The antidepressant fluvoxamine appears to prevent COVID-19 infections from worsening

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The antidepressant fluvoxamine appears to prevent COVID-19 infections from worsening and may help keep patients out of the hospital, a trial based on research from the University of Virginia School of Medicine suggests.

The clinical trial, conducted by the Washington University School of Medicine in St. Louis, compared fluvoxamine with a placebo in 152 adult outpatients infected with the coronavirus. None of the participants who received fluvoxamine saw “clinical deterioration” after 15 days, while six patients who received placebo did.

Of those six, four were hospitalized, for periods ranging from four to 21 days. One was on a ventilator for 10 days.

While the study size was small, the researchers say the results are statistically significant and that fluvoxamine warrants further study as a COVID-19 treatment. They plan to launch a larger trial in the next few weeks.

“The patients who took fluvoxamine did not develop serious breathing difficulties or require hospitalization for problems with lung function,” said Eric J. Lenze, MD, of the Washington University School of Medicine.

“Most investigational treatments for COVID-19 have been aimed at the very sickest patients, but it’s also important to find therapies that prevent patients from getting sick enough to require supplemental oxygen or to have to go to the hospital.

Our study suggests fluvoxamine may help fill that niche.”

Fluvoxamine and COVID-19

The Washington University researchers launched the randomized, double-blind trial based on a discovery by UVA’s Alban Gaultier, PhD, and former graduate student Dorian A Rosen, PhD. Gaultier and Rosen found last year that fluvoxamine may stop the deadly inflammation known as sepsis, in which the immune response spirals out of control.

The drug, they determined, reduced the production of cytokines, which have been linked to potentially deadly “cytokine storms” thought to occur in severe cases of COVID-19.

That connection prompted the Washington University team to investigate the possibility that fluvoxamine could have a protective effect for patients with COVID-19.

Perhaps, they thought, the drug could help prevent the immune system overreactions triggered by this strange new coronavirus. And their work suggests it may.

“Because elevated cytokines levels have been associated with COVID-19 severity, testing fluvoxamine in a clinical trial made a lot of sense to us,” said Gaultier, of UVA’s Department of Neuroscience and its Center for Brain Immunology and Glia (BIG).

“We are still unclear about the mode of action of fluvoxamine against SARS-CoV-2, but research is under way to find the answer.”

The Washington University team noted that recent research has raised questions about whether cytokines are really playing important roles in COVID-19 deaths.

If not, the researchers say, fluvoxamine may be having beneficial effects by some other mechanism not yet understood.

“There are several ways this drug might work to help COVID-19 patients, but we think it most likely may be interacting with the sigma-1 receptor to reduce the production of inflammatory molecules,” said Washington University’s Angela M Reiersen, MD. “Past research has demonstrated that fluvoxamine can reduce inflammation in animal models of sepsis, and it may be doing something similar in our patients.”

The researchers stressed that there were several limitations to their research. In addition to its small size, the trial was hampered by other factors, including that 20% of participants stopped answering surveys during the 15-day trial.

(The researchers determined that none of those participants required hospitalization or emergency-department visits, but they could not rule out that the participants sought treatment elsewhere, such as at urgent-care clinics.)

Because of these limitations, the researchers say that the trial’s results should not be treated as a measure of fluvoxamine’s effectiveness against COVID-19 but as an encouraging indicator that the drug warrants further testing.

“If a larger clinical trial (phase III) confirms the results, fluvoxamine would be a perfect treatment for COVID patients newly diagnosed,” Gaultier said. “Fluvoxamine is not an experimental drug, it is cheap and safe and could be available as a first line of defense to unburden the hospitals that are overwhelmed by the COVID health crisis.”


Stress associated with COVID-19

The pandemic of COVID-19 has shown to affect people physically and psychologically [13]. The associated stress, anxiety and depression had shown to be responsible for a part in the pathogenesis of COVID-19 [14], [15].

Stress is defined as the process by which environmental requirements transform the organism’s adaptability, leading to psychological and biological changes [14]. Clinical evidences have proved an association between specific mood disorders, caused by sustained or chronic stress and the immune dysregulation [15], [16], [17].

A study conducted on COVID-19 patients had reported that the severe cases are caused by a malfunction or deficiency in the immune system [18].

Immune dysregulation is a consequence of elevation of cortisol, the stress hormone, and reduction of serotonin [19]. This hormonal dysregulation might promote the initiation and progression of the infection [20].

In addition, stressful conditions associated with infection had shown to cause an elevation in the levels of the inflammatory mediator IL-6 that causes a decrease in the number and activity of cytotoxic T-cells and natural killer (NK) cells [21], [22].

Moreover, the resulted depression due to prolonged stress was found to be associated with higher levels of serum IL-6 and tumor necrosis factor- alfa (TNF-α) [22], catecholamines, inhibitory T cells and histamine [14].

The decreased counts of lymphocytes, monocytes, eosinophils and basophils associated with depression had shown to participate more in suppressing the immune response [23], [24].

These elevated inflammatory cytokines had shown also to precipitate depression and inflammations to many organs especially lung which is a serious condition and a main cause of mortality in COVID-19.

Serotonin role in regulating immunity and resistance to infection

Serotonin (5-HT) is a neurotransmitter and immunomodulator. It improves the mood and it is also responsible for feeling of happiness and calmness. 5-HT was found to regulate innate and adaptive immune responses.

In addition, it has shown to play important roles in brain function, hemostasis, sleeping, mood regulation, behaviors and phycological state. It also has important roles in many different peripheral tissues, central nervous system (CNS) and immune cells [25], [26]. The decrease in 5-HT levels is a major cause of depression like symptoms [27]

Pathological and physiological conditions may affect the role of serotonin in properly regulating the immune response [28]. Many researches had concluded that elevated serotonin levels plays a vital role in immunity against viral infections [29], [30].

On the other hand, lowered levels of 5-HT had shown a correlation with susceptibility to bacterial infections [27].

COVID-19 had shown to increase the levels of pro-inflammatory cytokines [31]. These elevated levels had shown to increase the rate of metabolism of serotonin due to activation of indoleamine-2,3-dioxygenase (IDO) enzyme that metabolizes tryptophan which is the precursor of serotonin [32].

Moreover, studies had reported that the elevated levels of C-reactive protein (CRP) had shown to be linked to depression like symptoms [33], [34], [35].

Statement of hypothesis

Generally, antidepressants are found to augment the immune system response through inhibiting pro-inflammatory factors, in particular CRP, TNF-α, IL-1β and IL-6 [36]. Selective serotonin reuptake inhibitors (SSRIs) are used as antidepressants and anxiolytics by manipulating serotonin within the brain.

SSRIs increase serotonin via proscribing its reuptake into the presynaptic cell then increasing the level of serotonin inside the synaptic cleft to bind the postsynaptic receptor [37].

SSRIs have shown an effective role in relieving symptoms of stress and anxiety, which enhances the role of immunity in confronting infection. This class had proved to prevent the elevation in cytokine levels which causes depression [38], [39], [40], [41].

Moreover, SSRIs use had resulted in lowering endotoxin-induced fatigue [39]. In vitro antibacterial effect and modulation of antibiotic activity were also associated with using SSRIs [42], [43], [44].

In COVID-19 patients, SSRIs may help in hindering cytokine release syndrome that is responsible for aggravating sickness progression and the subsequent increase in TNFα [45]. A study had reported the effective role of SSRIs in severe chronic obstructive pulmonary disease where a significant increase of patients’ oxygen saturation was observed [46].

Therefore, SSRIs family may help in controlling symptoms of COVID-19 patients due to its reported potent anti-inflammatory activity in different inflammatory disorders [39], [47]

Antioxidant and anticoagulant properties of SSRIs

Many researches had reported the high therapeutic efficacy of SSRIs via reversal of the oxidative damage by the protective enhancement of antioxidant status following a stress-induced decline [48]. It has shown a significant inhibitory effect on nitric oxide (NO) production in a dose-dependent manner [49]. As a consequence, SSRIs had shown anti-inflammatory and analgesic properties [50].

SSRIs have shown anticoagulant properties [51] making it a promising option for COVID-19 patients who mostly experience venous and arterial thrombosis that is the major cause of mortality.

Antiviral properties of SSRIs

Given the high replicative potential of COVID-19, it is possible that the very high viral burden in the lung leads to a large inflammatory response which is fatal. Fortunately, SSRI was found to have antiviral effects beside being a mood stabilizer.

A patent study had reported the efficiency of SSRIs treatment in reducing chemokine and cytokine expression in the infected cells and hence, it has a role in combating infections [52]. SSRIs had shown to potentiate the antiviral potency of certain antivirals [53].

SSRIs had reported HIV receptor and coreceptor downregulation [54], Ebola virus lowered activity [55] and reduced viral replication of Coxsackievirus B4 [56] by their use beside the antiviral.

Which SSRI are we going to use and why?

Sertraline is a member of SSRIs that is deeply suggested as a favorable therapeutic choice for COVID-19 patients because it has a wide therapeutic index and minimal anticholinergic activity which make it a safe option for elderly patients or those with underlying cardiovascular disorders [57].

Sertraline had strong anti-inflammatory effects via decreasing and regulating of pro-inflammatory cytokines [58], [59]. It had significantly increased the activity of antibiotics with some resistant strains of S. aureus, E. Coli and P. aeruginosa. Thus, sertraline is a resistance modifying agent when used in combination with the antibiotics [44].

Also sertraline had reported antiviral efficacy [60] when used effectively in reducing influenza-induced lung inflammation and lowering mortality rate when combined with oseltamivir in a mouse model [53].

Regarding the ideal timing of starting sertraline, it would be advisable to start once respiratory symptom began to be worse or, in other words, before the onset of acute lung injury which precedes the occurrence of the fatal pneumonia.

Conclusions

In this hypothesis, we needed to raise the effective role of serotonin in the activation of T-cells and enhancement of the immune system in COVID-19 patients. This may show a high usefulness for the vulnerable subjects and medical staff who are constantly exposed to fatigue, stress, anxiety and depression caused by COVID-19 pandemic and had shown to destroy the immunity against any viral attack.

SSRI would play important roles in COVID-19 infection via treating anxiety and stress, and increasing the number and function of immune cells. Cytokine release syndrome in COVID-19 is expected to be ameliorated by the use of sertraline that lower IL-6 and IL-10 levels.

Moreover, we suggest that sertraline may exhibit antiviral effect against COVID-19 but with unknown mechanism of action. We think that understanding the mechanism of halting the viral replication would be an important research area that might benefit the scientific field.

We advise giving sertraline to moderate cases of COVID- 19 patients as a prophylaxis against lethal pulmonary symptoms and it should be used as an adjuvant therapy to drugs used in the protocol of COVID-19 treatment.

This research hypothesis would provide a great benefit in fastening the recovery and reducing mortality rates in COVID-19 patients. Moreover, if using sertraline is found to be effective in preventing the associated ARDS, its global use would be highly beneficial to the humanity. Besides, it is safe, tolerable and highly affordable.

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Funding: The clinical trial was supported by the Taylor Family Institute for Innovative Psychiatric Treatment at Washington University and the COVID-19 Early Treatment Fund. Additional support was provided by the Center for Brain Research in Mood Disorders at Washington University, the Bantly Foundation and National Institutes of Health grant UL1TR002345.

Source: University of Virginia

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