ADHD, Attention Deficit Hyperactivity Disorder
Conditions
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
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.
Interventions
OTHERfMRI scans
2 fMRI scans 6-8 weeks apart
DRUGAtomoxetine arm
Flexible dose titration with atomoxetine prescribed at weekly visits for 6-8 weeks
DRUGMethylphenidate arm
Flexible dose titration with methylphenidate for 6-8 weeks, with optional post study stabilization visits.
Sponsors
National Institute of Mental Health (NIMH)
Icahn School of Medicine at Mount Sinai
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Years to 17 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Correct Inhibition in Participants Assessed With the Go-No go Task | 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
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impressions-Severity (CGI-S) | 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. |
| Response Time in Attention Networks Test (ANT) | 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. |
| Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (ADHD-RS) | 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. |
| Digit Span | 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. |
| Finger Windows | 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. |
| Continuous Performance Test (CPT) | 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment: 8/10/2012 - 4/30/17; Roll Over Year: 5/1/17 - 4/30/18; Youth with ADHD and Healthy Controls recruited from the community and clinics at Mount Sinai.
Participants by arm
| Arm | Count |
|---|---|
| Control Group fMRI Scans Only Healthy Control Group: will receive initial evaluation, and 2 fMRI (functional magnetic resonance imaging) scans each 6-8 weeks apart | 47 |
| 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. | 22 |
| 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. | 22 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | could not scan twice | 1 | 1 | 1 |
| Overall Study | scheduling conflicts | 0 | 0 | 1 |
| Overall Study | screen fail | 16 | 17 | 16 |
Baseline characteristics
| Characteristic | Control Group fMRI Scans Only | Atomoxetine Arm | Methylphenidate Arm | Total |
|---|---|---|---|---|
| Age, Continuous | 13 years STANDARD_DEVIATION 2.8 | 10 years STANDARD_DEVIATION 3.02 | 12 years STANDARD_DEVIATION 2.86 | 11 years STANDARD_DEVIATION 3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 14 Participants | 11 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 8 Participants | 11 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 3 Participants | 6 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 16 Participants | 14 Participants | 12 Participants | 42 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 12 Participants | 4 Participants | 3 Participants | 19 Participants |
| Sex: Female, Male Female | 15 Participants | 6 Participants | 6 Participants | 27 Participants |
| Sex: Female, Male Male | 32 Participants | 16 Participants | 16 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 22 | 0 / 22 |
| other Total, other adverse events | 3 / 47 | 6 / 22 | 4 / 22 |
| serious Total, serious adverse events | 0 / 47 | 0 / 22 | 0 / 22 |
Outcome results
Primary
Percentage of Correct Inhibition in Participants Assessed With the Go-No go Task
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).
Time frame: Baseline and at 6 weeks
Population: All participants in control group including the one subject who could not be scanned twice included in data analysis for the 6 weeks visit. Thirty-one (N=31) controls were scanned twice for this project, but the second scan data for 1 subject was excluded from the analysis for motion. Thus, 31 control subjects were included in the analyses of
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control Group fMRI Scans Only | Percentage of Correct Inhibition in Participants Assessed With the Go-No go Task | 6 weeks | 78.24 percent correct inhibition | Standard Deviation 16.57 |
| Control Group fMRI Scans Only | Percentage of Correct Inhibition in Participants Assessed With the Go-No go Task | Baseline | 79.08 percent correct inhibition | Standard Deviation 15.07 |
| Atomoxetine Arm | Percentage of Correct Inhibition in Participants Assessed With the Go-No go Task | 6 weeks | 80.72 percent correct inhibition | Standard Deviation 14.22 |
| Atomoxetine Arm | Percentage of Correct Inhibition in Participants Assessed With the Go-No go Task | Baseline | 79.43 percent correct inhibition | Standard Deviation 17.27 |
| Methylphenidate Arm | Percentage of Correct Inhibition in Participants Assessed With the Go-No go Task | Baseline | 77.98 percent correct inhibition | Standard Deviation 15.1 |
| Methylphenidate Arm | Percentage of Correct Inhibition in Participants Assessed With the Go-No go Task | 6 weeks | 81.81 percent correct inhibition | Standard Deviation 14.14 |
Secondary
Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (ADHD-RS)
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.
Time frame: 8 weeks
Population: All participants in control group including the one subject who could not be scanned twice included in data analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Group fMRI Scans Only | Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (ADHD-RS) | 1 score on a scale | Standard Deviation 2 |
| Atomoxetine Arm | Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (ADHD-RS) | 15 score on a scale | Standard Deviation 11 |
| Methylphenidate Arm | Adult Attention Deficit Hyperactivity Disorder Investigator Symptom Rating Scale (ADHD-RS) | 18 score on a scale | Standard Deviation 12 |
Secondary
Clinical Global Impressions-Severity (CGI-S)
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.
Time frame: up to 6 weeks
Population: All participants in control group including the one subject who could not be scanned twice included in data analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Control Group fMRI Scans Only | Clinical Global Impressions-Severity (CGI-S) | 1 score on a scale | Standard Deviation 0 |
| Atomoxetine Arm | Clinical Global Impressions-Severity (CGI-S) | 3.2 score on a scale | Standard Deviation 1.6 |
| Methylphenidate Arm | Clinical Global Impressions-Severity (CGI-S) | 3.4 score on a scale | Standard Deviation 1.2 |
Secondary
Continuous Performance Test (CPT)
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.
Time frame: baseline and at 6 weeks
Population: All participants in control group including the one subject who could not be scanned twice included in data analysis for the 6 weeks visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control Group fMRI Scans Only | Continuous Performance Test (CPT) | 6 weeks | 44.64 commissioned t-score | Standard Deviation 9.7 |
| Control Group fMRI Scans Only | Continuous Performance Test (CPT) | Baseline | 46.65 commissioned t-score | Standard Deviation 11.29 |
| Atomoxetine Arm | Continuous Performance Test (CPT) | Baseline | 55.26 commissioned t-score | Standard Deviation 5.62 |
| Atomoxetine Arm | Continuous Performance Test (CPT) | 6 weeks | 50.70 commissioned t-score | Standard Deviation 8.66 |
| Methylphenidate Arm | Continuous Performance Test (CPT) | Baseline | 52.94 commissioned t-score | Standard Deviation 9.19 |
| Methylphenidate Arm | Continuous Performance Test (CPT) | 6 weeks | 48.46 commissioned t-score | Standard Deviation 10.43 |
Secondary
Digit Span
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.
Time frame: baseline and at 6 weeks
Population: All participants in control group including the one subject who could not be scanned twice included in data analysis for the 6 weeks visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control Group fMRI Scans Only | Digit Span | Baseline | 13.30 score on a scale | Standard Deviation 18.76 |
| Control Group fMRI Scans Only | Digit Span | 6 weeks | 9.39 score on a scale | Standard Deviation 1.58 |
| Atomoxetine Arm | Digit Span | 6 weeks | 9.75 score on a scale | Standard Deviation 0.95 |
| Atomoxetine Arm | Digit Span | Baseline | 9.25 score on a scale | Standard Deviation 2.06 |
| Methylphenidate Arm | Digit Span | 6 weeks | 8.5 score on a scale | Standard Deviation 1.29 |
| Methylphenidate Arm | Digit Span | Baseline | 7.5 score on a scale | Standard Deviation 1.29 |
Secondary
Finger Windows
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.
Time frame: baseline and at 6 weeks
Population: All participants in control group including the one subject who could not be scanned twice included in data analysis for the 6 weeks visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control Group fMRI Scans Only | Finger Windows | Baseline | 17.04 score on a scale | Standard Deviation 3.69 |
| Control Group fMRI Scans Only | Finger Windows | 6 weeks | 17.65 score on a scale | Standard Deviation 5.33 |
| Atomoxetine Arm | Finger Windows | Baseline | 14.50 score on a scale | Standard Deviation 2.64 |
| Atomoxetine Arm | Finger Windows | 6 weeks | 16.25 score on a scale | Standard Deviation 6.65 |
| Methylphenidate Arm | Finger Windows | Baseline | 16.50 score on a scale | Standard Deviation 5.19 |
| Methylphenidate Arm | Finger Windows | 6 weeks | 16.25 score on a scale | Standard Deviation 6.39 |
Secondary
Response Time in Attention Networks Test (ANT)
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.
Time frame: baseline and at 6 weeks
Population: All participants in control group including the one subject who could not be scanned twice included in data analysis for the 6 weeks visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control Group fMRI Scans Only | Response Time in Attention Networks Test (ANT) | Baseline | 817.50 milliseconds | Standard Deviation 171.06 |
| Control Group fMRI Scans Only | Response Time in Attention Networks Test (ANT) | 6 weeks | 756.87 milliseconds | Standard Deviation 153.83 |
| Atomoxetine Arm | Response Time in Attention Networks Test (ANT) | Baseline | 856.60 milliseconds | Standard Deviation 179.34 |
| Atomoxetine Arm | Response Time in Attention Networks Test (ANT) | 6 weeks | 826.14 milliseconds | Standard Deviation 139.08 |
| Methylphenidate Arm | Response Time in Attention Networks Test (ANT) | Baseline | 885.68 milliseconds | Standard Deviation 170.76 |
| Methylphenidate Arm | Response Time in Attention Networks Test (ANT) | 6 weeks | 783.09 milliseconds | Standard Deviation 125.21 |