The Pharmacogenomic Era: Promise for Personalizing Attention Deficit Hyperactivity Disorder Therapy

Abstract

SynopsisCurrently, ADHD treatment is often determined empirically through trial and error until an adequate response is obtained or side effects occur. ADHD is highly heritable and there is wide individual variability in response to ADHD medications, suggesting that the mechanism of action of stimulant medications may provide clues for genetic predictors of response. The promise of ADHD pharmacogenetics is far reaching, and includes the potential to develop individualized medication regimens that improve symptom response, decrease risk for side effects, improve long-term tolerability, and thus contribute to long-term treatment compliance and improved general effectiveness. Early ADHD pharmacogenetic studies have focused predominantly on catecholamine pathway genes and response to methylphenidate. Future efforts will also examine a wider range of stimulant and non-stimulant medications on a range of outcome measures and time periods. Based upon these studies, the potential for personalizing ADHD treatment in clinical practice will be determined. IntroductionAttention-Deficit/Hyperactivity Disorder (ADHD) is a common and treatable behavioral syndrome that typically emerges during childhood or adolescence and often persists into adulthood. There are an increasing number of stimulant and non-stimulant medication options for ADHD, with numerous new compounds in development [1]. In acute treatment studies, stimulant medications generally demonstrate large effect sizes on ADHD symptom reduction relative to placebo, with slightly smaller effect sizes in adult studies [2]. Surprisingly, only a minority of children and adolescents with ADHD remain on medication consistently Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. despite persistence of symptoms and impairments. Even among responders, there is marked variability in optimal dosage, duration of effect, and tolerability. Moreover, in spite of acute symptom reduction from ADHD medications, as yet there is little evidence of long-term response and improvement in functioning among those children who received treatment [4,5]. Furthermore, there are few reliable predictors of medication response. In the absence of these data, treatment is often determined "empirically" in clinical practice through a gradual titration of different dosages and trial and error approach to different medications. NIH Public AccessADHD is a highly heritable disorder [6]. The search for candidate genes associated with ADHD has been largely driven by the understanding that medications for the disorder have drug targets in the catecholamine system [7]. Conve...

Norepinephrine transporter gene (SLC6A2) is involved with methylphenidate response in Korean children with attention deficit hyperactivity disorder

“…The genetic associations with the MPH response have been reported in many studies earlier (Froehlich et al, 2010;Stein and McGough, 2008). However, earlier many researches have focused on dopamine related genes.…”

Pharmacokinetic Variability of Long-Acting Stimulants in the Treatment of Children and Adults with Attention-Deficit Hyperactivity Disorder

“…[56] Another factor influencing differential responses from one stimulant to another may lie in genetic polymorphisms. [68,69] Nevertheless, formulation differences among various methylphenidate-and amfetamine-based stimulants may contribute to some of the observed variability in response to these treatments.…”

“…The metabolic products of methylphenidate are renally excreted, whereas amfetamine undergoes metabolism via CYP isozymes of the liver. [69] While an in-depth discussion of the metabolic fate of stimulants is beyond the scope of this review, methylphenidate is metabolized primarily by de-esterification [23] and amfetamine can be metabolized by hydroxylation and deamination. [46] The particular enzymes responsible have not yet been identified.…”

ADHD psychopharmacology across the lifespan

“…However, there are suggestions of substantial intersubject variability in treatment response to medications. Understanding the underpinnings of this heterogeneity may lead to more targeted and individualized treatment approaches [26]. For patients at high risk for substance abuse or with comorbid anxiety or tics, atomoxetine may be the preferred initial treatment [7].…”