Predictors of Improvements in Irritability and Aggression in Children With ADHD Treated With CNS Stimulants

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.

This is clinical trial of CNS stimulants will enroll 136 youth with ADHD and elevated levels of impulsive aggression and chronic irritability (IACI). It employs a 6 week open label dose optimization trial followed by a 2 week within subjects crossover phase of optimal dose versus placebo. In our preliminary work, the study team observed that about 50 to 60% of children will show moderate or greater improvements in IACI with CNS Stimulants dose optimization. This response appears independent of ADHD symptom change. Across studies, 5 to 10% of youth with ADHD experience increased IACI, but there are no reliable predictors of IACI worsening. Youth with IACI have multiple impairments with reinforcement learning that can manifest at the neural level as altered event response potentials (ERP) and at the behavioral level as impaired cognitive task performance. For example, investigators demonstrated that youth with IACI showed enhanced response to reward feedback and reduced capacity to allocate attention under frustration manifesting as alterations in the amplitude of the Reward Positivity (RewP) and P3b ERPs respectively. Others have demonstrated that youth with IACI have impairments in shifting set as captured by the switch positivity ERP (SwP). Not such impairments are seen in youth with ADHD but not elevated IACI levels. All three of these ERPs are impacted by CNS stimulants, and these medications have been shown to improve reinforcement learning (RL) in youth with ADHD when it is impaired. Therefore, the study team theorizes that the degree of IACI improvement in IACI seen with CNS stimulants will correlate with the level of ERP amplitude change seen with these medications. To test this theory, investigators will recruit 136 youth ages 8 to 12 with ADHD and elevated levels of IACI. All participants will first have their stimulant dose optimized (any oral FDA approved stimulant for ADHD that be can blinded) over 6 weekly visits using weekly ratings gathered from guardians and teachers. If ADHD symptoms show a 25% or greater improvement and there is not a moderate worsening in IACI levels (it is expected that 50%or more of participants will show reduced levels, 35% little change, 5-10% mild worsening and few if any will show moderate or worse impairment), then participants will be advanced to a 2 week within subjects double blind randomized controlled trial (RCT) phase using a within subjects crossover design with each participant receiving their optimal dose of CNS stimulant and placebo for one week apiece. A thrice daily ecological momentary assessment (EMA) protocol measuring ADHD and IACI levels will be completed in each of these two weeks levels to address the appreciable temporal fluctuations in IACI seen across the day at home. In each blinded week, guardians will complete three ratings per day of IACI and ADHD. During times when medication effects are active, participants will complete an approximately one-hour EEG testing battery within ea trial.show_full_description

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