Antidepressants and Risk of Mortality in People with Depressive Disorder and Co-Occurring Type 2 Diabetes Mellitus: A 20-Year Population-Based Cohort Study

INTRODUCTION: Depression and diabetes often co-occur and worsen clinical outcomes of both conditions. However, mortality risk among depression patients with diabetes exposed to antidepressant is understudied. We investigated whether antidepressant would decrease mortality risk in people with depression and incident diabetes. METHODS: This population-based cohort study identified 11,137 depression patients with incident type 2 diabetes between 2002 and 2021 in Hong Kong who were exposed to antidepressants, using territory-wide electronic medical-record database. Association between antidepressant exposure and mortality risk was analyzed by Cox proportional-hazards models for any antidepressant, specific drug classes, and individual agents, with stratified analysis by HbA1c level. A comprehensive array of covariates, including age, sex, calendar-year period, catchment-area, preexisting physical comorbidities, diabetic complications, substance/alcohol use disorders, cardiovascular/antidiabetes medications, and presence of antidepressants other than the specified drug was adjusted. Three sets of sensitivity analyses were conducted by restricting to patients (a) with cumulative drug exposure ≥90 days and ≥180 days, (b) with medication-possession ratio ≥80%, and (c) monotherapy. RESULTS: Lower risk of all-cause mortality was associated with exposure to any antidepressant (hazard ratio 0.79, 95% confidence interval 0.70-0.90) compared with no antidepressant in depression patients with incident diabetes. Lower mortality risk was associated with exposure to noradrenergic and specific-serotonergic antidepressants (0.77 [0.66-0.90]) compared with no antidepressant, and to mirtazapine (0.76 [0.65-0.88]) and trazodone (0.75 [0.63-0.90]). Sensitivity analyses affirmed that lower mortality risk was associated with mirtazapine. CONCLUSION: Depression patients with comorbid type 2 diabetes with exposure to several antidepressant are at decreased mortality risk. Further research is warranted to confirm our findings and clarify the mortality-reducing mechanisms of antidepressant in this vulnerable population.