Nonstimulants: A Better Option for ADHD?

 Children and adults with attention-deficit/hyperactivity disorder (ADHD) show greater improvement in symptoms with viloxazine extended release (ER) compared with treatment with atomoxetine, new research suggests.

Investigators studied patients who started out taking atomoxetine and, after a washout period, initiated treatment with viloxazine. Participants' ADHD symptoms were assessed prior to initiation of each treatment and after 4 weeks.

Children and adults showed significantly larger improvement in inattentiveness and hyperactivity/impulsivity when taking viloxazine vs atomoxetine, with almost all patients preferring the former to the latter.

In addition, close to one half of the study participants were taking a prior stimulant, and 85% were able to taper off stimulant treatment. Viloxazine's effects were also more rapid than were those of atomoxetine.

"It is timely to have a rapidly acting, and highly effective non-stimulant option across the full spectrum of ADHD symptoms, for both children and adults, in light of recent stimulant shortages and the new FDA [US Food and Drug Administration] boxed warnings regarding increased mortality associated with overuse of stimulants" study investigator Maxwell Z. Price, a medical student at Hackensack Meridian School of Medicine, told Medscape Medical News.

Nonstimulant Treatment Options

Study co-author Richard L. Price, MD, told Medscape Medical News that the study was conducted to find a more acceptable alternative to psychostimulant treatments for ADHD, which are currently considered the "gold standard."

Although they are effective, said Price, they are fraught with adverse effects, including appetite suppression, insomnia, exacerbation of mood disorders, anxiety, tics, or misuse.

Atomoxetine, a nonstimulant option, has been around for a few decades and is often used in combination with a stimulant medication. However, he said, the drug has a mild effect, requires frequent dosage adjustment, takes a long time to work, and people have "soured" on its utility, Price added.

Like atomoxetine, viloxazine is a selective norepinephrine inhibitor that has been used an antidepressant in Europe for 30 years. It was recently reformulated as an extended-release medication and approved by the FDA for pediatric and adult ADHD.

However, unlike atomoxetine, viloxazine is associated with increased prefrontal cortex 5-hydroxytrytamine, norepinephrine, and dopamine levels in vivo.

There have been no head-to-head trials comparing the two agents. However, even in head-to-head ADHD medication trials, the agents that are under investigation are typically compared in matched patients. The current investigators wanted to compare the two agents in the same patients whose insurers mandate a trial of generic atomoxetine prior to covering branded viloxazine.

"We wanted to find out whether patients taking atomoxetine for ADHD combined type would experience improvement in ADHD symptoms following voluntary, open-label switch to viloxazine," said Price.

The researchers studied 50 patients who presented with ADHD combined type and had no other psychiatric, medical, or substance-related comorbidities or prior exposure to atomoxetine or viloxazine.

The study included 35 children (mean age, 11.9 ± 2.9 years; 94.3% male) and 15 adults (mean age, 29.3 ± 9.0 years; 73.3% male). Of these, 42.9% and 73.3%, respectively, were taking concurrent stimulants.

Patients received mean doses of atomoxetine once daily followed by viloxazine once daily after a 5-day washout period between the two drugs. Participants were seen weekly for titration and monitoring.

At baseline, the pediatric ADHD-Rating Scale 5 (ADHD-RS-5) and the Adult Investigator Symptoms Rating Scale (AISRS) were completed, then again after 4 weeks of treatment with atomoxetine (or upon earlier response or discontinuation due to side effects, whichever came first), and 5 days after discontinuing atomoxetine, which "re-established the baseline score." The same protocol was then repeated with viloxazine.

'Paradigm Shift'

At baseline, the total ADHD-RS-5 mean score was 40.3 ± 10.3. Improvements at 4 weeks were greater in viloxazine vs atomoxetine, with scores of 13.9 ± 10.2 vs 33.1 ± 12.1, respectively (t = -10.12, P < .00001). In inattention and hyperactivity/impulsivity, the t values were -8.57 and -9.87, respectively (both Ps < .0001).

Similarly, from the baseline total, AISRS mean score of 37.3 ± 11.8, improvements were greater on viloxazine vs atomoxetine, with scores of 11.9 ± 9.4 vs 28.8 ± 14.9, respectively (t = −4.18, P = .0009 overall; for inattention, t = −3.50, P > .004 and for hyperactivity/impulsivity, t = 3.90, P > .002).

By 2 weeks, 86% of patients taking viloxazine reported a positive response vs 14% when taking atomoxetine.

Side effects were lower in viloxazine vs atomoxetine, with a total of 36% of patients discontinuing treatment with atomoxetine due to side effects that included gastrointestinal upset, irritability, fatigue, and insomnia vs 4% who discontinued viloxazine due to fatigue.

Almost all participants (96%) preferred viloxazine over atomoxetine and 85% were able to taper off stimulant treatment following stabilization on viloxazine.

"These were not small differences," commented Richard Price. "These were clinically and statistically meaningful differences."

The findings could represent "a paradigm shift for the field" because "we always think of starting ADHD treatment with stimulants, but perhaps treatment with viloxazine could help patients to avoid stimulants entirely," he suggested.

Real-World Study

Commenting for Medscape Medical News, Greg Mattingly, MD, associate Clinical Professor, Washington University, St. Louis, Missouri, called it "a timely addition to the clinical literature where for the first time ever we have 2 non-stimulant options approved for adults with ADHD."

This real-world clinic study "yields many answers," said Mattingly, who is also the president-elect of the American Professional Society of ADHD and Related Disorders (APSARD) and was not involved with the study.

"Simply put, this real-world study of 50 clinic patients found that viloxazine ER had faster onset, was significantly more effective, and was preferred by 96% of patients as compared to atomoxetine," he said.

"Another intriguing part of the study that will be of high interest to both patients and providers was that, of those initially treated concurrently with stimulant and viloxazine ER, 85% were able to discontinue their stimulant medication," Mattingly added.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The op en access fee was funded by the investigators. Maxwell Z. Price certifies that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. Richard L. Price has received honoraria from AbbVie, Alkermes, Idorsia, Intra-Cellular Therapies, Janssen, Jazz, Lundbeck, Neuronetics, Otsuka, and Supernus. Mattingly reports being a consultant to AbbVie, Alkermes, Axsome, Biogen, Corium, Eisai, Intracellular, Ironshore, Janssen, Lundbeck, Neos, Neurocrine Biosciences, Noven, Otsuka, Redax, Revibe, Roche, Rhodes, Sage Therapeutics, Skye Therapeutics, Sunovion, Supernus, Takeda, Teva, Trispharma;  being on the speakers bureau for AbbVie, Alkermes, Corium, Eisai, Intracellular, Ironshore, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Sunovion, Supernus, Takeda,  Trispharma and receiving grant research/support from AbbVie, Acadia, Alkermes, Akili, Axsome, Beohringer, Biogen, Eisai, Emalex, Idorsia, Intracellular, Janssen, Karuna, Lumos Labs, Medgenics, NLS-1 Plarma AG, Redax, Relmada, Roche, Sage, Sirtsei, Sunovion, Supernus, Takeda, and Teva.

CNS Drugs. Published online July 10, 2023. Full text

https://www.medscape.com/viewarticle/994659