About this trial

Pediatric attention deficit hyperactivity disorder (ADHD) affects up to 10% of children in the U.S. and more than 90% are prescribed stimulant medications according to clinical guidelines. The standard of care for pharmacological treatment of ADHD is a "trial-and-error" approach that requires frequent dose adjustments, side effects management, and communication among doctors, parents, and school personnel over weeks, months, and years. In the first year following prescription of stimulant medications, \>50% of doctors are not able to conduct the recommended follow-up with their patients. Many patients stop taking medications or keep taking medications that do not work well, as a result.

This investigation will use a non-invasive brain imaging technique called EEG to look for activity in the brain that can predict which children with ADHD will respond well to two commonly prescribed stimulant medication groups, methylphenidate and amphetamines. Based on a previous study, it is expected that EEG signals can differentiate among children whose ADHD symptoms will get better on methylphenidate, and those whose ADHD symptoms will get better on amphetamines.

220 participants ages 7-11 with ADHD will be enrolled. Participants will not have autism or intellectual disabiltiy. They will not currently be taking psychiatric medications. Participants will not have not taken stimulant medications before or have tried stimulant medications \>6 months or experienced an improvement in their ADHD symptoms by taking a stimulant medication before.

Study Participation Includes:

1. Participant and caregiver complete a 3-hour visit at the Arnett Laboratory at 2 Brookline Place. During this visit, participants complete a brief IQ test and an EEG while their caregiver completes questionnaires and a clinical interview. The caregiver will give permission to request survey responses from the participant's teacher. 2. The next day, the participant and caregiver will come back to the laboratory for a 1-hour visit. The participant will do another EEG while the caregiver fills out more surveys. The doctor will take the participant's vital signs and prescribe the medication. 3. The participant will be randomly assigned to take either methylphenidate HCl or amphetamines every morning for 3 weeks. At the end of each week, the caregiver and teacher will fill out a questionnaire about the participant's behaviors and symptoms, including side effects. 4. For one week, the participant will not take medications. They will come back into the lab for another EEG at the end of that week. 5. The participant will then take the other medication every morning for 3 weeks. At the end of each week, the caregiver and teacher will fill out a questionnaire about the participant's behaviors and symptoms, including side effects. 6. It will take participants about 7 weeks to complete this study. During this time, they will complete 3 in-person and 6 virtual study visits. 7. The research funds will cover cost associated with the study. The participant's health insurer will not be billed for the medications or treatment. Medications will be provided through the research pharmacy. 8. Participants will be given a report at the end of the study with details about the medication trials, symptom response, and any other findings. They will receive up to $270 for the completion of the study. Some travel-related costs will be covered by the study.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Ages 7:0 - 10:11 (years:months)

Has a diagnosis of ADHD or being evaluated for ADHD

Stimulant naïve or previously trialed stimulant medications for < 6 months without achieving symptom remission, per caregiver report and/or medical chart review (if available)

CGI-Severity rating of 4 "Moderately ill" through 6 "Severely ill."

Disqualifiers

Use of stimulants or other psychotropic medications within 7 days before Eligibility Visit

History of severe side effects to stimulants (suicidality, complete loss of appetite, cardiopulmonary complications) per caregiver report or medical chart review, determined by the study MD

Intellectual disability or IQ < 75 per medical chart review or performance on standardized cognitive testing during the Eligibility Visit

Diagnosis of Autism spectrum disorder (ASD) per medical chart review or caregiver report

Trial design

Design model

Crossover

Treatments tested in this trial

methylphenidate HCl
Drug
3-week titration of liquid Quillivant XR
Mixed amphetamine salts extended release
Drug
3-week titration of liquid Dyanavel XR

Treatment groups

220 Participants

are divided into 2 treatment groups

Group A: Methylphenidate HCl then Mixed AmphetaminesExperimental treatment 2 interventions

Group B: Mixed Amphetamines then Methylphenidate HClExperimental treatment 2 interventions

Trial outcomes

Primary outcomes

1

Medication A Clinical Global Impressions - Improvement Scale (CGI-I)

Clinician rating of participant ADHD symptom improvement on medication A. The Clinical Global Impressions - Improvement Scale (CGI-I) is rated by a trained study clinician on a scale of 1-7, with scores of 1 ("very much improved") and 2 ("much improved") corresponding to clinically significant symptom improvement. Scores of 3-7 will indicate no improvement or worsening of symptoms.

Time frame

Week 3 Virtual Visit (Day 22)

2

Medication B Clinical Global Impressions - Improvement Scale (CGI-I)

Clinician rating of participant ADHD symptom improvement on medication B. The Clinical Global Impressions - Improvement Scale (CGI-I) is rated by a trained study clinician on a scale of 1-7, with scores of 1 ("very much improved") and 2 ("much improved") corresponding to clinically significant symptom improvement. Scores of 3-7 will indicate no improvement or worsening of symptoms.

Time frame

End of Study Virtual Visit (Day 50)

3

Frontal Theta Beta Ratio

Theta-Beta Ratio (TBR): TBR will be calculated from periodic resting EEG. Periodic power isolates the oscillatory component of the EEG by subtracting the aperiodic power spectra from the total power. Periodic power is extracted with the Fitting Oscillations and One-Over-f (FOOOF) MATLAB toolbox which parametrizes resting state EEG data into aperiodic and periodic components. Resting spectral power values will be averaged over theta (4-6 Hz) and beta (13-30 Hz) frequencies across midline electrode clusters (frontal: Fz, F3, F4; central: Cz, C3, C4; parietal: Pz, P3, P4; occipital: Oz, O1, O2). Our primary analyses will focus on frontal TBR during the Lights-Off Resting condition.

Time frame

Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)

4

Aperiodic Dynamics

Aperiodic Dynamics: The aperiodic exponent for lights-off and lights-on resting conditions will be averaged across midline electrode clusters FOOOF MATLAB toolbox. Aperiodic dynamic values will be computed for each participant as the difference between lights-on and lights-off exponent, divided by the lights-off resting exponent, as in prior publications. Thus, higher scores will indicate greater exponents in the lights-on experiment. Primary analyses will use the central electrode cluster.

Time frame

Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)

Secondary outcomes

1

P100 Visual Evoked Potential Habituation

VEP P100 Amplitudes. The P100 VEP component will be derived from a passive pattern-reversal visual evoked potential (VEP) task that includes 200 500ms trials of a black and white checkerboard reversal over 3 minutes. P100 amplitudes will be averaged over an occipital electrode cluster (Oz, O1, O2) from approximately 75-150ms and extracted for each trial. Secondary analyses will focus on P100 amplitude changes over trial, i.e. habituation coefficients.

Time frame

Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)

2

Side Effects Rating Scale, Parent- and Teacher-Report

Adverse effects associated with stimulant treatment will be recorded by parents and teachers on a weekly basis on the Vanderbilt Follow-Up rating scales, which include an adapted version of the Pittsburgh Side Effects Rating Scale. 12 side effects symptoms are rated on a scale of 0 = not currently a problem to 3 = severe problem. Side effects will be used for clinical decision making. Secondary exploratory analysis will examine associations between EEG features and total severity of side effects by summing ratings from the 12 items.

Time frame

Baseline, Medication A Week 1, Medication A Week 2, Medication A Week 3, Crossover Week 4, Medication B Week 5, Medication B Week 6, End of Study Week 7

3

EEG Coherence

EEG coherence will be derived from resting state EEG as well as ERP tasks. Both global (i.e., long-range) and local (i.e., within region of interest) coherence will be examined in exploratory analyses.

Time frame

Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)

4

N2 Event Related Potential Amplitude

The HAPPE+ER pipeline will be used to extract N2 amplitudes during the Go-NoGo task, by condition and electrode. Mean amplitudes will be calculated for components across regions of interest, following visual inspection of temporal and topographic plots.

Time frame

Eligibility Visit (Day 0), Baseline Visit (Day 1), Crossover Visit (Day 29)

EEG Biomarkers for ADHD Stimulant Treatment

About this trial

Eligibility criteria

Qualifiers

Disqualifiers

Trial design

Treatments tested in this trial

Treatment groups

Trial outcomes

Primary outcomes

Secondary outcomes

Other outcomes

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