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

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 each condition (once on med/ once on placebo) measuring these ERP amplitudes. Participants, guardians and study staff will be masked to intervention status during the RCT phase but not the open label dose optimization phase. All EEG data collection will occur under blinded conditions. This within subjects design reduces inter subject variance which is essential for identification of treatment biomarkers by predetermining each participants optimal dose and then using each participant as their own control.

Participants will be 136 youth with ADHD and elevated levels of IACI ages 8 to 12. Elevated levels of IACI will be defined by guardian rating on the Affective Reactivity Index (ARI) and Revised Modified Overt Aggression Score (RMOAS) as both are representative of an impairing level of IACI. Children will also be required to have at least moderate impairment (4+) on the Impairment Rating Scale (IRS) and the ADHD Clinical Global Impressions Severity Score (CGI-S) and meet full diagnostic criteria for ADHD. ADHD will be assessed using the Disruptive Behaviors Disorder Guardian Interview given by masters level staff. It assesses all ADHD symptoms and all other DSM ADHD criteria. The guardian interview will be supplemented with teacher ratings of ADHD (Disruptive Behavior Disorder Rating Scale [DBD-RS]) and classroom functioning (IRS) to verify impairment and symptoms occur across settings. A dual clinician review by study MD/PhD will make a final diagnosis by integrating teacher and guardian report using the OR rule. Where disagreement occurs, a third clinician will be consulted. Many youth with ADHD and elevated IACI have comorbid behavioral health conditions. Consistent with past ADHD trials for IACI, investigators will exclude youth with prominent autism traits (defined as mean score above 3.2 on the Autism Symptoms Dimension Questionnaire) or current major depression. However, anxious or subthreshold depressive symptoms do not impede the ability of CNS stimulants to improve ADHD or IACI. Comorbid conditions will be assessed on the Kidde Schedule for Affective Disorders and Schizophrenia Computerized Version (KSADS-Comp). Cases scoring positive on the KSADS-Comp for current depression will be further assessed by parent interview with the KSADS Present and Lifetime module (KSADS-PL) to verify symptoms scoring positive as depression on the comp version are not due to overlapping ADHD symptoms (concentration problems) or stimulant side effects (insomnia or sleep delay) as the PL version has specific rule out prompts for these issues lacking in the COMP version. To better examine their impact on planned outcomes, depression and anxiety symptoms will also be measured dimensionally by guardian and youth report on the Revised Children's Anxiety and Depression Scale-25 (RCADS-25). Stimulant optimization is advised before considering other psychotropics for aggression, so antipsychotics will be exclusionary. Antidepressants, alpha agonists and psychotherapy will be allowed and examined as covariates if dose has been stable for 30+ days as they do not meaningfully change amplitude of the selected ERPs or the response to CNS stimulants. Doses of outside medication and therapy frequency/format/modality must be held stable for study duration. Children who lack the cognitive, visual or auditory capacity to complete laboratory tasks or have a medical/psychiatric contraindication to CNS stimulants will be excluded as will youth with 2+ fully optimized methylphenidate trials AND 2+ amphetamine trials. This last requirement should not lead to appreciable exclusions as CNS stimulants are often not titrated to optimal doses. Youth who are stimulant naïve will be allowed to enroll as long as they meet enrollment criteria and do not have medical conditions that would preclude use of CNS stimulants (seizure disorder, significant structural cardiac abnormalities, severe tics, etc.). Study staff will meet with families to review study goals and commitments and complete consent and assent. During the intake assessment, a MD clinician will complete a thorough medication history to review past medication trials of CNS stimulants as well as health variables that may impact tolerability of CNS stimulants (e.g. sleep and appetite). The clinician driven ADHD RS 5 interview and the clinician driven ARI interview (C-ARI) will be completed with parent and child to assess current level of ADHD symptoms and IACI levels and repeatedly weekly during the dose optimization phase. The Clinician-ARI Interview is a semi structured interview which codes levels of IACI on a 0-100 metric with separate ratings for levels of irritability and aggression, based on ratings of frequency, duration and severity for each. This relatively new measure will provide critical information about the timing of IACI, assisting with medication selection. It will be repeated at the end of dose optimization phase as part of a multimethod battery of IACI to compare agreement between guardian ratings of IACI and clinician assessment.

Dose Optimization Phase: An initial medication option will be selected based on the participant's past medication trials and current temporal patterns of impairment (time of day of greatest impairment) with a focus on improving ADHD levels across the day and IACI levels at home. All study medication will be prescribed by licensed physicians expert in the treatment of pediatric ADHD and IACI (three child psychiatrists and one general pediatrician that are study investigators). All study treatments consist of only CNS stimulants approved for the treatment of pediatric ADHD or placebo. Methylphenidate will be the preferred initial option based on prior IACI treatment trials but amphetamine products will also be allowed; however, any FDA approved medication in either of these stimulant classes can be employed as long as it can be blinded for the RCT phase (no liquids or dissolve tabs or transdermals unless our research pharmacy can obtain a comparable blind). Children will be taught to swallow capsules during the open label medication phase using established procedures from past trials in this same population. The employed dosing will be consistent with standard clinical practice and past trials in youth with IACI and ADHD, with doses adjusted by one dosing increment at a time. During the 6 week dose optimization period, study clinicians will adjust dose using weekly guardian and teacher ratings collected and direct interview of guardian using the ADHD RS 5 interview until optimal dose is achieved based on efficacy and tolerability ratings. Participants will complete weekly visits with study physicians to adjust CNS stimulant dose. At each weekly visit, guardians will complete the ARI and R-MOAS, a brief measure of functional impairment (IRS) as well medication tolerability with the Pittsburgh Side Effect Rating Scale (PSERS). Guardians will also be asked to identify for each dosing the day, the hour when medication benefits appear to onset and the hour when they appear to have fully dissipated in order to identify medicated and unmedicated time periods of the day to be used to define the EMA sampling times for the following RCT stage. Clinicians will complete the ADHD-RS interview to measure change in ADHD symptoms and the Clinical Global Impressions Severity and Improvement Scale (CGI S and I) separately for ADHD and IACI to assess change in each since baseline and total current severity of each construct over the past week. Every week, teachers will be sent a link to a secure survey for them to rate the current level of ADHD symptoms and oppositional behaviors (IOWA Conners) and IACI levels at school (6 item teacher version of ARI and 6 item abridged RMOAS). Clinicians will also complete the Columbia Suicide Severity Rating Scale (C-SSRS) each week with participants and guardians to measure risk for self-harm. In addition, guardian ratings of Oppositional Defiant Disorder and Conduct Disorder (DBD-RS will be collected). Expanded teacher ratings of ADHD, Conduct Disorder and Oppositional Defiant Disorder that capture every DSM symptom will also be collected at endpoint (DBD RS). Vitals (height, weight, blood pressure, pulse) will be collected at every in person office visit, with in-office visits required at least every two weeks. Alternating visits can be done via HIPAA compliant telehealth platforms. The dose optimization period can last up to 6 weeks but may end sooner if participants meet criteria for optimal dose. For dose to be considered optimal and the titration to end before week 6, CGI improvement (CGI-I) ratings for ADHD must be at much be much or very much improved levels with acceptable medication tolerability for at least two consecutive visits with clinicians deeming that further improvement is not expected or higher doses could not be tolerated. The study team has employed this same definition in prior NIH studies (MH083692). Once dose has been optimized, participants will be advanced to the next phase. As this study aims to identify markers of CNS stimulant response for IACI, it is important to assess predictors in participants evidencing a wide range of responses for IACI when treated with CNS stimulants versus limiting biomarker assessment to only robust responders. However, study treatments will only be continued in those participants evidencing at least partial improvement in ADHD symptoms (the FDA approved indication for all study medications) to ensure that all participants advancing to the next phase are experiencing some benefit. Similar criteria were used in past adjunctive pharmacotherapy trials for IACI. The ADHDRS-5 will be employed as the primary gating measure to ensure participants meet response criteria to advance to the next phase as study medications are FDA approved for treatment of ADHD versus IACI. Consistent with past ADHD trials, the threshold for ADHD response will be defined as at least a 25% improvement in ADHD symptoms as measured by the ADHD RS. To advance to the next stage, participants must also display improved, comparable or mildly worse IACI levels (any option except "much" or "very much" worse on IACI CGI-S). Based on prior work it is expected that 80% or more of youth will meet criteria to advance to the randomized controlled (RCT) phase.

RCT phase: Once participants complete the open label phase, they will be randomly assigned in a balanced fashion to one of two medication sequences (medication - placebo or placebo-medication). Dropout for other reasons or data loss is not estimated to be more than 10%, leaving at least 96 participants with full study data. The RCT phase will consist of two randomly assigned 7 days stretches of blinded optimal dose or matching placebo beginning on a Saturday and ending on a Friday. The order will be randomly assigned across participants (medication - placebo vs placebo-medication). An EEG testing battery will be completed once per week in each arm at a time when medication has been deemed to be active consistent with the extant literature and guardian report of medication effects during the open label dose optimization.