Combined Stimulant and Guanfacine Administration in Attention-Deficit/Hyperactivity Disorder: A Controlled, Comparative Study.

ObjectiveBecause models of attention-deficit/hyperactivity disorder (ADHD) therapeutics emphasize benefits of both enhanced dopaminergic and noradrenergic signaling, strategies to enhance D1 and α2A agonism may yield enhanced clinical and cognitive responses. This study tested the hypothesis that combined effects of a dopamine and noradrenergic agonist, d-methylphenidate extended-release (DMPH) with guanfacine (GUAN), an α2A receptor agonist, would be clinically superior to either monotherapy and would have equal tolerability.MethodAn 8-week, double-blind, 3-arm, comparative trial randomized 7- to 14-year-olds with DSM-IV ADHD to GUAN (1-3 mg/day), DMPH (5-20 mg/day), or a combination (COMB) with fixed-flexible dosing. Outcome measures were the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Data on adverse events and safety measures were obtained.ResultsA total of 207 participants were randomized and received drug. Analyses showed significant treatment group main effects for ADHD-RS-IV ADHD total (p = .0001) and inattentive symptoms (p = .0001). COMB demonstrated small but consistently greater reductions in ADHD-RS-IV Inattentive subscale scores versus monotherapies (DMPH: p = .05; f(2) = .02; and GUAN: p = .02; f(2) = .02), and was associated with a greater positive response rate by CGI-I (p = .01). No serious cardiovascular events occurred. Sedation, somnolence, lethargy, and fatigue were greater in both guanfacine groups. All treatments were well tolerated.ConclusionCOMB showed consistent evidence of clinical benefits over monotherapies, possibly reflecting advantages of greater combined dopaminergic and α2A agonism. Adverse events were generally mild to moderate, and COMB treatment showed no differences in safety or tolerability.Clinical trial registration informationSingle Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); http://clinicaltrials.gov/; NCT00429273

Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder.

ObjectivePsychostimulants are partially effective in reducing cognitive dysfunction associated with attention-deficit/hyperactivity disorder (ADHD). Cognitive effects of guanfacine, an alternative treatment, are poorly understood. Given its distinct action on α2A receptors, guanfacine may have different or complementary effects relative to stimulants. This study tested stimulant and guanfacine monotherapies relative to combined treatment on cognitive functions important in ADHD.MethodChildren with ADHD (n = 182; aged 7-14 years) completed an 8-week, double blind, randomized, controlled trial with 3 arms: d-methylphenidate (DMPH), guanfacine (GUAN), or combination treatment with DMPH and GUAN (COMB). A nonclinical comparison group (n = 93) had baseline testing, and a subset was retested 8 weeks later (n = 38). Analyses examined treatment effects in 4 cognitive domains (working memory, response inhibition, reaction time, and reaction time variability) constructed from 20 variables.ResultsThe ADHD group showed impaired working memory relative to the nonclinical comparison group (effect size = -0.53 SD unit). The treatments differed in effects on working memory but not other cognitive domains. Combination treatment improved working memory more than GUAN but was not significantly better than DMPH alone. Treatment did not fully normalize the initial deficit in ADHD relative to the comparison group.ConclusionCombined treatment with DMPH and GUAN yielded greater improvements in working memory than placebo or GUAN alone, but the combined treatment was not superior to DMPH alone and did not extend to other cognitive domains. Although GUAN may be a useful add-on treatment to psychostimulants, additional strategies appear to be necessary to achieve normalization of cognitive function in ADHD.Clinical trial registration informationSingle Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00429273

Effects of d-Methylphenidate, Guanfacine, and Their Combination on Electroencephalogram Resting State Spectral Power in Attention-Deficit/Hyperactivity Disorder.

ObjectivePsychostimulant medications are the gold standard of treatment for attention-deficit/hyperactivity disorder (ADHD); however, a significant minority (∼30%) of individuals with ADHD fail to respond favorably. Noradrenergic agents are increasingly used as ADHD monotherapies or adjuncts for suboptimal stimulant response, yet knowledge of their cortical effects is limited. This study is the first to examine comparative effects of guanfacine (an α adrenergic 2A agonist), psychostimulant, and their combination on resting state cortical activity in ADHD.MethodThe sample comprised 179 participants aged 7 to 14 years old with ADHD (113 boys, 55 girls). Participants were randomized to 1 of 3 blinded conditions: guanfacine (GUAN), d-methylphenidate (DMPH), or the combination (COMB). Electroencephalography (EEG) was performed pre-, mid-, and post-medication titration, with concomitant assessment of behavioral and cognitive functioning.ResultsAnalyses of spectral power measures during resting EEG suggested that each medication condition displayed a distinct profile of effects on cortical activity. Significant time effects suggested that GUAN decreased global alpha band (8-12 hertz [Hz]) power, DMPH and COMB increased centro-parietal beta band (13-21 Hz) power, and COMB resulted in decreased theta band (4-7 Hz) power. Relative to other medication groups, COMB was associated with significantly lower theta band power and DMPH with higher beta band power compared with those in the GUAN group. Medication-related changes in theta power were correlated with improvements in behavioral and cognitive functioning.ConclusionThese data reveal distinct underlying medication-related effects on neural mechanisms. The COMB condition uniquely exhibited an EEG profile that was associated with improved behavioral and cognitive functioning. Clinical trial registration information-Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00429273

Combined Stimulant and Guanfacine Administration in Attention-Deficit/Hyperactivity Disorder: A Controlled, Comparative Study.

ObjectiveBecause models of attention-deficit/hyperactivity disorder (ADHD) therapeutics emphasize benefits of both enhanced dopaminergic and noradrenergic signaling, strategies to enhance D1 and α2A agonism may yield enhanced clinical and cognitive responses. This study tested the hypothesis that combined effects of a dopamine and noradrenergic agonist, d-methylphenidate extended-release (DMPH) with guanfacine (GUAN), an α2A receptor agonist, would be clinically superior to either monotherapy and would have equal tolerability.MethodAn 8-week, double-blind, 3-arm, comparative trial randomized 7- to 14-year-olds with DSM-IV ADHD to GUAN (1-3 mg/day), DMPH (5-20 mg/day), or a combination (COMB) with fixed-flexible dosing. Outcome measures were the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Data on adverse events and safety measures were obtained.ResultsA total of 207 participants were randomized and received drug. Analyses showed significant treatment group main effects for ADHD-RS-IV ADHD total (p = .0001) and inattentive symptoms (p = .0001). COMB demonstrated small but consistently greater reductions in ADHD-RS-IV Inattentive subscale scores versus monotherapies (DMPH: p = .05; f(2) = .02; and GUAN: p = .02; f(2) = .02), and was associated with a greater positive response rate by CGI-I (p = .01). No serious cardiovascular events occurred. Sedation, somnolence, lethargy, and fatigue were greater in both guanfacine groups. All treatments were well tolerated.ConclusionCOMB showed consistent evidence of clinical benefits over monotherapies, possibly reflecting advantages of greater combined dopaminergic and α2A agonism. Adverse events were generally mild to moderate, and COMB treatment showed no differences in safety or tolerability.Clinical trial registration informationSingle Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); http://clinicaltrials.gov/; NCT00429273

Functional dysbiosis within the gut microbiota of patients with constipated-irritable bowel syndrome

International audienceThe role of the gut microbiota in patho-physiology of irritable bowel syndrome (IBS) is suggested by several studies. However, standard cultural and molecular methods used to date have not revealed specific and consistent IBS-related groups of microbes.Aim To explore the constipated-IBS (C-IBS) gut microbiota using a function-based approach.Methods The faecal microbiota from 14 C-IBS women and 12 sex-match healthy subjects were examined through a combined strictly anaerobic cultural evaluation of functional groups of microbes and fluorescent in situ hybridisation (16S rDNA gene targeting probes) to quantify main groups of bacteria. Starch fermentation by C-IBS and healthy faecal samples was evaluated in vitro.Results In C-IBS, the numbers of lactate-producing and lactate-utilising bacteria and the number of H-2-consuming populations, methanogens and reductive acetogens, were at least 10-fold lower (P < 0.05) compared with control subjects. Concomitantly, the number of lactate-and H-2-utilising sulphate-reducing population was 10 to 100 fold increased in C-IBS compared with healthy subjects. The butyrate-producing Roseburia - E. rectale group was in lower number (0.01 < P < 0.05) in C-IBS than in control. C-IBS faecal microbiota produced more sulphides and H-2 and less butyrate from starch fermentation than healthy ones.Conclusions A major functional dysbiosis was observed in constipated-irritable bowel syndrome gut microbiota, reflecting altered intestinal fermentation. Sulphate-reducing population increased in the gut of C-IBS and were accompanied by alterations in other microbial groups. This could be responsible for changes in the metabolic output and enhancement in toxic sulphide production which could in turn influence gut physiology and contribute to IBS pathogenesis

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

Attention deficit/hyperactivity disorder (ADHD) is a common heritable disorder with a childhood onset. Molecular genetic studies of ADHD have previously focused on examining the roles of specific candidate genes, primarily those involved in dopaminergic pathways. We have performed the first systematic genomewide linkage scan for loci influencing ADHD in 126 affected sib pairs, using a approximately 10-cM grid of microsatellite markers. Allele-sharing linkage methods enabled us to exclude any loci with a lambda(s) of &gt; or =3 from 96% of the genome and those with a lambda(s) of &gt; or =2.5 from 91%, indicating that there is unlikely to be a major gene involved in ADHD susceptibility in our sample. Under a strict diagnostic scheme we could exclude all screened regions of the X chromosome for a locus-specific lambda(s) of &gt;/=2 in brother-brother pairs, demonstrating that the excess of affected males with ADHD is probably not attributable to a major X-linked effect. Qualitative trait maximum LOD score analyses pointed to a number of chromosomal sites that may contain genetic risk factors of moderate effect. None exceeded genomewide significance thresholds, but LOD scores were &gt;1.5 for regions on 5p12, 10q26, 12q23, and 16p13. Quantitative-trait analysis of ADHD symptom counts implicated a region on 12p13 (maximum LOD 2.6) that also yielded a LOD &gt;1 when qualitative methods were used. A survey of regions containing 36 genes that have been proposed as candidates for ADHD indicated that 29 of these genes, including DRD4 and DAT1, could be excluded for a lambda(s) of 2. Only three of the candidates-DRD5, 5HTT, and CALCYON-coincided with sites of positive linkage identified by our screen. Two of the regions highlighted in the present study, 2q24 and 16p13, coincided with the top linkage peaks reported by a recent genome-scan study of autistic sib pairs

Conception et transfert de systèmes décisionnels pour la réduction des traitements en viticulture : le projet SyDéRéT

National audienceIn most cases, the protection of grapevine against powdery and downy mildews relies on systematic usage of fungicides. One mean to limit the amount of fungicides used is to design innovative and explicit decision strategies for treatments applied less systematically and at most opportune times. Within the SyDéRéT project, a decision workflow named Mildium® has been designed and implemented at the plot scale during several years in French vineyards. Mildium® made it possible to reduce by 30 to 50% the Treatment Frequency Index for these two diseases without altering, in more than 90% of the cases, the crop protection performance at harvest and without augmenting costs. Interviews of growers which were conducted during this project showed that technical and economical factors may hinder the adoption process for such decision tools and that technical support to growers is needed. A bio-economic model was developed during this project in order to investigate potential impacts of crop protection strategies against both diseases on crop and yield damage risks.La maîtrise du mildiou et de l’oïdium de la vigne repose majoritairement sur l’utilisation systématique de fongicides. Une des voies pour limiter quantitativement le recours aux fongicides est de proposer des stratégies de décisions explicites et innovantes pour des traitements moins systématiques et appliqués aux moments les plus opportuns. Dans le cadre du projet SyDéRéT, un processus opérationnel de décision nommé Mildium® a été conçu et testé à l’échelle parcellaire durant plusieurs années dans le vignoble français. Son application permet une réduction de 30% à 50% de l’indice de fréquence de traitement contre ces deux maladies sans altérer les performances de la récolte dans plus de 90% des situations et sans entraîner un surcoût de mise en oeuvre. Des enquêtes menées auprès des viticulteurs au cours de ce projet montrent cependant que des freins techniques et économiques à l’adoption de ce type de processus existent dans les exploitations et que la diffusion de ces pratiques nécessite un accompagnement étroit des viticulteurs. Un travail de modélisation bioéconomique conduit durant ce projet, permet d'analyser l'impact potentiel en termes de risques de perte de récolte de stratégies de protection contre ces deux bio-agresseurs