Response Trajectories and Temporal Trends of Viloxazine Treatment for Young People With ADHD: A Meta-Analysis.

Importance: Viloxazine is a novel nonstimulant medication approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). Objectives: To investigate the whether viloxazine is associated with effective and acceptable outcomes when treating children and adolescents with ADHD and to evaluate these outcomes' associations with viloxazine doses and duration of treatment. Data Sources: The MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, PsycINFO, and ClinicalTrial.gov databases were searched from database inception to June 23, 2024. Study Selection: Two reviewers independently screened for double-blind, fixed-dose randomized clinical trials (RCTs) that compared viloxazine with placebo for pediatric patients with ADHD. Data Extraction and Synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Data extraction was completed independently by 2 authors and cross-checked for errors. Random-effects pairwise and dose-response meta-analyses were conducted. Main Outcomes and Measures: The primary outcome was the improvement of ADHD symptoms (measured by ADHD Rating Scale-5), and the secondary outcomes were all-cause discontinuation, dropout due to adverse effects, and serious adverse effects. Results: A total of 5 dose-response RCTs were included, with 1560 participants (1011 [64.8%] male; mean [SD] age, 10.6 [6.7] years). Viloxazine was associated with better outcomes in ADHD treatment compared with placebo (mean difference, 5.47 points; 95% CI, 4.03-6.91 points). The dose-response curve was bell-shaped, suggesting that doses greater than 400 mg or greater than 7 mg/kg might not be associated with more efficacy. The temporal trends analysis showed ascent curves tapering off at approximately weeks 4 to 6. The curve for 100 mg/d declined more rapidly, while the curves for 200 mg/d and 400 mg/d declined more gradually. The overall discontinuation rate due to adverse effects was 4.15% in the viloxazine group (45 of 1084), while viloxazine compared with placebo was associated with 2.48-fold higher risk of discontinuation due to adverse effects (risk ratio, 2.48; 95% CI, 1.26-4.88). Conclusions and relevance: In this meta-analysis, viloxazine was associated with better efficacy in treating children and adolescents with ADHD than placebo. A moderate dose (200-400 mg or 6-8 mg/kg) may provide optimal treatment outcomes. Future studies are warranted to assess the long-term effect of viloxazine. Viloxazine was relatively well tolerated for children and adolescents with ADHD.