Lithium: The Depressing Case of Misrepresented Monitoring Data II
A guest epic continues!
Welcome to part II of the guest-authored epic five-part series on lithium monitoring. The Frontier Psychiatrists is a daily-enough health-themed newsletter, and today’s guest column picks up where yesterday’s part I left off. I will remind readers that a lithium primer is available in Inessential Pharmacology. (amazon link)….
The main reason I felt down listening to Dr Meyer’s webinar
In the same webinar video from part 1, “Baseline monitoring and dosing of lithium”, from 8:26 to 9:53, Dr. Meyer says:
I’ve talked in previous episodes about using lithium once a day, that is now the standard of care because multiple daily dosing causes more renal dysfunction. The other thing is multiple daily dosing distorts the level. If I’m on, for example 450mg twice a day and I get my level tomorrow morning, well it is a 12 hour level only for my evening dose, but the other half of the dose was taken 24 hours before. So what happens is if you take somebody on BID1 dosing you put it all to QHS2 then you recheck that 12 hour level, guess what that number will go up by 28%. We are still on the same amount of drug, right? Same amount of drug, but now you get that true 12 hour level that is not being distorted by BID and distributing the level over 24 hours for half of it before the level was obtained.
So it is important to notice we prefer to always give lithium once a day. You may have some patients who refuse to switch and if they refuse to switch, they should take that level that you are getting on BID dosing and multiply it by 1.28 because that is the level they would have if you put all the drug to QHS. You might recognise that you are giving them nephrotoxic levels of lithium because all of your decisions were previously based on the level obtained on BID dosing but we know that level is being distorted by the fact that it is spread out over 24 hours
As you can probably tell, it is not the clearest set of arguments, but given Dr Meyer seems to have given the webinar over many hours, some loss of clarity is understandable. My concern is that the language seems to show a lack of knowledge and understanding of lithium therapeutic monitoring. Let us take each of the bold highlighted statements in turn.
“Multiple daily dosing causes more renal dysfunction.”
I believe, taken at face value, there are problems with the structure of this statement. For instance, someone on a 200mg twice daily dose3 of lithium would probably be less likely to exhibit long-term renal dysfunction than someone on a 1200 mg Single Daily Dose. But I’m pretty sure Dr Meyer is not intending to be literal here. In an earlier video, “Lithium’s renal Journey…” he repeats that Multiple Daily Dosing causes more renal dysfunction claim, then says:
People who received lithium once a day had 20% lower risk for renal insufficiency
Citing a 2016 article by Castro et al. [1]. The key word is “risk” here. The Castro et al. paper makes no claim to causality. It only provides an odds ratio, a measure of association, between single daily dosing and reduced renal dysfunction. The association does not imply causality. A 2015 paper by Altman and Krzywinski [2] gives a succinct explanation:
Association should not be confused with causality; if X causes Y, then the two are associated (dependent). However, associations can arise between variables in the presence (i.e., X causes Y) and absence (i.e., they have a common cause) of a causal relationship…As an example, suppose we observe that people who daily drink more than 4 cups of coffee have a decreased chance of developing skin cancer. This does not necessarily mean that coffee confers resistance to cancer; one alternative explanation would be that people who drink a lot of coffee work indoors for long hours and thus have little exposure to the sun, a known risk. If this is the case, then the number of hours spent outdoors is a confounding variable—a cause common to both observations. In such a situation, a direct causal link cannot be inferred; the association merely suggests a hypothesis, such as a common cause, but does not offer proof. In addition, when many variables in complex systems are studied, spurious associations can arise. Thus, association does not imply causation.
We should be careful when we use the word “cause.” This brings us to the next bold highlighted statement from the webinar – which we shall cover in part III.
[1] V. M. Castro et al., “Stratifying Risk for Renal Insufficiency Among Lithium-Treated Patients: An Electronic Health Record Study,” Neuropsychopharmacology, vol. 41, no. 4, Art. no. 4, Mar. 2016, doi: 10.1038/npp.2015.254.
[2] N. Altman and M. Krzywinski, “Association, correlation and causation,” Nat. Methods, vol. 12, no. 10, pp. 899–900, Oct. 2015, doi: 10.1038/nmeth.3587.
Bis In Die - meaning “twice a day”
Quaque Hora Somni - meaning “every night at bedtime”
so 400mg total for the day - I chose this number because it is the lowest possible prescribable dose in the UK using slow-release lithium carbonate tablets. Theoretically, you could choose lower doses with liquid lithium citrate to prove the point (say 1mg twice per day)
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