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Original Investigation
September 2, 2020

Association of Selective Serotonin Reuptake Inhibitors With the Risk of Type 2 Diabetes in Children and Adolescents

Author Affiliations
  • 1Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 2Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 3Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
  • 4Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
  • 5Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
  • 6Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
JAMA Psychiatry. Published online September 2, 2020. doi:10.1001/jamapsychiatry.2020.2762
Key Points

Question  Is the treatment of children and adolescents with selective serotonin reuptake inhibitors (SSRIs) associated with an increased risk of type 2 diabetes?

Findings  In a US nationwide pediatric cohort study of more than 1 million publicly and privately insured patients, initiation of SSRI treatment was associated with a small increased risk of type 2 diabetes among publicly insured patients, corresponding to a number needed to harm of 1515 treated for at least 2 years for 1 patient to develop type 2 diabetes.

Meaning  Children and adolescents who initiate SSRI treatment may be at a small increased risk of developing type 2 diabetes, but the magnitude was more modest than previously reported, and the absolute risk was small.

Abstract

Importance  Concerns exist that use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of developing type 2 diabetes (T2D) in adults, but evidence in children and adolescents is limited. In the absence of a randomized clinical trial, evidence must be generated using real-world data.

Objective  To evaluate the safety of SSRI use in children and adolescents with respect to the associated risk of T2D.

Design, Setting, and Participants  This cohort study of patients aged 10 to 19 years with a diagnosis for an SSRI treatment indication was conducted within the nationwide Medicaid Analytic eXtract (MAX; January 1, 2000, to December 31, 2014) and the IBM MarketScan (January 1, 2003, to September 30, 2015) databases. Data were analyzed from November 1, 2018, to December 6, 2019.

Exposures  New users of an SSRI medication and comparator groups with no known metabolic adverse effects (no antidepressant exposure, bupropion hydrochloride exposure, or psychotherapy exposure). Within-class individual SSRI medications were compared with fluoxetine hydrochloride.

Main Outcomes and Measures  Incident T2D during follow-up. Intention-to-treat effects were estimated using Cox proportional hazards regression models, adjusting for confounding through propensity score stratification. As-treated effects to account for continuous treatment were estimated using inverse probability weighting and marginal structural models.

Results  A total of 1 582 914 patients were included in the analysis (58.3% female; mean [SD] age, 15.1 [2.3] years). The SSRI-treated group included 316 178 patients in the MAX database (publicly insured; mean [SD] age, 14.7 [2.1] years; 62.2% female) and 211 460 in the MarketScan database (privately insured; mean [SD] age, 15.8 [2.3] years; 63.9% female) with at least 2 SSRI prescriptions filled, followed up for a mean (SD) of 2.3 (2.0) and 2.2 (1.9) years, respectively. In publicly insured patients, initiation of SSRI treatment was associated with a 13% increased hazard of T2DM (intention-to-treat adjusted hazard ratio [aHR], 1.13; 95% CI, 1.04-1.22) compared with untreated patients. The association strengthened for continuous SSRI treatment (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. Adjusted HRs were lower in privately insured patients (intention-to-treat 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]), whereas no increased risk was observed compared with bupropion treatment 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.

Conclusions and Relevance  These findings suggest that children and adolescents initiating SSRI treatment may be at a small increased risk of developing T2D, particularly publicly insured patients. The magnitude of association was more modest than previously reported, and the absolute risk was small. The potential small risk should be viewed in relation to the efficacy of SSRIs for its major indications in young patients.

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    1 Comment for this article
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    Comment on: Association of Selective Serotonin Reuptake Inhibitors With the Risk of Type 2 Diabetes in Children and Adolescents
    Liang Xu, Master of Medicine | Department of Geriatric Psychiatry, Huzhou Third Municipal Hospital, the Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, China
    The researchers tried to examine the association between SSRIs and Type 2 Diabetes (T2D), with careful control for potential biases. However, I would like to raise some issues that should be clarified.
    First, a small increased risk of T2D associated with SSRI treatment was observed in children and adolescents among publicly insured patients, whereas the increased risk was not observed in privately insured patients. The researchers did not analyze the reasons for different underlying risks for T2D in-depth, only described the result as the main conclusion. Compared with privately insured patients, the publicly insured patients were of lower socioeconomic status,
    had more comorbidities, and were in a higher prevalence of risk factors for T2D.1 So the Medicaid Analytic eXtract Population (publicly insured) had a higher incidence rate of T2D (eTable10 in the Supplement). Theoretically, in the Medicaid Analytic eXtract Population, a cohort with more confounding factors and greater confounding intensity(low income, comorbidities, eating habits, daily exercise, health awareness, etc.), the SSRI treatment should have a weaker effect on the T2D compared in the IBM MarketScan Population.
    However, the result was just the opposite. Although more than 100 covariates were selected as confounders or proxies of confounders, there were still some covariables(family history of T2D, eating habits, daily exercise, health awareness, etc.) that could not be directly controlled, resulting in different risks for T2D. Further comprehensive analysis of the differences between the two populations might help understand why the risk for T2D was different between the two populations and provide more information on the association of SSRI with the risk of T2D in Children and Adolescents.
    Second, the researchers examined the associations between SSRIs and incidence of hyperlipidemia and asthma, expecting a null finding to provide indirect evidence of no substantial residual confounding or detection bias. But in the sensitivity analyses in ITT population(eTable 17), the adjusted hazard ratio(95% CI) of asthma and hyperlipidemia is 0.97 (0.95-0.99), 0.96 (0.92-1.00), respectively in MAX; 0.97 (0.94-1.01), 0.83 (0.78-0.88), respectively in MarketScan. It showed that residual confounders were present, which may influence these results.



    References:
    1.Shatin D, Levin R, Ireys HT, Haller V. Health care utilization by children with chronic illnesses: a comparison of Medicaid and employer-insured managed care. Pediatrics 1998;102(4):e44-e44
    CONFLICT OF INTEREST: None Reported
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