Neurofunctional Effects of Methylphenidate and Atomoxetine in Boys with Attention-Deficit/Hyperactivity Disorder During Time Discrimination

• Published in: Biological psychiatry (1969) 2013-10, Vol.74 (8), p.615-622
• Main Authors: Smith, Anna, Cubillo, Ana, Barrett, Nadia, Giampietro, Vincent, Simmons, Andrew, Brammer, Mick, Rubia, Katya
• Format: Article
• Language: English
• Subjects: Adolescent; atomoxetine; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity - drug therapy; Attention Deficit Disorder with Hyperactivity - physiopathology; Attention deficit disorders. Hyperactivity; Attention-deficit/hyperactivity disorder; Biological and medical sciences; Brain - drug effects; Brain - physiopathology; Brain Mapping; Child clinical studies; Cross-Over Studies; Discrimination (Psychology); Double-Blind Method; functional magnetic resonance imaging; Humans; Magnetic Resonance Imaging; Male; Medical sciences; methylphenidate; Methylphenidate - therapeutic use; Neuropharmacology; Pharmacology. Drug treatments; Prefrontal Cortex - drug effects; Prefrontal Cortex - physiopathology; Propylamines - therapeutic use; Psychiatry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; supplementary motor area; time discrimination; Time Factors
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2013.03.030

Background The catecholamine agonists methylphenidate and atomoxetine effectively treat attention-deficit/hyperactivity disorder (ADHD). Furthermore, dopamine agonists have shown to improve time estimation in ADHD, a core cognitive deficit. However, few have compared the effects of methylphenidate and atomoxetine on brain function in ADHD, and none during time estimation. Using single dose challenges, we investigated shared and drug-specific effects in ADHD adolescents on the neural substrates of time discrimination (TD). Methods Twenty ADHD adolescent male subjects were compared in a randomized double-blind cross-over design after single doses of methylphenidate, atomoxetine, and placebo in functional magnetic resonance imaging during TD. Normalization effects were assessed by comparing brain activation under each drug condition with that of 20 healthy age-matched control subjects. Results Relative to control subjects, patients under placebo showed TD deficits and reduced activation of ventrolateral prefrontal cortex (VLPFC)/insula, inferior frontal cortex, and supplementary motor area. Performance differences were normalized only by methylphenidate, relative to both atomoxetine and placebo. Both medications, however, significantly upregulated right VLPFC/insula activation within patients and normalized its underactivation in ADHD boys under placebo relative to control subjects. The supplementary motor area and inferior frontal cortex activation differences that were observed under placebo were reduced by methylphenidate and atomoxetine, respectively, but neither survived rigorous testing for normalization. Conclusions While only methylphenidate had a drug-specific effect of improving TD performance deficits, both drugs significantly upregulated and normalized right VLPFC underactivation in ADHD boys under placebo relative to control subjects, suggesting shared effects of stimulants and nonstimulants on a key prefrontal dysfunction during timing.