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The combination of d-methylphenidate and guanfacine (an α-2A agonist) has emerged as a potential alternative to either monotherapy in children with attention-deficit/hyperactivity disorder (ADHD), but it is unclear what predicts response to these treatments. This study is the first to investigate pretreatment clinical and electroencephalography (EEG) profiles as predictors of treatment outcome in children randomized to these different medications.A total of 181 children with ADHD (aged 7-14 years; 123 boys) completed an 8-week randomized, double-blind, comparative study with d-methylphenidate, guanfacine, or combined treatments. Pretreatment assessments included ratings on ADHD, anxiety, and oppositional behavior. EEG activity from cortical sources localized within midfrontal and midoccipital regions was measured during a spatial working memory task with encoding, maintenance, and retrieval phases. Analyses tested whether pretreatment clinical and EEG measures predicted treatment-related change in ADHD severity.Higher pretreatment hyperactivity-impulsivity and oppositional symptoms and lower anxiety predicted greater ADHD improvements across all medication groups. Pretreatment event-related midfrontal beta power predicted treatment outcome with combined and monotherapy treatments, albeit in different directions. Weaker beta modulations predicted improvements with combined treatment, whereas stronger modulation during encoding and retrieval predicted improvements with d-methylphenidate and guanfacine, respectively. A multivariate model including EEG and clinical measures explained twice as much variance in ADHD improvement with guanfacine and combined treatment (RWe identified treatment-specific and shared predictors of response to different pharmacotherapies in children with ADHD. If replicated, these findings would suggest that aggregating information from clinical and brain measures may aid personalized treatment decisions in ADHD.Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; https://clinicaltrials.gov; NCT00429273 DIVERSITYINCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list.

The combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with attention-deficit/hyperactivity disorder (ADHD). This study investigated the neural mechanisms underlying medication effects using cortical source analysis of electroencephalography (EEG) data.A total of 172 children with ADHD (aged 7-14; 118 boys) completed an 8-week randomized, double-blind, comparative study with 3 treatment arms: d-methylphenidate, guanfacine, or their combination. EEG modulations of brain oscillations at baseline and end point were measured during a spatial working memory task from cortical sources localized within the anterior cingulate (midfrontal) and primary visual cortex (midoccipital), based on previously reported ADHD and control differences. Linear mixed models examined treatment effects on EEG and performance measures.Combined treatment decreased midoccipital EEG power across most frequency bands and task phases. Several midoccipital EEG measures also showed significantly greater changes with combined treatment than with monotherapies. D-methylphenidate significantly increased midoccipital theta during retrieval, while guanfacine produced only trend-level reductions in midoccipital alpha during maintenance and retrieval. Task accuracy improved with combined treatment, was unchanged with d-methylphenidate, and worsened with guanfacine. Treatment-related changes in midoccipital power correlated with improvement in ADHD severity.These findings show that combined treatment ameliorates midoccipital neural activity associated with treatment-related behavioral improvements and previously implicated in visuo-attentional deficits in ADHD. Both monotherapies had limited effects on EEG measures, with guanfacine further showing detrimental effects on performance. The identified midoccipital EEG profile may aid future treatment monitoring for children with ADHD.Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); https://clinicaltrials.gov/; NCT00429273.We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. We actively worked to promote sex and gender balance in our author group.

ObjectiveThe current study applies a precision medicine approach to trigeminal nerve simulation (TNS), a Food and Drug Administration-approved neuromodulation treatment for attention-deficit/hyperactivity disorder (ADHD), by testing secondary outcomes of cognitive and electroencephalographic [EEG] predictors of treatment response among subjects from the original randomized controlled trial.MethodChildren aged 8 to 12 years with ADHD, were randomized to 4 weeks of active or sham TNS treatment, after which the sham group crossed over into 4 weeks of open-label treatment. TNS treatment responders (RESP) had an ADHD Rating Scale (ADHD-RS) Total score reduction of≥25%, whereas nonresponders (NR) had&nbsp

Objective Psychostimulants are partially effective in reducing cognitive dysfunction associated with attention-deficit/hyperactivity disorder (ADHD). Cognitive effects of guanfacine, an alternative treatment, are poorly understood. Given its distinct action on α 2A receptors, guanfacine may have different or complementary effects relative to stimulants. This study tested stimulant and guanfacine monotherapies relative to combined treatment on cognitive functions important in ADHD. Method Children with ADHD (n = 182; aged 7−14 years) completed an 8-week, double blind, randomized, controlled trial with 3 arms: d-methylphenidate (DMPH), guanfacine (GUAN), or combination treatment with DMPH and GUAN (COMB). A nonclinical comparison group (n = 93) had baseline testing, and a subset was retested 8 weeks later (n = 38). Analyses examined treatment effects in 4 cognitive domains (working memory, response inhibition, reaction time, and reaction time variability) constructed from 20 variables. Results The ADHD group showed impaired working memory relative to the nonclinical comparison group (effect size = −0.53 SD unit). The treatments differed in effects on working memory but not other cognitive domains. Combination treatment improved working memory more than GUAN but was not significantly better than DMPH alone. Treatment did not fully normalize the initial deficit in ADHD relative to the comparison group. Conclusion Combined treatment with DMPH and GUAN yielded greater improvements in working memory than placebo or GUAN alone, but the combined treatment was not superior to DMPH alone and did not extend to other cognitive domains. Although GUAN may be a useful add-on treatment to psychostimulants, additional strategies appear to be necessary to achieve normalization of cognitive function in ADHD. Clinical trial registration information : Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00429273

The purpose of this manuscript is to review the literature to determine evidence of associations between exposure to prenatal and postnatal environmental agents and the development of attention deficit hyperactivity disorder (ADHD) and related behaviors. A review of published research literature was conducted on associations between exposures to prenatal and postnatal cigarette smoke, prenatal exposure to alcohol, cocaine, and heroin, childhood exposure to lead, and prenatal exposure to organophosphate pesticides and outcomes of ADHD or behaviors related to ADHD. Review of the literature in these areas provides some evidence of associations between each of the exposures and ADHD-related behaviors, with the strongest evidence from prenatal cigarette and alcohol exposure and postnatal lead exposure. However, research on each exposure also produced evidence of weaknesses in these hypothesized links due to imprecise research methodologies and issues of confounding and inaccurate covariate adjustment. More rigorous studies are needed to provide definitive evidence of associations between each of these prenatal or postnatal exposures and the development of ADHD or symptoms of ADHD. Future studies need to clarify the underlying mechanisms between these exposures and the increased risk for ADHD and associated behaviors. More research is also needed utilizing study designs that include genetic information, as ADHD is highly heritable and there appear to be some protective mechanisms offered by certain genetic characteristics as evidenced in gene by environmental studies. Finally, while studies focusing on individual drugs and chemicals are an important first step, we cannot ignore the fact that children are exposed to combinations of drugs and chemicals, which can interact in complex ways with each other, as well as with the child's genetic makeup and psychosocial environment to influence ADHD risk.

Objective The current study tests electroencephalogram (EEG) measures as a potential endophenotype for attention deficit/hyperactivity disorder (ADHD) by examining sibling and parent–offspring similarity, familial clustering with the disorder, and association with the dopamine receptor D4 (DRD4) candidate gene. Method The sample consists of 531 participants (191 parents and 340 children) from 132 multiplex families with ADHD who participated in a larger genetics study. All members of the families underwent extensive assessment including semi-structured diagnostic interviews and EEG recording. Results Strong sibling similarity and parent–offspring correlations in EEG power emerged, suggesting high trait heritability. Increased theta power was observed among children with ADHD when compared with unaffected children, and there were no differences according to ADHD subtype. Within the parent sample, ADHD diagnostic status and ADHD subtype group differences emerged in the theta, alpha, and beta frequency bands. DRD4 effects for both parents and children were apparent in the beta frequency band and for children only in the theta frequency band. Conclusions This study suggests that EEG measures are a promising avenue of study in the search for putative endophenotypes for ADHD, and that variability at the DRD4 gene may contribute to this endophenotype.

The goal of the present study is to test whether there are Attention-Deficit Hyperactivity Disorder (ADHD)-related differences in brain electrical activity patterns across arousal, activation and vigilance states.The sample consists of 80 adults (38 with ADHD and 42 non-ADHD controls) who were recruited for a family study on the genetics of ADHD. Patterns of cortical activity were measured using electroencephalography (EEG) during baseline and sustained attention conditions and compared according to ADHD diagnostic status. Cortical activity was examined separately for the first, middle, and last 5-min of the sustained attention task to assess whether patterns differed over time and according to ADHD status.In frontal and parietal regions, patterns of activation in the alpha (8-10 Hz) range differed according to ADHD status, indicating increased cortical arousal among ADHD subjects. Beta power (13-14 and 17-18 Hz) also differed between ADHD and controls, indicating increased cortical activation is associated with ADHD. Behavioral performance on the sustained attention task did not differ significantly by diagnosis. EEG correlates of cognitive performance differed significantly ADHD diagnosis and were primarily in frontal regions. Brain activation patterns recorded during the sustained attention task suggest that the ADHD group exhibited significantly increased cortical activation at the end of the task when compared to controls.Adults with ADHD may have different neural organization primarily in frontal regions which results in the need for continually high levels of cortical activation to maintain sustained attention.

Objective The pediatric bipolar disorder profilme of the Child Behavior Checklist (CBCL-PBD), a parent-completed measure that avoids clinician ideological bias, has proven useful in differentiating patients with attention-deficit/hyperactivity disorder (ADHD). We used CBCL-PBD profiles to distinguish patterns of comorbidity and to search for quantitative trait loci in a genomewide scan in a sample of multiple affected ADHD sibling pairs. Method A total of 540 ADHD subjects ages 5 to 18 years were assessed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version and CBCL. Parents were assessed with the Schedule for Affective Disorders and Schizophrenia-Lifetime version supplemented by the Schedule for Affective Disorders and Schizophrenia for School-Age Children for disruptive behavioral disorders. Patterns of psychiatric comorbidity were contrasted based on the CBCL-PBD profile. A quantitative trait loci variance component analysis was used to identify potential genomic regions that may harbor susceptibility genes for the CBCL-PBD quantitative phenotype. Results Bipolar spectrum disorders represented less than 2% of the overall sample. The CBCL-PBD classification was associated with increased generalized anxiety disorder ( p = .001), oppositional defiant disorder ( p = .008), conduct disorder ( p = .003), and parental substance abuse ( p = .005). A moderately significant linkage signal (multipoint maximum lod score=2.5) was found on chromosome 2q. Conclusions The CBCL-PBD profile distinguishes a subset of ADHD patients with significant comorbidity. Linkage analysis of the CBCL-PBD phenotype suggests certain genomic regions that merit further investigation for genes predisposing to severe psychopathology.

Attention deficit hyperactivity disorder (ADHD) treatment is often determined empirically through trial and error until an adequate response is obtained or side effects occur. ADHD is highly heritable and individuals experience wide individual variability in response to ADHD medications, suggesting that the mechanism of action of stimulant medications may provide clues for genetic predictors of response. The promise of ADHD pharmacogenetics is far-reaching and includes the potential to develop individualized medication regimens that improve symptom response, decrease risk for side effects, improve long-term tolerability, and thus contribute to long-term treatment compliance and improved effectiveness. Early ADHD pharmacogenetic studies have focused predominantly on catecholamine pathway genes and response to methylphenidate. Future efforts will also examine a wider range of stimulant and nonstimulant medications on a range of outcome measures and durations. Based on these studies, the potential for personalizing ADHD treatment in clinical practice will be determined.

Objective The present study examined cognitive functioning in a population sample of adolescents with and without attention-deficit/hyperactivity disorder (ADHD) from the Northern Finland Birth Cohort 1986. Method The sample consisted of 457 adolescents ages 16 to 18 who were assessed using a battery of cognitive tasks. Performance according to diagnostic group (control, behavior disorder, and ADHD) and sex was compared. Then, the effect of executive function deficit (EFD) was assessed by diagnostic group status on behavioral and cognitive measures. Results When compared to non-ADHD groups, adolescents with ADHD exhibited deficits on almost all of the cognitive measures. The behavior disorder group obtained scores that were generally intermediate between the ADHD and control groups, but exhibited deficits in intelligence and executive function similar to the ADHD group. Approximately half the ADHD sample had EFD; however, the type and presence of EFDs were not differentially related to cognitive performance as a function of diagnosis. Conclusions These findings indicate that EFDs are more frequent in ADHD than control or behavior disorder groups. EFDs are a general risk factor for poor cognitive functioning across multiple domains, irrespective of diagnostic status.

Objective To study attention-deficit/hyperactivity disorder (ADHD) symptoms and DSM-IV subtypes in childhood and adolescence. Method A total of 457 adolescents ages 16 to 18 years from the Northern Finland Birth Cohort 1986 participated in an epidemiological survey for ADHD. After assessment with a diagnostic interview those with current or childhood ADHD were classified using DSM-IV criteria. Childhood diagnosis of ADHD was set according to retrospective recall. The characteristics and relationships in ADHD symptomatology in childhood and adolescence were studied in relation to behavioral problems and parental history of attentional problems. Results ADHD was reported more commonly in childhood than in adolescence and variations in subtype classification occurred. Those with childhood and adolescent diagnosis had endorsed specific inattentive symptoms more commonly, had greater comorbid major depression and/or oppositional defiant disorder, and had fathers with more reported attentional problems than those with only childhood diagnosis. In childhood, ADHD subtypes differed along symptom severity, but by adolescence these differences were no longer significant. Conclusions The persistence of ADHD from childhood to adolescence may be common. Specific inattentive symptoms, certain psychiatric comorbidity, and family history of attention problems (fathers specifically) contribute to the risk of persistent ADHD. ADHD subtype differences reflect symptom severity differences in childhood that are negligible by adolescence.

Objective Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset disorder with a significant impact on public health. Although a genetic contribution to risk is evident, predisposing genetic determinants remain largely unknown despite extensive research. So far, the most promising candidate genes have been those involved in dopamine and serotonin pathways. This study tests a series of allelic variants within such candidate genes to determine their potential influence on ADHD susceptibility. Method We used a population sample ascertained from a birth cohort of a subpopulation of Finland, characterized by founder effect and isolation, thus minimizing genetic heterogeneity. The subjects were systematically ascertained using DSM-IV diagnostic criteria for ADHD from the Northern Finland Birth Cohort 1986 of more than 9,000 individuals, resulting in the study sample of 188 ADHD cases and 166 controls. We genotyped markers in 13 candidate genes, including critical components of dopamine and serotonin pathways. Results We report evidence for association of ADHD with allelic variants of the dopamine β-hydroxylase (DBH) and dopamine receptor D2 (DRD2) genes. Conclusions Our study supports the involvement of the dopamine pathway in the etiology of ADHD; specifically the genes DBH and DRD2 deserve more attention in further studies.

This multicenter, randomized, fixed-dose, double-blind, placebo-controlled study evaluated efficacy of extended-release dexmethylphenidate (d-MPH-ER) in adults with attention-deficit/hyperactivity disorder (ADHD).Randomized adults with ADHD (n=221) received once-daily d-MPH-ER 20 mg, 30 mg, or 40 mg or placebo for 5 weeks. The primary efficacy variable was change from baseline to final visit in DSM-IV ADHD Rating Scale (ADHD-RS) total score. Secondary efficacy parameters included the proportion of patients with improvementor=30% in ADHD-RS total score and final scores on Clinical Global Impressions-Improvement (CGI-I) scale.Of 218 evaluable patients, 184 completed the study. All d-MPH-ER doses were significantly superior to placebo in improving ADHD-RS total scores. Placebo scores improved by 7.9; d-MPH-ER, 20 mg, improved by 13.7 (p=.006); d-MPH-ER, 30 mg, improved by 13.4 (p=.012); and d-MPH-ER, 40 mg, improved by 16.9 (p.001). Overall distribution of CGI-I ratings at final visit was significantly better with each d-MPH-ER dosage than with placebo. There were no unexpected safety or tolerability concerns, based on experience with racemic methylphenidate (MPH) in adults and dexmethylphenidate (d-MPH) in children.Once-daily d-MPH-ER at 20 mg, 30 mg, or 40 mg is a safe and effective treatment for adults with ADHD.

Lisdexamfetamme dimesylate (LDX) is a therapeutically inactive amphetamine prodrug. It was developed with the goal of providing an extended duration of effect that is consistent throughout the day, with a reduced potential for abuse, overdose toxicity, and drug tampering. Following ingestion, the pharmacologically active d-amphetamine molecule is gradually released by rate-limited hydrolysis.The aims of this study were to assess the efficacy and tolerability of LDX in school-aged children with attention-deficit/hyperactivity disorder (ADHD) treated in the community, and to characterize the duration of action of LDX compared with placebo.This Phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study was conducted at 40 centers across the United States. Male and female children aged 6 to 12 years with ADHD were randomly assigned to receive LDX 30, 50, or 70 mg with forced-dose titration, or placebo, PO QD for 4 weeks. Efficacy was assessed using the ADHD Rating Scale Version IV (ADHD-RS-IV), the Conners' Parent Rating Scale (CPR'), and the Clinical Global Impression of Improvement scale. Tolerability was assessed throughout the study.Of the 290 randomized patients (201 boys, 89 girls; mean [SD] age, 9 [1.8] years), 230 completed the trial (LDX 30 mg, n=56; LDX 50 mg, n=60; LDX 70 mg, n=60; and placebo, n=54). The most common reasons for study discontinuation (n=60) were lack of efficacy (LDX 30 mg, 1%; LDX 50 mg, 0%; LDX 70 mg, 1 %; and placebo, 17%) and adverse events (AEs) (LDX 30 mg, 9%; LDX 50 mg, 5%; LDX 70 mg, 14%; and placebo, 1%). Significant improvements in ADHD-RS-IV scores were seen with all doses of LDX compared with placebo (all, P0.001), and in CPRS scores with all LDX doses versus placebo throughout the day (all, P0.001 for all comparisons). Efficacy was observed by the first week of treatment, and improvements were observed throughout the day up to approximately 6 PM. The most frequently reported AEs among patients receiving LDX were typical of amphetamine products: decreased appetite (39% with active treatment vs 4% with placebo), insomnia (19% vs 3%), upper abdominal pain (12% vs 6%), headache (12% vs 10%), irritability (10% vs 0%), vomiting (9% vs 4%), weight decrease (9% vs 1%), and nausea (6% vs 3%); most were mild to moderate and occurred in the first week.In this population of children with ADHD, treatment once daily with the prodrug LDX at doses of 30 to 70 mg appeared to be effective and had a tolerability profile similar to those of currently marketed extended-release stimulants.

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 Family environmental factors as well as parental attention-deficit/hyperactivity disorder (ADHD) status have shown associations with variability in ADHD. The purpose of the present study was to examine the links among family environment, parental psychiatric diagnosis, and child impairment within a sample of ADHD-affected sibling pairs (ASPs) ages 5 to 18 years. Method Parents in 220 ASP families completed a measure of family functioning, the Family Environment Scale. Children's impairment was measured by clinical ratings of global functioning and by maternal ratings of behavior. Results Parents of children with ADHD rate their families as higher in conflict and lower in achievement and organization than normative samples. High family conflict is significantly associated with impairment in ADHD ASPs accounting for ∼40% of the sibling similarity in impairment. Parental psychiatric diagnosis revealed no significant direct link to sibling impairment, but rather a significant indirect link to impairment mediated by family conflict. Direct associations with parental diagnosis depend on birth order of the ASP members despite the comparable mean impairment scores for older and younger ADHD siblings. Conclusions There are strong links between impairment in children with ADHD and family environment. Different processes and mechanisms may contribute to impairment in different children in the same family. J. Am. Acad. Child Adolesc. Psychiatry , 2006;45(3):346-354.

Because the scientific literature on the pharmacotherapy of attention-deficit/hyperactivity disorder (ADHD) is almost entirely based on the results of studies in samples consisting primarily of boys, much is unknown about the treatment response in girls.This post hoc analysis compared the efficacy, tolerability, and time course of the effect of mixed amphetamine salts extended release (MAS XR) and atomoxetine in school-age girls with ADHD.This was an intent-to-treat subanalysis of the data from girls enrolled in a multicenter, 18-day, randomized, double-blind, parallel-group, forced dose-titration, laboratory school study enrolling boys and girls aged 6 to 12 years with ADHD. The study compared the efficacy, tolerability, and time course of the effect of increasing doses of MAS XR (10, 20, and 30 mg/d) and atomoxetine (0.5 and 1.2 mg/kg per day). The laboratory school sessions were organized in cycles to include 12 hours of observation. Efficacy measures included the SKAMP (Swanson, Kotkin, Agler, M-Flynn, and Pelham) deportment rating subscale, the SKAMP attention rating subscale, and academic testing (number of math problems attempted and answered correctly). Adverse events were assessed throughout the study period. Tolerability and efficacy measures were assessed during laboratory school visits on days 7, 14, and 21.This subanalysis included 57 girls (median age, 9 years; 49.1% white, 22.8% black, 17.5% Hispanic) with a diagnosis of ADHD, combined subtype. Twenty-six girls were randomized to receive MAS XR and 31 were randomized to receive atomoxetine. Mean SKAMP deportment and attention subscale scores in the 2 groups were similar at baseline. Mean changes from baseline were significantly greater for MAS XR compared with atomoxetine on the SKAMP deportment score (-0.48 vs -0.04, respectively; P0.001) and SKAMP attention score (-0.45 vs -0.05; P0.001). The time course of medication effect, based on change from baseline in SKAMP deportment scores, indicated 12-hour efficacy for MAS XR at hours 2, 4.5, 7, 9.5, and 12 (all time points, P0.01 vs baseline) but not for atomoxetine. At the end of the study, both treatment groups had a significant increase from baseline in the mean number of math problems attempted and answered correctly (P0.001). Girls who received MAS XR attempted significantly greater numbers of problems compared with those who received atomoxetine (P=0.04). Both MAS XR and atomoxetine were well tolerated. The most frequently occurring treatment-related adverse events in girls receiving MAS XR were decreased appetite (40.7%), upper abdominal pain (29.6%), insomnia (25.9%), and headache (14.8%). The most frequently occurring treatment-related adverse events in girls receiving atomoxetine were somnolence (28.1%), upper abdominal pain (15.6%), vomiting (15.6%), nausea (12.5%), and decreased appetite (12.5%).This post hoc analysis in a subpopulation of girls with ADHD, combined subtype, found that 18-day treatment with MAS XR was significantly more effective than atomoxetine in terms of ratings of classroom behavior, attention, and academic productivity.

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.

Introduction: cognitive/behavioral testing, structural imaging, and functional imaging, has demonstrated atypical cerebral asymmetries in patients with attention-deficit/hyperactivity disorder (ADHD). However, few studies directly examined the nature of hemispheric specialization and interaction in this population. Methods: the present experiment applied techniques from behavioral laterality research to assess directly left/right brain dynamics in unmedicated adults with ADHD (n=21) and controls (n=22). We used a lateralized lexical decision task to assess hemispheric differences in word recognition and cross-callosal interhemispheric transfer of linguistic information. Results: analysis of variance indicated that ADHD subjects were impaired relative to controls in identifying words in both hemispheres (P=0.001). Furthermore, ADHD subjects exhibited decreased effects for ‘word regularity’ (P=004), enhanced effects of ‘word frequency’ (P=007), and an increased bias for ‘nonword’ responses overall (P=03), as well as during left visual field trials in particular (P=01). Conclusions: adult subjects with ADHD demonstrated poor linguistic processing. Group differences in sensitivity to semantic and phonological linguistic variables, along with differences in response biases, suggested that ADHD subjects had reduced left hemisphere and enhanced right hemisphere involvement during our task. These findings are relevant to current research investigating ‘endophenotypes’ in ADHD, as laterality indices may prove useful in etiological research, particularly molecular genetic investigations, and highlights the relevance of brain laterality research in clinical psychiatry.

Although the efficacy of medications for attention-deficit/hyperactivity disorder (ADHD) is well demonstrated in clinical trials, substantial numbers of patients fail to remain on therapy, and there is tremendous variability in tolerability and treatment acceptance. The emerging science of pharmacogenomics seeks to identify patterns of genetic variation that will direct individually tailored treatment regimens and enhance long-term adherence. For this review, existing studies in ADHD pharmacogenomics were reviewed to assess current knowledge and provide a basis for planning future research. Twelve studies were identified. The majority investigated the role of candidate genes in predicting clinical response to methylphenidate. The most frequently studied is DAT1, although findings are inconsistent, with the 10-repeat polymorphism predicting both increased and decreased symptom reduction in various reports. Other candidates include DRD4, DRD5, DBH, 5HTT, SNAP-25, and COMT. One study was based on quantitative trait analyses in a genome-wide scan. Although interest in ADHD pharmacogenomics is encouraging, preliminary studies have been limited by small sample sizes, inconsistent research designs, retrospective reports, and a focus on symptom response. Future studies should emphasize large, prospective trials, assess multiple medications in individual subjects, and consider a full range of pharmacodynamic and pharmacokinetic outcomes.

We completed fine mapping of nine positional candidate regions for attention-deficit/hyperactivity disorder (ADHD) in an extended population sample of 308 affected sibling pairs (ASPs), constituting the largest linkage sample of families with ADHD published to date. The candidate chromosomal regions were selected from all three published genomewide scans for ADHD, and fine mapping was done to comprehensively validate these positional candidate regions in our sample. Multipoint maximum LOD score (MLS) analysis yielded significant evidence of linkage on 6q12 (MLS 3.30; empiric P=.024) and 17p11 (MLS 3.63; empiric P=.015), as well as suggestive evidence on 5p13 (MLS 2.55; empiric P=.091). In conjunction with the previously reported significant linkage on the basis of fine mapping 16p13 in the same sample as this report, the analyses presented here indicate that four chromosomal regions--5p13, 6q12, 16p13, and 17p11--are likely to harbor susceptibility genes for ADHD. The refinement of linkage within each of these regions lays the foundation for subsequent investigations using association methods to detect risk genes of moderate effect size.

Objectives This investigation was conducted primarily to assess the safety and efficacy of SLI381 (Adderall XR™), developed as a once-daily treatment for children with attention-deficit/hyperactivity disorder (ADHD). Secondary objectives included examination of the time course, pharmacokinetic, and pharmacodynamic properties of SLI381. Method This was a randomized, double-blind, crossover study of three doses of SLI381 (10, 20, and 30 mg), placebo, and an active control (Adderall ® 10 mg) given once daily to 51 children with ADHD. Weekly assessments in an analog classroom setting included blind ratings of attention and deportment and a performance measure (math test) obtained every 1.5 hours over a 12-hour period. Results SLI381 was well tolerated. All active treatment conditions displayed significant time course effects and were superior to placebo in improving efficacy measures. Dose-dependent improvements were evident for SLI381. SLI381 20 and 30 mg and Adderall all showed rapid improvements by 1.5 hours, but only the SLI381 20- and 30-mg doses showed continued activity at 10.5 and 12 hours for classroom behavior and math test performance versus placebo. Conclusions These data provide support for the benefit of this novel, once-daily amphetamine preparation in the treatment of ADHD. The longer duration of action of SLI381 has the potential to simplify psychostimulant dosing, thus reducing dose diversion and eliminating the need for in-school administration. SLI381 appears to be a useful treatment option for many children with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder in childhood and likely represents an extreme of normal behavior. ADHD significantly impacts learning in school-age children and leads to impaired functioning throughout the life span. There is strong evidence for a genetic etiology of the disorder, although putative alleles, principally in dopamine-related pathways suggested by candidate-gene studies, have very small effect sizes. We use affected-sib-pair analysis in 203 families to localize the first major susceptibility locus for ADHD to a 12-cM region on chromosome 16p13 (maximum LOD score 4.2; P=.000005), building upon an earlier genomewide scan of this disorder. The region overlaps that highlighted in three genome scans for autism, a disorder in which inattention and hyperactivity are common, and physically maps to a 7-Mb region on 16p13. These findings suggest that variations in a gene on 16p13 may contribute to common deficits found in both ADHD and autism.

Attention deficit/hyperactivity disorder (ADHD) is a common heritable disorder with a childhood onset. Molecular genetic studies of ADHD have previously focused on examining the roles of specific candidate genes, primarily those involved in dopaminergic pathways. We have performed the first systematic genomewide linkage scan for loci influencing ADHD in 126 affected sib pairs, using a approximately 10-cM grid of microsatellite markers. Allele-sharing linkage methods enabled us to exclude any loci with a lambda(s) of > or =3 from 96% of the genome and those with a lambda(s) of > or =2.5 from 91%, indicating that there is unlikely to be a major gene involved in ADHD susceptibility in our sample. Under a strict diagnostic scheme we could exclude all screened regions of the X chromosome for a locus-specific lambda(s) of >/=2 in brother-brother pairs, demonstrating that the excess of affected males with ADHD is probably not attributable to a major X-linked effect. Qualitative trait maximum LOD score analyses pointed to a number of chromosomal sites that may contain genetic risk factors of moderate effect. None exceeded genomewide significance thresholds, but LOD scores were >1.5 for regions on 5p12, 10q26, 12q23, and 16p13. Quantitative-trait analysis of ADHD symptom counts implicated a region on 12p13 (maximum LOD 2.6) that also yielded a LOD >1 when qualitative methods were used. A survey of regions containing 36 genes that have been proposed as candidates for ADHD indicated that 29 of these genes, including DRD4 and DAT1, could be excluded for a lambda(s) of 2. Only three of the candidates-DRD5, 5HTT, and CALCYON-coincided with sites of positive linkage identified by our screen. Two of the regions highlighted in the present study, 2q24 and 16p13, coincided with the top linkage peaks reported by a recent genome-scan study of autistic sib pairs.

Objective A potentially useful tool for understanding the distribution and determinants of emotional dysregulation in children is a Child Behavior Checklist profile, comprising the Attention Problems, Anxious/Depressed, and Aggressive Behavior clinical subscales (CBCL-DP). The CBCL-DP indexes a heritable trait that increases susceptibility for later psychopathology, including severe mood problems and aggressive behavior. We have conducted a genome-wide association study of the CBCL-DP in children with attention-deficit/hyperactivity disorder (ADHD). Method Families were ascertained at Massachusetts General Hospital and University of California, Los Angeles. Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. Genome-wide association analyses were conducted with the MQFAM multivariate extension of PLINK. Results CBCL data were available for 341 ADHD offspring from 339 ADHD affected trio families from the UCLA ( N = 128) and the MGH ( N = 213) sites. We found no genome-wide statistically significant associations but identified several plausible candidate genes among findings at p TMEM132D , LRRC7 , SEMA3A , ALK , and STIP1 . Conclusions We found suggestive evidence for developmentally expressed genes operant in hippocampal dependent memory and learning with the CBCL-DP.

Objective Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD. Method Families were ascertained at Massachusetts General Hospital (MGH; N=309 trios), Washington University at St. Louis (WASH-U; N=272 trios), and University of California at Los Angeles (UCLA; N=156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families. Results Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p=6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9. Conclusions We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders.