Not everyone with ADHD responds to stimulants like Ritalin, which increase dopamine levels in the brain. Now, new research suggests the drug’s effectiveness is less about the amount of dopamine it produces and more about the number and type of receptors that respond to it.
Conditions where a person’s attention is disrupted, such as attention-deficit hyperactivity disorder (ADHD), can interfere with their ability to study and work and have been associated with co-existing psychiatric illness. Beyond ADHD, “difficulty concentrating” is a symptom that is present in 17 different psychiatric diagnoses, which highlights how important maintaining attention is to everyday functioning.
Stimulant drugs like methylphenidate (Ritalin, Concerta) that are designed to improve attention are first-line treatments for ADHD. However, evidence suggests that up to 30% of people with ADHD don’t respond to them. Now, a new study co-led by the University of Maryland School of Medicine (UMSOM) and the National Institutes of Health (NIH) Clinical Center has identified why this is the case.
“We thought that the amount of dopamine Ritalin produced in a person would help us predict whether that individual would have enhanced attention performance, but what we found is more complicated,” said study lead and co-corresponding author Peter Manza, PhD, Assistant Professor of Psychiatry at UMSOM. “Instead, we found the types of dopamine receptors on the brain cells, and the ratio in which they are found, better predicted cognitive performance.”
Drugs like Ritalin boost dopamine levels in the brain by blocking the chemical’s reuptake. This means that dopamine stays longer in the synapses, the spaces between the neurons, enhancing communication between the neurons, particularly in areas of the brain involved in attention, focus, and impulse control. By increasing the availability of dopamine, Ritalin can improve ADHD symptoms.
To examine Ritalin’s effect on the brain, the researchers had 37 adults without ADHD undergo functional MRI (fMRI) scans to measure areas of brain activation while they performed concentration and attention tasks. Two fMRI scans were done on study participants: one after they’d been given a placebo and another after they’d been given 60 mg of Ritalin orally. Positron emission tomography (PET) scans were also conducted to measure dopamine levels and the ratio of types of dopamine receptors in participants’ brains.
There are five types of dopamine receptors, D1 through D5. While each type plays a different role in how dopamine affects mood, movement, and motivation, D1 and D2 receptors are particularly relevant to attention. D1 receptors promote cognitive functions like working memory, attention, and decision-making. When dopamine binds to D1 receptors, it helps enhance signal processing in areas of the brain crucial for focus and attention. On the other hand, D2 receptors are more involved in modulating the overall dopamine system. They help fine-tune the brain’s response to dopamine and are thought to play a role in controlling hyperactivity and impulsivity, which are core issues in ADHD. The ratio of D1 to D2 receptors is important because it influences how effectively dopamine signaling occurs in brain regions responsible for attention and concentration.
“Balanced signaling between D1 receptors and D2 receptors in the brain is needed for optimal brain function and variations in their relative signaling contributes both to differences in baseline cognitive performance and to why some people improve whereas others deteriorate their performance when given Ritalin,” said the study’s other corresponding author, Nora Volkow, MD, chief of the Laboratory of Neuroimaging at NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA). “What we found was that those with a higher D2 to D1 ratio had worse baseline cognitive performance but experienced a greater improvement when taking Ritalin compared to a placebo.”
The researchers found that in baseline testing, participants with a higher ratio of D1 to D2 receptors did better on memory tasks than those with a higher ratio of D2 to D1 receptors.
Those with a higher level of D1 receptors than D2 receptors tended to perform better on memory tasks. fMRI scans showed correspondingly high activation levels in the brain’s prefrontal cortex, an area crucial for higher-level functions like planning, decision-making, and self-control. However, the same participants did not show significant improvement in attention after they were given either a placebo or Ritalin, even though Ritalin increased their dopamine levels.
“A significant number of people without ADHD are taking stimulant medications in an unprescribed way to try and increase their performance, and it was important for us to gain an understanding of what these medications were doing to the brain,” said Manza, who is also a researcher at UMSOM’s Kahlert Institute for Addiction Medicine. “Our findings suggest that many of these people may not benefit from taking these medications, while taking on the risks of using stimulant drugs without medical supervision.”
The researchers want to build on these findings, conducting studies on people who’ve been diagnosed with ADHD to examine their D1-to-D2 receptor ratio to see if they have fewer D1 receptors overall compared to those without ADHD.
“It would be interesting to identify whether there is a subgroup of individuals with ADHD who have high levels of D1 receptors and determine whether they are more likely to be treatment-resistant to stimulant drugs like Ritalin,” said Mark Gladwin, MD, who is the Dean of UMSOM but was not involved in this study. “That could aid in our efforts to personalize care for these individuals and seek more beneficial treatments including cognitive behavioral therapies.”
The study was published in the journal PNAS.
Source: UMSOM