Selective serotonin reuptake inhibitors are associated with a much lower risk of type 2 diabetes (T2D) in children and adolescents than previously reported, new research shows.
Investigators found publicly insured patients treated with SSRIs had a 13% increased risk for T2D, compared with those not treated with these agents. In addition, those taking SSRIs continuously (defined as receiving one or more prescriptions every 3 months) had a 33% increased risk of T2D.
On the other hand, privately insured youth had a much lower increased risk — a finding that may be attributable to a lower prevalence of risk factors for T2D in this group.
“We cannot exclude that children and adolescents treated with SSRIs may be at a small increased risk of developing T2D, particularly publicly insured patients, but the magnitude of association was weaker than previous thought and much smaller than other known risk factors for T2DM, such as obesity, race, and poverty,” lead investigator Jenny Sun, PhD, told Medscape Medical News.
“When weighing the known benefits and risks of SSRI treatment in children and adolescents, our findings provide reassurance that the risk of T2DM is not as substantial as initially reported,” said Sun, a postdoctoral research fellow in the Department of Population Medicine at Harvard Medical School’s Harvard Pilgrim Health Care Institute.
The study was published online September 2 in JAMA Psychiatry.
Previous research suggested that SSRIs increase the risk of T2D by up to 90% in children and adolescents.
However, the investigators note, the study reporting this finding was too small to draw conclusions about the SSRI class as a whole also did not examine specific SSRIs.
In addition, although “several studies have reported that antidepressant use may be a risk factor for T2D in adults, evidence was limited in children and adolescents,” said Sun.
“Rapid changes in growth during childhood and adolescents can alter drugs’ pharmacokinetics and pharmacodynamics, so high-quality, age-specific data are needed to inform prescribing decisions,” she said.
For the current study, the researchers analyzed claims data on almost 1.6 million patients aged 10 to 19 years (58.3% female, mean age 15.1 years) from two large claims databases.
The analysis focused on those with a diagnosis warranting treatment with an SSRI, including depression, generalized or social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, panic disorder, or bulimia nervosa.
The Medicaid Analytic eXtract (MAX) database consisted of 316,178 patients insured through Medicaid or the Children’s Health Insurance Program (CHIP). The IBM MarketScan database consisted of 211,460 privately insured patients. Patients were followed up for a mean of 2.3 and 2.2 years, respectively.
Patients who initiated SSRI treatment were compared with those with a similar indication but who were not taking an SSRI. Secondary analyses compared new SSRI users with patients who recently initiated treatment with bupropion, which has no metabolic side effects, or with patients who recently initiated psychotherapy.
“In observational data, it is difficult to mimic a placebo group, often used in RCTs [randomized controlled trials], therefore several comparator groups were explored to broaden our understanding,” said Sun.
In addition, the researchers compared the individual SSRI medications, using fluoxetine as a comparator.
A wide range of more than 100 potential confounders or “proxies of confounders,” were taken into account, including demographic characteristics, psychiatric diagnoses, metabolic conditions, concomitant medications, and use of healthcare services.
The researchers conducted two analyses. They included an intention-to-treat (ITT) analysis that was restricted to patients with one or more additional SSRI prescriptions during the 6 months following the index exposure assessment period.
Close Monitoring Required
An as-treated analysis estimated the association of continuous SSRI treatment (vs untreated, bupropion treatment, and psychotherapy), with adherence assessed at 3-month intervals.
Initiation and continuation of SSRI treatment in publicly insured patients were both associated with a considerably higher risk of T2D compared with untreated patients, and a steeper risk compared with their privately insured counterparts.
For newly treated publicly insured patients initiated on SSRI treatment, the ITT adjusted hazard ratio (aHR) was 1.13 (95% CI, 1.04 – 1.22).
There was an even stronger association among continuously treated publicly insured patients, with an as-treated aHR of 1.33 (95% CI, 1.21 – 1.47). The authors note that this corresponds to 6.6 additional T2D cases per 10,000 patients continuously treated for at least 2 years.
The association was weaker in privately insured patients (ITT aHR 1.01; 95% CI, 0.84 – 1.23; as-treated aHR 1.10; 95% CI, 0.88 – 1.36).
The secondary analyses yielded similar findings: When SSRI treatment was compared with psychotherapy, the as-treated aHR for publicly insured patients was 1.44 (95% CI, 1.25 – 1.65), whereas the aHR for privately insured patients was lower at 1.21 (95% CI, 0.93 – 1.57)
The investigators found no increased risk when SSRIs were compared with bupropion, and the within-class analysis showed that none of the SSRIs carried an increased hazard of T2D when compared with fluoxetine.
“Publicly insured patients are enrolled in Medicaid and the Children’s Health Insurance Program, whereas privately insured patients are generally covered by their parent’s employer-sponsored insurance,” said Sun.
“Publicly insured patients are of lower socioeconomic status and represent a population with greater overall medical burden, more comorbidities, and a higher prevalence of risk factors for T2D, such as obesity, at the time of treatment initiation,” she added.
She added that high-risk children and youth should be closely monitored and clinicians should also consider recommending dietary modifications and increased exercise to offset T2D risk.
“Useful Real-World Data”
Commenting on the study for Medscape Medical News, William Cooper, MD, MPH, professor of pediatrics and health policy at Vanderbilt University Medical Center in Nashville, Tennessee, said that the study “provides a fascinating look at risks of SSRI medications in children and adolescents.”
Cooper, who was not involved with the study, said that the authors “draw from real-world data representing two different populations and carefully consider factors which might confound the associations.”
The results, he said, “provide important benefits for patients, families, and clinicians as they weigh the risks and benefits of using SSRIs for children who need treatment for depression and anxiety disorders.”
“As a pediatrician, I would find these results useful as I work with my patients, their families, and behavioral health colleagues in making important treatment decisions.”
The study was supported by a training grant from the Program in Pharmacoepidemiology at the Harvard T.H. Chan School of Public Health. Sun has disclosed no relevant financial relationships. The other authors’ disclosures are listed on the original article. Cooper has disclosed no relevant financial relationships.
JAMA Psychiatry. Published online September 2, 2020. Abstract