Is lithium a potential treatment for the novel Wuhan (2019-nCoV) coronavirus? A scoping review

Poznań, March 16^th, 2020

Dear Prof. Wei and Prof. Wang,

We would like to thank you for all the comments. They helped to improve the manuscript. Please find our responses below.

Sincerely yours,

Jan Nowak and Jarosław Walkowiak
 
The wide spread of infection of 2019-nCoV has arouse an international concern since its original outbreak  in Wuhan, China. Scientists and health workers around the world are currently working together to wipe out the virus and the novel coronavirus pneumonia (NCP), which has killed more than a thousand lives, by far, worldwide.
 With the current epidemic being so severe, it is necessary and urgent to make potentially reasonable recommendations for the treatment or prevention for 2019-nCoV or NCP. The two authors clearly proposed that lithium might be a potential treatment or prophylaxis for 2019-nCoV or NCP based on a summary of existing literature that reported the in vitro effects of lithium on coronaviral infections and discussed potential mechanisms, which sound reasonable to some extent, but still not rigorous.

We appreciate the critique, which has helped to improve our manuscript.

Specifically, there are few related studies available and only in vitro data have been reported. The authors may need more related studies and solid evidence to support their hypothesis to make it more scientific and rigorous.

More details are provided in the results. New paragraphs also discuss the antiviral activity in humans and cell cultures challenged with other viruses.

As reported, lithium can be toxic due to its side effects, mainly thyroid, renal, and cognitive disturbances. Readers may wish to see more clinical information of lithium in treating viral infection cases, if not available, or in treating other diseases.

Lithium cardiotoxicity is now discussed in more detail.

• “Lithium concentration may be, on the other hand, increased by loop or thiazide diuretics, angiotensin-converting enzyme inhibitors, and non-steroid anti-inflammatory drugs. It is also is not clear if the use of lithium would be safe in acute disease accompanied by dehydration and unstable electrolyte levels. Cardiotoxicity of lithium may occur not only with concentrations larger than 1.5 mmol/L, but also when levels of the ion rapidly change²¹. Although QTc prolongation is absent in most patients receiving lithium, QT dispersion ratio may increase; longer QT was also described in some cases. Concurrent use of lithium with chloroquine would need to be especially cautious in patients with QT prolongation.”

A paragraph on lithium and herpes infections in patients with affective disorders was added. The results of the cited studies are the best evidence for the antiviral activity of lithium that comes from studies conducted in patients.

• “There is some evidence that lithium may affect the course of viral diseases in humans. In a retrospective cohort study of patients with affective disorders a decrease in the rate of recurrent labial herpes was found in the lithium group (n = 177, p < 0.001) but not in the alternative treatment group (n = 59, p = 0.53)¹³. In research previously conducted by Prof. J. Rybakowski at our hospital, lithium prevented labial herpes recurrence in thirteen out of 28 eligible psychiatric patients. Lithium also seemed to bring improvement in a proof-of-concept randomized double-blind placebo-controlled trial involving eleven healthy adults with recurrent HSV infections¹⁴ and in a randomized study of ten women with genital herpes conducted by the same research group from Philadelphia.”

More information on the activity of lithium in other viral infections was also provided.

• “LiCl was shown to dose-dependently inhibit reovirus (10-60 mM)¹⁵ and food-and-mouth disease virus (10-40 mM)¹⁶. At 5 mM concentration LiCl reduced the replication of avian leukosis virus subgroup J in chicken embryo fibroblast cells¹⁷. Yet, lithium at 50 µM concentration (12-20 times smaller than usually maintained in bipolar disorder) significantly reduced hepatitis C virus copy number (P = 0.0002) in supernatant from Huh7.5 cell culture¹⁸. The latter study gives hope that lithium may indeed be efficient at clinically relevant levels.”

 In terms of discussion, the authors reviewed some existing literature and suggested a potential mechanism of reduced apoptosis by lithium, the glycogen synthase kinase 3-beta (GSK-3β) inhibitor. The possibility that targeting at GSK-3β by lithium may potentially affect the coronavirus is an interesting topic. However, direct in vitro evidence is lacking regarding 2019-nCoV or related coronaviruses including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses.

Certainly, the evidence is lacking. The discussion is speculative. We have added the following:

• "The major putative molecular mechanisms of antiviral activity and reduced apoptosis is the inhibition of glycogen synthase kinase 3-beta (GSK-3β)^7,8. However, lithium also inhibits GSK-3α, inositol monophosphatases, and may indirectly act via the electrolyte balance."

And also:

• “Chloroquine (hydroxychloroquine) – which is thought to be effective in COVID-2019¹¹ – was shown to inhibit GSK-3β and potentiate GSK-3β inhibition caused by lithium. This indicates that mechanistic studies could investigate not only 0.5-1.2 mM lithium, but lithium with chloroquine as well. This also brings zinc to the spotlight since zinc inhibits GSK-3β at micromolar concentrations¹².”

 Moreover, relevant literature is still needed although the authors state that there is no interaction between lithium carbonate and ribavirin, lopinavir, or ritonavir exist.

Information on tenofovir is now provided:

• “A randomized study in tenofovir-treated patients with HIV revealed that 24-week addition of lithium at target serum concentrations of 0.6-1.0 mmol/L was not associated with nephrotoxicity²⁰.”

Another aspect worth noting is that the authors indicate that monitoring serum lithium concentration can be helpful in preventing side effects of lithium, however it should be emphasized that the in vivo relationship between the effective dose and toxic dose of lithium is still unclear, with some studies reporting a dose-dependent manner of the inhibitory effect of lithium in vitro. Thus, it warrants more data, both in vitro and in vivo, to clarify this issue.

Throughout the results section, information on the concentrations of lithium were given and commented on.
Moreover, the discussion opens with:

• “The available evidence comes only from studies of cell cultures and indicates that lithium effectively inhibits coronaviral infections when administered at concentrations that are toxic to humans.”

 Collectively, this study proposes a potential role of lithium in treating or preventing 2019-nCoV or NCP with some possible mechanisms. However, by far, solid evidence is lacking to validate this hypothesis. The time of developing lithium orotate for clinical use, even in emergency, is not yet.

The reference to lithium orotate was removed.

The conclusion was changed:

• “In the light of the reviewed data lithium appears as a possible candidate for therapy of COVID-2019. We propose mechanistic investigation of the influence of lithium (0.5-1 mM) – alone and with chloroquine or other drugs – on the SARS-CoV-2 infection.”

We would like the reviewers for their input, which has guided us in improving the text.
 
Please note that following the remarks of Prof. Beaulieu and that change of the nomenclature (2019-nCoV no longer used) we have proposed a new title, which seems more neutral and therefore more representative of the softened conclusions:

• “Lithium and coronaviral infections. A scoping review.”

 
 
The references were updated
1 
Li HJ, Gao DS, Li YT, et al.: Antiviral effect of lithium chloride on porcine epidemic diarrhea virus in vitro. Res Vet Sci. 2018;118:288–94. 29547727 10.1016/j.rvsc.2018.03.002

2 
Cui J, Xie J, Gao M, et al.: Inhibitory effects of lithium chloride on replication of type II porcine reproductive and respiratory syndrome virus in vitro. Antivir Ther. 2015;20(6):565–72. 25560301 10.3851/IMP2924

3 
Ren X, Meng F, Yin J, et al.: Action mechanisms of lithium chloride on cell infection by transmissible gastroenteritis coronavirus. PLoS One. 2011;6(5):e18669. 21573100 10.1371/journal.pone.0018669 3089605

4 
Li J, Yin J, Sui X, et al.: Comparative analysis of the effect of glycyrrhizin diammonium and lithium chloride on infectious bronchitis virus infection in vitro. Avian Pathol. 2009;38(3):215–21. 19468938 10.1080/03079450902912184

5 
Harrison SM, Tarpey I, Rothwell L, et al.: Lithium chloride inhibits the coronavirus infectious bronchitis virus in cell culture. Avian Pathol. 2007;36(2):109–14. 17479370 10.1080/03079450601156083

6 
 Zhai X, Wang S, Zhu M, He W, Pan Z, Su S. Antiviral Effect of Lithium Chloride and Diammonium Glycyrrhizinate on Porcine Deltacoronavirus In Vitro. Pathogens. 2019 Sep;8(3):144.

7
Zaheer A, Knight S, Zaheer A, et al.: Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3beta and caspase-3. Brain Res. 2008;1190:206–14. 18054898 10.1016/j.brainres.2007.11.011 2343001

8 
Choi SE, Kang Y, Jang HJ, et al.: Involvement of glycogen synthase kinase-3beta in palmitate-induced human umbilical vein endothelial cell apoptosis. J Vasc Res. 2007;44(5):365–74. 17483602 10.1159/000102321

9 
Kong N, Wu Y, Meng Q, et al.: Suppression of Virulent Porcine Epidemic Diarrhea Virus Proliferation by the PI3K/Akt/GSK-3α/β Pathway. PLoS One. 2016;11(8):e0161508. 27560518 10.1371/journal.pone.0161508 4999130

10 
Wu CH, Chen PJ, Yeh SH: Nucleocapsid phosphorylation and RNA helicase DDX1 recruitment enables coronavirus transition from discontinuous to continuous transcription. Cell Host Microbe. 2014;16(4):462–72. 25299332 10.1016/j.chom.2014.09.009

11
Multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. [Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):185–8.

12
Eldar-Finkelman H, Martinez A. GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS. Front Mol Neurosci. 2011;4:32.

13
Amsterdam JD, Maislin G, Rybakowski J. A possible antiviral action of lithium carbonate in herpes simplex virus infections. Biol Psychiatry. 1990 Feb 15;27(4):447–53.

14
Amsterdam JD, Maislin G, Hooper MB. Suppression of herpes simplex virus infections with oral lithium carbonate--a possible antiviral activity. Pharmacotherapy. 1996 Dec;16(6):1070–5.

15
Chen Y, Kong D, Cai G, Jiang Z, Jiao Y, Shi Y, et al. Novel antiviral effect of lithium chloride on mammalian orthoreoviruses in vitro. Microb Pathog. 2016 Apr;93:152–7.

16
Zhao F-R, Xie Y-L, Liu Z-Z, Shao J-J, Li S-F, Zhang Y-G, et al. Lithium chloride inhibits early stages of foot-and-mouth disease virus (FMDV) replication in vitro. J Med Virol. 2017;89(11):2041–6.

17
Qian K, Cheng X, Zhang D, Shao H, Yao Y, Nair V, et al. Antiviral effect of lithium chloride on replication of avian leukosis virus subgroup J in cell culture. Arch Virol. 2018 Apr 1;163(4):987–95.

18
Sarhan MA, Abdel-Hakeem MS, Mason AL, Tyrrell DL, Houghton M. Glycogen synthase kinase 3β inhibitors prevent hepatitis C virus release/assembly through perturbation of lipid metabolism. Sci Rep [Internet]. 2017 May 31 [cited 2020 Mar 14];7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451429/

19 
Rybakowski JK: Challenging the Negative Perception of Lithium and Optimizing Its Long-Term Administration. Front Mol Neurosci. 2018;11:349. 30333722 10.3389/fnmol.2018.00349 6175994

20
Decloedt EH, Lesosky M, Maartens G, Joska JA. Renal safety of lithium in HIV-infected patients established on tenofovir disoproxil fumarate containing antiretroviral therapy: analysis from a randomized placebo-controlled trial. AIDS Res Ther. 2017 Feb 4;14(1):6.

21
Mehta N, Vannozzi R. Lithium-induced electrocardiographic changes: A complete review. Clinical Cardiology. 2017;40(12):1363–7.

22 
Nowak JK, Walkowiak J: PRISMA Scoping Review checklist for Nowak and Walkowiak 2020. Zenodo. 2020. http://www.doi.org/10.5281/zenodo.3637575