Article

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: 6.35). 11/2011; 50(11):1129-1139.e2. DOI: 10.1016/j.jaac.2011.08.002
Source: PubMed

ABSTRACT 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); http://www.clinicaltrials.gov; NCT01238822.

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    • "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]. "
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    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.
    BMC Psychiatry 09/2013; 13(1):237. DOI:10.1186/1471-244X-13-237 · 2.24 Impact Factor
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    • "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”. "
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    • "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). "
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