Candidate system analysis in ADHD: evaluation of nine genes involved in dopaminergic neurotransmission identifies association with DRD1.

OBJECTIVES: Several pharmacological and genetic studies support the involvement of the dopamine neurotransmitter system in the aetiology of attention-deficit hyperactivity disorder (ADHD). Based on this information we evaluated the contribution to ADHD of nine genes involved in dopaminergic neurotransmission (DRD1, DRD2, DRD3, DRD4, DRD5, DAT1, TH, DBH and COMT). METHODS: We genotyped a total of 61 tagging single nucleotide polymorphisms (SNPs) in a sample of 533 ADHD patients (322 children and 211 adults), 533 sex-matched unrelated controls and additional 196 nuclear ADHD families from Spain. RESULTS: The single- and multiple-marker analysis in both population and family-based approaches provided preliminary evidence for the contribution of DRD1 to combined-type ADHD in children (P=8.8e-04; OR=1.50 (1.18-1.90) and P=0.0061; OR=1.73 (1.23-2.45)) but not in adults. Subsequently, we tested positive results for replication in an independent sample of 353 German families with combined-type ADHD children and replicated the initial association between DRD1 and childhood ADHD (P=8.4e-05; OR=3.67 (2.04-6.63)). CONCLUSIONS: The replication of the association between DRD1 and ADHD in two European cohorts highlights the validity of our finding and supports the involvement of DRD1 in childhood ADHD.

Changes of urine dihydroxyphenylglycol to norepinephrine ratio in children with attention-deficit hyperactivity disorder (ADHD) treated with atomoxetine.

This study investigated changes in the urine dihydroxyphenylglycol to norepinephrine ratio in patients with attention-deficit hyperactivity disorder (ADHD) treated with atomoxetine. The possible relationship with clinical response was also explored. Newly ADHD diagnosed, treatment-naïve children or adolescents were double-blindly randomized (2:1) to atomoxetine (n = 28) or placebo (n = 13). The dihydroxyphenylglycol to norepinephrine ratio decreased in both groups, showing significantly greater changes with atomoxetine than with placebo at week 6 (-42% versus -14%; P = .001), when dosed at 1.2 mg/kg/day, than at week 2 (-20% versus -2%; P = .118) with a dose of 0.5 mg/kg/day. Although the significant dihydroxyphenylglycol to norepinephrine ratio decrease with atomoxetine indicated norepinephrine transporter blockade, no association with ADHD clinical response (ADHD Rating Scale-IV-Parent:Investigator) was found. Therefore, dihydroxyphenylglycol to norepinephrine ratio might be a useful pharmacodynamic/pharmacokinetic biomarker, although not sufficiently sensitive to predict clinical efficacy. It remains a possibility that this ratio might have value to facilitate personalized atomoxetine pharmacotherapy in ADHD patients.

Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naïve children and adolescents with attention deficit/hyperactivity disorder.

OBJECTIVE: To test the hypothesis that first-line treatment with atomoxetine provides superior efficacy than placebo for up to 12 weeks in improving the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). RESEARCH DESIGN AND METHODS: This double-blind, randomized, placebo-controlled, parallel clinical trial included 151 treatment-naïve children (n = 113) and adolescents (n = 38) with newly diagnosed (< or =3 months) ADHD. Atomoxetine dose was uptitrated from 0.5 to 1.2 mg/kg/day after two weeks. Outcome assessments included the ADHD Rating Scale-IV-Parent-reported Investigator-rated (ADHDRS-IV-Parent:Inv), the Clinical Global Impression of Severity of ADHD (CGI-ADHD-S), and the incidence of adverse events. Mixed-model repeated measures analysis was used to compare scale score changes between groups. CLINICAL TRIAL REGISTRATION: Trial registered at www.clinicaltrials.gov (study internal code: B4Z-XM-LYDM, identifier: NCT00191945). RESULTS: Most patients were male (79.2%), of caucasian origin (96.0%) and severely ill (72.5%). Their mean age was 10.3 years. Atomoxetine-treated patients showed greater reductions from baseline to week 12 of total ADHDRS-IV-Parent:Inv score than placebo-treated patients (least square mean difference: -7.9 [95% CI: -11.0 to -4.8], corresponding to a large effect size of 0.8). Between-group mean differences increased progressively with treatment exposure from week 6 to 12 (-2.7 [-4.9 to -0.6] for total and -1.6 [-2.9 to -0.3] for inattention scores). At the end of the study, 50% of atomoxetine-treated patients (14% with placebo) showed a reduction > or =40% in total ADHDRS-IV-Parent:Inv score, and only 29% (46% with placebo) were severely ill (by CGI-ADHD-S). Treatment-related adverse events were significantly more frequent with atomoxetine (65.0%) than with placebo (37.3%), the most frequent being decreased appetite and somnolence. Only one case of decreased appetite was rated as severe. No patient discontinued treatment because of adverse events. CONCLUSIONS: A continued improvement of symptoms is expectable until 12 weeks in treatment-naïve ADHD patients treated with atomoxetine as first-line medication. Chief limitations are the small, national sample size and the absence of data beyond the 12-week time-point.

Case-control study of six genes asymmetrically expressed in the two cerebral hemispheres: association of BAIAP2 with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neuropsychiatric disease that persists into adulthood in at least 30% of patients. There is evidence suggesting that abnormal left-right brain asymmetries in ADHD patients may be involved in a variety of ADHD-related cognitive processes, including sustained attention, working memory, response inhibition and planning. Although mechanisms underlying cerebral lateralization are unknown, left-right cortical asymmetry has been associated with transcriptional asymmetry at embryonic stages and several genes differentially expressed between hemispheres have been identified. METHODS: We selected six functional candidate genes showing at least 1.9-fold differential expression between hemispheres (BAIAP2, DAPPER1, LMO4, NEUROD6, ATP2B3, and ID2) and performed a case-control association study in an initial Spanish sample of 587 ADHD patients (270 adults and 317 children) and 587 control subjects. RESULTS: The single- and multiple-marker analysis provided evidence for a contribution of BAIAP2 to adulthood ADHD (p = .0026 and p = .0016, respectively). We thus tested BAIAP2 for replication in two independent adult samples from Germany (639 ADHD patients and 612 control subjects) and Norway (417 ADHD cases and 469 control subjects). While no significant results were observed in the Norwegian sample, we replicated the initial association between BAIAP2 and adulthood ADHD in the German population (p = .0062). CONCLUSIONS: Our results support the participation of BAIAP2 in the continuity of ADHD across life span, at least in some of the populations analyzed, and suggest that genetic factors potentially influencing abnormal cerebral lateralization may be involved in this disorder.

Association study of 10 genes encoding neurotrophic factors and their receptors in adult and child attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder that often persists into adolescence and adulthood and is characterized by inappropriate levels of inattention, hyperactivity, and/or impulsivity. Genetic and environmental factors are believed to be involved in the continuity of the disorder as well as in changes in ADHD symptomatology throughout life. Neurotrophic factors (NTFs), which participate in neuronal survival and synaptic efficiency, are strong candidates to contribute to the neuroplasticity changes that take place in the human central nervous system during childhood, adolescence, and early adulthood and might be involved in the genetic predisposition to ADHD. METHODS: We performed a population-based association study in 546 ADHD patients (216 adults and 330 children) and 546 gender-matched unrelated control subjects with 183 single nucleotide polymorphisms covering 10 candidate genes that encode four neurotrophins (NGF, BDNF, NTF3, and NTF4/5), a member of the cytokine family of NTFs (CNTF), and their receptors (NTRK1, NTRK2, NTRK3, NGFR, and CNTFR). RESULTS: The single-marker and haplotype-based analyses provided evidence of association between CNTFR and both adulthood (p = .0077, odds ratio [OR] = 1.38) and childhood ADHD (p = 9.1e-04, OR = 1.40) and also suggested a childhood-specific contribution of NTF3 (p = 3.0e-04, OR = 1.48) and NTRK2 (p = .0084, OR = 1.52) to ADHD. CONCLUSIONS: Our data suggest that variations in NTFs might be involved in the genetic susceptibility to ADHD, support the contribution of the CNTFR locus as a predisposition factor for the disorder, and suggest that NTF3 and NTRK2 might be involved in the molecular basis of the age-dependent changes in ADHD symptoms throughout life span.

Worse quality of life for children with newly diagnosed attention-deficit/hyperactivity disorder, compared with asthmatic and healthy children.

OBJECTIVE: To evaluate the quality of life (QOL) of untreated children with newly diagnosed attention-deficit/hyperactivity disorder (ADHD), compared with asthmatic and healthy children. METHODS: This prospective, case-control study included a group of 120 children, 6 to 12 years of age, with newly diagnosed ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Subjects were matched according to age, gender, and health care area with 2 control groups, ie, 93 asthmatic children and 120 healthy children. Sociodemographic characteristics and Child Health Questionnaire scores were collected. RESULTS: The QOL of children with ADHD was rated worse than that of asthmatic or healthy children for most Child Health Questionnaire domains. The greatest differences were found in behavior, social limitations attributable to physical problems, emotional impact on parents, and family activities. Almost every psychosocial domain was more affected in comparison with asthmatic children and both psychosocial and physical domains in comparison with healthy children. CONCLUSIONS: ADHD interferes with the daily lives of children, parents, and families even more than asthma, primarily in areas related to psychosocial functioning, although evidence of impaired physical functioning also emerged. Delays in recognition, assessment, and management of ADHD may affect negatively the QOL of those children.