Antidepressants Fluoxetine and Fluvoxamine in Treatment of COVID-19

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This entry is adapted from the peer-reviewed paper 10.3390/ijms23073812

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.

COVID-19 SARS-CoV-2 fluoxetine fluvoxamine acid sphingomyelinase SSRI sigma-1 receptors FIASMA SLC22A3 lysosomotropic agents clinical studies drug repurposing

1. Introduction

The COVID-19 pandemic has spread around the globe in several waves and close to 500 million confirmed cases have been reported, with more than six million deaths as of March 2022 ^[1]. As vaccinations became available in early 2021, by March 2022, roughly 65% of the world’s population has received at least one dose of vaccine, but 85% of people living in low-income countries have not yet received their first dose ^[2].

Severe COVID-19 develops in several steps and might require hospitalization or in many cases intensive care. It is of major importance to identify ways that can prevent severe COVID-19 and decrease the burden on the healthcare system in general and intensive care treatment facilities in particular. Several potential medications were tested during the pandemic period based on prior knowledge about the life cycle of the SARS-CoV virus ^[3]. Drugs known to be lysosomotropic agents were tested, such as azithromycin, chloroquine, hydroxychloroquine, and ivermectin, but were found to be ineffective in preventing severe COVID-19 and results of clinical trials on ivermectin use were also disappointing ^[4]^[5]^[6]. Other drug repurposing efforts were highly successful; such as using steroids to prevent the cytokine storm, budesonide to reduce local inflammation in the lung, and anti-IL-6 inhibitors, such as tocilizumab, to prevent the devastating results of an already initiated cytokine storm ^[7].

2. Clinical Evidence for the Potential Benefits of Using Fluoxetine and Fluvoxamine in COVID-19 Therapy

There are multiple studies available from the past two years that assess the effectiveness of different SSRI medications for patients with COVID-19 infection. Clinical trials mainly focused on fluoxetine and fluvoxamine, while observational studies investigated the possible beneficial effects of other antidepressants as well.

2.1. The First Clinical Trial

The first clinical trial was conducted by Lenze et al. in St Louis, USA, during the very early phase of the pandemic in the summer of 2020 ^[8]. It used a double-blind, randomized, placebo-controlled design, patients were non-hospitalized adults in a community setting. Symptom onset was within 7 days, and patients with low saturation levels (<92%) and other severe underlying medical conditions (COPD, heart failure, and immunocompromised status, etc.) were excluded from the study. Participants either received 3 × 100 mg of fluvoxamine (if tolerated) or a placebo for 15 days, and they did not receive specific antiviral medication as part of the protocol. The primary endpoint was clinical deterioration, which was defined as a low saturation level (<92%) or dyspnoea. Results showed that no patient receiving fluvoxamine reached the primary endpoint, whereas 6 of 72 on placebo had either shortness of breath or low oxygen levels. Only one of them needed ventilator support and no participants died. There were several limitations to this study (including a low number of participants, a small number of endpoints, and no long-term follow-up, etc.); results, however, were encouraging, and it appeared that fluvoxamine could be used in the early phase of the infection to prevent the deterioration of symptoms.

2.2. The First Open-Label, Real-World, Prospective Cohort Study

Based on the initial promising results of the above-mentioned study, Seftel et al. launched an open-label, real-world, prospective cohort study, in which fluvoxamine (2 × 50 mg for 14 days) was offered as a therapeutic option for patients living in an occupational setting, during a mass outbreak in November-December of 2020 ^[9]. A total of 65 patients accepted fluvoxamine, whereas 48 chose only observation, with no specific treatment as an option. There were no major differences regarding basic demographics between the two groups, however, only 38% of those who received fluvoxamine were asymptomatic, compared to 58% in the observation group. A total of 30% of the patients had one or more chronic medical conditions, and the median age was 42. Results heavily favoured fluvoxamine, as no one on this medication needed hospitalization, contrary to 12.5% (6 of 48) in the observation group (p = 0.005). Of the patients, two required intensive care treatment and one of them died. Although initial symptoms were more prevalent in the fluvoxamine group, at day 14 the participants were symptomless, whereas 60% (29 of 48) of the patients in the observation groups still had ongoing symptoms (p < 0.001), such as anxiety, memory problems, fatigue, and headaches, etc. As a small-scale, open-label, non-randomized trial, it has its obvious weaknesses; however, it provides valuable information about a real-world setting on how fluvoxamine could be used in occupational settings.

2.3. The First Double-Blind, Placebo-Controlled Study

The largest scale, randomized, double-blind, placebo-controlled study was conducted by Gilmar Reis et al. in Brazil ^[10].

TOGETHER is a multicentre clinical trial in which high-risk outpatients received either fluvoxamine (2 × 100 mg) or placebo for ten days, while other medications (hydroxychloroquine, lopinavir-ritonavir, metformin, ivermectin, doxazosin, and interferon lambda) were also tested during this time, therefore, patients were randomized into other treatment arms as well. Only patients with early symptoms (<7 days) and who had at least one other major medical condition (diabetes, cardiovascular disease, and asthma, etc.), and were thus characterized as belonging to a high-risk group, could participate in the trial. The primary outcome was hospitalization or observation in Emergency Care, which lasted longer than 6 h (without waiting times). Secondary outcomes were—among others—viral clearance, time to clinical improvement, number of days with respiratory symptoms, and mortality. Follow-up was 28 days long. Altogether, 741 patients received fluvoxamine and 756 placebo, and no major differences were present between the groups regarding demography and comorbidities. A total of 11% (79 of 741) of participants in the fluvoxamine group and 16% (119 of 756) of the placebo group had a primary outcome event, most of which were hospitalizations. Per-protocol analysis showed a larger beneficial effect in the fluvoxamine groups, therefore, the Data Safety Monitoring Committee decided that randomization of patients had to be stopped, given the superiority of the active arm compared to placebo. No other investigated active compound proved to be effective in this trial. That trial showed the first strong piece of evidence that supported the use of fluvoxamine in the early stages of COVID-19, although it needs to be taken into consideration that the primary endpoint (the number of hospitalizations and longer observations in ER settings) is determined by multiple factors including anxiety. Fluvoxamine, as an excellent antidepressant, can act as an anxiolytic drug after only one week of treatment, which can cast a bias on this study design.

2.4. Observational and Retrospective Studies

2.4.1. A Hungarian, Retrospective, Case-Control Study

Németh et al., at Uzsoki Street Hospital, Budapest, investigated whether fluoxetine improves clinical outcome among hospitalized patients with severe COVID-19 ^[11].

The rationale behind this approach was that fluoxetine—as a potent antidepressant—can decrease anxiety and improve a patient’s mood during the sometimes lengthy hospital stay, and therefore, would improve the general outcome. Medical records of patients treated between 17 March and 22 April 2021 were analysed retrospectively. Indication of fluoxetine was up to the physician’s discretion, however, as positive experiences with the medications arose, it became part of the protocol, therefore, it was more widely used. Altogether, 110 patients received fluoxetine (20 mg/day) and 159 received treatment as usual (TAU), which included—based on the physician’s decision—favipiravir, remdesivir, and baricitimib. Overall mortality was significantly lower in the fluoxetine group (15/110 vs. 49/159, p = 0.002), whereas there were no significant differences between other treatment groups. It should also be noted that although fluoxetine was often co-administered with remdesivir, the effect of fluoxetine seems to be independent of it.

This study has serious limitations, which derive from the retrospective manner used and the fact that patients were not randomized into different subgroups. However, in contrast to the previously mentioned trials, most patients were not in the early phases of their infection when they were given fluoxetine, which suggests that SSRI medication can be effective in later stages of COVID-19 as well.

It should also be noted that antidepressants, regardless of COVID-19 effects, may improve outcomes for patients who are treated in intensive care settings or who are hospitalized over a long duration, because depression itself increases the mortality of this patient group ^[12].It has been reported that SSRIs can have a neuroprotective effect during COVID-19 ^[13]. Results of this study are therefore probably partially related to the antidepressant effect of fluoxetine and are not necessarily linked to the COVID-19 pathology itself. Overall, in a clinical context, the improvement of depression and anxiety should be considered an important confounder in relation to somatic improvement, because psychiatric improvement has been shown to have a direct effect on somatic endpoints ^[14]^[15]. Therefore, changes in depressive and anxiety symptoms should also be screened in future studies assessing the effectiveness of antidepressants in COVID-19 patients, making the control of this cofactor possible.

2.4.2. The Observational Multicentre Retrospective Cohort Study from the Paris Region

This study was conducted by Hoertel et al. in 2020 based on the Health Data Warehouse “Assistance Publique-Hôpitaux de Paris (AP-HP)” ^[16]. The study examined the possible beneficial effects of various antidepressants (AD). Only data of hospitalized patients were analysed, which suggests that most of them had moderate or severe symptoms. Patients who received an antidepressant within 48h of hospitalization (N = 345) were compared to the control group (N = 6885), furthermore, the AD group was divided into SSRI (N = 195) and non-SSRI (N = 150) subgroups during the analytic process. The primary endpoints were intubation and death. There were no significant differences in patient characteristics between the matched analysed samples. Results showed that all ADs were associated with a significantly reduced risk of intubation or death among hospitalized patients. SSRIs, such as escitalopram, fluoxetine, paroxetine, and an SNRI, venlafaxine, showed the strongest association with better outcomes, but sample sizes were low in the case of some medications (only one patient received fluvoxamine). Overall, the study suggests that a broad spectrum of ADs can improve clinical outcomes, perhaps with different pathomechanisms, moreover it shows that—as it was seen in the previously mentioned publication—SSRIs can be effective not only in the early but also the later stages of the disease.

2.4.3. The San Francisco Region Health Records Analysis

Oskotsky et al. analysed the health records of 490,373 patients in the USA’s San Francisco region who were diagnosed with COVID-19 and had either been hospitalized, observed in an emergency department, or had received urgent care in the community ^[17].

Similarly to the previous study, it used a retrospective cohort design, whereby patients were matched by demographic characteristics and major comorbidities. A total of 3401 adults received SSRIs at the time of confirmed COVID-19 infection, of whom 481 patients received either fluoxetine or fluvoxamine. The primary endpoint was death. There was a significantly lower death rate in the SSRI group compared to matched controls (14.6% vs. 16.6%), furthermore, the association was even more robust among patients on fluoxetine and fluvoxamine (10.0% vs. 13.3%); however, mortality among patients who received another SSRI did not differ significantly from the control group (15.4% vs. 17.0%). These results suggest that fluoxetine and fluvoxamine may have a superior effect compared to other SSRIs, however, it should be kept in mind that only 10 patients received fluvoxamine, which barely has statistical relevance in this kind of setting.

Even though all available studies support the theory that SSRIs, such as fluoxetine and fluvoxamine, could be effective against the development of severe outcomes of COVID-19 infection, very few randomized, placebo-controlled trials have been launched to verify this. One of these ongoing trials is currently recruiting patients with moderate to severe COVID-19 pneumonia in Hungary at multiple sites under the title “Fluvoxamine Administration in Moderate SARS-CoV-2 (COVID-19) Infected Patients”. A total of 100 participants are planned to be enrolled, all of whom are hospitalized due to COVID-19 symptoms. Contrary to the above-mentioned clinical trials, fluvoxamine is administered for a much longer period (74 days) in this setting. The primary outcome measure is the time to clinical recovery after treatment. It will be interesting to know whether the initial encouraging results seen in the “TOGETHER” study can be replicated amongst hospitalized patients in a later stage of the pandemic, when “treatment as usual” is more developed and effective than during earlier stages of the COVID-19 era.

Table 1 summarizes the published clinical studies.

Table 1. Summary of the available clinical data on the potential benefit of fluoxetine and fluvoxamine in preventing severe COVID-19.

Study	Author	Study Design	Type of Antidepressant	Number of Patients Enrolled	Primary Endpoints	Results
Fluvoxamine vs. Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19	Lenze et al. ^[8]	Randomized, double-blinded, placebo-controlled study	Fluvoxamine 3 × 100 mg (15 days)	N(FLUV) = 80, N(PLC) = 72	Clinical deterioration (dyspnoea or low saturation level)	0/80 (FLUV) vs. 6/72 (PLC)
Prospective Cohort of Fluvoxamine for Early Treatment of Coronavirus Disease 19	Seftel et al. ^[9]	Prospective, open-label, real-world, cohort study	Fluvoxamine 2 × 50 mg (14 days)	N(FLUV) = 65, N(Obs) = 48	Hospitalisation, ICU/death, symptoms on day 14	Hosp.: 0/65 (FLUV) vs. 6/48 (Obs) ICU: 0 vs. 2 Death: 0 vs. 1 Symp. on D14: 0/65 vs. 29/48
Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial	Reis et al. ^[10]	Randomized, double-blinded, placebo-controlled study	Fluvoxamine 2 × 100 mg (10 days)	N(FLUV) = 741, N(PLC) = 756	Primary: hospitalisation and emergency care setting (longer than 6 h)	Primary endpoint: 10.66% (FLUV) vs. 15.75% (PLC)
Fluoxetine use is associated with improved survival of patients with COVID-19 pneumonia: a retrospective case-control study	Németh et al. ^[11]	Retrospective, case-control study	Fluoxetine 1 × 20 mg	N(FLUO) = 110, N(TAU) = 159	Death	Mortality: 13.6% (FLUO) vs. 23.8% (TAU) p = 0.002
Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study	Hoertel et al. ^[16]	Retrospective, cohort study	All antidepressants	N(AD) = 345, N(SSRI) = 195, N(non-SSRI) = 150, N(control) = 6885	Intubation/death	Antidepressant use was significantly associated with reduced risk of intubation or death.
Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants	Oskotsky et al. ^[17]	Retrospective, cohort study	All SSRIs	N(all) = 490373, N(SSRI) = 3401, N(FLUO + FLUV) = 481	Death	Mortality: 14.6% (SSRI) vs. 16.3% (control) 10% (FLUV+FLUO) vs. 13.3% (control) 15.4% (other SSRI) vs. 17% (control)

Abbreviations: FLUV: fluvoxamine, FLUO: fluoxetine, PLC: placebo, Obs.: observation, ICU: intensive care unit, Symp.: symptomatic, TAU: treatment as usual, AD: antidepressants, SSRI: selective serotonin reuptake inhibitor.

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