key: cord-1044436-m7bviik1 authors: Meikle, Claire Kyung Sun; Creeden, Justin Fortune; McCullumsmith, Cheryl; Worth, Randall G. title: SSRIs: Applications in inflammatory lung disease and implications for COVID‐19 date: 2021-07-13 journal: Neuropsychopharmacol Rep DOI: 10.1002/npr2.12194 sha: 3010cc3a7f4c5787c44a2db4633966cad74a8ca1 doc_id: 1044436 cord_uid: m7bviik1 Selective serotonin reuptake inhibitors (SSRIs) have anti‐inflammatory properties that may have clinical utility in treating severe pulmonary manifestations of COVID‐19. SSRIs exert anti‐inflammatory effects at three mechanistic levels: (a) inhibition of proinflammatory transcription factor activity, including NF‐κB and STAT3; (b) downregulation of lung tissue damage and proinflammatory cell recruitment via inhibition of cytokines, including IL‐6, IL‐8, TNF‐α, and IL‐1β; and (c) direct suppression inflammatory cells, including T cells, macrophages, and platelets. These pathways are implicated in the pathogenesis of COVID‐19. In this review, we will compare the pathogenesis of lung inflammation in pulmonary diseases including COVID‐19, ARDS, and chronic obstructive pulmonary disease (COPD), describe the anti‐inflammatory properties of SSRIs, and discuss the applications of SSRIS in treating COVID‐19‐associated inflammatory lung disease. The COVID-19 pandemic has led to press need for treatments and preventative strategies to manage acute and chronic lung disease. Given the rapid spread of COVID-19, it is expeditious to utilize medications that are already FDA-approved and that are known to have limited side effects. Selective serotonin reuptake inhibitors (SSRIs) have been explored as anti-inflammatory agents in the context of autoimmune and inflammatory diseases, and research suggests that SSRIs may inhibit inflammatory pathways implicated in acute and chronic lung disease. In this review, we will explore the utility of SSRIs in treatment and prevention of inflammatory lung disease and discuss the application of these findings to COVID-19. COVID-19 is caused by the SARS-CoV-2 virus, an enveloped, singlestranded positive-sense RNA betacoronavirus. 1,2 Alveolar macrophages detect viral components, leading to a T-cell-mediated immune response. [1] [2] [3] [4] Cells infected with the virus also stimulate interferon and cytokine release via interferon regulatory factor and transcription factor NF-κB activation, 5 and recruit more immune cells to the site of infection. 1 These immune cells propagate release of more proinflammatory molecules, leading to pulmonary and systemic disease. 4 COVID-19 presents a variety of problems to clinicians, including rapid onset of severe disease, various manifestations of pathology, [6] [7] [8] and paucity of demonstrably effective treatments. 9-12 SARS-CoV-2 infection initially manifests as fever, cough, and fatigue, among other symptoms, which can progress to severe pneumonia and hypoxemic respiratory failure. 13 On imaging, patients with COVID-19 have bilateral ground-glass opacities 7 and upper lobe infiltrates associated with dyspnea and hypoxemia. 13, 14 These severe manifestations are mediated by several proinflammatory cytokines, including IL-6, TNFα, IL-17, GM-CSF, and G-CSF. 1, 7, [15] [16] [17] [18] [19] [20] Cytokines involved in COVID-19 pathogenesis are summarized in Table 1 . Cytokine storm in COVID-19 infection can cause acute respiratory distress syndrome (ARDS), an inflammatory state in which increased vascular permeability leads to pulmonary edema and tissue destruction. 21, 22 A major cause of ARDS is sepsis secondary to bacterial pneumonia, [23] [24] [25] [26] [27] and influenza A 28 and coronaviruses [29] [30] [31] ARDS is characterized by a primary insult, such as infection or trauma, leading to a secondary insult of inflammation and tissue damage. These insults cause capillary leakage in lung parenchyma which ultimately impairs oxygenation. 32, 33 Macrophages, endothelial cells, epithelial cells, and neutrophils release proinflammatory signaling molecules including IL-6, IL-8, TNFα, and IL-1β, further increasing vascular permeability. [34] [35] [36] More inflammatory cells are recruited, become activated and propagate the inflammatory response. 37, 38 Many cells and cytokines involved in the inflammatory response in ARDS pathology are implicated in COVID-19 infection 39 and are summarized in Table 1 . Comorbid pulmonary disease, specifically chronic obstructive pulmonary disease (COPD), is an important risk factor for poor outcomes in COVID-19. 40 Interestingly, patients with COVID-19 rarely reported comorbid COPD overall, potentially due to underdiagnosis. 41 COPD and COVID-19 cause lung damage through a shared mechanism of increased inflammation, dysregulated immunity, and impaired repair function. [42] [43] [44] [45] These effects are summarized in Table 1 and Figure 1 . Selective serotonin reuptake inhibitors (SSRIs) were first used in the 1980s, 46 where they found success in treating depression by blocking reuptake and subsequent degradation of serotonin at the synaptic cleft and potentiating serotonin signal transduction at the postsynaptic neuron. [47] [48] [49] SSRIs were hailed as a breakthrough medication for depression with fewer side effects than tricyclic antidepressants and without the addictive potential of benzodiazepines. 46, 50 More recently, the anti-inflammatory properties of SSRIs have been explored. SSRIs inhibit inflammationinduced lung tissue destruction at three mechanistic levels: inhibition of proinflammatory transcription factors, 51 reduced production of inflammatory cytokines through canonical serotonergic mechanisms, 52 and inhibition of inflammatory cellular responses 53, 54 (Figure 1 ). Selective serotonin reuptake inhibitors alter the transcriptional regulation of genes encoding non-serotonergic neurotransmitter systems and inflammatory factors. 51 Serotonin receptor activation decreases activity of signal transducer and activator of transcription 3 (STAT3) 55 and NF-κB, 53, 56 leading to reduced downstream expression of proinflammatory markers TNFα, IL-1β, IL-6, and cyclooxygenase-2. [57] [58] [59] The inhibitory effects of SSRIs on inflammatory transcription factors may have implications for treating inflammation-mediated damage caused by SARS-CoV-2 infection. [60] [61] [62] In lung tissue, STAT3 and NF-κB are implicated in a variety of inflammatory processes including pathogen-induced acute lung injury, pulmonary inflammation, pulmonary fibrosis, and pulmonary vascular remodeling. [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] SSRIs may decrease inflammation by suppressing the proinflammatory activities of STAT3, NF-κB, or both. Patients with depression have been found to have increased levels of inflammatory cytokines at baseline, [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] and cytokines modulate the hypothalamic-pituitary-adrenocortical (HPA) axis leading to increased production of corticotropin releasing hormone and glucocorticoid receptor resistance. 83, 86 Loss of negative feedback at glucocorticoid receptors leads to dysregulated proinflammatory response. 87, 88 Fluoxetine inhibited HPA axis-mediated inflammatory edema in a rat model, 89 and clinical studies have demonstrated the ability of antidepressants to modulate glucocorticoid receptor function in humans. 90 Several specific proinflammatory cytokines are implicated in pathogenesis of depression. Levels of TNFα, IL-6, and IFNγ, among others, are significantly higher in patients with depression when compared to non-depressed controls. 84,91-95 IL-1β, TNFα, and IFNγ reduce serotonin production and increase tryptophan and serotonin uptake in the brain, leading to overall depletion of serotonin 96 and depression-like behavior. 97 Conversely, serotonin influences macrophage activity in a dose-dependent manner, increasing production of IL-1 at physiologic concentrations of serotonin and inhibiting proinflammatory activity at elevated concentrations. 98 Serotonin can, therefore, influence proinflammatory cytokine pathways, and SSRIs have been explored as immune modulators. Selective serotonin reuptake inhibitors directly inhibit proinflammatory pathways. Administration of SSRIs inhibit TNFα production in a mouse model of inflammation 99, 100 and impair TNFα release from monocytes 101 and microglia. 102 TNFα has neuromodulatory effects on norepinephrine secretion that are reversible with antidepressant administration. 103 INFα and IL-2 treatment induced reversible depressive symptoms in patients, 86, 104 and administration of serotonin reduced TNFα and IL-6 in human blood. 105 to inhibit LPS-induced IL-6 production 106 and NLRP3 inflammasome activation and downstream IL-1β production in macrophages. 107 Acute administration of SSRIs leads to release of proinflammatory 5-HT, 108 whereas chronic administration leads to overall depletion of serotonin. [109] [110] [111] Effects of SSRIs on proinflammatory cytokines are summarized in Figure 1. Selective serotonin reuptake inhibitors inhibit presynaptic reuptake of serotonin to increase extracellular serotonin concentrations, thereby ameliorating depressive symptoms, 112 inhibited T-cell proliferation and promoted apoptosis. 119 SSRIs also directly suppress antigen-presenting cells. 127 SSRIs also exert direct (non-serotonergic) activation of serotonin receptors through direct binding. Fluoxetine binds with high affinity to 5-HT 2B serotonin receptors to induce antidepressant effects that are abrogated in 5-HT 2B knockouts. 128 Fluoxetine transitions macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype. 129 Strategies to combat COVID-19 continue to develop, and treatments currently under investigation include antiviral and antimalarial agents, 12, 130, 131 immunosuppressant medications, 6,132 and anti-IL-6 modulators. 17, 133, 134 Olanzapine, an atypical antipsychotic and potent H1 antagonist, has been proposed as a therapeutic IL-6 modulator for COVID-19 infection. 135 The inflammatory processes implicated in the pathogenesis of COVID-19 overlap with mechanisms in acute and chronic lung disease, and SSRIs modulate these pathways at several distinct points. Chronic administration of SSRIs reduce levels of IL-6 and TNFα 136 to the degree that decreased IL-6 can be used as a marker for SSRI efficacy. 137 SSRIs, therefore, may have clinical utility in targeting IL-6 to treat COVID-19. Selective serotonin reuptake inhibitors have been studied as modulators in lung disease. Fluoxetine was found to be protective F I G U R E 1 Mechanism of SSRI modulation in pulmonary inflammatory disease. Infectious and inflammatory insults stimulate NF-κB translocation and cytokine release in alveolar macrophages and epithelial cells. These cytokines recruit neutrophils to the lung, leading to tissue damage and apoptosis. In acute inflammatory disease, M1 macrophages stimulate platelet activation and endothelial injury, and activated platelets recruit neutrophils and promote NET formation, mediating further tissue damage. In chronic disease, T cells lead to direct and indirect tissue damage and promote remodeling associated with decreased pulmonary function. SSRIs reduce pulmonary inflammation in each of these pathways by inhibiting 1 NF-κB activity, (2) downstream cytokine release, and (3) cellular activity by impairing serotonin reuptake by SERT against asthma and depression in a rat model, 138 and patients with comorbid asthma and depression had improved asthma outcomes when treated with a SSRI. 139 Fluoxetine also protects against chronic methamphetamine-induced pulmonary inflammation. 140 Patients with COPD reported improvements in dyspnea when a SSRI was added, [141] [142] [143] [144] and improved walking distances correlated with improvements in depressive symptoms over time. [145] [146] [147] SSRIs have therapeutic utility in pulmonary arterial hypertension (PAH), a common sequela of COPD associated with pulmonary vascular remodeling. 148 Fluoxetine prevents and reverses PAH in mice 149 and inhibits remodeling and inflammation in rat lung tissue. 150 SSRI use correlated with 50% reduction in risk of death in patients with PAH, 151 and baseline SSRI use was associated with a reduced incidence of PAH and decreased mortality in PAH. 152 However, one study found increased morbidity and mortality among elderly adults who were newly started on a SSRI medication. 153 Selective serotonin reuptake inhibitors modulate inflammatory pathways that are shared in acute and chronic lung inflammation. SSRIs have therapeutic utility in pulmonary arterial hypertension (PAH), a common sequela of COPD associated with pulmonary vascular remodeling. 148 Fluoxetine prevents and reverses PAH in mice 149 and inhibits remodeling and inflammation in rat lung tissue. 150 and cardiac QT prolongation 159 although these are exceedingly rare. SSRIs have also been linked to interstitial lung disease in elderly patients, especially women. 160, 161 SSRIs interact with antiplatelet medications including aspirin and clopidogrel 162, 163 and nonsteroidal anti-inflammatory drugs (NSAIDs) 164, 165 and can cause serotonin syndrome when combined with other serotonergic medications including tricyclic antidepressants, monoamine oxidase inhibitors, and serotonin-norepinephrine reuptake inhibitors. 169 These are important considerations for patients presenting with COVID-19, especially as antiplatelet and anticoagulant medications are sometimes used in treatment of ARDS. 167, 168 Notably, however, high-quality randomized trials demonstrate SSRIs are not associated with increased bleeding events. 170 Ultimately, clinical studies are needed to understand the potential risks and benefits associated with SSRI use in COVID-19. The authors have no funding or disclosures for this study. The authors have no competing financial interested in relation to this work. Claire Kyung Sun Meikle wrote and edited the manuscript. Justin Fortune Creeden wrote and edited the manuscript. Cheryl McCullumsmith wrote and edited the manuscript. Randall G. Worth edited the manuscript. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Randall G. Worth https://orcid.org/0000-0002-2626-7964 Coronavirus infections and immune responses The pathogenesis and treatment of the `Cytokine Storm' in COVID-19 Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19) COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? 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