Safety Outcomes / Cardiovascular

2B-03 - Associations of the most prevalent antidepressants with mortality and cardiovascular disease: a retrospective comparative safety study in a nationwide cohort of Veterans with major depressive disorder.

Sunday, August 24, 2025

4:00 PM - 4:15 PM ET

Presenting Author(s)

SE

Svetlana Eden, PhD

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA, United States

Co-Author(s)

JS

Jesse Stewart, PhD

Department of Psychology, Indiana University Indianapolis, Indianapolis, IN, USA, United States
RG

Robert Greevy, PhD

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA, United States
CA

Charles Alcorn, MA

University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA, United States
AA

Amy Anderson-Mellies, MPH

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA, United States
KS

Kaku So-Armah, PhD

Division of General Internal Medicine, Boston University Medical Center, Boston University Medical School, Boston, MA, USA, United States
SK

Suman Kundu, PhD

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA, United States
HT

Hilary Tindle, MD, MPH

Department of General Internal Medicine and Public Health, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA, United States
MF

Matthew Freiberg, MD, MSc

1) Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; 2) Geriatric Research Education and Clinical Centers (GRECC), Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA, United States

Background: Antidepressants (ADs) are commonly prescribed, yet their associated age-specific mortality and cardiovascular disease (CVD) risk are understudied.

Objectives: We examined associations of most prevalent ADs with mortality and incident CVD, stratified by age, in US Veterans with major depressive disorder (MDD).

Methods: This retrospective cohort included Veterans with established medical home in the US Veterans Health Administration (VA) system between 2000-2020 diagnosed with MDD and AD naïve prior to the first prescription fill of either sertraline, citalopram, escitalopram, fluoxetine, paroxetine, venlafaxine, trazodone, bupropion, mirtazapine, amitriptyline, or nortriptyline.
Mortality was ascertained from VA, Medicare, and Social Security Administration death records. CVD was defined as time to first inpatient or second outpatient ischemic stroke, heart failure, acute myocardial infarction, or revascularization collected from the VA, Medicare, and fee for service data. Follow-up was censored at end of study (5-years or 12/31/20), last medical touch, discontinuation of treatment (90 days after last prescription coverage day), start of another AD, and death (for CVD outcome).
Baseline covariates (n=25) were balanced using inverse probability weights (IPW). IPW-weighted Cox proportional hazards regression was used to compute adjusted hazard ratios (sertraline=reference) in age groups (≤45, 45-65, ≥65). Final sample was 367,021 patients with AD-specific samples ranging from 3,280 (nortriptyline) to 94,704 (sertraline).

Results: Unadjusted mortality incidence rate (IR) in the sertraline group was 31.9, 95%CI [30.7, 33.2], per 1000 person-years (PY). Bupropion had lowest mortality in younger (HR=0.47, 95%CI [0.25, 0.89]) and middle age (HR=0.56, 95%CI [0.43, 0.72]) groups. Paroxetine had lower mortality in older group (HR=0.82, 95%CI [0.69, 0.97]). Mirtazapine had higher mortality in younger (HR=1.82, 95%CI [1.10, 3.03], middle age (HR=1.49, 95%CI [1.22, 1.81]), and older (HR=1.12, 95%CI [1.03, 1.22]) groups. Nortriptyline had the highest mortality in younger group (HR=4. 91, 95%CI [1.56, 15.49]). Unadjusted CVD IR in the sertraline group was 23.4, 95%CI [22.2, 24.6], per 1000 PY. Compared to sertraline, citalopram had lower risk for middle age (HR=0.85, 95%CI [0.74, 0.97] and older (HR=0.84, 95%CI [0.73, 0.96]) groups, and bupropion had lowest risk for middle aged (HR=0.82, 95%CI [0.69, 0.98] and older (HR=0.79, 95%CI [0.63, 0.99]) groups.

Conclusions: In veterans with MDD receiving ADs, compared to sertraline, mirtazapine and nortriptyline had higher mortality risk, paroxetine had lower mortality risk, bupropion had lower mortality and CVD risk, and citalopram had lower CVD risk.