Answering Questions About Risks, Benefits of ADHD Medication Through Better Research Design

Can improved research designs answer questions that come up between doctors and patients, like better understanding the risks and benefits of prescription medicine for attention-deficit/hyperactivity disorder (ADHD)?

Brian M. D'Onofrio, PhD, director of clinical training at Indiana University’s Department of Psychological and Brain Sciences, presented on translational epidemiology in a talk called "The Risks and Benefits of ADHD: A Pharmacoepidemiologic Perspecitive" to answer those questions at the 2018 annual meeting of the American Professional Society of ADHD and Related Disorders (APSARD).

Drawing a laugh from the audience, he joked that putting “translational” in front of the word “epidemiology” is not a way to try and convince the National Institutes of Health to give you money, but rather, his aim is to convince people that using big, large-scale data could be used to answer clinical questions immediately and put certain questions to rest.

In the case of ADHD medication, D’Onofrio used the example of mainstream media headlines questioning possible associations about stimulant medicines and substance abuse, as well as various randomized control trials (RCTs) published in scholarly journals.

RCTs have limitations, he said, and cannot control for everything. If there is an exposure that is associated with an outcome, one needs to rule out all alternative explanations, as statistical covariates are not perfect and there can be measurement error.

Better research design can account for casual inferences, he said. For instance, when studying side effects, is the medication the cause of the problem, or is it the underlying condition for which a patient is receiving the medication? To try and get at that answer, D’Onofrio looked at what happened to patients in the month prior to an emergency department (ED) visit for substance use problems. Were they on or off their medication?

In a RCT, males with ADHD were 3.2% more likely to go to an ED for substance use problems compared with 1.2% of males without ADHD, and females with ADHD were 2.6% more likely compared with 0.8% without. D’Onofrio said his research showed that when a specific male patient received his ADHD medication in the month prior compared with it not being received, he had a 35% reduced chance of going to the ED for a substance use problem.

D’Onofrio used a large-scale dataset from individuals who had private employer insurance from 2005 to 2014. It included approximately 146 million individuals. In 2013, 51% were female, and 78% had drug coverage. Because it was a dataset of private, job-based insurance, individuals were covered for different amounts of time. From that, he pulled inpatient, outpatient, and filled prescription claims for almost 3 million ADHD patients.

He performed a “within-individual analyses,” where each person serves as his/her own control. Risks were compared from when the same individual is on, versus off, their medication. The analysis accounted for all stable factors and adjusted for time-varying covariates to help rule out dynamic confounding.

From there, D'Onofrio examined the odds ratio of the risk of a serious outcome, like a trip to the ED for a substance use problem, in the month when a patient was on an ADHD medication, compared with when the patient was off.

For every concurrent within-individual comparison D’Onofrio looked at, there were decreased risks (an odds ratio of less than 1) of going to the ED for patients who fell into these categories:

• No other psychiatric medications
• No psychotherapy
• Incident diagnosis cohort
• First events only
• 1-month extended medicated period
• Stimulant medication only
• Ambulance, inpatient or emergency events
• Selective serotonin reuptake inhibitor medication

In addition, the associations held 2 years later. The same associations also held when looking at ED visits for motor vehicle accidents by people on ADHD medications.

D’Onofrio said the results should help ease concerns about rare, but serious, concerns about ADHD medications, and said there could be clinical concerns with not prescribing ADHD medications.