Shared and Drug-Specific Effects of Atomoxetine and Methylphenidate on Inhibitory Brain Dysfunction in Medication-Naive ADHD Boys

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Abstract

The stimulant methylphenidate (MPX) and the nonstimulant atomoxetine (ATX) are the most commonly prescribed medications for attention deficit hyperactivity disorder (ADHD). However, no functional magnetic resonance imaging (fMRI) study has as yet investigated the effects of ATX on inhibitory or any other brain function in ADHD patients or compared its effects with those of MPX. A randomized, double-blind, placebo-controlled, crossover pharmacological design was used to compare the neurofunctional effects of single doses of MPX, ATX, and placebo during a stop task, combined with fMRI within 19 medication-naive ADHD boys, and their potential normalization effects relative to 29 age-matched healthy boys. Compared with controls, ADHD boys under placebo showed bilateral ventrolateral prefrontal, middle temporal, and cerebellar underactivation. Within patients, MPX relative to ATX and placebo significantly upregulated right ventrolateral prefrontal activation, which correlated with enhanced inhibitory capacity. Relative to controls, both drugs significantly normalized the left ventrolateral prefrontal underactivation observed under placebo, while MPX had a drug-specific effect of normalizing right ventrolateral prefrontal and cerebellar underactivation observed under both placebo and ATX. The findings show shared and drug-specific effects of MPX and ATX on performance and brain activation during inhibitory control in ADHD patients with superior upregulation and normalization effects of MPX.

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Through a widespread efferent projection system, the locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. Initial studies provided critical insight into the basic organization and properties of this system. More recent work identifies a complicated array of behavioral and electrophysiological actions that have in common the facilitation of processing of relevant, or salient, information. This involves two basic levels of action. First, the system contributes to the initiation and maintenance of behavioral and forebrain neuronal activity states appropriate for the collection of sensory information (e.g. waking). Second, within the waking state, this system modulates the collection and processing of salient sensory information through a diversity of concentration-dependent actions within cortical and subcortical sensory, attention, and memory circuits. Norepinephrine-dependent modulation of long-term alterations in synaptic strength, gene transcription and other processes suggest a potentially critical role of this neurotransmitter system in experience-dependent alterations in neural function and behavior. The ability of a given stimulus to increase locus coeruleus discharge activity appears independent of affective valence (appetitive vs. aversive). Combined, these observations suggest that the locus coeruleus-noradrenergic system is a critical component of the neural architecture supporting interaction with, and navigation through, a complex world. These observations further suggest that dysregulation of locus coeruleus-noradrenergic neurotransmission may contribute to cognitive and/or arousal dysfunction associated with a variety of psychiatric disorders, including attention-deficit hyperactivity disorder, sleep and arousal disorders, as well as certain affective disorders, including post-traumatic stress disorder. Independent of an etiological role in these disorders, the locus coeruleus-noradrenergic system represents an appropriate target for pharmacological treatment of specific attention, memory and/or arousal dysfunction associated with a variety of behavioral/cognitive disorders.

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Author and article information

Journal

Journal ID (nlm-ta): Cereb Cortex

Journal ID (iso-abbrev): Cereb. Cortex

Journal ID (publisher-id): cercor

Journal ID (hwp): cercor

Title: Cerebral Cortex (New York, NY)

Publisher: Oxford University Press

ISSN (Print): 1047-3211

ISSN (Electronic): 1460-2199

Publication date (Print): January 2014

Publication date (Electronic): 9 October 2012

Publication date PMC-release: 9 October 2012

Volume: 24

Issue: 1

Pages: 174-185

Affiliations

[1 ]Department of Child Psychiatry,

[2 ]Department of Neuroimaging,

[3 ]Center for Neurodegeneration Research ,

[4 ]NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Trust, Institute of Psychiatry, King's College London , London, UK

Author notes

A.C. and A.B.S. have equally contributed to first authorship.

Address correspondence to Katya Rubia, Department of Child Psychiatry/SGDP, P046, Institute of Psychiatry, 16 De Crespigny Park, London SE5 8AF, UK. Email: katya.rubia@ 123456kcl.ac.uk

Article

Publisher ID: bhs296

DOI: 10.1093/cercor/bhs296

PMC ID: 3862268

PubMed ID: 23048018

SO-VID: f9b23e12-70f9-4f2e-991e-6f079c86b5fe

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License( http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.

Shared and Drug-Specific Effects of Atomoxetine and Methylphenidate on Inhibitory Brain Dysfunction in Medication-Naive ADHD Boys

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Most cited references 69

The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes.

Why IQ is not a covariate in cognitive studies of neurodevelopmental disorders.

Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain.

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