subscales decreased (improved, Study 1) significant only for CSHQ Night Wakings (p

Problems with occupational performance, emotional adjustment, legal involvement, and educational attainment are common in adults who had been diagnosed during childhood with attention-deficit/hyperactivity disorder.1 The National Institute of Health (NIMH) Multimodal Treatment Study of Attention-Deficit/Hyperactivity Disorder (ADHD) (MTA study) reported that of their cohort of 579 youth diagnosed with ADHD, combined type, age 7 to 9 years, half endorsed 4 persistent symptoms of ADHD when evaluated 16 years later at a mean age of 24.7 years.2 In fact, 41% persisted in meeting full ADHD symptomatic and impairment criteria as adults. This subgroup continued to experience problems with incomplete postsecondary education, job instability, lower current income, receipt of public assistance, and risky sexual behavior.3 Although the persistence of ADHD symptoms in the MTA study follow-up study was not associated with increased jail time, other studies concluded that a childhood diagnosis of ADHD was associated with a two- to threefold increased risk of later arrests, convictions, and incarcerations.4 Furthermore, although ADHD medications were not associated with better outcomes after 16 years of follow-up of the MTA cohort,5 Lichtenstein et al.6 reported that ADHD medication exerted a possible protective effect against incarceration.

This chapter describes the long-term outcomes in the Multimodal Treatment study of ADHD (MTA), which began in 1994 and ended in 2014. First, we provide a short history of the origin of the MTA. Second, we review the design as a 14-month randomized clinical trial and the transition to a long-term follow-up. Third, we present findings from 12 key publications describing outcomes in four stages of the MTA from childhood to adulthood. Fourth, we discuss how the final adult assessments of the MTA address critical issues about symptomatic persistence of ADHD, functional outcomes outside the parental home, and cost-benefit analyses of residual effects of treatment with medication.

Nathan S Teuscher,1 Akwete Adjei,2 Robert L Findling,3,4 Laurence L Greenhill,5 Robert J Kupper,2 Sharon Wigal6 1PK/PD Associates, Trophy Club, TX, 2Rhodes Pharmaceuticals L.P., Coventry, RI, 3Department of Psychiatric Services and Research, Kennedy Krieger Institute, Baltimore, MD, 4Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, 5Department of Psychiatry, Division of Child and Adolescent Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY, 6AVIDA Inc., Newport Beach, CA, USA Abstract: A new multilayer-bead formulation of extended-release methylphenidate hydrochloride (MPH-MLR) has been evaluated in pharmacokinetic studies in healthy adults and in Phase III efficacy/safety studies in children and adolescents with attention deficit hyperactivity disorder (ADHD). Using available data in healthy adults, a two-input, one-compartment, first-order elimination population pharmacokinetic model was developed using nonlinear mixed-effect modeling. The model was then extended to pediatric subjects, and was found to adequately describe plasma concentration–time data for this population. A pharmacokinetic/pharmacodynamic model was also developed using change from baseline in the ADHD Rating Scale (ADHD-RS)-IV total scores from a pediatric Phase III trial and simulated plasma concentration–time data. During simulations for each MPH-MLR dose level (10–80 mg), increased body weight resulted in decreased maximum concentration. Additionally, as maximum concentration increased, ADHD-RS-IV total score improved (decreased). Knowledge of the relationship between dose, body weight, and clinical response following the administration of MPH-MLR in children and adolescents may be useful for clinicians selecting initial dosing of MPH-MLR. Additional study is needed to confirm these results. Keywords: population pharmacokinetics, Aptensio XR™, MPH-MLR, methylphenidate

AIMS: To examine the association between developmental trajectories of inattention, hyperactivity-impulsivity, and delinquency through childhood and adolescence (ages 8-16) and subsequent binge drinking and marijuana use in early adulthood (age 21). DESIGN: 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. SETTING: 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. PARTICIPANTS: 579 children with DSM-IV ADHD combined type, aged 7.0 and 9.9 years old at baseline (M=8.5, SD=.80). MEASUREMENTS: 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 (M age 21). FINDINGS: 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, 22 p-values CONCLUSIONS: Worsening inattention symptoms and delinquency during adolescence are associated with increased levels of early adult substance use; this pattern may reflect a developmental course of vulnerability to elevated substance use in early adulthood. Language: en

The purpose of this study was to evaluate the relative bioavailability and safety of a multilayer extended-release bead methylphenidate (MPH) hydrochloride 80 mg (MPH-MLR) capsule or sprinkles (37% immediate-release [IR]) versus MPH hydrochloride IR(Ritalin(®)) tablets, and to develop a pharmacokinetic (PK) model simulating MPH concentration-time data for different MPH-MLR dosage strengths.This was a single-center, randomized, open-label, three-period crossover study conducted in 26 fasted healthy adults (mean weight±standard deviation, 70.4±11.7 kg) assigned to single-dose oral MPH-MLR 80 mg capsule or sprinkles with applesauce, or Ritalin IR 25 mg (1×5 mg and 1×20 mg tablet) administered at 0, 4, and 8 hours.MPH-MLR 80 mg capsule and sprinkles were bioequivalent; ratios for maximum concentration (Cmax), area under plasma drug concentration versus time curve (AUC)0-t, and AUC0-inf were 1.04 (95% confidence interval [CI], 96.3-112.4), 0.99 (95% CI, 95.3-102.8), and 0.99 (95% CI, 95.4-103.0), respectively. MPH-MLR capsule/sprinkles produced highly comparable, biphasic profiles of plasma MPH concentrations characterized by rapid initial peak, followed by moderate decline until 5 hours postdose, and gradual increase until 7 hours postdose, culminating in an attenuated second peak. Based on 90% CIs, total systemic exposure to MPH-MLR 80 mg capsule/sprinkles was similar to that for Ritalin IR 25 mg three times daily, but marked differences in Cmax values indicated that MPH-MLR regimens were not bioequivalent to Ritalin. MPH Cmax and total systemic exposure over the first 4 hours postdose with MPH-MLR capsule/sprinkles was markedly higher than that associated with the first dose of Ritalin. All study drugs were safe and well tolerated. The PK modeling in adults suggested that differences in MPH pharmacokinetics between MPH-MLR and Ritalin are the result of dosage form design attributes and the associated absorption profiles of MPH.MPH-MLR 80 mg provides a long-acting biphasic pattern of plasma MPH concentrations with one less peak and trough than Ritalin IR.

OBJECTIVES: Offspring of depressed parents are at increased risk for psychiatric disorders. Although bipolar disorder (BD) and major depressive disorder (MDD) are both found in the same families, it is not clear whether transmission to offspring of BD or MDD tends to occur from parents with the same mood disorder subtype. Our primary hypothesis was that the offspring of parents with BD would be at increased risk for BD and other comorbid disorders common to BD, such as anxiety and substance use, relative to the offspring of parents with MDD. The offspring of parents with BD versus those with MDD were also hypothesized to be at greater risk for externalizing disorders (i.e., conduct disorder, attention-deficit hyperactivity disorder, or antisocial personality disorder). METHODS: Parents (n = 320) with mood disorders and their offspring (n = 679) were studied. Adult offspring were administered the Structured Clinical Interview for DSM-IV Axis I Disorders to establish the presence of psychopathology. Offspring aged 10-18 years were assessed using the School Aged Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version, and parents of children under the age of ten completed the Child Behavioral Checklist. Data were examined using Cox proportional hazard regression. RESULTS: There was no difference in hazard of mood disorders in the offspring of parents with BD as compared to the offspring of parents with MDD. However, a number of other parent and offspring characteristics increased the risk of mood, anxiety, externalizing, and substance use disorders in the offspring, including self-reported childhood abuse in the parent or offspring, offspring impulsive aggression, and the age at onset of parental mood disorder. CONCLUSIONS: Mood disorders are highly familial, a finding that appears independent of whether the parent's condition is unipolar or bipolar, suggesting considerable overlap in the heritability of MDD and BD. Although parental characteristics had a limited influence on the risk of offspring psychopathology, reported childhood adversity, be it in the parent or child, is a harbinger of negative outcomes. These risk factors extend previous findings, and are consistent with diathesis-stress conceptualizations. Language: en

Childhood sexual abuse has been consistently associated with suicidal behavior. We studied suicide attempt features in depressed individuals sexually abused as children. On average, sexual abuse started before age 9. It frequently coexisted with physical abuse. Suicide attempters more often had personality disorders and had endured abuse for longer, but did not differ in terms of other clinical characteristics from non-attempters. Earlier onset of sexual abuse and its duration were associated with more suicide attempts. However, when personality disorders were included in the regression model, only these disorders predicted number of attempts. The severity of sexual abuse and the coexistence of physical abuse were correlated with age at first suicide attempt. However, only severity of sexual abuse was marginally associated with age at first suicide attempt in the regression model. Finally, the earlier the age of onset of sexual abuse, the higher the intent, even after controlling for age, sex and personality disorders. This suggests that the characteristics of childhood sexual abuse, especially age of onset, should be considered when studying the risk for suicidal behavior in abused populations.

Objective To compare educational, occupational, legal, emotional, substance use disorder, and sexual behavior outcomes in young adults with persistent and desistent attention-deficit/hyperactivity disorder (ADHD) symptoms and a local normative comparison group (LNCG) in the Multimodal Treatment Study of Children with ADHD (MTA). Method Data were collected 12, 14, and 16 years postbaseline (mean age 24.7 years at 16 years postbaseline) from 476 participants with ADHD diagnosed at age 7 to 9 years, and 241 age- and sex-matched classmates. Probands were subgrouped on persistence versus desistence of DSM-5 symptom count. Orthogonal comparisons contrasted ADHD versus LNCG and symptom-persistent (50%) versus symptom-desistent (50%) subgroups. Functional outcomes were measured with standardized and demographic instruments. Results Three patterns of functional outcomes emerged. Post−secondary education, times fired/quit a job, current income, receiving public assistance, and risky sexual behavior showed the most common pattern: the LNCG group fared best, symptom-persistent ADHD group worst, and symptom-desistent ADHD group between, with the largest effect sizes between LNCG and symptom-persistent ADHD. In the second pattern, seen with emotional outcomes (emotional lability, neuroticism, anxiety disorder, mood disorder) and substance use outcomes, the LNCG and symptom-desistent ADHD group did not differ, but both fared better than the symptom-persistent ADHD group. In the third pattern, noted with jail time (rare), alcohol use disorder (common), and number of jobs held, group differences were not significant. The ADHD group had 10 deaths compared to one death in the LNCG. Conclusion Adult functioning after childhood ADHD varies by domain and is generally worse when ADHD symptoms persist. It is important to identify factors and interventions that promote better functional outcomes.

Objective:It is unknown whether prolonged childhood exposure to stimulant medication for the treatment of attention deficit hyperactivity disorder (ADHD) increases the risk for developing abnormalities in blood pressure or heart rate. The authors examined the association between stimulant medication and blood pressure and heart rate over 10 years. Method:A total of 579 children, ages 7–9, were randomly assigned to 14 months of medication treatment, behavioral therapy, the combination of the two, or usual community treatment. The controlled trial was followed by naturalistic treatment with periodic assessments. Blood pressure and heart rate data were first analyzed with linear regression models based on an intent-to-treat approach, using raw data and the blood pressure categories of prehypertension and hypertension. Currently medicated patients were then compared with never or previously medicated patients. Associations between cumulative stimulant exposure and blood pressure or heart rate were assessed. R...

article i nfo This study investigated the relationship between the five common polymorphisms (rs2242446, rs5568, rs5569, rs998424, and rs1616905) in the norepinephrine transporter (NET) gene and the OROS-methylphenidate response in a medication-naive Korean attention-deficit hyperactivity disorder (ADHD) sample. One hundred thirty-seven patients with ADHD were recruited from the child and adolescent psychiatric outpatient units. The trial was an eight-week, open-label study of OROS-methylphenidate monotherapy, and treatment outcomes were measured using the Korean version of the ADHD Rating Scales-IV (K-ARS) for the parents, the Clinician Global Impression Severity Scale (CGI-S) and the Clinician Global Impression Improvement Scale (CGI-I). Associations between the five NET polymorphisms and the drug response were analyzed using genotype and allele frequencies at each locus. There was no significant difference in genotype and allele distribution for each NET polymorphism between responders and non-responders (PN0.05). There were no significant differences in change of the K-ARS score, change of CGI-S scores or CGI-I scores at 8 weeks among each genotype and allele of five NET polymorphisms (PN0.05). Although there were no significant positive results, our findings may have several implications and offer direction for future studies.

OBJECTIVE This study explores the results of mental health screening in Korean first graders in association with the amount of time the children spent in extracurricular education. METHOD The study included a community sample of 761 boys and girls, with a mean age of 6.6 years, collected from 5 elementary schools in Gunpo-si, South Korea, in July 2007. Primary caregivers completed a questionnaire that included information on demographic characteristics, the amount of time the children spent in extracurricular education and other activities, and an adapted form of the Behavior Assessment System for Children, Second Edition (BASC-2) to screen for mental health problems. RESULTS These first graders spent a mean of a little over 2 hours each day in extracurricular education. Extracurricular education demonstrated positive correlations with 4 BASC-2 domains, including hyperactivity (r = 0.092, P < .05), aggression (r = 0.073, P < .05), conduct problems (r = 0.073, P < .05) and depression (r = 0.137, P < .01). A positive linear relationship between depression and extracurricular education was also evident in regression analyses (F = 2.25, R(2) = 0.022, P = .001). The relationship held true even when controlling for time spent with parents, time spent with friends, and time spent asleep. Post hoc analyses revealed that children receiving more than 4 hours of extracurricular education per day showed a sharp increase in depressive symptoms as well as a decrease in the amount of time spent with caregivers. CONCLUSIONS Results of this study demonstrate that excessive amounts of time spent in extracurricular education (greater than 4 hours per day) may be associated with depression in school-aged children. These findings have relevance for mental health screening and educational policy.

The role of the thalamus in the genesis of attention deficit hyperactivity disorder (ADHD) remains poorly understood. The authors used anatomical MRI to examine the morphology of the thalamus in youths with ADHD and healthy comparison youths.The authors examined 46 youths with ADHD and 59 comparison youths 8-18 years of age in a cross-sectional case-control study. Conventional volumes and measures of surface morphology of the thalamus served as the main outcome measures.A mixed-effects model comparing whole thalamic volumes revealed no significant differences between groups. Maps of the thalamic surface revealed significantly smaller regional volumes bilaterally in the pulvinar in youths with ADHD relative to comparison subjects. Post hoc analyses showed that ADHD patients who received stimulants (N=31) had larger conventional thalamic volumes than untreated youths with ADHD, and maps of the thalamic surface showed enlargement over the pulvinar in those receiving stimulants. Smaller regional volumes in the right lateral and left posterior thalamic surfaces were associated with more severe hyperactivity symptoms, whereas larger regional volumes in the right medial thalamic surfaces were associated with more severe symptoms of inattention.These findings demonstrate reduced pulvinar volumes in youths with ADHD and indicate that this same area is relatively enlarged in patients treated with stimulants compared to those untreated. Associations of hyperactivity scores with smaller regional volumes on the lateral thalamic surface and inattention scores with larger regional volumes on the medial thalamic surface suggest the differential involvement of thalamic subcircuits in the pathogenesis of differing ADHD symptoms.

Objective: To examine the course of depression during the treatment of adolescents with depression who had recently attempted suicide. Method: Adolescents (N = 124), ages 12 to 18 years, with a 90-day history of suicide attempt, a current diagnosis of depressive disorder (96.0% had major depressive disorder), and a Children’s Depression Rating Scale-Revised (CDRS-R) score of 36 or higher, entered a 6-month treatment with antidepressant medication, cognitive-behavioral therapy focused on suicide prevention, or their combination (Comb), at five academic sites. Treatment assignment could be either random or chosen by study participants. Intent-to-treat, mixed effects regression models of depression and other relevant ratings were estimated. Improvement and remission rates were computed with the last observation carried forward. Results: Most patients (n = 104 or 84%) chose treatment assignment, and overall, three fourths (n = 93) received Comb. In Comb, CDRS-R declined from a baseline adjusted mean of 49.6 (SD 12.3) to 38.3 (8.0) at week 12 and to 27.0 (10.1) at week 24 (p < .0001), with a Clinical Global Impressionjdefined improvement rate of 58.0% at week 12 and 72.2% at week 24 and a remission (CDRS-R e28) rate of 32.5% at week 12 and 50.0% at week 24. The CDRS-R and the Scale for Suicidal Ideation scores were correlated at baseline (r =0 .43,p < .0001) and declined in parallel. Conclusions: When vigorously treated with a combination of medication and psychotherapy, adolescents with depression who have recently attempted suicide show rates of improvement and remission of depression that seem comparable to those observed in nonsuicidal adolescents with depression. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(10):997Y1004. Key Words: adolescents, suicide, depression, treatment. Clinical trial registration informationVTreatment of Adolescent Suicide Attempters (TASA). URL: http:// clinicaltrials.gov. Unique identifier: NCT00080158.

The authors sought to determine whether a significant association exists between the use of stimulants and the rare event of sudden unexplained death in children and adolescents.A matched case-control design was performed. Mortality data from 1985-1996 state vital statistics were used to identify 564 cases of sudden death occurring at ages 7 through 19 years across the United States along with a matched group of 564 young people who died as passengers in motor vehicle traffic accidents. The primary exposure measure was the presence of amphetamine, dextroamphetamine, methamphetamine, or methylphenidate according to informant reports or as noted in medical examiner records, toxicology results, or death certificates.In 10 (1.8%) of the sudden unexplained deaths it was determined that the youths were taking stimulants, specifically methylphenidate; in contrast, use of stimulants was found in only two subjects in the motor vehicle accident comparison group (0.4%), with only one involving methylphenidate use. A significant association of stimulant use with sudden unexplained death emerged from the primary analysis, which was based on exact conditional logistic regression (odds ratio=7.4, 95% CI=1.4 to 74.9). A comprehensive series of sensitivity analyses yielded qualitatively similar findings.This case-control study provides support for an association between the use of stimulants and sudden unexplained death among children and adolescents. Although sudden unexplained death is a rare event, this finding should be considered in the context of other data about the risk and benefit of stimulants in medical treatment.

Objective Several neuroanatomic abnormalities have been reported in patients with attention-deficit/hyperactivity disorder (ADHD). However, findings are not always consistent, perhaps because of heterogeneous subject samples. Studying youths with documented familial ADHD provides an opportunity to examine a more homogeneous population. Method Twenty-four youths with a confirmed history of familial ADHD and 10 control youths underwent high-resolution structural magnetic resonance imaging examinations. Archived magnetic resonance imaging scan data from 12 control youths were included in the analysis to increase statistical power. Individually drawn region-of-interest methods were used to examine the frontal lobe gyri and caudate. Results Cerebral total tissue was similar between groups. The volumes of the right caudate and right inferior frontal lobe were larger in the ADHD youths compared with the control youths. Data from a subgroup of the ADHD youths suggest that increasing left caudate volume is associated with decreasing functional activation of this region. Conclusions Because previous studies have focused primarily on younger subjects or used an extended age range, the present results may reflect neurodevelopmental changes specific to late adolescence in familial ADHD.

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. TPH2 is a recently discovered isoform that is expressed predominantly in serotonin neurons. Associations are reported of TPH2 polymorphisms with MDD, bipolar disorder and suicidal behavior. This study examines a single nucleotide polymorphism in the putative promoter region of the TPH2 gene.One hundred nine bipolar, 324 major depressive disorder, and 130 healthy volunteers were genotyped for the rs4131347 (-C8347G) promoter SNP. Association was assessed with diagnosis, suicide attempt status, severity of psychopathology and cerebrospinal fluid monoamine metabolite levels of 5-HIAA, HVA, and MHPG. General linear models and logistic regression tested the effect of genotype*childhood abuse interactions on psychopathology severity and suicide attempt.There was no association between genotype and either mood disorder, suicide attempt status, psychopathology severity or CSF monoamine metabolite levels.No association was detected between the rs4131347 (-C8347G) SNP in the promoter region of the TPH2 gene and mood disorders, suicidal behavior or monoamine function.

Systematic research and practice guidelines addressing preschool psychopharmacological treatment in very young children are limited, despite evidence of increasing clinical use of medications in this population. The Preschool Psychopharmacology Working Group (PPWG) was developed to review existing literature relevant to preschool psychopharmacology treatment and to develop treatment recommendations to guide clinicians considering psychopharmacological treatment in very young children. This article reviews the developmental considerations related to preschool psychopharmacological treatment, presents current evidence bases for specific disorders in early childhood, and describes the recommended algorithms for medication use. The purpose of this effort is to promote responsible treatment of young children, recognizing that this will sometimes involve the use of medications.

This practice parameter describes the epidemiology, clinical picture, differential diagnosis, course, risk factors, and pharmacological and psychotherapy treatments of children and adolescents with major depressive or dysthymic disorders. Side effects of the antidepressants, particularly the risk of suicidal ideation and behaviors are discussed. Recommendations regarding the assessment and the acute, continuation, and maintenance treatment of these disorders are based on the existent scientific evidence as well as the current clinical practice. J. Am. Acad. Child Adolesc. Psychiatry, 2007; 46(11):1503Y1526. Key Words: major depressive disorder, dysthymic disorder, evaluation, treatment, antidepressants, selective serotonin reuptake inhibitors, psychotherapy, practice parameter. Depressive disorders are often familial recurrent illnesses associated with increased psychosocial morbidity and mortality. Early identification and effective treatment may reduce the impact of depression on the family, social, and academic functioning in youths and may reduce the risk of suicide, substance abuse, and persistence of depressive disorders into adulthood. Evidencesupported treatment interventions have emerged in psychotherapy and medication treatment of childhood depressive disorders that can guide clinicians to improve outcomes in this population.

Many studies have linked the structure and function of frontostriatal circuitry to cognitive control deficits in attention deficit hyperactivity disorder (ADHD). Few studies have examined the role of white matter tracts between these structures or the extent to which white matter tract myelination and regularity correlate in family members with the disorder.Functional imaging maps from a go/nogo task were used to identify portions of the ventral prefrontal cortex and striatum involved in suppressing an inappropriate action (i.e., cognitive control) in 30 parent-child dyads (N=60), including 20 dyads (N=40) with ADHD and 10 dyads (N=20) without ADHD. An automated fiber-tracking algorithm was used to delineate white matter fibers adjacent to these functionally defined regions based on diffusion tensor images. Fractional anisotropy, an index of white matter tract myelination and regularity derived from diffusion tensor images, was calculated to characterize the associations between white matter tracts and function.Fractional anisotropy in right prefrontal fiber tracts correlated with both functional activity in the inferior frontal gyrus and caudate nucleus and performance of a go/nogo task in parent-child dyads with ADHD, even after controlling for age. Prefrontal fiber tract measures were tightly associated between ADHD parents and their children.Collectively, these findings support previous studies suggesting heritability of frontostriatal structures among individuals with ADHD and suggest disruption in frontostriatal white matter tracts as one possible pathway to the disorder.

To assess parent-teacher concordance on ratings of DSM-IV symptoms of attention-deficit/hyperactivity disorder (ADHD) in a sample of preschool children referred for an ADHD treatment study.Parent and teacher symptom ratings were compared for 452 children aged 3-5 years. Agreement was calculated using Pearson correlations, Cohen's kappa, and conditional probabilities.The correlations between parent and teacher ratings were low for both Inattentive (r = .24) and Hyperactive-Impulsive (r = .26) symptom domains, with individual symptoms ranging from .01-.28. Kappa values for specific symptoms were even lower. Conditional probabilities suggest that teachers are only moderately likely to agree with parents on the presence or absence of symptoms. Parents were quite likely to agree with teachers' endorsement of symptoms, but much less likely to agree when teachers indicated that a symptom was not present.Results provide important data regarding base rates and concordance rates in this age group and support the hypothesis that preschool-aged children at risk for ADHD exhibit significant differences in behavior patterns across settings. Obtaining ratings from multiple informants is therefore considered critical for obtaining a full picture of young children's functioning.

Objective: The aim of this study was to examine immediate-release methylphenidate effectiveness during the 10-month open-label continuation phase of the Preschoolers with attention-deficit/hyperactivity disorder (ADHD) Treatment Study (PATS). Methods: One hundred and forty preschoolers with ADHD, who had improved with acute immediate-release methylphenidate (IR-MPH) treatment, entered a 10-month, open-label medication maintenance at six sites. Assessments included the Clinical Global Impression-Severity (CGI-S), CGI-Improvement (CGI-I), Children's Global Assessment Scale (C-GAS), Swanson, Nolan, and Pelham Questionnaire (SNAP), Scale Strengths and Weaknesses of ADHD-Symptoms and Normal Behaviors (SWAN), Social Competence Scale, Social Skills Rating System (SSRS), and Parenting Stress Index–Short Form (PSI-SF). Results: For the 95 children who completed the 10-month treatment, improvement occurred on the CGI-S (p = 0.02), CGI-I (p < 0.01), C-GAS (p = 0.001), and SSRS (p = 0.01). SNAP and SWAN scor...

The aim of this study was to describe the clinical presentation of preschoolers diagnosed with moderate to severe attention-deficit/hyperactivity disorder (ADHD) recruited for the multisite Preschool ADHD Treatment Study (PATS). The diagnosis and evaluation process will also be described.A comprehensive multidimensional, multi-informant assessment protocol was implemented including the semistructured PATS Diagnostic Interview. Parent and teacher-report measures were used to supplement information from interviews. Consensus agreement by a cross-site panel on each participant's diagnoses was required. Analyses were conducted to describe the sample and to test associations between ADHD severity and demographic and clinical variables.The assessment protocol identified 303 preschoolers (3-5.5 years) with moderate to severe ADHD Hyperactive/Impulsive or Combined type. The majority of participants (n = 211, 69.6%) experienced co-morbid disorders, with oppositional defiant disorder, communication disorders, and anxiety disorders being the most common. Participants with co-morbid communication disorders were found to be more anxious and depressed. ADHD severity was found to correlate with more internalizing difficulties and lower functioning. Although boys and girls had similar symptom presentations, younger children had significantly higher ADHD severity.Preschoolers with moderate to severe ADHD experience high co-morbidity and impairment, which have implications for both assessment and treatment.

This study examines one-, two-, and three-factor models of attention-deficit/hyperactivity disorder (ADHD) using the existing 18 Diagnostic and Statistical Manual of Mental Disorder, 4th edition (DSM-IV) symptoms in a sample of symptomatic preschoolers.Parent and/or teacher ratings of DSM-IV symptoms were obtained for 532 children (aged 3-5.5) who were screened for the Preschool ADHD Treatment Study (PATS). Confirmatory factor analysis (CFA) using symptoms identified on the Conners' Parent and Teacher Rating Scales was conducted to assess a two-factor model representing the DSM-IV dimensions of inattention (IN) and hyperactivity/impulsivity (H/I), a three-factor model reflecting inattention, hyperactivity, and impulsivity, and a single-factor model of all ADHD symptoms. Exploratory factor analysis (EFA) was subsequently used to examine the latent structure of the data.For parent ratings, the two-factor and three-factor models were marginally acceptable according to several widely used fit indices, whereas the one-factor model failed to meet minimum thresholds for goodness-of-fit. For teachers, none of the models was a solid fit for the data. Maximum likelihood EFAs resulted in satisfactory two and three-factor models for both parents and teachers, although all models contained several moderate cross loadings. Factor loadings were generally concordant with those published for older children and community-based samples.ADHD subtypes according to current DSM-IV specifications may not be the best descriptors of the disorder in the preschool age group.

Objective: To evaluate two hypotheses: that self-selection bias contributed to lack of medication advantage at the 36-month assessment of the Multimodal Treatment Study of Children With ADHD (MTA) and that overall improvement over time obscured treatment effects in subgroups with different outcome trajectories. Method: Propensity score analyses, using baseline characteristics and severity of attention-deficit/hyperactivity disorder symptoms at follow-up, established five subgroups (quintiles) based on tendency to take medication at the 36-month assessment. Growth mixture model (GMM) analyses were performed to identify subgroups (classes) with different patterns of outcome over time. Results: All five propensity subgroups showed initial advantage of medication that disappeared by the 36-month assessment. GMM analyses identified heterogeneity of trajectories over time and three classes: class 1 (34% of the MTA sample) with initial small improvement followed by gradual improvement that produced significant medication effects; class 2 (52%) with initial large improvement maintained for 3 years and overrepresentation of cases treated with the MTA Medication Algorithm; and class 3 (14%) with initial large improvement followed by deterioration. Conclusions: We failed to confirm the self-selection hypothesis. We found suggestive evidence of residual but not current benefits of assigned medication in class 2 and small current benefits of actual treatment with medication in class 1.

Objective: In the intent-to-treat analysis of the Multimodal Treatment Study of Children With ADHD (MTA), the effects of medication management (MedMgt), behavior therapy (Beh), their combination (Comb), and usual community care (CC) differed at 14 and 24 months due to superiority of treatments that used the MTA medication algorithm (Comb+MedMgt) over those that did not (Beh+CC). This report examines 36-month outcomes, 2 years after treatment by the study ended. Method: For primary outcome measures (attention-deficit/hyperactivity disorder [ADHD] and oppositional defiant disorder [ODD] symptoms, social skills, reading scores, impairment, and diagnostic status), mixed-effects regression models and orthogonal contrasts examined 36-month outcomes. Results: At 3 years, 485 of the original 579 subjects (83.8%) participated in the follow-up, now at ages 10 to 13 years, (mean 11.9 years). In contrast to the significant advantage of MedMgt+Comb over Beh+CC for ADHD symptoms at 14 and 24 months, treatment groups did not differ significantly on any measure at 36 months. The percentage of children taking medication >50% of the time changed between 14 and 36 months across the initial treatment groups: Beh significantly increased (14% to 45%), MedMed+Comb significantly decreased (91% to 71%), and CC remained constant (60%-62%). Regardless of their treatment use changes, all of the groups showed symptom improvement over baseline. Notably, initial symptom severity, sex (male), comorbidity, public assistance, and parental psychopathology (ADHD) did not moderate children's 36-month treatment responses, but these factors predicted worse outcomes over 36 months, regardless of original treatment assignment. Conclusions: By 36 months, the earlier advantage of having had 14 months of the medication algorithm was no longer apparent, possibly due to age-related decline in ADHD symptoms, changes in medication management intensity, starting or stopping medications altogether, or other factors not yet evaluated.

Background: Several studies have documented fronto-striatal dysfunction in children and adolescents with attention deficit/hyperactivity disorder (ADHD) using response inhibition tasks. Our objective was to examine functional brain abnormalities among youths and adults with ADHD and to examine the relations between these neurobiological abnormalities and response to stimulant medication. Method: A group of concordantly diagnosed ADHD parent–child dyads was compared to a matched sample of normal parent–child dyads. In addition, ADHD dyads were administered double-blind methylphenidate and placebo in a counterbalanced fashion over two consecutive days of testing. Frontostriatal function was measured using functional magnetic resonance imaging (fMRI) during performance of a go/no-go task. Results: Youths and adults with ADHD showed attenuated activity in fronto-striatal regions. In addition, adults with ADHD appeared to activate non-fronto-striatal regions more than normals. A stimulant medication trial showed that among youths, stimulant medication increased activation in fronto-striatal and cerebellar regions. In adults with ADHD, increases in activation were observed in the striatum and cerebellum, but not in prefrontal regions. Conclusions: This study extends findings of fronto-striatal dysfunction to adults with ADHD and highlights the importance of frontostriatal and frontocerebellar circuitry in this disorder, providing evidence of an endophenotype for examining the genetics of ADHD. Keywords: ADHD, adolescence, adulthood, brain imaging, development,fMRI,methylphenidate,neuropsychology,children,parents. Abbreviations: MTA:Multimodal Treatment Study of ADHD; LNCG: local normative comparison group; CAADID: Conners Adult ADHD Diagnostic Interview for DSM-IV.

The purpose of this study was to assess the effectiveness and tolerability of atomoxetine during acute treatment of attention-deficit/hyperactivity disorder (ADHD) in 5 and 6 year olds.Twenty two children (male n = 19, 86%) with ADHD were treated with atomoxetine for 8 weeks in a three-site, open-label pilot study. Dosing was flexible, with titration to a maximum of 1.8 mg/kg per day. Parent education on behavior management was provided as part of each pharmacotherapy visit.Subjects demonstrated a mean decrease of 20.68 points (SD = 12.80, p0.001)) on the ADHD Rating Scale-IV (ADHD-IV-RS) total score, 10.18 (SD = 7.48, p0.001) on the inattentive subscale and 10.50 (SD = 7.04, p0.001) on the hyperactive/impulsive subscale. Clinical Global Impression-Severity (CGI-S) was improved in 82% of the children (95% CI, 66-98%) and Children's Global Assessment (CGAS) scores improved 18.91 points on average (SD = 12.20, p0.001). The mean final dose of atomoxetine was 1.25 mg/kg per day (SD = 0.35 mg/kg per day). Mood lability was the most commonly reported adverse event (n = 12, 54.5%). Eleven subjects (50%) reported decreased appetite and a mean weight loss of 1.04 kg (SD = 0.80 kg) (p0.001) was observed for the group. Vital sign changes were mild and not clinically significant. There were no discontinuations due to adverse events or lack of efficacy.Atomoxetine was generally effective for reducing core ADHD symptoms in the 5 and 6 year olds in this open-label study.

AimTo determine the prevalence of bipolar disorder (BD) and sub-threshold symptoms in children with attention deficit hyperactivity disorder (ADHD) through 14 years' follow-up, when participants were between 21-24 years old.MethodsFirst, we examined rates of BD type I and II diagnoses in youth participating in the NIMH-funded Multimodal Treatment Study of ADHD (MTA). We used the diagnostic interview schedule for children (DISC), administered to both parents (DISC-P) and youth (DISCY). We compared the MTA study subjects with ADHD (n = 579) to a local normative comparison group (LNCG, n = 289) at 4 different assessment points: 6, 8, 12, and 14 years of follow-ups. To evaluate the bipolar variants, we compared total symptom counts (TSC) of DSM manic and hypomanic symptoms that were generated by DISC in ADHD and LNCG subjects. Then we sub-divided the TSC into pathognomonic manic (PM) and non-specific manic (NSM) symptoms. We compared the PM and NSM in ADHD and LNCG at each assessment point and over time. We also evaluated the irritability as category A2 manic symptom in both groups and over time. Finally, we studied the irritability symptom in correlation with PM and NSM in ADHD and LNCG subjects.ResultsDISC-generated BD diagnosis did not differ significantly in rates between ADHD (1.89%) and LNCG 1.38%). Interestingly, no participant met BD diagnosis more than once in the 4 assessment points in 14 years. However, on the symptom level, ADHD subjects reported significantly higher mean TSC scores: ADHD 3.0; LNCG 1.7; P < 0.001. ADHD status was associated with higher mean NSM: ADHD 2.0 vs LNCG 1.1; P < 0.0001. Also, ADHD subjects had higher PM symptoms than LNCG, with PM means over all time points of 1.3 ADHD; 0.9 LNCG; P = 0.0001. Examining both NSM and PM, ADHD status associated with greater NSM than PM. However, Over 14 years, the NSM symptoms declined and changed to PM over time (df 3, 2523; F = 20.1; P < 0.0001). Finally, Irritability (BD DSM criterion-A2) rates were significantly higher in ADHD than LNCG (χ(2) = 122.2, P < 0.0001), but irritability was associated more strongly with NSM than PM (df 3, 2538; F = 43.2; P < 0.0001).ConclusionIndividuals with ADHD do not appear to be at significantly greater risk for developing BD, but do show higher rates of BD symptoms, especially NSM. The greater linkage of irritability to NSM than to PM suggests caution when making BD diagnoses based on irritability alone as one of 2 (A-level) symptoms for BD diagnosis, particularly in view of its frequent presentation with other psychopathologies.

More than 225 placebo-controlled type 1 investigations demonstrate that psychostimulants are highly effective in reducing core symptoms of attention-deficit/hyperactivity disorder (ADHD) in children and adults. In contrast, there are limited type I studies demonstrating that psychopharmacological management with U.S. Food & Drug Administration-approved agents for ADHD (stimulants and nonstimulants), atypical antipsychotics, and mood stabilizers decrease the defiant and aggressive behavior characteristic of disruptive behavior disorders. Stimulant treatment evidence has been supplemented by two large multisite randomized controlled trials. Randomized controlled trials from the past 15 years continue to report several key adverse events associated with stimulants but have not supported rarer and more serious problems. Although psychostimulants have been shown to retain their efficacy for as long as 14 months, their long-term academic and social benefits are not as robust. Nonstimulant agents for which there is more limited evidence of efficacy include atomoxetine, alpha-agonists, modafinil, and bupropion.

Objective To describe the rationale and design of the Preschool ADHD Treatment Study (PATS). Method PATS was a National Institutes of Mental Health-funded, multicenter, randomized, efficacy trial designed to evaluate the short-term (5 weeks) efficacy and long-term (40 weeks) safety of methylphenidate (MPH) in preschoolers with attention-deficit/hyperactivity disorder (ADHD). Three hundred three subjects ages 3 to 5.5 years old who met criteria for a primary DSM-IV diagnosis of ADHD entered the trial. Subjects participated in an 8-phase, 70-week trial that included screening, parent training, baseline, open-label safety lead-in, double-blind crossover titration, double-blind parallel efficacy, open-label maintenance, and double-blind discontinuation. Medication response was assessed during the crossover titration phase using a combination of parent and teacher ratings. Special ethical considerations throughout the trial warranted a number of design changes. Results This report describes the design of this trial, the rationale for reevaluation and modification of the design, and the methods used to conduct the trial. Conclusions The PATS adds to a limited literature and improves our understanding of the safety and efficacy of MPH in the treatment of preschoolers with ADHD, but changes in the design and problems in implementation of this study impose some specific limitations that need to be addressed in future studies.

Objective The authors explored genetic moderators of symptom reduction and side effects in methylphenidate-treated preschool-age children diagnosed with attention-deficit/hyperactivity disorder (ADHD). Method DNA was isolated from 81 subjects in a double-blind, placebo-controlled, crossover methylphenidate titration. Parents and teachers completed ADHD symptom scales and side effect ratings for each of five randomly administered weekly conditions that included immediate-release methylphenidate 1.25, 2.5, 5.0, 7.5 mg and placebo given three times daily. Candidate genes hypothesized to influence stimulant effects or individual risks for ADHD were genotyped. Results Although the primary analysis did not indicate significant genetic effects, secondary analyses revealed associations between symptom response and variants at the dopamine receptor (DRD4) promoter (p = .05) and synaptosomal-associated protein 25 (SNAP25) allelesT1065G (p = .03) andT1069C (p = .05). SNAP25 variants were also associated with tics (p = .02), buccal-lingual movements (p = .01), and irritability (p =.04). DRD4 variants were also associated with picking (p = .03). Increasing dose predicted irritability (p = .05) and social withdrawal (p = .03) with DRD4 variants. There were no significant effects for the dopamine transporter (DAT1). Conclusions Emerging evidence suggests the potential for understanding the individual variability of response to and side effects of ADHD medications from the study of genetics, although additional research is required before these findings are proven to have clinical utility.

The Preschool ADHD Treatment Study (PATS) was a NIMH-funded, six-center, randomized, controlled trial to determine the efficacy and safety of immediate-release methylphenidate (MPH-IR), given t.i.d. to children ages 3 to 5.5 years with attention-deficit/hyperactivity disorder (ADHD).The 8-phase, 70-week PATS protocol included two double-blind, controlled phases, a crossover-titration trial followed by a placebo-controlled parallel trial. The crossover-titration phase's primary efficacy measure was a combined score from the Swanson, Kotkin, Atkins, M-Flynn, and Pelham (SKAMP) plus the Conners, Loney, and Milich (CLAM) rating scales; the parallel phase's primary outcome measure was excellent response, based on composite scores on the Swanson, Nolan, and Pelham (SNAP) rating scale.Of 303 preschoolers enrolled, 165 were randomized into the titration trial. Compared with placebo, significant decreases in ADHD symptoms were found on MPH at 2.5 mg (p.01), 5 mg (p.001), and 7.5 mg (p.001) t.i.d. doses, but not for 1.25 mg (p.06). The mean optimal MPH total daily dose for the entire group was 14.2 +/- 8.1 mg/day (0.7+/-0.4 mg/kg/day). For the preschoolers (n=114) later randomized into the parallel phase, only 21% on best-dose MPH and 13% on placebo achieved MTA-defined categorical criterion for remission set for school-age children with ADHD.MPH-IR, delivered in 2.5-, 5-, and 7.5-mg doses t.i.d., produced significant reductions on ADHD symptom scales in preschoolers compared to placebo, although effect sizes (0.4-0.8) were smaller than those cited for school-age children on the same medication.

Objective: The purpose of this 13-study (seven double-blind/placebo-controlled, six open-label) meta-analysis is to determine the effectiveness and tolerability of long-term atomoxetine treatment among young children with attention-deficit/hyperactivity disorder (ADHD). Method: Data were pooled from 6- and 7-year-olds ( N = 272) who met DSM-IV criteria for ADHD, received atomoxetine treatment, and were enrolled in clinical trials of ≥2 years. Of these, 97 subjects reached the 24-month time point, providing data for long-term trend analysis of safety and effectiveness. Results: Effectiveness for most subjects was maintained over long-term treatment, as demonstrated by total scores and total T scores on the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version, investigator administered and scored. During the 2-year period, 25.7% discontinued because of lack of effectiveness, but adverse events were clinically minor and transient, and only 4.0% of children discontinued because of an adverse event. Notable effects on growth were seen during early phases of the study, with attenuation occurring by the 2-year time point. Statistically significant increases in pulse and blood pressure and decreases in cardiac PR interval were seen, but no changes were deemed both statistically significant and clinically meaningful among any vital signs, electrocardiographic measures, or laboratory tests. Conclusion: Long-term atomoxetine treatment appears generally well tolerated and effective in the treatment of young children with ADHD.

Background: Whilestudieshaveincreasinglyinvestigateddeficitsinreactiontime(RT)andRTvariabilityin children with attention deficit/hyperactivity disorder (ADHD), few studies have examined the effectsof stimulant medication on these important neuropsychological outcome measures. Methods: 316children who participated in the Multimodal Treatment Study of Children with ADHD (MTA) completedthe Conners’ Continuous Performance Test (CPT) at the 24-month assessment point. Outcomemeasures included standard CPT outcomes (e.g., errors of commission, mean hit reaction time (RT))and RT indicators derived from an Ex-Gaussian distributional model (i.e., mu, sigma, andtau). Results: Analyses revealed significant effects of medication across all neuropsychological out-come measures. Results on the Ex-Gaussian outcome measures revealed that stimulant medicationslows RT and reduces RT variability. Conclusions: This demonstrates the importance of includinganalytic strategies that can accurately model the actual distributional pattern, including the positiveskew. Further, the results of the study relate to several theoretical models of ADHD. Key-words: ADHD/ADD, go/no-go test, stimulants, reaction time, distributions, neuropsychology, phar-macology.A significant body of literature has documented thebehavioral benefits of stimulant medications inchildren with attention deficit/hyperactivity disorder(ADHD; Swanson et al., 1995). A majority of thesestudies have used behavioral indices such as parentand teacher rating scales and interviews to docu-ment medication effects. A minority of these studieshave utilized neuropsychological indices to assessmedication effects (see Denney & Rapport, 2001 forreview). The most commonly used neuropsycholo-gical tests across studies have been tests of attentionand inhibition. Stimulant medications appear to re-duce inhibition errors. Medication also appears tosignificantly quicken reaction time (RT) and reduceRT variability, especially on continuous performancetests (see Riccio, Reynolds, & Lowe, 2001 for review).RT variability and to a lesser extent mean RT areincreasingly becoming an area of focus in neuro-psychological studies comparing the performance ofpatients with ADHD to a control group. Significantand reliable differences in RT variability betweenADHD and normal control groups have been docu-mented on response inhibition tests (Conners, Ep-stein, Angold, & Klaric, 2003), discrimination tests(Leth-Steenson, Elbaz, & Douglas, 2000), and con-tinuous performance tests (Riccio et al., 2001). Fur-ther, Epstein et al. (2003) have shown that RTvariability demonstrated the strongest and most re-liable relationship to actual ADHD symptomatologycompared to other outcome measures on a com-monly used neuropsychological test, the Conners’CPT. The general pattern of RT differences has beenthat ADHD patients have slower and more variableRTs than normal controls (Riccio et al., 2001). Fur-ther, ADHD medications appear to accelerate meanRT and reduce RT variability (Riccio et al., 2001).Innovative new analytic techniques have beenintroduced to more accurately examine RT patternsamong ADHD patients. As pointed out by Castell-anos and Tannock (2002), the intra-individual vari-ability or moment by moment process of taskperformance in which individuals with ADHD

Objective To evaluate the efficacy and tolerability of modafinil in children and adolescents, ages 7 to 17, with attention-deficit/hyperactivity disorder (ADHD). Method In this 9-week, double-blind, flexible-dose study, patients were randomized to once-daily modafinil (170-425 mg) or placebo. Assessments included ADHD Rating Scale-IV (ADHD-RS-IV) School and Home Versions and Clinical Global Impression of Improvement (CGI-I) scale. Results Two hundred patients were randomized. Modafinil produced significant reductions in ADHD-RS-IV total scores at school (n = 128; mean change ± SD: −17.5 ± 13.1 points) compared with placebo (n = 66; −9.7 ± 10.3 points; p < .0001). Similarly, modafinil reduced ADHD-RS-IV total scores at home compared with placebo (−17.6 ± 13.3 versus −7.5 ± 11.8 points; p < .0001). Fifty-two percent of patients randomized to modafinil and 18% of those randomized to placebo met prestudy criteria for responder on the CGI-I (p < .0001). Randomization to modafinil was associated with significantly more insomnia, headache, decreased appetite, and weight loss than randomization to placebo, but discontinuation attributed to adverse events did not differ statistically between treatment groups (modafinil, 5%; placebo, 6%). Conclusion Modafinil was well tolerated and reduced ADHD symptoms at school and home compared with placebo.

Few of the increasing number of pediatric clinical trials of selective serotonin reuptake inhibitors (SSRIs) in children have been evaluated for level of blindness of investigators, children, and parents. The success of the masking procedures used in a double-blind, pediatric trial of fluvoxamine in children was examined.Clinical evaluators, parents, and children were asked to guess individual treatment assignment at the end of an 8-week, placebo-controlled trial of fluvoxamine conducted in 128 outpatients (6-17 years of age) with anxiety disorders. The relationship between treatment attribution and improvement status or presence of adverse events was examined.The rate of correct guesses was significantly greater than chance among clinical evaluators (78%), parents (81%), and children (67%) (for all, p0.001). Attribution to fluvoxamine was associated with presence of clinical improvement, and attribution to placebo with lack of improvement (p0.001) in both the fluvoxamine and placebo group. There was no association between presence of adverse events and direction of the guess. Accuracy of the guess did not improve with time.The tendency to attribute improvement to active treatment and lack of improvement to placebo was consistent across investigators, parents, and children and was applied regardless of actual treatment received by the patient. Adverse events did not influence treatment attribution.

Objective To give academic researchers, government officials, and industry scientists an opportunity to assess the state of pediatric psychopharmacology and identify challenges facing professionals in the field. Method Increased federal spending and the introduction of pediatric exclusivity led to large increases in pediatric psychopharmacology research in the 1990s. Despite the increase in research, concerns exist about methods and incentives for making new medications available for use in pediatric psychiatric disorders. In recognition of these concerns, the Duke Clinical Research Institute held a roundtable in September 2004. Participants from the National Institutes of Health, regulatory agencies, academia, and the pharmaceutical industry spoke about the effects of government regulations such as the U.S. Food and Drug Administration Modernization Act and the Pediatric Research Equity Act on pediatric research from academic, clinical, and industry perspectives, and bioethical considerations of such research. Conclusions To ensure development of new drugs for treating psychiatric disorders in children and adolescents, we must address the challenges posed by the regulatory environment governing pediatric psychopharmacology research. Strategies were identified for improving the evidence base for psychopharmacologic interventions in youth before widespread use and for more effectively defining a research agenda for the future.

Objective: The objective of this fixed-dose study was to determine the efficacy and safety of a new formulation of modafinil (modafinil film-coated tablets) in children and adolescents with attention-deficit/hyperactivitydisorder (ADHD). In addition, the effect of abrupt discontinuation of modafinil was evaluated in a 2-week observation period. Method: Patients aged 6 to 17 years with DSM-IV-TR-defined ADHD were randomly assigned to 7 weeks of double-blind treatment with modafinil or placebo in a 2:1 ratio, followed by abrupt discontinuation of modafinil and a 2-week, double-blind observation period in which 46% of patients receiving modafinil were switched to placebo without tapering and half continued to receive modafinil. Study drug was administered once daily and titrated over the first 7 to 9 days to daily doses of 340 mg for patients < 30 kg or 425 mg for patients ≥ 30 kg. Assessment instruments included the Attention-Deficit/ Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) School and Home Versions and Clinical Global Impressions-Improvement scale (CGI-I). The study was conducted from November 2003 to June 2004. Results: A total of 190 patients were randomly assigned to receive modafinil (340 mg, N = 44; 425 mg, N = 82) or placebo (N = 64). 189 patients were evaluated for safety. Modafinil significantly improved symptoms of ADHD as shown by reductions in ADHD-RS-IV School Version total scores compared with placebo at all visits (p ≤.009), including the final visit of the double-blind phase (p

The present study examined treatment outcomes for objectively measured parenting behavior in the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (ADHD). Five hundred seventy-nine ethnically and socioeconomically diverse children with ADHD-combined type (ages 7.0-9.9 years) and their parent(s) were recruited at 6 sites in the United States and Canada and randomly assigned to 1 of 4 treatment groups for 14 months of active intervention: medication management (MedMgt), intensive behavior therapy, combination of the 2 (Comb), or a community-treated comparison (CC). Baseline and posttreatment laboratory observations of parent-child interactions were coded by observers blind to treatment condition. Comb produced significantly greater improvements in constructive parenting than did MedMgt or CC, with effect sizes approaching medium for these contrasts. Treatment effects on child behaviors were not significant. The authors discuss the importance of changes in parenting behavior for families of children with ADHD and the need for reliable and objective measures in evaluating treatment outcome.

A 41⁄2-year-old girl with ADHD, combined subtype, and oppositional defiant disorder presents for evaluation and initiation of treatment. She has severe symptoms of inattention, hyperactivity, and impulsivity, leading to significant impairment in multiple domains. Peer relationships are strained, and she was admitted to the emergency department twice last year (once after darting in front of a car and once when she tipped her chair over backward in class). The child was recently expelled from her second preschool this year because of disruptive and out-of-control behavior. The parents received training in behavior modification (parent training), but despite their close adherence, little improvement in the child’s behavior was noted.