Opportunities for Drug Repurposing of Serotonin Reuptake Inhibitors: Potential Uses in Inflammation, Infection, Cancer, Neuroprotection, and Alzheimer’s Disease Prevention

Abstract

Serotonin reuptake inhibitors (SRIs) are safe and widely used for a variety of indications including depressive disorders, anxiety, and chronic pain. Besides inhibiting the serotonin transporter, these medications have broad-spectrum properties in many systems. Their roles have been studied in cancer, Alzheimer’s disease, and infectious processes. The COVID-19 pandemic highlighted the importance of drug repurposing of medications already in use. We conducted a narrative review of current evidence and ongoing research on drug repurposing of SRIs, with a focus on immunomodulatory, antiproliferative, and neuroprotective activity. SRIs may have clinical use as repurposed agents for a wide variety of conditions including but not limited to COVID-19, Alzheimer’s disease, and neoplastic processes. Further research, particularly randomized controlled trials, will be necessary to confirm the utility of SRIs for new indications.

Key words

Selective serotonin reuptake inhibitors (SSRIs) - Drug Repurposing - Alzheimer-s disease (AD) - COVID 19 - Antiinflammatory agents

Publikationsverlauf

Eingereicht: 16. Juli 2021
Eingereicht: 22. Oktober 2021

Angenommen: 26. Oktober 2021

Artikel online veröffentlicht:
07. Dezember 2021

• References

• 1 Lenze EJ, Mattar C, Zorumski CF. et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: A randomized clinical trial. JAMA 2020; 324: 2292-2300
• 2 Amson R, Auclair C, André F. et al. Targeting TCTP with sertraline and thioridazine in cancer treatment. Results Probl Cell Differ 2017; 64: 283-290
• 3 Mandrioli R, Protti M, Mercolini L. New-generation, non-SSRI antidepressants: Therapeutic drug monitoring and pharmacological interactions. Part 1: SNRIs, SMSs, SARIs. Curr Med Chem 2018; 25: 772-792
• 4 Wan M, Ding L, Wang D. et al. Serotonin: A potent immune cell modulator in autoimmune diseases. Front Immunol 2020; 11: 186
• 5 Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 1997; 32: 1-21
• 6 Schoenichen C, Bode C, Duerschmied D. Role of platelet serotonin in innate immune cell recruitment. Front Biosci (Landmark Ed) 2019; 24: 514-526
• 7 Hyttel J, Bøgesø KP, Perregaard J. et al. The pharmacological effect of citalopram residues in the (S)-(+)-enantiomer. J Neural Transm Gen Sect 1992; 88: 157-160
• 8 Sanchez C, Asin KE, Artigas F. Vortioxetine, a novel antidepressant with multimodal activity: Review of preclinical and clinical data. Pharmacol Ther 2015; 145: 43-57
• 9 Sanchez C, Reines EH, Montgomery SA. A comparative review of escitalopram, paroxetine, and sertraline: Are they all alike?. Int Clin Psychopharmacol 2014; 29: 185-196
• 10 Gilmor ML, Owens MJ, Nemeroff CB. Inhibition of norepinephrine uptake in patients with major depression treated with paroxetine. Am J Psychiatry 2002; 159: 1702-1710
• 11 Shelton RC. Serotonin and norepinephrine reuptake inhibitors. Handb Exp Pharmacol 2019; 250: 145-180
• 12 Andrade C, Sandarsh S, Chethan KB. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: A review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry 2010; 71: 1565-1575
• 13 Sitges M, Gómez CD, Aldana BI. Sertraline reduces IL-1β and TNF-α mRNA expression and overcomes their rise induced by seizures in the rat hippocampus. PLoS One 2014; 9: 11
• 14 Duerschmied D, Suidan GL, Demers M. et al. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood 2012; 121: 1008-1015
• 15 Hamed MGM, Hagag RS. The possible immunoregulatory and anti-inflammatory effects of selective serotonin reuptake inhibitors in coronavirus disease patients. Med Hypotheses 2020; 144: 110-140
• 16 Köhler CA, Freitas TH, Stubbs B. et al. Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: Systematic review and meta-analysis. Mol Neurobiol 2018; 55: 4195-4206
• 17 Pinna G, Costa E, Guidotti A. SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake. Curr Opin Pharmacol 2009; 9: 24-30
• 18 Hashimoto K. Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication. J Pharmacol Sci 2015; 127: 6-9
• 19 Nazimek K, Kozlowski M, Bryniarski P. et al. Repeatedly administered antidepressant drugs modulate humoral and cellular immune response in mice through action on macrophages. Exp Biol Med 2016; 241: 1540-1550
• 20 Cloonan SM, Drozgowska A, Fayne D. et al. The antidepressants maprotiline and fluoxetine have potent selective antiproliferative effects against Burkitt lymphoma independently of the norepinephrine and serotonin transporters. Leuk Lymphoma 2010; 51: 523-539
• 21 Ishima T, Fujita Y, Hashimoto K. Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells. Eur J Pharmacol 2014; 727: 167-173
• 22 Rosen DA, Seki SM, Fernández-Castañeda A. et al. Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci Transl Med 2019; 11: 478
• 23 Hashimoto K. Sigma-1 receptor chaperone and brain-derived neurotrophic factor: Emerging links between cardiovascular disease and depression. Prog Neurobiol 2013; 100: 15-29
• 24 Kim JM, Stewart R, Lee YS. et al. Effect of escitalopram vs placebo treatment for depression on long-term cardiac outcomes in patients with acute coronary syndrome: A randomized clinical trial. JAMA 2018; 320: 350-358
• 25 Tagashira H, Bhuiyan MS, Shioda N. et al. Fluvoxamine rescues mitochondrial Ca2+transport and ATP production through σ(1)-receptor in hypertrophic cardiomyocytes. Life Sci 2014; 95: 89-100
• 26 Yaman OM, Erman H, Guner I. et al. Remote myocardial injury: the protective role of fluoxetine. Can J Physiol Pharmacol 2018; 96: 319-327
• 27 Aksu U, Guner I, Yaman OM. et al. Fluoxetine ameliorates imbalance of redox homeostasis and inflammation in an acute kidney injury model. J Physiol Biochem 2014; 70: 925-934
• 28 Cannavo A, Komici K, Bencivenga L. et al. GRK2 as a therapeutic target for heart failure. Expert Opin Ther Targets 2018; 22: 75-83
• 29 Ji P, Zhu J, Zhong Z. et al. Association of elevated inflammatory markers and severe COVID-19: A meta-analysis. Medicine (Baltimore) 2020; 99: e23315
• 30 Sukhatme VP, Reiersen AM, Vayttaden SJ. et al. Fluvoxamine: A review of its mechanism of action and its role in COVID-19. Front Pharmacol 2021; 12: 652-688
• 31 Hashimoto K. Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor. Eur Arch Psychiatry Clin Neurosci 2021; 271: 249-258
• 32 Reis G, Silva E, Silva D. et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalization among patients with COVID-19: The TOGETHER randomized platform clinical trial. Lancet Glob Health. 2021 in-press
• 33 Hoertel N, Sánchez-Rico M, Vernet R. et al. Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: Results from an observational study. Mol Psychiatry 2021;
• 34 Zimniak M, Kirschner L, Hilpert H. et al. The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2 in human lung tissue. Sci Rep 2021; 11: 5890
• 35 Liu K, Yang S, Lin Y. et al. Shen, Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis. Oncotarget 2015; 6: 5088-5101
• 36 Fang Y, Chou C, Pan C. et al. Paroxetine-induced Ca2+movement and death in OC2 human oral cancer cells. Chin J Physiol 2012; 54: 310-317
• 37 Huang J, Chang H, Chou C. et al. The mechanism of sertraline-induced [Ca2] rise in human PC3 prostate cancer cells. Basic Clin. Pharmacol Toxicol 2011; 109: 103-110
• 38 Serafeim A, Holder MJ, Grafton G. et al. Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells. Blood 2003; 101: 3212-3219
• 39 Reddy KK, Lefkove B, Chen LB. et al. The antidepressant sertraline downregulates Akt and has activity against melanoma cells. Pigment Cell Melanoma Res 2008; 21: 451-456
• 40 Gao H, Zhang IY, Zhang L. et al. S100B suppression alters polarization of infiltrating myeloid-derived cells in gliomas and inhibits tumor growth. Cancer Lett 2018; 439: 91-100
• 41 Kannen V, Garcia SB, Silva WA. et al. Oncostatic effects of fluoxetine in experimental colon cancer models. Cell Signal 2015; 27: 1781-1788
• 42 Lee CS, Kim YJ, Jang ER. Fluoxetine induces apoptosis in ovarian carcinoma cell line OVCAR-3 through reactive oxygen species- dependent activation of nuclear factor-kB, Basic Clin. Pharmacol Toxicol 2009; 106: 446-453
• 43 Levkovitz Y, Gil-Ad I, Zeldich E. et al. Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines: Evidence for p-c-Jun, cytochrome c, and caspase-3 involvement. J Mol Neurosci 2005; 27: 029-042
• 44 Chinnapaka S, Bakthavachalam V, Munirathinam G. Repurposing antidepressant sertraline as a pharmacological drug to target prostate cancer stem cells: dual activation of apoptosis and autophagy signaling by deregulating redox balance. Am J Cancer Res 2020; 10: 2043-2065
• 45 Peer D, Dekel Y, Melikhov D. et al. Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models. Cancer Res 2004; 64: 7562-7569
• 46 Ma J, Yang Y, Chen W. et al. Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells. Oncol Rep 2016; 36: 676-684
• 47 Tzadok S, Beery E, Israeli M. et al. In vitro novel combinations of psychotropics and anti-cancer modalities in U87 human glioblastoma cells. Int J Oncol 2010; 37: 1043-1051
• 48 Jiang X, Lu W, Shen X. et al. Repurposing sertraline sensitizes non-small cell lung cancer cells to erlotinib by inducing autophagy. JCI Insight 2018; 3: e98921
• 49 Hallett RM, Girgis-Gabardo A, Gwynne WD. et al. Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer. Oncotarget 2016; 7: 53137-53152
• 50 Geeraerts SL, Kampen KR, Rinaldi G. et al. Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis-addicted breast tumor growth. Mol Cancer Ther 2021; 20: 50-63
• 51 Kast RE, Boockvar JA, Brüning A. et al. A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget 2013; 4: 502-530
• 52 Lash TL, Cronin-Fenton D, Ahern TP. et al. Pedersen, breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen. Acta Oncol 2010; 49: 305-312
• 53 Busby J, Mills K, Zhang SD. et al. Selective serotonin reuptake inhibitor use and breast cancer survival: a population-based cohort study. Breast Cancer Res 2018; 20: 4
• 54 Kelly CM, Juurlink DN, Gomes T. et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010; 340: c693
• 55 Lash TL, Pedersen L, Cronin-Fenton D. et al. Tamoxifen's protection against breast cancer recurrence is not reduced by concurrent use of the SSRI citalopram. Br. J. Cancer 2008; 99: 616-621
• 56 Cirrito JR, Disabato BM, Restivo JL. et al. Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc Natl Acad Sci U S A 2011; 108: 14968-14973
• 57 Sheline YI, West T, Yarasheski K. et al. An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice. Science Translational Medicine 2014; 6: 236re4
• 58 Mdawar B, Ghossoub E, Khoury R. Selective serotonin reuptake inhibitors and Alzheimer’s disease. Neural Regen Res 2020; 15: 41-46
• 59 Cirrito JR, Wallace CE, Yan P. et al. Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model. Neurology 2020; 95: e2666-e2674
• 60 Sheline YI, Snider BJ, Beer JC. et al. Effect of escitalopram dose and treatment duration on CSF Aβ levels in healthy older adults: A controlled clinical trial. Neurology 2020; 95: e2658-e2665
• 61 Tin G, Mohamed T, Shakeri A. et al. Interactions of selective serotonin reuptake inhibitors with β-amyloid. ACS Chem Neurosci 2019; 10: 226-234
• 62 Bartels C, Wagner M, Wolfsgruber S. et al. Alzheimer’s Disease Neuroimaging Initiative: Impact of SSRI therapy on risk of conversion from mild cognitive impairment to Alzheimer’s dementia in individuals with previous depression. Am J Psychiatry 2018; 175: 232-241
• 63 Rosenblat JD, Kakar R, McIntyre RS. The cognitive effects of antidepressants in major depressive disorder: A systematic review and meta-analysis of randomized clinical trials. Int J Neuropsychopharmacol 2015; 19: pyv082
• 64 Menza M, Marin H, Kaufman K. et al. Citalopram treatment of depression in Parkinson's disease: The impact on anxiety, disability, and cognition. J Neuropsychiatry Clin Neurosci 2004; 16: 315-319
• 65 Heath L, Gray SL, Boudreau DM. et al. Cumulative antidepressant use and risk of dementia in a prospective cohort study. J Am Geriatr Soc 2018; 66: 1948-1955
• 66 Huang Y-M, Shen J, Zhao H-L. Major clinical trials failed the amyloid hypothesis of Alzheimer's disease. J Am Geriatr Soc 2019; 67: 841-844