Old drug fluvoxamine, new hope for COVID-19

Abstract: European Archives of Psychiatry and Clinical Neuroscience https://doi.org/10.1007/s00406-021-01326-z LETTER TO THE EDITOR Old drug fluvoxamine, new hope for COVID‑19 Yaeko Hashimoto1,2 · Takuji Suzuki1 · Kenji Hashimoto2 Received: 24 August 2021 / Accepted: 27 August 2021 © Springer-Verlag GmbH Germany, part of Springer Nature 2021 The coronavirus disease 2019 (COVID-19) is an acute respiratory disease caused by the novel coronavirus SARSCoV-2. Despite the second vaccination for SARS-CoV-2, the number of individuals infected with SARS-CoV-2 variants (i.e., delta and lambda) has markedly increased worldwide. Although approximately 80% of individuals infected with SARS-CoV-2 is mild to moderate, a part of them may convert to severe clinical stages in about 1 week, ultimately resulting in the intubation or death. Using drug repurposing, it is, therefore, necessary to discover drugs that can prevent clinical deterioration [1]. Here, we discuss the emergent use of the old antidepressant fluvoxamine which may block clinical deterioration in mild to moderate patients infected with SARS-CoV-2. In November 2020, Dr. Lenze and his colleagues reported that fluvoxamine could prevent clinical deterioration in adult outpatients infected with SARS-CoV-2. In the study, clinical deterioration occurred in 0 of the fluvoxamine group (n = 80) and in 6 of placebo group (n = 72) [2]. Although sample size of this study was small, this study strongly encouraged further trials using a large sample size. In February 2021, Dr. Seftel and his colleague reported a prospective, non-randomized observational cohort study of fluvoxamine in outpatients (n = 113) infected with SARS-CoV-2 at the Golden Gate Fields horse racing track in Berkeley, California [3]. Incidence of hospitalization was 0 of the fluvoxamine-treated group (n = 65) and 6 of the observation alone group (n = 48). Two patients required intensive care unit stay with mechanical ventilation, one of them died. On April 23, 2021, fluvoxamine was added in the US National Institutes of Health (NIH) COVID-19 Guidelines Panel although there is insufficient evidence for the efficacy of fluvoxamine. * Kenji Hashimoto hashimoto@faculty.chiba-u.jp 1 Department of Respirology, Chiba University Graduate School of Medicine, Chiba 260‑8670, Japan 2 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1‑8‑1 Inohana, Chiba 260‑8670, Japan On August 6, 2021, the interim results of TOGETHER trial (NCT04727424) by a multinational group in Canada and Brazil were presented at the NIH symposium. They compared three compounds, fluvoxamine, the antidiabetic drug metformin, and the antiparasitic drug ivermectin. Although metformin and ivermectin did not show beneficial effects, fluvoxamine was much more promising. Among the randomized participants (n = 1,480), fluvoxamine significantly reduced the risk of disease progression by 29% (95% confidence interval 0.54–0.93) [4]. Detailed mechanisms of action of fluvoxamine for COVID-19 are currently unknown. In 1996, we reported that fluvoxamine binds to endoplasmic reticulum (ER) protein sigma-1 receptor with high affinity, suggesting a role of sigma-1 receptor in the mechanisms of its action [5]. Subsequent studies suggest that fluvoxamine is a potent agonist at sigma-1 receptor which plays a key role in inflammation [1, 5, 6]. Among the antidepressants, fluvoxamine was the most potent at sigma-1 receptor [1, 5, 6]. Furthermore, fluvoxamine has..