Neurophysiological Markers of Pediatric Irritability and Its Response to Intervention

NCT03279952 | Terminated Phase 4 Results FDA Drug

• 1 other identifier: IRB: 00008087
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

There has been an increasing focus on the adverse impacts of irritability, defined as increased tendency towards anger. Irritability worsens peer relationships, family functioning, academic performance and is a risk factor for depression, suicide and substance use and is one of the main reasons why children get referred for treatment. It has been identified as transdiagnostic entity meriting investigation as a treatment target for personalized intervention given its prevalence and morbidity. Most children with prominent irritability also meet criteria for Attention Deficit Hyperactivity Disorder (ADHD) but only a subset of children with ADHD manifest impairing levels of irritability. Irritability levels are only minimally correlated with severity of ADHD symptoms suggesting that irritability is not simply a manifestation of severe ADHD. The first line treatment for irritability in children with ADHD is to optimize the dose of the CNS stimulant. However, there is great heterogeneity in response, with baseline mood lability being the best marker for both improving and worsening irritability. In addition, increased irritability is one of the most common reasons why parents stop these medications. The unpredictability in response to CNS stimulants has led to the increasing use of antipsychotics and other non-evidence based treatments for ADHD. It is unknown what drives this heterogeneity in response in part because little is known about the underlying causal mechanisms for irritability in youth with ADHD. Two areas theorized to contribute to irritability include impairments in learning from experience (instrumental learning) and sensitivity to reward and loss.1 There are objective methods for measuring these domains in children through the use of even-related potentials (ERPs)- synchronous neural activity in response to a stimulus. Reward positivity (RewP) is an ERP component occurring in response to feedback on task performance that can be broken down to separate reward and loss components. Irritability is thought to arise due to the combination of an enhanced drive for reward coupled with an excessive response to loss. No prior work has examined associations of RewP with irritability in ADHD. However, abnormalities in RewP and elevated irritability have both been established as risk factors for depression, suggesting that RewP may also predict irritability. Error related negativity (ERN) reflects the preconscious detection of potential conflict serving as an early warning signal for errors. Error detection is one of the first steps for instrumental learning. It is impaired in some youth with ADHD, with a suppressed ERN correlated with reduced error processing. CNS stimulants improve ERN amplitude and impaired error processing. We theorize that abnormalities in RewP and ERN in children with ADHD will serve as respective markers for severity of irritability and subsequent treatment response to CNS stimulants. If successful, we will have identified a causal pathway for irritability that will aide treatment development and identified a reliable biomarker for the current first line treatment for irritability in ADHD (CNS Stimulants), while providing care to a significantly impaired group of local children for whom few evidence-based treatments exist.

Conditions

ADHD

Outcome Measures

Primary Outcomes (3)

• Change in Parent Rated Irritability on the IOWA Connor Irritability Score From Baseline to 6 Weeks.

  The primary outcome in this study was that change in parent rated irritability on the IOWA Connor irritability score. Parent Rating Scale rating symptoms on a 0-3 likert. Higher scores mean severe symptoms This scales has 3 items, which are reported as Not at all (0), just a little (1), pretty much (2) and very much (3) Total score is calculated by summiting all items. Total Score Ranges (0-9), higher score indicates more irritability.

  Baseline and 6 weeks

• Change in Parent-rated ADHD Symptoms, as Measured by the IOWA Conners Score, From Baseline to 6 Weeks.

  Symptom severity for ADHD symptoms will be assessed using the IOWA Connor Parent Rating Scale rating symptoms on a 0-3 likert. Higher scores mean severe symptoms This scale has 5 items, which are reported as Not at all (0), just a little (1), pretty much (2) and very much (3) Total score is calculated by summiting all items. Total Score Ranges (0-15). higher score indication of more ADHD symptoms.

  Baseline and 6 weeks

• Change in Parent-rated ODD Symptoms, as Measured by the IOWA Conners Score, From Baseline to 6 Weeks.

  Oppositional Defiant Disorder (ODD) symptoms were assessed using the IOWA Connor Parent Rating Scale rating symptoms on a 0-3 likert. Higher scores mean severe symptoms This scale has 5 items, which are reported as Not at all (0), just a little (1), pretty much (2) and very much (3) Total score is calculated by summiting all items. Total Score Ranges (0-15). Higher scores reflect greater levels ODD symptoms

  Baseline and 6 weeks

Secondary Outcomes (5)

• Change in Parent-rated Impairment, as Measured by the Impairment Rating Scale (IRS), From Baseline to 6 Weeks.

  Baseline and 6 weeks

• Modified Overt Aggression Scale (MOAS)

  Baseline

• Inventory of Callous Unemotional Traits

  Baseline

• Change in Parent-rated Affective Reactivity Index Total Score, as Measured by the Affective Reactivity Index, From Baseline to 6 Weeks.

  Baseline and 6 weeks

• Change in Parent-rated Side Effects, as Measured by the Pittsburgh Side Effects Rating Scale (PSERS), From Baseline to 6 Weeks

  Baseline and 6 weeks

Study Arms (1)

medication arm

OTHER

CNS Stimulant

Drug: CNS Stimulant

Interventions

CNS Stimulant DRUG

Participants will be stabilized by any FDA approved CNS stimulant medication during open label trial.

medication arm

Eligibility Criteria

• Age: 5 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• \. Meets diagnostic criteria for any presentation type of ADHD. ADHD status will be assessed on the NIMH Computerized Diagnostic Interview Schedule for Children (C-DISC).54 The C-DISC will also be used to assess psychiatric comorbidity, with diagnoses confirmed by an MD/PhD prior to eligibility decisions. Symptom severity for ADHD, irritability and Oppositional Defiant Disorder (ODD) will be assessed using the Disruptive Behavior Disorders (DBD) Parent Rating Scale which is similar to the Vanderbilt, rating symptoms on a 0-3 likert.24 In accordance with previous studies of irritability in ADHD, the DBD irritability score (range 0-9) will be the primary outcome, with a moderate level of irritability (≥5) required for entry.12 DMDD status will be assessed using Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (KSADS-PL) but DMDD will not be required for entry as subthreshold levels of irritability produce significant impairment.7 3. Sex: male or female 4. Fluent in written and spoken English.

You may not qualify if:

• Age \<5 years of age or \>12 years of age.
• Children with significant visual or hearing deficits or sensitivity to loud noises as test performance requires intact hearing and vision.
• Children with a latex allergy as the sensors used in electrophysiology assessments have a latex component.
• Serious neurological conditions that impacts cognition, such as an active seizure disorder
• Current psychotropics other than FDA approved ADHD medications, as medication will be withheld on testing days. Unlike most other psychotropic medications, CNS stimulants can be withheld for brief periods and acutely restarted with no safety risks and lengthy titration process. Numerous ADHD studies have safely withdrawn these medications or substituted inert placebo for testing or clinical observation. Children taking an approved nonstimulant for ADHD plus a CNS Stimulant medication will be allowed to participate and will just have their CNS stimulant dose withheld on testing days.
• Prominent traits of autism spectrum disorder (Social Communication Questionnaire Score \>15), marked developmental delay or psychiatric conditions requiring urgent treatment (mania, psychoses, suicidal ideation).
• Parent or child not fluent in English

Sponsors & Collaborators

• Milton S. Hershey Medical Center: lead

Study Sites (1)

Penn State Hershey

Hershey, Pennsylvania, 17036, United States

Location

MeSH Terms

Conditions

Attention Deficit Disorder with Hyperactivity

Interventions

Central Nervous System Stimulants

Condition Hierarchy (Ancestors)

Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Central Nervous System Agents; Therapeutic Uses

Results Point of Contact

• Title: Raman Baweja, MD
• Organization: Penn State College of Medicine

rbaweja@pennstatehealth.psu.edu

7175318521

Study Officials

• Raman Baweja, MD, MS

  Penn State Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: September 8, 2017
• First Posted: September 12, 2017
• Study Start: June 1, 2018
• Primary Completion: June 30, 2024
• Study Completion: June 30, 2024
• Last Updated: August 26, 2025
• Results First Posted: August 26, 2025

Record last verified: 2025-08

Locations

US (1)