Minor differences in ADHD-related difficulties between boys and girls treated with atomoxetine for attention-deficit/hyperactivity disorder

Atomoxetine may improve ADHD-related difficulties and hence the quality of life (QoL) in children and adolescents. Perception of these difficulties may differ with the rater perspective (patient, parent, physician) or patients' sex. The objective of this study was to investigate QoL as reflected by perceived ADHD-related difficulties perceived from these three perspectives and compare boys and girls. Patients aged 6-17 with ADHD were treated with atomoxetine (target dose 0.5-1.2 mg/kg/day) in two studies. In both studies, ADHD-related difficulties were assessed after 8 and 24 weeks using the Global Impression of Perceived Difficulties (GIPD) instrument, which can be taken to reflect the patient's QoL from the three perspectives. Data from the two studies were combined and analyzed together in order to compare boys and girls. Four hundred and twenty-one patients were treated with atomoxetine, 338 boys and 83 girls. Three hundred and fifty-five patients completed the 8-week study period. QoL, as reflected by perceived ADHD-related difficulties (measured with GIPD), improved over time. Mean GIPD total scores showed a similar course over time for all rater groups, although the patients rated the degree of difficulties significantly lower than parents and physicians. The sexes did not differ significantly in mean GIPD total scores. The GIPD scores over time suggest that patients' QoL, as reflected by perceived ADHD-related difficulties, improved with time on atomoxetine. However, improvement did not differ significantly between boys and girls. Trial Registration: ClinicalTrials.gov Identifiers NCT00191516 and NCT00191737.     

Predictors of relapse or maintenance of response in pediatric and adult patients with attention-deficit/hyperactivity disorder following discontinuation of long-term treatment with atomoxetine

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.     

Relationship between attention-deficit/hyperactivity disorder and sedentary behavior in adolescence: a cross-sectional study

Existing studies reveal that high levels of sedentary behavior are associated with more inattention and hyperactivity problems. Since most previous studies used screen time as an indicator of sedentary behavior and assessed symptoms of attention-deficit/hyperactivity disorder (ADHD) by short screening measures which do not allow to distinguish between subtypes of ADHD, the current study aimed to investigate association between different types of sedentary behavior and symptoms and subtypes of ADHD. The current cross-sectional study analyzed data of 913 students (46.1% girls) aged 13–17 years (M = 15.0, SD = 0.6). Using a self-administered questionnaire, screen-based and non-screen-based sedentary behavior and ADHD symptoms were assessed. Linear and logistic regression analyses were conducted. All analyses were adjusted for age, gender, moderate to vigorous physical activity and body mass index. Screen time was related to the total ADHD score (p < 0.001) as well as to the subscales inattention (p ≤ 0.016) and hyperactivity/impulsivity (p ≤ 0.008). Sedentary time without screens was virtually not associated with ADHD. As far as ADHD symptoms are considered as a correlate of sedentary behavior, the type of activity which is pursued sedentarily seems to matter: screen time, but not other non-screen-based sedentary activities should be considered as being a risk factor for ADHD.     

Developmental comorbidity in attention-deficit/hyperactivity disorder

With the present review, we intend to highlight the importance of considering the age- and development-dependent occurrence of comorbidity in ADHD and to outline distinct trajectories of symptom progression with possible impact on course and outcome of ADHD. The review will focus on introducing the concepts of "developmental epidemiology" and "developmental comorbidity". Psychiatric and non-psychiatric age-dependent comorbidity can be seen in the majority of children, adolescents and adults with ADHD, resulting in a severe impairment of everyday life with considerable functional and psychosocial problems. Concerning the temporal order of occurrence, psychiatric conditions may be present before the appearance of first definite ADHD symptoms ("pre-comorbidity", such as temperament factors, sleep disturbance, autism spectrum disorders and atopic eczema). They may coincide with the time when ADHD symptoms reach a clinically significant level ("simultaneous comorbidity": enuresis, encopresis, developmental dyslexia). The majority of comorbidity, however, appears after the onset of ADHD in the course of disease ("post-comorbidity": tic disorder, depression and suicidality, anxiety disorders, obsessive compulsive disorder, bipolar disorder, conduct and substance use disorders, obesity and personality disorders). The aetio-pathophysiology of ADHD and its comorbid disorders and also the nature of comorbidity itself being highly heterogeneous, we additionally discuss possible models of comorbidity. In the future, longitudinal data on distinct patterns of symptom and comorbidity progression would help to refine disease classification systems, strengthen the power of future genetic studies and finally allow for more specific treatment strategies.     

Human plasma glycome in attention-deficit hyperactivity disorder and autism spectrum disorders

Over a half of all proteins are glycosylated, and their proper glycosylation is essential for normal function. Unfortunately, because of structural complexity of nonlinear branched glycans and the absence of genetic template for their synthesis, the knowledge about glycans is lagging significantly behind the knowledge about proteins or DNA. Using a recently developed quantitative high throughput glycan analysis method we quantified components of the plasma N-glycome in 99 children with attention-deficit hyperactivity disorder (ADHD), 81 child and 5 adults with autism spectrum disorder, and a total of 340 matching healthy controls. No changes in plasma glycome were found to associate with autism spectrum disorder, but several highly significant associations were observed with ADHD. Further structural analysis of plasma glycans revealed that ADHD is associated with increased antennary fucosylation of biantennary glycans and decreased levels of some complex glycans with three or four antennas. The design of this study prevented any functional conclusions about the observed associations, but specific differences in glycosylation appears to be strongly associated with ADHD and warrants further studies in this direction.     

Diagnosing and treating attention-deficit/hyperactivity disorder in adults

Adult attention deficit/hyperactivity disorder (ADHD) is a valid and impairing psychiatric disorder. In this article, we review the diagnosis of ADHD in adults, focusing on symptom presentation differences between pediatric and adult ADHD as well as the importance of assessing functional impairments. Differentiating ADHD from other clinical disorders is often the most difficult part of making an ADHD diagnosis in adults. Psychiatric comorbidities are also described and discussed as potential impact factors upon not only diagnosing ADHD but also treatment of adult ADHD. Especially in those adults with psychiatric comorbidities, treatments need to be multimodal and include both pharmacotherapy and psychosocial interventions.     

Self-esteem in adolescent patients with attention-deficit/hyperactivity disorder during open-label atomoxetine treatment: psychometric evaluation of the Rosenberg Self-Esteem Scale and clinical findings

To report on (1) psychometric properties of the Rosenberg Self-Esteem Scale (SES) studied in adolescents with ADHD, (2) correlations of SES with ADHD scale scores, and (3) change in patient-reported self-esteem with atomoxetine treatment. ADHD patients (12–17 years), treated in an open-label study for 24 weeks. Secondary analyses on ADHD symptoms (assessed with ADHD-RS, CGI, GIPD scales) and self-esteem (SES) were performed. One hundred and fifty-nine patients were treated. A dichotomous structure of the SES could be confirmed. Reliability and internal consistency were moderate to excellent. Highest coefficients were found for the correlation between SES and GIPD scores. Self-esteem significantly increased over time, accompanied by an improvement of ADHD symptoms and related perceived difficulties. The Rosenberg SES was shown to be internally consistent, reliable, and sensitive to treatment-related changes of self-esteem. According to these findings, self-esteem may be an important individual patient outcome beyond the core symptoms of ADHD.     

Differentiation between attention-deficit/hyperactivity disorder and autism spectrum disorder by the Social Communication Questionnaire

The differentiation of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) poses a clinical challenge. In children, overlap of psychopathological and cognitive findings has been found for both disorders. In addition, some children suffer from both disorders. The Social Communication Questionnaire (SCQ) is a screening instrument for ASD symptoms which indicates the presence of ASD in a rapid and economic way. However, validity to differentiate ASD and ADHD as differential or comorbid diagnoses has not been studied. Here, the differential validity was compared in groups of children with ASD, ADHD, ASD + ADHD, and typically developing (TD) children and IQ > 70. ROC analyses indicated an excellent differentiation between ASD and TD with ROC–AUC = .941 and between ASD + ADHD with ROC–AUC = .993. The optimal cutoff was below the originally recommended one of 15. The differentiation between children with ASD with (ROC–AUC = .982) or without ADHD (ROC–AUC = .864) and ADHD alone also showed acceptable differential validity, and here, the optimal cutoff corresponded to the recommended. Taken together, the SCQ can be recommended as a screening instrument for a first differentiation between children with ASD and typically developing children as well as children with ADHD.     

Emotional dysregulation in children with attention-deficit/hyperactivity disorder

Emotional dysregulation is increasingly recognized as a core feature of attention-deficit/hyperactivity disorder (ADHD). The purpose of the present systematic literature review was to identify published data related to the neuropsychology of emotional dysregulation in children with ADHD. The literature obtained is discussed in the contexts of deficits in emotional control, impairments in executive function, the emotional components of comorbidities, neurophysiological and autonomic correlates of emotional dysregulation, and the significance of multiple neuropsychological pathways of ADHD on emotional dysregulation. These various lines of evidence are used to create a patient-oriented conceptual model framework of the pathway from stimulus to inappropriate internalized (sadness, moodiness) or externalized (anger, aggressiveness) emotional responses. The article concludes by calling for continued research into the development of reliable and universally accepted measures of emotional dysregulation in order to provide children affected with ADHD, and their caregivers, some explanation for their emotional lability and, ultimately, to be used as tools to evaluate potential treatments.     

Omega-3 fatty acid status in attention-deficit/hyperactivity disorder

Lower levels of long-chain polyunsaturated fatty acids, particularly omega-3 fatty acids, in blood have repeatedly been associated with a variety of behavioral disorders including attention-deficit/hyperactivity disorder (ADHD). The exact nature of this relationship is not yet clear. We have studied children with ADHD who exhibited skin and thirst symptoms classically associated with essential fatty acid (EFA) deficiency, altered plasma and red blood cell fatty acid profiles, and dietary intake patterns that do not differ significantly from controls. This led us to focus on a potential metabolic insufficiency as the cause for the altered fatty acid phenotype. Here we review previous work and present new data expanding our observations into the young adult population. The frequency of thirst and skin symptoms was greater in newly diagnosed individuals with ADHD (n = 35) versus control individuals without behavioral problems (n = 112) drawn from the Purdue student population. A follow up case-control study with participants willing to provide a blood sample, a urine sample, a questionnaire about their general health, and dietary intake records was conducted with balancing based on gender, age, body mass index, smoking and ethnicity. A number of biochemical measures were analyzed including status markers for several nutrients and antioxidants, markers of oxidative stress, inflammation markers, and fatty acid profiles in the blood. The proportion of omega-3 fatty acids was found to be significantly lower in plasma phospholipids and erythrocytes in the ADHD group versus controls whereas saturated fatty acid proportions were higher. Intake of saturated fat was 30% higher in the ADHD group, but intake of all other nutrients was not different. Surprisingly, no evidence of elevated oxidative stress was found based on analysis of blood and urine samples. Indeed, serum ferritin, magnesium, and ascorbate concentrations were higher in the ADHD group, but iron, zinc, and vitamin B6 were not different. Our brief survey of biochemical and nutritional parameters did not give us any insight into the etiology of lower omega-3 fatty acids, but considering the consistency of the observation in multiple ADHD populations continued research in this field is encouraged.     

Neurofeedback treatment for attention-deficit/hyperactivity disorder in children: a comparison with methylphenidate

Clinical trials have suggested that neurofeedback may be efficient in treating attention-deficit/hyperactivity disorder (ADHD). We compared the effects of a 3-month electroencephalographic feedback program providing reinforcement contingent on the production of cortical sensorimotor rhythm (12–15 Hz) and beta1 activity (15–18 Hz) with stimulant medication. Participants were N = 34 children aged 8–12 years, 22 of which were assigned to the neurofeedback group and 12 to the methylphenidate group according to their parents' preference. Both neurofeedback and methylphenidate were associated with improvements on all subscales of the Test of Variables of Attention, and on the speed and accuracy measures of the d2 Attention Endurance Test. Furthermore, behaviors related to the disorder were rated as significantly reduced in both groups by both teachers and parents on the IOWA-Conners Behavior Rating Scale. These findings suggest that neurofeedback was efficient in improving some of the behavioral concomitants of ADHD in children whose parents favored a nonpharmacological treatment.     

Olfactory and gustatory sensitivity in adults with attention-deficit/hyperactivity disorder

Recently, research on olfactory functions in attention-deficit/hyperactivity disorder (ADHD) has become prominent, whereas gustation has never been investigated. Increased odor sensitivity was found in medication-na?ve children with ADHD, but not in adult ADHD, which might be due to a dopaminergic dysregulation presumed to underlie this disorder. Taste sensitivity, in particular bitter sensitivity as a hereditary trait, also might be altered in ADHD. To examine olfactory and gustatory functions in adult ADHD patients, we assessed odor sensitivity by Sniffin' Sticks, taste sensitivity by taste strips, and bitter sensitivity by the one-solution test in women with ADHD (n = 12), Bulimia Nervosa (n = 12), and healthy control women (n = 12). Bulimia Nervosa as second patient group was included to control for effects of impulsivity. Preliminary results indicate that ADHD patients were significantly more often classified as tasters, i.e. perceived the bitter taste as more intense, compared to both bulimic patients and healthy controls. No group differences were found with regard to general odor and taste sensitivity. It is proposed that the higher frequency of tasters in ADHD patients might underlie a genetic variation of the bitter receptor-dependent signaling pathway associated with ADHD.     

Intolerance of uncertainty in children with attention-deficit/hyperactivity disorder

Intolerance of uncertainty (IU) has often been studied in the context of internalizing disorders, but no studies to our knowledge have explored the relation between IU and externalizing disorders. Given the proposed link between IU and emotion regulation, the current study sought to examine levels of IU in an externalizing clinical population with known emotion regulation difficulties—attention-deficit/hyperactivity disorder (ADHD). IU levels in this population were compared to a clinical population known to experience elevated levels of IU. Participants in present study were ninety-three children (36 anxiety disorder, 28 ADHD, 29 unaffected children) ages 7–13, who completed the Intolerance of Uncertainty Scale—Short Version (IUS). Responses on the IUS were converted to total IU, prospective IU, and inhibitory IU. A linear mixed model analysis of covariance was conducted while controlling for age, sex, and ADHD medications. A significant interaction was observed between diagnostic status and IU scale. Planned contrasts indicated that children with anxiety disorders and ADHD reported significantly higher levels of IU relative to unaffected children, and children with ADHD reported comparable levels of inhibitory IU relative to children with anxiety disorders. The current results contribute to a growing literature on the link between IU and psychopathology. IU appears to be a transdiagnostic construct present among children with internalizing and externalizing disorders, and may be broadly associated with emotion regulation deficits rather than specific disorder symptoms.     

miRNA profiling in the hippocampus of attention-deficit/hyperactivity disorder rats

Attention-deficit/hyperactivity disorder (ADHD) is characterized by attention deficit, hyperactivity, impulsivity, and learning and memory impairment. Although the pathogenesis of learning and memory impairment is still unknown, some studies have suggested an association with hippocampus dysfunction. We aimed to explore the role of miRNAs in the learning and memory impairments observed in ADHD. Differentially expressed hippocampal micro-ribonucleic acids (miRNAs) in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) were detected on an Illumina HiSeq. 2000 genome analyzer. A total of 25 differentially expressed miRNAs (fold-change ≥ 2 and P-value < 0.05) were identified. The target genes of these differentially expressed miRNAs were predicted using online tools (TargetScan and miRDB). Gene ontology and pathway analysis of the predicted target genes were carried out to assess their putative biological functions. Meanwhile, quantitative real-time PCR was used to validate the HiSeq results, revealing that three miRNAs (miR-1-b, miR-741-3p, and miR-206-3p) were upregulated and four (miR-182, miR-471-5p, miR-183-5p, and miR-211-5p) were downregulated in the SHR group compared with the WKY group. In addition, we confirmed that Dyrk1a is regulated by miR-211-5p. These results help us understand the contribution of miRNAs in the hippocampus to ADHD and provide new insights into the pathogenesis of this condition.     

A genomewide scan for loci involved in attention-deficit/hyperactivity disorder

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.     

The potential role of fatty acids in attention-deficit/hyperactivity disorder

As currently defined, attention-deficit/hyperactivity disorder (ADHD) encompasses a broad constellation of behavioural and learning problems and its definition and diagnosis remain controversial. The aetiology of ADHD is acknowledged to be both complex and multifactorial. The proposal considered here is that at least some features of ADHD may reflect an underlying abnormality of fatty acid metabolism. Clinical and biochemical evidence is discussed which suggests that a functional deficiency of certain long-chain polyunsaturated fatty acids could contribute to many of the features associated with this condition. The implications in terms of fatty acid treatment proposals are also discussed; such a form of treatment is relatively safe compared to existing pharmacological interventions, although further studies are still needed in order to evaluate its potential efficacy in the management of ADHD symptoms.