The Effects of ADHD Medication (TEAM) Study: Neurobehavioral Effects of Abrupt Methylphenidate Discontinuation

The Effects of ADHD Medication (TEAM) Study

Sponsors

Lead sponsor: Children's Hospital Medical Center, Cincinnati

Collaborator: Seattle Children's Hospital

Source Children's Hospital Medical Center, Cincinnati
Brief Summary

This study evaluates the effects of receiving and then discontinuing methylphenidate (MPH) in children with ADHD. After receiving MPH for 8 weeks, participants will be randomized to either discontinue MPH (and receive placebo) OR remain on MPH for 4 weeks.

Detailed Description

The stimulant methylphenidate (MPH) is the most commonly prescribed psychoactive medication in children. An abundance of studies attest to the efficacy of MPH for attenuating inattentive, hyperactive, and impulsive symptoms in children with ADHD. Despite its efficacy, most children with ADHD who are prescribed MPH have poor continuity of treatment for a variety of reasons, including forgetting to administer the medication and delays obtaining refills. In addition, it is an accepted clinical practice for physicians to omit MPH for periods of time, such as during the summer or on weekends (i.e., drug holidays). Since MPH discontinuation is considered to be benign, many clinicians do not employ any special procedures or inform families of any special precautions in regard to its cessation. However, increasing evidence suggests that the pharmacological effects of MPH cause lasting changes in brain neurochemistry that persist beyond medication discontinuation. Moreover, these neurobiological effects of discontinuation appear to have neurobehavioral consequences. There is a critical need to better understand the breadth and magnitude of the neurobehavioral effects caused by MPH discontinuation as well as to better understand the temporal trajectory of these deleterious effects. Hence, the primary goal of the proposed research is to conduct the first randomized, double-blind, placebo-controlled trial specifically designed to study the negative effects of MPH discontinuation at multiple time points. 180 children diagnosed with ADHD will participate across two recruitment sites. After undergoing a 4-week MPH titration trial and 4-week MPH maintenance phase, participants will be randomized to either discontinue MPH (and receive placebo) OR remain on MPH for 4 weeks. Comprehensive multi-time point, multi-informant (parents, teachers, study staff) and multi-modal (behavior/mood/affect ratings scales, direct behavior observations, standardized testing) assessments will be used to assess a broad range of neurobehavioral outcomes. We will examine the magnitude and time course of effects of MPH discontinuation on behavioral as well as cognitive and academic functioning in children with ADHD. Furthermore, we will examine moderators of the adverse effects of MPH discontinuation on these outcomes to aid in the identification of those who are at increased risk.

Overall Status Recruiting
Start Date January 2015
Completion Date June 1, 2020
Primary Completion Date June 1, 2020
Phase Phase 4
Study Type Interventional
Primary Outcome
Measure Time Frame
ADHD symptom scores baseline, study weeks 1, 2, 3, 4, 8, 9, 10 &12
Off-task behavior baseline, study weeks 1, 8, 9, 10 & 12
Inhibitory control reaction time variability baseline, study weeks 1, 8, 9, 10 & 12
Math computation baseline, study weeks 1, 8, 9, 10 & 12
Secondary Outcome
Measure Time Frame
Sluggish cognitive tempo (SCT) ratings baseline, study weeks 1, 2, 3, 4, 8, 9, 10 &12
Executive function ratings baseline, study weeks 1, 8, 9, 10 &12
Child ratings of depression baseline, study weeks 1, 8, 9, 10 &12
Child ratings of anxiety baseline, study weeks 1, 8, 9, 10 &12
Child ratings of suicidality baseline, study weeks 1, 8, 9, 10 &12
Parent ratings of emotional regulation baseline, study weeks 1, 8, 9, 10 &12
Side effect ratings baseline, study weeks 1, 2, 3, 4, 8, 9, 10 &12
Sleep ratings baseline, study weeks 1, 8, 9, 10 &12
Ecological Momentary Assessment Baseline, weeks 1, 8, and 9-12
School observations baseline, study weeks 1, 8, 9, 10 &12
Spatial working memory baseline, study weeks 1, 8, 9, 10 &12
Math reasoning baseline, study weeks 1, 8, 9, 10 &12
Reading fluency and comprehension baseline, study weeks 1, 8, 9, 10 &12
Written expression baseline, study weeks 1, 8, 9, 10 &12
Spelling baseline, study weeks 1, 8, 9, 10 &12
Enrollment 180
Condition
Intervention

Intervention type: Drug

Intervention name: OROS-Methylphenidate (MPH)

Description: OROS-methylphenidate will be taken orally once daily at doses that have been approved for the study age group by the U.S. FDA.

Other name: Concerta

Eligibility

Criteria:

Inclusion Criteria:

1. ADHD Diagnostic Status: Meets DSM-V criteria for ADHD, with Clinical Global Impression (CGI) rating corresponding to at least "moderately ill."

2. Cognitive and Academic Functioning: Intelligence Quotient (IQ) of >80 as estimated by Vocabulary and Block Design subtests of the Wechsler Intelligence Scale for Children-4th Edition and scaled scores >80 on the Wechsler Individual Achievement Test-2nd edition Reading and Math subtests

3. Physical Health: Physical exam and ECG findings are judged to be normal for age and sex by study physician and/or medical consultant, and there is no co-existing condition for which MPH is contraindicated 4. School: Enrolled in a school setting rather than a home-school program. This ensures that we can obtain parent and teacher ratings from separate individuals for diagnosis and outcome assessment

Exclusion Criteria:

1. Psychiatric Medications: Current or prior use of any medication for psychological/psychiatric problems

2. Behavioral Interventions: Current active participation in ADHD-related behavioral interventions, given that improvements due to these interventions may confound our group comparisons

3. Psychiatric or Neurobehavioral Conditions: Children with mania/hypomania, schizophrenia, or severe depressive disorder, as determined by the K-SADS, will be excluded since ADHD medications may not be an appropriate first line of treatment for children with these comorbid disorders

4. Organic Brain Injury: History of head trauma, neurological disorder (including epilepsy), or other disorder affecting brain function due to potential differences in neurophysiology of ADHD phenotype

5. Cardiovascular Risk Factors: Children with a personal history or family history of cardiovascular risk factors will be excluded, or given the option of participating in the study after obtaining an EKG and verification from a pediatric cardiologist regarding the safety of their participation in a trial of methylphenidate. In this case, families will be responsible for the costs of EKG and any necessary cardiologist evaluation

6. Pregnancy: The safety of MPH use during pregnancy has not been established

Gender: All

Minimum age: 7 Years

Maximum age: 11 Years

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Tanya E. Froehlich, MD Principal Investigator Children's Hospital Medical Center, Cincinnati
Overall Contact

Last name: Tanya E. Froehlich, MD

Phone: 513-636-1154

Email: [email protected]

Location
facility status contact
Children's Hospital Medical Center | Cincinnati, Ohio, 45229, United States Recruiting Tanya E. Froehlich, MD 513-636-1154 [email protected]
Seattle Children's Hospital | Seattle, Washington, 98105, United States Not yet recruiting Mark A. Stein, PhD 206-987-2164 [email protected]
Location Countries

United States

Verification Date

April 2020

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Number Of Arms 2
Arm Group

Arm group label: MPH Discontinuation

Arm group type: Placebo Comparator

Description: Double-blind (DB) placebo-controlled 4-week methylphenidate (MPH) titration trial. Pts will receive 3 active dosages of MPH (children <25kg: 18mg, 27mg, 36mg; children >25kg: 18mg, 36mg, 54mg for) as well as 1 random week of placebo, given qAM. Pts will begin on the lowest dose (or a randomized placebo week) and proceed through all dose conditions in an incremental fashion. DB 4-week MPH maintenance phase. The clinician, parent, and teacher ratings of behavior and side effects from the titration trial weeks will be graphed. Two doctors will blindly review the graphs and judge which week was the optimal dose week. Pts will then receive their optimal dose of MPH (qAM) for 4 weeks. DB 4-week MPH Discontinuation Phase. Pts in this arm will receive placebo (qAM).

Arm group label: Sustained MPH

Arm group type: Active Comparator

Description: Double-blind (DB) placebo-controlled 4-week methylphenidate (MPH) titration trial. Pts will receive 3 active dosages of MPH (children <25kg: 18mg, 27mg, 36mg; children >25kg: 18mg, 36mg, 54mg for) as well as 1 random week of placebo, given qAM. Pts will begin on the lowest dose (or a randomized placebo week) and proceed through all dose conditions in an incremental fashion. DB 4-week MPH maintenance phase. The clinician, parent, and teacher ratings of behavior and side effects from the titration trial weeks will be graphed. Two doctors will blindly review the graphs and judge which week was the optimal dose week. Pts will then receive their optimal dose of MPH (qAM) for 4 weeks. DB 4-week MPH Discontinuation Phase. Pts in this arm will continue their optimal MPH dose (qAM).

Acronym TEAM
Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov