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Neurophysiological Markers of Pediatric Irritability and Its Response to Intervention

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03279952
Recruitment Status : Recruiting
First Posted : September 12, 2017
Last Update Posted : July 19, 2021
Information provided by (Responsible Party):
Raman Baweja, Milton S. Hershey Medical Center

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.

Condition or disease Intervention/treatment Phase
ADHD Drug: CNS Stimulant Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 47 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Neurophysiological Markers of Pediatric Irritability and Its Response to Intervention
Actual Study Start Date : January 1, 2018
Estimated Primary Completion Date : July 1, 2022
Estimated Study Completion Date : July 1, 2022

Arm Intervention/treatment
medication arm
CNS Stimulant
Drug: CNS Stimulant
Participants will be stabilized by any FDA approved CNS stimulant medication during open label trial.

Primary Outcome Measures :
  1. change in parent rated irritability on the DBD irritability score [ Time Frame: Baseline and 6 weeks ]
    The primary outcome in this study will be the change in parent rated irritability on the DBD irritability score. Irritability will be assessed using the Disruptive Behavior Disorders (DBD) Parent Rating Scale rating symptoms on a 0-3 likert

  2. ADHD symptoms [ Time Frame: Baseline and 6 weeks ]
    Symptom severity for ADHD symptoms will be assessed using the Disruptive Behavior Disorders (DBD) Parent Rating Scale rating symptoms on a 0-3 likert

  3. ODD symptoms [ Time Frame: Baseline and 6 weeks ]
    Oppositional Defiant Disorder (ODD) symptoms will be assessed using the Disruptive Behavior Disorders (DBD) Parent Rating Scale rating symptoms on a 0-3 likert

Secondary Outcome Measures :
  1. Impairment Rating Scale (IRS) [ Time Frame: Baseline and 6 weeks ]
    Parents will complete the Impairment Rating Scale (IRS) to measure functioning across multiple domains.

  2. Modified Overt Aggression Scale (MOAS) [ Time Frame: Baseline and 6 weeks ]
    Parents will complete the Modified Overt Aggression Scale (MOAS) to measure aggression.

  3. Inventory of Callous Unemotional Traits [ Time Frame: Baseline and 6 weeks ]
    Parents will complete and Inventory of Callous Unemotional Traits to measure aggression.

  4. Affective Reactivity Index [ Time Frame: Baseline and 6 weeks ]
    Parents will complete the Affective Reactivity Index as an additional measure of irritability.

  5. Pittsburgh Side Effects Rating Scale (PSERS [ Time Frame: Baseline and 6 weeks ]
    Parents will complete the Pittsburgh Side Effects Rating Scale (PSERS) to evaluate side effects.

  6. Event related potentials (ERP) [ Time Frame: Baseline and 6 weeks ]
    We will also examine if loss and gain sensitivity on the ERP will be positively correlated with parent ratings of irritability

  7. Error related negativity (ERN) amplitude [ Time Frame: Baseline and 6 weeks ]
    we will examine if ERN amplitude in the response inhibition task when unmedicated will be inversely correlated with degree of improvement in irritability following optimization of CNS stimulant dose

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   5 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria: 1. Ages 5-12: CNS stimulant medications are commonly used and well studies in this age range (Mixed amphetamine salt has been approved for children age 3 + and methylphenidate has been used in FDA funded studies on preschool children; American Pediatric Association guidelines are also recommend for the preschool children) and these are the age ranges where children are most likely to present for treatment of irritability.

2. 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.

Exclusion Criteria:

  1. Age <5 years of age or >12 years of age.
  2. Children with significant visual or hearing deficits or sensitivity to loud noises as test performance requires intact hearing and vision.
  3. Children with a latex allergy as the sensors used in electrophysiology assessments have a latex component.
  4. Serious neurological conditions that impacts cognition, such as an active seizure disorder
  5. 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.
  6. Prominent traits of autism spectrum disorder (Social Communication Questionnaire Score >15), marked developmental delay or psychiatric conditions requiring urgent treatment (mania, psychoses, suicidal ideation).
  7. Parent or child not fluent in English

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03279952

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Contact: Raman Baweja, MD, MS 717 531 8134

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United States, Pennsylvania
Penn State Hershey Recruiting
Hershey, Pennsylvania, United States, 17036
Contact: Sara Mills, MS    717-531-0003 ext 285968   
Sponsors and Collaborators
Milton S. Hershey Medical Center
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Principal Investigator: Raman Baweja, MD, MS Penn State Health
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Responsible Party: Raman Baweja, Associate Professor, Milton S. Hershey Medical Center Identifier: NCT03279952    
Other Study ID Numbers: IRB: 00008087
First Posted: September 12, 2017    Key Record Dates
Last Update Posted: July 19, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Central Nervous System Stimulants
Physiological Effects of Drugs