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Association of the Adrenergic 2A Receptor Gene With Methylphenidate Improvement of Inattentive Symptoms in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder

Guilherme Polanczyk, MD; Cristian Zeni, MD; Julia P. Genro, BSc; Ana P. Guimarães, BSc; Tatiana Roman, PhD; Mara H. Hutz, PhD; Luis A. Rohde, MD

Arch Gen Psychiatry. 2007;64(2):218-224.

Context  Preclinical studies have demonstrated the relevance of adrenergic 2A receptor on the attentional process and the mechanism of action of methylphenidate hydrochloride. Several molecular genetic investigations suggest a role for the adrenergic 2A 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.

Objective  To evaluate the association between the ADRA2A –1291 C>G polymorphism and the clinical response to methylphenidate treatment in children and adolescents with ADHD.

Design  A pharmacogenomic study was undertaken between November 1, 2002, and May 1, 2004, using a nonrandom assignment, quasi-experimental design.

Setting  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.

Main Outcome Measures  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.

Results  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).

Conclusions  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.

Author Affiliations: Attention-Deficit/Hyperactivity Disorder Outpatient Clinic, Child and Adolescent Psychiatric Division, Hospital de Clínicas de Porto Alegre (Drs Polanczyk, Zeni, and Rohde), and Department of Genetics (Mss Genro and Guimarães and Dr Hutz), Federal University of Rio Grande do Sul, and Department of Morphological Sciences, Federal School of Medical Sciences of Porto Alegre (Dr Roman), Porto Alegre, Rio Grande do Sul, Brazil.