The possible immunoregulatory and anti-inflammatory effects of selective serotonin reuptake inhibitors in coronavirus disease patients

Hamed, Mohammed Gaber Mohamed; Hagag, Radwa Samir

doi:10.1016/j.mehy.2020.110140

Cited by 36 publications

(42 citation statements)

References 52 publications

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“…Maprotiline, a TCA, structurally different from other TCAs, had a strong negative connection in our analysis. Antidepressants such as TCAs and selective serotonin reuptake inhibitors have previously reported antiviral, immunomodulatory effects and antioxidant properties [ 65 ]. Although data are limited on the innate and adaptive immune effects of TCAs, they appear to have anti-inflammatory effects detected via TNF-α and IL-6 [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets

Duche

Sayer

et al. 2021

BMC Genomics

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Background The ongoing COVID-19 outbreak has caused devastating mortality and posed a significant threat to public health worldwide. Despite the severity of this illness and 2.3 million worldwide deaths, the disease mechanism is mostly unknown. Previous studies that characterized differential gene expression due to SARS-CoV-2 infection lacked robust validation. Although vaccines are now available, effective treatment options are still out of reach. Results To characterize the transcriptional activity of SARS-CoV-2 infection, a gene signature consisting of 25 genes was generated using a publicly available RNA-Sequencing (RNA-Seq) dataset of cultured cells infected with SARS-CoV-2. The signature estimated infection level accurately in bronchoalveolar lavage fluid (BALF) cells and peripheral blood mononuclear cells (PBMCs) from healthy and infected patients (mean 0.001 vs. 0.958; P < 0.0001). These signature genes were investigated in their ability to distinguish the severity of SARS-CoV-2 infection in a single-cell RNA-Sequencing dataset. TNFAIP3, PPP1R15A, NFKBIA, and IFIT2 had shown bimodal gene expression in various immune cells from severely infected patients compared to healthy or moderate infection cases. Finally, this signature was assessed using the publicly available ConnectivityMap database to identify potential disease mechanisms and drug repurposing candidates. Pharmacological classes of tricyclic antidepressants, SRC-inhibitors, HDAC inhibitors, MEK inhibitors, and drugs such as atorvastatin, ibuprofen, and ketoconazole showed strong negative associations (connectivity score < − 90), highlighting the need for further evaluation of these candidates for their efficacy in treating SARS-CoV-2 infection. Conclusions Thus, using the 25-gene SARS-CoV-2 infection signature, the SARS-CoV-2 infection status was captured in BALF cells, PBMCs and postmortem lung biopsies. In addition, candidate SARS-CoV-2 therapies with known safety profiles were identified. The signature genes could potentially also be used to characterize the COVID-19 disease severity in patients’ expression profiles of BALF cells.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets

Duche

Sayer

et al. 2021

BMC Genomics

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“…However, no clinical study has been done with a view to correcting the 5-HT deficiency of coronavirus patients as the possibility of such 5-HT deficiency has not been considered earlier. Nevertheless, on the basis of the existing knowledge that some SSRIs have anti-inflammatory, antiviral, immunoregulatory and neuroprotective properties, a few studies [114] , [115] , [116] , [117] , [118] have been carried out to explore the effect of SSRIs on the coronavirus patients, where SSRIs like fluvoxamine, fluoxetine and escitalopram have been found to somewhat decrease the severity of COVID-19. This observation is in line with the present hypothesis, though, as anticipated from the hypothesis, a significant improvement is lacking.…”

Section: Implications and Importance Of The Hypothesismentioning

confidence: 99%

Does serotonin deficiency lead to anosmia, ageusia, dysfunctional chemesthesis and increased severity of illness in COVID-19?

Sen¹

2021

Medical Hypotheses

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Different mechanisms forwarded to understand anosmia and ageusia in coronavirus patients are not adequate to explain reversible anosmia and ageusia, which are resolved quickly. In addition, the reason behind the impaired chemesthetic sensations in some coronavirus patients remains unknown. In the present paper it is proposed that SARS-CoV-2 patients suffer from depletion of tryptophan, as ACE2, a key element in the process of absorption of tryptophan from the food, is significantly reduced in the patients as coronavirus uses ACE2 as the receptor to enter the host cells. The tryptophan depletion leads to a deficit of serotonin (5-HT) in SARS-COV-2 patients because tryptophan is the precursor in the synthesis of 5-HT. Such 5-HT deficiency can explain anosmia, ageusia and dysfunctional chemesthesis in COVID-19, given the fact that 5-HT is an important neuromodulator in the olfactory neurons, taste receptor cells and transient receptor potential channels (TRP channels) involved in chemesthesis. In addition, 5-HT deficiency worsens silent hypoxemia and depresses hypoxic pulmonary vasoconstriction leading to increased severity of the disease. Also, the levels of anti-inflammatory melatonin (synthesized from 5-HT) and nicotinamide adenine dinucleotide (NAD + , produced from niacin whose precursor is the tryptophan) might decrease in coronavirus patients resulting in the aggravation of the disease. Interestingly, selective serotonin reuptake inhibitors (SSRIs) may not be of much help in correcting the 5-HT deficiency in COVID-19 patients, as their efficacy goes down significantly when there is depletion of tryptophan in the system. Hence, tryptophan supplementation may herald a radical change in the treatment of COVID-19 and accordingly, clinical trials (therapeutic / prophylactic) should be conducted on coronavirus patients to find out how tryptophan supplementation (oral or parenteral, the latter in severe cases where there is hardly any absorption of tryptophan from the food) helps in curing, relieving or preventing the olfactory, gustatory and chemesthetic dysfunctions and in lessening the severity of the disease.

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“…About 40% of the patients treated in the critical care unit display an acute respiratory distress syndrome associated with pneumonia (Guan et al, 2020). In summary, COVID-19 may lead to overstimulation of the immune system (Giamarellos-Bourboulis et al, 2020) and it has been suggested that inhibition of serotonin reuptake may reduce exacerbated inflammation (Hamed and Hagag, 2020). Remarkably, this hypothesis has been supported by a recent study reporting less risk of intubation or death in patients taking antidepressant medication (Hoertel et al, 2021).…”

Section: Atpmentioning

confidence: 96%

5-Hydroxytryptamine, Glutamate, and ATP: Much More Than Neurotransmitters

Franco

Rivas‐Santisteban

Lillo

et al. 2021

Front. Cell Dev. Biol.

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5-hydroxytryptamine (5-HT) is derived from the essential amino acid L-tryptophan. Although the compound has been studied extensively for its neuronal handling and synaptic actions, serotonin 5-HT receptors can be found extra-synaptically and not only in neurons but in many types of mammalian cells, inside and outside the central nervous system (CNS). In sharp contrast, glutamate (Glu) and ATP are better known as metabolism-related molecules, but they also are neurotransmitters, and their receptors are expressed on almost any type of cell inside and outside the nervous system. Whereas 5-hydroxytryptamine and Glu are key regulators of the immune system, ATP actions are more general. 5-hydroxytryptamine, ATP and Glu act through both G protein-coupled receptors (GPCRs), and ionotropic receptors, i.e., ligand gated ion channels. These are the three examples of neurotransmitters whose actions as holistic regulatory molecules are briefly put into perspective here.

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The possible immunoregulatory and anti-inflammatory effects of selective serotonin reuptake inhibitors in coronavirus disease patients

Cited by 36 publications

References 52 publications

SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets

SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets

Does serotonin deficiency lead to anosmia, ageusia, dysfunctional chemesthesis and increased severity of illness in COVID-19?

5-Hydroxytryptamine, Glutamate, and ATP: Much More Than Neurotransmitters

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