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

Article (PDF Available)inJournal of the American Academy of Child and Adolescent Psychiatry 50(11):1129-1139.e2 · November 2011with73 Reads
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.
    • "This may in part account for some discrepancies in the reported effects of MPH on RT in the CPT. For example, Michael, Klorman, Salzman, Borgstedt, and Dainer (Bellgrove et al., 2005; Cook et al., 1995; Cummins et al., 2012; Gilbert et al., 2006; Froehlich et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction Recent evidence suggests that attention deficit hyperactivity disorder (ADHD) is associated with a range of brain functional connectivity abnormalities, with one of the most prominent being reduced inhibition of the default mode network (DMN) while performing a cognitive task. In this study, we examine the effects of a methylphenidate dose on brain functional connectivity in boys diagnosed with ADHD while they performed a cognitive task. Method Brain functional connectivity was estimated using steady‐state visual evoked potential partial coherence before and 90 min after the administration of a methylphenidate dose to 42 stimulant drug‐naïve boys newly diagnosed with ADHD while they performed the A‐X version of the continuous performance task (CPT A‐X). Results Methylphenidate robustly reversed the transient functional connectivity increase in the A‐X interval seen premedication to a postmedication decrease during this interval. In addition, methylphenidate‐induced reductions in individual reaction time were correlated with corresponding reductions in functional connectivity. Conclusion These findings suggest that methylphenidate suppresses the increased functional connectivity observed in ADHD and that such suppression is associated with improved performance. Our findings support the suggestion that the increased functional connectivity we have observed in ADHD is associated with abnormal DMN activity. In addition, we comment on the significance of specific frequency channels mediating top‐down communication within the cortex and the extent to which our findings are selectively sensitive to top‐down intracortical communication.
    Full-text · Article · Sep 2016
    • "Although abundant data indicate that stimulant medications improve symptoms of inattention, notable variability exists in their optimal dosage. To date no consistent predictors of MPH-dose response in ADHD have been identified, although several genetic polymorphisms related to dopaminergic transmission have been associated with individual variability (Froehlich et al., 2011). In this respect, the finding that lower hypnotizability at baseline was correlated with higher doses of MPH treatment is intriguing. "
    [Show abstract] [Hide abstract] ABSTRACT: Impaired attention may impede learning of adaptive skills in ADHD. While manipulations that reduce competition between attentional processes, including hypnosis, could boost learning, their feasibility in ADHD is unknown. Because hypnotic phenomena rely on attentional mechanisms, the authors aimed to assess whether stimulants could enhance hypnotizability in ADHD. In the current study, stimulant-naïve patients seeking treatment for ADHD-related symptoms were assessed with the Stanford Hypnotic Susceptibility Scale (SHSS) at baseline and during methylphenidate treatment. Methylphenidate dose and SHSS increase were negatively correlated with baseline SHSS scores. Upon reaching effective doses, mean SHSS scores increased significantly. All patients who had been poorly hypnotizable at baseline demonstrated moderate-to-high hypnotizability at follow-up. The data support methylphenidate enhancement of hypnotizability in ADHD, thus highlighting novel treatment approaches for this disabling disorder.
    Full-text · Article · Jul 2015
    • "The fact that MPH doses showed no association in this protocol did not discard this possibility, as the study design is not adequate to investigate the association between genotype and MPH dose. Most studies that used a fixed-dose range found that medication response is dose dependent (Froehlich et al. 2011). As usual, the challenge faced by research into the genetic basis of psychopharmacological drug responses is to identify genes of relatively small and/or moderate effects against a background of substantial genetic and environmental variation. "
    [Show abstract] [Hide abstract] ABSTRACT: Latrophilin 3 (LPHN3) is a brain-specific member of the G-protein coupled receptor family associated to both Attention-Deficit/Hyperactivity Disorder (ADHD) genetic susceptibility and methylphenidate pharmacogenetics.. Interactions of LPHN3 variants with variants harbored in the 11q chromosome improve the prediction of ADHD development and medication response. The aim of the present study was to evaluate the role LPHN3 variants in childhood ADHD susceptibility and treatment response in a naturalistic clinical cohort. The association between LPHN3 and ADHD was evaluated in 523 children and adolescents with ADHD and 132 controls. In the pharmacogenetics study, 172 children with ADHD were investigated. The primary outcome measure was the parent-rated Swanson, Nolan, and Pelham Scale - version IV applied at baseline, first and third months of treatment with methylphenidate. The results reported herein suggest the CGC haplotype derived from SNPs rs6813183, rs1355368, rs734644 as an ADHD risk haplotype (P = 0.02; OR = 1.46). Although non-significant after multiple testing correction, its interaction with the 11q chromosome SNP rs965560 slightly increases risk (nominal P = 0.03; OR = 1.55). Homozygous individuals for the CGC haplotype showed faster response to MPH treatment as a significant interaction effect between CGC haplotype and treatment over time was observed (P < 0.001). Homozygous individuals for the GT haplotype derived from SNPs rs6551665 and rs1947275 showed a significant interaction with treatment over time (nominal P = 0.04). Our findings replicate previous findings reporting that LPHN3 confers ADHD susceptibility, and moderates MPH treatment response in children and adolescents with ADHD. This article is protected by copyright. All rights reserved.
    Full-text · Article · May 2015
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