Attention 2.0 Professional Edition Autumn 2010

The Latest Published Research


Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis
Williams, Nigel M.; Zaharieva, Irina; Martin, Andrew; Langley, Kate; et al.
Lancet, September 29, 2010, Online Early.
BACKGROUND: Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in neurodevelopmental disorders similar to attention-deficit hyperactivity disorder (ADHD). We aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia. METHODS: We undertook a genome-wide analysis of CNVs in 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort. Children of white UK origin, aged 5?17 years, who met diagnostic criteria for ADHD or hyperkinetic disorder, but not schizophrenia and autism, were recruited from community child psychiatry and paediatric outpatient clinics. Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD and control groups with two arrays; CNV analysis was limited to SNPs common to both arrays and included only samples with high-quality data. CNVs in the ADHD group were validated with comparative genomic hybridisation. We assessed the genome-wide burden of large (>500 kb), rare (<1% population frequency) CNVs according to the average number of CNVs per sample, with significance assessed via permutation. Locus-specific tests of association were undertaken for test regions defined for all identified CNVs and for 20 loci implicated in autism or schizophrenia. Findings were replicated in 825 Icelandic patients with ADHD and 35 243 Icelandic controls. FINDINGS: Data for full analyses were available for 366 children with ADHD and 1047 controls. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD (0•156 vs 0•075; p=8•9×10(−5)). This increased rate of CNVs was particularly high in those with intellectual disability (0•424; p=2•0×10(−6)), although there was also a significant excess in cases with no such disability (0•125, p=0•0077). An excess of chromosome 16p13.11 duplications was noted in the ADHD group (p=0•0008 after correction for multiple testing), a finding that was replicated in the Icelandic sample (p=0•031). CNVs identified in our ADHD cohort were significantly enriched for loci previously reported in both autism (p=0•0095) and schizophrenia (p=0•010). INTERPRETATION: Our findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct.

National Trends in Child and Adolescent Psychotropic Polypharmacy in Office-Based Practice, 1996-2007
Comer, Jonathan S.; Olfson, Mark; Mojtabai, Ramin
Journal of the American Academy of Child & Adolescent Psychiatry, October 2010, v49 n10, pp. 1001-1010.
OBJECTIVE: To examine patterns and recent trends in multiclass psychotropic treatment among youth visits to office-based physicians in the United States. METHOD: Annual data from the 1996-2007 National Ambulatory Medical Care Surveys were analyzed to examine patterns and trends in multiclass psychotropic treatment within a nationally representative sample of 3,466 child and adolescent visits to office-based physicians in which a psychotropic medication was prescribed. RESULTS: There was an increase in the percentage of child visits in which psychotropic medications were prescribed that included at least two psychotropic classes. Across the 12 year period, multiclass psychotropic treatment rose from 14.3% of child psychotropic visits (1996-1999) to 20.2% (2004-2007) (adjusted odds ratio [AOR] = 1.89, 95% confidence interval [CI] = 1.22- 2.94, p < .01). Among medical visits in which a current mental disorder was diagnosed, the percentage with multiclass psychotropic treatment increased from 22.2% (1996-1999) to 32.2% (2004-2007) (AOR = 2.23, 95% CI = 1.42- 3.52, p < .001). Over time, there were significant increases in multiclass psychotropic visits in which ADHD medications, antidepressants, or antipsychotics were prescribed, and a decrease in those visits in which mood stabilizers were prescribed. There were also specific increases in co-prescription of ADHD medications and antipsychotic medications (AOR = 6.22, 95% CI = 2.82-13.70, p < .001) and co-prescription of antidepressant and antipsychotic medications (AOR = 5.77, 95% CI = 2.88-11.60, p < .001). CONCLUSIONS: Although little is known about the safety and efficacy of regimens that involve concomitant use of two or more psychotropic agents for children and adolescents, multiclass psychotropic pharmacy is becoming increasingly common in outpatient practice.

Racial Differences in the Effects of Postnatal Environmental Tobacco Smoke on Neurodevelopment
Xu, Xiaohui; Cook, Robert L.; Ilacqua, Vito A.; Kan, Haidong; Talbott, Evelyn O.
Pediatrics, September 20, 2010, Online Early.
OBJECTIVES: We used the 2001-2004 National Health and Nutrition Examination Survey to examine the association between postnatal environmental tobacco smoke exposure, measured as serum cotinine levels, and attention-deficit/hyperactivity disorder (ADHD) among children 4 to 15 years of age. We further investigated the interactions of race and serum cotinine levels with ADHD. METHODS: Logistic regression models were used to evaluate associations. RESULTS: This study found that the prevalence of ADHD increased as blood cotinine levels increased. The effects of blood cotinine levels on ADHD differed according to race. Compared with children of the same racial group with the lowest blood cotinine levels, the odds ratios were 2.72 (95% confidence interval: 1.25-5.93) for Mexican American children and 5.32 (95% confidence interval: 1.55-18.3) for children in other racial groups with the highest blood cotinine levels, with controlling for the effect of maternal smoking during pregnancy. However, no significant associations between blood cotinine levels and ADHD were observed among non-Hispanic white or non-Hispanic black children. CONCLUSIONS: The findings of this study underscore the possibility of racial disparities in the effects of environmental tobacco smoke on behavioral problems in children. These findings warrant further investigation.

Core ADHD Symptom Improvement With Atomoxetine Versus Methylphenidate: A Direct Comparison Meta-Analysis
Hazell, Philip L.; Kohn, Michael R.; Dickson, Ruth; Walton, Richard J. ; Granger, Renee E.; van Wyk, Gregory W.
Journal of Attention Disorders, September 13, 2010, Online Early.
OBJECTIVE: Previous studies comparing atomoxetine and methylphenidate to treat ADHD symptoms have been equivocal. This noninferiority meta-analysis compared core ADHD symptom response between atomoxetine and methylphenidate in children and adolescents. METHOD: Selection criteria included randomized, controlled design; duration 6 weeks; and assessment of ADHD Rating Scale-IV- Parent Version: Investigator Administered and Scored (ADHDRS) scores. Six-week response rates, defined as >/= 40% reduction in ADHDRS total score, were compared using a noninferiority margin of -15%. RESULTS: Seven studies met inclusion criteria (N = 1,368). After 6 weeks, 53.6% (95% confidence interval [CI] 48.6% - 58.4%) of atomoxetine-treated patients (n = 811) had responded compared with 54.4% (47.6% - 1.1%) for methylphenidate (n = 557), with atomoxetine demonstrating noninferiority to methylphenidate (absolute difference -0.9%, 95% CI -9.2%-7.5%). CONCLUSION: After 6 weeks of treatment atomoxetine and methylphenidate had comparable efficacy in reducing core ADHD symptoms in children and adolescents.

Are Maternal Genitourinary Infection and Pre-Eclampsia Associated With ADHD in School Aged Children?
Mann, Joshua R.; McDermott, Suzanne
Journal of Attention Disorders, September 13, 2010, Online Early.
OBJECTIVE: To investigate the hypothesis that maternal genitourinary infection (GU) infection is associated with increased risk of ADHD. METHOD: The authors obtained linked Medicaid billing data for pregnant women and their children in South Carolina, with births from 1996 through 2002 and follow-up data through 2008. Maternal GU infections and pre- eclampsia were identified on the basis of diagnoses made during pregnancy, and cases of ADHD were identified on the basis of diagnoses made in the child's Medicaid file. RESULTS: There were 84,721 children in the data set used for analyses. Maternal genitourinary infection was associated with significantly increased odds of ADHD (OR = 1.29, 95% CI = 1.23-1.35). Pre-eclampsia was also associated with increased risk (OR = 1.19, 95% CI = 1.07-1.32). Children whose mothers had both GU infection and pre- eclampsia were 53% more likely to have ADHD, compared to those with neither exposure. When we examined specific infection diagnoses, chlamydia/nongonococcal urethritis, trichomoniasis, urinary tract infection, and candidiasis were associated with increased risk of ADHD, whereas gonorrhea was not. DISCUSSION: Maternal GU infection appeared to be associated with increased risk of ADHD, and based on the findings it was concluded that further research is needed to describe the mechanism(s) underlying the association.

Meta-Analysis of Genome-Wide Association Studies of Attention-Deficit/Hyperactivity Disorder
Neale, Benjamin M.; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; et al.
Journal of the American Academy of Child & Adolescent Psychiatry, September 2010, v49 n9, pp. 884-897 [August 1, 2010, Online Early]
OBJECTIVE: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. METHOD: We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta- analysis.RESULTS: No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. CONCLUSIONS: Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.

Effects of guanfacine extended release on oppositional symptoms in children aged 6-12 years with attention-deficit hyperactivity disorder and oppositional symptoms: a randomized, double-blind, placebo-controlled trial
Connor, Daniel F.; Findling, Robert L.; Kollins, Scott H.; Sallee, Floyd; et al.
CNS Drugs, September 2010, v24 n9, pp. 755-768.
OBJECTIVE: To evaluate the efficacy and safety of guanfacine extended release (XR, Intuniv; Shire Development Inc., Wayne, PA, USA) in the treatment of oppositional symptoms in children aged 6-12 years with a diagnosis of attention-deficit hyperactivity disorder (ADHD) and the presence of oppositional symptoms. SUBJECTS AND METHODS: In this randomized, double-blind, placebo- controlled, multicentre, flexible-dose, dose- optimization study, children aged 6-12 years were randomized to receive guanfacine XR (1-4 mg/day) or placebo for 9 weeks. Screening and washout periods were followed by a 5-week dose-optimization period, a 3-week dose- maintenance period and a 1-week tapering period. The primary efficacy measure was change from baseline to endpoint in the oppositional subscale of the Conners' Parent Rating Scale-Revised: Long Form (CPRS-R:L) score. Change in ADHD Rating Scale IV (ADHD- RS-IV) total score was a secondary efficacy measure. Safety assessments included adverse events (AEs), vital signs, ECG readings and laboratory studies. RESULTS: A total of 217 children were enrolled: 138 were randomized to receive guanfacine XR and 79 to receive placebo. Least-squares mean reductions from baseline to endpoint in CPRS-R:L oppositional subscale scores were 10.9 in the guanfacine XR group compared with 6.8 in the placebo group (p < 0.001; effect size = 0.59). A significantly greater reduction in ADHD-RS-IV total score from baseline to endpoint was also seen in the guanfacine-treated group compared with the placebo group (23.8 vs 11.5, respectively; p < 0.001; effect size = 0.92). A post hoc correlation analysis between percentage reduction from baseline to endpoint in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores indicated that the decreases in oppositional symptoms and ADHD symptoms were highly correlated (r = 0.74). The most commonly reported, treatment- emergent AEs (TEAEs) in the guanfacine XR group were somnolence (50.7%), headache (22.1%), sedation (13.2%), upper abdominal pain (11.8%) and fatigue (11.0%) and most were mild or moderate in severity. TEAEs of sedation, somnolence or hypersomnia were experienced by 62.5% of subjects in the guanfacine XR group. These events were most common during the dose-titration period but most (63.5%) resolved prior to the taper period. TEAEs of fatigue, lethargy and asthenia were reported in 11.0%, 3.7% and 0.0% of subjects in the guanfacine XR group, respectively. Most subjects receiving guanfacine XR demonstrated modest changes in blood pressure, pulse rate and ECG readings that were not considered clinically significant. CONCLUSIONS: In this population of children aged 6-12 years with ADHD and the presence of oppositional symptoms, significant reductions in CPRS-R:L oppositional subscale and ADHD-RS-IV total scores were observed with guanfacine XR treatment compared with placebo. Treatment with guanfacine XR at optimized doses was associated with mostly mild or moderate TEAEs. The findings of this study support the efficacy of guanfacine XR in the treatment of children with ADHD and the presence of oppositional symptoms. Clinical Trial Registration Number: NCT00367835.
http://adisonline.com/cnsdrugs/Abstract/2010/24 090/Effects_of_Guanfacine_Extended_Release_on.4.aspx

RLS in middle aged women and attention deficit/hyperactivity disorder in their offspring
Gao, Xiang; Lyall, Kristen; Palacios, Natalia; Walters, Arthur S.; Ascherio, Alberto
Sleep Medicine, August 30, 2010, Online Early.
BACKGROUND: Previous studies have suggested that attention deficit/hyperactivity disorder (ADHD) and restless legs syndrome (RLS) could share some common genetic backgrounds, but the effect of these genetic components could be modest. To test this hypothesis, we conducted a large-scaled cross-sectional study to examine whether women with a child with ADHD had a higher risk of having RLS than women of unaffected children. METHODS: We included 65,554 women free of diabetes, arthritis, and pregnancy in the current analyses. Information on RLS was assessed using a set of standardized questions. Participants were considered to have RLS if they met four RLS diagnostic criteria recommended by the International RLS Study Group and had restless legs 5 times/month. Information on ADHD in offspring was collected via questionnaire. RESULTS: We observed a significant association between presence of ADHD in the offspring and risk of having RLS; the multivariate-adjusted OR for RLS was 1.27 (95% CI: 1.15, 1.41; P<0.0001), after adjusting for age, body mass index, number of deliveries during life time and other covariates. CONCLUSION: We found that mothers of children with ADHD had an increased risk of having RLS. Further studies are warranted to explore biological mechanisms underling this association.

Cognitive Behavioral Therapy vs Relaxation With Educational Support for Medication-Treated Adults With ADHD and Persistent Symptoms
Safren, Steven A.; Sprich, Susan; Mimiaga, Matthew J.; Surman, Craig; et al.
 JAMA: Journal of the American Medical Association, August 25, 2010, v304 n8, pp. 875-880.
CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) in adulthood is a prevalent, distressing, and impairing condition that is not fully treated by pharmacotherapy alone and lacks evidence-based psychosocial treatments. OBJECTIVE: To test cognitive behavioral therapy for ADHD in adults treated with medication but who still have clinically significant symptoms. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial assessing the efficacy of cognitive behavioral therapy for 86 symptomatic adults with ADHD who were already being treated with medication. The study was conducted at a US hospital between November 2004 and June 2008 (follow-up was conducted through July 2009). Of the 86 patients randomized, 79 completed treatment and 70 completed the follow-up assessments. INTERVENTIONS: Patients were randomized to 12 individual sessions of either cognitive behavioral therapy or relaxation with educational support (which is an attention-matched comparison). MAIN OUTCOME MEASURES: The primary measures were ADHD symptoms rated by an assessor (ADHD rating scale and Clinical Global Impression scale) at baseline, posttreatment, and at 6- and 12-month follow-up. The assessor was blinded to treatment condition assignment. The secondary outcome measure was self-report of ADHD symptoms. RESULTS: Cognitive behavioral therapy achieved lower posttreatment scores on both the Clinical Global Impression scale (magnitude -0.0531; 95% confidence interval [CI], -1.01 to -0.05; P = .03) and the ADHD rating scale (magnitude -4.631; 95% CI, -8.30 to -0.963; P = .02) compared with relaxation with educational support. Throughout treatment, self-reported symptoms were also significantly more improved for cognitive behavioral therapy (beta = -0.41; 95% CI, -0.64 to -0.17; P <001), and there were more treatment responders in cognitive behavioral therapy for both the Clinical Global Impression scale (53% vs 23%; odds ratio [OR], 3.80; 95% CI, 1.50 to 9.59; P = .01) and the ADHD rating scale (67% vs 33%; OR, 4.29; 95% CI, 1.74 to 10.58; P = .002). Responders and partial responders in the cognitive behavioral therapy condition maintained their gains over 6 and 12 months. CONCLUSION: Among adults with persistent ADHD symptoms treated with medication, the use of cognitive behavioral therapy compared with relaxation with educational support resulted in improved ADHD symptoms, which were maintained at 12 months. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00118911.

Organophosphate Pesticide Exposure and Attention in Young Mexican-American Children
Marks, Amy R.; Harley, Kim; Bradman, Asa; Kogut, Katherine; et al.
Environmental Health Perspectives, August 19, 2010, Online Early.
BACKGROUND: In utero exposure to organophosphate (OP) pesticides, well-known neurotoxicants, has been associated with neurobehavioral deficits in children. OBJECTIVES: We investigated whether OP exposure, as measured by maternal urinary dialkyl phosphate (DAP) metabolites during pregnancy, was associated with attention- related outcomes among Mexican-American children living in the agricultural Salinas Valley and followed to ages 3 1/2 (n=331) and 5 (n=323) years. METHODS: Mothers completed the Child Behavior Checklist (CBCL). We administered the NEPSY-II visual attention subtest to children at 3 1/2 years and the Conners’ Kiddie Continuous Performance Test (K-CPT) at 5 years. The K-CPT yielded a standardized attention deficit/hyperactivity disorder (ADHD) Confidence Index score. Psychometricians scored 5-year olds? behavior during testing using the Hillside Behavior Rating Scale (HBRS). RESULTS: Prenatal DAPs were non-significantly associated with maternal report of attention problems and ADHD at age 3 1/2, but were significantly related at age 5 (Attention: Beta = 0.7; 95% confidence interval (CI), 0.2, 1.2; ADHD: Beta =1.3; 95% CI, 0.4, 2.1). DAPs were associated with the K-CPT ADHD Confidence Index (OR=5.1; 95% CI, 1.7, 15.7) and non- significantly associated with HBRS ADHD (Beta = 0.4, 95% CI, -0.04, 0.9). DAPs were also associated with a composite ADHD indicator of the various measures (OR=3.6, 95% CI, 1.2, 11.0). Some outcomes exhibited interaction by sex with associations found only among boys. CONCLUSIONS: In utero DAPs were associated adversely with attention in young children as assessed by maternal report, psychometrician observation, and direct assessment. These associations were more robust at 5 than 3 1/2 years and stronger in boys.

The Delinquency Outcomes of Boys with ADHD with and Without Comorbidity
Sibley, Margaret H.; Pelham, William E.; Molina, Brooke S. G.; Gnagy, Elizabeth M.; et al.
Journal of Abnormal Child Psychology, August 10, 2010, Online Early.
This study examined the association between childhood ADHD and juvenile delinquency by examining data from the Pittsburgh ADHD Longitudinal Study (PALS), a follow-up study of individuals diagnosed with ADHD in childhood (ages 5-12) and recontacted in adolescence and young adulthood for yearly follow-up (age at first follow-up interview M = 17.26, SD = 3.17). Participants were 288 males with childhood ADHD and 209 demographically similar males without ADHD who were recruited into the follow-up study. Delinquency information gathered yearly during the second through eighth follow-up provided a comprehensive history of juvenile delinquency for all participants. Four childhood diagnostic groups [ADHD-only (N = 47), ADHD + ODD (N = 135), ADHD + CD (N = 106), and comparison (N = 209)] were used to examine group differences on delinquency outcomes. Analyses were conducted across three dimensions of delinquency (i.e., severity, age of initiation, and variety). Individuals with childhood ADHD + CD displayed significantly worse delinquency outcomes than the other three groups, across almost all indices of offending. When compared to comparison participants, boys with ADHD-only and ADHD + ODD in childhood displayed earlier ages of delinquency initiation, a greater variety of offending, and higher prevalence of severe delinquency. These findings suggest that although childhood ADHD + CD creates the greatest risk for delinquency, boys with ADHD-only and ADHD + ODD also appear at a higher risk for later offending. The patterns of offending that emerged from the PALS are discussed in the context of the relationship between ADHD, comorbidity, and delinquency.

The influences of environmental enrichment, cognitive enhancement, and physical exercise on brain development: Can we alter the developmental trajectory of ADHD?
Halperin, Jeffrey M.; Healey, Dione M.
Neuroscience & Biobehavioral Reviews, August 5, 2010, Online Early.
Attention-deficit/Hyperactivity Disorder (ADHD) is characterized by a pervasive pattern of developmentally inappropriate inattentive, impulsive and hyperactive behaviors that typically begin during the preschool years and often persist into adulthood. The most effective and widely used treatments for ADHD are medication and behavior modification. These empirically- supported interventions are generally successful in reducing ADHD symptoms, but treatment effects are rarely maintained beyond the active intervention. Because ADHD is now generally thought of as a chronic disorder that is often present well into adolescence and early adulthood, the need for continued treatment throughout the lifetime is both costly and problematic for a number of logistical reasons. Therefore, it would be highly beneficial if treatments would have lasting effects that remain after the intervention is terminated. This review examines the burgeoning literature on the underlying neural determinants of ADHD along with research demonstrating powerful influences of environmental factors on brain development and functioning. Based upon these largely distinct scientific literatures, we propose an approach that employs directed play and physical exercise to promote brain growth which, in turn, could lead to the development of potentially more enduring treatments for the disorder.

Measuring inappropriate medical diagnosis and treatment in survey data: The case of ADHD among school-age children
Evans, William N.; Morrill, Melinda S.; Parente, Stephen T.
Journal of Health Economics, August 4, 2010, Online Early.
We exploit the discontinuity in age when children start kindergarten generated by state eligibility laws to examine whether relative age is a significant determinant of ADHD diagnosis and treatment. Using a regression discontinuity model and exact dates of birth, we find that children born just after the cutoff, who are relatively old- for-grade, have a significantly lower incidence of ADHD diagnosis and treatment compared with similar children born just before the cutoff date, who are relatively young-for-grade. Since ADHD is an underlying neurological problem where incidence rates should not change dramatically from one birth date to the next, these results suggest that age relative to peers in class, and the resulting differences in behavior, directly affects a child's probability of being diagnosed with and treated for ADHD.

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