Review and Meta-analysis on the Impact of the ADRA2A Variant rs1800544 on Methylphenidate Outcomes in Attention-Deficit/Hyperactivity Disorder

BACKGROUND: Methylphenidate is among the most prescribed medications for treating attention-deficit/ hyperactivity disorder (ADHD). However, 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 use of alternative treatment options for ADHD. This article aimed to summarize findings from studies of the 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: Fourteen studies met inclusion criteria for review, 9 of which were eligible for meta-analysis. The included studies compared methylphenidate outcomes in patients with ADHD categorized by rs1800544 genotype. G-allele carriers experienced significantly greater improvements in ADHD symptom scores (Swanson, Nolan, and Pelham Version-IV Scale or ADHD Rating Scale-IV) relative to noncarriers (odds ratio 3.08, 95% confidence interval 1.71-5.56, p = .0002) and greater response rates as measured by a $50% improvement in symptom scores (odds ratio 2.68, 95% confidence interval 1.23-5.82, p = .01); no significant difference in response rate as measured by Clinical Global Impressions score #2 was found. Stouffer's z-score method showed significant improvement across all methylphenidate outcomes in G-allele carriers relative to noncarriers (z = 3.03, p = .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 are required to determine if rs1800544 carrier status should influence clinical recommendations for treatment of ADHD symptoms.