Neuroimaging Study of Risk Factors for Adolescent Bipolar Disorder (NERF)

The main purpose of this study is to see the affects of the study medication called mixed amphetamine salts-extended release (MAS-XR) on brain function by taking brain pictures. The researchers also want to see if MAS-XR makes your child more or less likely to develop problems like acting out (i.e. periods of irritability, agitation, aggression).

MAS-XR is approved by the United States Food and Drug Administration (FDA) to treat attention deficit hyperactivity disorder (ADHD) in adults, children and adolescents.

Study Overview

• Status: Completed
• Conditions: Attention Deficit Hyperactivity Disorder
• Intervention / Treatment: Drug: mixed amphetamine salts-extended release (MAS-XR); Drug: Placebo

Detailed Description

A 12-week prospective study of two groups of adolescents (ages 10-18 years) with attention deficit/hyperactivity disorder (ADHD); 1) ADHD adolescents with a first degree relative with bipolar disorder ("high-risk") and 2) ADHD adolescents without any first or second degree-relatives with a mood disorder ("low-risk"). Patients will be evaluated using diagnostic interviews and symptom ratings, will receive neuroimaging scans (fMRI, DTI, 1H MRS), and will then be assigned to treatment. Low-risk ADHD adolescents (n=60) will receive treatment with open-label mixed amphetamine salts-extended release (MAS-XR), which is approved by the United States Food and Drug Administration (USFDA) for the treatment of ADHD and is a commonly prescribed psychostimulant medication for adolescents with ADHD. High-risk ADHD adolescents will be randomized to double-blind treatment with MAS-XR (n=60) or placebo (n=60). Following initiation of treatment, the ADHD adolescents will have regularly scheduled visits during which symptom and tolerability ratings will be performed. Healthy subjects (n=60) will be recruited from the community and will not receive medication but will undergo magnetic resonance imaging (MRI) scans at the same intervals to assess normal variability in imaging parameters between time points as well as to adjust and interpret comparisons within patients (i.e., whether patient values are changing toward or away from those of healthy adolescents). Neuroimaging (fMRI, DTI,1H MRS) evaluations will be performed at baseline and Week 12 (or termination).

• Study Type: Interventional
• Enrollment (Actual): 153
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati, Department of Psychiatry and Behavioral Neuroscience

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Ages 10-18years old
• If female, not pregnant
• Fluent in English
• No contraindication to an MRI scan (e.g., braces or claustrophobia)
• An IQ > 80
• No unstable or major medical or neurological illness
• No lifetime DSM-5 substance use disorder
• Lives <100 miles from the University of Cincinnati
• Provision of written informed consent/assent
• At least one biological first degree relative with bipolar I disorder ('high-risk' only)
• No first- or second-degree relative with a mood or psychotic disorder ('low-risk' and healthy controls only) with the exception of late onset depressive disorders.
• No lifetime DSM-5 Axis I disorder (other than specific phobias, healthy controls only).
• No medications with CNS effects within 5 half-lives from baseline MR scan (healthy controls only).

Inclusion criteria for 'high-risk' and 'low-risk' ADHD subjects :

• Meets DSM-5 criteria for ADHD, inattentive, hyperactive/impulsive, or combined type
• No exposure to psychostimulants or ADHD medications in the 3 months prior to baseline
• No lifetime exposure to mood stabilizers or antipsychotic medications
• No concomitant use of any psychotropic medication other than study medications during study participation
• No history of intolerance, hypersensitivity, or non-response to MAS-XR
• No comorbid mood, anxiety, conduct, eating or psychotic disorder that in the opinion of the primary investigator is the current and primary focus of treatment. No Tourette's disorder, chronic tic disorder, or autism spectrum disorder.
• No clinically significant ECG or blood pressure abnormalities
• No family history of sudden death or ventricular arrhythmia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LR-MAS - Low-risk ADHD adolescents; ADHD adolescents without any first or second degree-relatives with bipolar disorder. Low-risk ADHD adolescents (n=60) will receive treatment with open-label mixed amphetamine salts-extended release (MAS-XR), which is approved by the United States Food and Drug Administration (USFDA) for the treatment of ADHD and is a commonly prescribed psychostimulant medication for adolescents with ADHD.	Drug: mixed amphetamine salts-extended release (MAS-XR); MAS-XR is a psychostimulant medication composed of amphetamine and dextroamphetamine, has been systematically studied in adolescents with ADHD, and is FDA-approved for the treatment of ADHD in adolescents.; Other Names: AdderallXR
Experimental: HR-MAS - High-risk ADHD adolescents; ADHD adolescents with a parent with bipolar disorder ("high-risk"). High-risk ADHD adolescents will be randomized to double-blind treatment with MAS-XR (n=60) or placebo (n=60). The subjects in this group will receive mixed amphetamine salts-extended release( MAS-XR), which is approved by the United States Food and Drug Administration (USFDA) for the treatment of ADHD and is a commonly prescribed psychostimulant medication for adolescents with ADHD.	Drug: mixed amphetamine salts-extended release (MAS-XR); MAS-XR is a psychostimulant medication composed of amphetamine and dextroamphetamine, has been systematically studied in adolescents with ADHD, and is FDA-approved for the treatment of ADHD in adolescents.; Other Names: AdderallXR
Placebo Comparator: HR-P - High-risk ADHD on Placebo; ADHD adolescents with a parent with bipolar disorder ("high-risk"). High-risk ADHD adolescents will be randomized to double-blind treatment with MAS-XR (n=60) or placebo (n=60). Following initiation of treatment, the ADHD adolescents will have regularly scheduled visits during which symptom and tolerability ratings will be performed.	Drug: Placebo; Pills with no medication in it
No Intervention: HC (Healthy Controls); Healthy subjects (n=60) will be recruited from the community and will not receive medication but will undergo MR scans at the same intervals to assess normal variability in imaging parameters between time points as well as to adjust and interpret comparisons within patients (i.e., whether patient values are changing toward or away from those of healthy adolescents). Neuroimaging evaluations will be performed at baseline and Week 12 (or termination).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-endpoint change in prefrontal-amygdala functional connectivity by fMRI.	Using functional magnetic resonance imaging (fMRI), change in prefrontal-amygdala functional connectivity will be determined by contrasting baseline and endpoint blood oxygen level-dependent (BOLD) activity in the amygdala and prefrontal cortex (BA47) during performance of the CPT-END task, and determining the prefrontal-amygdala interrelationship using a seed-region (amygdala) based functional connectivity analysis.	Baseline and up to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-endpoint change in uncinate fasciculus white matter integrity by DTI	Change in uncinate fasciculus white matter integrity will be determined by contrasting baseline and endpoint fractional anisotropy using diffusion tensor imaging (DTI).	Baseline and up to 12 weeks
Baseline-endpoint change in glutamate (Glu) and N-acetyl aspartate (NAA) concentrations in the prefrontal cortex (BA47) by 1H MRS.	This is a composite measure of change in right and left prefrontal cortex (BA47) Glu and NAA concentrations (mM). It will be determined by contrasting baseline and endpoint levels using proton magnetic resonance spectroscopy (1H MRS).	Baseline and up to 12 weeks

Collaborators and Investigators

• Sponsor: University of Cincinnati
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Study Director: Robert McNamara, PhD, University of Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): August 1, 2022
• Study Completion (Actual): December 1, 2022

Study Registration Dates

• First Submitted: June 15, 2015
• First Submitted That Met QC Criteria: June 18, 2015
• First Posted (Estimated): June 23, 2015

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 19, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: ADHD
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Bipolar and Related Disorders; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Bipolar Disorder; Attention Deficit Disorder with Hyperactivity; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Sympathomimetics; Adrenergic Uptake Inhibitors; Amphetamine
• Other Study ID Numbers: DelBello/McNamara Neuroimaging; R01MH097818-01A1 (U.S. NIH Grant/Contract)