Stimulant vs Non-stimulant Treatments for ADHD

(MPH-ATX Trial)

Overseen By Iliyan Ivanov, MD

Age: < 18

Sex: Any

Trial Phase: Phase 4

Sponsor: Icahn School of Medicine at Mount Sinai

Must not be taking: Stimulants

Disqualifiers: Neurological illness, Head injury, Psychiatric disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 3 weeks

44 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how two different ADHD medications, one stimulant (Methylphenidate) and one non-stimulant (Atomoxetine), affect the brain's reward system in children. Researchers will use brain scans (fMRI) to identify differences in how these medications work, particularly in those with additional conditions like Oppositional Defiant Disorder (ODD) or Conduct Disorder (CD). Participants should be children aged 7-12 diagnosed with ADHD and possibly ODD or CD, who have not previously received stimulant treatment. As a Phase 4 trial, this study focuses on understanding how these FDA-approved and effective treatments can benefit more patients.

Will I have to stop taking my current medications?

If you are currently taking stimulant medications, you will need to stop as prior or current treatment with stimulants is not allowed. If you are on non-stimulant medications, you must stop taking them for 2 weeks before the study begins.

What is the safety track record for these treatments?

Research has shown that both atomoxetine and methylphenidate have been thoroughly studied for treating ADHD and are generally considered safe.

For atomoxetine, many studies indicate it significantly improves ADHD symptoms. However, about 37.6% of patients experienced some side effects, which are not uncommon.

Methylphenidate is also considered safe for long-term use, with research showing no major risk of serious heart problems. It is usually well-tolerated by most people, even over extended periods.

Both medications are approved by the FDA for treating ADHD, indicating they have passed strict safety tests. While they can cause side effects, these are usually manageable and not severe for most people. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for ADHD because they offer different approaches to managing the condition. Methylphenidate, a stimulant, is a well-known treatment that works by increasing certain chemicals in the brain to improve attention and focus. Atomoxetine, on the other hand, is a non-stimulant that targets norepinephrine, a different brain chemical, and may offer benefits for those who can't tolerate stimulants. This variety in treatment options means more personalized care for individuals with ADHD, potentially leading to better outcomes with fewer side effects.

What evidence suggests that this trial's treatments could be effective for ADHD?

This trial will compare the effectiveness of atomoxetine and methylphenidate in treating ADHD. Research has shown that both atomoxetine and methylphenidate effectively manage ADHD. Studies have found that atomoxetine improves attention and reduces hyperactivity better than a placebo, with benefits increasing over time and showing moderate improvements after six months. In contrast, methylphenidate helps children and teens manage ADHD symptoms effectively, with noticeable improvements after 12 weeks. Both medications reduce ADHD symptoms and enhance the quality of life for those affected. ^{2 6 7 8 9}

Who Is on the Research Team?

Iliyan Ivanov, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Jeffrey Newcorn, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Are You a Good Fit for This Trial?

This trial is for children aged 7-12 with ADHD, who may also have ODD or CD. They must be drug-naive to stimulants, pre-pubertal, and able to undergo fMRI scans without issues like claustrophobia. Children with a history of significant head injury, substance exposure in utero, suicidal behavior, low IQ (<75), major psychiatric disorders other than ADHD/ODD/CD or metal implants that can't be removed are excluded.

Inclusion Criteria

I am in the early stages of puberty.

I am between 7 and 12 years old.

ADHD as determined by computerized DISC (C-DISC) parent interview

Exclusion Criteria

You have metal in your body that cannot be taken out, like braces or a metal plate.

I have not taken stimulant medications recently, but non-stimulants are okay.

I don't have conditions like severe fear of enclosed spaces or extreme obesity that prevent me from undergoing scans.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either methylphenidate or atomoxetine to assess effects on brain reward systems

3 weeks

Weekly visits for medication administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Atomoxetine
• Methylphenidate

Trial Overview

The study is testing the effects of two FDA-approved medications for ADHD: Atomoxetine (a non-stimulant) and Methylphenidate (a stimulant). It aims to see how these drugs affect brain reward systems in youth with ADHD by using fMRI imaging technology.

How Is the Trial Designed?

Group I: Methylphenidate Active Control 1 Intervention

0.5 mg/kg for 1 week and 1 mg/kg for 2 weeks

Group II: Atomoxetine Active Control 1 Intervention

0.5 mg/kg for 1 week and 1 mg/kg for 2 weeks

Atomoxetine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in European Union as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in Canada as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Who Is Running the Clinical Trial?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Published Research Related to This Trial

Longer-acting stimulant medications and the nonstimulant atomoxetine have been found to be as effective and safe as traditional short-acting treatments for ADHD, offering similar efficacy with the added benefit of convenience.

These newer treatments provide greater clinical utility by reducing the frequency of dosing, which can improve adherence and flexibility in managing ADHD symptoms, although more direct comparisons between these options are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Innovations in attention-deficit/hyperactivity disorder pharmacotherapy: long-acting stimulant and nonstimulant treatments. Stein, MA.[2005]

The review covers the safety and efficacy of various extended-delivery stimulant medications and atomoxetine for treating ADHD, including nine methylphenidate and five amphetamine formulations, with a focus on long-acting options that can be taken once daily.

Most of the reviewed medications, including six methylphenidate and three amphetamine formulations, are designed for extended release, which may improve adherence and management of ADHD symptoms throughout the day.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy of attention-deficit hyperactivity disorder in children and adolescents: update on new stimulant preparations, atomoxetine, and novel treatments. Prince, JB.[2015]

Atomoxetine, a non-stimulant medication for adults with ADHD, was associated with a higher rate of treatment discontinuation compared to placebo, indicating a poor benefit-risk balance (Odds Ratio = 1.39).

While atomoxetine showed modest efficacy in reducing ADHD symptoms, it also had a significantly higher rate of discontinuation due to adverse events compared to placebo (Odds Ratio = 2.57), suggesting caution in its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atomoxetine for attention deficit hyperactivity disorder in the adulthood: a meta-analysis and meta-regression. Cunill, R., Castells, X., Tobias, A., et al.[2018]

A meta-analysis of nine trials involving 2762 participants found that both methylphenidate and atomoxetine have comparable efficacy in treating ADHD, with no significant difference in overall effectiveness (SMD=0.09).

However, OROS methylphenidate showed a significant advantage over atomoxetine, suggesting it may be a better first-line treatment option for children and adolescents with ADHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis. Hanwella, R., Senanayake, M., de Silva, V.[2022]

Atomoxetine is the only nonstimulant medication approved in the U.S. for treating ADHD, providing an alternative for patients who do not respond to or cannot tolerate traditional stimulant treatments.

The review discusses atomoxetine's mechanism of action as a norepinephrine reuptake inhibitor, along with its pharmacokinetics, metabolism, and demonstrated efficacy and safety in acute clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atomoxetine--treatment of attention deficit hyperactivity disorder: beyond stimulants. Thomason, C., Michelson, D.[2019]

In a 5-year study involving 2103 children with ADHD, those treated with methylphenidate experienced significantly fewer adverse events (AEs) compared to those treated with atomoxetine, indicating a better safety profile for methylphenidate.

Overall, 26.8% of participants reported mild AEs and 3.9% reported severe AEs, with atomoxetine associated with higher rates of both mild and severe AEs, including gastrointestinal and neuropsychiatric issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Methylphenidate and Atomoxetine in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): Data from the Italian National ADHD Registry. Cortese, S., Panei, P., Arcieri, R., et al.[2018]

Atomoxetine has been evaluated for safety and efficacy in treating ADHD in over 4000 patients across various studies, including randomized controlled trials and longitudinal studies.

Recent large cohort studies indicate that atomoxetine is both effective and well-tolerated for children and adolescents, providing important insights into its long-term safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atomoxetine in the treatment of children and adolescents with attention deficit hyperactivity disorder. Kohn, MR., Tsang, TW., Clarke, SD.[2021]

In a study of 84 ADHD patients aged 5 to 18 treated for about 8 months, both atomoxetine and stimulant medications resulted in a modest improvement in quality of life, with no significant differences between the two treatments.

Patients who started with lower quality of life scores experienced the most improvement, suggesting that those with greater initial challenges may benefit more from either treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Both atomoxetine and stimulants improve quality of life in an ADHD population treated in a community clinic. Bastiaens, L.[2021]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5069588/

Atomoxetine Increased Effect over Time in Adults ...

Atomoxetine treatment in adults with ADHD was associated with small effect sizes after 4 weeks and moderate effect sizes by 6 months of treatment.

2.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S1876201815300654

The efficacy of atomoxetine in treating adult attention deficit ...

The results indicate that atomoxetine is far superior to placebo in treating adult ADHD and significantly more efficacious in treating inattention than ...

3.

acamh.onlinelibrary.wiley.com

acamh.onlinelibrary.wiley.com/doi/10.1002/jcv2.70022

Systematic review: Safety and efficacy of atomoxetine in ...

Results demonstrated a significant improvement in ADHD-RS scores for the Atomoxetine group than the placebo group. Likewise, the Atomoxetine ...

4.

eneuro.org

eneuro.org/content/12/4/ENEURO.0371-24.2025

Clinical Efficacy of Atomoxetine Hydrochloride Combined ...

It is also demonstrated to improve inattention and hyperactivity/impulsivity scores in patients with ADHD (Micoulaud-Franchi et al., 2014).

5.

cureus.com

cureus.com/articles/326373-effectiveness-of-atomoxetine-and-stimulant-combination-in-attention-deficithyperactivity-disorder-adhd-treatment-a-systematic-review

Effectiveness of Atomoxetine and Stimulant Combination in ...

Mean CGI-S score was significantly reduced (P = 0.003) from before CMAP (5.08) compared to after CMAP (3.08), with 75% of patients (9 out of 12) ...

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/15766294/

Long-term, open-label study of the safety and efficacy ...

Results: Significant improvement was noted with atomoxetine therapy, with mean CAARS-Inv:SV total ADHD symptom scores decreasing 33.2% from 29.2 (baseline of ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8863678/

The Mechanism, Clinical Efficacy, Safety, and Dosage ...

The results showed that the short-term atomoxetine treatment can significantly improve the core symptoms. As objectively measured by performance-based tests, ...

8.

sciencedirect.com

sciencedirect.com/science/article/pii/S0924977X12001988

Long-term efficacy and safety of treatment with stimulants ...

At 24 weeks, the response rate was greater for atomoxetine (68%) compared with placebo (42%; p<0.001). This yields an NNT of 4. On the CGI-ADHD-S, improvement ...

9.

mdpi.com

mdpi.com/2227-9067/11/2/163

Atomoxetine Treatment of Attention Deficit/Hyperactivity ...

The primary endpoint was the evaluation of the safety profile of atomoxetine. In total, 50 patients (37.6%) experienced adverse events (AEs), ...