Imaging Stimulant and Non Stimulant Treatments for ADHD: A Network Based Approach

• ClinicalTrials.gov Identifier: NCT01678209
• Recruitment Status: Completed
• First Posted: September 3, 2012
• Results First Posted: July 24, 2020
• Last Update Posted: July 24, 2020
• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): Jeffrey Newcorn, Icahn School of Medicine at Mount Sinai

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Attention Deficit Hyperactivity Disorder; ADHD	Other: fMRI scans; Drug: Atomoxetine arm; Drug: Methylphenidate arm	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 127 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Imaging Stimulant and Non Stimulant Treatments for ADHD: A Network Based Approach
• Study Start Date: October 2012
• Actual Primary Completion Date: April 30, 2018
• Actual Study Completion Date: April 30, 2018

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: fMRI scans; Healthy Control Group: will receive initial evaluation, and 2 fMRI (functional magnetic resonance imaging) scans each 6-8 weeks apart	Other: fMRI scans; 2 fMRI scans 6-8 weeks apart
Experimental: Atomoxetine arm; These subjects will receive initial evaluation and baseline fMRI scan, flexible dose titration with atomoxetine for 6-8 weeks, and fMRI postscan, with optional post study stabilization visits.	Other: fMRI scans; 2 fMRI scans 6-8 weeks apart; Drug: Atomoxetine arm; Flexible dose titration with atomoxetine prescribed at weekly visits for 6-8 weeks; Other Names: Strattera; ATX
Experimental: Methylphenidate arm; Subjects will receive initial evaluation, baseline fMRI scan, flexible dose titration with methylphenidate (Concerta) for 6-8 weeks, and fMRI scan post treatment.	Other: fMRI scans; 2 fMRI scans 6-8 weeks apart; Drug: Methylphenidate arm; Flexible dose titration with methylphenidate for 6-8 weeks, with optional post study stabilization visits.; Other Names: Concerta; MPH

Outcome Measures

Primary Outcome Measures :

1. Percentage of Correct Inhibition in Participants Assessed With the Go-No go Task [ Time Frame: Baseline and at 6 weeks ]
   Comparison of Go-Nogo at 6 weeks from baseline. Performance on a go-nogo task inside the scanner (fMRI). In the go/no-go task, participants respond to certain stimuli ("go" stimuli) and make no response for others ("no-go" stimuli).

Secondary Outcome Measures :

1. Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (ADHD-RS) [ Time Frame: 8 weeks ]
   ADHD-RS is an 18-item list of core ADHD symptoms, each item are scored on a 4-point scale from 0-3, with total 0-54, with higher score indicating more symptoms.
2. Clinical Global Impressions-Severity (CGI-S) [ Time Frame: up to 6 weeks ]
   a clinician rated measure of symptom severity. CGI-S is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
3. Response Time in Attention Networks Test (ANT) [ Time Frame: baseline and at 6 weeks ]
   A neuropsychological assessment of attention compared at 6 weeks from baseline by looking at response time. The ANT is a task designed to test three attentional networks in children and adults: alerting, orienting, and executive control. The response time were summed.
4. Continuous Performance Test (CPT) [ Time Frame: baseline and at 6 weeks ]
   A neuropsychological assessment of attention compared at 6 weeks from baseline. CPT is a task-oriented computerized assessment of attention-related problems.This score indicates the number of times the client responded but no target was presented. A fast reaction time and high commission error rate points to difficulties with impulsivity. A slow reaction time with high commission and omission errors, indicates inattention in general. Scores are compared with the normative scores for the age, group and gender of the person being tested and represented as a commissioned T-score. The T-score indicates the degree to which performance in CPT task is higher or lower than the performance of a healthy individual matched in age. A T-score of 50 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of more attention-related problems.
5. Digit Span [ Time Frame: baseline and at 6 weeks ]
   A cognitive/neuropsychological measure of auditory/verbal working memory compared at 6 weeks from baseline. Digit Span. Memory span is the longest list of items that a person can repeat back in correct order immediately after presentation on 50% of all trials. Items may include words, numbers, or letters. The task is known as digit span when numbers are used. Memory span is a common measure of short-term memory. A digit-span task is used to measure working memory's number storage capacity.The item score is the sum of the scores on the two trials for that item (range=0-2). The total raw score for backwards digit span is the sum of the item scores; maximum backwards digit span total raw score is 0-16 points. Higher score indicates better health outcomes.
6. Finger Windows [ Time Frame: baseline and at 6 weeks ]
   A neuropsychological measure of motor skill and visual-spatial working memory compared at 6 weeks from baseline. The Finger Windows subtest is a measure of nonverbal, rote sequential recall. scaled scores ranging from 1 to 19, with higher score indicating better attention or concentration.

Eligibility Criteria

• Ages Eligible for Study: 7 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

United States, New York

Icahn School of Medicine at Mount Sinai

New York, New York, United States, 10029

Sponsors and Collaborators

Icahn School of Medicine at Mount Sinai

National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Jeffrey Newcorn, MD; Icahn School of Medicine at Mount Sinai
• Principal Investigator: Kurt Schulz, PhD; Icahn School of Medicine at Mount Sinai

  Study Documents (Full-Text)

Documents provided by Jeffrey Newcorn, Icahn School of Medicine at Mount Sinai:

Study Protocol  [PDF] May 6, 2019

Statistical Analysis Plan  [PDF] May 22, 2019

More Information

• Responsible Party: Jeffrey Newcorn, Director Division of Child and Adolescent Psychiatry, Associate Professor Psychiatry and Pediatrics, Medical Director Center for Excellence for ADHD and Related Disorders, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT01678209
• Other Study ID Numbers: GCO 11-0161; 5R01MH095766-02 ( U.S. NIH Grant/Contract )
• First Posted: September 3, 2012
• Results First Posted: July 24, 2020
• Last Update Posted: July 24, 2020
• Last Verified: July 2020

Keywords provided by Jeffrey Newcorn, Icahn School of Medicine at Mount Sinai:

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

Additional relevant MeSH terms:

Hyperkinesis; Attention Deficit Disorder with Hyperactivity; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders; Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Methylphenidate; Atomoxetine Hydrochloride; Central Nervous System Stimulants; Physiological Effects of Drugs; Dopamine Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Dopamine Agents; Neurotransmitter Agents; Adrenergic Uptake Inhibitors; Adrenergic Agents