A recent multicenter study has revealed that fluoxetine, a selective serotonin reuptake inhibitor commonly used for depression, may improve survival rates in patients with sepsis by activating interleukin-10–dependent immunometabolic mechanisms.
In the study, published in Science Advances, researchers conducted a series of in vivo and in vitro experiments assessing fluoxetine’s impact on immune response and metabolic pathways in sepsis-induced murine models. Fluoxetine administration led to a marked increase in interleukin (IL)-10 production, a cytokine known for its anti-inflammatory properties. Elevated IL-10 levels corresponded with reduced pro-inflammatory cytokines and enhanced survival outcomes. Fluoxetine-treated mice demonstrated a survival rate increase of over 50% compared with control groups (P < .001). Notably, when IL-10 signaling was blocked, these protective effects were nullified, underscoring IL-10’s pivotal role in mediating fluoxetine’s benefits.
The study, which involved comprehensive preclinical models, highlighted the potential for repurposing fluoxetine as a novel adjunctive therapy in sepsis management, a condition responsible for substantial morbidity and mortality worldwide.
Further analysis revealed that fluoxetine induced metabolic reprogramming, enhancing mitochondrial respiration and glycolytic capacity in macrophages. This adaptation facilitated efficient energy utilization during septic challenges. Transcriptomic analysis showed upregulation of genes associated with oxidative phosphorylation and downregulation of inflammatory pathways, suggesting dual immunometabolic modulation.
"Our study mechanistically links the anti-inflammatory and metabolic effects of a [selective serotonin reuptake inhibitor] (SSRI) and demonstrates that fluoxetine can be used as a prophylactic to protect from sepsis-induced lethality by orchestrating protective immunometabolic mechanisms, which may be leveraged and further explored by future studies," explained lead study author Robert M. Gallant, of the Molecular and Systems Physiology Laboratory at the Salk Institute for Biological Studies, and his colleagues.
Pharmacokinetic assessments showed that fluoxetine achieved therapeutic plasma concentrations without adverse cardiac effects, a common concern with SSRIs. Additionally, cardiac function analyses in septic mice treated with fluoxetine displayed improved left ventricular performance and reduced biomarkers of myocardial injury. The findings aligned with clinical observations in which sepsis-related cardiac dysfunction significantly contributed to mortality.
Despite the positive outcomes, the researchers emphasized the need for randomized clinical trials to assess fluoxetine’s efficacy and safety in patients with sepsis, focusing on optimal dosing strategies and potential drug interactions in critically ill patients.
The study disclosed no competing interests, and all experimental protocols adhered to ethical guidelines for animal research.
