Efficacy and safety of fluvoxamine for the treatment of COVID-19 patients: a systematic review and meta-analysis.

Dear Editor,

We read with great interest the recent article by Zheng et al. that reported the efficacy of paxlovid for the treatment of COVID-19 patients . However, the cost of currently approved oral antivirals, paxlovid and molnupiravir restricts their access in developing countries , . Therefore, it is crucial to find affordable, widely accessible, and potent treatments for COVID-19. Particularly appealing is the idea of repurposing currently available medications that are widely accessible and have known safety characteristics .

Fluvoxamine, a widely available, inexpensive drug that is one of the selective serotonin reuptake inhibitors (SSRIs), has shown potential for treating COVID-19 as an early outpatient treatment, despite many recommended repurposed medicines failing . The underlying mechanism of the fluvoxamine effect in COVID-19 is currently unclear, but it is thought to be multifactorial. In addition to functioning as an SSRI, fluvoxamine has a strong affinity for the σ-1 receptor (S1R), which is believed to be the mechanism by which it achieves its anti-inflammatory and immunomodulatory properties. S1R stimulation is thought to have an immunomodulatory effect by lowering stress in the endoplasmic reticulum brought on by viral replication, which in turn lowers the generation of inflammatory cytokines . In order to combine the existing data and assess the efficiency and safety of fluvoxamine as a treatment for COVID-19, we undertook this updated meta-analysis.

Our pre-registered meta-analysis (PROSPERO CRD42022361850) was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, the Cochrane Library and ClinicalTrials.gov were searched from inception to September 2022 using a search strategy consisting of terms related to “fluvoxamine”, “SSRIs” and “COVID-19”. The reference lists of the relevant records were also checked. All randomized controlled trials (RCTs) and comparative observational studies evaluating fluvoxamine use for the treatment of COVID-19 patients were included in this review. After screening, five RCTs 7, 8, 9, 10, 11, one quasi-randomized trial and two prospective cohort studies , were found to be eligible for our meta-analysis. Table 1 provides a summary of the features of the included studies. For quality assessments of the RCTs, we used the revised Cochrane Risk of Bias tool (RoB2) (Supplementary Figure 1) while for the non-randomized studies, we used the New-Castle-Ottawa scale (NOS) (Supplementary Table 1). Our primary outcome was all-cause mortality and the secondary outcomes were the risk of hospitalization and COVID-19 progression, and the incidence of adverse events. The meta-analysis was performed using RevMan 5.4 with risk ratio (RR) as the effect measure.

Table 1

Characteristics of included studies.

Sr No	Author, year	Study Design	Country	Sample size	Age	Sex	Population	Intervention	Comparator
1	Lenze 2020	Phase 2, Double-Blind RCT	USA	152	46.0±13.0	Male: 43 (28.3) Female: 109 (71.7)	Adults with SARS-CoV-2 infection confirmed by polymerase chain reaction assay and who were symptomatic within 7 days of the first dose of study medication	Participants received a dose of 50 mg of fluvoxamine immediately after inclusion, then for 2 days at a dose of 100 mg twice daily as tolerated, and then increasing to a dose of 100 mg 3 times daily as tolerated through day 15 then stopped.	Participants received a dose of 50 mg of placebo immediately after inclusion, then for 2 days at a dose of 100 mg twice daily as tolerated, and then increasing to a dose of 100 mg 3 times daily as tolerated through day 15 then stopped.
2	STOP COVID 2, unpublished	Phase 3, triple-blind RCT	USA and Canada	547	47 (IQR 40-55) for Fluvoxamine group, 48 (IQR 41-56) for control	Male: 208 (38) Female: 339 (62)	Patients with age greater than 30 years who are unvaccinated and positive PCR result within 6 days of symptoms onset and a criterion of high risk	100 mg Fluvoxamine twice a day for 15 days	Placebo
3	Calusic 2021	Prospective cohort study	Croatia	102	NA	Male: 68 (66.7) Female: 34 (33.3)	Patients over age 18, with positive SARS-COV2 PCR test and acute COVID-19 infection requiring ICU admission	100 mg Fluvoxamine three times a day for 15 days, then taper off to 50 mg for the next 7 days	Standard care
4	Seftel 2021	Prospective cohort study	USA	113	42 (IQR 33-56)	Male: 85(75) Female: 28 (25)	Patients with positive COVID-19 antigen cards test coupled with PCR confirmation who consented to treatment with fluvoxamine	Fluvoxamine at a 50- to 100-mg loading dose, then 50 mg twice daily for 14 days	Standard care
5	Seo 2022	Phase 2 Single-blind RCT	Korea	52	53 (IQR 43.3-60)	Male: 31 (60)Female: 21 (40)	Patients over 18 with symptoms consistent with COVID-19 with onset less than 7 days after randomization and had positive RT-PCR results within 3 days of randomization	50 mg of fluvoxamine on day 1, then an increased dose of 100 mg twice daily, as tolerated, until discharge from the CTC (about 10 days).	50 mg of placebo (ursodeoxycholate) on day 1, then an increased dose of 100 mg twice daily, as tolerated, until discharge from the CTC (about 10 days).
6	Bramante 2022	Phase 3, Double-Blind RCT	USA	661	46 (IQR 38-53) for the intervention group, 43 (IQR 37-53) for the control group	Male: 273 (41.3) Female: 388 (58.7)	Patients from age 30 to 85 years; with a body-mass index (BMI) associated with overweight or obesity; proof of SARS-CoV-2 infection within the past 3 days; and the onset of symptoms within 7 days before randomization*	Fluvoxamine 50mg twice daily alone for 15 days or fluvoxamine 50 mg twice daily plus metformin up to 1500 mg for 15 days	Placebo or metformin up to 1500 mg for 15 days alone
7	Reis 2021	Phase 3, Double-Blind RCT	Brazil	1497	50 (IQR 18-102)	Male: 635 (42.4) Female: 862 (57.5)	Patients over 18 presenting to the OPD with symptoms consistent with COVID 19 or a positive SARS-COV2 antigen test at screening or 7 days within symptoms onset	Fluvoxamine# 100 mg twice a day	Placebo 100 mg twice a day
8	Pineda 2022	Prospective cohort study	Honduras	657	48.1 (mean)	Male: 330 (50.2)Female: 327 (49.8)	Patients fifteen years of age or older, with mild to moderateCOVID-19 with a positive SARS-CoV-2 antigen or RT-PCR	Fluvoxamine 50 mg orally twice daily for three days and titratedup to 100 mg two or three times a day depending on patient tolerance and diseaseseverity to complete a fourteen-day course	Standard care

The six trial groups were assigned to receive the following drugs or combinations of drugs: group 1, metformin plus fluvoxamine; group 2, metformin plus ivermectin; group 3, metformin plus placebo; group 4, placebo plus fluvoxamine; group 5, placebo plus ivermectin; and group 6, placebo plus placebo.

741 patients received fluvoxamine, 756 were allocated to receive placebo while 1826 were allocated to other treatment groups like hydroxycholorquine, liponavir-ritonavir, previous placebo, metformin, ivermectin, doxazosin or interferon lambda.

Our findings demonstrated that fluvoxamine was associated with a nonsignificant reduction in the risk of mortality (RR 0.49; 95% CI: 0.21-1.17; I2=78%; Figure 1 A) and hospitalization (RR 0.46; 95% CI: 0.21-1.02; I2=54%; Figure 1B) in COVID-19 patients. However, it did not reduce the risk of COVID-19 progression (RR 0.74; 95% CI: 0.21-2.57; I2=44%; Supplementary Figure 2). The incidence of adverse events did not differ significantly between the fluvoxamine and the control groups (RR 0.94; 95% CI: 0.79-1.11; I2=0%; Supplementary Figure 3). In one study, one patient receiving fluvoxamine reported a serious adverse event as compared to six patients in the control group. In sensitivity analyses by excluding Bramante et al. in which patients in the control group received metformin, a drug known to be beneficial for COVID-19, the results for hospitalization (RR 0.37; 95% CI: 0.14-0.95; I2=58%) became significant in favor of fluvoxamine but the outcome of COVID-19 progression (RR: 0.33; 95% CI: 0.03-4.35; I2=57%) remained non-significant.

Figure 1

Effect of fluvoxamine on: A) all-cause mortality and B) hospitalization in COVID-19 patients.

To the best of our knowledge, this is the largest meta-analysis to date to evaluate the potential effectiveness of fluvoxamine as a COVID-19 treatment. Our findings showed that fluvoxamine use was associated with a large but statistically non-significant reduction in mortality and hospitalization rates in patients with COVID-19 without increasing the incidence of adverse events. Our findings agree with a previous meta-analysis which showed that fluvoxamine did not decrease the risk of mortality or hospitalization . However, this meta-analysis was based on only three studies and therefore, was relatively underpowered. After excluding a trial with an active comparator, we showed that fluvoxamine did reduce the risk of hospitalization in contrast with the previous meta-analyses which did not find any benefits of fluvoxamine use. , Moreover, the TOGETHER trial found that fluvoxamine decreased the risk of hospitalization in high-risk COVID-19 patients . This suggests that fluvoxamine may not be effective for every patient on a routine basis and that outpatient populations with an elevated risk of comorbidities must be identified to maximize the benefits of fluvoxamine therapy .

Fluvoxamine may be beneficial for treating COVID-19 because of its easy accessibility and affordable price. A 10-day regimen of fluvoxamine costs about $4; hence, in low-income countries, it is a cost-effective treatment for COVID-19 if compared with other approved oral antivirals, including paxlovid and molnupiravir .

Due to the small number of available trials and the inclusion of observational studies, our study has several limitations, including low statistical power and a risk of confounding bias. Additionally, we could not assess long-term outcomes as they were not reported by the studies.

In conclusion, treatment with fluvoxamine did not decrease mortality and hospitalization rates in patients with COVID-19 but due to the imprecise CIs, a large possible benefit cannot be ruled out. The sensitivity analysis showing a statistically significant reduction in risk of hospitalization further reinforces this point and is highly encouraging. To strengthen these findings, further large-scale RCTs are needed especially for longer-term outcomes are needed.

Financial support

No financial support was received for this study.

Availability of data

The data that support the findings of this study are available from the corresponding author, HAC, upon reasonable request.

Authors’ Contribution

Concept and design: HAC, AS, AAE and UJ; acquisition, analysis and interpretation of data: UJ, HAC, MA, ME, RUA; drafting of the manuscript: AAE, ME, AS and UJ; critical revision of the manuscript: HAC, MA, RUA and SS. All authors finally approved the manuscript.

Conflicts of interest

The authors report no relationships that could be construed as a conflict of interest.