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Hi! David Rosenberg here for the Psychopharmacology Institute. In this Child and Adolescent Psychiatry Smart Take, we will look at a recent report examining whether SSRI treatment in children and adolescents is associated with increased risk for type 2 diabetes. We know that much concern has been raised about the risk for diabetes and other metabolic disorders for patients treated with other medications, particularly second-generation antipsychotics. We also know that children and adolescents may be at significantly increased risk. However, we know much less about other psychotropic medications commonly used in children and adolescents.
This association between SSRIs and type 2 diabetes has been reported in adults, but as often happens, children and adolescents remain the diagnostic and therapeutic orphans and are often not studied or understudied.
Well, what is nice is that an excellent study was done, and the authors carefully looked at whether SSRIs are associated with type 2 diabetes in children. Furthermore, I think this is an exciting part of the study: They looked at differences between particular SSRIs. So, is fluoxetine more or less favorable or more or less of a risk than sertraline or any of the other SSRIs? The authors examined real-world data of children and adolescents 10–19 years of age with a diagnosis treated with SSRIs, such as depression, anxiety, OCD, PTSD, panic disorder, and bulimia. They examined 2 nationwide healthcare databases consisting of claims from Medicaid and privately insured children.
Moreover, they found that SSRI treatment was associated with a minimal but statistically significant increased risk of type 2 diabetes in publicly insured but not privately insured children. Overall, the absolute risk was relatively small—so small that it is unclear whether this was a clinically significant difference. This may have been statistically significant but not clinically significant.
Interestingly, when they looked at the in-class comparison of individual SSRIs receiving fluoxetine vs citalopram, escitalopram, fluvoxamine, paroxetine, or sertraline, they found absolutely no difference. So, there was no SSRI associated with a greater risk of type 2 diabetes than another SSRI.
What I like about this study is that given the likelihood that this kind of randomized controlled trial is unlikely to occur anytime soon, this real-world analysis is very valuable. However, I want to emphasize this very small association was seen only in publicly insured children and adolescents treated with SSRIs, not privately insured children and adolescents. Moreover, it appears to be smaller than was previously suggested and different from a cause-and-effect relationship.
What do I mean by that? Finding an association can be interesting, but it is a big step away from a cause-and-effect relationship.
One example I like to give students when teaching the psychopharmacology course is to imagine that every time I talk with them for the 12-week psychopharmacology class, it rains.
There could be an association between my talking with the students and raining that day. However, it is a big stretch to say that because I talked with students when teaching psychopharmacology, that caused it to rain all those days. So, there is no cause and effect.
Moreover, when we looked at the difference between the small statistically significant increased risk in privately insured children but not publicly insured children, that raises the question of their health at baseline. What other factors could be involved and increase the risk rather than just SSRI?
The bottom line is that this study still raises far more questions than it answers. It does not mean we should not use or prescribe SSRIs in youth, but it is something to keep in mind when we individualize treatment and consider metabolic changes in those children and adolescents treated with SSRIs. So, a tiny likely not very common risk but one to keep on file and in mind.
Abstract
Association of Selective Serotonin Reuptake Inhibitors With the Risk of Type 2 Diabetes in Children and Adolescents
Jenny W Sun, Sonia Hernández-Díaz, Sebastien Haneuse, Florence T Bourgeois, Seanna M Vine, Mark Olfson, Brian T Bateman, Krista F Huybrechts
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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Reference
Sun, J. W., Hernández-Díaz, S., Haneuse, S., Bourgeois, F. T., Vine, S. M., Olfson, M., Bateman, B. T., & Huybrechts, K. F. (2021). Association of selective serotonin reuptake inhibitors with the risk of type 2 diabetes in children and adolescents. JAMA Psychiatry, 78(1), 91-100.
