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

Trial Summary

What is the purpose of this trial?

The study team will examine the effects of FDA approved stimulant and non-stimulant medications for ADHD, among youth with ADHD and with and without Oppositional Defiant Disorder (ODD) or Conduct Disorder (CD), on reward systems of the brain using fMRI.

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 data supports the effectiveness of stimulant and non-stimulant drugs for treating ADHD?

Research shows that both stimulant drugs like methylphenidate and non-stimulant drugs like atomoxetine are effective in treating ADHD. Studies have found that these drugs can improve symptoms and quality of life for people with ADHD, with long-acting versions offering more convenience and similar effectiveness to short-acting ones. ^{1 2 3 4 5}

What safety data exists for stimulant and non-stimulant treatments for ADHD?

Research shows that both stimulant medications like methylphenidate and non-stimulant medications like atomoxetine have been studied for safety in treating ADHD. These studies, involving thousands of patients, indicate that both types of medications are generally safe, though they can have side effects. Long-term studies have also been conducted to assess their safety over time. ^{1 2 5 6 7}

How do the drugs atomoxetine and methylphenidate differ in treating ADHD?

Atomoxetine is a non-stimulant drug that works by affecting norepinephrine (a brain chemical), while methylphenidate is a stimulant that affects dopamine (another brain chemical). Atomoxetine is often used when stimulants are not effective or tolerated, and both drugs offer long-acting formulations for more convenient once-daily dosing. ^{1 2 3 5 8}

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

Eligibility Criteria

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.

Signed consent/assent

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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 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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

Atomoxetine for attention deficit hyperactivity disorder in the adulthood: a meta-analysis and meta-regression. [2018]

3. England 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

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

5. United States pubmed.ncbi.nlm.nih.gov

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

6. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atomoxetine in the treatment of children and adolescents with attention deficit hyperactivity disorder. [2021]

7. New Zealand 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. [2018]

8. Spain pubmed.ncbi.nlm.nih.gov

Atomoxetine--treatment of attention deficit hyperactivity disorder: beyond stimulants. [2019]