Introduction

Fluvoxamine, a selective serotonin re-uptake inhibitor (SSRI) has attracted much attention in efforts on drug repurposing for COVID-19 disease. Two randomized controlled trials (RCTs) [1,2] indicated that it reduced the risk of disease deterioration when started early upon diagnosis, but other RCTs indicated no benefit [3-6]. Fluvoxamine came into focus based on a reasonably sound pharmacodynamic rationale [7], but also owing to early non-randomized observations (reviewed in [8,9]): fluvoxamine was either proactively offerred and patients opted to take it or not, or “standard” pharmacoepidemiological studies (on administrative data) were performed. Regarding the former, it should be noted that besides other potential limitations (like sample size, confouding), studies of this type are burdened by uncorrectable selection bias. Regarding the latter, it should be appreciated that in the setting of fluvoxamine for COVID-19 outpatients, such studies of interventions face obstacles beyond their standard limitations [10]. Since fluvoxamine has no approved use in infectious/inflammatory conditions, people treated with fluvoxamine during early COVID-19 are treated for some underlying psychiatric disorder, and mental disorders might contribute to poorer COVID-19 outcomes (reviewed in e.g. [11,12]). Hence, when using such data to evaluate benefits/harms of fluvoxamine, one needs to separate the effects of two co-exposures (fluvoxamine, underlying psychiatric condition): fluvoxamine exposed and non-exposed subjects should come from the same population (i.e., people suffering psychiatric difficulties). This limits the exposed vs. non-exposed comparison to only a subset of people with COVID-19 and data are informative about the treatment in broader terms (i.e., are generlizable) only if its effect is not conditional on the presence/absence of psychiatric difficulties. Furthermore, if participants in such studies are identified in databases of hospitalized patients or patients seeking help for COVID-19, estimates about the “fluvoxamine effect” are likely to be biased: by selective inclusion one conditions on a factor (a non-mild disease form) on a path between the cause (COVID-19 infection) and the outcome (hospitalization/death) and this is likely to generate spurious associations between the intervention of interest (fluvoxamine) and the outcome [13]. On the other hand, population-based studies embracing COVID-19 outpatients at the time of the diagnosis are likely to be devoid of such biases, even if including only COVID-19 positive patients, since there is considerable evidence that psychiatric disorders (including mood disorders and their treatments) do not affect one’s susceptibility to SarsCov2 infection [14]. An important step is such an effort is definition of “fluvoxamine non-exposed” subjects. People suffering conditions requiring antidepressant/anxiolytic treatment not treated with fluvoxamine are likely exposed to other treatments. Biological (mechanistic) rationale to support their use in COVID-19 has been argued for a range of antidepressants/anxiolytics not only for SSRIs [8,9], with, seemingly, an emphasis on fluvoxamine and fluoxetine [15]. One early observational study based on administrative data on COVID-19 patients identfied based on the fact of emergency department vistis of hospitalizations suggested that those prescribed fluoxetine (n=470) had by 28% lower mortality than propensity score-matched controls not prescribed with any SSRI [16]. However, unlike for fluvoxamine, there are no RCTs pertainting to fluoxetine or any other SSRI or non-SSRI antidepressant/anxiolytic to indicate clinical benefit (reviewed in [8,9]; we also could not identify any data by searching PubMed and OVID Medline, Scopus, Web of Science, ClinicalTrials.gov and the International Clinical Trials Registry Platform; September 25, 2022). Therefore, “no exposure to fluvoxamine” seems to be an adequate definition of a control condition vs. “exposure to fluvoxamine”.In an attempt to estimate whether in adults diagnosed with COVID-19 in outpatient settings the fact of being prescribed with (and presumably exposed to) fluvoxamine at the time around the COVID-19 diagnosis affected the probability of subsequent hospitalization or death, we conducted two population-based matched cohort studies comparing fluvoxamine-exposed outpatients to their non-exposed peers. Although the study (primarily) pertains to people who at the time of COVID-19 diagnosis suffered psychiatric conditions for which fluvoxamine was one of the possible treatments, it may still contribute to the overall knowledge on utility of fluvoxamine in early COVID-19 treatment by providing complementary information in the sense of being in agreement or not with the estimates generated in RCTs.