CAN VILOXAZINE IMPROVE EMOTIONAL, BEHAVIORAL, AND EXECUTIVE FUNCTIONING IN ADHD CHILDREN AND ADOLESCENTS? A META- ANALYSIS AND SYSTEMATIC REVIEW OF RANDOMIZED, CONTROLLED TRIALS
Authors: Maneeton *Benchalak , Maneeton Prapinpatch , Winichaikul Yanisa , Kawilapat Suttipong , Kienngam Nongluck , Maneeton Narong 
Published: February 2025

Abstract

Background
Although previous evidence illustrated some efficacy of non-stimulants in the reduction of Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms,1,2 they have not reported their efficacy in emotional and behavioral problems or executive function.

Objectives
We aimed to systematically review the efficacy of viloxazine for treating disturbances of emotions and behavior and improving executive function in children and adolescents with ADHD.

Methods
We searched and assessed the risk of bias in the relevant randomized, controlled trials (RCTs) in the CINAHL, ClincalTrial.gov, Cochrane Library, PubMed, and Scopus databases. The efficacy of outcomes was mainly evaluated by pooled mean change difference of standardized rating scales, which are widely used assessment tools for ADHD and related behavioral disorders: the Conners 3rd Edition Parent Short (Conners 3-PS) and the Weiss Functional Impairment Rating Scale— Parent Report (WFIRS- P). We calculated pooled mean changes with 95% confidence intervals using an inverse variance weighting method. The overall discontinuation rate (acceptability), and the discontinuation due to adverse events (tolerability) were evaluated through relative risk (RR) calculations, using the Mantel- Haenszel method for dichotomous outcomes in the included RCTs.

Results
1,619 randomized patients from five RCTs were included in the synthesis of this review. The pooled mean changes of the Conners 3-PS composite in the viloxazine-treated group for children and adolescents were significantly greater than those of the placebo-treated group [mean difference (MD) with 95% CI = -3.88 (-5.12, -2.64), I2 = 0%, and -1.69 (-3.03, -0.36), I2 = 0%, respectively]. For children, all Conners 3-PS subscales showed significant improvement, whereas, for adolescents, only the subscales assessing inattention, hyperactivity, learning difficulties, and executive functioning showed a significant improvement, except for those measuring defiance/aggression and peer relations. The pooled mean changes of the WFIRS-P found that in children, the viloxazine-treated group had significantly greater than the placebo group in several subscale scores, including family, school, life skills, social activities, and risky activities, except for self-concept [MD (95% CI) = -0.13 (-0.18, -0.08), I2=0%].
Meanwhile, the adolescent-treated group demonstrated improvements only in family, school, life skills, and risky activities, then the WFIRS-P total scores were not different from placebo, as the MD was -0.03 (95% CI: -0.08, 0.02) with an I2 of 39%. The overall discontinuation rates of viloxazine-treated groups were comparable to placebo in ADHD children and higher than placebo in adolescents. Furthermore, rates of discontinuation due to adverse events of viloxazine-treated groups were greater than placebo in both children and adolescents.

Conclusion
Viloxazine could improve learning problems and executive functioning in ADHD children and adolescents. However, it can improve overall functioning in children but not in adolescents. Its acceptability is comparable to a placebo in ADHD children and less than a placebo in the adolescent group. Additionally, those children and adolescents are not well tolerated by viloxazine. Thus, the use of this non-stimulant should be balanced between risk and benefit. Further well-defined studies should be carried out to verify those findings.

References
1.MANEETON, N., MANEETON, B., INTAPRASERT, S. & WOOTTILUK, P. 2014. A systematic review of randomized controlled trials of bupropion versus methylphenidate in the treatment of attention- deficit/hyperactivity disorder. Neuropsychiatr Dis Treat, 10, 1439-49.
2.MANEETON, N., MANEETON, B., SRISURAPANONT, M. & MARTIN, S. D. 2011. Bupropion for adults with attention-deficit hyperactivity disorder: meta-analysis of randomized, placebo-controlled trials. Psychiatry Clin Neurosci, 65, 611-7.