Effectiveness of Atomoxetine and Stimulant Combination in Attention-Deficit/Hyperactivity Disorder (ADHD) Treatment: A Systematic Review

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that can present with inattention, impulsivity, hyperactivity, or any combination of the three. For ADHD treatment, stimulants are widely considered first-line medications, with methylphenidate formulations being the most commonly prescribed. In patients who do not tolerate stimulants at higher doses, non-stimulant augmentation is a potential treatment strategy. Atomoxetine, as the first approved non-stimulant for ADHD by the United States Food and Drug Administration, has also been evaluated in several studies for combination therapies over the years. This review aims to investigate the effectiveness of combining stimulants such as methylphenidate with atomoxetine based on all newer studies, which came after the last major systematic review published in 2013. Six retrospective studies were included based on eligibility criteria among all studies published from 2012 to 2024 that were relevant to the research question. Three out of the six studies contained data regarding efficacy: one reported no significant difference in ADHD severity reduction between atomoxetine monotherapy and combination therapy overall, while two reported significantly decreased ADHD severity among treatment-resistant monotherapy patients after switching to combined methylphenidate and atomoxetine therapy. Four out of the six studies measured adherence: three reported significantly greater adherence with combined therapy versus monotherapy, while one reported that concomitant prescription of atomoxetine with methylphenidate significantly contributed to methylphenidate discontinuation. Limitations to this review include a limited quantity of total studies relevant based on the defined research question and the eligibility criteria, and lower certainty of evidence among them due to study limitations and even conflicts of interests. The heterogeneity in definitions and metrics carries over into population characteristics and analyses of each study, all of which contribute to the overall indirectness of evidence toward the defined question. For future studies, the current research question should be narrowed down to investigate specific ADHD patient subpopulations, with standardized protocols with consistent definitions and statistical methods to conduct prospective randomized controlled studies across multiple sites with longer follow-up periods, to have more meaningful answers regarding optimal combinations of atomoxetine with various stimulant formulations for long-term outcomes.