Neuroimaging Study of Risk Factors for Adolescent Bipolar Disorder

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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Neuroimaging Study of Risk Factors for Adolescent Bipolar Disorder

Conditions
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Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Drug: mixed amphetamine salts-extended release (MAS-XR)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LR-MAS - Low-risk ADHD adolescents<br>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)<br>* 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.<br>* Other names: AdderallXR;|
| Experimental: HR-MAS - High-risk ADHD adolescents<br>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)<br>* 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.<br>* Other names: AdderallXR;|
| Placebo Comparator: HR-P - High-risk ADHD on Placebo<br>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<br>* Pills with no medication in it<br>|
| No Intervention: HC (Healthy Controls)<br>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?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADHD