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Integrative genomic analysis of methylphenidate response in attention-deficit/hyperactivity disorder.

ABSTRACT: Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P?

SUBMITTER: Pagerols M

PROVIDER: S-EPMC5789875 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Integrative genomic analysis of methylphenidate response in attention-deficit/hyperactivity disorder.

Pagerols Mireia M Richarte Vanesa V Sánchez-Mora Cristina C Rovira Paula P Soler Artigas María M Garcia-Martínez Iris I Calvo-Sánchez Eva E Corrales Montse M da Silva Bruna Santos BS Mota Nina Roth NR Victor Marcelo Moraes MM Rohde Luis Augusto LA Grevet Eugenio Horacio EH Bau Claiton Henrique Dotto CHD Cormand Bru B Casas Miguel M Ramos-Quiroga Josep Antoni JA Ribasés Marta M

Scientific reports 20180130 1

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was sig ...[more]

PMID: 29382897

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Effect of methylphenidate on gene expression profiles of Attention Deficit Hyperactivity Disorder patients and unaffected controls.

Project description:Attention deficit hyperactivity disorder (ADHD) is a common psychiatric condition of children with a prevalence of 5-10% worldwide. Up to 30% of adults with a history of childhood ADHD maintain symptoms in later life; these adult ADHD patients are severely impaired in social and professional life due to persistence of ADHD core symptoms like impulsivity, attention deficit and hyperactivity as well as frequently observed co-morbidities like alcohol and drug abuse, major depression, bipolar and personality disorders. Pharmaceutical treatment options include methylphenidate (MPH), which is amongst others an inhibitor of the dopamine transporter and therefore increases dopamine levels in the brain. However, not all ADHD patients are MPH responders with clinical features to distinguish responders and non-responders being not at hand so far. Likewise, neurobiological reasons for drug response are still elusive. Here, we examined the global transcriptional response of MPH on lymphoblastoid cell lines (LCLs) derived from ADHD patients and unaffected controls.

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Effect of methylphenidate on gene expression profiles of Attention Deficit Hyperactivity Disorder patients and unaffected controls.

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Methylphenidate improves response inhibition but not reflection-impulsivity in children with attention deficit hyperactivity disorder (ADHD).

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Methylphenidate normalizes frontocingulate underactivation during error processing in attention-deficit/hyperactivity disorder.

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Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder: long-term effects.

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Individualizing the dosage of Methylphenidate in children with attention deficit hyperactivity disorder.

Project description:BackgroundAttention deficit hyperactivity disorder (ADHD) is one of the most common childhood mental health disorders. Stimulant drugs as the most commonly used treatment and first-line therapy for ADHD have side effects. One of the newest approaches to select the best choices and optimize dosages of medications is personalized medicine.MethodsThis historical cohort study was carried out on the data taken from the period of 2008 to 2015. Eligible subjects were included in the study randomly. We used mixed-effects logistic regression models to personalize the dosage of Methylphenidate (MPH) in ADHD. The patients' heterogeneity was considered using subject-specific random effects, which are treated as the realizations of a stochastic process. To recommend a personalized dosage for a new patient, a two-step procedure was proposed. In the first step, we obtained estimates for population parameters. In the second step, the dosage of the drug for a new patient was updated at each follow-up.ResultsOf the 221 children enrolled in the study, 169 (76.5%) were male and 52 (23.5%) were females. The overall mean age at the beginning of the study is 82.5 (± 26.5) months. In multivariable mixed logit model, three variables (severity of ADHD, time duration receiving MPH, and dosage of MPH) had a significant relationship with improvement. Based on this model the personalized dosage of MPH was obtained.ConclusionsTo determine the dosage of MPH for a new patient, the more the severity of baseline is, the more of an initial dose is required. To recommend the dose in the next times, first, the estimation of random coefficient should be updated. The optimum dose increased when the severity of ADHD increased. Also, the results show that the optimum dose of MPH as one proceeds through the period of treatment will decreased.

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Sleep-Associated Adverse Events During Methylphenidate Treatment of Attention-Deficit/Hyperactivity Disorder: A Meta-Analysis.

Project description:ObjectiveSleep disturbances are a feature of attention-deficit/hyperactivity disorder (ADHD) and an adverse event (AE) of methylphenidate treatment. The authors sought to clarify methylphenidate-associated sleep problems and how studies are affected by confounding factors.Data sourcesPublished studies in English collected via online databases and unpublished data from www.clinicaltrials.gov and US Food and Drug Administration websites. Sources were searched from inception to August 2017.Study selectionIncluded were blinded placebo-controlled studies of youth with ADHD conducted in naturalistic settings, leading to 35 studies yielding 75 observations of sleep-related AEs. These studies comprised 3,079 drug-exposed and 2,606 placebo-treated patients.Data extractionTwo PhD-level reviewers reviewed each study for inclusion. Four PhD/PharmD-level reviewers extracted data in duplicate. Discrepancies were resolved by discussion or, if needed, by the senior author.ResultsIncreased pooled relative risks (RRs) were found for methylphenidate-associated sleep-related AEs for insomnia (general), initial insomnia, middle insomnia, combined insomnia, and sleep disorder. Several sample or study design features were significantly associated with the RR for sleep-related AEs and the methylphenidate formulation studied (P < .05). After correction for confounding variables, significant differences among drugs were found for initial insomnia, insomnia (general), and sleep disorder (P < .0001) as the other categories could not be tested due to insufficient studies. The findings also show that the RR and its interpretation are constrained by the placebo AE rate.ConclusionsSeveral types of insomnia and sleep problems are associated with methylphenidate treatment. Study design and sample features influence the RR statistic. By showing that the rate of placebo AEs impacts the RR, this study provides the field with a useful covariate for adjusting RR statistics.

| S-EPMC8074661 | biostudies-literature

Methylphenidate normalizes resting-state brain dysfunction in boys with attention deficit hyperactivity disorder.

Project description:We used resting-state functional magnetic resonance imaging (RS-fMRI) to investigate the acute effects of methylphenidate hydrochloride (MPH) on spontaneous brain activity in children with attention deficit hyperactivity disorder (ADHD). In all, 23 boys with ADHD were scanned twice, under either 10?mg dose of MPH or placebo, in a randomized, cross-over, counterbalanced placebo-controlled design. 32 Matched healthy controls were scanned once for comparison. Seven of the 23 ADHD boys participated in a follow-up 8-week MPH treatment. A regional homogeneity (ReHo) method was applied to characterize the local synchronization of spontaneous brain activity. ADHD boys under placebo compared with controls showed decreased ReHo in bilateral dorsolateral prefrontal cortices and increased ReHo in bilateral sensorimotor and parieto-visual cortices. Relative to placebo, MPH upregulated ReHo in bilateral ventral prefrontal cortices and cerebellar vermis, and downregulated ReHo in right parietal and visual areas that overlapped with the abnormally enhanced activities. When under MPH, ReHo differences between patients and controls were no longer observed. The preliminary prediction analysis revealed that the decreased ReHo in right parietal cortex after the acute MPH was positively correlated with the decreased symptom scores after the 8-week MPH treatment in the seven patients. We show that an acute dose of MPH normalized all fronto-parieto-cerebellar dysfunctions in boys with ADHD during the resting state. Preliminary findings furthermore suggest the potential of RS-fMRI as a prognostic imaging tool to identify response to MPH treatment.

| S-EPMC3656372 | biostudies-literature

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