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Low-dose vs. Normal-dose Psychostimulants on Executive Functions in Individuals With ADHD

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ClinicalTrials.gov Identifier: NCT02167048
Recruitment Status : Unknown
Verified November 2018 by Adele Diamond, University of British Columbia.
Recruitment status was:  Recruiting
First Posted : June 18, 2014
Last Update Posted : November 29, 2018
Sponsor:
Information provided by (Responsible Party):
Adele Diamond, University of British Columbia

Brief Summary:

This double-blind crossover study aims to compare cognitive performance (e.g., working memory, selective attention and cognitive flexibility) of children ages 6-18 years diagnosed with ADHD of the combined type (ADHD-C) or inattentive-type (ADHD-IA) and currently on > 20 mg/day of psychostimulants (psychostimulants) on: a) their current dose of psychostimulants, vs. b) a lower-dose of psychostimulants (half of their current dose).

The investigators hypothesize that the lower-dose psychostimulants will result in better cognitive performance than moderate-to-high doses of psychostimulants.


Condition or disease Intervention/treatment Phase
Attention Deficit Hyperactivity Disorders Drug: Psychostimulants Phase 1 Phase 2

Detailed Description:

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by attention deficits, hyperactivity, or impulsive actions that are not appropriate for the individuals' age (Barkley 1997). These behavioural issues arise relatively early in life, typically before the age of 12, and continue to persist into adulthood in many cases (Barkley 1997). In school-aged children, ADHD is associated with low academic achievement, poor school performance, anxiety and depression.

Symptoms are divided into inattention (e.g., easily distracted, difficulty focusing on & completing a task), hyperactivity (e.g., constantly in motion, fidgets, squirms, talks non-stop), and impulsivity (e.g., difficult waiting one's turn, interrupting others). Three subtypes of ADHD have been identified: predominantly inattentive (ADHD-I), predominantly hyperactive-impulsive (ADHD-H), and the combined type (ADHD-C).

Psychostimulants in medium to high doses acts to inhibit re-uptake of dopamine by the dopamine transporter (DAT), resulting in increased dopamine concentrations in the synapse. DAT is abundant in the striatum, which is implicated in hyperactivity and impulsivity aspects of ADHD. However, DAT is sparse in prefrontal cortex (PFC), which plays a critical role in subserving executive functions. Executive functions (EFs; also called cognitive control or self-regulation) are a group of processes involved in concentration, focused attention, self-control, cognitive flexibility, problem-solving, and working memory (refs: Diamond, 2013; Jacques & Marcovitch, 2010). Thus the number of high risk alleles of the gene that codes for the dopamine transporter (DAT1) are associated with hyperactivity (which depends on the striatum) but not inattention or EF deficits (which depend on PFC; refs: Jucaite et al., 2005; Waldman et al., 1998.

The action of low doses of psychostimulants has been shown to be different, however. At low doses psychostimulants has been demonstrated to act preferentially on PFC, increasing dopamine release (refs: Berridge et al., 2006; Schmeichel & Berridge, 2013; Spencer et al, 2012). Thus, moderate to high doses of psychostimulants (doses most often prescribed for children and youths with ADHD) probably do not improve PFC function or EFs, or worse, may actually impair cognitive function, leaving a patient feeling more in a daze.

Optimal dosing for psychostimulants in children and youths with ADHD is usually determined by parents' reports of improved behaviour, almost never by performance on cognitive measures. We propose to look at cognitive performance on measures of attention, working memory, planning, etc. in children and youths with ADHD on their current dose of psychostimulants and on half that much (order counterbalanced across participants).

Purpose/Objectives: This double-blind crossover study aims to compare cognitive performance (e.g., working memory, selective attention and cognitive flexibility) of children ages 6-18 years diagnosed with ADHD of the combined type (ADHD-C) or inattentive-type (ADHD-IA) and currently on > 20 mg/day of psychostimulants on their current dose of psychostimulants and on a lower-dose of psychostimulants (half of their current dose), order counterbalanced across subjects.

To give us an estimate of order effects to help us correct for better performance in the 2nd session due simply to taking the same cognitive tests twice (note: the tests are Version A and B), we will also be recruiting healthy volunteers to serve as a control group. This control group will be strictly no intervention.

Hypotheses: The investigators hypothesize that lower-dose psychostimulants will result in better cognitive performance than moderate-to-high doses of psychostimulants.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Low-dose Versus Normal-dose Psychostimulants on Executive Functions in Individuals With Attention-Deficit Hyperactivity Disorder
Study Start Date : June 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Normal-dose Psychostimulant, Low-dose
Normal-dose: Dose participants are currently taking as part of their prescription (on more than or equals to 20 mg/day of Psychostimulants) Low-dose: Half the normal dose
Drug: Psychostimulants

Participants will be tested twice 2 weeks apart. All will continue on their normal Psychostimulant dose up until 3 days before the testing day. 3 days before their 1st testing session, half the participants will start on either their current-dose of Psychostimulant or half their current dose depending on the arm they were randomized to (we provide those pills).

To control for different pharmacokinetics of the Psychostimulant medications, a given participant will be tested at roughly the peak time for his/her specific version of Psychostimulant and at the same time of day for his/her two testing sessions.


Active Comparator: Low-dose Psychostimulants, Normal-dose
Normal-dose: Dose participants are currently taking as part of their prescription (on more than or equals to 20 mg/day of Psychostimulants) Low-dose: Half the normal dose
Drug: Psychostimulants

Participants will be tested twice 2 weeks apart. All will continue on their normal Psychostimulant dose up until 3 days before the testing day. 3 days before their 1st testing session, half the participants will start on either their current-dose of Psychostimulant or half their current dose depending on the arm they were randomized to (we provide those pills).

To control for different pharmacokinetics of the Psychostimulant medications, a given participant will be tested at roughly the peak time for his/her specific version of Psychostimulant and at the same time of day for his/her two testing sessions.


No Intervention: No intervention, No intervention
This arm is completely no intervention, and is ONLY for healthy volunteers. We are testing healthy volunteers of the same age to give us an estimate of order effects to help us correct for better performance in the 2nd session due simply to taking the same tests twice (note: the tests are Version A and B).



Primary Outcome Measures :
  1. Executive Functions (difference in performance on the two Psychostimulants doses) [ Time Frame: Day 1 ]
    Executive Functions consist of selective attention, working memory, response inhibition, reasoning, and set switching. Each of those component abilities will be assessed, scores converted to z scores, and a composite score assigned to each subject for each test session.

  2. Executive Functions (difference in performance on the two Psychostimulant doses) [ Time Frame: 2 weeks ]
    Executive Functions consist of selective attention, working memory, response inhibition, reasoning, and set switching. Each of those component abilities will be assessed, scores converted to z scores, and a composite score assigned to each subject for each test session.



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Between the chronological ages of 6 and 18 years
  • Average to above-average IQ (Parental report of an IQ above 90; we will take their word for it)
  • Meet DSM-V criteria for ADHD (Combined type or Inattentive type)
  • Currently treated with and responding to oral Psychostimulants >= 20 mg/day and not on a "drug holiday"
  • Stable on current Psychostimulant dose for at least 2 weeks
  • Able to communicate (understand, speak, and write) in English without the aid of an interpreter
  • Able to execute simple manual response (button-press) as required for our tasks
  • The child and parent give assent and consent respectively for the child's participation in this study

Exclusion Criteria:

  • Patients with significant prior or current medical conditions that could impact neuropsychological performance such as traumatic brain injury, hypoxia, or unstable diabetes.
  • Have any medical condition that could markedly increase sympathetic nervous system activity (e.g. catecholamine-secreting neural tumor), or who are taking a medication on a daily basis (e.g. pseudoephedrine, oral steroids) that has sympathomimetic activity. Note: regular on-label use of inhalers for asthma (e.g., albuterol, steroidal) is permitted
  • Taking any psychotropic medication other than on-label Psychostimulants specifically prescribed to treat ADHD
  • Have a major, uncorrected sensory impairment (e.g. significant hearing impairment despite hearing aids)
  • Lack sufficient English language skills to perform our tasks
  • Are taking medications other than their specifically prescribed Psychostimulants that may affect cognitive skills
  • Have a documented history of Dyslexia (this may skew results on our cognitive measures), Bipolar I or II, psychosis, Depression, Autism Spectrum Disorders, or Disruptive Mood Dysregulation Disorder
  • Have a past history of any severe adverse reaction to lowering of Psychostiumlant dose
  • Patient has been non-compliant with Psychostimulants or is on a "drug holiday"
  • Parental report of an IQ below 90 (we will take their word for it)

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 ClinicalTrials.gov identifier (NCT number): NCT02167048


Contacts
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Contact: Daphne Ling, B.Sc. (Hon) 604-827-3074 daphne.ling@ubc.ca
Contact: David Abbott, B.Sc. (Hon) 604-827-3074 david.abbott@ubc.ca

Locations
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Canada, British Columbia
Developmental Cognitive Neuroscience Lab, Department of Psychiatry, University of British Columbia Recruiting
Vancouver, British Columbia, Canada, V6T 2A1
Contact: Daphne Ling, B.Sc. (Hon)    604-827-3074    daphne.ling@ubc.ca   
Contact: David Abbott, B.Sc. (Hon)    604-827-3074    david.abbott@ubc.ca   
Principal Investigator: Adele Diamond, Ph.D.         
Sponsors and Collaborators
University of British Columbia
Investigators
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Principal Investigator: Adele Diamond, Ph.D. Department of Psychiatry, University of British Columbia
Publications:
Jacques, S., & Marcovitch, S. (2010). Development of executive function across the life span. In W. F. Overton (Ed.), Cognition, biology and methods across the lifespan: Volume 1 of the handbook of life-span development (pp. 431-466). Hoboken, NJ: Wiley.

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Responsible Party: Adele Diamond, Principal Investigator, University of British Columbia
ClinicalTrials.gov Identifier: NCT02167048    
Other Study ID Numbers: H14-00224
First Posted: June 18, 2014    Key Record Dates
Last Update Posted: November 29, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Adele Diamond, University of British Columbia:
Attention Deficit Hyperactivity Disorders
Executive Function
Methylphenidate
Psychostimulants
Adolescent
Child
Working Memory
Prefrontal Cortex
Attention
Cognitive Function
Inhibition
Additional relevant MeSH terms:
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Hyperkinesis
Attention Deficit Disorder with Hyperactivity
Attention Deficit and Disruptive Behavior Disorders
Neurodevelopmental Disorders
Mental Disorders
Dyskinesias
Neurologic Manifestations
Nervous System Diseases