Association of the Adrenergic α2A Receptor Gene With Methylphenidate Improvement of Inattentive Symptoms in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder

TLDR

Preclinical and genetic studies implicate the adrenergic α2A receptor in attentional processes and suggest that the ADRA2A gene, particularly the –1291 C>G polymorphism, may contribute to the inattentive dimension of ADHD. This pharmacogenomic study aimed to determine whether the ADRA2A –1291 C>G polymorphism predicts clinical response to methylphenidate in children and adolescents with ADHD. One hundred six ADHD patients were genotyped for ADRA2A –1291 C>G and treated with escalating doses of short‑acting methylphenidate, with parent‑rated inattentive, hyperactivity‑impulsivity, and side‑effect scales assessed by blinded psychiatrists at baseline, 1, and 3 months. The presence of the G allele was associated with a significant interaction with methylphenidate treatment over 3 months, yielding greater improvement in inattentive symptoms and indicating a noradrenergic contribution to drug efficacy.

Abstract

Preclinical studies have demonstrated the relevance of adrenergic alpha2A receptor on the attentional process and the mechanism of action of methylphenidate hydrochloride. Several molecular genetic investigations suggest a role for the adrenergic alpha2A receptor gene (ADRA2A) in attention-deficit/hyperactivity disorder (ADHD), especially in the inattentive dimension. However, the effect of ADRA2A in the response to methylphenidate in humans has not been previously investigated, to our knowledge.To evaluate the association between the ADRA2A -1291 C>G polymorphism and the clinical response to methylphenidate treatment in children and adolescents with ADHD.A pharmacogenomic study was undertaken between November 1, 2002, and May 1, 2004, using a nonrandom assignment, quasi-experimental design.An ADHD outpatient program at a university hospital in Brazil. Patients One hundred six patients consecutively diagnosed as having ADHD were genotyped for the ADRA2A -1291 C>G polymorphism and were included in the analyses. Intervention Short-acting methylphenidate administered in increasing dosages until no further clinical improvement was detected or until limited adverse effects occurred.The primary outcome measure was the parent-rated inattentive subscale of the Swanson, Nolan, and Pelham Scale version IV. Secondary outcome measures included the Barkley Side Effect Rating Scale and the parent-rated hyperactivity-impulsivity subscale of the Swanson, Nolan, and Pelham Scale version IV. Scales were applied by child psychiatrists blinded to genotype at baseline and at 1 and 3 months of treatment.A significant interaction effect between the presence of the G allele and treatment with methylphenidate over time on inattentive scores was detected during the 3 months of treatment (n = 106; F(2,198) = 4.30; P = .02).We documented the effect of the G allele at the ADRA2A -1291 C>G polymorphism on the improvement of inattentive symptoms with methylphenidate treatment in children and adolescents with ADHD. Our findings provide clinical evidence for the involvement of the noradrenergic system in the modulation of methylphenidate action.