SSRIs Associated With Slight Increase in T2D Risk Among Children, Adolescents

Children and adolescents initiating selective serotonin reuptake inhibitors (SSRIs) for pediatric depression and anxiety disorders may be at a small increased risk of developing type 2 diabetes (T2D), according to a recent study published in JAMA Psychiatry.

Results of the study found that this increase is particularly apparent in publicly insured patients, but the magnitude of association was more modest than previously reported and absolute risk was small overall.

Given the increasing prevalence of depression and other mental health issues in young patients, SSRI use in this population remains widespread. In particular, rates of mood disorders and suicide-related outcomes have increased significantly over the last decade among these age groups, more often affecting females and those who are wealthier.

“In 2012, an estimated 3.5% of children (aged 10-14 years) and 6.2% of adolescents (aged 15-19 years) in the United States were taking an antidepressant, with 72% of these patients treated with an SSRI,” researchers wrote.

Previous studies have found SSRIs are associated with development of T2D in adults, with weight gain functioning as a potential biological mechanism. However, children and adolescents are often excluded from randomized clinical trials, resulting in a lack of evidence on medication safety and widespread off-label prescribing, authors wrote.

Using real-world data from 2 nationwide health care databases, researchers conducted a cohort study to better understand the association between SSRIs and T2D, with careful control for potential sources of bias.

A total of 1,582,914 patients were included in the study. Participants’ data were gleaned from the Medicaid Analytic eXtract database between January 1, 2000, and December 31, 2014. All patients included in this database were enrolled in Medicaid and the Children’s Health Insurance Program (CHIP) during the study window. Additional data were collected from the IBM MarketScan database between January 1, 2003, and September 30, 2015, which consisted of privately insured patients.

All individuals aged 10 to 19 years with a diagnosis for an SSRI indication (eg, depression, panic disorder, bulimia nervosa) were included in the analyses. New users were classified based on the index date for first observed SSRI dispensing. Investigators then compared patients who initiated SSRI treatment with those with a diagnosis for an SSRI but no antidepressant exposure.

To reduce the risk of confounding, researchers included 2 active comparators with no known metabolic adverse effects in a secondary analysis. Individual SSRI medications (citalopram hydrobromide, escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine hydrochloride or paroxetine mesylate, and sertraline hydrochloride) were also compared, with patients receiving fluoxetine hydrochloride serving as the reference group.

In the primary intention-to-treat (ITT) analysis (58.3% female; 41.7% male) the 316,178 patients who initiated SSRI treatment were compared with 632,356 age-matched intreated controls from the MAX database (publicly insured). An additional 211,460 patients who initiated SSRI treatment were compared with 422,920 untreated patients in the MarketScan database (privately insured). Patients were followed up with for a mean (SD) of 2.3 (2) and 2.2 (1.9) years, respectively.

In as-treated analyses, researchers assessed whether patients remained adherent to their index exposure groups at each 3-month window of follow-up.

Analyses revealed:

• In publicly insured patients, initiation of SSRI treatment was associated with a 13% increased hazard of T2D (ITT adjusted hazard ratio [aHR], 1.13; 95% CI, 1.04-1.22) compared with untreated patients.
• This association strengthened for continuous SSRI treatment in the publicly insured group (as-treated aHR, 1.33; 95% CI, 1.21-1.47), corresponding to 6.6 (95% CI, 4.2-10.4) additional cases of T2D per 10,000 patients treated for at least 2 years.
• aHRs were lower 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]).
• Findings were similar when comparing SSRI treatment with psychotherapy (publicly insured as-treated aHR, 1.44 [95% CI, 1.25-1.65]; privately insured as-treated aHR, 1.21 [95% CI, 0.93-1.57]).
• No increased risk was observed compared with bupropion treatment, a dopamine reuptake inhibitor (publicly insured as-treated aHR, 1.01 [95% CI, 0.79-1.29]; privately insured as-treated aHR, 0.87 [95% CI, 0.44-1.70]).
• For the within-class analysis, no medication had an increased hazard of T2D compared with fluoxetine.

Overall, the association between SSRI use and T2D incidence was not apparent during the first year of treatment and only strengthened slightly during longer follow-up periods.

However, the data included did not allow researchers to further analyze the association between SSRIs and weight gain. In children and adolescents, evidence regarding SSRIs and glucose metabolism is limited.

“The long-term metabolic effects of SSRI treatment remain poorly characterized, with mixed evidence regarding the association between antidepressants and T2D, insulin resistance, and intermediate markers of T2D,” researchers wrote.

Researchers also pointed out increased risk of T2D already exists in publicly insured patients with lower socioeconomic statuses, as they tend to have a greater overall medical burden, more comorbidities, and a higher prevalence of risk factors of T2D.

Authors concluded the potential risk of increased T2D “should be weighed against the known benefits and risks of SSRI treatment to help inform treatment decision making in the pediatric population.”

Reference

Sun JW, Hernández-Díaz S, Haneuse S, et al. Association of selective serotonin reuptake inhibitors with the risk of type 2 diabetes in children and adolescents. JAMA Psychiatry. Published online September 2, 2020. doi:10.1001/jamapsychiatry.2020.2762