Title : Infectious disease risk among patients prescribed amoxapine or trifluoperazine: A retrospective cohort study using real-world data
Abstract:
Rising rates of antimicrobial resistance combined with the lack of new antibiotic development has brought new focus to drug repurposing strategies. Early evidence suggests that certain centrally acting psychotropic drugs, including trifluoperazine (TFP) and amoxapine (AXPN), may have antimicrobial or immuno-modulatory properties. However, their effects on infection risk in human populations remain poorly understood. The current study aims to evaluate whether exposure to TFP or AXPN is associated with altered risks of infectious illnesses and of systemic inflammation compared to fluoxetine, a commonly prescribed antidepressant which has been shown to have some benefits in these settings.
To evaluate potential differences in rates of infectious diseases and inflammation, a retrospective cohort study was conducted by collecting human data via TriNetX, a federated network of de-identified electronic health records that together cover over 75 million patients across multiple healthcare systems. Study data included patients aged 18-90 who received a TFP, AXPN, or fluoxetine prescription. Eligible candidates were identified and classified into mutually exclusive, non-overlapping cohorts. Age- and sexmatched cohorts between TFP and fluoxetine, and between AXPN and fluoxetine, were compared on six outcomes, including: C. difficile infection, pneumonia, sepsis, COVID-19, neutrophilia, and increased Creactive protein. Risk ratios (RR), odds ratios (OR), 95% confidence intervals, and p-values were calculated to evaluate differences between fluoxetine cohorts and their corresponding age- and sex-matched treatment groups. Outcomes that achieved statistically significant differences between groups were analyzed further using Kaplan-Meier survival analysis.
Study results showed that TFP use was associated with a significantly lower risk of C. difficile infection (p = 0.007), COVID-19 (p = 0.002), and higher levels of CRP (p = 0.045) when compared to those prescribed fluoxetine. On the other hand, statistical differences in incidences of pneumonia, sepsis, or neutrophilia were not found between TFP and fluoxetine users. Additionally, Kaplan-Meier analyses supported a lower cumulative incidence of COVID-19 and C. difficile in patients treated with TFP compared to fluoxetine controls. In contrast, when AXPN users were compared to fluoxetine users, AXPN did not show significant differences in incidence for any of the six outcomes examined.
As a retrospective observational study, the results of the study are limited due to residual confounders and therefore do not support causal inferences. Data limitations preclude adjusting for adherence to medications, dosing, or risk behavior, which could not be controlled for in this observational study. Additionally, the analysis relied on coded diagnosis, which may have been variably reported across health systems.
Nevertheless, in comparison to those prescribed fluoxetine, patients receiving TFP were associated with reduced incidence of severe infectious and inflammatory conditions, suggesting potential repurposing opportunities in infection treatment. These findings call for further mechanistic and clinical investigations to evaluate TFP’s therapeutic role under infectious disease conditions. Although AXPN may still be associated with benefits of infectious or inflammatory conditions, it showed no such differences in incidence of these outcomes when compared to the standard treatment drug, fluoxetine.
