Stimulant vs. Non-stimulant Treatments and Reward Processing in Drug-naive Youth at SUD Risk (MPH-ATX)

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.

Study Overview

• Status: Recruiting
• Conditions: ADHD; Attention Deficit Hyperactivity Disorder
• Intervention / Treatment: Drug: Methylphenidate; Drug: Atomoxetine

Detailed Description

Longitudinal studies have shown that childhood Attention Deficit/Hyperactivity Disorder (ADHD) and child disruptive behavior disorders play an important role in the development of later Substance Use Disorders (SUD). Although available evidence suggests that abnormal reward processing is likely to mediate vulnerability for addiction, the functioning of the brain reward systems in at-risk individuals preceding the exposure to drugs remains largely unknown. Better understanding the baseline characteristics of reward processing in drug-naïve individuals at risk for later SUD is an important initial step in refining our knowledge of the neurobiological basis of addiction. Reward processing in at-risk individuals may be further influenced by exposure to first-line treatments (e.g. methylphenidate (MPH)) for ADHD that also happen to be controlled substances.

Findings from animal research have raised the possibility that stimulants such as methylphenidate (MPH) may have "sensitization" effects - which prime the brain reward system for enhanced responding to the rewarding effects of abusable substances, whereas non-stimulants such as atomoxetine (ATX) may diminish drug self-administration. However, no studies have examined the purported different effects of stimulants vs. non-stimulants on the brain reward system utilizing a targeted biomarker approach linked to an a priori model, which focuses on intermediate phenotypes. Such research could provide important knowledge regarding the biological basis of addiction vulnerability and aid in the development of preventive interventions.

This proposal will provide pilot data for the hypotheses that stimulant and non-stimulant medications have differential effects on activation in the brain reward system in High Risk (HR) youth, and that differences activation will be related to changes in measures of reward sensitivity on psychometric tests. The study team believes that this protocol is uniquely innovative in its approach to study drug-naïve children at the highest levels of risk for SUD, thus providing an opportunity to delineate differential effects of medication treatment in relation to SUD risk. This research is also significant since it will be the first neuroimaging study to assess the biological correlates of the effects of stimulants on reward sensitivity in HR children, and especially in relation to purported changes in reward processing.

• Study Type: Interventional
• Enrollment (Anticipated): 44
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Beth Krone, PhD; Phone Number: 212-241-8012; Email: beth.krone@mssm.edu
• Study Contact Backup: Name: Jeffrey Newcorn, MD

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Icahn School of Medicine at Mount Sinai
      • Contact: Beth Krone, PhD; Phone Number: 212-241-8012; Email: beth.krone@mssm.edu
      • Principal Investigator: Jeffrey Newcorn, MD
      • Principal Investigator: Iliyan Ivanov, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 12 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pre-pubertal (e.g. Tanner stage 1 or 2)
• Age 7-12 inclusive
• Signed consent/assent
• Parent communicates sufficiently in English to provide informed consent and complete assessment instruments;
• ADHD as determined by computerized DISC (C-DISC) parent interview
• ADHD-Rating Scale-5 total score (interview with parent )
• SNAP ADHD total score (teacher) of 1.5 SD > age/sex norms
• CD or severe ODD: CD or ODD + 2 symptoms of CD on C-DISC
• SNAP ODD/CD subscale (parent and teacher) 1.5 SD > age/sex norms

Exclusion Criteria:

• Major neurological/medical illness
• History of head injury
• Fetal exposure to alcohol/drugs
• Diagnosis of major psychiatric disorder (e.g., schizophrenia, bipolar disorder, major depression, generalized anxiety, social phobia, Tourette's Disorder, PTSD, autism spectrum disorder)
• Current suicidal ideation or past history of suicide attempt
• Wechsler Abbreviated Scale of Intelligence (WASI)75 score <75
• Prior or current treatment with stimulants (prior or current treatment with non-stimulants is permitted, but participants must be off medication for 2 weeks at baseline)
• Current or past alcohol/drug use (DISC interview; urine toxicology)
• Psychological or medical condition which precludes being in the scanner (e.g., claustrophobia, morbid obesity)
• Metal in the body that cannot be removed (e.g., braces, metal plate)
• Visual disturbances that may impair task performance
• Precocious puberty (e.g. Tanner stage >2) or pregnancy

Notes:

• History of SUD in a 1st degree relative is permitted, and is expected in ~1/2 of the subjects
• Ongoing psychosocial treatment is allowed but should not be initiated during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Methylphenidate; 0.5 mg/kg for 1 week and 1 mg/kg for 2 weeks	Drug: Methylphenidate; stimulant medication; Other Names: MPH
Active Comparator: Atomoxetine; 0.5 mg/kg for 1 week and 1 mg/kg for 2 weeks	Drug: Atomoxetine; non-stimulant medication; Other Names: ATX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
fMRI Measure	Bold activation change within the reward system (e.g., ventral striatum, insula and orbitofrontal cortex)	3 Weeks

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Iliyan Ivanov, MD, Icahn School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start (Actual): June 4, 2019
• Primary Completion (Anticipated): November 1, 2024
• Study Completion (Anticipated): November 1, 2024

Study Registration Dates

• First Submitted: December 18, 2018
• First Submitted That Met QC Criteria: December 18, 2018
• First Posted (Actual): December 20, 2018

Study Record Updates

• Last Update Posted (Actual): April 18, 2023
• Last Update Submitted That Met QC Criteria: April 14, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Methylphenidate; Atomoxetine; MPH; ATX; fMRI Study; Reward System; Substance Abuse Risk
• Additional Relevant MeSH Terms: Mental Disorders; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Attention Deficit Disorder with Hyperactivity; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Adrenergic Uptake Inhibitors; Methylphenidate; Atomoxetine Hydrochloride
• Other Study ID Numbers: GCO 17-0423; 1R21DA045218-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No