Serotonergic antidepressant use as a risk factor for nonunion after closed long bone fractures

To evaluate whether preoperative use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) is associated with increased risk of reoperation, nonunion, infection, hospital readmission, or emergency department (ED) visits following operative fixation of isolated long bone fractures.

This retrospective, multicenter cohort study was conducted using the TriNetX Research Network. Adults (≥18 years) who underwent operative fixation of isolated tibial, femoral, or humeral shaft fractures between 2012 and 2024 were included. Patients prescribed an SSRI or SNRI within 180 days prior to fracture and within 12 months after surgery were compared with controls without antidepressant prescriptions before or within 12 months after fracture. Polytrauma, pathologic fractures, and prior surgery at the same site were excluded. Propensity score matching (1:1) was performed for demographics, fracture location, and relevant medical and psychiatric comorbidities. The primary outcome was reoperation within 12 months. Secondary outcomes included nonunion, infection, hospital readmission, and ED visits. Analyses were stratified by fracture type (open vs closed) and location.

A total of 5293 SSRI/SNRI users were matched to 5293 controls. In closed fractures, antidepressant use was associated with higher rates of nonunion (5.2% vs 4.0%; RR 1.29, 95% CI 1.06-1.56). Open fractures demonstrated a trend towards greater rates of nonunion (4.8% vs 3.1%) and reoperation (15.2% vs 13.9%); however, this was not significant. 30-day ED visits, 30-day surgical site infection, and 90-day readmissions were comparable between groups.

Preoperative SSRI or SNRI use was associated with increased risk of nonunion following operative fixation of closed long bone fractures. Outcomes following open fractures were largely unaffected, likely due to the dominant biological and mechanical risks inherent to open injuries. These findings suggest the need for increased clinical vigilance in patients with closed fractures receiving serotonergic antidepressants and highlight the importance of prospective studies to further clarify causality and guide management strategies.