In this issue of the American Journal of Therapeutics, we published a systematic review and meta-analysis of fluvoxamine effect on the major clinical outcomes of outpatients with COVID-19 acute infection.1 The study relied on a thorough search of the Web of Science, PubMed, Embase, and Cochrane Library databases,2 completed on February 1, 2022. The search identified 3 useable trials: a large randomized trials in which 741 patients were treated with fluvoxamine and 756 with placebo,3 a small randomized trial in which 80 patients received fluvoxamine and 72 placebo,2 and a small, nonrandomized, placebo controlled trial comprising 65 fluvoxamine cases and 48 patients treated with placebo.4 The meta-analysis indicated no fluvoxamine effect on the rates of hospitalization, mechanical ventilation, or mortality of patients with acute COVID-19 infection. The lack of effect was interpreted to reflect lack of statistical power and substantial nonadherence to treatment.1
The United States National Institute of Health has released, on December 16, 2021 the following statement: “Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is approved by the Food and Drug Administration for the treatment of obsessive-compulsive disorder and is used for other conditions, including depression. Fluvoxamine is not Food and Drug Administration-approved for the treatment of any infection.”6 No further updates have been issued. The serotonergic mechanism of action of fluvoxamine was demonstrated in 19777 and the first placebo-controlled trial for the treatment of depression published in 1983.8 Fluvoxamine and other SSRIs have been continuously prescribed world-wide for the past 40 years to millions of persons,9 are available as a generic drug, and have a well-established record of safety. The placebo-controlled trials of fluvoxamine for COVID-19 infection hypothesized that the drug has anti-inflammatory properties that will decrease the risk of significant pulmonary impairment and the prevalence and severity of the systemic inflammatory response syndrome.2–4
In our view, the failure of fluvoxamine to change the outcome of acute COVID-19 infection should be examined through the prism of hypothesis formulation, that is, by asking whether there were any sound reasons to think it would work. The framework for this examination is provided by Bradford Hill's guidelines, which were developed and widely used to test association versus causation and then expanded to evaluate evidence hierarchies.5 Based on this framework, we evaluated the pre-COVID pandemic data regarding the strength, consistency, temporality, biological gradient, plausibility, and coherence of a possible effect of fluvoxamine in this condition, by searching Medline from inception to March 1, 2022 using the key words fluvoxamine, selective serotonin reuptake inhibitors, viral respiratory infections, pneumonia, inflammation, asthma, chronic obstructive pulmonary disease (COPD), and sepsis in clinical and experimental work with humans.
Neither fluvoxamine, nor any other SSRIs have been used for the treatment of any infection before the COVID-19 pandemic. There are reports of interstitial lung disease10 or acute eosinophilic pneumonia11 temporally related to treatment with SSRIs. In older adults with COPD, a condition with a significant inflammatory component, the new use of serotonergic antidepressant increased the outpatient acute exacerbations, emergency medicine visits and hospital admissions for exacerbations or pneumonia, and their mortality, and all-cause mortality rate.12 These findings have been confirmed in a study that indicated that co-treatment with SSRI in COPD is associated with the highest odds of acute exacerbations.13 In Crohn's disease, the epitome of devastating inflammation in humans, the addition of fluoxetine to standard treatment had no effect whatsoever on the activity of the inflammatory bowel disease.14 A biological gradient was conspicuously absent in patients treated with escitolapram for depression, as treatment-nonresponders had higher levels of tumor necrosis factor alpha.15 In patients with bipolar depression, the SSRI had no effect on inflammatory parameters, which were corrected, as expected, only after the addition of an anti-inflammatory drug, celecoxib.16
To sum up, prepandemic research offered no reason to believe that fluvoxamine or other SSRIs could improve the clinical outcome of a severe viral respiratory infection. Misguided enthusiasm and haste must be replaced by a clear-headed, critical analysis of existing data before starting costly and possibly harmful clinical trials.
1. Bhuta S, et al. Fluvoxamine in non-hospitalized patients with acute COVID-19 infection and the lack of efficacy in reducing rates of hospitalization, mechanical ventilation and mortality in placebo controlled trials: A systematic review and meta-analysis. Am J Ther. 2022 (In press).
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