Pharmacopsychiatry 2022; 55(01): 16-23
DOI: 10.1055/a-1551-3756
Review

Candidate Psychotropics against SARS – CoV – 2: A Narrative Review

Department of Psychiatry and Clinical Psychology, Zahedan University of Medical Sciences, Zahedan, Iran
› Author Affiliations

Abstract

Since few therapeutic options are clinically accessible for coronavirus disease 2019 (COVID-19), effective, safe, and globally available pharmaceuticals need to be urgently developed to prevent severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and alleviate the severity of COVID-19. In this regard, the present paper is intended to provide an extensive review of the clinical and preclinical evidence on the psychotropics’ anti-SARS-CoV-2 effects, giving an insight into their potential applications for patients with a proven or high likelihood of COVID-19 pneumonia. The results showed that psychotropic drugs such as melatonin, lithium carbonate, valproate, olanzapine, quetiapine, clozapine, fluoxetine, escitalopram, fluvoxamine, and cannabidiol could help lower the mortality due to SARS-CoV-2 infection. According to these medications’ direct immunomodulatory actions against the destructive cytokine storm, as well as other direct/indirect mechanisms (e. g., the endolysosomal pathway modulation, interactions with specific receptors, and membrane fusion), it was perceived that such drugs could effectively weaken the worsened immune response and avoid adult respiratory distress syndrome and acute lung injury. According to the author’s analysis of the currently available evidence, there is significant support for psychotropics as complementary interventions during SARS-CoV-2 infection. However, further studies need to be carried out to assess the effects of the above psychotropic drugs in vitro and clinical settings.



Publication History

Received: 18 May 2021
Received: 04 July 2021

Accepted: 09 July 2021

Article published online:
16 August 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Wiersinga WJ, Rhodes A, Cheng AC. et al Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. J Am Med Assoc 2020; 324: 782-793
  • 2 Rizk JG, Kalantar-Zadeh K, Mehra MR. et al Pharmaco-immunomodulatory therapy in COVID-19. Drugs 2020; 80: 1267-1292
  • 3 Alijotas-Reig J, Esteve-Valverde E, Belizna C. et al Immunomodulatory therapy for the management of severe COVID-19. Beyond the antiviral therapy: a comprehensive review. Autoimmun Rev 2020; 19: 102569
  • 4 Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol 2020; 38: 1-9
  • 5 Pedersen SF, Ho YC. SARS-CoV-2: a storm is raging. J Clin Invest 2020; 130: 2202-2205
  • 6 Lu L, Zhang H, Zhan M. et al Preventing mortality in COVID-19 patients: which cytokine to target in a raging storm?. Front Cell Dev Biol 2020; 8: 677
  • 7 Toubasi AA, AbuAnzeh RB, Tawileh HB. et al A meta-analysis: the mortality and severity of COVID-19 among patients with mental disorders. Psychiatry Res 2021; 299: 113856
  • 8 Villoutreix BO, Beaune PH, Tamouza R. et al Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders. Drug Discov Today 2020; 25: 1287-1290
  • 9 MacLure M. ‘Clarity Bordering on Stupidity’: Where’s the Quality in Systematic Review?. 1st ed. London: Routledge; 2007
  • 10 Reiter RJ, Abreu-Gonzalez P, Marik PE. et al Therapeutic algorithm for use of melatonin in patients with COVID-19. Front Med 2020; 7: 226
  • 11 Anderson G, Reiter RJ. Melatonin: roles in influenza, Covid-19, and other viral infections. Rev Med Virol 2020; 30: e2109
  • 12 Sehirli AO, Sayiner S, Serakinci N. Role of melatonin in the treatment of COVID-19; as an adjuvant through cluster differentiation 147 (CD147). Mol Biol Rep 2020; 47: 8229-8233
  • 13 Juybari KB, Pourhanifeh MH, Hosseinzadeh A. et al Melatonin potentials against viral infections including COVID-19: current evidence and new findings. Virus Res 2020; 287: 198108
  • 14 Castillo RR, Quizon GR, Juco MJ. et al Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): a case series. Melatonin Research 2020; 3: 297-310
  • 15 Tan DX, Hardeland R. Targeting host defense system and rescuing compromised mitochondria to increase tolerance against pathogens by melatonin may impact outcome of deadly virus infection pertinent to COVID-19. Molecules 2020; 25: 4410
  • 16 Chen G, Wu DI, Guo W. et al Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020; 130: 2620-2629
  • 17 Reiter RJ, Sharma R, Ma Q, Dominquez-Rodriguez A. et al Melatonin inhibits COVID-19-induced cytokine storm by reversing aerobic glycolysis in immune cells: a mechanistic analysis. Med Drug Discov 2020; 6: 100044
  • 18 Loh D. The potential of melatonin in the prevention and attenuation of oxidative hemolysis and myocardial injury from cd147 SARS-CoV-2 spike protein receptor binding. Melatonin Research 2020; 3: 380-416
  • 19 Artigas L, Coma M, Matos-Filipe P. et al In-silico drug repurposing study predicts the combination of pirfenidone and melatonin as a promising candidate therapy to reduce SARS-CoV-2 infection progression and respiratory distress caused by cytokine storm. PLoS One 2020; 15: e0240149
  • 20 Feitosa EL, Júnior FT, Neto JA. et al COVID-19: Rational discovery of the therapeutic potential of Melatonin as a SARS-CoV-2 main Protease Inhibitor. Int J Med Sci 2020; 17: 2133-2146
  • 21 Grifoni A, Weiskopf D, Ramirez SI. et al Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 2020; 181: 1489-1501.e15
  • 22 Maestroni G. Exogenous melatonin as potential adjuvant in anti-SarsCov2 vaccines. J Neuroimmune Pharmacol 2020; 15: 572-573
  • 23 Rajkumar RP. Lithium as a candidate treatment for COVID-19: Promises and pitfalls. Drug Dev Res 2020; 81: 782-785
  • 24 Spuch C, López-García M, Rivera-Baltanás T. et al Does lithium deserve a place in the treatment against COVID-19? A preliminary observational study in six patients, case report. Front Pharmacol 2020; 11: 557629
  • 25 Murru A, Manchia M, Hajek T. et al Lithium’s antiviral effects: a potential drug for CoViD-19 disease?. Int J Bipolar Disord 2020; 8: 21
  • 26 Ishii N, Terao T, Hirakawa H. Association between trace levels of lithium in drinking water and COVID-19–associated mortality. Bipolar Disord 2021; 23: 100
  • 27 Unal G, Turan B, Balcioglu YH. Immunopharmacological management of COVID-19: potential therapeutic role of valproic acid. Med Hypotheses 2020; 143: 109891
  • 28 Wu SY, Tang SE, Ko FC. et al Valproic acid attenuates acute lung injury induced by ischemia-reperfusion in rats. Anesthesiology 2015; 122: 1327-1337
  • 29 Royce SG, Dang W, Ververis K. et al Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease. Epigenetics 2011; 6: 1463-1470
  • 30 Ichiyama T, Okada K, Lipton JM. et al Sodium valproate inhibits production of TNF-α and IL-6 and activation of NF-κB. Brain Res 2000; 857: 246-251
  • 31 Pitt B, Sutton NR, Wang Z. et al Potential repurposing of the HDAC inhibitor valproic acid for patients with COVID-19. Eur J Pharmacol 2021; 898: 173988
  • 32 Bhargava P, Panda P, Ostwal V. et al Repurposing valproate to prevent acute respiratory distress syndrome/acute lung injury in COVID-19: a review of immunomodulatory action. Cancer Res Stat Treat 2020; 3: 65
  • 33 Gordon DE, Jang GM, Bouhaddou M. et al A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020; 583: 459-468
  • 34 Hoertel N, Sánchez-Rico M, Vernet R. et al Observational study of haloperidol in hospitalized patients with COVID-19. PLoS One 2021; 16: e0247122
  • 35 Triggiani M, Gentile M, Secondo A. et al Histamine induces exocytosis and IL-6 production from human lung macrophages through interaction with H1 receptors. J Immunol 2001; 166: 4083-4091
  • 36 Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors: focus on newer generation compounds. Life Sci 2000; 68: 29-39
  • 37 Altschuler EL, Kast RE. Using histamine (H1) antagonists, in particular atypical antipsychotics, to treat anemia of chronic disease via interleukin-6 suppression. Med Hypotheses 2005; 65: 65-67
  • 38 Altschuler EL, Kast RE. Dapsone, colchicine and olanzapine as treatment adjuncts to prevent COVID-19 associated adult respiratory distress syndrome (ARDS). Med Hypotheses 2020; 141: 109774
  • 39 Hawkins M, Sockalingam S, Bonato S. et al A rapid review of the pathoetiology, presentation, and management of delirium in adults with COVID-19. J Psychosom Res 2021; 141: 110350
  • 40 Khosravi M. Quetiapine versus clozapine in treating psychiatric patients with Severe COVID-19: a netosis-based opinion. Electron J Gen Med 2021; 18: em301
  • 41 Khosravi M. COVID-19 Pandemic: what are the risks and challenges for schizophrenia?. Clin Schizophr Relat Psychoses 2020; 14: 110320
  • 42 Hamed MG, Hagag RS. The possible immunoregulatory and anti-inflammatory effects of selective serotonin reuptake inhibitors in coronavirus disease patients. Med Hypotheses 2020; 144: 110140
  • 43 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
  • 44 Schloer S, Brunotte L, Goretzko J. et al Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine. Emerg Microbes Infect 2020; 9: 2245-2255
  • 45 Hoffmann M, Kleine-Weber H, Schroeder S. et al SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181: 271-280.e8
  • 46 Zimniak M, Kirschner L, Hilpert H. et al The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2. Sci Rep 2021; 11: 5890
  • 47 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
  • 48 Homolak J, Kodvanj I. Widely available lysosome targeting agents should be considered as potential therapy for COVID-19. Int J Antimicrob Agents 2020; 56: 106044
  • 49 Fung TS, Liu DX. The ER stress sensor IRE1 and MAP kinase ERK modulate autophagy induction in cells infected with coronavirus infectious bronchitis virus. Virology 2019; 533: 34-44
  • 50 Schlienger RG, Meier CR. Effect of selective serotonin reuptake inhibitors on platelet activation. Am J Cardiovasc Drugs 2003; 3: 149-162
  • 51 Anil SM, Shalev N, Vinayaka AC. et al Cannabis compounds exhibit anti-inflammatory activity in vitro in COVID-19-related inflammation in lung epithelial cells and proinflammatory activity in macrophages. Sci Rep 2021; 11: 1462
  • 52 Wang B, Kovalchuk A, Li D. et al In search of preventive strategies: novel high-CBD Cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues. Aging 2020; 12: 22425-22444
  • 53 Nagoor Meeran MF, Sharma C, Goyal SN. et al CB2 receptor-selective agonists as candidates for targeting infection, inflammation, and immunity in SARS-CoV-2 infections. Drug Dev Res 2021; 82: 7-11
  • 54 O'Sullivan SE, Kendall DA. Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease. Immunobiology 2010; 215: 611-616
  • 55 Huang S, Goplen NP, Zhu B. et al Macrophage PPAR-γ suppresses long-term lung fibrotic sequelae following acute influenza infection. PLoS One 2019; 14: e0223430
  • 56 Lowe HI, Toyang NJ, McLaughlin W. Potential of cannabidiol for the treatment of viral hepatitis. Pharmacognosy Res 2017; 9: 116-118
  • 57 Milam JE, Keshamouni VG, Phan SH. et al PPAR-γ agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2008; 294: L891-L901
  • 58 Esposito G, Pesce M, Seguella L. et al The potential of cannabidiol in the COVID-19 pandemic. Br J Pharmacol 2020; 177: 4967-4970
  • 59 Larsen C, Shahinas J. Dosage, efficacy and safety of cannabidiol administration in adults: a systematic review of human trials. J Clin Med Res 2020; 12: 129-141
  • 60 DeRoo SS, Pudalov NJ, Fu LY. Planning for a COVID-19 vaccination program. JAMA 2020; 323: 2458-2459
  • 61 Khosravi M. Ursodeoxycholic Acid in Patients with Treatment-Resistant Schizophrenia Suffering From Coronavirus Disease 2019: A Hypothesis Letter. Front Psychiatry 2021; 12: 657316