Towards an Understanding of the Mechanism of Action of Methylphenidate in ADHD

Understanding the Mechanism of Action of Methylphenidate in ADHD: A Computational Psychiatry Approach

Approximately 1-in-20 children worldwide have Attention Deficit Hyperactivity Disorder (ADHD), a condition associated with disabling inattention, hyperactivity and impulsivity. These problems can manifest as poor inhibitory control (e.g., difficulty holding back impulsive actions) and atypical reward processing (e.g., failing to learn from adverse outcomes). Poorly treated ADHD is associated with negative academic and socioeconomic consequences.

This project aims to ultimately improve clinical management of children with ADHD. Methylphenidate, a stimulant medication, is used as the first-option pharmacological treatment for ADHD and often successfully reduces problem behaviour. Although Methylphenidate can be extremely effective, it does not work for every child. There is currently no 'objective' way (e.g., blood test or brain scan) to measure if a child is genuinely responding to Methylphenidate. Instead, clinicians must rely on reports from parents and teachers, an approach that is problematic and that often leads to delays in optimising ADHD treatment. The absence of a biological test to quantify Methylphenidate response is primarily because we do not understand exactly how Methylphenidate changes behaviours to produce the known beneficial effects. This lack of knowledge is despite the very common use of this medication.

This project will investigate the specific brain processes that are affected by Methylphenidate by recording brain activity and behaviour in children with ADHD (who have already been prescribed Methylphenidate as part of their clinical care) when they are on and off this medication. Brain activity will be recorded using two separate approaches, which are both non-invasive and routinely used in Trinity College Institute of Neuroscience: electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Brain activity data will be collected while children with ADHD are performing two computer-game like tasks. One task measures the child's ability to hold back impulsive actions (inhibition) and the other assesses how they learn from positive and negative outcomes (reward processing). The data from the two tasks, the EEG recording and the fMRI scan will be analysed using advanced computer-modelling approaches to determine exactly how Methylphenidate changes behaviour.

This project is important because if we can understand the brain mechanisms affected by Methylphenidate, we can ultimately develop a computerised measure that will allow clinicians to predict whether a child is going to respond to this treatment or not. Such a measure would allow clinicians to treat ADHD more effectively and would result in children with ADHD experiencing faster relief from symptoms.

Study Overview

• Status: Not yet recruiting
• Conditions: Attention Deficit Hyperactivity Disorder
• Intervention / Treatment: Drug: Methylphenidate

Detailed Description

This project will investigate the specific brain processes that are affected by Methylphenidate by recording brain activity and behaviour in children with ADHD (who have already been prescribed Methylphenidate as part of their clinical care) when they are on and off this medication.

This is a quantitative double-blind placebo-controlled study investigating the acute effects of methylphenidate on brain activity using two non-invasive methods, EEG and fMRI.

Brain activity will be recorded using two separate approaches, which are both non-invasive and routinely used in Trinity College Institute of Neuroscience: electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Brain activity data will be collected while children with ADHD are performing two computer-game like tasks. One task measures the child's ability to hold back impulsive actions (inhibition) and the other assesses how they learn from positive and negative outcomes (reward processing). The data from the two tasks, the EEG recording, and the fMRI scan will be analysed using advanced computer-modelling approaches to determine exactly how Methylphenidate changes behaviour.

• Study Type: Observational
• Enrollment (Anticipated): 35

Contacts and Locations

• Study Contact: Name: Julia Paterson, BSc, BCompSci; Phone Number: 0896164340; Email: jpaterso@tcd.ie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Approximately 35 participants aged 14-17 years old will be recruited.

As previous research on ADHD has overwhelmingly focussed on cisgender men, this study will recruit people who are 'Assigned Female At Birth' (AFAB). This is to include cisgender women alongside those who may not identify with womanhood such as those who are non-binary but AFAB or transgender men who have not undergone hormonal/medical transition.

Description

Inclusion Criteria:

AFAB Clinical diagnosis of ADHD Must be able to swallow tablets Regular menstrual cycles Good response to medication

Exclusion Criteria:

Intellectual Disability Specific Learning Disabilities

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
ADHD; This study will recruit people aged 14-17 with ADHD who are 'Assigned Female At Birth' (AFAB). This is to include cisgender women alongside those who may not identify with womanhood such as those who are non-binary but AFAB or transgender men who have not undergone hormonal/medical transition.	Drug: Methylphenidate; Participants will take their regular medication or a placebo (vitamin C)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI	structural, diffusion, functional	2023-2026

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stop Signal Task	behavioural measures	2023-2026

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
EEG	during SST	2023-2026

Collaborators and Investigators

• Sponsor: University of Dublin, Trinity College
• Collaborators: St. James's Hospital, Ireland

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2023
• Primary Completion (Anticipated): June 1, 2026
• Study Completion (Anticipated): September 1, 2026

Study Registration Dates

• First Submitted: October 26, 2022
• First Submitted That Met QC Criteria: October 26, 2022
• First Posted (Actual): November 1, 2022

Study Record Updates

• Last Update Posted (Actual): May 15, 2023
• Last Update Submitted That Met QC Criteria: May 10, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Attention Deficit Disorder with Hyperactivity; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Methylphenidate
• Other Study ID Numbers: MPH2022TCD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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