Lithium: The Depressing Case of Misrepresented Monitoring Data IV
The saga continues
Welcome to The Frontier Psychiatrists, a daily-enough health-themed newsletter edited by Owen Scott Muir, M.D., DFAACAP. I am a child, adolescent, and adult psychiatrist, and today, I'm welcoming back part four of a series shared with me by a physicist…his pen name is
. It's on lithium, the third element on the periodic table, and a star of my recent book—Inessential Pharmacology. (amazon link)This series is about the depressing reality that is, in Alex’s view, sloppy thinking when it comes to the dosing and blood level measurement for lithium. It's important to understand that our patients might have some extremely valid thoughts regarding the medicines they are being prescribed. They might even have more of a vested interest in efficacy and measurement than we do as physicians. Sometimes, physicians are also patients. Lithium isn't trivial, and today is part four out of five, a mini testament to that complexity.
The prior articles are:
And now, part IV:
In science, nothing is clear, and everything is complicated
Many science communicators suffer from a fairly common malady I like to call SSS or Single Study Syndrome. This is where an academic or clinician will make a bold claim, then only cite a single study to back it up. Almost every scientist (including me) will suffer SSS from time to time.
Contrary to popular media articles, scientific “facts” are not determined through single studies. They are determined through consensus. This is where hundreds, sometimes thousands of academic papers studying different angles of the same problem come to similar if not the same conclusion. And papers that don’t will have been shown to have methodological issues or an error.
Instead of citing the Castro et al. [1] paper in part 2, Dr Meyer could have referenced a 2020 review paper1 by Schoot et al. [2], but that would have given a slightly more mixed picture. 3 of the 8 studies reviewed for Lithium-induced Nephrogenic Diabetes Insipidus (Li-NDI) showed Single Daily Dosing (SDD) as superior to Multiple Daily Dosing, 2 of the studies had methodological issues, and 3 studies reported no benefit of SDD on urinary concentration benefit. For clinical practice, Schoot et al. [2] recommend:
…once daily dosing instead of multiple daily dosing. Although convincing evidence for the superiority in the prevention of Li-NDI is lacking…
Schoot et al. [2] considered only one study for their review of the prevention and treatment of lithium nephropathy—Castro et al. [1]. The most recent study looking at the impact of SDD vs MDD on renal dysfunction was a 2024 paper by Harada and Kato [3]. They found “no significant difference in renal dysfunction between the single-dose group and multiple-dose group.” Not exactly a consensus.
This is not to say there isn’t any validity to the claim that SDD regimens may reduce the long-term risk of renal dysfunction compared with MDD regimens for patients with the same average serum concentration. In 1982, Plenge et al. [4] first postulated that the lower concentrations of lithium found in SDD regimens from ~18-24 hours compared with MDD might allow the kidneys to regenerate any damage caused by the higher peak lithium serum level found in SDD. More recently, a 2016 paper by Gong et al. [5] suggested mechanisms of action that would mean a paradoxical protective effect of lithium on the kidneys at low serum concentrations. Unfortunately, I have not found any papers that refuted nor built on the work by Gong et al. [5].
However, Malhi and Tanious point out in a 2011 paper [6] that “although lower trough plasma lithium concentrations are observed with a single dose regimen compared with a multiple-dose regimen, the difference is not statistically significant,” citing a 1981 study by Perry [7]. Malhi and Tanious [6] also mention that from a “clinical perspective, the plasma concentration stays within the therapeutic range with both regimens [8], [9], [10]”.
Thank you for joining us for part IV. The thrilling conclusion is tomorrow. Give
a subscribe![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] T. S. Schoot, T. H. J. Molmans, K. P. Grootens, and A. P. M. Kerckhoffs, “Systematic review and practical guideline for the prevention and management of the renal side effects of lithium therapy,” Eur. Neuropsychopharmacol., vol. 31, pp. 16–32, Feb. 2020, doi: 10.1016/j.euroneuro.2019.11.006.
[3] H. Harada and T. Kato, “Impact of single versus multiple dose lithium on renal dysfunction in bipolar patients: A retrospective cohort study,” Psychiatry Clin. Neurosci. Rep., vol. 3, no. 2, p. e205, 2024, doi: 10.1002/pcn5.205.
[4] P. Plenge et al., “Lithium treatment: does the kidney prefer one daily dose instead of two?,” Acta Psychiatr. Scand., vol. 66, no. 2, pp. 121–128, 1982, doi: 10.1111/j.1600-0447.1982.tb00920.x.
[5] R. Gong, P. Wang, and L. Dworkin, “What we need to know about the effect of lithium on the kidney,” Am. J. Physiol.-Ren. Physiol., vol. 311, no. 6, pp. F1168–F1171, Dec. 2016, doi: 10.1152/ajprenal.00145.2016.
[6] G. S. Malhi and M. Tanious, “Optimal Frequency of Lithium Administration in the Treatment of Bipolar Disorder,” CNS Drugs, vol. 25, no. 4, pp. 289–298, Apr. 2011, doi: 10.2165/11586970-000000000-00000.
[7] P. J. Perry, F. J. Dunner, R. L. Hahn, M. T. Tsuang, and M. J. Berg, “Lithium kinetics in single daily dosing,” Acta Psychiatr. Scand., vol. 64, no. 4, pp. 281–294, 1981, doi: 10.1111/j.1600-0447.1981.tb00785.x.
[8] M. Gitlin, “Lithium and the Kidney,” Drug Saf., vol. 20, no. 3, pp. 231–243, Mar. 1999, doi: 10.2165/00002018-199920030-00004.
[9] D. Ljubicic, M. Letica-Crepulja, D. Vitezic, I. L. Bistrovic, and R. Ljubicic, “Lithium Treatments: Single and Multiple Daily Dosing,” Can. J. Psychiatry, vol. 53, no. 5, pp. 323–331, May 2008, doi: 10.1177/070674370805300507.
[10] R. Hunter, “Steady-state pharmacokinetics of lithium carbonate in healthy subjects.,” Br. J. Clin. Pharmacol., vol. 25, no. 3, pp. 375–380, 1988, doi: 10.1111/j.1365-2125.1988.tb03316.x.
articles that pour over previous studies in an attempt to determine the current state of affairs for a particular research problem/question - can be used as waymarkers to see how close academics are to a consensus
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