Antidepressant cuts COVID-19 hospital cases 30% to 65%

Older man reading pill bottle instructions
Older man reading pill bottle instructions

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The inexpensive antidepressant fluvoxamine reduced the need for a long emergency department (ED) observation or a hospital stay among high-risk, symptomatic COVID-19 outpatients treated within 7 days of symptom onset as much as 30% to 65%, finds a Brazilian platform clinical trial yesterday in The Lancet Global Health.

In the largest such trial to date, a team led by researchers in Brazil, the United States, and Canada randomly assigned 1,497 adult COVID-19 patients, most of them unvaccinated, in 11 cities to either 100 milligrams of fluvoxamine twice daily for 10 days or a placebo from Jan 20 to Aug 5, 2021.

Average patient age was 50 years, 58% were female, 95% were of mixed race, and all had at least one predisposing medical condition. Patients were followed for 28 days.

The study was part of the ongoing TOGETHER trial, which has evaluated eight possible COVID-19 treatments (eg, lopinavir-ritonavir, metformin). The fluvoxamine arm was stopped early because preliminary results showed that it was more effective than placebo.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) used since the 1990s to treat mental illnesses such as obsessive compulsive disorder and depression. Possible mechanisms of action in COVID-19 are its anti-inflammatory, antiplatelet, and possible antiviral properties. The cost of a 10-day course of fluvoxamine is about $4, regardless of world region.

Patients who took all doses saw a 65% lower risk

Of the 741 patients receiving fluvoxamine, 79 (11%) were observed for more than 6 hours in an ED or transferred to a tertiary care hospital, compared with 119 of 756 (16%) in the placebo group (relative risk [RR], 0.68). Of both possible outcomes, 87% were hospitalizations. An intention-to-treat analysis showed a similar outcome (RR, 0.69), and a per-protocol analysis found a larger treatment effect (RR, 0.34).

The probability of superiority of fluvoxamine relative to placebo was 99.8%, surpassing the study's superiority threshold of 97.6% (risk difference, 5.0%).

In the intention-to-treat analysis, 17 patients in the fluvoxamine group and 25 in the placebo group died (odds ratio [OR], 0.68). In the per-protocol analysis, 1 patient died in the fluvoxamine group, as did 12 in the placebo group (OR, 0.09), and there was a significant treatment effect among patients who reported higher than 80% treatment adherence (RR, 0.34 for hospitalization; OR, 0.09).

Differences in the number of adverse events possibly related to treatment were not significant among the two groups. Nor were there significant differences for viral clearance at day 7, COVID-19 hospitalization, time to hospitalization, length of hospital stay, death, time to death, length of time on mechanical ventilation, time to recovery, or scores on physical or mental scales.

In a news release from McMaster University in Ontario, senior author Edward Mills, PhD, a McMaster researcher, said of the drug, "It could be one of our most powerful weapons against the virus, and its effectiveness is one of the most important discoveries we have made since the pandemic began." He called it a "massive boon to public health."

Potential impact on treatment guidelines

The study authors noted the dearth of effective COVID-19 treatments, which is particularly problematic in regions of the world with low access to coronavirus vaccines.

"Identifying inexpensive, widely available, and effective therapies against COVID-19 is, therefore, of great importance," they wrote. "Given fluvoxamine's safety, tolerability, ease of use, low cost, and widespread availability, these findings might influence national and international guidelines on the clinical management of COVID-19."

The researchers said that it is unknown what absolute reduction in risk of clinical deterioration would motivate patients to choose fluvoxamine but speculated that it may be about 5.0%, as was observed in the trial. "These considerations raise the importance of the development of a validated prediction rule for deterioration in patients in the early stages of COVID-19 infection," they wrote.

In a commentary in the same journal, Otavio Berwanger, MD, PhD, of Hospital Israelita Albert Einstein in Sao Paolo, said that questions remain as to the effectiveness and safety of fluvoxamine in terms of death and hospitalization rates and whether it has an additive effect on other COVID-19 therapies, such as monoclonal antibodies.

"Finally, it is still unclear whether the results from the TOGETHER trial extend to other outpatient populations with COVID-19, including those without risk factors for disease progression, those who are fully vaccinated, and those infected with the delta variant or other variants," he wrote.

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