Review and Meta-analysis on the Impact of the Alpha-2A Adrenergic Receptor Variant rs1800544 on Methylphenidate Outcomes in Attention-Deficit/Hyperactivity Disorder

Abstract

ABSTRACT BACKGROUND Methylphenidate is among the most prescribed medications for treating attention-deficit/hyperactivity disorder (ADHD). Despite this, nearly half of pediatric patients with ADHD do not respond to methylphenidate treatment. Pharmacogenetic testing can aid in identifying patients for whom methylphenidate is unlikely to be safe or effective, leading to improved methylphenidate outcomes and increased utilization of alternative treatment options for ADHD. This review aims to summarize findings from studies of the alpha-2A adrenergic receptor (ADRA2A) gene variant, rs1800544, and its association with methylphenidate outcomes in ADHD. METHODS We systematically reviewed and meta-analyzed available literature on the impact of rs1800544 on methylphenidate outcomes in ADHD. RESULTS 14 studies met inclusion criteria for review, 9 of which were eligible for meta-analysis. The included studies compared methylphenidate outcomes in ADHD patients categorized by rs1800544 genotype. G-allele carriers experienced significantly greater improvements in ADHD symptom scores (SNAP-IV or ARS-IV) relative to non-carriers (OR=3.08 [1.71, 5.56]; p=0.0002) and greater response rates as measured by a ≥50% improvement in symptom scores (OR=2.68 [1.23, 5.82]; p=0.01); no significant difference in response rate as measured by CGI score ≤ 2 was found. Stouffer’s Z-score method showed significant improvement across all methylphenidate outcomes in G-allele carriers relative to non-carriers (Z=3.03; p=0.002). CONCLUSIONS These findings suggest that carriers of rs1800544 may have improved ADHD outcomes following methylphenidate treatment. However, the extent to which these improvements are clinically impactful remain unclear. Additional studies will be required to determine if rs1800544 carrier status should influence clinical recommendations for the treatment of ADHD symptoms.