Endogenous Lithium Levels in Humans

The best replicated and latest data indicate that typical endogenous serum lithium levels are around 0.0003 mmol/L and levels seem to show low variation (~ 0.0001 -0.0005) in relation to typical dietary ingestion amounts (which are < 1 mg/day).

We were always taught that naturally (i.e. in people not taking any form of lithium treatment) there was no endogenous lithium the human body, and many doctors may still think that. It is a question of “LODs/LOQs”, limits of detection/quantification: for usual laboratory methods, these are way above background levels (i.e. insufficiently sensitive to measure them), and they are therefore not detected by usual routine medical laboratory tests.

It is helpful to note, at the outset, that the measurement of nano-gram levels of endogenous lithium (and other trace metals) in biological tissues and fluids involves technical challenges and difficulties (1-3) and some reported measurements may require corroboration and replication before one can have confidence in them.

A recent very large sample of endogenous lithium levels in humans is from Bochud (4).

Various groups have measured the ratio between the human red blood cell and serum lithium, often denoted as R(Li), but any useful rationale behind this is doubtful. Whether it gives an indication of intracellular lithium generally, or neuronal cell levels of lithium, which are presumably more relevant, is uncertain — and, in any case, neuronal levels vary between brain regions. I suspect the reason it has been done is because red blood cells are easily available and easily separated for measurement. Such results, whether accurate or not, are of no clear relevance or usefulness. Therefore, papers attempting to link red cell/plasma lithium concentration ratio R(Li) values to anything (diagnosis, treatment, prognosis etc.) have not yielded useful results, for reviews — none recent, people, rightly, seem to have given up on this — see: (5, 6).

The paper by Clarke (3) seems to have been uncited since its publication 10 years ago. They found an R(Li) value (red cell to plasma ratio) of 0.3 from values of plasma at 0.74 and red cells at 0.24 ng/g. That R(Li) value agrees with those obtained at therapeutic lithium levels using atomic absorption methods (7-10). Other accessible papers with data on endogenous lithium in human serum are: (8, 11-14).

Tap-water: one tenth of daily intake

The data indicating that tap-water constitutes only one tenth of typical daily dietary lithium intake is clear and relevant, because various researchers have sought to link the amount of lithium in tap-water to, among other things, suicide rates and violence (see discussion concerning endogenous lithium and suicide below).

Municipal reticulated water supply (tap-water) and serum levels

The data of Bochud et. al. (4) which, like Clarke’s work, has never been cited by any psychiatric publication on lithium, measured both serum & urinary lithium concentrations in 745 subjects, and also in the tap-water they consumed (in Belgium & South Africa).

The average concentration of lithium in tap water in Belgium was 0.01 mg/L, & in South Africa was 0.00021 mg/L — a fifty-fold difference. The 24-hour urinary lithium excretion was 0.055 mg & 0.021 mg per 24 hours) much higher and more variable in Belgium than in South Africa (because a large proportion of Belgians consume more high lithium content mineral water?).

Bochud concluded their results indicated that food, not water, determines the dietary intake of lithium (from the info herein, that is hardly a surprise). Serum lithium levels were almost identical: Belgium 0.0022 mg/L vs. South Africa = 0.0023 mg/L. And that in relation to a fifty-fold difference in tap-water lithium concentration.

That demonstrates serum lithium is tightly regulated even when there are variations in dietary intake (at these intake levels from natural dietary sources of < 1 mg/day). Remember that at the 1000 times higher therapeutic intake levels, of ~ 1,000 mg/d, serum lithium is determined by glomerular filtration rate and is therefore directly proportion to daily dose: i.e. the relationship is linear, so if 500 mg gives a steady state level of 0.3 mmol/L then 1,000 mg will give 0.6 mmol/L.

Other results (for the record, but all minute sample sizes compared to Bochud’s 745): Miller found serum lithium levels around 0.00016 mmol/Liter for normal subjects dwelling in the Denver metropolitan area, and the mean 24-hr excretion rate was 0.005 mmol/day (15). Folkerd (16) healthy volunteers (n = 25), mean 0.00027 +/- 0.02 mmol/L (range 0.00013-0.00055 mmol/L). Lehmann, small sample maximum of 0.06 mg/L (0.009 mmol/L) (17). Those older assays may be less accurate.

Human health

There is now strong evidence that lithium has a beneficial effect on various aspects of human health in concentrations that are much lower, than those used for treating manic depressive illness (2, 18-22). Evidence has been advanced regarding various effects, especially in nerve cells, for instance: that it enhances the re-myelination of peripheral nerves after various forms of nerve damage (23); has beneficial effects in ameliorating the consequences of oxidative stress (24); protects against ischaemic damage post-stroke (25, 26); reduces inflammation (27); increases expression of brain-derived neurotrophic factor (28), that may be important in depression; is beneficial in slowing Alzheimer’s dementia  (29-34); protects against mitochondrial damage (18, 35, 36). Many of these actions have been detailed in a recent review by Manji’s team in Quiroz et al (37).

Lithium and white blood cells

I have long been puzzled by the fact that lithium has not been widely recognised for its haematological effects. After a decade or two of relative inaction, more comment and research is now being published (24, 26, 27, 32, 38-42). It was established long ago that patients on lithium had an increased white blood cell count and that lithium increased the number and activity of primitive blood cell precursors thereby increasing the total number of white blood cells and also the entry of white blood cells into tissues (43-45).

Psychiatrists appear to be insufficiently informed concerning the actions of this important drug. In my experience, relatively few of them have been aware that it induces leucocytosis, i.e. an increase in white blood cells. I have heard repeated questions throughout my career about why a patient on lithium should have an increased white count.

In the 1% or so of clozapine treated patients who develop neutropenia lithium does appear to be an effective treatment (46-52). Unfortunately, most of the literature is case reports with no apparent prospective or long-term studies. This seems a shame since these would be quite simple to do. Probably another example of a little used out of patent drug attracting little funding for research.

However, Bayesian logic suggests that since replicated experimental evidence convincingly demonstrates that lithium affects granulocyte colony-stimulating factor (G-CSF) and promotes white cell production (41, 53) it is a logical course of action. Note that, from a practical clinical point of view, such a combination may have particular problems with toxicity and side effects (54-56) and require close and expert supervision. It is not something to be undertaken without clear, definite and properly documented justification (57).

Endogenous Lithium levels and Suicide

Somewhat dubiously, it has been claimed that violence and the suicide rate is lower in areas where natural lithium intake from municipal reticulated drinking-water supplies is higher (58-64) and that it has a beneficial effect on various violent and anti-social behaviours (65).

Note, the Knudsen (66) and Kessing (67) studies were negative. Nevertheless, what a waste of research effort.

First, the lower limit of detection (LOD) for most hospital laboratories is about 1 mg/L for lithium (0.14 mmol/L), lower levels are inaccurate unless performed in a specialised laboratory. Some papers published may not have used accurate assay techniques (1).

The information below indicates that such speculative associative epidemiology concerning suicide and violence is highly unlikely to be correct, or to reveal any cause-effect relationship.

A brief examination of one recent paper by Kapusta et al.(62), published in the British J of Psychiatry, a prestigious journal, and a follow up effort (61), will illustrate the kind of nonsensical material that is being published. The paper seeks to make a correlation between population suicide rates and the differing concentrations of lithium in tap-water in various districts in Austria. The majority of the sample were exposed to low levels of lithium in the tap-water in their districts, and also within a relatively narrow range of concentrations (0.002-0.01 mg/L). Since the established range in fresh water is <0.000005 to 0.356 mg/L that constitutes a small window into the overall range.

The most recent best estimate of dietary lithium intake is, as above, around 0.5 mg per day (68, 69), intake from tap-water must represent less than one tenth of total daily intake — if typical tap-water is 0.002mg/L then drinking 2L per day is only 1% of the total 0.5 mg estimated total daily intake. Lithium in food probably contributes ten times as much as tap-water. Not only that, but many of the foods (especially sea-food) and vegetables, and bottled water, in peoples’ diet have come from different districts and different countries: which indicates that where you live has little to do with lithium intake.

The consumption of bottled spring-water is a multi-billion-dollar industry and bottled waters have, on average, a five times higher lithium concentration: viz. median level of bottled waters is 0.010 mg/L vs. 002 mg/L for tap water. In Europe, the EU average for 2015 was 110 L per capita per year, Austrian data indicates around 90 l per year.

Source: European Federation of Bottled Waters. http://www.efbw.org/index.php?id=90

Bearing in mind that babies are unlikely to drink mineral water, we can estimate the typical adult is drinking about 150 L per year, or 3 L per week. That is equivalent to 15 L of ordinary tap water in terms of lithium content, based on the assumption from the data above, that the average difference between mineral water and tap water is five-fold.

That makes it likely that a substantial proportion of Kapusta’s sample (or any other sample) will have been ingesting far more lithium from bottled spring-water than from tap-water, certainly enough to make a nonsense of their data.

Lastly, Kapusta did not measure serum levels of lithium of a sample of people in areas exposed to different levels of lithium in their tap-water in order to demonstrate a correlation between the tap-water level and the serum level: that is the essential and simple requirement needed to establish a relationship between those two variables.

Note that Bochud’s study of two large samples ingesting water with a fifty-fold concentration difference found identical serum levels: they therefore concluded that, at those levels of intake, serum levels are tightly regulated and vary little with intake.

Without the correlation between blood levels and lithium concentration in tap-water (which we can infer from Bochud’s data is not present) it is obvious the paper is of no value. It is laughable and I feel a sorry for them. What is more of a worry is the ‘expert referees’ who decided to waste money by giving them a research grant and the journal’s referees who missed all these pretty obvious and major mistakes which should have caused the paper to be rejected.

Lastly, in regard to not having accounted for the consumption of lithium either in bottled water, or in the diet, Kapusta et al. blithely state: ‘For obvious reasons, data for both of these factors are not available at aggregate levels; hence we were unable to consider these factors.’ That statement is incorrect, because TDS1 had already published results (68) and estimates of bottled water sales/consumption are readily available. How facile is that? to so blithely dismiss a failure in a key assumption at the heart of the paper.

I hope the data and reasoning above persuades my readers that Kapusta et al. (and all the other silly papers seeking to establish such links) are quite obviously incorrect, and that all such similar efforts to correlate lithium in tap-water with suicide, violence or in-growing toenails etc. are fundamentally and fatally flawed.

References

1.         Subramanian, KS, Determination of metals in biofluids and tissues: sample preparation methods for atomic spectroscopic techniques. Spectrochimica Acta Part B: Atomic Spectroscopy, 1996. 51(3): p. 291-319.

2.         Dell'Osso, L, Del Grande, C, Gesi, C, Carmassi, C, et al., A new look at an old drug: neuroprotective effects and therapeutic potentials of lithium salts. Neuropsychiatr Dis Treat, 2016. 12: p. 1687-703.

https://www.ncbi.nlm.nih.gov/pubmed/27468233

3.         Clarke, WB, Guscott, R, Downing, RG, and Lindstrom, RM, Endogenous lithium and boron red cell-plasma ratios: normal subjects versus bipolar patients not on lithium therapy. Biol. Trace Elem. Res., 2004. 97(2): p. 105-16.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14985621

4.         Bochud, M, Staessen, JA, Woodiwiss, A, Norton, G, et al., Context dependency of serum and urinary lithium: implications for measurement of proximal sodium reabsorption. Hypertension, 2007. 49(5): p. e34.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17389251

5.         Carroll, BJ, Prediction of treatment outcome with lithium. Arch. Gen. Psychiatry, 1979. 36(8 Spec No): p. 870-8.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=454106

6.         Jefferson, JM, Greist, JH, and Ackerman, D, Lithium Encyclopedia for Clinical Practice. 1987: American Psychiatric Press, Washington, DC.

7.         Elizur, A, Shopsin, B, Gershon, S, and Ehlenberger, A, Intra:extracellular lithium ratios and clinical course in affective states. Clin Pharmacol Ther, 1972. 13(6): p. 947-53.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=5081607

8.         Mendels, J and Frazer, A, Intracellular lithium concentration and clinical response: towards a membrane theory of depression. J. Psychiatr. Res., 1973. 10(1): p. 9-18.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4730006

9.         Rybakowski, J, Chlopocka, M, Kapelski, Z, Hernacka, B, et al., Red blood cell lithium index in patients with affective disorders in the course of lithium prophylaxis. Int. Pharmacopsychiatry, 1974. 9(3): p. 166-71.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4430569

10.        Dorus, E, Pandey, GN, Shaughnessy, R, Gaviria, M, et al., Lithium transport across red cell membrane: a cell membrane abnormality in manic-depressive illness. Science, 1979. 205(4409): p. 932-4.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=472716

11.        Frazer, A, Mendels, J, Secunda, SK, Cochrane, CM, et al., The prediction of brain lithium concentrations from plasma or erythrocyte measures. J. Psychiatr. Res., 1973. 10(1): p. 1-7.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4730001

12.        Knorring, L, Oreland, L, Perris, C, and Wiberg, A, Evaluation of the lithium RBC/plasma ratio as a predictor of the prophylactic effect of lithium treatment in affective disorders. Pharmakopsychiatr. Neuropsychopharmakol., 1976. 9(2): p. 81-4.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=981325

13.        Flemenbaum, A, Weddige, R, and Miller, J, Jr., Lithium erythrocyte/plasma ratio as a predictor of response. Am J Psychiatry, 1978. 135(3): p. 336-8.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=626224

14.        Upadhyaya, AK, Varma, VK, Sankaranarayanan, A, and Goel, A, Lithium in prophylactic therapy of manic-depressive illness: biochemical correlates of response. Biol Psychiatry, 1985. 20(2): p. 202-5.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3971001

15.        Miller, NL, Durr, JA, and Alfrey, AC, Measurement of endogenous lithium levels in serum and urine by electrothermal atomic absorption spectrometry: a method with potential clinical applications. Anal. Biochem., 1989. 182(2): p. 245-9.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2610339

16.        Folkerd, E, Singer, DR, Cappuccio, FP, Markandu, ND, et al., Clearance of endogenous lithium in humans: altered dietary salt intake and comparison with exogenous lithium clearance. Am. J. Physiol., 1995. 268(4 Pt 2): p. F718-22.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7733329

17.        Lehmann, K, Endogenous lithium levels. Pharmacopsychiatry, 1994. 27(3): p. 130-2.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8078955

18.        Motaghinejad, M, Seyedjavadein, Z, Motevalian, M, and Asadi, M, The neuroprotective effect of lithium against high dose methylphenidate: Possible role of BDNF. Neurotoxicology, 2016. 56: p. 40-54.

https://www.ncbi.nlm.nih.gov/pubmed/27343358

19.        Leu, SJ, Yang, YY, Liu, HC, Cheng, CY, et al., Valproic Acid and Lithium Meditate Anti-Inflammatory Effects by Differentially Modulating Dendritic Cell Differentiation and Function. J. Cell. Physiol., 2017. 232(5): p. 1176-1186.

https://www.ncbi.nlm.nih.gov/pubmed/27639185

20.        Zheng, J, Liu, Z, Li, W, Tang, J, et al., Lithium posttreatment confers neuroprotection through glycogen synthase kinase-3beta inhibition in intracerebral hemorrhage rats. J. Neurosurg., 2016: p. 1-9.

https://www.ncbi.nlm.nih.gov/pubmed/27739937

21.        De-Paula, VJ, Gattaz, WF, and Forlenza, OV, Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations. Bipolar Disord, 2016. 18(8): p. 692-695.

https://www.ncbi.nlm.nih.gov/pubmed/27882645

22.        Bosche, B, Molcanyi, M, Rej, S, Doeppner, TR, et al., Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner. Front Physiol, 2016. 7: p. 593.

https://www.ncbi.nlm.nih.gov/pubmed/27999548

23.        Makoukji, J, Belle, M, Meffre, D, Stassart, R, et al., Lithium enhances remyelination of peripheral nerves. Proc Natl Acad Sci USA, 2012.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22355115

http://www.pnas.org/content/109/10/3973.long

24.        Arraf, Z, Amit, T, Youdim, MB, and Farah, R, Lithium and oxidative stress lessons from the MPTP model of Parkinson's disease. Neurosci. Lett., 2012. 516(1): p. 57-61.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22480690

25.        Kang, K, Kim, YJ, Kim, YH, Roh, JN, et al., Lithium pretreatment reduces brain injury after intracerebral hemorrhage in rats. Neurol. Res., 2012. 34(5): p. 447-54.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22450252

26.        Gold, AB, Herrmann, N, and Lanctot, KL, Lithium and its neuroprotective and neurotrophic effects: potential treatment for post-ischemic stroke sequelae. Curr Drug Targets, 2011. 12(2): p. 243-55.

https://www.ncbi.nlm.nih.gov/pubmed/20863277

27.        Green, HF and Nolan, YM, GSK-3 mediates the release of IL-1beta, TNF-alpha and IL-10 from cortical glia. Neurochem. Int., 2012.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22796213

28.        Park, SW, Lee, JG, Seo, MK, Cho, HY, et al., Effects of mood-stabilizing drugs on dendritic outgrowth and synaptic protein levels in primary hippocampal neurons. Bipolar Disord, 2015. 17(3): p. 278-90.

https://www.ncbi.nlm.nih.gov/pubmed/25307211

29.        Matsunaga, S, Kishi, T, Annas, P, Basun, H, et al., Lithium as a Treatment for Alzheimer's Disease: A Systematic Review and Meta-Analysis. J Alzheimers Dis, 2015. 48(2): p. 403-10.

https://www.ncbi.nlm.nih.gov/pubmed/26402004

30.        Zhang, X, Heng, X, Li, T, Li, L, et al., Long-term treatment with lithium alleviates memory deficits and reduces amyloid-beta production in an aged Alzheimer's disease transgenic mouse model. J Alzheimers Dis, 2011. 24(4): p. 739-49.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21321394

31.        Sudduth, TL, Wilson, JG, Everhart, A, Colton, CA, et al., Lithium treatment of APPSwDI/NOS2-/- mice leads to reduced hyperphosphorylated tau, increased amyloid deposition and altered inflammatory phenotype. PLoS One, 2012. 7(2): p. e31993.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22347510

32.        Forlenza, OV, de Paula, VJ, Machado-Vieira, R, Diniz, BS, et al., Does lithium prevent Alzheimer's disease? Drugs Aging, 2012. 29(5): p. 335-42.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22500970

33.        Nunes, MA, Viel, TA, and Buck, HS, Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimers disease. Curr Alzheimer Res, 2012.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22746245

34.        Moore, GJ, Cortese, BM, Glitz, DA, Zajac-Benitez, C, et al., A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients. J Clin Psychiatry, 2009. 70(5): p. 699-705.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19389332

35.        Fessel, J, Amyloid is essential but insufficient for Alzheimer causation: addition of subcellular cofactors is required for dementia. Int. J. Geriatr. Psychiatry, 2017.

https://www.ncbi.nlm.nih.gov/pubmed/28509380

36.        Bachmann, RF, Wang, Y, Yuan, P, Zhou, R, et al., Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage. Int J Neuropsychopharmacol, 2009. 12(6): p. 805-22.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19149911

37.        Quiroz, JA, Machado-Vieira, R, Zarate, CA, Jr., and Manji, HK, Novel insights into lithium's mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology, 2010. 62(1): p. 50-60.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20453535

38.        Ferensztajn-Rochowiak, E, Kucharska-Mazur, J, Samochowiec, J, Ratajczak, MZ, et al., The effect of long-term lithium treatment of bipolar disorder on stem cells circulating in peripheral blood. The World Journal of Biological Psychiatry, 2017. 18(1): p. 54-62.

39.        Qi, L, Tang, Y, He, W, Pan, H, et al., Lithium chloride promotes neuronal differentiation of rat neural stem cells and enhances neural regeneration in Parkinson’s disease model. Cytotechnology, 2017. 69(2): p. 277-287.

40.        Ferensztajn-Rochowiak, E and Rybakowski, JK, The effect of lithium on hematopoietic, mesenchymal and neural stem cells. Pharmacol Rep, 2016. 68(2): p. 224-30.

https://www.ncbi.nlm.nih.gov/pubmed/26922521

41.        Petrini, M and Azzara, A, Lithium in the treatment of neutropenia. Curr. Opin. Hematol., 2012. 19(1): p. 52-7.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22123660

42.        Sofola, O, Kerr, F, Rogers, I, Killick, R, et al., Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease. PLoS Genet, 2010. 6(9).

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20824130

43.        Boggs, DR and Joyce, RA, The hematopoietic effects of lithium. Semin. Hematol., 1983. 20(2): p. 129-38.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=6348956

44.        Hammond, WP and Dale, DC, Lithium therapy of canine cyclic hematopoiesis. Blood, 1980. 55(1): p. 26-8.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7350939

45.        Rossof, AH and Coltman, CA, Jr., The effect of lithium carbonate on the granulocyte phagocytic index. Experientia, 1976. 32(2): p. 238-9.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=944641

46.        Silverstone, PH, Prevention of clozapine-induced neutropenia by pretreatment with lithium. J Clin Psychopharmacol, 1998. 18(1): p. 86-8.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9472850

47.        Blier, P, Slater, S, Measham, T, Koch, M, et al., Lithium and clozapine-induced neutropenia/agranulocytosis. Int. Clin. Psychopharmacol., 1998. 13(3): p. 137-40.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9690982

48.        Sporn, A, Gogtay, N, Ortiz-Aguayo, R, Alfaro, C, et al., Clozapine-induced neutropenia in children: management with lithium carbonate. J. Child Adolesc. Psychopharmacol., 2003. 13(3): p. 401-4.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14642024

49.        Esposito, D, Rouillon, F, and Limosin, F, Continuing clozapine treatment despite neutropenia. Eur. J. Clin. Pharmacol., 2005. 60(11): p. 759-64.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15660271

50.        Kanaan, RA and Kerwin, RW, Lithium and clozapine rechallenge: a retrospective case analysis. J Clin Psychiatry, 2006. 67(5): p. 756-60.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16841625

51.        Mattai, A, Fung, L, Bakalar, J, Overman, G, et al., Adjunctive use of lithium carbonate for the management of neutropenia in clozapine-treated children. Hum Psychopharmacol, 2009. 24(7): p. 584-9.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19743394

52.        Hodgson, RE and Mendis, S, Lithium enabling use of clozapine in a patient with pre-existing neutropenia. Br J Hosp Med (Lond), 2010. 71(9): p. 535.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20852555

53.        Focosi, D, Azzara, A, Kast, RE, Carulli, G, et al., Lithium and hematology: established and proposed uses. J. Leukoc. Biol., 2009. 85(1): p. 20-8.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18809733

54.        Caviness, JN and Evidente, VG, Cortical myoclonus during lithium exposure. Arch. Neurol., 2003. 60(3): p. 401-4.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12633152

55.        Lee, SH and Yang, YY, Reversible neurotoxicity induced by a combination of clozapine and lithium: a case report. Zhonghua Yi Xue Za Zhi (Taipei), 1999. 62(3): p. 184-7.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10222608

56.        Small, JG, Klapper, MH, Malloy, FW, and Steadman, TM, Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder. J Clin Psychopharmacol, 2003. 23(3): p. 223-8.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12826983

57.        Whiskey, E and Taylor, D, Restarting clozapine after neutropenia: evaluating the possibilities and practicalities. CNS Drugs, 2007. 21(1): p. 25-35.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17190527

58.        Liaugaudaite, V, Mickuviene, N, Raskauskiene, N, Naginiene, R, et al., Lithium levels in the public drinking water supply and risk of suicide: a pilot study. J. Trace Elem. Med. Biol., 2017.

59.        Vita, A, De Peri, L, and Sacchetti, E, Lithium in drinking water and suicide prevention: a review of the evidence. Int. Clin. Psychopharmacol., 2015. 30(1): p. 1-5.

http://www.ncbi.nlm.nih.gov/pubmed/25025988

60.        Helbich, M, Leitner, M, and Kapusta, ND, Lithium in drinking water and suicide mortality: interplay with lithium prescriptions. Br J Psychiatry, 2015. 207(1): p. 64-71.

http://www.ncbi.nlm.nih.gov/pubmed/25953888

61.        Bluml, V, Regier, MD, HLAVIN, G, ROCKETT, IR, et al., Lithium in the public water supply and suicide mortality in Texas. J. Psychiatr. Res., 2013. 47(3): p. 407-411.

62.        Kapusta, ND, Mossaheb, N, Etzersdorfer, E, Hlavin, G, et al., Lithium in drinking water and suicide mortality. Br J Psychiatry, 2011. 198(5): p. 346-50.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21525518

63.        Kabacs, N, Memon, A, Obinwa, T, Stochl, J, et al., Lithium in drinking water and suicide rates across the East of England. Br J Psychiatry, 2011. 198(5): p. 406-7.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21525523

64.        Ohgami, H, Terao, T, Shiotsuki, I, Ishii, N, et al., Lithium levels in drinking water and risk of suicide. Br J Psychiatry, 2009. 194(5): p. 464-5; discussion 446.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19407280

65.        Dawson, EB, The relationship of tap water and physiological levels of lithium to mental hospital admission and homicide in Texas. Lithium in Biology and Medicine, ed. GN Schrauzer and KF Klippel. 1991, Weinheim: : VCH Verlag.

66.        Knudsen, NN, Schullehner, J, Hansen, B, Jørgensen, LF, et al., Lithium in Drinking Water and Incidence of Suicide: A Nationwide Individual-Level Cohort Study with 22 Years of Follow-Up. International Journal of Environmental Research and Public Health, 2017. 14(6): p. 627.

67.        Kessing, LV, Vradi, E, and Andersen, PK, Nationwide and population-based prescription patterns in bipolar disorder. Bipolar Disord, 2016. 18(2): p. 174-82.

http://www.ncbi.nlm.nih.gov/pubmed/26890465

68.        Leblanc, J-C, Dietary exposure estimates of 18 elements from the 1st French Total Diet Study. Food additives and contaminants 22.7: 624-641. 2005.

69.        Anon, Second French Total Diet Study (TDS 2): Report 1 Inorganic contaminants, minerals, persistent organic pollutants, mycotoxins and phytoestrogens. 2012: p. http://www.tds-exposure.eu/sites/default/files/WP1/RapportEAT2EN1.pdf.