Stimulant Versus Nonstimulant Medication for Attention Deficit Hyperactivity Disorder in Children

Measuring and Predicting Response to Atomoxetine and Methylphenidate

This study will determine the effectiveness of stimulant and nonstimulant medication in treating the symptoms of attention deficit hyperactivity disorder (ADHD) in children and adolescents.

Study Overview

• Status: Completed
• Conditions: Attention Deficit Disorder With Hyperactivity
• Intervention / Treatment: Drug: Atomoxetine; Drug: Methylphenidate

Detailed Description

ADHD is one of the most frequently occurring disorders of children and adolescents and is a significant public health problem. The most common treatment for the condition is stimulant medication. However, there are an increasing number of children who are experiencing negative side effects from stimulants, such as dizziness, loss of appetite, and headaches; these side effects have made the need for alternative treatments all the more important. This study will compare the stimulant methylphenidate to the nonstimulant atomoxetine to determine which is more effective in treating ADHD symptoms in children and adolescents. The two medications differ in the neurotransmitters they influence. Stimulants such as methylphenidate act upon the neurotransmitter dopamine, while atomoxetine works on norepinephrine. It has been proposed that the difference in neurotransmitter stimulation may result in differences in an ADHD patient's response to treatment.

Participants will be randomly assigned to receive either methylphenidate or atomoxetine for between 4 to 6 weeks, depending on how soon they respond to the treatment. After the 4 to 6 week period, participants will be crossed-over to receive whichever medication they did not receive in the first part of the study.

Participants will have up to 14 weekly study visits. Over the first two visits, participants will undergo psychological and intelligence tests, a medical history, an electrocardiogram, blood and urine collection, and a physical exam. The remaining visits will occur weekly. During these visits, participants will receive their assigned medication and, along with their parents, will complete questionnaires about their response to treatment and any side effects they may be experiencing. The teachers of all participants will be asked to complete a questionnaire about their student's behavior at 4 different times during the study. Participant, parent, and teacher questionnaires will be used to assess the ADHD symptoms of participants, as well as self-report clinical scales completed by the participants.

• Study Type: Interventional
• Enrollment (Actual): 232
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois, Chicago - Institute for Juvenile Research
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Meets DSM-IV-TR criteria for ADHD
• Scores at least 1.5 standard deviation higher than age and gender mean on ADHD-RS keyed to ADHD subtype
• CGI Severity ADHD Rating greater than or equal to 4
• Currently attends school with at least 3 months left in high school
• Currently lives at home with parent(s) or legal guardian(s), now and for the past year before study entry, and is expected to remain there
• Normal physical exam, laboratory tests, and electrocardiogram
• Pulse and blood pressure within 95% of age and gender mean
• Full Scale IQ is greater than or equal to 75 OR if the results of testing indicate that Full Scale IQ is not a good indicator of intellectual ability, a General Ability Index greater than or equal to 75
• Weight is between 20 and 85 kilograms
• Able to swallow pills
• Parent or guardian willing to provide informed consent

Exclusion Criteria:

• History of atomoxetine or methylphenidate intolerance
• Any existing medical condition for which study medications are contraindicated
• If the child is in psychotherapy, no changes in therapy expected during the study trial
• Presence of any of the following: autism, mental retardation, schizophrenia, a psychotic disorder, bipolar disorder, severe depression, or conduct disorder
• Presence of a comorbid disorder that should be the primary focus of treatment
• Presence of a medical or neurological disorder precluding study medications or assessing ADHD
• Allergic reactions to multiple medications
• History of alcohol or drug abuse in the 3 months before study entry, or positive urine toxic screen that is not explained by a time limited medical circumstance
• Involved in a medication treatment study in the 30 days before study entry
• Female who is sexually active and is unwilling to use birth control
• Evidence of child abuse or neglect

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Atomoxetine; Participants will receive treatment for ADHD with the non-stimulant atomoxetine	Drug: Atomoxetine; Participants will be randomly assigned to receive either methylphenidate or atomoxetine for either 2 or 5 weeks, depending on how soon they respond to the treatment. After the 2- or 5-week period, participants will be crossed-over to receive whichever medication they did not receive in the first part of the study.; Drug: Methylphenidate; Participants will be randomly assigned to receive either methylphenidate or atomoxetine for either 2 or 5 weeks, depending on how soon they respond to the treatment. After the 2- or 5-week period, participants will be crossed-over to receive whichever medication they did not receive in the first part of the study.
Active Comparator: Methylphenidate; Participants will receive treatment for ADHD with the stimulant methylphenidate	Drug: Atomoxetine; Participants will be randomly assigned to receive either methylphenidate or atomoxetine for either 2 or 5 weeks, depending on how soon they respond to the treatment. After the 2- or 5-week period, participants will be crossed-over to receive whichever medication they did not receive in the first part of the study.; Drug: Methylphenidate; Participants will be randomly assigned to receive either methylphenidate or atomoxetine for either 2 or 5 weeks, depending on how soon they respond to the treatment. After the 2- or 5-week period, participants will be crossed-over to receive whichever medication they did not receive in the first part of the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ADHD-RS Total Score	ADHD-RS Total Score Attention Deficit Hyperactivity Disorder Rating Scale. Each item on the 18-item measure is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), yielding a possible total score of 0-54. Higher score indicates higher probability of diagnosis.	up to 14 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Preference Survey		Measured at ends of treatments one and two
ADHD - H/I	Attention deficit/hyperactivity disorder - hyperactivity/impulsivity (ADHD- H/I). Each item on the 18-item measure is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), yielding a possible total score of 0-27. Higher score indicates higher probability of diagnosis.	up to 14 weeks
ADHD-RS Inattention	Each item on the 18-item measure is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), yielding a possible total score of 0-27. Higher score indicates higher probability of diagnosis.	up to 14 weeks
Clinical Global Impressions (CGI)- Severity	The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.	up to 14 weeks
Social Skills Rating Scale (SSRS)- Parent Version	Measure of social skills, higher score is better. This scale is based on t-scores and does not have psychometrics available.	up to 14 weeks
Child Conflict Index (CCI)	Measure of conflict within the home over the past 24 hours. The CCI is a validated measure of family conflicts in the home and is completed by parents. It consists of 42 items (for boys) or 36 items (for girls) reflecting attention-seeking and conflictual behavior, as well as negativity and withdrawal. Items are scored as yes (1 point) or no (0 points). Mean score between 0 and 1 reported, with higher score indicating greater conflict.	up to 14 weeks
Continuous Performance Test (CPT)	CPT Commissions, impulsive responses, higher score is worse. This scale is based on t-scores and does not have psychometrics available.	up to 14 weeks
Children's Sleep Questionnaire	Children's Sleep Problems Severity, sum of scores, higher is worse.The scale assessed contains 16 items, each scored 0 to 3, with 0 representing no problems and 3 representing daily problems. total range from 0 to 48. This score does not have psychometrics available.	up to 14 weeks
Assessment of Affective Range (AAR)	Affective problems. This scale consists of 8 items, scored 0-3, with 0 representing no problems and 3 representing extreme problems. This analysis presents sum of scores, higher is worse. Full range from 0 to 24. This score does not have psychometrics available.	up to 14 weeks
Tics: Total Motor	Modified Yale Global Tic Severity Scale, sum, higher is worse. This score does not have psychometrics available. The Yale Global Tic Severity Scale (YGTSS) is a semistructured clinician-rated instrument that assesses the severity and frequency of motor and phonic tics over the previous week. Five index scores are obtained during the assessment, where higher scores indicate greater frequency or severity. These indices are: Total Motor Tic Score (0-25), Total Phonic Tic Score (0-25), Total Tic Score (0-50) Overall Impairment Rating (0-50).	up to 14 weeks
Tics: Total Phonic	Modified Yale Global Tic Severity Scale, sum, higher is worse. This score does not have psychometrics available. The Yale Global Tic Severity Scale (YGTSS) is a semistructured clinician-rated instrument that assesses the severity and frequency of motor and phonic tics over the previous week. Five index scores are obtained during the assessment, where higher scores indicate greater frequency or severity. These indices are: Total Motor Tic Score (0-25), Total Phonic Tic Score (0-25), Total Tic Score (0-50) Overall Impairment Rating (0-50).	up to 14 weeks
Tics: Total Impairment	Modified Yale Global Tic Severity Scale, sum, higher is worse. This score does not have psychometrics available. The Yale Global Tic Severity Scale (YGTSS) is a semistructured clinician-rated instrument that assesses the severity and frequency of motor and phonic tics over the previous week. Five index scores are obtained during the assessment, where higher scores indicate greater frequency or severity. These indices are: Total Motor Tic Score (0-25), Total Phonic Tic Score (0-25), Total Tic Score (0-50) Overall Impairment Rating (0-50).	up to 14 weeks
Vital Signs - Systolic Blood Pressure	Systolic blood pressure - the amount of pressure in arteries during contraction of the heart muscle Normal range varies by age, sex, height and weight and can range from 80mm Hg to 130mmHg	up to 14 weeks
Vital Signs - Diastolic Blood Pressure	Diastole blood pressure - blood pressure when the heart muscle is between beats. normal range varies by age, sex, height and weight and can range from 34mm Hg to 90mmHg	up to 14 weeks
Vital Signs - Pulse	Heartbeats per minute. Range varies from 50-205 depending on age and level of activity.	up to 14 weeks
SES (Hollingshead)	Measure of socioeconomic status, score calculated from averaging likert responses, lower = worse	up to 14 weeks
Conners-Wells Adolescent Self Report	Standardized measure of ADHD symptoms and severity, norm referenced T scores, higher = worse	up to 14 weeks
Conners Teacher Rating Scale- Short	Standardized measure of ADHD symptoms and severity, norm referenced T scores, higher = worse	up to 14 weeks
Child Behavior Checklist (CBCL)	CBCL Total Score, measure of psychosocial problems, higher is worse.	Measured at screening
Social Skills Rating Scale (SSRS)- Teacher Version	Measure of social skills, higher score is better. This scale is based on t-scores and does not have psychometrics available.	up to 14 weeks
Permanent Mathematics Product Test (PERMP)	Measure of fluency in performance of simple mathematics, sum, lower = worse	up to 14 weeks
Actigraphy	Measure of physical activity	Measured daily throughout the study
Sleep Logs	Questionnaire, qualitative	Measured daily throughout the study
Hyperactivity, Attention, and Learning Problems (HALP) Medical and Developmental History Questionnaire	Questionnaire, qualitative designed to collect family history, prenatal environmental influences, and developmental history.	Measured at screening
HALP Rebound Effects Questionnaire	Questionnaire, qualitative assesses symptoms of rebound (moodiness, irritability, aggression, and ADHD symptoms) when the medication wears off at night.	up to 14 weeks

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Jeffrey H. Newcorn, MD, Icahn School of Medicine at Mount Sinai; Principal Investigator: Mark A. Stein, PhD, University of Illinois, Chicago - Institute for Juvenile Research

Publications and helpful links

General Publications

• Bedard AC, Stein MA, Halperin JM, Krone B, Rajwan E, Newcorn JH. Differential impact of methylphenidate and atomoxetine on sustained attention in youth with attention-deficit/hyperactivity disorder. J Child Psychol Psychiatry. 2015 Jan;56(1):40-8. doi: 10.1111/jcpp.12272. Epub 2014 Jun 19.
• Schulz KP, Bedard AV, Fan J, Hildebrandt TB, Stein MA, Ivanov I, Halperin JM, Newcorn JH. Striatal Activation Predicts Differential Therapeutic Responses to Methylphenidate and Atomoxetine. J Am Acad Child Adolesc Psychiatry. 2017 Jul;56(7):602-609.e2. doi: 10.1016/j.jaac.2017.04.005. Epub 2017 May 10.

Study record dates

Study Major Dates

• Study Start: July 1, 2005
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): June 1, 2011

Study Registration Dates

• First Submitted: September 13, 2005
• First Submitted That Met QC Criteria: September 13, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Actual): June 6, 2018
• Last Update Submitted That Met QC Criteria: May 4, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Adolescent; Child; ADHD; School
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Dyskinesias; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Attention Deficit Disorder with Hyperactivity; Hyperkinesis; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Adrenergic Uptake Inhibitors; Methylphenidate; Atomoxetine Hydrochloride
• Other Study ID Numbers: GCO 03-0612-00002; R01MH070935 (U.S. NIH Grant/Contract); R01MH070564 (U.S. NIH Grant/Contract); DSIR 84-CTM

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No