Fluoxetine as Adjunct Therapy Improves Outcomes in Severe Sepsis, Suggests Study
Egypt: Adjunctive fluoxetine use in patients with severe sepsis significantly reduced vasopressor duration and shortened ICU length of stay. It also improved organ dysfunction scores and metabolic recovery, though it did not significantly lower short-term mortality. The evidence supporting these findings is rated Level 1 (excellent), highlighting fluoxetine’s potential role in improving clinical recovery in sepsis.
Sepsis remains a major cause of morbidity and mortality in intensive care units, driven by an uncontrolled inflammatory response to infection that can lead to circulatory collapse and multi-organ failure. While standard treatment focuses on early antibiotics, source control, and hemodynamic support, there is increasing interest in repurposing existing drugs that may modulate immune and metabolic pathways involved in sepsis.
In a study published in PLOS ONE, Islam Abdelaal Abdelmouty Taher from the Department of Anesthesia, Intensive Care and Pain Management, Ain Shams University, Cairo, and colleagues evaluated the clinical impact of fluoxetine, a selective serotonin reuptake inhibitor, when used as an adjunct to standard sepsis care. Beyond its antidepressant effects, fluoxetine has been shown in experimental settings to influence inflammatory and immunometabolic processes.
The single-center, randomized, double-blind, placebo-controlled trial was conducted at Ain Shams University Hospitals between December 2024 and June 2025. A total of 46 adult patients with severe sepsis were randomized in a 1:1 ratio to receive either fluoxetine at 40 mg per day or a placebo, alongside conventional treatment. The primary outcome was the duration of vasopressor therapy, reflecting the severity and persistence of circulatory failure. Secondary outcomes included organ dysfunction scores, inflammatory biomarkers, lactate levels, ICU length of stay, and 28-day mortality.
The following findings were reported:
- Patients treated with fluoxetine required vasopressor support for a significantly shorter duration compared with those receiving a placebo.
- The fluoxetine group had a shorter ICU length of stay, indicating faster clinical stabilization.
- By day seven, levels of key inflammatory markers—including tumor necrosis factor-alpha, interleukin-1, C-reactive protein, and procalcitonin—were significantly lower in patients receiving fluoxetine.
- Sequential Organ Failure Assessment (SOFA) scores were improved in the fluoxetine group on days seven and ten.
- APACHE II scores were also lower on days seven and ten, reflecting better overall disease severity.
- There was no statistically significant difference in 28-day mortality between the fluoxetine and placebo groups.
- Although mortality was numerically lower in the fluoxetine group, the difference did not reach statistical significance, likely due to the small sample size and limited statistical power.
The authors acknowledge several limitations. The single-center design and small cohort limit generalizability, particularly for mortality outcomes. Fluoxetine was administered after sepsis onset; long-term outcomes were not assessed, and variability in pharmacokinetics and sepsis etiologies may have influenced results. Additionally, some key immunoregulatory biomarkers were not measured.
Overall, the study suggests that fluoxetine may be a promising adjunctive therapy in severe sepsis by reducing vasopressor dependence, attenuating inflammation, and improving organ dysfunction. Larger, multicenter trials are needed to confirm these benefits and clarify whether fluoxetine can improve survival in critically ill patients with sepsis.
Reference:
Abdelmouty Taher, I. A., Eldin, F. K., Wareth Eissa, M. A., Saleh, L. A., Mohammed, O. A., Doghish, A. S., & Abdel Kway, A. S. (2026). Effect of fluoxetine on organ dysfunction and mortality in severe sepsis. PLOS ONE, 21(1), e0340669. https://doi.org/10.1371/journal.pone.0340669
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