Clinical trial NCT01678209: Imaging Stimulant and Non Stimulant Treatments for ADHD: A Network Based Approach
Official title: Imaging Stimulant and Non Stimulant Treatments for ADHD: A Network Based Approach
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Attention Deficit Hyperactivity Disorder
ADHD
Keywords: Attention Deficit Hyperactivity Disorder
Stimulant
Non-stimulant
Drug
Methylphenidate
Atomoxetine
Strattera
Concerta
MACRO
Medication
Treatment
Youth
Adolescent
Functional Magnetic Resonance Imaging
Brain scan
Imaging
Response inhibition
Inattentive
Hyperactive
Combined
Medication Treatment
Brain Imaging
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2012-09-03
Enrollment: 127
Sex: ALL
Minimum age (years): 7
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The growing number of medications used to treat attention-deficit/hyperactivity disorder (ADHD) raises important questions about whether different medications have similar or different therapeutic mechanisms of action. We have recently shown that the stimulant methylphenidate (MPH) and the non-stimulant atomoxetine (ATX) produce clinical improvement via a common mechanism in motor cortex, and distinct actions in frontostriatal and midline cingulate-precuneus regions. These exciting findings offer a window into the common and unique neurophysiological mechanisms of response to stimulant and non-stimulant treatments. However, the interpretation and clinical utility of these results would be greatly enhanced by in-depth investigation of the impact of the two treatments on relevant neural networks, and analyses which evaluate whether improvement is achieved via normalization or other adaptive changes in brain function.

Detailed description: The specific aims of this project are to use functional magnetic resonance imaging (fMRI) to determine the significance of activation changes over treatment related to clinical improvement, and the impact of treatment on neural connectivity within and between the anti-correlated frontostriatal 'task-positive' circuit and cingulate-precuneus 'task-negative' network. Our central hypotheses are that clinical improvement is associated with: (i) normalization of reduced connectivity of regions within the 'task-positive' network, with resultant increased inhibition of motor cortex, and (ii) normalization of low task-related connectivity in regions within the task-negative network for MPH and the 'task-positive' network for ATX.

This research proposes to test a model which posits a neurophysiological basis of mechanisms of response to stimulant and non-stimulant medications, and fits with our long term objectives of being able to match treatments to individual patients. Testing this model requires large samples of youth scanned using fMRI before and after treatment, and matched healthy controls also scanned twice. We will use an innovative network-based approach to study the effects of treatment, building on results from our current fMRI treatment study, and incorporating new theoretical approaches to understanding ADHD and its treatment.

Eligibility criteria: Inclusion Criteria:

General inclusion criteria for subjects with ADHD and healthy controls are:

* aged 7-17 years;
* Wechsler Intelligence Scale for Children (WISC) scores ≥ 75;
* informed consent and assent to study participation.

Specific inclusion criteria for youth with ADHD are:

* diagnosis of ADHD, any subtype, determined by Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Versions (K-SADS-PL);
* ADHD Rating Scale-IV-Parent Version: Investigator Administered (ADHD-RSIV) total score ≥ 1.5 SD above age and gender means for subtype
* Clinical Global Impressions-ADHD-Severity (CGI-S) score \> 4;
* ADHD must be the primary diagnosis and focus of treatment, and the treatments offered in the study must not be contraindicated for the comorbid disorder.

Exclusion Criteria:

General exclusion criteria are:

* history of head injury with loss of consciousness or any CNS disease that is likely to affect brain function;
* diagnosis of autism or pervasive developmental, psychotic, major mood, and Tourette's disorder;
* alcohol or drug abuse in the past 3 months or a positive urinary toxic screen on initial evaluation;
* use of psychotropic medication within 2 weeks of the study (8 weeks for fluoxetine);
* pre-existing medical or psychological condition which precludes being in the scanner (e.g., claustrophobia, morbid obesity);
* metal in the body that precludes scanning (e.g., braces, metal plate);
* positive urine pregnancy test.

Specific exclusion criteria for the treatment trial include:

* previous unsuccessful trial of MPH or ATX that was adequately dosed (≥ 1 mg/kg for MPH or 1.0 mg/kg for ATX) and of adequate duration (≥ 4 weeks);
* abnormal findings on physical exam, or vital signs
* pulse and blood pressure \> 95% of age and gender mean;
* inability to swallow capsules;
* weight is \< 20 kg or \> 85 kg.

Specific exclusion criteria for control youth include:

* no past history or current diagnosis of any psychiatric disorder, determined by the K-SADS-PL interview;
* ADHD-RS-IV and CBCL scores for each symptom domain ≤ 1 SD of age and gender means.

Primary outcomes:
measure: Percentage of Correct Inhibition in Participants Assessed With the Go-No go Task
timeFrame: Baseline and at 6 weeks
Secondary outcomes:
measure: Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (ADHD-RS)
timeFrame: 8 weeks
measure: Clinical Global Impressions-Severity (CGI-S)
timeFrame: up to 6 weeks
measure: Response Time in Attention Networks Test (ANT)
timeFrame: baseline and at 6 weeks
measure: Continuous Performance Test (CPT)
timeFrame: baseline and at 6 weeks
measure: Digit Span
timeFrame: baseline and at 6 weeks
measure: Finger Windows
timeFrame: baseline and at 6 weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Jeffrey Newcorn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Icahn School of Medicine at Mount Sinai
name: Kurt Schulz, PhD
role: PRINCIPAL_INVESTIGATOR
References: