ABSTRACT. Objective. OROS methylphenidate HCL (MPH) is a recently developed long-acting stimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD). This study was conducted to examine dosage effects on ADHD symptoms and stimulant side effects and to explore potential moderating effects of ADHD subtype.Methods. Children with ADHD combined type (ADHD-CT) or predominantly inattentive type (ADHD-PI; n ‫؍‬ 47), ages 5 to 16 years, underwent a placebocontrolled, crossover trial using forced titration with weekly switches at 3 dosage levels. Parent and teacher ratings of ADHD symptoms were used to evaluate efficacy. In addition, vital signs and standardized measures of stimulant side effects were obtained weekly.Results. Parent ratings were more sensitive to treatment effects than teacher ratings. ADHD symptoms and Clinical Global Impressions Severity Index ratings at each dose condition differed significantly from placebo and baseline ratings, which did not differ from one another. For those with ADHD-CT, there was a clear linear dose-response relationship, with clinically significant reductions in ADHD Rating Scale-IV scores occurring in two thirds to three fourths of the subjects during either 36-or 54-mg dose conditions. Children with ADHD-PI, conversely, were more likely to respond optimally to lower doses and derived less benefit from higher doses, with 60% displaying significant improvement on the ADHD Rating Scale-IV at 36 mg or lower. Mild stimulant side effects were reported during placebo and at all dosage levels. With the exception of insomnia and decreased appetite, which were more common at higher doses, parent report of side effects was not related to dose. In addition, younger and smaller children were more likely to display sleep difficulties and decreased appetite at the higher dose levels Although pulse rate increased slightly with increasing dose, there were no dose effects on blood pressure.Conclusions. In children with ADHD-CT, the most common subtype of ADHD, increasing doses of stimulant medication were associated with increased improvement of inattention and hyperactivity symptoms. In children with ADHD-PI, symptom improvement occurred at lower doses and less benefit was derived from higher doses. In both ADHD subtypes, higher doses were associated with parent ratings of increased insomnia and decreased appetite. Pediatrics 2003;112:e404 -e413. URL: http://www.pediatrics.org/cgi/content/full/112/5/e404; attention-deficit/hyperactivity disorder, methylphenidate, pharmacologic treatment.ABBREVIATIONS. ADHD, attention-deficit/hyperactivity disorder; MPH, methylphenidate; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; ADHD-PI, attentiondeficit/hyperactivity disorder predominantly inattentive type; ADD, attention-deficit disorder; ADHD-CT, attention-deficit/hyperactivity disorder combined type; ODD, oppositional defiant disorder; ADHD RS-IV, ADHD Rating Scale-IV: Home Edition; CGI, Clinical Global Impressions Severity Index; SERS, Side Effect R...

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Stimulant medications, such as methylphenidate (MPH), are the most commonly used, effective treatment for ADHD. MPH acts primarily by inhibiting the dopamine transporter (DAT), a protein responsible for the reuptake of dopamine from the synapse into presynaptic terminals. We sought to evaluate the relationship between DAT1 3 0 -untranslated region (3 0 -UTR) variable number tandem repeats (VNTR) genotypes and dose response to MPH. Children with ADHD (n ¼ 47), ages 5-16 years (mean ¼ 9.02 years), underwent a 4-week, double-blinded, crossover trial with forced weekly dosage changes. Children were genotyped for the DAT1 VNTR and evaluated on placebo and three dosage levels of OROS s MPH. Parents and clinicians who were blind to genotype and medication status rated ADHD symptoms, impairment, and stimulant side effects each week. Children who were homozygous for the less common, 9-repeat DAT1 3 0 -UTR genotype displayed a distinct dose-response curve from that of the other genotype groups, with an absence of typical linear improvement when the dose was increased from 18 mg to 36 and 54 mg. Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype, and to determine if this group responds differentially to alternative treatments.

Spatial normalization of brains to a standardized space is a widely used approach for group studies in functional magnetic resonance imaging (fMRI) data. Commonly used templatebased approaches are complicated by signal dropout and distortions in echo planar imaging (EPI) data. The most widely used software packages implement two common template-based strategies:(1) affine transformation of the EPI data to an EPI template followed by nonlinear registration to an EPI template (EPInorm) and (2) affine transformation of the EPI data to the anatomic image for a given subject, followed by nonlinear registration of the anatomic data to an anatomic template, which produces a transformation that is applied to the EPI data (T1norm). EPI distortion correction can be used to adjust for geometric distortion of EPI relative to the T1 images. However, in practice, this EPI distortion correction step is often skipped. We compare these template-based strategies empirically in four large datasets. We find that the EPInorm approach consistently shows reduced variability across subjects, especially in the case when distortion correction is not applied. EPInorm also shows lower estimates for coregistration distances among subjects (i.e., within-dataset similarity is higher). Finally, the EPInorm approach shows higher T values in a task-based dataset. Thus, the EPInorm approach appears to amplify the power of the sample compared to the T1norm approach when not using distortion correction (i.e., the EPInorm boosts the effective sample size by 12-25%). In sum, these results argue for the use of EPInorm over the T1norm when no distortion correction is used. Hum Brain Mapp 38:5331-5342, 2017.

This study examined the extent to which maternal attention-deficit/hyperactivity disorder (ADHD) symptoms predict improvement in child behavior following brief behavioral parent training. Change in parenting was examined as a potential mediator of the negative relationship between maternal ADHD symptoms and improvement in child behavior. Seventy mothers of 6–10 year old children with ADHD underwent a comprehensive assessment of adult ADHD prior to participating in an abbreviated parent training program. Before and after treatment, parenting was assessed via maternal reports and observations and child disruptive behavior was measured via maternal report. Controlling for pre-treatment levels, maternal ADHD symptomatology predicted post-treatment child disruptive behavior problems. The relation between maternal ADHD symptomatology and improvement in child behavior was mediated by change in observed maternal negative parenting. This study replicated findings linking maternal ADHD symptoms with attenuated child improvement following parent training, and is the first to demonstrate that negative parenting at least partially explains this relationship. Innovative approaches combining evidence-based treatment for adult ADHD with parent training may therefore be necessary for families in which both the mother and child have ADHD. Larger-scale studies using a full evidence-based parent training program are needed to replicate these findings.

A significant body of longitudinal research suggests increased rates of mood disorders as well as depressive symptoms in youth diagnosed with attentiondeficit/hyperactivity disorder (ADHD) in contrast to non-ADHD comparison youth.Furthermore, individuals with co-occurring ADHD and mood disorders experience more serious impairments and worse outcomes than those with either disorder alone. iii

The purpose of this study was to examine the longitudinal relationship between attention-deficit/ hyperactivity disorder (ADHD) symptoms, emotion regulation (ER) ability, and depressive symptoms within a diverse community sample of 277 youth, ages 9–12 (56 % male). Participants were drawn from a larger study examining adolescent risk behaviors, and completed annual assessments over 3 years. Youth ADHD symptoms were assessed at Time 1 (T1) using the parent-reported Disruptive Behavior Disorders Rating Scale, ER was assessed with the parent-reported Emotion Regulation Checklist at Time 2 (T2), and youth depressive symptoms were assessed using the self-reported Revised Child Anxiety and Depression Scales at Time 3 (T3). Analyses examined T2 ER as a mediator between T1 ADHD symptoms (including the unique contributions of inattentive [IA] versus hyperactive/impulsive [HI] symptoms) and T3 depressive symptoms. Structural equation modeling (SEM) indicated the path model specified provided an excellent fit to the data. Tests of indirect effects suggested that T2 ER appears to be a significant mechanism that underlies the relationship between T1 ADHD and T3 depression, even when accounting for T1 oppositional defiant and depressive symptoms. Furthermore, while both T1 IA and HI symptoms had significant indirect effects on T3 depression through the mechanism T2 ER, HI proved a more robust predictor of T2 ER than IA. Results of this prospective study support cross-sectional findings pointing to ER as a potential mechanism linking ADHD and depressive symptoms in youth. Clinical implications and future directions are discussed.

Objective More than 50% of mothers of children with attention-deficit/hyperactivity disorder (ADHD) have a lifetime history of major depressive disorder (MDD). Maternal depressive symptoms are associated with impaired parenting and predict adverse developmental and treatment outcomes for children with ADHD. For these reasons, we developed and examined the preliminary efficacy of an integrated treatment targeting parenting and depressive symptoms for mothers of children with ADHD. This integrated intervention incorporated elements of 2 evidence-based treatments: behavioral parent training (BPT) and cognitive behavioral depression treatment. Method Ninety-eight mothers with at least mild depressive symptoms were randomized to receive either standard BPT (n = 51) or the integrated parenting intervention for ADHD (IPI-A; n = 47). Participants were assessed at baseline, posttreatment, and 3- to 6-month follow-up on measures of (a) self-reported maternal depressive symptoms, (b) observed positive and negative parenting, and (c) observed and mother-reported child disruptive behavior and mother-reported child and family impairment. Results The IPI-A produced effects of small to moderate magnitude relative to BPT on maternal depressive symptoms, observed negative parenting, observed child deviance, and child impairment at posttreatment and on maternal depressive symptoms, child disruptive behavior, child impairment and family functioning at follow-up. Contrary to expectations, the BPT group demonstrated moderate to large effects relative to IPI-A on observed positive parenting at follow-up. Conclusions This treatment development study provides encouraging preliminary support for the integrated intervention targeting parenting and depressive symptoms in mothers of children with ADHD. Future studies should examine whether this integrated intervention improves long-term developmental outcomes for children with ADHD.