Difference in the Risk of Fall and Related Injuries among First-line Treatments in Older Adults with Depression: A Target Trial Emulation with Cloning-Censoring-Weighting Approach

Background: One-third of older adults in the US had depression, often treated with psychotherapy and antidepressants. Previous studies suggest an increased risk of falls and related injuries (FRI) with antidepressant use may be affected by confounding by indication (as depression independently contributes to FRI risk) or immortal time bias (as patients may not initiate antidepressants when first diagnosed).

Objectives: To evaluate the association between FRI risks and first-line treatments (psychotherapy, sertraline, escitalopram, citalopram, mirtazapine, duloxetine, trazodone, fluoxetine, bupropion, paroxetine, and venlafaxine) in older adults with depression.

Methods: We used the target trial emulation framework with a cloning-censoring-weighting approach to mitigate confounding and immortal time bias. The study cohort comprised fee-for-service Medicare beneficiaries aged 65+ years newly diagnosed with depression (index date). We excluded those with prior depression treatment or FRI events within 1 year before the index date. Beneficiaries were followed from the index date to FRI occurrence, death, transition to Medicare Advantage plans, hospice services or nursing facility utilization, antidepressant switching or discontinuation, or the end of the 1-year follow-up, whichever occurred first. Cloning all eligible patients at baseline, we assigned each clone to a treatment arm, allowing a 182-day grace period for treatment initiation and marking the censoring point for each clone. To address artificial censoring-related selection bias, we applied inverse-probability-of-censoring weighting to up-weight patients in the risk set. Non-parametric bootstrapping was employed to estimate FRI incidence, restricted mean survival time (RMST), and adjusted hazard ratio (aHR) with 95% confidence intervals (95%CI) for each depression treatment.

Results: Among 101,953 eligible beneficiaries (mean age=76 years, SD=8), the majority were female (62%) and White (80%). For the control group (i.e., no treatment), the FRI incidence was 78/1000 person-year, and the RMST was 351 days. For the treated groups, the FRI incidence ranged from 63 (venlafaxine) to 77 (psychotherapy)/1000 person-year. The RMST ranged from 351 (psychotherapy) to 353 (venlafaxine) days. The aHR (95%CI) ranged from 0.78 (0.59-1.51, venlafaxine) to 0.97 (0.67-2.22, psychotherapy) compared to controls.

Conclusions: Our study suggests that first-line depression treatments, including psychotherapy and various antidepressants, were not associated with an increased FRI risk compared to untreated individuals. These findings provide valuable insights into the safety profiles of these treatments, aiding clinicians in their consideration for treating depression in older adults.