In a preliminary, unblinded University of Florida study of trauma patients with fractures, nine months of fluoxetine was associated with declining PTSD symptoms and less pain over a year.

Breaking a leg or a pelvis in a car crash or a fall is a physical ordeal. For many people, it is also a psychological one. Roughly half of patients who suffer a traumatic injury experience some decline in their mental health, according to researchers at the University of Florida, and some go on to develop post-traumatic stress disorder.

Doctors usually treat PTSD after symptoms appear. A small study from the University of Florida explored whether an antidepressant given soon after injury might help prevent them. The results were published in the Journal of Orthopaedic Trauma.

“We want to actually try and prevent or mitigate the symptoms before they happen, instead of reacting to their development,” said Jennifer Hagen, a professor of orthopedic surgery at the university, who led the study. “This is a frameshift in the thinking around pharmaceutical management of mental health.”

Fluoxetine versus calcium

The trial was carried out at UF Health Shands, a Level I trauma center, and enrolled 68 patients with serious injuries such as broken limbs and pelvic fractures. Participants were randomly assigned to take either fluoxetine, sold under the brand name Prozac, or calcium for nine months. They were then followed for another three months.

Fluoxetine belongs to a class of antidepressants called selective serotonin reuptake inhibitors, or SSRIs. Two other SSRIs, sertraline and paroxetine, are approved by the U.S. Food and Drug Administration for treating PTSD, but research on using such drugs to prevent the disorder has produced mixed results.

PTSD can develop after events involving actual or threatened death or serious injury. Symptoms include intrusive memories or nightmares, avoidance of reminders of the event, negative changes in mood and thinking, and heightened arousal, such as being easily startled or having trouble sleeping. For a diagnosis, symptoms must last more than a month and cause significant distress or impairment.

Over the year, patients taking fluoxetine showed a statistically significant decline in PTSD symptoms, while symptoms in the calcium group stayed roughly the same. Patients on fluoxetine also reported less pain over the following year.

Important caveats

The researchers describe the study as preliminary, and it has significant limitations. It was unblinded, meaning patients and researchers knew who was receiving which treatment, which can influence how people report symptoms. Calcium was used as a comparison rather than an inert placebo.

Many participants also dropped out. Of the 68 patients enrolled, 35 were followed for six months, and only 29 contributed data at one year. High dropout can skew results if those who leave differ from those who stay.

Small trials can also produce results that look promising but fail to hold up in larger studies, a pattern seen repeatedly in medical research. With only a few dozen participants completing follow-up, even a modest imbalance between the groups could affect the outcome.

Recruitment is itself a challenge in this field. “One of the biggest hurdles that we deal with in our studies is that mental health is very stigmatized in society,” said Diana Rijo, a research assistant and co-author.

The team is now enrolling patients in a larger, placebo-controlled, double-blind study, a design that would provide much stronger evidence.

Why orthopedic surgeons care

Mental health after injury affects physical recovery as well as quality of life. Depression and PTSD have been linked to more pain, slower return to work and poorer functional outcomes after fractures. Orthopedic trauma surgeons see patients at a critical moment, soon after injury, when intervention might be most effective.

“The ultimate goal of this line of work is to empower our trauma teams with a tool to protect their patients’ mental health,” Hagen said.

The pain findings are intriguing. SSRIs affect pathways involved in pain processing, and some antidepressants are used to treat chronic pain. But in an unblinded study, reduced pain reports could also reflect expectations or improved mood.

A cautious step

Using medication to prevent a psychiatric condition in people who may never develop it raises questions. Antidepressants can cause side effects, including sleep disturbances, sexual dysfunction and, in rare cases, bleeding problems, which may be relevant for injured patients. Any preventive approach would need to weigh those risks against the benefits.

Other strategies for preventing PTSD after trauma, including early psychological interventions, have also produced mixed results, and no approach is widely established. Larger, rigorous trials such as the one now underway will be needed to determine whether fluoxetine has a role.

Patients should not start or change medication based on this study and should discuss mental health concerns after an injury with their care team.

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Notes

1. “Nine Months of Fluoxetine Aids in the Reduction of Posttraumatic Stress Symptoms following a Traumatic Musculoskeletal Injury: A Randomized Controlled Trial.” Journal of Orthopaedic Trauma, 13 July 2026. DOI: 10.1097/BOT.0000000000003243.
2. University of Florida. “Prozac appears to blunt formation of PTSD symptoms after traumatic injury in small study.” EurekAlert!, 3 August 2026. https://www.eurekalert.org/news-releases/1138591.

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