What predicts improvement in irritability and aggression in children with ADHD on stimulant medication

Identification of Neural Markers of Aggression and Irritability and Their Capacity to Predict Treatment Response to CNS Stimulant Medication in Youth With ADHD

This study sees if optimizing stimulant medication helps children with ADHD who have high irritability and aggression and whether brain and learning tests can predict who improves.

Quick facts

• Phase: PHASE4
• Study type: Interventional
• Enrollment: 136 (estimated)
• Ages: 7 Years to 12 Years
• Sex: All
• Sponsor: Milton S. Hershey Medical Center (other)
• Locations: 1 site (Hershey, Pennsylvania)
• Trial ID: NCT06871488 on ClinicalTrials.gov

What this trial studies

This trial will enroll 136 children with ADHD and elevated irritability or aggression and use a 6-week open-label dose-optimization phase of CNS stimulants followed by a 2-week within-subject crossover comparing each child’s optimal dose with placebo. Participants complete behavioral reinforcement-learning tasks and EEG recordings (event-related potentials) to measure brain responses related to reward feedback, attention under frustration, and set shifting. Investigators will relate changes in irritability and aggression to these neural and behavioral markers to identify predictors of improvement or risk of worsening. Prior work suggests about 50–60% of children improve with stimulant dose optimization while 5–10% may experience increased irritability or aggression.

Who should consider this trial

Good fit: Children with any presentation of ADHD who have moderate or worse impairment and elevated irritability or aggression, who speak English with their guardian, and whose guardian is willing to try stimulant medication are ideal candidates.

Not a fit: Children with autism spectrum disorder, bipolar disorder, intellectual/developmental delay, current major depressive episode or suicidal ideation, medical contraindications to stimulants, current antipsychotic or mood stabilizer use, or those who have failed fully optimized trials of both methylphenidate and amphetamine products are unlikely to benefit or be eligible.

Why it matters

Potential benefit: If successful, the results could help clinicians predict which children will benefit from stimulants, reduce unnecessary antipsychotic use, and tailor treatment to avoid worsening symptoms.

How similar studies have performed: Previous research shows dose optimization of stimulants improves irritability in roughly half of affected youth and stimulants alter the same EEG markers, but using EEG and reinforcement-learning measures to predict individual response is a relatively novel approach.

Eligibility criteria

Inclusion Criteria:

1. Meet criteria for any presentation of ADHD
2. Moderate or worse impairment related to ADHD
3. Elevated levels of irritability and/or aggression on guardian ratings of Affective Reactivity Index and Retrospective Modified Overt Aggression Scale
4. fluent in English for child and guardian
5. Guardian and child are willing to have child take CNS stimulant medication for ADHD

Exclusion Criteria:

1. Medical contraindications to use of CNS stimulants
2. Autism Spectrum Disorder,
3. Bipolar Disorder,
4. Intellectual/Developmental Delay
5. current use of antipsychotic, mood stabilizing
6. Use of other medications that impact EEG data collection (e.g. benzodiazepenes)
7. hearing or visual deficits that impede ability to do computer tasks
8. Current Major Depressive Episode
9. Current suicidal ideation
10. child has failed two fully optimized trials of methylphenidate products AND two for amphetamine products

Where this trial is running

Hershey, Pennsylvania

• Penn State Health Dept of Psychiatry — Hershey, Pennsylvania, United States (RECRUITING)

Study contacts

• Study coordinator: James G Waxmonsky, MD

Conditions: ADHD - Attention Deficit Disorder With Hyperactivity, Irritability, Aggression Childhood, ADHD, CNS Stimulants, Aggression