The orphan receptor GPR88 controls impulsivity and is a risk factor for Attention-Deficit/Hyperactivity Disorder.

The neural orphan G protein coupled receptor GPR88 is predominant in the striatum and cortex of both rodents and humans, and considered a potential target for brain disorders. Previous studies have shown multiple behavioral phenotypes in Gpr88 knockout mice, and human genetic studies have reported association with psychosis. Here we tested the possibility that GPR88 contributes to Attention Deficit Hyperactivity Disorder (ADHD). In the mouse, we tested Gpr88 knockout mice in three behavioral paradigms, best translatable between rodents and humans, and found higher motor impulsivity and reduced attention together with the reported hyperactivity. Atomoxetine, a typical ADHD drug, reduced impulsivity in mutant mice. Conditional Gpr88 knockout mice in either D1R-type or D2R-type medium spiny neurons revealed distinct implications of the two receptor populations in waiting and stopping impulsivity. Thus, animal data demonstrate that deficient GPR88 activity causally promotes ADHD-like behaviors, and identify circuit mechanisms underlying GPR88-regulated impulsivity. In humans, we performed a family-based genetic study including 567 nuclear families with DSM-IV diagnosis of ADHD. There was a minor association for SNP rs2036212 with diagnosis, treatment response and cognition. A stronger association was found for SNP rs2809817 upon patient stratification, suggesting that the T allele is a risk factor when prenatal stress is involved. Human data therefore identify GPR88 variants associated with the disease, and highlight a potential role of life trajectories to modulate GPR88 function. Overall, animal and human data concur to suggest that GPR88 signaling should be considered a key factor for diagnostic and treatment of ADHD.

Bipolar disorder risk gene FOXO6 modulates negative symptoms in schizophrenia: a neuroimaging genetics study.

BACKGROUND: Despite being diagnostically associated uniquely with schizophrenia, negative symptoms are also observed in bipolar disorder (BD). Genome-wide association studies (GWAS) have uncovered a number of shared risk genes between schizophrenia and BD. The objectives of this study were to examine whether previously identified risk genes for BD are associated with negative symptom severity within a first-episode schizophrenia (FES) cohort and to examine whether such genes influence brain morphology. METHODS: Patients experiencing FES were genotyped for 21 previously identified BD risk genes; a series of univariate analyses of covariance examined the association between negative symptom severity, as measured using the Scale for the Assessment of Negative Symptoms (SANS), and genotype. A subset of participants underwent a structural 1.5 T MRI T1 scan, analyzed for surface area and cortical thickness changes via the CIVET pipeline and LPBA40 atlas. RESULTS: We included 133 patients with FES in our analysis; 61 of them underwent structural MRI. We observed a significant association between negative symptom severity and the BD risk gene FOXO6 (rs4660531). Individuals with the CC genotype presented significantly higher negative symptoms (Cohen d = 0.46, F = 5.854, p = 0.017) and significantly smaller surface area within the right middle orbitofrontal gyrus (Cohen d = 0.69, F = 7.289, p = 0.009) than carriers of allele A. LIMITATIONS: Limitations of this study include its modest sample size and lack of a control sample. CONCLUSION: Lacking the FOXO6 risk allele was associated with an increase in negative symptoms and surface area reduction in the right orbitofrontal gyrus - an area previously associated with negative symptoms - suggesting that presence of the FOXO6 risk allele confers resistance against negative symptoms and associated neuroanatomical changes in individuals with FES.

Parental psychopathology in families of children with attention-deficit/hyperactivity disorder and exposed to maternal smoking during pregnancy.

BACKGROUND: Both genetic and environmental factors have been implicated in the etiology of attention-deficit/hyperactivity disorder (ADHD). We had previously suggested that exposure to maternal smoking during pregnancy (MSDP) may be a valid basis for delineating a distinct subtype of ADHD, where children exposed to MSDP present with a more severe clinical picture. Here, we examine the psychopathology of parents in this group, to better understand the etiology of ADHD. METHODS: Using the Family Interview for Genetic Studies in a sample of 514 families of children with ADHD, we collected data pertaining to lifetime parental psychopathology. Families were stratified based on maternal smoking during the complete gestational period. The frequency of different disorders was compared using the χ2 statistic. RESULTS: In the group where mothers smoked during pregnancy, both parents were significantly more likely to have antisocial personality disorder, and problems with alcohol and drug abuse. Mothers had a significantly higher frequency of major depressive disorder (MDD), while fathers showed a trend for both MDD and bipolar disorder. CONCLUSIONS: Based on the pattern of psychopathology in parents of children exposed to MSDP, as well as earlier reports of the severe clinical, behavioral, and cognitive phenotype in these children, combined with the large body of epidemiological evidence, we propose that these children present a distinct subtype of ADHD with comorbid conduct disorder. Furthermore, we propose that MSDP may be a proxy measure to help delineate this subtype.

Association of a risk allele of ANK3 with cognitive performance and cortical thickness in patients with first-episode psychosis.

BACKGROUND: The gene ANK3 is implicated in bipolar disorder and schizophrenia. The present study investigated the influence of this gene on cognitive performance and brain structure among individuals with first-episode psychosis (FEP). The brief illness duration of an FEP sample makes it well suited for studying the effects of genetic variation. METHODS: We genotyped 2 single nucleotide polymorphisms (SNPs; rs1938526 and rs10994336) in ANK3 in patients with FEP. Multivariate analysis of variance compared risk allele carriers and noncarriers on 6 domains of cognition consistent with MATRICS consensus. A subsample of 82 patients was assessed using magnetic resonance imaging. We compared brain structure between carriers and noncarriers using cortical thickness analysis and voxel-based morphometry on white matter. RESULTS: In the 173 patients with FEP included in our study, rs1938526 and rs10994336 were in very high linkage disequilibrium (d' = 0.95), and analyses were therefore only carried out on the SNP (rs1938526) with the highest minor allele frequency (G). Allele G of rs1938526, was associated with lower cognitive performance across domains (F6,164 = 2.38, p = 0.030) and significantly lower scores on the domains of verbal memory (p = 0.015), working memory (p = 0.006) and attention (p = 0.019). The significant effects of this SNP on cognition were not maintained when controlling for IQ. Cortical thinning was observed in risk allele carriers at diverse sites across cortical lobes bilaterally at a threshold of p < 0.01, false discovery rate-corrected. Risk-allele carriers did not show any regions of reduced white matter volume. LIMITATIONS: The sample size is modest given that a low-frequency variant was being examined. CONCLUSION: The ANK3 risk allele rs1938526 appears to be associated with general cognitive impairment and widespread cortical thinning in patients with FEP.

Maternal smoking during pregnancy and ADHD: a comprehensive clinical and neurocognitive characterization.

INTRODUCTION: Evidence from epidemiological studies has consistently shown an association between maternal smoking during pregnancy (MSDP) and attention-deficit/hyperactivity disorder (ADHD). The objective of this study is to test the hypothesis that children with ADHD exposed to MSDP show a distinctive clinical and neurocognitive profile when compared with unexposed children. METHODS: Four hundred and thirty-six children diagnosed with ADHD were stratified by exposure to MSDP and compared with regard to severity of illness, comorbidity, IQ, and executive function as assessed by a battery of neuropsychological tests. All comparisons were adjusted for socioeconomic status, ethnicity, mother's age at child's birth, and maternal alcohol consumption during pregnancy. RESULTS: Exposed children had more severe behavioral problems with greater externalizing symptoms and more conduct and oppositional defiant disorder items, lower verbal IQ, and a sluggish cognitive profile on the Continuous Performance Test (CPT). Linear regression analyses revealed a dose-response relationship between the average number of cigarettes smoked per day during pregnancy and verbal IQ, CPT omission errors T score and several other clinical variables. CONCLUSIONS: These results suggest that MSDP is associated with a more severe form of ADHD, characterized by more severe clinical manifestations and poorer neuropsychological performance. This phenotypic signature associated with MSDP may help to identify a more homogenous subgroup of children with ADHD.

LPHN3 and attention-deficit/hyperactivity disorder: interaction with maternal stress during pregnancy.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous behavioral disorder, complex both in etiology and clinical expression. Both genetic and environmental factors have been implicated, and it has been suggested that gene-environment interactions may play a pivotal role in the disorder. Recently, a significant association was reported between ADHD and LPHN3 (which codes for latrophilin 3), and replicated in independent samples. METHODS: We have examined the association between tag single nucleotide polymorphisms (SNPs) in LPHN3 within the region previously implicated in ADHD. Family based association tests (FBAT) were conducted (n = 380 families) with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, and response to treatment (given a fixed dose of methylphenidate, 0.5 mg/day). Stratified FBAT analyses, based on maternal smoking and stress during pregnancy, was conducted. RESULTS: Whereas limited association was observed in the total sample, highly significant interaction between four LPHN3 tag SNPs (rs6551665, rs1947274, rs6858066, rs2345039) and maternal stress during pregnancy was noted. Analysis conducted in the sub-group of mothers exposed to minimal stress during pregnancy showed significant associations with ADHD, behavioral and cognitive dimensions related to ADHD, as well as treatment response. Although extensive association was observed with the candidate SNPs, the findings are partially inconsistent with previously published results with the opposite alleles over-transmitted in these studies. CONCLUSIONS: These results provide evidence for the interaction between a genetic and environmental factor independently shown to be associated with ADHD. If confirmed in independent large studies, they may present a step forward in unraveling the complex etiology of ADHD.

Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype.

BACKGROUND: Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD. METHODS: Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT. RESULTS: A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5' region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplo-type block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2. LIMITATIONS: The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype. CONCLUSION: The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.

Refining psychiatric phenotypes for response to treatment: contribution of LPHN3 in ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder characterized by inappropriate levels of attention, hyperactivity, and impulsivity. Although a strong genetic component to the disorder has been established, the molecular genetic underpinnings of this disorder remain elusive. Recently, several studies have reported an association between polymorphisms within the latrophilin 3 gene (LPHN3) and ADHD. Interestingly, the same single-nucleotide polymorphism conferring susceptibility to ADHD has also been found to predict efficacy of stimulant medication in children. The main objectives of the current article are: (i) To tackle the phenotype heterogeneity issue in ADHD by defining an objective and quantitative measure of response to treatment in a sample of ADHD children based on a hand held automatic device (Actiwatch) and (ii) to use this measure to reproduce for the first time the association between LPHN3 variants and response to methylphenidate (MPH) using a double-blind, placebo-controlled crossover experimental design. The results of our study confirm the hypothesis that LPHN3 is associated with response to MPH in ADHD children. Although this will require further validation, our work suggests that the use of an objective measure of response to treatment, such as the change in the child's motor activity measured by Actiwatch, has the potential to uncover genetic association signals that in some conditions might not be obtained using more subjective measures, such as the clinical consensus rating, for example.

A polymorphism in the glutamate metabotropic receptor 7 is associated with cognitive deficits in the early phases of psychosis.

Schizophrenia is an illness characterized by positive symptoms, negative symptoms, and cognitive impairments. Cognitive impairments occur before the onset of psychosis and could reflect glutamatergic dysregulation. Thus, identifying associations between genetic variations in genes coding for glutamatergic receptors and cognitive impairment in schizophrenia may help in understanding the basis of these deficits and in identifying potential drug targets. In a discovery cohort of 144 first-episode of psychosis patients (FEP), we genotyped 58 candidate Single Nucleotide Polymorphisms (SNPs) located in NMDA and metabotropic glutamatergic receptors. These SNPs were selected according to the results from the Psychiatric Genomic Consortium and were tested for association with intellectual quotient (IQ) as assessed with the Wechsler Intelligence Scales. For replication, we used the ICAAR cohort including 121 ultra-high-risk patients (UHR) with the same cognitive assessment. A polymorphism located in GRM7, rs1396409, was significantly associated with performance IQ in the discovery cohort of FEP. This association was replicated in the UHR cohort. This polymorphism is also associated with total IQ and verbal IQ in the merged dataset, with a predominant effect on the arithmetic subtest. The rs1396409 polymorphism is significantly associated with cognitive impairment during the onset of psychosis. This genetic association highlights the possible impact of glutamatergic genes in cognitive deficits in the early phases of psychosis and enforces the interest for new therapeutic interventions targeting the glutamatergic pathway.

Relation between therapeutic response and side effects induced by methylphenidate as observed by parents and teachers of children with ADHD.

BACKGROUND: The desired (therapeutic) and undesired (side) effects of methylphenidate might have underlying correlations. The aim of this study was to explore the strength and the possible sources of these correlations. METHODS: One hundred and fifty-seven children with ADHD (6-12 years) were administered placebo and methylphenidate (0.5 mg/kg in a divided b.i.d. dose), each for a one-week period, in a double-blind, crossover trial. Therapeutic response was assessed using the Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers), while side effects were assessed using the Barkley Side Effects Rating Scale (SERS). RESULTS: The side effect profile as assessed by the SERS was similar to that of previous studies with insomnia, decreased appetite, and headaches showing significant treatment effects (p < 0.005). These "somatic/physical" side effects did not correlate with CGI-Parents or CGI-Teachers. However, the side effects of "irritability", "proneness to crying", and "anxiousness" showed significant relationships with CGI-Parents. These "mood/anxiety" side effects showed no significant correlations with the CGI-Teachers. CONCLUSION: The greater "mood/anxiety" side effects on methylphenidate and placebo, the less the parents observe improvement of their children while treated with methylphenidate. This suggests that the correlations between "mood/anxiety" side effects and poor response to treatment may be driven by observer effects rather than biological commonalities between therapeutic and side effects of methylphenidate.

COMT by DRD3 Epistatic Interaction in Modulating Behaviors in Children with ADHD: A Pharmaco-Dynamic Behavioral Approach.

OBJECTIVE: Examining the joint effect of two functional variants in two dopamine-related genes (DRD3 and COMT) on ADHD-relevant behaviors under three experimental conditions (EC). METHOD: 362 children with ADHD were assessed by parents and teachers during a week of baseline evaluation, followed by 1 week of MPH and placebo, administered in a double-blind crossover design. RESULTS: Statistically significant 3-way (DRD3-by-COMT-by-EC; p = .004) and 2-way interactions (COMT by EC; p = .002) were observed on Conners'-Teachers scores. Children with the COMT Met/Met genotype had lower scores at baseline and on placebo compared to the other genotype groups. Furthermore, stratifying the children according to their COMT genotypes helped to detect statistically significant and biologically meaningful effects of DRD3 genotype. CONCLUSIONS: These findings suggest that COMT and DRD3 genetic variants may together play a role in ADHD symptomatology and response to treatment through gene-gene interaction.

Association between COMT methylation and response to treatment in children with ADHD.

BACKGROUND: COMT had been considered a promising candidate gene in pharmacogenetic studies in ADHD; yet the findings from these studies have been inconsistent. Part of these inconsistencies could be related to epigenetic mechanisms (including DNA methylation). Here we investigated the role of genetic variants of the COMT gene on the methylation levels of CpG sites in the same gene and explored the effect of methylation on methylphenidate (MPH) and placebo (PBO) response in children with ADHD. METHODS: Two hundred and thirty children with ADHD (6-12 years) participated in a randomized, double-blind, placebo-controlled crossover trial with MPH. Univariate analysis was performed to examine the associations between genotypes in the COMT gene and DNA methylation in the same genetic loci. Association between the DNA methylation of 11 CpG sites and PBO/MPH responses were then assessed using spearman's correlation analysis in 212 children. Multiple linear regression analyses were performed to test the interaction between these factors while accounting for sex. RESULTS: Associations were observed between specific genetic variants and methylation level of cg20709110. Homozygous genotypes of GG (rs6269), CC (rs4633), GG (rs4818), Val/Val (rs4680) and the haplotype (ACCVal/GCGVal) were significantly associated with higher level of methylation. This CpG showed a significant correlation with placebo response (r = -0.15, P = 0.045) according to the teachers' evaluation, and a close-to significance correlation with response to MPH according to parents' evaluation (r = -0.134, p = 0.051). Regression analysis showed that in the model including rs4818, sex and DNA methylation of cg20709110 contributed significantly to treatment response. CONCLUSIONS: These preliminary results could provide evidence for the effect of genetic variations on methylation level and the involvement of the epigenetic variation of COMT loci in modulating the response to treatment in ADHD. TRIAL REGISTRATION: clinicaltrials.gov, number NCT00483106.

Cumulative exposure to ADHD medication is inversely related to hippocampus subregional volume in children.

BACKGROUND: Although there is some evidence for a normalization of brain structure following exposure to ADHD medication, literature on the effects of duration and dose of continued use on the brain is scarce. Here, we investigated the association between cumulative exposure to medication (range 1 week to 4.69 years) and cortical structures and subcortical volumes in a clinical sample of children with ADHD taking medication (n = 109). To the best of our knowledge, this is the first structural MRI study investigating the effects of cumulative exposure to medication on subregional volumes in children treated for ADHD. METHODS: Cumulative exposure to ADHD medication (CEM) was defined as the product of duration on medication (days) and dose (mg/day), yielding the area under the curve (total mg). Cortical thickness and surface area measurements (CIVET-1.1.12), and subcortical volumes in 51 regions (MAGeT-Brain) were analyzed using general linear modelling. RESULTS: Significant effects of CEM were found in two subregions of the left hippocampus, the CA1 (df = 95; q = 0.003) and the strata radiatum/lacunosum/moleculare (df = 95; q = 0.003). Specifically, higher CEM was associated with smaller volumes within these subregions. No effects of medication exposure were detected on cortical thickness or surface area. CONCLUSIONS: Although this study is cross-sectional, the results found within this sample of children show that prolonged ADHD medication use at higher doses is significantly associated with smaller hippocampus volumes in specific subregions. More research is required to determine whether these results are reproduced in other samples of children of ADHD, and further, whether these are beneficial or off-target effects of the medication.

Sex-dependent complex association of TPH2 with multiple dimensions of ADHD.

BACKGROUND: Tryptophan hydroxylase 2 (TPH2) is a key enzyme in the biosynthesis of serotonin in the brain. This study aims to investigate the role of a functional variant in TPH2 (rs17110747) in the pathophysiology of ADHD. This variant has been implicated in mood disorders in recent meta-analysis. This study uses a comprehensive approach that combines association testing and pharmaco-dynamic evaluation of behaviour, in a large sample of children with ADHD (n = 570). METHODS: The association between various ADHD relevant traits and rs17110747 was analyzed using family-based association tests (FBAT). Children were assessed by parents, teachers and research staff under three experimental conditions (EC): baseline, placebo, and methylphenidate using a double-blind placebo-controlled crossover trial. OUTCOMES: FBAT analysis conducted in a sample stratified based on sex of the proband, showed that there was a highly significant overtransmission of the G allele from parents to affected girls. In addition, significant association with several behavioral and cognitive dimensions of ADHD was observed only when the proband was female. Further, girls with the G/G genotype (rs17110747) had greater response to placebo when evaluated by parents. INTERPRETATION: These results suggest that there may be a complex association of TPH2 in the etiology of ADHD, with a sex-specific effect.

The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD.

BACKGROUND: Animal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) and the response of ADHD relevant behaviors with methylphenidate treatment. METHODS: Patients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the SLC6A4 gene. MAIN OUTCOME MEASURE: Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene x treatment interaction effects. RESULTS: Mixed model analysis of variance revealed a gene x treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (s+lG = s') responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (lA). No genotype main effects on either CGI-Parents or CGI-teachers were observed. CONCLUSIONS: A double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the SLC6A4 gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding. TRIAL REGISTRATION: ClinicalTrials.gov NCT00483106.

Therapeutic Response to Methylphenidate in ADHD: Role of Child and Observer Gender.

OBJECTIVE: This study aims to examine the interaction between the gender of the child and the gender of the observers (teachers, parents) on the therapeutic response (TR) noted with methylphenidate (MPH) in children with ADHD. METHOD: Children with ADHD participated in a two week double-blind, randomized, cross-over clinical trial with MPH and placebo, and the difference between the week of treatment with MPH and placebo was calculated for each measure to obtain the treatment response (TR) with MPH. The TR for differences based on the gender of child and the observer was examined by using a univariate analysis of covariance (ANCOVA). RESULTS: 299 children (269-male, 30-female; average age 8.9±1.8 years) were evaluated by 52 male teachers, 212 female teachers; 269 female parents and 30 male parents. For the baseline week, the ANCOVA analysis for teachers yielded a significant teacher's gender x child's gender interaction. For the evaluation of TR, the ANCOVA analysis revealed a significant teacher's gender x child's gender interaction whereas no parent's gender x child's gender interactions were noted, all noted interactions were of a small effect size (eta squared <0.02). CONCLUSIONS: These results suggest that there are differences in symptom assessment between parents and teachers at baseline and with TR based on the gender of the observer and the child. While clinicians need to be aware of these interactions, it remains unclear if these interactions will be clinically useful due to the small effect sizes.

OBJECTIF: La présente étude vise à examiner l'interaction entre le sexe de l'enfant et le sexe des observateurs (enseignants, parents) dans le cadre de la réponse thérapeutique (RT) notée au méthylphénidate (MPH) chez les enfants souffrant du trouble de déficit de l'attention avec hyperactivité (TDAH). MÉTHODE: Des enfants souffrant du TDAH ont participé à un essai clinique randomisé croisé de deux semaines à double insu avec MPH et placebo, et la différence entre la semaine de traitement avec MPH et celle avec placebo a été calculée pour chaque mesure afin d'obtenir la réponse au traitement (RT) avec MPH. La RT pour les différences basées sur le sexe de l'enfant et de l'observateur a été examinée à l'aide d'une analyse univariée de la variance (ANCOVA). RÉSULTATS: Deux cent quatre-vingt-dix-neuf enfants (269 garçons, 30 filles; âge moyen 8,9±1,8 ans) ont été évalués par 52 enseignants de sexe masculin, 212 enseignantes de sexe féminin; 269 parents de sexe féminin et 30 parents de sexe masculin. Pour la semaine de départ, l'analyse ANCOVA des enseignants a dégagé une interaction significative entre le sexe de l'enseignant et le sexe de l'enfant. Pour l'évaluation des RT, l'analyse ANCOVA a révélé une interaction significative entre le sexe de l'enseignant et le sexe de l'enfant, alors qu'aucune interaction n'a été notée entre le sexe d'un parent et le sexe de l'enfant. Toutes les interactions notées étaient d'une petite taille de l'effet (êta carré < 0,02). CONCLUSIONS: Ces résultats suggèrent qu'il y a des différences d'évaluation des symptômes entre parents et enseignants au départ, et de la RT selon le sexe de l'observateur et le sexe de l'enfant. Bien que les cliniciens doivent être conscients de ces interactions, il demeure incertain si ces interactions seront utiles sur le plan clinique en raison des petites tailles de l'effet.

Therapeutic response in children with ADHD: role of observers and settings.

BACKGROUND: This study aims at characterizing the extent of correlation of treatment response (TR) obtained in various observation settings (home, school, clinic) by different observers (parents, teachers, clinicians). METHODS: Children with attention deficit hyperactivity disorder (ADHD) underwent a 2-week double-blind, randomized, cross-over clinical trial with methylphenidate and placebo, and various measures were obtained during the 2 weeks. Interrelationships of TR were examined using Pearson's correlation coefficients. RESULTS: The study included 526 children (420 male, 106 female) with ADHD. TR between different observers shows a variable correlation between parents and teachers. No correlation is seen between parents/teacher evaluation of TR and laboratory-based measures (Continuous Performance Task; Restricted Academic Situation Scale). CONCLUSION: The results firmly support the need to synthesize information from many sources in evaluating TR in ADHD.

Facing the Methodological Challenge in Dissecting the Genetics of ADHD: A Case for Deep Phenotyping and Heterogeneity Reduction.

OBJECTIVE: The aetiology of ADHD is complex, with genetic and environmental factors both implicated in the disorder. The most recent ADHD genome-wide association study identified 12 loci that showed significant association with the disorder. However, as highlighted by the authors, these loci "only capture a tiny fraction" of the risk for ADHD. It has been suggested that it may be important to disentangle: (1) the clinical complexity of the disorder, and (2) the complex interaction between genetic and environmental factors, in order to better dissect the aetiology of the disorder. METHOD: We have conducted a clinically-relevant Pharmaco-Behavioural Genetic study in a large group of children with ADHD (~850 families) over the last 15 years. The study includes detailed evaluation of quantitative behavioural and neuropsychological phenotypes, as well as short-term response of these phenotypes to treatment with a fixed dose of methylphenidate (0.5mg/kg in a b.i.d. dose). Specific genetic markers and environmental factors were examined for their association with these dimensions. RESULTS: Here we present results that highlight the importance of examining genetic association with quantitative traits, including those constructs having relevance to Research Domain Criteria (RDoC). Further, we demonstrate that by conducting association analysis in groups of children stratified based on exposure to key environmental exposure (maternal smoking or stress during pregnancy), we are able to increase the sensitivity for finding genes involved in the disorder. CONCLUSION: These results suggest that deep phenotyping and heterogeneity reduction may be imperative in order to uncover the "missing heritability" of the disorder.

OBJECTIF: L'étiologie du trouble de déficit d'attention avec hyperactivité (TDAH) est complexe, puisque des facteurs tant génétiques qu'environnementaux y sont impliqués. L'étude d'association pangénomique du TDAH la plus récente a identifié 12 loci qui présentaient une association significative avec le trouble. Toutefois, comme le soulignent les auteurs, ces loci ne « représentent qu'une infime fraction ¼ du risque de TDAH. Il est suggéré qu'il peut être important de démêler: (1) la complexité clinique du trouble et (2) l'interaction complexe entre les facteurs génétiques et environnementaux, afin de mieux décortiquer l'étiologie du trouble. MÉTHODE: Nous avons mené une étude de génétique pharmaco-comportementale importante sur le plan clinique auprès d'un groupe nombreux d'enfants souffrant du TDAH (~850 familles) au cours des 15 dernières années. L'étude comporte une évaluation détaillée des phénotypes comportementaux et neuropsychologiques quantitatifs, ainsi que la réponse à court terme de ces phénotypes au traitement par dose fixe de méthylphénidate (0,5 mg/kg dans une dose deux fois par jour). Les marqueurs génétiques spécifiques et les facteurs environnementaux ont été examinés relativement à leur association à ces dimensions. RÉSULTATS: Nous présentons ici les résultats qui soulignent l'importance d'examiner l'association génétique avec les traits quantitatifs, y compris ces construits qui ont rapport aux critères du domaine de recherche (RDoC). En outre, nous démontrons qu'en menant une analyse d'association dans des groupes d'enfants stratifiés selon leur exposition à une exposition environnementale principale (le tabagisme maternel ou le stress durant la grossesse), nous sommes capables d'accroître la sensibilité propice à trouver des gènes impliqués dans le trouble. CONCLUSION: Ces résultats suggèrent qu'un phénotypage profond et une réduction de l'hétérogénéité peuvent être impératifs afin de découvrir « l'héritabilité manquante ¼ du trouble.

Acute blood pressure change with methylphenidate is associated with improvement in attention performance in children with ADHD.

This exploratory study aims to determine whether the change in systolic blood pressure (sBP) after acute methylphenidate (MPH) administration (ΔBPMPH) is associated with the neurocognitive response to MPH in the Conners Continuous Performance Test (CPT) in 513 children with ADHD (aged 6 to 12 years old). We noted that higher increases in sBP were associated with larger improvement in CPT performance with MPH. In the univariate regression model, the ΔBPMPH accounted for an additional 2% of the variance in the change in CPT-Overall Index (OI) after controlling for covariates (p < .001). Linear regression analysis also indicated that ΔBPMPH significantly contributed to predict a change in omission errors, reaction time, and reaction time variability (p < .001, p < .01, p = .001, respectively), but not in commission errors or detectability index (d`). Participants with a clinically meaningful sBP increase of at least 5 mmHg (n = 191) improved by 4.8 points on the CPT-OI score (p < .001), compared to an improvement of only 0.6 points for participants whose sBP declined by at least 5 mmHg (n = 121). In conclusion, larger sBP increases after MPH administration were associated with greater enhancement in CPT performance. These results could be useful in informing MPH dosing in clinical practice.

Candidate genes and neuropsychological phenotypes in children with ADHD: review of association studies.

BACKGROUND: We reviewed systematically the results of genetic studies investigating associations between putative susceptibility genes for attention-deficit hyperactivity disorder (ADHD) and neuropsychological traits relevant for this disorder. METHODS: We identified papers for review through the PubMed database. RESULTS: Twenty-nine studies examined 10 genes (DRD4, DAT1, COMT, DBH, MAOA, DRD5, ADRA2A, GRIN2A, BDNF and TPH2) in relation to neuropsychological traits relevant for ADHD. For DRD4, the continuous performance test (CPT) and derived tasks were the most used tests. Association of high reaction time variability with the 7-repeat allele absence appears to be the most consistent result and seems to be specific to ADHD. Speed of processing, set-shifting and cognitive impulsiveness were less frequently investigated but seem to be altered in the 7-repeat allele carriers. No effect of genotype was found on response inhibition (the stop and go/no-go tasks). For DAT1, 4 studies provide conflicting results in relation to omission and commission errors from CPT and derived tasks. High reaction time variability seems to be the most replicated cognitive marker associated with the 10-repeat homozygosity. The other genes have attracted fewer studies, and the reported findings need to be replicated. LIMITATIONS: Although we aimed to perform a formal meta-analysis, this was not possible because the number of studies using the same neurocognitive endophenotypes was limited. We referred only minimally to the various theoretical frameworks in this field of research; more detail would have been beyond the scope of our systematic review. Finally, sample sizes in most of the studies we reviewed were small. Thus, some negative findings could be attributed to a lack of statistical power, and positive results should be considered preliminary until they are replicated in extended samples. CONCLUSION: Several methodological issues, including measurement errors, developmental changes in cognitive abilities, sex, psychostimulant effects and presence of comorbid conditions, represent confounding factors and may explain conflicting results.