National Institute of Mental Health awards $3.6M grant to advance ADHD medication response research

Approximately 7 million children in the United States between the ages of three and 17 have been diagnosed with attention deficit hyperactivity disorder (ADHD), according to the Centers For Disease Control and Prevention. Up to 50% of children with ADHD also have severe problems with impulsive aggression and persistent irritability, according to James Waxmonsky, professor of psychiatry and University Chair in Child Psychiatry at the Penn State College of Medicine. These children can experience intense and extended emotional outbursts, which can severely impact how they function at home, at school and with peers. While certain medications can help reduce these outbursts in some children with ADHD, there's no good way to predict which children will respond well - and which won't - based on their behavior, genetics or background alone.

Now, with a five-year, $3.6 million grant from the National Institute of Mental Health, a team of researchers, led by Waxmonsky, is setting out to identify better and more precise ways to predict which children with ADHD - who also have high levels of aggression and irritability - will benefit from medication treatment. The researchers will examine how their brains process reward and frustration in order to understand why some children show improvements with ADHD medication while others do not.

At the end of the day, it's all about helping children improve. Aggression is one of the most common reasons children present for emergency assessment so identifying safe, well-studied treatments that are effective could have a sizable impact."

James Waxmonsky, professor of psychiatry and University Chair in Child Psychiatry, Penn State College of Medicine

Waxmonsky has studied child psychiatry for 30 years, primarily focused on ADHD and how medication for the disorder impacts long-term outcomes for children. He explained that while medication for ADHD, known as central nervous system stimulants, has been found to help with both ADHD and aggressive and irritable behaviors, the response rate can vary. Over 50% of children will become less aggressive, 40% show no change in anger levels and a small percentage may experience more challenges managing anger. This uncertainty in response can lead to avoiding or prematurely abandoning ADHD medication and resorting to more intense interventions like antipsychotic medications and inpatient mental health treatment to help with behavior.

"Antipsychotic medications can reduce aggression in children, but there's a potential long-term risk for obesity and other metabolic problems that isn't seen with ADHD medications," Waxmonsky said. "We're trying to find the children who will respond to established, safe, Food and Drug Administration-approved treatments for ADHD so that we can limit the use of these more intensive medications that have more complex side effects."

The research team will recruit children between the ages of seven and 12 who have been diagnosed with ADHD and who experience frequent anger outbursts. The study's doctors will work with participants to identify the optimal medication dosage over a six-week period.

Participants will interact with computer-based games in the laboratory, and the research team will measure how their brain reacts to winning and losing. Then, parents will report on their child's behavior at home for one week. Participants will complete the trial twice - once while taking the best dose of their medication and once while on placebo.

Waxmonsky explained that children with ADHD and significant problems with anger often have difficultly learning from their environment and responding to reward and punishment cues and that ADHD medication can help with these challenges.

"We think what goes on in the brain may tell us more about predicting a response to medication than the behavior we can observe. We want to see if the difference in the brain's response during these tests while on medication versus off medication predicts their behavior at home, particularly for reducing anger outbursts," Waxmonsky said.

Since most children, even those with severe outbursts, are much less likely to have behavior problems in a doctor's office or lab setting versus at home, Waxmonsky explained that parents will respond to surveys on their cellphone three times a day. These surveys, called ecological momentary assessments, allow parents to report at-home behavior in-the-moment and capture fluctuations throughout the day.

Ecological momentary assessments are more precise compared to traditional surveys where parents must recall behavior over days or weeks. This type of assessment also allows the research team to understand the relationship between behavior and medication timing, for example, if behavior worsens because of the medication wearing off or if the behavior change is a result of an adverse response to the medication.

"The novelty of this work is the package of components," Waxmonsky said. "Integrating methods to examine how the medicines work in the brain with precision assessments of how they change behavior at home."

The team said it hopes that the findings from this grant will aid the development of assessments to select the best treatment options and inform the development of new treatments for aggression and irritability.

Other Penn State researchers involved in the grant include Lisa Gatzke-Kopp, professor of human development and family studies; Michael Russell, associate professor of biobehavioral health; Raman Baweja, professor of psychiatry and behavioral health and of public health sciences; Dara Babinski, associate professor and Ling and Esther Tan Early Career Professor of psychiatry and behavioral health; Usman Hameed, associate professor of psychiatry and behavioral health; and Banku Jairath, associate professor of pediatrics. The research team also includes Autumn Kujawa, associate professor of psychology and human development at Vanderbilt University.