A team of researchers from the University of Maryland School of Pharmacy and the University of Maryland School of Medicine found that current (prolonged) use of serotonin reuptake inhibitors – a major class of antidepressant medications – in children and adolescents was associated with a nearly two-fold increased risk of developing type 2 diabetes when compared to youths who formerly used (but eventually discontinued) those medications.
This study, published Oct. 16 in JAMA Pediatrics, is the first population-based study that comprehensively examines pediatric patients' risk of developing type 2 diabetes after beginning treatment with an antidepressant.
"Antidepressants are one of the most commonly used psychotropic medication classes among youth in the United States, with serotonin reuptake inhibitors representing a majority of total antidepressant use in this population," says Mehmet Burcu, PhD, a May 2017 graduate of the doctoral program housed within the Department of Pharmaceutical Health Services Research (PHSR) at the School of Pharmacy, who led the study for his dissertation. "These findings provide new information on the risk of a rare, but serious adverse outcome that is often difficult to assess in clinical trials due to limited sample size and inadequate follow up."
According to Burcu and colleagues, there has been a marked increase in the percentage of children and adolescents in the United States who use antidepressants over the past two decades – from 1.5 percent in 1996-1998 to 2.6 percent in 2010-2012. This increase has been largely driven by a rise in the number of antidepressants prescribed by pediatricians and other primary care providers. Although a number of studies have demonstrated a link between antidepressant use and risk for type 2 diabetes in adults, evidence of a similar risk among children and adolescents remains limited.
For their study, Burcu and his team analyzed Medicaid administrative claim files for nearly 120,000 children and adolescents ages 5-20 from California, Florida, Illinois, and New Jersey, who initiated treatment with an antidepressant between January 1, 2005 and December 31, 2009, for conditions such as depressive disorder, attention-deficit/hyperactivity disorder, and anxiety disorders. Medications that patients were prescribed included serotonin reuptake inhibitors, tricyclic or other cyclic antidepressants, and other antidepressants.
The team applied rigorous design and statistical approaches to compare incident cases of diabetes in current antidepressant users to former users, rather than non-users (children and adolescents who were never prescribed an antidepressant). "This approach represented a methodological strength of our study, as the comparison of current users to non-users could potentially lead to biased estimates due to several factors, such as confounding by indication and medical care utilization intensity bias," Burcu says.
"I am proud of Dr. Burcu's ability to use the most sophisticated methods available to address the question of whether antidepressant use in children elevates their risk for developing type 2 diabetes," says Julie Zito, BSPharm, PhD, professor in PHSR, who served as Burcu's advisor and is a co-author on the study. "The nested cohort approach that he employed offers a fair comparison of those children who are currently using an antidepressant versus those children who previously used an antidepressant. It helps reduces bias in the research, which is often a challenge with safety studies such as this."
In their analysis, the team uncovered 233 incident cases of type 2 diabetes, of which 156 occurred during current use and 77 occurred during former use of antidepressants, demonstrating that current use of antidepressants in children and adolescents was associated with a two-fold increased risk of developing type 2 diabetes.
In addition, within current users, the team assessed the risk of incident diabetes according to duration of use, cumulative dose, and average daily dose. This secondary analysis showed that the risk for children and adolescents who were prescribed serotonin reuptake inhibitors further intensified with an increasing duration of use (long-term use), cumulative dose, and average daily dose.
"The increased risk of type 2 diabetes following prolonged use of serotonin reuptake inhibitor antidepressants in youth is clearly supported by these findings, with the data showing a greater effect on those youths who were prescribed the medications over longer durations and at higher doses," says Daniel J. Safer, MD, associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and adjunct professor in PHSR.
"We know that long-term use of these antidepressants is not without risk, and further research on outcomes, especially for current, long-term users, is warranted to assure a favorable benefit-risk balance for patients," says Safer, who has practiced for more than 40 years in the field of child psychiatry and is a co-author of the study.
Other co-authors include Susan dosReis, BSPharm, PhD, and Fadia T. Shaya, PhD, MPH, professors in PHSR; and Geoffrey L. Rosenthal, MD, PhD, professor in pediatrics at the School of Medicine.
Burcu and his colleagues hope their study paves the way for further research on the biological mechanisms underlying the relationship between antidepressant use and increased risk for type 2 diabetes in children and adolescents, noting that their results can be used to spur policy development to improve patient monitoring and ensure these medications are used both safely and effectively.