Marginal structural models for the estimation of the risk of Diabetes Mellitus in the presence of elevated depressive symptoms and antidepressant medication use in the Women’s Health Initiative observational and clinical trial cohorts

Abstract

BackgroundWe evaluate the combined effect of the presence of elevated depressive symptoms and antidepressant medication use with respect to risk of type 2 diabetes among approximately 120,000 women enrolled in the Women’s Health Initiative (WHI), and compare several different statistical models appropriate for causal inference in non-randomized settings.MethodsData were analyzed for 52,326 women in the Women’s Health Initiative Clinical Trials (CT) Cohort and 68,169 women in the Observational Study (OS) Cohort after exclusions. We included follow-up to 2005, resulting in a median duration of 7.6 years of follow up after enrollment. Results from three multivariable Cox models were compared to those from marginal structural models that included time varying measures of antidepressant medication use, presence of elevated depressive symptoms and BMI, while adjusting for potential confounders including age, ethnicity, education, minutes of recreational physical activity per week, total energy intake, hormone therapy use, family history of diabetes and smoking status.ResultsOur results are consistent with previous studies examining the relationship of antidepressant medication use and risk of type 2 diabetes. All models showed a significant increase in diabetes risk for those taking antidepressants. The Cox Proportional Hazards models using baseline covariates showed the lowest increase in risk , with hazard ratios of 1.19 (95 % CI 1.06 – 1.35) and 1.14 (95 % CI 1.01 – 1.30) in the OS and CT, respectively. Hazard ratios from marginal structural models comparing antidepressant users to non-users were 1.35 (95 % CI 1.21 – 1.51) and 1.27 (95 % CI 1.13 – 1.43) in the WHI OS and CT, respectively – however, differences among estimates from traditional Cox models and marginal structural models were not statistically significant in both cohorts. One explanation suggests that time-dependent confounding was not a substantial factor in these data, however other explanations exist. Unadjusted Cox Proportional Hazards models showed that women with elevated depressive symptoms had a significant increase in diabetes risk that remained after adjustment for confounders. However, this association missed the threshold for statistical significance in propensity score adjusted and marginal structural models.ConclusionsResults from the multiple approaches provide further evidence of an increase in risk of type 2 diabetes for those on antidepressants.

Long‐Term Physical Activity and Subsequent Risk for Rheumatoid Arthritis Among Women: A Prospective Cohort Study

“…These results also suggest that physical activity may have different biologic effects on each RA subphenotype. An alternative strategy for the mediation analysis would be to perform analyses using marginal structural models, but previous literature suggests that a marginal structural model would produce findings similar to those obtained with our approach . Our findings add to the literature demonstrating differences based on BMI and other measures of adiposity for RA risk by serologic phenotype .…”

The risk of new-onset diabetes in antidepressant users – A systematic review and meta-analysis

“…Thus, 17 papers met our selection criteria. Two papers reported results from more than one study [ 23 , 24 ]; the reported estimates of the single studies used by Pan and Frisard were used in the present analysis. Thus, 20 estimates were included in the main analysis ( Table 1 ).…”

“…Five studies previously included in the meta-analyses of Yoon and Bhattacharjee were excluded from the present review [ 7 , 8 ]. For two of these studies updated results were available [ 10 , 24 ], and thus they were included in our meta-analysis instead of the old ones [ 25 , 26 ]. The remaining three studies were excluded because one was restricted to children and adolescents [ 27 ], one had a cross-sectional design [ 28 ] and the last one was based on spontaneous reports of hyperglycemia rather than on new-onset diabetes [ 29 ].…”

“…The remaining three studies were excluded because one was restricted to children and adolescents [ 27 ], one had a cross-sectional design [ 28 ] and the last one was based on spontaneous reports of hyperglycemia rather than on new-onset diabetes [ 29 ]. Among the 20 studies included in our systematic review, fourteen used a cohort design [ 9 – 12 , 23 , 24 , 30 – 35 ], four used a nested case–control study design [ 4 , 36 – 38 ], two were randomized controlled trials (RCT) [ 24 , 39 ]. Eleven studies were from North America (USA and Canada), six from Europe, two from Asia and one from Australia.…”

Depressive symptoms mediate the relationship between sleep disturbances and type 2 diabetes mellitus

“…The exact biological mechanisms underlying the relationship between depressive symptoms, sleep disturbances, and T2DM are not well understood. 39 However, evidence suggests that both depression and sleep disturbances may hinder glycemic control by causing deregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Specifically, depression 40,41 and disturbed sleep 42 are associated with increased secretion of cortisol.…”