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Common and Unique Therapeutic Mechanisms of Stimulant and Nonstimulant Treatments for Attention-Deficit/Hyperactivity Disorder
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CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing psychiatric disorder that affects both children and adults. There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD; however, little is known about the mechanisms by which these different treatments exert their therapeutic effects. OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylphenidate hydrochloride vs the nonstimulant atomoxetine hydrochloride. DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylphenidate (n = 18) or atomoxetine (n = 18) using a parallel-groups design. SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine, New York, New York. PARTICIPANTS Thirty-six youth with ADHD (mean [SD] age, 11.2 [2.7] years; 27 boys) recruited from randomized clinical trials. MAIN OUTCOME MEASURES Changes in brain activation during a go/no-go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version. RESULTS Treatment with methylphenidate vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean (SD) improvements in ratings of ADHD symptoms (55% [30%] vs 57% [25%]). Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments. Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylphenidate in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex. These findings were not attributable to baseline differences in activation. CONCLUSIONS Treatment with methylphenidate and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic actions in frontoparietal regions that have been implicated in the pathophysiology of ADHD. These results represent a first step in delineating the neurobiological basis of differential response to stimulant and nonstimulant medications for ADHD.
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“However, it remains unknown whether dissociable therapeutic responses to medications are mediated by shared or distinct neural underpinnings”
From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Schulz et al., 2012
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“the overlapping mechanism between the neuropharmacological effects of stimulants and nonstimulants was mapped in the inhibited activation patterns of the left SMA that coactivated with the CEN.”
From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Schulz et al., 2012
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“The normalization of SMA activation patterns may correspond directly to drug action given the massive presence in DAT and NET expression in the motor cortex, while also being associated with indirect and downstream effects modulated by responses of the prefrontal cortex”
From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Schulz et al., 2012
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“stimulants and nonstimulants act to alter the abnormal neural responses in ADHD patients through α2-adrenergic and dopamine D1 receptors to improve cognitive functions through the reactivity of the prefrontal cortex based on its high sensitivity to catecholamines”
From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Schulz et al., 2012
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“A recent fMRI study found an association between clinical improvement after 6 to 8 weeks of methylphenidate and brain activation reduction over this time in motor, IFC, and ACC cortices (88).”
From Effects of stimulants on brain function in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis (2014) · cites this paper as [88]
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“These shared and distinct substrates may delineate a novel therapeutic target for effective interventions and could account for different therapeutic responses to stimulants and nonstimulants among individuals with ADHD”
From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Schulz et al., 2012
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“and studies that directly compare the neural bases of stimulants and nonstimulants are limited”
From Overlapping and differential neuropharmacological mechanisms of stimulants and nonstimulants for attention-deficit/hyperactivity disorder: A comparative neuroimaging analysis (2024) · cites this paper as Schulz et al., 2012
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Metadata
- Authors
- Schulz, K. P., Fan, J., Bédard, A.-C. V., Clerkin, S. M., Ivanov, I., Tang, C. Y., Halperin, J. M., & Newcorn, J. H.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Queens College, CUNY (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2012-09-01
- Volume
- 69
- Issue
- 9
- Pages
- 952
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC12858410
- OpenAlex
- W2110045849
- Cited by
- 114
- References
- 66
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 5 · 2018: 4 · 2017: 9 · 2016: 14 · 2015: 19 · 2014: 17 · 2013: 11
- FWCI
- 10.74
- Type
- journal article
- Language
- en
- Open access
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH070935, K01MH070892, R01MH095766)
- National Center for Research Resources (UL1RR029887)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- attention deficit hyperactivity disorder, methylphenidate, atomoxetine, stimulant medication, non-stimulant medication, response inhibition, go/no-go task, brain activation, motor cortex, inferior frontal gyrus, anterior cingulate cortex, supplementary motor area, posterior cingulate cortex, therapeutic mechanisms
- MeSH terms
- Atomoxetine Hydrochloride, Central Nervous System Stimulants, Attention Deficit Disorder with Hyperactivity, Brain, Brain Mapping, Child, Female, Frontal Lobe, Gyrus Cinguli, Humans, Image Interpretation, Computer-Assisted, Image Processing, Computer-Assisted, Inhibition, Psychological, Magnetic Resonance Imaging, Male, Methylphenidate, Motor Cortex, Neural Pathways, Neuropsychological Tests, Parietal Lobe, Propylamines, Psychomotor Performance, Treatment Outcome, Adrenergic Uptake Inhibitors, Imaging, Three-Dimensional
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