A randomized crossover clinical study showing that methylphenidate-SODAS improves attention-deficit/hyperactivity disorder symptoms in adolescents with substance use disorder

Our objective was to evaluate the effectiveness of a long-acting formulation of methylphenidate (MPH-SODAS) on attention-deficit/hyperactivity disorder (ADHD) symptoms in an outpatient sample of adolescents with ADHD and substance use disorders (SUD). Secondary goals were to evaluate the tolerability and impact on drug use of MPH-SODAS. This was a 6-week, single-blind, placebo-controlled crossover study assessing efficacy of escalated doses of MPH-SODAS on ADHD symptoms in 16 adolescents with ADHD/SUD. Participants were randomly allocated to either group A (weeks 1-3 on MPH-SODAS, weeks 4-6 on placebo) or group B (reverse order). The primary outcome measures were the Swanson, Nolan and Pelham Scale, version IV (SNAP-IV) and the Clinical Global Impression Scale (CGI). We also evaluated the adverse effects of MPH-SODAS using the Barkley Side Effect Rating Scale and subject reports of drug use during the study. The sample consisted of marijuana (N = 16; 100%) and cocaine users (N = 7; 43.8%). Subjects had a significantly greater reduction in SNAP-IV and CGI scores (P < 0.001 for all analyses) during MPH-SODAS treatment compared to placebo. No significant effects for period or sequence were found in analyses with the SNAP-IV and CGI scales. There was no significant effect on drug use. MPH-SODAS was well tolerated but was associated with more severe appetite reduction than placebo (P < 0.001). MPH-SODAS was more effective than placebo in reducing ADHD symptoms in a non-abstinent outpatient sample of adolescents with comorbid SUD. Randomized clinical trials, with larger samples and SUD intervention, are recommended.

Physical activity of children with developmental coordination disorder in the presence of attention deficit hyperactivity disorder : does gender matter?

Baerg, S., Cairney, J., Hay, J., Rempel, L. and Faught, B.E. (2009). Physical Activity of Children with Developmental Coordination Disorder in the Presence of Attention Deficit Hyperactivity Disorder: Does Gender Matter? Brock University, St. Catharines, Ontario, CANADA. Children with Developmental Coordination Disorder (DCD) have difficulties in motor coordination. Attention-deficit hyperactive disorder (ADHD) is considered the condition most co-morbid with DCD at approximately 50%. Children with DCD are generally less physically active (PA) than their peers, while children with ADHD are often considered more physically active. It is not known if the physical activity patterns of children with DCD-ADHD resemble those of children with primarily DCD or that of their healthy peers. The primary objective of this research was to contrast physical activity patterns between children with DCD, DCD-ADHD, and healthy controls. Since boys are generally reported as more physically active than girls, a secondary objective was to determine if gender moderated the association between groups and physical activity. A sample of males (n=66) and females (n=44) were recruited from the Physical Health Activity Study Team (PHAST) longitudinal study. The Movement Assessment Battery for Children (2nd Ed.) was used to identify probable cases of DCD, and Connor's Revised Parent Rating Scale- Short Version to identify ADHD. Subjects (mean age=12.8±.4 yrs) were allocated to three groups; DCD (n=32), DCD-ADHD (n=30) and control (n=48). Physical activity was monitored for seven days with the Actical® accelerometer (activity count, step count and energy expenditure). Children completed the Participation Questionnaire (PQ) during the in-school session of data collection for the PHAST study. Height, weight and body mass index (BMI) were also determined. Analysis of variance showed significant group differences for activity count (F(2,56)=5.36, p=.007) and PQ (F(2,44 )=6. 71, p=.003) in males, while a significant group difference for step count (F(2,37)=3.55, p=.04) was found in females. Post hoc comparison tests (Tukey) identified significantly lower PQ and activity count between males with OCD and controls (p=.004) and males with DCD-ADHD and controls (p=.003). Conversely, females with DCD-ADHD had significantly more step counts than their controls (p=.01). Analysis of covariance demonstrated a gender by DCD groups negative interaction for males (activity count) (F(2,92):;:3.11, p=.049) and a positive interaction for females (step count) (F(1,92)=4.92, p=.009). Hyperactivity in females with DCD-ADHD appears to contribute to more physical activity, whereas DCD may contribute to decreased activity in males with DCD and DCDADHD. Further research is needed to examine gender differences in physical activity within the context of DCD and ADHD.

Effects of low doses of polyunsaturated fatty acids on the attention deficit/Hyperactivity disorder of children: A systematic review

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Analysis of cardiac autonomic modulation of children with attention deficit hyperactivity disorder

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Social cognition in attention-deficit hyperactivity disorder (ADHD)

Attention-deficit hyperactivity disorder (ADHD) is associated with a range of cognitive deficits and social cognition impairments, which might be interpreted in the context of fronto-striatal dysfunction. So far only few studies have addressed the issue of social cognition deficits in ADHD.

Genome-wide association study in German patients with attention deficit/hyperactivity disorder

The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 × 10(-7)) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values ≤ 7.57 × 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD.

Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder

Children with attention-deficit/hyperactivity disorder (ADHD) have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. We examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). We screened 32 obesity risk alleles of single nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS) for ADHD based on 495 patients and 1,300 population-based controls and performed in silico analyses of the SNPs in an ADHD meta-analysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X-type motif 3) was associated with ADHD risk (OR: 1.39; P = 3.4 × 10(-4) ; Pcorr  = 0.01). In the meta-analysis data we found rs6497416 in the intronic region of the GPRC5B gene (G protein-coupled receptor, family C, group 5, member B; P = 7.2 × 10(-4) ; Pcorr  = 0.02) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample rs206936 (NUDT3) and rs10938397 in the glucosamine-6-phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen-activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta-analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/impulsivity. Our results justify further research on the elucidation of the common genetic background of ADHD and obesity.

Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency 1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.Molecular Psychiatry advance online publication, 20 November 2012; doi:10.1038/mp.2012.161.

Intra-subject variability in attention-deficit hyperactivity disorder

BACKGROUND: This study is based on a comprehensive survey of the neuropsychological attention-deficit hyperactivity disorder (ADHD) literature and presents the first psychometric analyses of different parameters of intra-subject variability (ISV) in patients with ADHD compared to healthy controls, using the Continuous Performance Test, a Go-NoGo task, a Stop Signal Task, as well as N-back tasks. METHODS: Data of 57 patients with ADHD and 53 age- and gender-matched controls were available for statistical analysis. Different parameters were used to describe central tendency (arithmetic mean, median), dispersion (standard deviation, coefficient of variation, consecutive variance), and shape (skewness, excess) of reaction time distributions, as well as errors (commissions and omissions). RESULTS: Group comparisons revealed by far the strongest effect sizes for measures of dispersion, followed by measures of central tendency, and by commission errors. Statistical control of ISV reduced group differences in the other measures substantially. One (patients) or two (controls) principal components explained up to 67% of the inter-individual differences in intra-individual variability. CONCLUSIONS: Results suggest that, across a variety of neuropsychological tests, measures of ISV contribute best to group discrimination, with limited incremental validity of measures of central tendency and errors. Furthermore, increased ISV might be a unitary construct in ADHD.

Diminished prefrontal brain function in adults with psychopathology in childhood related to attention deficit hyperactivity disorder

The aim of the present study was to investigate prefrontal brain function and cognitive response control in patients with personality disorders who either suffered or did not suffer from psychopathology related to attention deficit hyperactivity disorder (ADHD) during childhood. For this purpose, 36 psychiatric out-patients with personality disorders--24 of whom showed ADHD-related psychopathology during childhood assessed by the German short form of the Wender Utah Rating Scale--and 24 healthy controls were investigated electrophysiologically by means of a cued Go-NoGo task (Continuous Performance Test). Topographical analyses were conducted to individually quantify the NoGo anteriorisation (NGA), a neurophysiological correlate of prefrontal response control that has been suggested to reflect activation of the anterior cingulate cortex. ADHD patients exhibited a significantly reduced mean NGA and diminished amplitudes of the Global Field Power, as well as a reduced increase of fronto-central P300 amplitudes, in NoGo-trials compared with the healthy controls, whereas patients with personality disorders alone did not differ from the control group in any of the electrophysiological parameters. The results indicate that ADHD-related psychopathology is associated with prefrontal brain dysfunction, probably related to processes of response inhibition and/or cognitive response control.

Selective effects of methylphenidate in attention deficit hyperactivity disorder: A functional magnetic resonance study

Functional MRI revealed differences between children with Attention Deficit Hyperactivity Disorder (ADHD) and healthy controls in their frontal–striatal function and its modulation by methylphenidate during response inhibition. Children performed two go/no-go tasks with and without drug. ADHD children had impaired inhibitory control on both tasks. Off-drug frontal–striatal activation during response inhibition differed between ADHD and healthy children: ADHD children had greater frontal activation on one task and reduced striatal activation on the other task. Drug effects differed between ADHD and healthy children: The drug improved response inhibition in both groups on one task and only in ADHD children on the other task. The drug modulated brain activation during response inhibition on only one task: It increased frontal activation to an equal extent in both groups. In contrast, it increased striatal activation in ADHD children but reduced it in healthy children. These results suggest that ADHD is characterized by atypical frontal–striatal function and that methylphenidate affects striatal activation differently in ADHD than in healthy children.

Relationship Maintenance in Couples with a Partner Who Has Attention Deficit Hyperactivity Disorder

The body of research on the relationship functioning of adults with attention deficit hyperactivity disorder (ADHD) is relatively small; the aim of the present study is to advance our understanding of this topic. It has been estimated that three to ten percent of children and one to five percent of adults have impairing symptoms of ADHD, which is a total of 4 million children and 4-5 million adults in the U.S. (Wender, 2000). A recent prevalence study found that approximately 4.4% of adults in the U.S. meet the criteria for a diagnosis of ADHD (Kessler et al., 2006). Children with ADHD show innate temperamental characteristics, usually inattentiveness, distractibility, impulsivity, restlessness, demandingness, hyperreactivity, low tolerance for frustration, temperoutbursts, bossiness and stubbornness, and mood lability, along with an innate proclivity for academic underachievement. It has been estimated that one- to two-thirds of children with ADHD have symptoms that continue into adulthood, and for 40-50% of these adults, these symptoms are serious enough to cause impairment in functioning (Everett & Everett, 1999; Wender, 2000). Research suggests that the majority of cases are transmitted genetically, but some may be due to exposure to environmental toxins such as lead. Consumption of excess sugar or allergies to food may exacerbate or mimic ADHD symptoms in some children, but they are not a cause of ADHD (Wender, 2000). One hypothesized cause of the symptoms associated with ADHD is a deficit in the brain's executive functioning (Barkley & Gordon, 2002). Executive functioning can be conceptualized as the ability to inhibit, organize, and plan behaviors. Barkley and Gordon (2002) define it as the abilityto self-direct and regulate behaviors toward future goals, including social behaviors and goals. Other research suggests that executive functioning consists of inhibition, control of interference, verbal and nonverbal working memory, emotional regulation, attention, verbal fluency, visual scanning, and processing speed. Studies have shown impairments in these areas among adults with ADHD (Barkley & Gordon, 2002; Barkley, Murphy & Kwasnik, 1996; Goldstein, 2002).

An n-of-1 trial service in clinical practice: Testing the effectiveness of stimulants for attention-deficit/hyperactivity disorder

OBJECTIVE. We sought to describe the clinical use of n-of-1 trials for attention-deficit/hyperactivity disorder in publicly and privately funded family and specialized pediatric practice in Australia. METHODS. We used a within-patient randomized, double-blind, crossover comparison of stimulant (dexamphetamine or methylphenidate) versus placebo or alternative stimulant using 3 pairs of treatment periods. Trials were conducted from a central location using mail and telephone communication, with local supervision by the patients' clinicians. PATIENTS. Our study population included children with clinically diagnosed attention-deficit/ hyperactivity disorder who were aged 5 to 16 years and previously stabilized on an optimal dose of stimulant. They were selected because treatment effectiveness was uncertain. MAIN OUTCOME MEASURES. Our measures included number of patients recruited, number of doctors who used the service, geographic spread, completion rates, response rate, and post-n-of-1 trial decisions. RESULTS. Forty-five doctors across Australia requested 108 n-of-1 trials, of which 86 were completed. In 69 drug-versus-placebo comparisons, 29 children responded better to stimulant than placebo. Immediately posttrial, 19 of 25 drug-versus-placebo responders stayed on the same stimulant, and 13 of 24 nonresponders ceased or switched stimulants. In 40 of 63 for which data were available, posttrial management was consistent with the trial results. For all types of n-of-1 trials, management changed for 28 of 64 children for whom information was available. DISCUSSION. Attention-deficit/hyperactivity disorder n-of-1 trials can be implemented successfully by mail and telephone communication. This type of trial can be valuable in clarifying treatment effect when it is uncertain, and in this series, they had a noticeable impact on short-term management.