In outpatients with mild to moderate COVID-19, low-dose fluvoxamine did not reduce time to sustained recovery.

SOURCE CITATION: McCarthy MW, Naggie S, Boulware DR, et al. Effect of fluvoxamine vs placebo on time to sustained recovery in outpatients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2023;329:296-305. 36633838.

Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19 : A Randomized Platform Trial.

BACKGROUND: Previous trials have demonstrated the effects of fluvoxamine alone and inhaled budesonide alone for prevention of disease progression among outpatients with COVID-19. OBJECTIVE: To determine whether the combination of fluvoxamine and inhaled budesonide would increase treatment effects in a highly vaccinated population. DESIGN: Randomized, placebo-controlled, adaptive platform trial. (ClinicalTrials.gov: NCT04727424). SETTING: 12 clinical sites in Brazil. PARTICIPANTS: Symptomatic adults with confirmed SARS-CoV-2 infection and a known risk factor for progression to severe disease. INTERVENTION: Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) plus inhaled budesonide (800 mcg twice daily for 10 days) or matching placebos. MEASUREMENTS: The primary outcome was a composite of emergency setting retention for COVID-19 for more than 6 hours, hospitalization, and/or suspected complications due to clinical progression of COVID-19 within 28 days of randomization. Secondary outcomes included health care attendance (defined as hospitalization for any cause or emergency department visit lasting >6 hours), time to hospitalization, mortality, patient-reported outcomes, and adverse drug reactions. RESULTS: Randomization occurred from 15 January to 6 July 2022. A total of 738 participants were allocated to oral fluvoxamine plus inhaled budesonide, and 738 received placebo. The proportion of patients observed in an emergency setting for COVID-19 for more than 6 hours or hospitalized due to COVID-19 was lower in the treatment group than the placebo group (1.8% [95% credible interval {CrI}, 1.1% to 3.0%] vs. 3.7% [95% CrI, 2.5% to 5.3%]; relative risk, 0.50 [95% CrI, 0.25 to 0.92]), with a probability of superiority of 98.7%. No relative effects were found between groups for any of the secondary outcomes. More adverse events occurred in the intervention group than the placebo group, but no important differences between the groups were detected. LIMITATION: Low event rate overall, consistent with contemporary trials in vaccinated populations. CONCLUSION: Treatment with oral fluvoxamine plus inhaled budesonide among high-risk outpatients with early COVID-19 reduced the incidence of severe disease requiring advanced care. PRIMARY FUNDING SOURCE: Latona Foundation, FastGrants, and Rainwater Charitable Foundation.

Trial Sequential Analysis and Updated Meta-Analysis of Fluvoxamine on Clinical Deterioration in Adult Patients with Symptomatic COVID-19 Infection.

Preliminary meta-analyses suggested that fluvoxamine was effective in treating COVID-19 infection. However, the reliability of this evidence has not yet been examined. MEDLINE, CENTRAL, EMBASE, PsycINFO, and ClinicalTrials.gov were searched to identify any randomized controlled trials (RCTs) from the inception of the databases to 5 February 2023. We used trial sequential analysis (TSA) to examine the reliability of the current existing evidence on the benefits of fluvoxamine on COVID-19 infection. The primary outcome was clinical deterioration, as defined in the original study (reported as odds ratio (OR), with 95% confidence intervals), and the secondary outcome was hospitalization. In the TSA, we used the relative risk reduction thresholds of 10, 20, and 30%. The updated meta-analysis of the five RCTs showed that fluvoxamine was not associated with lower odds of clinical deterioration when compared with a placebo (OR: 0.81; 0.59-1.11). The effect of fluvoxamine lay within the futility boundary (i.e., lack of effect) when using a 30% relative risk reduction threshold. The effect estimates lay between the superiority and futility boundary using the 10% and 20% threshold, and the required size of information was not reached for these two thresholds. The effect of fluvoxamine on the odds of hospitalization was not statistically significant (0.76; 0.56-1.03). In conclusion, there is no reliable evidence that fluvoxamine, when compared to a placebo, reduces the relative risk of clinical deterioration among adult patients with COVID-19 infection by 30%, and a relative risk reduction of 20% or 10% is still uncertain. The role of fluvoxamine as a COVID-19 treatment cannot be justified.

Beyond "Psychotropic": Repurposing Psychiatric Drugs for COVID-19, Alzheimer's Disease, and Cancer.

Importance: "Psychotropic" drugs have widespread reach and impact throughout the brain and body. Thus, many of these drugs could be repurposed for non-psychiatric indications of high public health impact.Observations: The selective serotonin reuptake inhibitor (SSRI) fluvoxamine was shown efficacious as a COVID-19 treatment based on randomized controlled trials (RCTs), and a benefit of other antidepressants has been posited based on observational and preclinical studies. In this review, we illuminate features of SSRIs and other psychiatric drugs that make them candidates to repurpose for non-psychiatric indications. We summarize research that led to fluvoxamine's use in COVID-19 and provide guidance on how to use it safely. We summarize studies suggestive of benefit of other antidepressants versus COVID-19 and long COVID. We also describe putative mechanisms of psychiatric drugs in treating long COVID, Alzheimer's disease, cancer, and other conditions.Conclusion and Relevance: There is a potentially great clinical and public health impact of psychotropic drug repurposing. Challenges exist to such repurposing efforts, but solutions exist for researchers, regulators, and funders that overcome these challenges.

Effect of fluvoxamine on preventing neuropsychiatric symptoms of post COVID syndrome in mild to moderate patients, a randomized placebo-controlled double-blind clinical trial.

BACKGROUND: Shortly after the Coronavirus disease 2019 (COVID-19) pandemic, a considerable number of recovered patients reported persisting symptoms, especially neuropsychological manifestations, which were later named post-COVID syndrome (PCS). Immune dysregulation was suggested as one of the main mechanisms for PCS. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) that is mostly used to treat depression, anxiety disorders, and obsessive-compulsive disorder, has been suggested as an anti-COVID drug due to its anti-inflammatory effects, mainly through the sigma-1 receptor. Therefore, we aimed to evaluate fluvoxamine's effect on PCS neuropsychiatric symptoms. METHOD: In this double-blind randomized clinical trial, we included confirmed mild to moderate COVID-19 outpatients using polymerase chain reaction (PCR) by an infectious disease specialist. The presence of severe COVID-19 symptoms was evaluated by the infectious disease specialist and included dyspnea, SpO2 < 94% on room air, PaO2/FiO2 < 300 mm Hg, a respiratory rate > 30 breaths/min, and lung infiltrates > 50%. Then we performed permuted block randomization and assigned patients 1:1 into two groups to either receive fluvoxamine 100 mg tablet or a placebo daily for 10 days. Eligible patients were evaluated after 12 weeks for the presence of fatigue, as the primary, and other PCS symptoms as secondary outcomes. RESULTS: We screened a total of 486 patients from March to June 2022. After 12 weeks, 42 patients receiving fluvoxamine and 43 patients receiving Placebo were evaluated for PCS. Patients had a mean age of 38.5 ± 14.1 and 48% of them were women. Fatigue was significantly lower in the fluvoxamine group (p-value 0.026). No significant differences were observed in other symptoms. CONCLUSION: We concluded that taking fluvoxamine during active COVID-19 can reduce the chance of fatigue but the advantage of fluvoxamine was not observed for other symptoms. Further studies are necessary to confirm these preliminary results.

Outpatients prescribed with fluvoxamine around the time of COVID-19 diagnosis are not at a reduced risk of subsequent hospitalization and death compared to their non-prescribed peers: population-based matched cohort study.

PURPOSE: To assess the effect of exposure to fluvoxamine around the COVID-19 diagnosis on subsequent hospitalizations and mortality in COVID-19 outpatients in a real-life setting. METHODS: Using nationwide administrative data, we identified adult COVID-19 outpatients diagnosed up to August 15, 2021 and conducted two cohort studies. Study 1 included subjects prescribed fluvoxamine around the index COVID-19 diagnosis (Cohort A), their peers suffering similar psychiatric difficulties but not prescribed fluvoxamine (Cohort B) and those free of psychiatric difficulties/treatments (Cohort C). Study 2 included subjects prescribed fluvoxamine (Cohort Fluvoxamine) and their peers prescribed paroxetine (Cohort Paroxetine). Cohorts were mutually exactly matched and incidence of COVID-19-related hospitalization, 30-day all-cause hospitalization and of COVID-19-related mortality was estimated. RESULTS: Of the 416,030 first-episode outpatients, Study 1 included 1016 Cohort A, 95,984 Cohort B and 275,804 Cohort C patients. Matched Cohort A (n = 749) vs. Cohort B (n = 31,336) relative risks (95%CI/CrI), frequentist and Bayes with skeptical, otpimistic and pesimistic priors, were COVID-related hospitalization 1.37 (0.56-3.33), 1.15 (0.55-2.11), 1.03 (0.56.1.96) and 1.43 (0.63-2.94), respectively; 30-day all-cause hospitalization 1.88 (0.76-4.67), 1.76 (1.39-2.25), 1.76 (1.39-2.24) and 1.86 (1.43-2.38), respectively; COVID-19-related mortality 0.73 (0.35-1.55), 0.93 (0.53-1.76), 0.79 (0.40-1.54) and 0.88 (0.37-2.11), respectively. Matched Cohort A vs. C (866 vs. 222,792) comparison yielded similar estimates, as did the matched Cohort Fluvoxamine vs. Paroxetine comparison in Study 2 (344 of 994 matched to 535 of 1796 patients). CONSLUSION: Outpatients prescribed fluvoxamine around the time of COVID-19 diagnosis were not at a reduced risk of hospitalizations and mortality compared to their non-prescribed peers.

Antidepressants for COVID-19: A systematic review.

OBJECTIVE: To systematically examine the efficacy and safety of antidepressants for the treatment of coronavirus disease 2019 (COVID-19). METHODS: A systematic search was performed independently by two researchers based on Chinese Journal Net, WanFang, PsycINFO, Cochrane Library, PubMed, and EMBASE. RESULTS: Seven studies (n = 92,947) including three retrospective studies (n = 91,083), two randomized clinical trials (RCTs, n = 1649), two prospective cohort study (n = 215) involving (n = 92,947) patients with COVID-19 were examined. For RCTs, fluvoxamine outperformed placebo in reducing clinical deterioration and hospitalisation for COVID-19 patients. For retrospective studies, antidepressants (2 studies) and fluoxetine (1 study) possibly reduced the risk of mortality in patients with COVID-19. Results from two remaining studies supported the superiority of fluvoxamine in reducing risk of mortality in COVID-19 patients. The two RCTs that examined the safety of fluvoxamine for COVID-19 patients found inconsistent results but no significant group differences in the dropout rate. CONCLUSION: This systematic review found emerging evidence for fluvoxamine in reducing the risk of mortality and hospitalisation in COVID-19 patients, but inconsistent evidence for the safety of fluvoxamine in COVID-19 patients. More studies are needed to determine the efficacy and safety of antidepressants for the treatment of COVID-19.

SSRIs differentially modulate the effects of pro-inflammatory stimulation on hippocampal plasticity and memory via sigma 1 receptors and neurosteroids.

Certain selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory effects in preclinical models, and recent clinical studies suggest that fluvoxamine can prevent deterioration in patients with COVID-19, possibly through activating sigma 1 receptors (S1Rs). Here we examined potential mechanisms contributing to these effects of fluvoxamine and other SSRIs using a well-characterized model of pro-inflammatory stress in rat hippocampal slices. When hippocampal slices are exposed acutely to lipopolysaccharide (LPS), a strong pro-inflammatory stimulus, basal synaptic transmission in the CA1 region remains intact, but induction of long-term potentiation (LTP), a form of synaptic plasticity thought to contribute to learning and memory, is completely disrupted. Administration of low micromolar concentrations of fluvoxamine and fluoxetine prior to and during LPS administration overcame this LTP inhibition. Effects of fluvoxamine required both activation of S1Rs and local synthesis of 5-alpha reduced neurosteroids. In contrast, the effects of fluoxetine did not involve S1Rs but required neurosteroid production. The ability of fluvoxamine to modulate LTP and neurosteroid production was mimicked by a selective S1R agonist. Additionally, fluvoxamine and fluoxetine prevented learning impairments induced by LPS in vivo. Sertraline differed from the other SSRIs in blocking LTP in control slices likely via S1R inverse agonism. These results provide strong support for the hypothesis that S1Rs and neurosteroids play key roles in the anti-inflammatory effects of certain SSRIs and that these SSRIs could be beneficial in disorders involving inflammatory stress including psychiatric and neurodegenerative illnesses.

Potential Role of the Antidepressants Fluoxetine and Fluvoxamine in the Treatment of COVID-19.

Mapping non-canonical cellular pathways affected by approved medications can accelerate drug repurposing efforts, which are crucial in situations with a global impact such as the COVID-19 pandemic. Fluoxetine and fluvoxamine are well-established and widely-used antidepressive agents that act as serotonin reuptake inhibitors (SSRI-s). Interestingly, these drugs have been reported earlier to act as lysosomotropic agents, inhibitors of acid sphingomyelinase in the lysosomes, and as ligands of sigma-1 receptors, mechanisms that might be used to fight severe outcomes of COVID-19. In certain cases, these drugs were administered for selected COVID-19 patients because of their antidepressive effects, while in other cases, clinical studies were performed to assess the effect of these drugs on treating COVID-19 patients. Clinical studies produced promising data that encourage the further investigation of fluoxetine and fluvoxamine regarding their use in COVID-19. In this review, we summarize experimental data and the results of the performed clinical studies. We also provide an overview of previous knowledge on the tissue distribution of these drugs and by integrating this information with the published experimental results, we highlight the real opportunity of using these drugs in our fight against COVID-19.

Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Importance: The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear. Objective: To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US. Interventions: Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28. Results: Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Efficacy and safety of selective serotonin reuptake inhibitors in COVID-19 management: a systematic review and meta-analysis.

BACKGROUND: The efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of acute COVID-19 is still under investigation, with conflicting results reported from randomized controlled trials (RCTs). Different dosing regimens may have contributed to the contradictory findings. OBJECTIVES: To evaluate the efficacy and safety of SSRIs and the effect of different dosing regimens on the treatment of acute COVID-19. DATA SOURCES: Seven databases were searched from January 2020 to December 2022. Trial registries, previous reviews, and preprint servers were hand-searched. STUDY ELIGIBILITY CRITERIA: RCTs and observational studies with no language restrictions. PARTICIPANTS: COVID-19 inpatients/outpatients. INTERVENTIONS: SSRIs prescribed after diagnosis were compared against a placebo or standard of care. ASSESSMENT OF RISK OF BIAS: Risk of bias was rated using the revised Cochrane Risk of Bias Tool for Randomized Trials version 2.0 and Risk of Bias in Non-Randomized Studies of Interventions. METHODS OF DATA SYNTHESIS: Outcomes were mortality, hospitalization, composite of hospitalization/emergency room visits, hypoxemia, requirement for supplemental oxygen, ventilator support, and serious adverse events. RCT data were pooled in random-effects meta-analyses. Observational findings were narratively described. Subgroup analyses were performed on the basis of SSRI dose, and sensitivity analyses were performed excluding studies with a high risk of bias. The Grading of Recommendations, Assessment, Development and Evaluations framework was used to assess the quality of evidence. RESULTS: Six RCTs (N = 4197) and five observational studies (N = 1156) were included. Meta-analyses associated fluvoxamine with reduced mortality (risk ratio, 0.72; 95% CI, 0.63-0.82) and hospitalization (risk ratio, 0.79; 95% CI, 0.64-0.99) on the basis of moderate quality of evidence. Medium-dose fluvoxamine (100 mg twice a day) was associated with reduced mortality, hospitalization, and composite of hospitalization/emergency room visits, but low-dose fluvoxamine (50 mg twice a day) was not. Fluvoxamine was not associated with increased serious adverse events. Observational studies support the use of fluvoxamine and highlight fluoxetine as a possible alternative to SSRIs for the treatment of COVID-19. DISCUSSION: Fluvoxamine remains a candidate pharmacotherapy for treating COVID-19 in outpatients. Medium-dose fluvoxamine may be preferable over low-dose fluvoxamine.

Potential targets of severe acute respiratory syndrome coronavirus 2 of clinical drug fluvoxamine: Docking and molecular dynamics studies to elucidate viral action.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued evolving for survival and adaptation by mutating itself into different variants of concern, including omicron. Several studies and clinical trials found fluvoxamine, an Food and Drug Administration-approved antidepressant drug, to be effective at preventing mild coronavirus disease 2019 (COVID-19) from progressing to severe diseases. However, the mechanism of fluvoxamine's direct antiviral action against COVID-19 is still unknown. Fluvoxamine was docked with 11 SARS-CoV-2 targets and subjected to stability, conformational changes, and binding free energy analyses to explore its mode of action. Of the targets, nonstructural protein 14 (NSP14), main protease (Mpro), and papain-like protease (PLpro) had the best docking scores with fluvoxamine. Consistent with the docking results, it was confirmed by molecular dynamics simulations that the NSP14 N7-MTase ((N7-guanine)-methyltransferase)-fluvoxamine, Mpro-fluvoxamine, and PLpro-fluvoxamine complexes are stable, with the lowest binding free energies of -105.1, -82.7, and - 38.5 kJ/mol, respectively. A number of hotspot residues involved in the interaction were also identified. These include Glu166, Asp187, His41, and Cys145 in Mpro, Gly163 and Arg166 in PLpro, and Glu302, Gly333, and Phe426 in NSP14, which could aid in the development of better antivirals against SARS-CoV-2.