Phase 4 Trial of Viloxazine ER Shows Real-World Gains for ADHD With Comorbid Depression, Anxiety

CONFERENCE REPORTER

Adults with ADHD and comorbid depression or anxiety saw symptoms drop by

roughly half across all 3 conditions in a new real-world trial of viloxazine ER (Qelbree), and the trial didn't screen them out for using nicotine or cannabis, a common exclusion in ADHD research, according to Amber Graves, PharmD, RPh. Graves, a senior medical science liaison at Supernus Pharmaceuticals, presented the findings on the company's behalf at the 2026 Southern California Psychiatry Conference in Huntington Beach, California.^1,2

A Trial Designed to Reflect Real-World Practice

Patients with comorbidities are routinely excluded from research, Graves told attendees. With that in mind, this phase 4 trial (NCT06185985) was built as a course correction, deliberately enrolling patients with mood and anxiety symptoms. The study also allowed for nicotine and cannabis use, as investigators realize these substances are often used by individuals with ADHD. The goal, she said, was to reflect "real-world perspectives of these patients, as you see on a day-in and day-out basis, that come into your door with comorbid depression, anxiety, and with ADHD."

Participants (mean age 39.4 years; 75.8% female) required a primary ADHD diagnosis confirmed by the Mini-International Neuropsychiatric Interview, an ADHD symptom score of at least 24, and clinically significant depression and/or anxiety at baseline. Ultimately, 104 individuals completed the 14-week trial, in which they received 200 mg once daily and were titrated to 400 mg beginning week 2, with flexibility up to 600 mg.

ADHD, Depression, and Daily Function Improved

Graves reported that the results were positive. By week 14, clinician-rated ADHD symptoms (AISRS) fell 45.3% and patient-rated symptoms (ASRS) fell 50.9% from baseline. In addition, 71.8% of participants achieved at least a 30% symptom reduction, and 45.6% achieved at least 50%. Depression scores (MADRS) and anxiety scores (HAM-A) improved by roughly 50% or more for many participants, with gains statistically significant at every study visit across all 3 domains.

Graves attributed the overlapping gains to viloxazine's activity on serotonin receptors. Beyond its primary norepinephrine effect, the drug is a partial agonist at 5-HT2C and has antagonist activity at 5-HT2B and 5-HT7 receptors, systems that are tied to mood, anxiety, and sleep regulation. Interestingly, its immediate-release form was also used as an antidepressant in Europe before viloxazine ER was developed for ADHD. Still, Graves was careful not to overstate the science behind the results. "Whether these pharmacological properties of these specific receptors contribute to clinical response in depression and anxiety is unknown, and requires a controlled study to dive into that further."

Work productivity (WPAI) improved across all four measured domains (ie, absenteeism, presenteeism, regular activity, and overall productivity), which Graves noted was a meaningful finding given that roughly 73% of participants were employed. Cognitive impairment, depression, and anxiety compound to affect a patient's ability to function at work, which is why the trial looked past symptom scores alone to what Graves called "daily experience and daily life within their work productivity."

Safety: A Boxed Warning and Close Monitoring

Viloxazine ER was well tolerated, Graves told attendees. In the trial, 70.8% of participants had a treatment-emergent adverse event, most mild to moderate; the most common were nausea, insomnia, constipation, headache, fatigue, and dry mouth. TEAEs led 14.9% of participants to discontinue treatment, including 3 who discontinued due to suicidal ideation (2 considered treatment-related). Six participants (3.7%) had serious TEAEs, including the aforementioned 2 associated with suicidal ideation.

In addition, Graves said viloxazine ER carries a boxed warning for suicidal thoughts and behaviors. As a result, she recommends clinicians “monitor your patients very closely for emerging or worsening signs and symptoms of suicidal thoughts and behaviors.”

What This Means for Clinical Practice

Graves was direct about the trial's limitations, noting it was open-label with no comparator group, ran only 14 weeks, and the population was mostly White and female, limiting generalizability. Whether the drug's effect on mood is a direct effect or secondary to ADHD symptom improvement also remains unanswered.

Even with those caveats, Graves said, the trial's design is the point: "This gives a glimpse into the real world of how these patients are responding."

References

1. Adler LA, Lieberman VR, Brijbasi L, et al. Viloxazine Extended Release in Adults With Attention-Deficit/Hyperactivity Disorder and Depression and/or Anxiety Symptoms: Results From a Decentralized, Open-Label, Phase 4 Trial. J Clin Psychiatry. 2026;87(2):25m16234.

2. Graves A. Phase IV Treatment Study in Adults With ADHD and Depression and/or Anxiety Symptoms. Presented at the 2026 Southern California Psychiatry Conference; July 10-11, 2026; Huntington Beach, California.