Viloxazine ER’s Impact on Comorbid Conditions: A Broader Approach to ADHD Management

Managing attention-deficit/hyperactivity disorder (ADHD) often means navigating a maze of overlapping conditions—mood instability, anxiety, executive dysfunction, and more. This article explores how viloxazine ER, a non-stimulant with dual norepinephrine and serotonergic activity, provides more than just relief from core symptoms. With compelling data from Phase 3 trials and post-hoc analyses, viloxazine ER demonstrates effectiveness in reducing emotional lability and enhancing executive functioning, making it particularly advantageous for patients with comorbid anxiety, depression, autism spectrum disorder, or stimulant intolerance. Its unique pharmacologic profile, low potential for abuse, and good tolerability establish it as a cornerstone in holistic, precision-based ADHD management. 

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition affecting approximately 5% to 7% of children and 2% to 5% of adults, with up to 80% of patients experiencing comorbid psychiatric conditions such as anxiety, depression, or emotional dysregulation.^1-3  While stimulants remain first-line therapies, their side effects—including exacerbation of anxiety, insomnia, and cardiovascular risks—limit utility for many patients.^2,4 Viloxazine extended release (ER), a non-stimulant approved for pediatric and adult ADHD, offers a dual mechanism of action targeting both core symptoms and emotional comorbidities, positioning it as a versatile option for comprehensive management.⁵

Dual Mechanism of Action: Bridging Symptom Control and Emotional Stability

Viloxazine ER’s efficacy stems from its unique pharmacological profile as a selective norepinephrine reuptake inhibitor (NRI) and serotonin 5-HT_2C receptor antagonist.⁶ By enhancing norepinephrine signaling in the prefrontal cortex, it improves attention, impulse control, and hyperactivity.⁶ Simultaneously, its modulation of 5-HT_2C receptors regulates dopamine and norepinephrine release in limbic regions, which may stabilize mood and reduce emotional lability.⁶ This dual activity differentiates it from pure NRIs, such as atomoxetine, and addresses the intertwined nature of ADHD symptoms and emotional dysregulation. Phase 3 trials demonstrate significant reductions in ADHD Rating Scale (ADHD-RS) scores in both pediatric and adult populations, with improvements observed within one week.⁵ 

Clinical Benefits Beyond Core Symptoms

Beyond reducing hyperactivity and inattention, viloxazine ER shows promise in mitigating comorbid emotional and executive functioning challenges. Post-hoc analyses of clinical trials revealed reductions in emotional lability scores and improvements in executive function metrics, such as the Conners 3rd Edition Parent Short Form—Executive Function (C3PS-EF) content scale.⁷ A pooled analysis of 4 phase III trials demonstrated that 52.5% of viloxazine ER-treated patients achieved significant improvements in executive function or ADHD symptoms, compared to 35.4% on placebo (number needed to treat [NNT]=5.8).⁷  These findings suggest particular benefits for patients with ADHD, where emotional dysregulation is prevalent.⁷  

Target Populations: Precision in ADHD Management

Viloxazine ER is particularly advantageous for specific subgroups:

• Stimulant-intolerant patients: Viloxazine ER is a suitable option for individuals who cannot tolerate stimulants due to cardiovascular concerns, insomnia, or appetite disturbances.²
• Emotionally dysregulated patients: Viloxazine ER provides targeted support for those with comorbid ASD, mood disorders, or trauma-related symptoms.⁷ 
• Adults with executive dysfunction: Emerging data support its efficacy in adults with late-onset ADHD and organizational deficits.⁸

Sleep disturbances, which affect 50% to 80% of children with ADHD and exacerbate family stress, may also benefit from viloxazine ER’s non-stimulant profile.⁹ Qualitative studies highlight how ADHD-related sleep issues strain parental mental health and family dynamics, underscoring the need for treatments that avoid sleep-worsening side effects.⁹ 

Ongoing research explores viloxazine ER’s potential in combination therapies (eg, with stimulants for partial responders) and its long-term neurocognitive benefits. Its serotonergic modulation may also bridge gaps in treating ADHD with overlapping anxiety or depressive symptoms.⁸ 

Conclusion

Viloxazine ER represents a paradigm shift in ADHD management, integrating symptom control with emotional and cognitive remediation. Its dual mechanism, tolerability, and expanding evidence base position it as a cornerstone for psychiatrists managing ADHD across the lifespan, particularly in patients with complex comorbidities. By addressing both core symptoms and associated impairments, viloxazine ER exemplifies a holistic approach to ADHD care.

References:

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association Publishing; 2013.
2. Qelbree. Prescribing information. Supernus Pharmaceuticals. Revised January 2025. Accessed May 12, 2025. https://www.supernus.com/sites/default/files/Qelbree-Prescribing-Info.pdf
3. Koyuncu A, Ayan T, Ince Guliyev E, et al. ADHD and anxiety disorder comorbidity in children and adults: Diagnostic and therapeutic challenges. Curr Psychiatry Rep. 2022;24(2):129-140. doi:10.1007/s11920-022-01324-5. 
4. Cortese S, Coghill D. Twenty years of research on attention-deficit/hyperactivity disorder (ADHD): looking back, looking forward. Evid Based Ment Health. 2018;21(4):173-176. doi:10.1136/ebmental-2018-300050.
5. Nasser A, Hull JT, Chaturvedi SA, et al. A phase III, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of viloxazine extended-release capsules in adults with attention-deficit/hyperactivity disorder. CNS Drugs. 2022;36(8):897-915. doi:10.1007/s40263-022-00938-w.
6. Stahl SM. Stahl’s Essential Psychopharmacology. 5th ed. Cambridge University Press; 2021.
7. Faraone SV, Gomeni R, Hull JT, et al. Executive function outcome of treatment with viloxazine extended-release capsules in children and adolescents with attention-deficit/hyperactivity disorder: a post-hoc analysis of four randomized clinical trials. Paediatr Drugs. 2021;23(6):583–589. doi:10.1007/s40272-021-00470-2
8. Maletic V, Mattingly GW, Earnest J. Viloxazine extended-release capsules as an emerging treatment for attention-deficit/hyperactivity disorder in children and adolescents. Expert Rev Neurother. 2024;24(5):443-455. doi:10.1080/14737175.2024.2327533
9. French B, Quain E, Kilgariff J, Lockwood J, Daley D. The impact of sleep difficulties in children with attention deficit hyperactivity disorder on the family: a thematic analysis. J Clin Sleep Med. 2023;19(10):1735-1741. doi:10.5664/jcsm.10662