Differential task-related fMRI effects of a single dose of guanfacine and lisdexamfetamine in youth with ADHD: a randomised, double-blind, placebo-controlled crossover study
- 1Department of Child & Adolescent Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK
Abstract
BackgroundStimulant and non-stimulant medications increase fronto-striato-thalamic activation in youth with Attention-Deficit/Hyperactivity Disorder (ADHD). However, comparative effects of the more recently licensed stimulant lisdexamfetamine and non-stimulant guanfacine on functional magnetic resonance imaging (fMRI) correlates in ADHD are unknown.
MethodsThis exploratory randomised, placebo-controlled, double-blind, crossover study compared fMRI activation in youth with ADHD during a tracking stop-signal task (SST; N = 12), a working memory task (N-back; N = 11) and a sustained attention task (SAT; N = 10), after single clinical doses of either guanfacine extended-release, lisdexamfetamine, or placebo, with one-week washouts. Twenty-one demographically matched typically developing controls (TD) were assessed once to test for potential normalisation of case-control activation differences.
ResultsRegion of interest analysis showed increased right caudate and putamen activation for lisdexamfetamine versus placebo during N-back and SAT, respectively. Both drugs shared an increase in left superior temporal activation versus placebo during N-back. In whole-brain analyses only lisdexamfetamine increased precuneus/posterior cingulate activation during SST versus guanfacine, and during N-back in pre- and postcentral and occipital cortices versus placebo. During SST, placebo-treated ADHD versus TD showed reduced putamen, insula, parietal and occipital activation that was potentially attenuated/normalised under lisdexamfetamine, while under guanfacine lingual gyrus underactivation remained, with additional precuneus and middle temporal underactivation. Also, only lisdexamfetamine improved and normalised SST performance.
ConclusionLisdexamfetamine appears to have stronger and drug-exclusive upregulation and potential attenuation/normalisation effects than guanfacine on basal ganglia, posterior parieto-occipital and sensorimotor activation during ADHD-relevant executive function tasks with some shared superior temporal and putamen effects.
Trial registrationClinicalTrials.gov (NCT03333668; https://clinicaltrials.gov/study/NCT03333668).
Related
- Intravenous [Pyr¹]apelin-13 in Healthy Volunteers with Artificially-Induced Syndrome of Inappropriate Antidiuresis - a double-blind, randomised, placebo-controlled crossover study
- Effects of Acute Ecklonia cava Supplementation on Submaximal Cycling and Repeated-Sprint Performance in Trained Cyclists: A Randomised Double-Blind Placebo-Controlled Crossover Trial
- Gut Regulated Associations of Neuronal Signalling in High Blood Pressure (GRAINS-BP): a double-blinded randomised crossover placebo-controlled trial.
- Differential physical activity responses to diabetes risk reduction interventions according to prediabetes phenotype in at-risk individuals: pooled analysis from three randomised controlled trials
- Long-Term Effects of Paced Heart Rate on Central Blood Pressure in Patients with Sinus Node Dysfunction and Hypertension: A Randomised Crossover Study
BibTeX
@misc{masri2026differential,
title = {{Differential task-related fMRI effects of a single dose of guanfacine and lisdexamfetamine in youth with ADHD: a randomised, double-blind, placebo-controlled crossover study}},
author = {S. El Masri and O. S. Kowalczyk and M. Criaud and S. Lukito and N. Mazibuko and G. Salazar de Pablo and V. Perez-Rodriguez and O. Makos and S.-L. Lam and S. Westwood and A. Eaton-Turner and N. Bozhilova and A. A. Conti and S. Stephenson and M. Rogdaki and N. Adamo and L. Johansson and D. Ougrin and F. Almowasi and P. Santosh and V. Roessner and G. Kohls and M. A. Mehta and K. Rubia},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.26364506},
url = {https://www.medrxiv.org/content/10.64898/2026.10.01.26364506v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Differential task-related fMRI effects of a single dose of guanfacine and lisdexamfetamine in youth with ADHD: a randomised, double-blind, placebo-controlled crossover study
AU - S. El Masri
AU - O. S. Kowalczyk
AU - M. Criaud
AU - S. Lukito
AU - N. Mazibuko
AU - G. Salazar de Pablo
AU - V. Perez-Rodriguez
AU - O. Makos
AU - S.-L. Lam
AU - S. Westwood
AU - A. Eaton-Turner
AU - N. Bozhilova
AU - A. A. Conti
AU - S. Stephenson
AU - M. Rogdaki
AU - N. Adamo
AU - L. Johansson
AU - D. Ougrin
AU - F. Almowasi
AU - P. Santosh
AU - V. Roessner
AU - G. Kohls
AU - M. A. Mehta
AU - K. Rubia
PY - 2026
DA - 2026/10/01
PB - medRxiv
DO - 10.64898/2026.10.01.26364506
UR - https://www.medrxiv.org/content/10.64898/2026.10.01.26364506v1
AB - BackgroundStimulant and non-stimulant medications increase fronto-striato-thalamic activation in youth with Attention-Deficit/Hyperactivity Disorder (ADHD). However, comparative effects of the more recently licensed stimulant lisdexamfetamine and non-stimulant guanfacine on functional magnetic resonance imaging (fMRI) correlates in ADHD are unknown. MethodsThis exploratory randomised, placebo-controlled, double-blind, crossover study compared fMRI activation in youth with ADHD during a tracking stop-signal task (SST; N = 12), a working memory task (N-back; N = 11) and a sustained attention task (SAT; N = 10), after single clinical doses of either guanfacine extended-release, lisdexamfetamine, or placebo, with one-week washouts. Twenty-one demographically matched typically developing controls (TD) were assessed once to test for potential normalisation of case-control activation differences. ResultsRegion of interest analysis showed increased right caudate and putamen activation for lisdexamfetamine versus placebo during N-back and SAT, respectively. Both drugs shared an increase in left superior temporal activation versus placebo during N-back. In whole-brain analyses only lisdexamfetamine increased precuneus/posterior cingulate activation during SST versus guanfacine, and during N-back in pre- and postcentral and occipital cortices versus placebo. During SST, placebo-treated ADHD versus TD showed reduced putamen, insula, parietal and occipital activation that was potentially attenuated/normalised under lisdexamfetamine, while under guanfacine lingual gyrus underactivation remained, with additional precuneus and middle temporal underactivation. Also, only lisdexamfetamine improved and normalised SST performance. ConclusionLisdexamfetamine appears to have stronger and drug-exclusive upregulation and potential attenuation/normalisation effects than guanfacine on basal ganglia, posterior parieto-occipital and sensorimotor activation during ADHD-relevant executive function tasks with some shared superior temporal and putamen effects. Trial registrationClinicalTrials.gov (NCT03333668; https://clinicaltrials.gov/study/NCT03333668).
ER -