Half a dozen research papers suggest that lithium’s anti-viral properties may extend to the coronavirus. But the idea is far from tested, and patients with coronavirus are also at higher risk for lithium toxicity. We also touch on a safer and simpler way to prevent COVID-19: Vitamin D. How to order vitamin D: Vitamin D, 25-Hydroxy (Diagnostic code=E55.9 How to interpret vitamin D levels : Target = 30-60 ng/ml. Possible harms above 60 ng/ml (evidence is not definitive). 20-30 is a mild low; below 12 ng/ml is putting the bones at risk. How to correct vitamin D levels: Mild low (20-30): Vitamin D3 2,000 IU PO QD. Moderate-severe low (<20): 6000 IU PO QD or 50,000 IU PO Qweek.

Published On: 9/21/20

Duration: 18 minutes, 28 seconds

Rough Transcript:

Smoking. Hypertension. Cardiovascular disease. Diabetes. Metabolic syndrome. Obesity. Vitamin D Deficiency. All of these foretell a greater risk of developing COVID-19, and they are all more common in bipolar and other psychiatric disorders. 

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

Kellie: In this month’s Carlat report we feature an interview with a pioneer of lithium research, Janusz Rybakowski. Like many bipolar specialists, Dr. Rybakowski believes that lithium is underutilized. 

[Quote on 1 in 3 bipolar patients are excellent lithium responders – meaning that it not only gets them well but keeps them well.]

In the article we have a useful table that highlights who is likely to respond to lithium. But lithium use is on the decline  - Here’s some new data from the USA: in the 1990’s 38% of bipolar patients took lithium, and today it’s 14%. Lithium has held its ground better in countries with socialized medicine, where care is driven more by evidenced-based edicts like the NICE guidelines than pharmaceutical dinner talks. But even there there are signs of slippage in Germany: lithium use in bipolar has declined in the last decade from 31 to 26%. Dr. Rybakowski speculated on the possible reasons why:

Dr. Aiken: I shared those biases when I started practice 20 years ago – I thought of lithium as something toxic to the body and intolerable to the patient. But if we look at the raw numbers, patients generally tolerate lithium much better than atypical antipsychotics. And while high levels of lithium are toxic, and lithium does have medical risks like hypothyroidism, renal insufficiency, and cardiac arrhythmia,  it also has medical benefits that are relevant to bipolar disorder. Those include lowers the risks of stroke, heart disease, cancer, and neurologic illnesses, particularly dementia – none of this data is definitive, and most of it is fairly new.

Kellie: But lithium also has antiviral properties – and that’s actually old news. In 1970 lithium was found to disrupt the adenovirus in a laboratory study, and in 1973 it degraded the Herpes simplex virus. The first human studies of lithium’s antiviral activity date back to 1980 when they found that labial herpes infections went away when bipolar disorder was treated with lithium and returned when the lithium was taken away. Dr. Rybakowski was a key player in that line of research, which later confirmed that this anti-herpetic effect was unique to lithium and was not seen with the antidepressants.  

Dr. Aiken: It’s against herpes that we have the best evidence for lithium – in fact the only randomized controlled trials of lithium as an antiviral agent were done in herpes and both of those studies – though positive – were small. In other viruses lithium has positive results only in animal or petri dishes, or in human studies that were observational and uncontrolled, for example patients have lower rates of the flu on lithium but not on other psychotropics. Those include over a dozen viruses, including DNA viruses like pseudorabies, vaccinia, measles, parvoviruses, Epstein Barr virus and Cytomegalovirus. But those are DNA viruses, and the coronavirus is in the RNA family. Lithium has also impeded the replication of RNA viruses murine leukaemia retrovirus, foot-and-mouth disease virus, feline calicivirus, mammalian orthoreoviruses, porcine diarrheoa virus, and several in the coronavirus family. 

Kellie: Does lithium treat the coronavirus?

Dr. Aiken: We don’t know, but there are a half dozen theoretical papers out there suggesting it might. One problem with using lithium against the coronavirus is that it has risks of its own, particularly toxicity. Now, in the herpes research they were able to suppress the virus with blood levels similar to what we use in bipolar 0.5-0.8, but there is some evidence that higher levels like 1.2 might be necessary to fight off viruses, and those levels are potentially toxic. So it’s unlikely that lithium will be used against the coronavirus

Kellie: Then why are we yapping about it in this podcast?

Dr. Aiken: Well, there are two things you need to know about lithium and the coronavirus right now. 

1. Patient education. Patients with mental illness often feel like they have to take these drugs and that the psych meds they take are doing nothing but harm to their body. So here’s a situation where patients on a particular psych med – lithium – may be getting a benefit that no one else in the population gets. Besides these antiviral properties, lithium also improves immune function increasing neutrophil count as well as lymphocytes, leukocytes, and natural killer cells. And that’s also important for psychoeducation because patients on lithium usually have a high white blood count and if their PCP isn’t aware of that association they think the patient has an infection or even cancer when they see that elevation.


2. You might consider lithium for a patient with bipolar disorder who tests positive for coronavirus


3. On the other hand, patients on lithium are at greater risk for lithium toxicity if they get COVID. Last May Drs. Suwanwongse and Shabarek in New York City report on two patients who developed lithium toxicity as a result of COVID infection. Patients with viral illnesses have long been known to have a higher risk of lithium toxicity – mainly because of dehydration from fever, diarrhea, and poor oral intake. NSAID use during a fever adds to the problem, and COVID adds an additional risk – renal function can decline during severe COVID illness.

Kellie: That’s disappointing that lithium isn’t likely to be used against COVID, but are there other medications that do similar things that might fight the virus?

Dr. Aiken: Yes. There are many meds in the anti-COVID pipeline, and at least one of them has lithium like properties. That’s Ebselen, Ebselen is an experimental drug that’s being investigated for bipolar disorder as well as COVID-19. Like lithium, dampens phosphodiesterase signaling by inhibiting inositol phosphate-phosphatase. Ebselen also induces lithium-behaviors in mice. It’s being tested for COVID because it inhibits the main protease that COVID uses to replicate – called 3C protease. Alprazolam – xanax – was also found to inhibit a COVID protease in the lab but I don’t think they are testing alprazolam any further because more suitable candidates for this effect were found: Celecoxib and Carprofen. 

Kellie: Celecoxib – the NSAID? I’d bet you’d want to avoid that with lithium.

Dr. Aiken: Yes, but as we’ve reported this year in the online journal Celecoxib is the anti-inflammatory with the best evidence in depression – overall, it had a large effect size in both bipolar and unipolar depression. There’s a new study in treatment resistant bipolar depression with Celecoxib – it’s a small study but it worked surprisingly well – bringing half the patients to full remission after they’d failed to respond to 3-4 other medications.

Kellie: And now for the word of the day. Vitamin D Deficiency.

Dr. Aiken: Lots of psychiatrists are checking vitamin D because low levels have been associated with depression. While that association is pretty well established, what’s less well established is whether corrected the levels does anything to help depression – in fact most good trials of that strategy have failed to show a difference. It’s possible that the deficiencies we’re seeing in depression are due to something else that goes along with depression – for example obesity, older age, poor diet, lack of sunlight, and even taking Carbamazepine can all reduce vitamin D.

Still, it’s worthwhile to check because deficiencies are very common in the psychiatric population and correcting them can lower the risk of bone disease, cancer, and COVID-19 infection. In fact Dr. Anthony Fauci recently revealed the two supplements he and his wife take to prevent COVID: Vitamin D and Vitamin C. But let’s look at the basics of how to assess it. I’ve put all these numbers in the show notes:

How to order vitamin D: Vitamin D, 25-Hydroxy (Diagnostic code=E55.9)

How to interpret vitamin D levels : You want them to be between 30-60 ng/ml  . There’s some evidence of harms, like increased mortality, in the higher ranges so no need to go overboard with this. 20-30 is a mild low level and it’s difficult to show much harm in that range, but definitely below 12 ng/ml is going to be inadequate for bone health.

How to correct vitamin D levels: Start with Vitamin D3. The patient can take it over the counter as 2,000 IU daily for mild deficiency or if more severe prescribe 6000 IU daily 50,000 IU weekly. Recheck the levels, if it does not rise refer to PCP – obesity and malabsorption may prevent it from rising.

Vitamin D may prevent COVID-19 through regulating the renin-angiotensin system or the immune system. People with low vitamin D were 1.77 times more likely to contract COVID-19. Once they get COVID, people with low vitamin D are 20% more likely to die from the infection. While suggestive, these results don’t prove causation, but we do have confirmation from a small randomized controlled trial of 76 patients with COVID who were randomized to high dose 25-hydroxyvitamin D3, the main metabolite vitamin D3.

Kellie: Join us next week for a look at how the pandemic is affecting the psychopathology of everyday life: The Mental Toll of Quarantine

 

References:

• Gimeno A, Mestres-Truyol J, Ojeda-Montes MJ, et al. Prediction of Novel Inhibitors of the Main Protease (M-pro) of SARS-CoV-2 through Consensus Docking and Drug Reposition. Int J Mol Sci. 2020;21(11):3793. [Link]


• 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(1):21. Published 2020 May 20. [Link]


• Suwanwongse K, Shabarek N. Lithium Toxicity in Two Coronavirus Disease 2019 (COVID-19) Patients. Cureus. 2020;12(5):e8384. Published 2020 May 31. [Link]


• Halaris A, Cantos A, Johnson K, Hakimi M, Sinacore J. Modulation of the inflammatory response benefits treatment-resistant bipolar depression: A randomized clinical trial. J Affect Disord. 020;261:145-152. [Link]


• Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J Steroid Biochem Mol Biol. 2020;203:105751. [Link]