October 17, 2017
In a retrospective cohort study of more than 119,000 youths 5 to 20 years of age, the risk for incident type 2 diabetes was nearly twice as high among current users of certain types of antidepressants as among former users, Mehmet Burcu, PhD, and colleagues report in an article published online October 16 in JAMA Pediatrics. The risk intensified with increasing duration of use, greater cumulative doses, and higher daily doses of these antidepressants.
The findings point to a growing need for closer monitoring of these products, including greater balancing of risks and benefits, in the pediatric population, the authors caution.
They undertook the study because, despite growing evidence of an association between antidepressant use and an increased risk for type 2 diabetes in adults, similar research in pediatric patients was scarce. "To our knowledge, this is the first population-based study of youths that comprehensively examines the risk of incident type 2 diabetes following treatment initiation with an antidepressant," they write.
For this study, Dr. Burcu, from the Department of Pharmaceutical Health Services Research at the University of Maryland, Baltimore, and colleagues examined Medicaid claim files from California, Florida, Illinois, and New Jersey from January 1, 2004, through December 31, 2009. They restricted the cohort to patients 5 to 20 years of age who began treatment with antidepressants between January 1, 2005, and December 31, 2009. The day on which antidepressant use was initiated was considered the index date.
The medication classes included selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic or other cyclic antidepressants (TCAs), and other antidepressants. Patients who had taken any of these agents within the 365 days before the index date were excluded from the study. Other exclusion criteria included a diabetes-related health issue in the 365 days before the index date and maternal gestational diabetes.
To examine the relationship between antidepressants and diabetes, the authors compared incident cases of diabetes among current users of antidepressants — patients who had not discontinued the medications for more than 90 days during the study period — with those in former users. The analysis was adjusted for numerous possible confounders.
The cohort consisted of 119,608 youths; 50.6% were boys, 47.3% were white, and most (69.5%) were aged 10 to 17 years.
Depressive disorders were the most common diagnosis (37.4%), followed by attention-deficit/hyperactivity disorder (25.9%) and anxiety disorders (17.7%). Disruptive behavior disorder, adjustment disorder, and bipolar disorder were other common diagnoses. Within the year before the index date, 35.4% of patients had used psychiatric medications other than antidepressants, including attention-deficit/hyperactivity disorder drugs and atypical antipsychotics.
SSRIs and SNRIs were the most common antidepressant classes, used by a total of 79,285 patients (66.3%), for a mean of 179.7 days (median, 90.0 days; interquartile range, 30.0-213.0 days). TCA use was reported by 22,143 patients (18.5%), followed by other antidepressants.
With a mean follow-up of 22.8 months, 156 current antidepressant users were diagnosed with type 2 diabetes compared with 77 cases among former users. The absolute risks for the two groups were 1.16 per 10,000 person-months and 0.56 per 10,000 person-months, respectively.
"Overall," the authors write, "when compared with former use, current use of antidepressants was associated with a 1.92-fold increased risk of type 2 diabetes (95% confidence interval [CI], 1.43-fold to 2.57-fold increased risk)," after adjusting for disease risk and time from study entry.
When analyzed by drug class, all three of the most common antidepressant classes were associated with elevated diabetes risk. Among current users of SSRIs or SNRIs, the absolute risk for diabetes was 1.29 per 10,000 person-months compared with 0.64 per 10,000 person-months among former users (relative risk [RR], 1.88; 95% CI, 1.34 - 2.64). Current use of TCAs was associated with absolute risks of 0.89 vs 0.48 per 10,000 person-months among current and for former users, respectively (RR, 2.15; 95% CI, 1.06 - 4.36).
The other types of antidepressants were not associated with greater diabetes risk (absolute risk, 1.15 per 10,000 person-months among current users vs 1.12 per 10,000 person-months for former users; RR, 0.99; 95% CI, 0.66-1.50).
For users of SSRIs or SNRIs, diabetes risk also intensified with duration of use: more than 210 days was associated with an RR of 2.66 (95% CI, 1.45 - 4.88), and use for 151 to 210 days with an RR of 2.56 (95% CI, 1.29 - 5.08) compared with 1 to 90 days of use.
Similarly, the risk for diabetes increased with higher cumulative doses of SSRIs or SNRIs and with use for more than 150 days at doses greater than 15.0 mg/day.
TCAs and other antidepressants did not exhibit these effects, although that finding may have been influenced by the more limited exposure to these agents, the authors explain.
The reasons why serotonin reuptake inhibitors in particular are associated with an elevated risk for type 2 diabetes in both children and adults remain unclear, they write. Although weight gain may play a role, other possible mechanisms include "disturbances in glucose homeostasis, decreased pancreatic insulin secretion, and increased cellular insulin resistance."
The authors also warn that these findings should be interpreted cautiously because "causality cannot be inferred from observational studies," although they used a rigorous design and approaches to account for statistical confounding.
Also, depression itself has been associated with weight gain, and with it, a greater risk for type 2 diabetes. However, the authors point out that most of the patients in this study (62.6%) were taking the antidepressants for something other than a depressive disorder.
These findings "support the need for further research to shed light on the underlying biological mechanisms of treatment-emergent type 2 diabetes associated with antidepressants," the authors conclude. The results also "provide an impetus for policy development to improve monitoring for the benefits vs risks of antidepressant use in pediatric care models, specifically for serotonin reuptake inhibitors, the most commonly used antidepressant class."
The authors have disclosed no relevant financial relationships.