Neuroimaging Study of Risk Factors for Adolescent Bipolar Disorder

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).

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