How Do ADHD Medications Work?

Answers from a new study in Biological Psychiatry

Philadelphia, PA, October 16, 2013

There is a swirling controversy regarding the suspicion that medications prescribed for the treatment of ADHD (attention-deficit/hyperactivity disorder) primarily act to control disruptive behavior as opposed to having primary effects on the ability to attend to the environment. Thus, there is a continued need to better understand the neural basis of ADHD medication effects.

A new study in Biological Psychiatry now provides evidence that methylphenidate and atomoxetine, two FDA-approved medications for the treatment of ADHD, both improve the brain's activation when attempting to make fine temporal distinctions, but have differential effects on performance.

Time estimation, and particularly temporal discrimination, is impaired in individuals diagnosed with ADHD. Additionally, research using imaging scans show that the brain is under-activated when they perform such cognitive tasks.

This led researchers at King's College London to evaluate and compare stimulant and non-stimulant treatments for ADHD in the way they affect performance and brain activation. They recruited twenty adolescent males with ADHD who underwent 3 imaging scans while performing a time discrimination task after receiving single doses of methylphenidate, atomoxetine, and placebo, each administered one week apart. They also compared those results with a control group of 20 healthy males.

First author Dr. Anna Smith explains their findings: "We show here that the stimulant methylphenidate acts quickly with immediate effects upon performance on a timing task we know children with ADHD find challenging. Crucially however, acute doses of either methylphenidate or the non-stimulant atomoxetine increase brain activation in the frontal lobes, typically under-recruited in children with ADHD, so that these key under-functioning frontal brain regions operate at the normal levels seen in other children."

"This exciting finding suggests that both stimulants and non-stimulants share similar mechanisms of action and are both comparable in the way they normalise the activity of important frontal brain regions in children with ADHD. This could explain why both types of drug improve behaviour in children with ADHD, namely by normalizing the reduced activity in the frontal lobes that typifies the disorder," she added.

Methylphenidate and atomoxetine are interesting drugs to compare. Methylphenidate blocks both norepinephrine and dopamine transporters, while atomoxetine blocks only the norepinephrine transporter.

On the surface, this study appears to be a comparison of the role of dopamine and norepinephrine systems in the regulation of attention. However, norepinephrine transporters also contribute to the inactivation of dopamine in the cortex. Thus, this study might be seen as comparing two drugs that potently block norepinephrine uptake, but which differ in the extent to which they raise cortical dopamine levels.

"From this perspective, it is interesting that both drugs enhanced cortical activation during temporal discrimination, but only methylphenidate improved behavior. The reason for this dissociation is unknown," said Dr. John Krystal, Editor of Biological Psychiatry. "We cannot tell whether this is related to the extent to which dopamine is raised in the cortex or whether raising dopamine levels in other brain regions is important. Nonetheless, the findings appear to suggest that methylphenidate influences ADHD-related behaviors more potently than does atomoxetine."

The article is "Neurofunctional Effects of Methylphenidate and Atomoxetine in Boys with Attention-Deficit/Hyperactivity Disorder During Time Discrimination" by Anna Smith, Ana Cubillo, Nadia Barrett, Vincent Giampietro, Andrew Simmons, Mick Brammer, and Katya Rubia (doi: 10.1016/j.biopsych. 2013.03.030). The article appears in Biological Psychiatry, Volume 74, Issue 8 (October 15, 2013), published by Elsevier.


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Notes for editors

Full text of the article is available to credentialed journalists upon request; contact Rhiannon Bugno at +1 214 648 0880 or Biol.Psych@utsouthwestern.edu. Journalists wishing to interview the authors may contact Anna Smith at +44 207 848 0463 or anna.smith@kcl.ac.uk.

The authors' affiliations, and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, M.D., is Chairman of the Department of Psychiatry at the Yale University School of Medicine and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

About Biological Psychiatry
Biological Psychiatry
is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry
is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 4th out of 135 Psychiatry titles and 13th out of 251 Neurosciences titles in the Journal Citations Reports® published by Thomson Reuters. The 2012 Impact Factor score for Biological Psychiatry is 9.247.

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