Fluvoxamine may prevent clinical deterioration in COVID-19 outpatients

In a fully remote, preliminary study evaluating adult outpatients with mild COVID-19, the likelihood of clinical deterioration* over 15 days was lower among those treated with fluvoxamine – an SSRI** and a strong σ-1 receptor (S1R) agonist – compared with those receiving placebo.

“Clinical deterioration typically occurs during the second week of illness … [Our findings show that] no fluvoxamine-treated patients met the criteria for clinical deterioration as defined in the study, whereas 8.3 percent of patients taking placebo met this endpoint,” said the researchers.

Clinical deterioration occurred in none of the fluvoxamine recipients, as opposed to six in the placebo arm (absolute difference, 8.7 percent from survival analysis; p_log-rank=0.009). Of the six placebo recipients, four were hospitalized for COVID-19; one required mechanical ventilation for 10 days. There were no deaths. [JAMA 2020;324:2292-2300]

Fluvoxamine was also associated with fewer serious adverse events (n=1 vs 6) compared with placebo.

S1R-IRE1 pathway

“[Our] study was prompted by a hypothesis involving the influence of fluvoxamine on the S1R-IRE1*** pathway,” said the researchers. Evidence shows that, through the S1R-IRE1 pathway, fluvoxamine was able to reduce shock in murine sepsis models, [Sci Transl Med 2019;11:eaau5266] as well as damages from the inflammatory response during sepsis.

To ascertain the potential of S1R agonism in immune modulation, the investigators sought to evaluate the efficacy of fluvoxamine in 152 community-dwelling, self-quarantined adults (mean age 46 years, 72 percent female) with confirmed SARS-CoV-2^# infection with symptom onset within 7 days of the first study medication dose. Participants were randomized 1:1 to receive fluvoxamine or matching placebo for 15 days. Of these, 76 percent completed the trial.

Fluvoxamine was given at a dose of 50 mg in the evening immediately following baseline evaluation and eligibility confirmation, increasing to 100 mg BID for 2 days then to 100 mg TID as tolerated through day 15. Following which, fluvoxamine was stopped.

“The potential advantages of fluvoxamine for outpatient treatment of COVID-19 include its safety, widespread availability, low cost, and oral administration,” said the researchers. Moreover, unlike other SSRIs, fluvoxamine does not promote QT prolongation. [J AmSoc Nephrol 2019;30:611-623]

Other mechanisms that could account for the benefit of fluvoxamine in this setting are SSRI inhibition of platelet activation, its direct antiviral effect driven by its lysosomotropic properties, and modulation of IRE1 effects on autophagy. [Am J Cardiovasc Drugs 2003;3:149-162; Int J Antimicrob Agents 2020;56:106044; Virology 2019;533:34-44]

“If fluvoxamine is determined to be effective in treating COVID-19, the underlying mechanisms need further clarification,” they said.

However, the clinical deterioration could be a reflection of the comparative baseline oxygen saturation distributions and not a treatment effect. It should also be noted that 20 percent of participants stopped responding to surveys. Although none required hospitalization or emergency department visits, some may have sought treatment at an urgent care facility outside major regional hospital systems.

The small sample size may have also limited the results. “[As such,] these findings need to be interpreted as hypothesis-generating rather than as a demonstration of efficacy … The study needs to be replicated in larger trials with a more heterogeneous study population,” they said. Longer trials are also warranted to ascertain the effect of fluvoxamine on late deterioration or persistent symptoms.

Cardiopulmonary function should also be explored in future trials to verify the apparent cardioprotective effect of S1R agonists, [Prog Neurobiol 2013;100:15-29] as the development of cardiac injury is not uncommon in COVID-19 patients, even for those who have recovered or those with mild cases. [Prog Cardiovasc Dis 2020;63:390-391; JAMA Cardiol 2020;5:1265-1273]