To investigate the comparative effectiveness of commonly used selective serotonin reuptake inhibitors (SSRIs) for comorbid depression in older adults with chronic somatic diseases by applying a target-trial-emulation framework.

Danish target-trial-emulation study including 43,061 individuals aged ≥65 years (54.1% females, mean age 77.8 years) with a first redeemed prescription for depression with sertraline (n = 6673), escitalopram (n = 7104) or citalopram (n = 29,284) in 2006–2017. Individuals had cancer, cardiovascular diseases (CVD), chronic-obstructive-pulmonary-disease (COPD)/asthma, diabetes, neurodegenerative disorders, or osteoporosis. Outcomes were treatment switching, combination/augmentation, psychiatric hospital contact for depression, and any psychiatric in-patient care. Follow-up was one year and adjusted Cox regression analyses calculated hazard rate ratios (HRR) within each somatic disease.

Across all six disease groups and four outcomes, we found that citalopram use, compared with sertraline, was associated with lower risks in several analyses, with statistically significant results in cancer, CVD, COPD/asthma, and diabetes (e.g., HRRs for psychiatric hospital contacts for depression/any psychiatric in-patient care ranging between 0.47 and 0.61). For escitalopram, compared with sertraline, some analyses indicated poorer outcomes with significantly higher risks for combination/augmentation treatment (HRRs ranging between 1.15 and 1.40).

Although observational studies are prone to confounding, these findings indicate clinically relevant differences between the SSRIs, with better outcomes in citalopram users and poorer outcomes in escitalopram users than sertraline, urging the need for clinical studies in this vulnerable patient population.