Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Journal of the American Academy of Child and Adolescent Psychiatry (Impact Factor: 7.26). 11/2011; 50(11):1129-1139.e2. DOI: 10.1016/j.jaac.2011.08.002
Source: PubMed


Because of significant individual variability in attention-deficit/hyperactivity disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examined the role of four catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response.
Eighty-nine stimulant-naive children with ADHD 7 to 11 years old participated in a randomized, double-blind, crossover trial of long-acting MPH. Parents and teachers assessed each child's response on placebo and three MPH dosage levels using the Vanderbilt ADHD rating scales. Children were genotyped for polymorphisms in the 3' untranslated region of dopamine transporter (DAT), exon 3 on dopamine receptor D(4) (DRD4), codon 158 on catechol-O-methyltransferase, and the adrenergic α(2A)-receptor promoter. Linear mixed models evaluated gene, dose (milligrams per kilogram per day), and gene-by-dose effects on inattentive and hyperactive-impulsive domain outcomes.
The most statistically significant gene-by-dose interactions were observed on hyperactive-impulsive symptoms for DRD4 and DAT polymorphisms, with participants lacking the DAT 10-repeat allele showing greater improvements in symptoms with increasing dose compared with 10-repeat carriers (p = .008) and those lacking the DRD4 4-repeat allele showing less improvement across MPH doses compared with 4-repeat carriers (p = 0.02).
This study suggests that DAT and DRD4 polymorphisms may be associated with individual variability in MPH dose-response, although further research in larger samples is required to confirm these findings and their clinical utility.
Response Variability in Children with Attention-Deficit/Hyperactivity Disorder (ADHD);; NCT01238822.

Download full-text


Available from: Tanya E Froehlich
  • Source
    • "Response to MPH in the treatment of ADHD varies between patients. While MPH is effective in the majority of children in the short term, there is significant variation in individual response to treatment, with a minority not achieving adequate symptom control and others unable to tolerate MPH due to adverse effects [14-16]. Optimization of dose and treatment regimen is needed, therefore, and continued monitoring of response throughout the treatment period is required [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The stimulant methylphenidate (MPH) has been a mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD) for many years. Owing to the short half-life and the issues associated with multiple daily dosing of immediate-release MPH formulations, a new generation of long-acting MPH formulations has emerged. Direct head-to-head studies of these long-acting MPH formulations are important to facilitate an evaluation of their comparative pharmacokinetics and efficacy; however, to date, relatively few head-to-head studies have been performed.The objective of this systematic review was to compare the evidence available from head-to-head studies of long-acting MPH formulations and provide information that can guide treatment selection. A systematic literature search was conducted in MEDLINE and PsycINFO in March 2012 using the MeSH terms: attention deficit disorder with hyperactivity/drug therapy; methylphenidate/therapeutic use and All Fields: Concerta; Ritalin LA; OROS and ADHD; Medikinet; Equasym XL and ADHD; long-acting methylphenidate; Diffucaps and ADHD; SODAS and methylphenidate. No filters were applied and no language, publication date or publication status limitations were imposed. Articles were selected if the title indicated a comparison of two or more long-acting MPH preparations in human subjects of any age; non-systematic review articles and unpublished data were not included. Of 15,295 references returned in the literature search and screened by title, 34 articles were identified for inclusion: nine articles from pharmacokinetic studies (nine studies); nine articles from laboratory school studies (six studies); two articles from randomized controlled trials (two studies); three articles from switching studies (two studies) and three articles from one observational study. Emerging head-to-head studies provide important data on the comparative efficacy of the formulations available. At a group level, efficacy across the day generally follows the pharmacokinetic profile of the MPH formulation. No formulation is clearly superior to another; careful consideration of patient needs and subtle differences between formulations is required to optimize treatment. For patients achieving suboptimal symptom control, switching long-acting MPH formulations may be beneficial. When switching formulations, it is usually appropriate to titrate the immediate-release component of the formulation; a limitation of current studies is a focus on total daily dose rather than equivalent immediate-release components. Further studies are necessary to provide guidance in clinical practice, particularly in the treatment of adults and pre-school children and the impact of comorbidities and symptom severity on treatment response.
    Full-text · Article · Sep 2013 · BMC Psychiatry
  • Source
    • "Unfortunately, clear predictors for this and successful symptom reduction are lacking. At the moment pharmacogenetic approaches are en vogue, but before the field can offer data to be used for personalized ADHD treatment, pharmacogenetic studies with larger samples and range of outcomes related to efficacy, effectiveness, and safety are needed to determine the utility of genomic information [16]). Their data and methodological limitations allowed only a rough conclusion, namely “that DAT and DRD4 polymorphisms may be associated with individual variability in MPH dose-response”. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Opinion statement Within the last 2 years the bulk of information on evidence based treatments in ADHD was reviewed quite intensively and new empirical studies could be added. This update reports comprehensively about actual and essential facts in the field related to brain development and sensitive periods, predictors of treatment, safety of medication, value of naturalistic studies, new drugs and complementary medicine, behavioral interventions including neurofeedback and psychosocial treatment, treatment of comorbidity, and ethical considerations including preventive aspects. The updated combination of well selected evidence based treatments (ie, pharma plus non-pharma) seems to be clinically and ethically recommended as also suggested by the European and American guidelines on ADHD.
    Preview · Article · Sep 2012 · Current Treatment Options in Neurology
  • Source
    • "Investigations into the neurobiological basis of ADHD have found that it is highly heritable (60–75%) (Nyman et al., 2007; Faraone and Mick, 2010) and that it involves dopaminergic pathways in both the disease manifestation and the response to pharmaceutical treatment (Froehlich et al., 2011). This is consistent with observations that ADHD subjects have altered levels of dopamine (DA) transporter densities in striatal regions lateralized to the right hemisphere (McGough, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Attention deficit hyperactivity disorder (ADHD) currently is diagnosed in children by clinicians via subjective ADHD-specific behavioral instruments and by reports from the parents and teachers. Considering its high prevalence and large economic and societal costs, a quantitative tool that aids in diagnosis by characterizing underlying neurobiology would be extremely valuable. This provided motivation for the ADHD-200 machine learning (ML) competition, a multisite collaborative effort to investigate imaging classifiers for ADHD. Here we present our ML approach, which used structural and functional magnetic resonance imaging data, combined with demographic information, to predict diagnostic status of individuals with ADHD from typically developing children across eight different research sites. Structural features included quantitative metrics from 113 cortical and non-cortical regions. Functional features included Pearson correlation functional connectivity matrices, nodal and global graph theoretical measures, nodal power spectra, voxelwise global connectivity, and voxelwise regional homogeneity. We performed feature ranking for each site and modality using the multiple support vector machine recursive feature elimination algorithm, and feature subset selection by optimizing the expected generalization performance of a radial basis function kernel SVM (RBF-SVM) trained across a range of the top features. Site-specific RBF-SVMs using these optimal feature sets from each imaging modality were used to predict the class labels of an independent hold-out test set. A voting approach was used to combine these multiple predictions and assign final class labels. With this methodology we were able to predict diagnosis of ADHD with 55% accuracy (versus a 39% chance level in this sample), 33% sensitivity, and 80% specificity. This approach also allowed us to evaluate predictive structural and functional features giving insight into abnormal brain circuitry in ADHD.
    Full-text · Article · Aug 2012 · Frontiers in Systems Neuroscience
Show more