NCT06871488 · Milton S. Hershey Medical Center
Predictors of Improvements in Irritability and Aggression in Children With ADHD Treated With CNS Stimulants
What this study is about
Impulsive Aggression and chronic irritability (IACI) often occur together and are one of the most common reasons children present for behavioral health (BH) care. ADHD frequently associated with IACI as upwards of 50% of youth with ADHD manifest impairing IACI levels. IACI is the most common reason that children with ADHD are prescribed antipsychotics and admitted to inpatient BH units.
View original scientific description
Impulsive Aggression and chronic irritability (IACI) often occur together and are one of the most common reasons children present for behavioral health (BH) care. ADHD frequently associated with IACI as upwards of 50% of youth with ADHD manifest impairing IACI levels. IACI is the most common reason that children with ADHD are prescribed antipsychotics and admitted to inpatient BH units. Systematic dose optimization of CNS stimulants improves levels of IACI, reducing the need for these more intensive and burdensome treatments. However, response varies, with over half of children with ADHD showing meaningful improvement, upwards of 40% receiving minimal benefit and 3 to 10% exhibiting increased IACI levels. Symptom levels of ADHD or IACI and other demographic variables are of limited utility for predicting response, suggesting the need to move beyond symptoms in the search for treatment predictors. Youth with ADHD and IACI struggle with multiple aspects reinforcement learning (RL), defined as learning from interactions with the environment to reach a goal. Successful RL efforts tap multiple cognitive functions. In controlled laboratory tasks, youth with IACI and various BH disorders exhibit excessive behavioral and neural response to receiving reward (reward responsiveness), difficulty processing environmental cues to adapt behavior to meet a goal (set shifting/goal updating) and impaired ability to flexibly attend to relevant stimuli when blocked from a goal (frustrative nonreward). Event related potentials (ERP) are small electrical responses in the brain in response to specific events or stimuli measured by electroencephalogram (EEG) testing. ERPs exist that can serve as established neural measures of each of these cognitive functions offering a child friendly means to assess their contribution to observable levels of IACI. CNS stimulants improve functioning in these specific realms and impact associated ERPs to the degree that differences between ADHD and non-ADHD youth disappear. This study will examine the capacity of these ERPs to predict levels of IACI exhibited by children with ADHD when at home. Investigators will then assess if variability across children in the capacity of CNS stimulants to impact RL associated ERPs accounts for differences in the clinical effects of CNS stimulant medications to improve IACI at home using a multimethod battery integrating ERPs, parent report and task performance. Specifically, investigators will examine variance in the reward positivity (RewP) ERP when receiving reward feedback, the switch positivity (SwP) ERP measuring mental effort when cued to shift set and the change in P3b amplitude measuring attention allocation when transitioning from reward to nonreward on a go-no-go task. To achieve these aims, 136 children with ADHD and elevated IACI levels will have their CNS stimulant dose optimized over six weeks and then complete a two week within subjects crossover trial of placebo versus optimal dose. ERP collection will be completed within each blinded week. Parent ratings will be gathered 3 times per day including during peak and off-peak times of medication efficacy to capture the variance in IACI levels within the day and disentangle reports of worsening IACI related to loss of previously beneficial medication effects versus those most likely related to a direct adverse response to medication.
Interventions
DRUG
CNS Stimulant
The second treatment phase (blinded within subjects crossover) will compare one week of the optimal dose of CNS Stimulant (from the prior phase) to one week of placebo for a total of 14 days of data collection.
DRUG
Placebo
Placebo is only used during the second of two treatment phases. The second treatment phase (blinded within subjects crossover) will compare one week of the optimal dose of CNS Stimulant (from the prior phase) to one week of placebo.
OTHER
CNS Stimulant open label first phase
The first treatment phase will optimize CNS stimulant dose under open label conditions using any approved FDA medication for pediatric ADHD at the FDA approved doses.
Primary outcome measures
RCT phase: Guardian rated Affective reactivity Index (ARI)
Time frame: 7 days on med and for 7 days on placebo for 14 days of data collection
Thus study examines response markers for CNS stimulants to improve irritability and to improve aggression. For this second treatment phase comprised of the within subjects crossover of optimal med vs placebo, the primary outcome for irritability is the drug placebo difference in the guardian rated Affective Reactivity Index collected for 7 days over the blinded within subjects crossover phase. ARI has 6 items rated 0-2 for range of - to 14 with higher scores representing greater irritability levels. drug placebo difference on this measure will be correlated with drug placebo difference for RewP, P3b and switch positivity ERP
Open label dose opt: ADHD RS 5 clinician interview
Time frame: 6 visits (over a max duration of 12 weeks)
For the first treatment phase (open label dose optimization) the primary outcome is the change in ADHD symptoms as measured by clinician interview using the ADHD RS 5. it has 18 items rates 0-3 with more symptoms reflecting higher scores. will measure change over time with drug;
RCT phase abridged Revised modified overt aggression scale (RMOAS)
Time frame: 7 days on med and 7 days on placebo for 14 days of data collection
The primary rating for aggression is the drug placebo difference in the guardian rated abridged (6 reduced to 6 items) Retrospective Modified Overt Aggression Scale (RMOAS) collected for 7 days over the blinded within subjects crossover phase. The RMOAS abridged version has 6 items rated 0-3 with higher scores equating to greater levels of aggression ; drug placebo difference on this measure will be correlated with drug placebo difference for RewP, P3b and switch positivity ERP
Who can participate
This study lists these criteria on ClinicalTrials.gov. A study coordinator reviews eligibility during screening — this page does not determine whether you qualify.
Inclusion criteria
- Meet criteria for any presentation of ADHD
- Moderate or worse impairment related to ADHD
- Elevated levels of irritability and/or aggression on guardian ratings of Affective Reactivity Index and Retrospective Modified Overt Aggression Scale
- fluent in English for child and guardian
- Guardian and child are willing to have child take CNS stimulant medication for ADHD
Exclusion criteria
- Medical contraindications to use of CNS stimulants
- Autism Spectrum Disorder,
- Bipolar Disorder,
- Intellectual/Developmental Delay
- current use of antipsychotic, mood stabilizing
- Use of other medications that impact EEG data collection (e.g. benzodiazepenes)
- hearing or visual deficits that impede ability to do computer tasks
- Current Major Depressive Episode
- Current suicidal ideation
- child has failed two fully optimized trials of methylphenidate products AND two for amphetamine products
Where
- Hershey, Pennsylvania
Related conditions & keywords
Frequently asked questions
What is a clinical trial?
A clinical trial is a research study that tests new medical treatments, drugs, devices, or procedures to determine their safety and effectiveness. Trials are carefully designed and monitored to protect participants while advancing medical knowledge.
Is it safe to participate?
Clinical trials follow strict safety guidelines and ethical standards. Trials must be reviewed and approved, and participants are closely monitored by medical professionals throughout the study. You can withdraw at any time if you choose.
Will I be compensated?
Many clinical trials offer compensation for your time, travel expenses, and inconvenience. The specific compensation varies by study and will be discussed during the screening process. All study-related medical care is typically provided at no cost to participants.
Will I receive a placebo instead of treatment?
When effective treatment exists, participants typically receive either the standard treatment plus the study intervention, or the standard treatment plus placebo. You would not be denied effective care. Placebos are primarily used when no proven treatment is available, or in addition to standard care. Your trial consent form will clearly explain what treatments you may receive.
Can I leave a trial if I change my mind?
Absolutely. Participation in clinical trials is completely voluntary. You have the right to withdraw from the study at any time, for any reason, without penalty or loss of benefits to which you are otherwise entitled.
How long does a clinical trial last?
Trial duration varies widely depending on the study design and purpose. Some trials last just a few weeks, while others may continue for months or years. The study coordinator will provide specific timeline information during your screening call.
Data: ClinicalTrials.gov · synced Apr 20, 2026 · Source of record for eligibility and locations