Lithium In The Drinking Water

 

Lithium In The Drinking Water

 

The title is an inside joke for any physicians trained in my generation. It was a standard line to indicate how common it is to prescribe a certain medication.  The first time I heard it I was an intern in the emergency department (ED) at St. Paul-Ramsey Medical Center.  It was (and is) a very busy ED and one of 3 Level I trauma centers in the Minneapolis St. Paul area with a population of about 3.6M people.  In those days there were no urgent care centers so the ED was informally split into a trauma and high acuity side and a low acuity side.  The interns would rotate from one side to the other every other day.  I had just assessed a couple of sisters on the low acuity side and diagnosed otitis media (ear infection) and was writing scripts for amoxicillin while I waiting for my attending to confirm the diagnosis.  He came out, agreed with the diagnosis and treatment plan and said: “We should put amoxicillin in the drinking water.”

And so it went.  Since that day I have heard the same thing about H-2 blockers, proton pump inhibitors, and statins.  All medications that are commonly prescribed for common problems.  Nobody has ever said that about lithium. In the conversations I have had about lithium over the past 30 years – people generally slow down, look concerned, and say something like: “That is a heavy-duty med isn’t it doc?” 

Lithium apparently got that reputation after it when it started to be widely used by psychiatrists for the treatment of bipolar disorder.  It was approved by the FDA in 1970 but was used as early as 1894 that for both bipolar disorder and melancholic depression (1).  It was also used in popular beverages and sought in the form of mineral water.  From 1929 to 1948 it was in 7-UP Lithiated Soda – a brand that eventually became 7-UP.  Lithium citrate was the active form and there is no reliable information on the concentration it originally contained.  One source suggests 5 mg/L (8) but it is not clear if this is as Li or a compound.  In psychiatry, that would be a trivial dose as either lithium carbonate or lithium citrate.  If it was really 5 milliequivalents (mEq) of lithium that would be roughly equivalent to 300 mg of lithium carbonate (Li₂CO₃) or 550 mg of lithium citrate (Li₃C₆H₅O₇).  Practically all the lithium prescribed by psychiatrists in the US is lithium carbonate in a range of 600-1800 mg/day.      

Lithium is considered a disease modifying drug in psychiatry for long term stabilization of bipolar disorder.  It is probably underutilized in the United States for both antidepressant augmentation and treatment of depression.  It may be underprescribed in general because it requires monitoring, has a narrow therapeutic index, can cause renal and thyroid complications, and has the potential for significant drug-drug interactions with a variety of medications that are commonly prescribed.  Investigations of its mechanism of action has led to some speculation that it may prevent neurodegeneration and be effective against psychiatric disorders even in very low doses.  These studies look at lithium exposure in the water supply and in animal models of neurodegeneration.  A recent paper suggests that lithium deficiency may cause Alzheimer’s dementia.

Before I get to a discussion of that paper, I thought I would review the ecology of lithium in the environment that is primarily focused on water chemistry.  I am referencing two major studies of lithium in the drinking water in the United States.  The first (3) looks at groundwater measurements at 18,027 states and uses that data to model lithium in the groundwater across the US.  They map that data and the maps are shown along with the original sampling sites at the maps at the top of this post.  As noted in the table, about 15% of these sites have a concentration of lithium that is greater than >30 μg/L.  That is significant because the Health Based Screening Level (HBSL) is 10 μg/L.  HBSLs are non-enforceable good faith benchmarks based on the latest drinking water and toxicity data.  Some of the sites measured in this study were exceeded by 1500 fold.  Lithium is the 32nd most abundant element in the Earth and distribution in nature is variable.  

The second study was more specific for drinking water because it looked at samples directly from drinking water treatment plants (DWTP) (4).  Even though DWTPs have no specific processes for removal of lithium, the levels are significantly lower in range than the groundwater survey.  The surface water had a median level below the HBSL and groundwater level was higher.   The authors noted that 56% of the groundwater and 13% of the surface water sources of DWTPs exceeded the HBSL. 

In terms of pharmaceutical doses of lithium – the lowest dose I have ever prescribed was 150 mg as lithium carbonate.  Lithium carbonate is 18.79% lithium; therefore, each tablet or capsule contains about 28.185 mg of Li or 28,185 μg.  Looking at the range of concentration in the Lombard study (3) it would take ingesting 1.88 to 28M liters of those waters to be equivalent to a single 150 mg capsule per day.  In the case of the median groundwater and surface water from the Sharma (4) study it would take 176 to 216 liters to take in the equivalent amount. That study also suggests that drinking water sourced for treatment for human use is less likely to have extraordinary levels but does have levels that are currently flagged as a potential health risk.  Most people on lithium maintenance for bipolar disorder have much higher exposure to lithium than is likely from any drinking water source.  There are some commercially available lithium mineral waters that advertise a lithium level of 490 μg as Lithium Bicarbonate (LiHCO₃). That is equivalent to 50.3 μg Li (per liter) putting it in the range of both studies.

What does all of this say about the ecology and water chemistry of lithium?  Cleary there is a lot of variability.  Most water sources are not problematic but some with very high levels may be.  Drinking water surveillance appears to be a good approach to reducing exposure to high levels and many municipalities test for uncommon elements and organic compounds. Any attempts to correlate lithium in the water with medical or psychiatric outcomes needs to account for this variability and it is significant.  In the study that used machine learning to predict lithium levels with meteorological and geological variables – the results were modest.  I agree with the opinion that since the long-term effects of Li as a micronutrient are unknown and there is some toxicological concern as evidenced by the HBSL it should be studied (4).

That brings me to the recent study that has been heavily covered in the news (9).  I have received several questions about it and the most common questions are: “Does lithium prevent Alzheimer’s Disease?” and “If it does should I take it.”  I will preface my comments by saying this is a very well-done study.  It is also an intense study that is typical of what is published in both Nature and Science.  There are a mix of experiments using state of the art technology and they are all presented as crowded and very small graphics in the paper.  There is also a supplemental document (in this case 13 pages) of additional graphs and figures). 

The experimental sections of the paper can be broken down into a naturalistic look at a panel of metals concentrations in the brain and blood of subjects with normal cognition versus Alzheimer’s Disease (AD) or mild cognitive impairment, the effect of lithium deficiency in normal and mouse models of AD (3xTg and J20Ag), the effect of lithium on glycogen synthase kinase 3β  (GSK3β), the effect of lithium replacement, the impact of lithium on brain ageing in wild type mice, and determining an optimal form of lithium for replacement. 

The human brain samples depending on the experiment were from groups with no cognitive impairment (NCI)(n=22 - 133), Alzheimer’s Disease (AD)(n=5 - 105), and mild cognitive impairment (MCI)(n=7 - 66).  Brain samples were fractionated to check for metallic ion gradients and 27 ions were investigated.  Only Li showed lower levels in the cortex in both MCI and AD and it was also concentrated in the Aβ plaques.  The authors conclude that this shows a significant problem with Li homeostasis in both MCI and AD.  Some of the sampled ions like lead and arsenic are known neurotoxins.

Results of the experiments in mice are depicted in the diagram below.  3xTg mice are transgenic mice with three mutations (APPswe, PS1M146V, and TauP301L) associated with AD.  As noted, they accumulate amyloid- β protein (Aβ) and tau protein.  The J20Ag mice are transgenic mice that results in overexpression of amyloid precursor protein (APP).  Both mouse lines are considered models of AD.  In all cases lithium deficiency leads to accumulation of amyloid-β protein and other processes (where measured) consistent with AD like neurodegeneration at the behavioral, ultrastructural, and biochemical level. 

The authors demonstrate that lithium supplementation in mice prevents these changes in wild type mice.  They illustrate how blocking GSK3β prevents AD like changes.  They also demonstrate how a lithium compound (lithium orotate) with low solubility prevents lithium form being sequestered in Aβ plaques.  All experiments considered they provide a compelling backdrop for considering lithium as a therapy for MCI and AD.  Are there any other considerations?

First, there have been clinical trials of lithium in a number of neurodegenerative diseases including AD. After some initial isolated enthusiasm for Li in the 1970s and 1980s for Parkinson's, some syndromes associated with Parkinson's (on-off, anergia), and Huntington’s – most of the reported research started in 2009.   Since then, there has been research on AD (10-13), ALS (14-19), MSA (20), MCI (21-23), Niemann Pick Disease (24), Machado Joseph Disease (26-27), and Spinocerebellar Ataxia, Type 2 (28).  In most of these papers the authors cite putative mechanisms of action of lithium based on preclinical trials and some positive pilot studies – but the overwhelming results were negative.  In all cases, the trials were approached from the perspective of using lithium in pharmaceutical ranges except for the trial that states it used microdosing on the range of 300 μg.  Tolerability varied widely among research subjects due to varying diagnoses, but even from study to study using modest doses.

My experience treating people with lithium in all age ranges leads me to a few conclusions that may apply here.  First, I have treated patients with lithium who have been on it for decades and developed AD. I recall one patient in particular who had marked cortical atrophy on brain imaging despite all of those years on lithium and no episodes of toxicity.  That obviously does not rule out lithium as a neuron sparing therapy but it does suggest that it will not work for everybody.  Second, part of the population will not be able to tolerate it or will not want to take it. I am fairly certain that any psychiatrist experienced in prescribing it will have no problems minimizing or preventing side effects.  In most 50-70 year olds that would be lithium carbonate in the range of 150-600 daily.  In the experiments cited above, microdoses of lithium orotate (4.3 μEq/L) for 12-14 months was the dose that prevented brain aging in mice (microgliosis and astrogliosis) and reduced pro-inflammatory cytokines.  That oral dose is roughly 1/1,000 the lowest prescribed pharmaceutical dose.  Third, I am not aware of any cases of lithium toxicity from people drinking groundwater or surface water with high Li concentrations.  The commonest reasons for lithium toxicity in people taking pharmaceutical doses include water and salt imbalances like dehydration, drug-drug interactions, and improper dosing and/or monitoring.   

The question on many minds is “Should I start taking lithium to prevent Alzheimer’s Disease?”  The answer lies in the way the authors frame the discussion section of their paper.  Despite a lot of positive findings they state that “Disruption of Li homeostasis may contribute to the long prodromal period of neuropathological changes that occur prior to the onset of clinical AD.”    And – “Li deficiency is therefore a potential common mechanism for the multisystem degeneration of the brain that leads to the onset of AD”.  It is going to take replication and more work before these findings are widely accepted.  There are still a lot of unknowns about GSK3β signaling.  There have been mistakes made extrapolating from the preclinical studies in mice in the past.  Some of those mistakes were attributed to differences in mouse and human genetics and less heterogeneity in mice.   

That said, I know that will not prevent people from attempts at biohacking and taking supplemental lithium. If you are in that category, you should keep a few things in mind.  First, you have to know about drug dosing and the difference between pharmacological doses and supplemental doses. Lithium at pharmacological doses has a low therapeutic index (toxic dose range to therapeutic dose range) and it can cause kidney, thyroid, and parathyroid problems.  Second, there are many lithium orotate supplements currently available in a wide range of doses (5, 10, 20, 130 mg). They are advertised for "memory, state of mind, and behavioral health". None of these are clinical or FDA approved indications.  Any use of these products has to be considered experimental at this time and I recommend waiting for further data.

In summary, this is an excellent study that synthesizes clinical and preclinical data across a wide array of parameters that I have just touched on here.  If I was a young researcher just starting out, this would be the kind of research team I would be interested in joining.  It was an exciting paper to read.  At the same time it is a good test of how research may or may not be reproducible.  A common misconception about a lack of reproducibility is that it means the researchers did something wrong.  It seems obvious that it can happen just based on the sheer complexity. 

 

George Dawson, MD, DFAPA

Technical Note:

I forgot to add a technical note to the above summary about why the authors chose lithium orotate as the source of their supplement.  They abbreviate it LiO.  All of the details are contained in Extended Data Figure 7.  In that data you will notice that they tested 16 different lithium salts - 8 organic and 8 inorganic for conductivity (µS/cm) (microsiemens per centimeter).  They were concerned about partitioning Li between the plaque and non-plaque fractions and chose the salt with the lowest conductivity.  This degree of precision is important in a tightly controlled experiment - but in the real world the conductivity of tap water can be a significant factor whether it contains lithium or not. 

Supplementary 1:

I am really interested in the mechanism of action of Li and all the links to GSK3β signaling.  I ran out of space in the above post and hope to elaborate on the mechanism soon.

Graphics Credit:

The lead graphic for this post is from reference 3 per the open access CC-BY-NC-ND 4.0 license. The remaining graphic and table were made by me from data in the given references.

 

References:

1:  Shorter E. The history of lithium therapy. Bipolar Disord. 2009 Jun;11 Suppl 2(Suppl 2):4-9. doi: 10.1111/j.1399-5618.2009.00706.x. PMID: 19538681; PMCID: PMC3712976.

2:  Coppen A. 50 years of lithium treatment of mood disorders. Bipolar Disord. 1999 Sep;1(1):3-4. doi: 10.1034/j.1399-5618.1999.10102.x. PMID: 11256652.

3:  Lombard MA, Brown EE, Saftner DM, Arienzo MM, Fuller-Thomson E, Brown CJ, Ayotte JD. Estimating Lithium Concentrations in Groundwater Used as Drinking Water for the Conterminous United States. Environ Sci Technol. 2024 Jan 16;58(2):1255-1264. doi: 10.1021/acs.est.3c03315. Epub 2024 Jan 2. PMID: 38164924; PMCID: PMC10795177.

4:  Sharma N, Westerhoff P, Zeng C. Lithium occurrence in drinking water sources of the United States. Chemosphere. 2022 Oct;305:135458. doi: 10.1016/j.chemosphere.2022.135458. Epub 2022 Jun 23. PMID: 35752313; PMCID: PMC9724211.

5:  Norman JE, Toccalino PL, Morman SA, 2018. Health-Based Screening Levels for evaluating water-quality data (2d ed.). U.S. Geological Survey web page, accessible at https://water.usgs.gov/water-resources/hbsl/, doi:10.5066/F71C1TWP

6:  Seidel U, Jans K, Hommen N, Ipharraguerre IR, Lüersen K, Birringer M, Rimbach G. Lithium Content of 160 Beverages and Its Impact on Lithium Status in Drosophila melanogaster. Foods. 2020 Jun 17;9(6):795. doi: 10.3390/foods9060795. PMID: 32560287; PMCID: PMC7353479.

7:  El-Mallakh RS, Roberts RJ. Lithiated lemon-lime sodas. Am J Psychiatry. 2007 Nov;164(11):1662. doi: 10.1176/appi.ajp.2007.07081255. PMID: 17974929.

8:  Neves MO, Marques J, Eggenkamp HGM. Lithium in Portuguese Bottled Natural Mineral Waters-Potential for Health Benefits? Int J Environ Res Public Health. 2020 Nov 12;17(22):8369. doi: 10.3390/ijerph17228369. PMID: 33198207; PMCID: PMC7696288.

One of the most popular soft drinks in the world was launched in 1929; the “Lithiated Lemon Soda” that was supplemented with 5 mg Li (as Li citrate/L) until 1948 [16], when it was banned by the government. It was believed to cure alcohol-induced hangover symptoms, make people more energetic and give lust for life and on the top of that shinier hair and brighter eyes [17]. In fact, it is still on the market but since 1936 its name changed to 7UP. In 1949, John Cade discovered that higher Li concentrations were toxic. Nowadays, according Seidel et al. [16] 7UP only contains 1.4 µg Li/L.

9:  Aron L, Ngian ZK, Qiu C, Choi J, Liang M, Drake DM, Hamplova SE, Lacey EK, Roche P, Yuan M, Hazaveh SS, Lee EA, Bennett DA, Yankner BA. Lithium deficiency and the onset of Alzheimer's disease. Nature. 2025 Aug 6. doi: 10.1038/s41586-025-09335-x. Open Access.

The paper suggests that Li may be a critical micronutrient in terms of brain function.

AD: 

10:  Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease. Curr Alzheimer Res. 2013 Jan;10(1):104-7. doi: 10.2174/1567205011310010014. PMID: 22746245.

As lithium is highly toxic in regular doses, our group evaluated the effect of a microdose of 300 μg, administered once daily on AD patients for 15 months

11:  Hampel H, Ewers M, Bürger K, Annas P, Mörtberg A, Bogstedt A, Frölich L, Schröder J, Schönknecht P, Riepe MW, Kraft I, Gasser T, Leyhe T, Möller HJ, Kurz A, Basun H. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry. 2009 Jun;70(6):922-31. PMID: 19573486.

“The current results do not support the notion that lithium treatment may lead to reduced hyperphosphorylation of tau protein after a short 10-week treatment in the Alzheimer's disease target population.”

12:  Macdonald A, Briggs K, Poppe M, Higgins A, Velayudhan L, Lovestone S. A feasibility and tolerability study of lithium in Alzheimer's disease. Int J Geriatr Psychiatry. 2008 Jul;23(7):704-11. doi: 10.1002/gps.1964. PMID: 18181229.

“Lithium treatment in elderly people with AD has relatively few side effects and those that were apparently due to treatment were mild and reversible. Nonetheless discontinuation rates are high. The use of lithium as a potential disease modification therapy in AD should be explored further but is not without problems.”

13:  Leyhe T, Eschweiler GW, Stransky E, Gasser T, Annas P, Basun H, Laske C. Increase of BDNF serum concentration in lithium treated patients with early Alzheimer's disease. J Alzheimers Dis. 2009;16(3):649-56. doi: 10.3233/JAD-2009-1004. PMID: 19276559.

“We assessed the influence of a lithium treatment on BDNF serum concentration in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. In AD patients treated with lithium, a significant increase of BDNF serum levels, and additionally a significant decrease of ADAS-Cog sum scores in comparison to placebo-treated patients, were found.”

ALS:

14:  Boll MC, Alcaraz-Zubeldia M, Rios C, González-Esquivel D, Montes S. A phase 2, double-blind, placebo-controlled trial of a valproate/lithium combination in ALS patients. Neurologia (Engl Ed). 2025 Jan-Feb;40(1):32-40. doi: 10.1016/j.nrleng.2022.07.003. Epub 2022 Aug 29. PMID: 36049647.

15:  UKMND-LiCALS Study Group; Morrison KE, Dhariwal S, Hornabrook R, et al. Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2013 Apr;12(4):339-45. doi: 10.1016/S1474-4422(13)70037-1. Epub 2013 Feb 27. Erratum in: Lancet Neurol. 2013 Sep;12(9):846. PMID: 23453347; PMCID: PMC3610091.

16:  Verstraete E, Veldink JH, Huisman MH, Draak T, Uijtendaal EV, van der Kooi AJ, Schelhaas HJ, de Visser M, van der Tweel I, van den Berg LH. Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial. J Neurol Neurosurg Psychiatry. 2012 May;83(5):557-64. doi: 10.1136/jnnp-2011-302021. Epub 2012 Feb 29. PMID: 22378918.

17:  Miller RG, Moore DH, Forshew DA, Katz JS, Barohn RJ, Valan M, Bromberg MB, Goslin KL, Graves MC, McCluskey LF, McVey AL, Mozaffar T, Florence JM, Pestronk A, Ross M, Simpson EP, Appel SH; WALS Study Group. Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. Neurology. 2011 Sep 6;77(10):973-9. doi: 10.1212/WNL.0b013e31822dc7a5. Epub 2011 Aug 3. PMID: 21813790; PMCID: PMC3171956.

18:  Chiò A, Borghero G, Calvo A, Capasso M, Caponnetto C, Corbo M, Giannini F, Logroscino G, Mandrioli J, Marcello N, Mazzini L, Moglia C, Monsurrò MR, Mora G, Patti F, Perini M, Pietrini V, Pisano F, Pupillo E, Sabatelli M, Salvi F, Silani V, Simone IL, Sorarù G, Tola MR, Volanti P, Beghi E; LITALS Study Group. Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial. Neurology. 2010 Aug 17;75(7):619-25. doi: 10.1212/WNL.0b013e3181ed9e7c. Epub 2010 Aug 11. PMID: 20702794.

“Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS.”

19:  Aggarwal SP, Zinman L, Simpson E, McKinley J, Jackson KE, Pinto H, Kaufman P, Conwit RA, Schoenfeld D, Shefner J, Cudkowicz M; Northeast and Canadian Amyotrophic Lateral Sclerosis consortia. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010 May;9(5):481-8. doi: 10.1016/S1474-4422(10)70068-5. Epub 2010 Apr 1. PMID: 20363190; PMCID: PMC3071495.

Multiple System Atrophy (MSA)

20:  Saccà F, Marsili A, Quarantelli M, Brescia Morra V, Brunetti A, Carbone R, Pane C, Puorro G, Russo CV, Salvatore E, Tucci T, De Michele G, Filla A. A randomized clinical trial of lithium in multiple system atrophy. J Neurol. 2013 Feb;260(2):458-61. doi: 10.1007/s00415-012-6655-7. Epub 2012 Aug 30. PMID: 22932748.

MCI: 

21:  Damiano RF, Loureiro JC, Pais MV, Pereira RF, Corradi MM, Di Santi T, Bezerra GAM, Radanovic M, Talib LL, Forlenza OV. Revisiting global cognitive and functional state 13 years after a clinical trial of lithium for mild cognitive impairment. Braz J Psychiatry. 2023 Mar 11;45(1):46-49. doi: 10.47626/1516-4446-2022-2767. PMID: 36049127; PMCID: PMC9976922.

22:  Forlenza OV, Radanovic M, Talib LL, Gattaz WF. Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial. Br J Psychiatry. 2019 Nov;215(5):668-674. doi: 10.1192/bjp.2019.76. PMID: 30947755.

23:  Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011 May;198(5):351-6. doi: 10.1192/bjp.bp.110.080044. PMID: 21525519.

Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P = 0.03) and better performance on the cognitive subscale of the Alzheimer's Disease Assessment.

Niemann Pick Disease:

24:  Han S, Zhang H, Yi M, Liu X, Maegawa GHB, Zou Y, Wang Q, Wu D, Ye Z. Potential Disease-Modifying Effects of Lithium Carbonate in Niemann-Pick Disease, Type C1. Front Pharmacol. 2021 Jun 9;12:667361. doi: 10.3389/fphar.2021.667361. PMID: 34177581; PMCID: PMC8220070.

MS:

25:  Rinker JR 2nd, Meador WR, King P. Randomized feasibility trial to assess tolerance and clinical effects of lithium in progressive multiple sclerosis. Heliyon. 2020 Jul 28;6(7):e04528. doi: 10.1016/j.heliyon.2020.e04528. PMID: 32760832; PMCID: PMC7393418.

Machado Joseph Disease:

26:  Saute JA, Rieder CR, Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis KC, D'Ávila R, Souza GN, Russo AD, Furtado GV, Gheno TC, Souza DO, Saraiva-Pereira ML, Portela LV, Camey S, Torman VB, Jardim LB. Planning future clinical trials in Machado Joseph disease: Lessons from a phase 2 trial. J Neurol Sci. 2015 Nov 15;358(1-2):72-6. doi: 10.1016/j.jns.2015.08.019. Epub 2015 Aug 14. PMID: 26297649.

27:  Saute JA, de Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis KC, D'Ávila R, Souza GN, Russo AD, Furtado GV, Gheno TC, de Souza DO, Portela LV, Saraiva-Pereira ML, Camey SA, Torman VB, de Mello Rieder CR, Jardim LB. A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease. Mov Disord. 2014 Apr;29(4):568-73. doi: 10.1002/mds.25803. Epub 2014 Jan 7. PMID: 24399647.

Spinocerebellar Ataxia Type 2:

28:  Saccà F, Puorro G, Brunetti A, Capasso G, Cervo A, Cocozza S, de Leva M, Marsili A, Pane C, Quarantelli M, Russo CV, Trepiccione F, De Michele G, Filla A, Morra VB. A randomized controlled pilot trial of lithium in spinocerebellar ataxia type 2. J Neurol. 2015 Jan;262(1):149-53. doi: 10.1007/s00415-014-7551-0. Epub 2014 Oct 28. PMID: 25346067.

Huntington’s Disease:

29:  Aminoff MJ, Marshall J. Treatment of Huntington's chorea with lithium carbonate. A double-blind trial. Lancet. 1974 Jan 26;1(7848):107-9. doi: 10.1016/s0140-6736(74)92339-3. PMID: 4130308.

Lithium for Depression.....

I bought a copy of Manic Depressive Illness when it first came out in 1990.  One of the more interesting aspects of the book was the commentary on the use of lithium monotherapy for unipolar depression.  That discussion is limited to about three pages and reviewed the work to date.  In the opening paragraph there is this astonishing line:  "Overall, the result of open studies suggest that lithium is as effective in preventing unipolar illness as it is in preventing bipolar illness."  At the time there were 4 controlled studies (3-6) looking at the issue of maintenance therapy in mixed unipolar and bipolar groups.  Three of the four studies showed no difference between groups.  The fourth study was inconlusive due to a high dropout rate.  Subsequent analyses by Schou and Baldessarini and Tohen concluded that the protective effects of lithium in preventing recurrent depressive episodes was good.  In Schou's reanalysis he showed that the relapse rate in one year on lithium for unipolar depression was 22% (compared with a 20% relapse rate for bipolar disorder) and the rates for antidepressants at one year were 35% for unipolar depression and 65% for bipolar disorder (relative to placebo of 67-68% relapse rate).

Since that early open research there has been only randomized controlled clinical trial (RCT) of lithium versus placebo antidepressant augmentation (7).  In that study 7/15 patients treated with placebo relapsed and one suicided.  In the lithium treated group 0/14 relapsed.  The authors recommended that patients who respond to lithium augmentation be maintained on it for at least 6 months.  Additional clinical parameters of interest in the treated group was an average lithium dose of 980 mg, an average Li level of 0.65 mmol/L, and a response time of 17.5 days in acute treatment.  This is interesting because many psychiatrists using lithium augmentation were taught to stop at 600 mg/day and accept the associated lower levels.

My point in the introductory paragraph here is that it has been known for some time that lithium may have a role in maintenance of unipolar depression in addition to bipolar depression - even though it is hardly ever used that way int he United States.  In the US, patients typically endure a long series of antidepressant trials or augmentation strategies if the initial trails are ineffective.  There is always the problems of whether the antidepressant has lost its effect or not and the associated difficulty of trying to determine what other factors may be operative.  Lithium has been used for the past three decades as an augmenting agent - added to antidepressants.  Typically a lower dose is used (600 mg/day) and that may offer a lower chance of toxicity and less need for monitoring blood levels.

Against this backdrop, a very interesting paper by Tiihonen, et al came out last year (2). For reasons that will follow, I consider this to be one of the most important papers for clinical psychiatrists from 2017.  The authors provide a sound rationale for their study, specifically the advantages of a large scale epidemiological/observational study over an RCT or the Cochrane meta-analysis of RCTs.  That meta-analysis (like most Cochrane meta-analyses) concluded that the number of subjects included was too small to come to a statistically significant conclusion.

The study was conducted in Finland.  The authors point out that each citizen has a unique identifier that facilitates the design of large inclusive observational studies across health care databases.  The sample in this case was a study cohort (N= 123,712) of patients who had been admitted to a hospital for unipolar depression between January 1, 1987 and December 31, 2012.  They had a comparison incident cohort (N=30004) that looked at new patients beginning on December 31, 1996 with no mental health diagnosis, hospital admissions for depression, exposure to the medications of interest, or history of outpatient care in the year prior to the start.  The purpose of the incident cohort was to look at the issue of survival bias. The primary outcome measure was risk of readmission in all patients admitted  for unipolar depression at least once between 1987 and 2012.  All cause admissions were a secondary outcome measure.  Medication use was estimated using the PRE2DUP mathematical modelling of the patient medication purchasing.  Each patient was used as their own control to eliminate selection bias.  I did not have access to the appendices from this study, so I will forgo further discussion of the statistical methodology without that data.

Mean hospitalizations for people who had used lithium was 4.3 (SD 6.9) for psychiatric admission and 7.8 (SD 9.1) for all cause admissions compared to 2.2(SD 3.1) and 5.8(SD 7.0) for those who had not indicating the lithium treated patient were more severely ill.  Using lithium significantly decreased the relapse risk.  Mean daily lithium dose was noted to be 765 mg.  Forest plots are contained in the body of the article looking at the hazard rations of readmission for several pharmacological treatments in both the study cohort and the incident cohort.  Forest plots looked at benzodiazepines, hypnotics, antipsychotics, and lithium +/- antidepressants.

Lithium monotherapy was superior to all other studied pharmacotherapies in preventing hospital readmissions.  Older antidepressants (amitriptyline and doxepin) and antipsychotics (clozapine sulpride, aripiprazole, and quetiapine) showed some efficacy in preventing hosptializations.  Benzodiazepines did not.  In the incident cohort where (survival bias was eliminated) the lithium effect on decreased rehospitalizations was more robust suggesting the effect size was more valid than for the total cohort.  They also did a secondary mortality assessment and showed that both lithium and antidepressants were associated with decreased overall mortality and no difference was observed for antipsychotics.

The authors recognize that there are significant adverse effects and limitations with the use of lithium.  They point out there are also possible advantages outside the treatment of mood disorders but there is a significant burden associated with taking it.  They recommend that is be considered for maintenance of a broader group of patients with unipolar depression.  In our antidepressant-centric society, I agree with their conclusion.  The effects in this study really cannot be ignored.  Lithium augmentation of antidepressants has been around for over 30 years.  It surfaced again the the STAR*D protocol.  I see patients who have been exclusively been treated by other physicians or prescribers and in the past 8 years I have seen exactly 1 patient with unipolar depression who was being treated with lithium augmentation.  It is far more common to see patient taking 2-4 antidepressants (typically SSRI + bupropion + trazodone or mirtazapine) or an antidepressant plus lamotrigine as the augmentation strategy.  A similar study with a cohort of American patients would be very useful to look at questions about the efficacy of lithium versus the antidepressant polypharmacy or lamotrigine - but my concern would be that there would not be a large enough sample of patients taking lithium.

It may be up to clinicians who are used to lithium therapy and the application to unipolar depression to reintroduce the practice and collect data on what the outcomes are relative to standard antidepressant augmentation strategies. Overall this study from a group of pharmacoepidemiologists provides compelling data to take a second look at an old strategy instead of just adding more antidepressants.  The data looks so good, lithium is so inexpensive, and in the USA we are in an absolute vacuum of lithium non-use for unipolar depression.   Inpatient treatment for depression has become so atrocious that it has never been more important to help people stay out of the hospital. That is why I considered this to be an important paper. 


George Dawson, MD, DFAPA

       

References:

1:   Goodwin, FK, Jamison, KR. Manic-depressive illness. New York: Oxford University Press, 1990: pp.693-696.

2: Tiihonen J, Tanskanen A, Hoti F, Vattulainen P, Taipale H, Mehtälä J,Lähteenvuo M. Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. Lancet Psychiatry. 2017 Jul;4(7):547-553. doi: 10.1016/S2215-0366(17)30134-7. Epub 2017 Jun 1. PubMed PMID: 28578901.

3: Prien RF, Klett CJ, Caffey EM Jr. Lithium carbonate and imipramine inprevention of affective episodes. A comparison in recurrent affective illness. Arch Gen Psychiatry. 1973 Sep;29(3):420-5. PubMed PMID: 4579507.

4: Prien RF, Caffey EM Jr, Klett CJ. Prophylactic efficacy of lithium carbonate in manic-depressive illness. Report of the Veterans Administration and National Institute of Mental Health collaborative study group. Arch Gen Psychiatry. 1973 Mar;28(3):337-41. PubMed PMID: 4569674.

5: Coppen A, Noguera R, Bailey J, Burns BH, Swani MS, Hare EH, Gardner R, MaggsR. Prophylactic lithium in affective disorders. Controlled trial. Lancet. 1971 Aug 7;2(7719):275-9. PubMed PMID: 4104974.

6: Baastrup PC, Poulsen JC, Schou M, Thomsen K, Amdisen A. Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders. Lancet. 1970 Aug 15;2(7668):326-30. PubMed PMID: 4194439.

7: Bauer M, Bschor T, Kunz D, Berghöfer A, Ströhle A, Müller-Oerlinghausen B.Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry. 2000 Sep;157(9):1429-35. PubMed PMID: 10964859.


Supplementary:

Figure 1 above is directly from reference 2 with permission from Elsevier.  Licensing agreement #4270040486127.

If Your Patient Really Needs Lithium.......

I had the good fortune to work in an intense medical setting for about 22 years where I was responsible for the medical care of my patients.  In that setting I had access to excellent specialists, in fact some of the finest physicians I have seen anywhere.  They were typically involved when I had identified a medical problem that potentially complicated the psychiatric care of my patients.  In those cases - no matter what the problem was it usually came down to the question: "If your patient really needs this medication we need to continue it."  One of the most significant complications was renal failure of varying degrees while taking lithium.  Some patients on my unit were hospitalized because they had been stable on lithium but were developing renal failure and needed to be tried on another agent.  In some cases they experienced severe associated complications including delirium either from the bipolar disorder or medications used in the transition.  In some cases, they needed dialysis and renal medicine consultants would advise me on the lithium dose to try while they were receiving hemodialysis.  All of this experience led me to have a very low threshold for recognizing and acting on potential adverse effects of lithium as early as possible. 

At various points in my career, there was a question of renal failure occurred in cohorts on lithium or it was due to a different cause.  As an example, the Lithium Encyclopedia from 1983 (1) stated concisely: "There have been a growing number of reports of morphological and functional kidney damage associated with lithium use.  The actual incidence of lithium nephrotoxicity is not known.  Most researchers believe that irreversible damage is not widespread but that risk increases with length of treatment and serum lithium level."

At the time there were opinions that up to 20% of patients on long term lithium maintenance had morphological changes and functional changes primarily with water absorption but no reduced glomerular filtration rate (GFR) or renal insufficiency.  My favorite renal and electrolyte disorders text cited lithium as a compound that caused vasopressin resistant nephrogenic diabetes insipidus (NDI) (2).  More recent evidence suggests that 15-20% of patients on lithium develop a progressive decrease in GFR typically does not progress to end stage renal disease (ESRD) and dialysis but in some cases it clearly does.  These generalizations are usually based on low numbers of patients who have been identified as having a specific creatinine or GFR.  A creatinine of 2.5 mg/dl predicted progression to ESRD in most patients.  A larger study in Sweden of 3369 patients, suggested a lower threshold. In that study,  13 patients had been off lithium for 2 years before starting dialysis and 11 had a creatinine of > 1.4.  Some were lower but there had been a progressive increase from baseline suggesting the rate of change is important.  Additional factors such as the use of NSAIDS and ACE inhibitors like lisinopril as well as other intrinsic kidney diseases can be a factor.

There have been a recent increase in studies that look at the side effects of lithium and in one case (6) compare lithium side effects to other typical mood stabilizers (valproate, olanzapine, questiapine).  One of the studies uses descriptive statistics and the other two involve calculations of hazard ratios for specific risks.  The results are fairly uniform in their conclusions and have been known in most psychiatry training programs for the past 10-20 years.  The articles here use the Kidney Disease Outcomes Quality Initiative (KDOQI) staging of chronic kidney disease published in 2002.   The range is from stage 1 (eGFR ≥ 90 ml/min/1.73 m² ) to stage 5 (eGFR < 15 ml/min/1.73 m² or dialysis).  For the purpose of these papers Stage 2 is an eGFR of 60-89 and Stage 3 is 30-59. As previously noted progression can occur in some cases even years after the lithium has been stopped.

The most interesting of the three papers is probably from Hayes, et al because of their strategy to look at lithium toxicity but in the context of other commonly used mood stabilizers (valproate, olanzapine, quetiapine) and the associated toxicities of these other mood stabilizers.  As a result they have a table entitled Table 2. Adverse effects during maintenance treatment that looks at these mood stabilizers and CKD (stage 3 and 4), hypothyroidism, hyperthyroidism, hypercalcemia, Type 2 diabetes mellitus, cardiovascular disease, hypertension, hepatotoxicity, and weight gain (greater than 7% and greater than 15%).  Hazard ratios care calculated for all of these adverse effects using lithium as the reference.  The number of events in each category is relatively low compared with the total events in a large clinical sample.  The adverse events described were expected.  They estimated the rate of severe CKD (stage 4 or 5) as 1 in 100 person years at risk.  The estimated rates of stage 3 and stage 4 CKD were 9 in 100 per years at risk.  Hepatotoxicity was rare in the sample and was elevated in the quetiapine group.  Weight gain was most significant for olanzapine, quetiapine, and valproate relative to lithium.  Olanzapine also had the highest rate of new onset hypertension.

None of this information deters me from offering lithium to people who I think are good candidates.  The rationale is that lithium can be a life changing medication, especially for people who have generally never achieved mood stabilization with all of the typical medications prescribed for mood disorders these days.  Informed consent should include this potential complication.  I generally advise people that there is a 40% risk of NDI of varying severity, the need for ongoing testing, the need to avoid additional medications that may complicate the use of lithium, and finally close self monitoring of both side effects and any situation that can complicate lithium therapy like conditions leading to dehydration.  I will add the risk of mild CKD and explain to the patient what that means.

One of the interesting aspects of these articles is that ongoing screening for patients on lithium therapy varies considerably from setting to setting.  National guidelines seem to help.  In these large scale studies there is not enough discussion of work at the clinical level incorporating the red flags from the research.  For example it is obviously important to know about new medications, especially ACEIs, NSAIDs, and serotonergic medications.  Medications that may complicate interpretation of lab finding like Vitamin D and Calcium supplementation in the case of hypercalcemia are also important.  The review of systems is also important anywhere along the spectrum of side effects including neurological, cognitive, gastrointestinal, and renal symptoms.  I generally advise patients that increasing nocturia, polyuria, and polydipsia with associated laboratory finding increases the risk of irreversible renal changes including a low risk of progression to ESRD.  The presence of edema may indicate the rare onset of a nephrotic syndrome that can occur is some people with acute treatment.

The good news is that even now there is an accumulating literature on the potential complications of lithium therapy and some general ideas about what psychiatrists should do about it.  Although the methodology of these studies varies significantly they generally come to similar conclusions about the effect of lithium on renal function, thyroid function, and calcium metabolism.  All of these systems require close monitoring by assessing the patients clinical status and lab testing.  Numerous changes in clinical status should result in departures from any monitoring routine.  The critical elements is communication with the patient and education about when the psychiatrist should be contacted.
   

George Dawson, MD, DFAPA 


References:

1:  Jefferson JW, Greist JH, Ackerman DL.  Lithium Encyclopedia for Clinical Practice.  American Psychiatric Press, Inc. 1983: p151.  

2:  Schrier RW (ed).  Renal and Electrolyte Disorders, 2nd Ed.  Little, Brown and Company, Inc.  Boston 1980: p. 31.

3:  Lerma VE.  Renal toxicity of lithium. In UpToDate.  Sterns RH, Sheridan AM (eds) (Accessed on January 2, 2018).

4: Bendz H, Schön S, Attman PO, Aurell M. Renal failure occurs in chronic lithiumtreatment but is uncommon. Kidney Int. 2010 Feb;77(3):219-24. doi: 10.1038/ki.2009.433. Epub 2009 Nov 25. PubMed PMID: 19940841. (see open access text).

5:  Dineen R,  Bogdanet D,  Thompson D, Thompson CJ,  Behan LA,  McKay AP, Boran G,  Wall C, Gibney J, O’Keane VO, Sherlock M.   Endocrinopathies and renal outcomes in lithium therapy: impact of lithium toxicity.  QJM: An International Journal of Medicine, Volume 110, Issue 12, 1 December 2017, Pages 821–827, https://doi.org/10.1093/qjmed/hcx171

6: Hayes JF, Marston L, Walters K, Geddes JR, King M, Osborn DP. Adverse Renal, Endocrine, Hepatic, and Metabolic Events during Maintenance Mood Stabilizer Treatment for Bipolar Disorder: A Population-Based Cohort Study. PLoS Med. 2016 Aug 2;13(8):e1002058. doi: 10.1371/journal.pmed.1002058. eCollection 2016 Aug. PubMed PMID: 27483368.

7: Shine B, McKnight RF, Leaver L, Geddes JR. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet. 2015 Aug 1;386(9992):461-8. doi: 10.1016/S0140-6736(14)61842-0. Epub 2015 May 20. PubMed PMID: 26003379.
    

Lithium and Pregnancy - The Latest From the NEJM

Lithium and pregnancy have always been a major concern for psychiatrists, obstetricians, and of course women who need to take the medication for mood stabilization.  In the Lithium Encyclopedia (published in 1983) - there is a chapter on the physiological effects of pregnancy and how that potentially affects lithium balance and a separate chapter on teratogenesis.  That chapter describes the Lithium Baby Registry that was established in 1970 to collect information on the effects of lithium in pregnancy.  In the first 10 years, 225 infants exposed to lithium were described and 25 had congenital malformations.  Of these births 18/25 had cardiovascular abnormalities including Ebstein's anomaly, 7 were stillborn, 2 had Down's syndrome and 1 had intracerebral toxoplasmosis.  The results suggested that lithium was a cardiovascular teratogen, but there was a question of reporting bias.  That is, results consistent with the study concern about lithium being a teratogen were more likely to be reported than normal births.  

Those references set the knowledge about lithium and  pregnancy for all residents trained in my era in the late 1980s.  The standard question by attendings and on examinations was: "What is the cardiac anomaly associated with intrauterine exposure to lithium?".  The answer was Ebstein's anomaly.  The follow up question was expected: "And what is Ebstein's anomaly?"  In those days the short answer was downward displacement of the tricuspid valve into the right ventricle.  Today Ebstein anomaly (no longer a possessive) is described in greater detail. A modern reference describes the extension of the tricupsid valve into the right atrium to the extent that most of the functional chamber chamber is collapse to a very small volume.  In some cases it is collapsed to the right ventricular outflow tract.  The downward valve displacement is due to a number of morphological abnormalities in the tricuspid valve.  The myocardium is also abnormal because the valve tissue has failed to completely separate from the myocardium during fetal development - a process called delamination.  That is associated with a thin and poorly contractile myocardium and poor right ventricle performance. There are several associated cardiac abnormalities including ventricular septal defect, patent foramen ovale, patent ductus arterious, and accessory conduction pathways that can lead to arrhythmias.  The associated clinical syndromes of cyanosis, congestive heart failure and arrhythmia can occur in infancy to adulthood depending on the degree of anatomical disruption.  The complications can be fatal at any age (2).

Ebstein abnormality is a preventable complication and one that must be avoided.  In real life that is easier to say than do.  In a controlled hospital or clinic environment it is a very straightforward process to take a history and determine the obstetric history and last menstrual period.  Urine and serum pregnancy tests can be done for confirmation.  The best advice to physicians in this situation is to treat very woman of childbearing age as if they were pregnant until proven otherwise.  In my experience life is less regimented.  There are lapses in contraception and planning that lead to pregnancies in women taking lithium who know that exposure to the infant is an avoidable risk.  Many of these women are on lithium maintenance.  Since lithium remains a mainstay of treatment for bipolar disorder and may be a superior agent in postpartum psychosis - the question of teratogenicity remains an important one.

There have been a number of estimates of congenital malformations due to psychiatric medications and I recently reviewed a few of them and cited extensive database references.  In one of the reviews very large databases were examined looking for major congenital malformations to lithium exposed women especially Ebstein anomaly.

The New England Journal of Medicine published another large retrospective database study of the question of lithium exposure in pregnancy and risk of cardiac malformations.  Their database involve a Medicaid cohort of 1,325,563 pregnancies over the ten year period between 2000 and 2010.  In this cohort there were cardiac malformations noted in 16 of 663 (2.4%) lithium exposed infants.  Lower rates of cardiac malformations were noted in nonexposed infants (1.15%) and lamotrigine exposed infants (1.39%).  In addition there appeared to be a dose related effect with increasing risk ratio noted with increasing doses of lithium.  For example at the dose of 600 mg or less/day the risk ratio was 1.11 but the risk ratio increased to 1.11 and 3.22 for doses of 601-900 mg/day and greater than 900 mg respectively.

The authors have a detailed report on how the cardiac malformations were determined.  They make an interesting point that a misclassification bias can occur with Ebstein anomaly.  Some clinicians may make the diagnosis of right ventricular outflow tract obstruction defects or Ebstein anomaly based on whether or not there has been a history of exposure to lithium.  That may make it more likely to misclassify Ebstein anomaly.  They provide data for the total prevalence of all cardiac malformations and cardiac malformations classified as right ventricular outflow obstruction.  They were focused on "major cardiac defects that were likely to be consequential for the infant."  The diagnostic codes had to be listed several times or associated with surgery.

The calculated prevalence of Ebstein abnormality in unexposed pregnancies was 7 cases per 100,000 live births.  They did not provide the prevalence of Ebstein anomaly in the lithium exposed due to the low number.  After a detailed analysis and analysis of possible sources of error like terminate pregnancies where lithium exposure occurred the authors conclude that lithium had a modest effect in terms of increased risk of cardiac malformations.  Their final estimate was an increased risk of 1 additional case per 100 live births if the exposure occurred early in the pregnancy.  They describe this as a modest increase in risk of cardiac malformations due to lithium.  The difference in the ratio of cardiac malformations in this study (16/663) compared with the Lithium Baby Registry (18/225) is probably due to a more rigorous methodology.

The authors looked at five sources of error in their final discussion of the results.  For clinical psychiatrists the most relevant point was that other factors affecting treatment decisions in pregnancy were not investigated.  They are considerable given that it is highly likely that the women being treated with lithium have severe mood disorders and suicide in the postpartum period in the number one cause of death.  This study can best be viewed as a study that supports current clinical practice to avoid first trimester exposure to lithium by careful screening and then planning if additional adjustments need to be made for planned pregnancies based on the trimester.  In those cases of accidental exposure, consultation with high risk obstetrics and a decision based on a detailed discussion with the patient is usually the preferred option.                 




George Dawson, MD, DFAPA




References:

1.  Jefferson JW, Greist JH, Ackerman DL. Lithium Encyclopedia for Clinical Practice.  Washington, DC; American Psychiatric Press, Inc., 1983: 264-265.

2.  Connolly HM, Qureshi, MY.  Clinical manifestations and diagnosis of Ebstein anomaly. In UpToDate,  Greutmann M, Fulton DR, Yeon SB (Accessed on June 9, 2017).

3.  Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H, Cohen LS, Hernandez-Diaz S. Lithium Use in Pregnancy and the Risk of Cardiac Malformations. N Engl J Med. 2017 Jun 8;376(23):2245-2254. doi: 10.1056/NEJMoa1612222.

Mechanism Of Action Of Lithium - A Brief History

As a chemistry major and a psychiatrist Lithium has a special place in my consciousness.  During the years that I took organic chemistry lithium aluminum hydride was a favorite reducing agent when creating certain organic syntheses.  Most chemistry majors remember metallic lithium as one of those highly reactive metals that was packed under oil to prevent contact with water or even moisture in the air.  Lithium's reactivity is why the free metal does not exist in nature.  The most common form used as a medication is lithium carbonate in various preparations.

There has been a lot of speculation about the mechanism of action of lithium since its discovery.  Early in my career the definitive source of information for all things lithium-related was the Lithium Information Center at the University of Wisconsin Department of Psychiatry.  It was possible to call them and ask them anything about lithium and get the relevant references sent to you.  They also produced the Lithium Encyclopedia for Clinical Practice.  The mechanism of action was described as unknown at the time but ongoing research was cited (p. 7) in "ion substitution with subsequent effects on amine metabolism, membrane transport, glucose metabolism, and neurotransmitter synthesis and degradation."  An entire chapter was dedicated to mechanism of action.  In that chapter, the review of what was known about the mechanism of action at the time is interesting.  The major neurotransmitter systems being studied at the time were catecholamines, serotonin, and acetylcholine.  Animal studies showed acute changes on norepinephrine turnover that was only slight to non-existent with chronic use.  Results on serotonin turnover were conflicting, but it prevented hyperaggressive behavior resulting from a serotonin depleting compound that blocked tryptophan hydroxylase (parachlorophenylalanine).  Acute administration did not alter dopamine turnover.  Chronic administration resulted in increased turnover in mesolimbic and striatal areas but not the cortex.  These observations led to theories that lithium worked by altering post synaptic receptor sensitivity including decreased beta adrenoreceptor effects, stabilized opioid receptors, and preventing dopamine receptor hypersensitivity.

There was some speculation about endocrine mechanisms since it was known that lithium blocks release of thyroid hormone (T4).  It was also believed to reduce testosterone levels as a possible role in the anti-aggressive properties of the medication.  Studies at the time showed that in patients treated for aggression and closely followed, they had increased levels of luteinizing hormone but normal testosterone levels.  A significant theory at the time was that lithium worked by reducing T4 levels and this reduced beta-adrenoreceptor potentiation in mood disorders.  Lithium was also thought  to possibly work by the effect it had on the intracellular concentration of other ions like sodium, calcium, potassium, and magnesium in neurons. The 1980s was a decade when research interest on cell signalling was becoming more widespread after Sutherland's Nobel Prize for the discovery of cyclic AMP (cAMP).  Lithium was noted to inhibit adenylate cyclase the enzyme that produces cAMP.  Specific forms linked to beta-adrenoreceptors and prostaglandin-E1 were noted to be blocked leading to speculation that these mechanisms were related to mania.  

Another definitive source of drug mechanisms over the same era was The Biochemical Basis of Neuropharmacology.  My collection of these texts starts in 1984 with the fourth edition of that text.  There was a single paragraph on the action of lithium and its effect on catecholamines.  They used the term facilitated recapture mechanism (2) suggesting that the overall block  of stimulus related norepinephrine (NE) release may be due to facilitated uptake of NE.  They also point out the difference in acute and chronic effects with supersensitive NE responses with chronic administration.  By the fifth edition of this text (3), the speculative mechanisms had expanded to include inhibiting inositol-1-phosphatase in the phosphoinositide pathway (p. 114), the same NE mechanism as the previous edition (p. 306), and a new observation that lithium facilitates tryptophan uptake initially but with chronic administration tryptophan production normalizes despite increased uptake due to decreased enzymatic conversion to serotonin (5HT).  Shifting the balance between synthesis and uptake was suggested as a more stable mechanism.  By the seventh edition, lithium was back to being mentioned on single page  as part of the larger discussion of deficits in the catecholamine hypothesis of mood disorders - a theme the authors started in the fourth edition.  By the eighth and final version of this text there was no mention of lithium at all.  Two of the authors were involved in a successive text called Introduction to Neuropsychopharmacology (5).  That text describes lithium as "one of the major achievements of psychopharmacology of the past 50 years (p. 321).  The authors acknowledge that the mechanism of action remained unclear but the theories included inhibition of inositol monophosphatase, inhibition of glycogen synthase kinase-β, and modulating g protein function (p. 321).

Another excellent source of the evolution of lithium theory was the American College of Neuropsychopharmacology's (ACNP) Generation of Progress series.  The series has been discontinued.  I have the third to the fifth editions and the most substantial section on lithium action was in the Fifth Generation of Progress (6).  This chapter begins with an overview of the time course of mood stabilizer action and how the focus had changed over the previous 20 years from changes in neurotransmitter release and regulation to changes in cell signalling and morphological changes consistent with "altered signalling in critical regions of the brain."  The chapter is an overview of the complex effects of lithium on ion transport, neurotransmitter release, signal transduction, circadian rhythm, gene expression, and neuroplasticity.  The data showing that lithium and in some cases valproate and carbamazepine can regulate gene expression via transcription factors is reviewed.  Some of the changes produced a neuroprotective effect against a number of factors and at about that time neuroprotection was considered a potential positive effect form both mood stabilizer and antidepressants.  It was very interesting to reread the section on neuroplasticity.  Lithium was known to be an inhibitor of glycogen synthase kinase-3 beta (GSK-3β).  This molecule is a component of the wnt signalling pathway (see diagram).  This inhibition results in reduced phosphorylation of tau protein and the overall effect of  increased microtubule assembly.  Phosphorylation of MAP-1β is also inhibited by lithium and this results in increased axonal spreading and increased growth cone area and perimeter.  Long term down regulation of protein kinase C (PKC) substrate myrisolated alanine-rich c-kinase substrate (MARCKS) via phosphoinositide signalling was also shown to MARCKS expression is high in developmentally important structures like neuronal growth cones necessary for brain development.  It is also high in limbic structures in the human brain that retain the potential for plasticity - like learning and memory.  The authors conclude that section by pointing out that by its action on PI/PKC and GSK-3β signalling cascades, lithium "may alter presynaptic and post-synaptic structure to stabilize aberrant neuronal activity in critical areas of the brain involved in the regulation of mood."  In the space of just a few years, lithium was suddenly implicated in neuroplasticity and neuroprotection.  Maybe the Decade of the Brain did produce some benefits?  

That brings me to the latest piece of the puzzle.  A paper from Molecular Psychiatry (7) this October further examines the role of these signalling systems and how everything comes together.  The authors propose that one common biochemical pathway that may confer susceptibility to psychiatric disorders is the Wnt/ β-catenin pathway.  This is a pathway that is critical in all multicellular organisms for cell differentiation, growth, proliferation and morphology across a number of organ systems.  At least part of the pathway has a direct influence on the cytoskeleton.  It has been implicated in human diseases especially tumors and the metabolism of tumors.  The pathway was discovered about 34 years ago.  The  authors also looked at DIX domain containing-1 (DIXDC1) as a cytoplasmic transducer of the Wnt/ β-catenin pathway.  DIXDC1 interacts with disrupted in schizophrenia-1 (DISC-1) gene that has been implicated in the genetics of schizophrenia, bipolar disorder, and autism spectrum disorder.  DIXDC1 also has a restricted distribution in the nervous system depending on developmental stages.

Like most modern papers this article has an intense experimental section.  The authors prepared a DIXDC1 knockout mouse model and looked at several experimental manipulations.  They used several behavioral pharmacology approaches to model anxiety, depression, and social interaction among the mice.  On these models the Dixdc1KO (knock out) mice showed increased depression, increased anxiety, and less socialization than the Dixdc1WT (wild type) mice.  These behavioral phenotypes correlated with histological changes and the Dixdc1KO mice had reduced spine density and an increased number of filopodial or immature spines on pyramidal cell dendrites.  The authors confirmed that these reduced spine neurons functioned in an electrophysiologically expected manner.  They analyzed the reduced spines in the Dixdc1KO mutants and found that there was a decreased density of glutamatergic synapses along the dendrites of pyramidal neurons.  In order to determine if the Dixdc1KO Wnt/ β-catenin pathway would be impaired by the loss of cytoplasmic signal transduction proteins.  They found that treating the KO and WT neurons with and activator (Wnt3a) - the  level of β-catenin rose as expected in the WT neurons.  Wnt3a also failed to effect spine maturity or glutamatergic synapse density on the KO type neurons.

Most importantly for psychiatrists, the authors hypothesized that lithium would correct both the behavioral phenotype and structural defects in the Dixdc1KO type mice by inhibition of GSK3.  Injection of lithium or the specific GSK inhibitor GSK3i corrected the behavioral phenotypes and spine density, spine morphology, and glutamatergic synapse density in the pyramidal neurons of Dixdc1KO mice.                        

In a separate experiment the authors looked at a large database of patients with psychiatric disorders.  The first database contained 6000 cases of autism spectrum disorder (ASD) and 7000 controls.  The ASD cases had a greater number of sequence disrupting single-nucleotide variants (SNVs) that were judged to be likely to disrupt DIXDC1 function.  They showed the same pattern in patients with bipolar disorder (BD) and schizophrenia (Scz) versus controls.  In the end they had 4 patient data sets totaling 9000 cases (versus 11000 controls) with significantly more rare sequence disrupting SNVs.

The authors also used a cell based Wnt/ β-catenin signalling assay (compared to WT) to test specific missense SNVs from both psychiatric patients (BD, Scz) and ASD patients.  They found that rare missense SNV from ASD patients either increased or decreased Wnt/ β-catenin pathway activation.  Rare missense SNVs from psychiatric patients did not rescue spine density and synaptic deficits but the WT did.  A number of Wnt/ β-catenin pathway hyperactivating SNVs cased the expected decreased spine density, decreased glutamatergic synapse density and increased immature spine density.

The authors conclude that there may be other mechanisms in play that they could have missed.  They cite a downstream mechanism that is independent of the Wnt/ β-catenin pathway that leads to the structural changes they monitored in this study.  There are also different isoforms of DIXDC1 - some more active than others.  They do a great job of summarizing 20 years of research in the following lines:

"Several different biochemical mechanisms have been proposed to underlie the anxiolytic, antidepressant and mood stabilizing properties of lithium, a drug whose systemic use in modern psychiatry began in the first half of the last century.  Lithium's best validated mechanisms of action are inhibitory on IMP and INPP1, central phosphatases in the phosphoinositide pathway and on GSK3, the central kinase in the Wnt/ β-catenin pathway and AKT pathways."  (p. 8).  

 The story of lithium is similar to a lot of stories in biomedicine.  Research on lithium reflects a lot of popular theories of the day rather than any particular unique theory by one scientist.  That says a lot about the difference between physical sciences and biological sciences.  The technique of applying the most popular theories and lab techniques at the time is still common in medicine and neuroscience.  Like most neuroscience there needs to be further testing, replication, and debate about this mechanism but it does seem to be a lot clearer now than at any time in the past.  If the mechanism does check out there may be more than the few applications that currently involve lithium.  A lithium like effect from safer medications is potentially a very interesting one.  Applications may be as diverse as treating addiction - where glutamatergic innervation is thought to be an important component of top down control from the frontal cortex to neurodegenerative disorders and neuroprotection of synaptic complexity.

George Dawson, MD, DFAPA



References:

1:  James W. Jefferson, John H. Griest, Deborah L. Ackerman.  Lithium Encyclopedia for Clinical Practice.  American Psychiatric Press,  Washington, DC; 1983.

2:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology.  4th ed. Oxford, England: Oxford University Press, 1982: 214.

3:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology. 5th ed.  Oxford, England: Oxford University Press, 1985: 115, 306, 319.

4:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology.  7th ed. Oxford, England: Oxford University Press, 1996: 490.

5:  Leslie L. Iverson, Susan D. Iverson, Floyd E. Bloom, Robert H. Roth.  Introduction to Neuropsychopharamcology.  New York, New York: Oxford University Press, 2009: 321-322.

6:  Robert H. Lenox, Alan Frazer.  Mechanism of action of antidepressants and mood stabilizers. In:  Davis KL, Charney D, Coyle JT, Nemeroff C, eds.  Neuropsychopharmacology: The Fifth Generation of Progress. Philadelphia, Pennsylvania: Lippincott, Williams, and Wilkins, 2002: 1139-1163.

7:   Martin PM, Stanley RE, Ross AP, Freitas AE, Moyer CE, Brumback AC, Iafrati J, Stapornwongkul KS, Dominguez S, Kivimäe S, Mulligan KA, Pirooznia M, McCombie WR, Potash JB, Zandi PP, Purcell SM, Sanders SJ, Zuo Y, Sohal VS, Cheyette BN.  DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling.  Mol Psychiatry. 2016 Oct 18. doi: 10.1038/mp.2016.184. [Epub ahead of print] PubMed PMID: 27752079.

8:  Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A, Lee E. The way Wnt works: components and mechanism. Growth Factors. 2013 Feb;31(1):1-31. doi: 10.3109/08977194.2012.752737. Review. PubMed PMID: 23256519

Attribution:

Wnt signalling pathway is from VisiScience and their ScienceSlides 2016 slide set.

Say What You Mean.........

I read an elegant editorial piece during breakfast this morning.  It was in the regular section in JAMA called "A Piece Of My Mind".  Amanda Fantrey, MD writes about some of the insights she developed as a family member in an ICU setting after her brother was involved in a motor vehicle accident and sustained a traumatic brain injury and coma.  She describes the pull on doctors to make statements that offer hope and frequently diverge from the realistic medical appraisal of the situation.  She describes this as "the seismic gap between what was said by staff (both physicians and nurses) and what was heard by family."  A common example is the staff remembering the one patient with a miraculous recovery and bringing that up in discussions with the family as a way to give them hope.  Dr. Fantrey points out the origins of this behavior as wanting to reassure a traumatized and grieving family.  She gives a clear example of how this plays out in a discussion between the neurosurgical team and her parents.  What seems like a grim prognosis is suddenly being moderated by qualifiers. With enough modification the initial grim prognosis becomes the expectation of recovery.  She also points out that another level this is self preservation - a bias toward recalling the miracle cases and saves.  That without it practicing medicine and surgery is just too grim to contemplate.  This is an excellent essay that I would recommend to any medical student or resident as an example of the power of affective communication, language, and interpersonal dynamics.

The interactions that Dr. Fantrey describes on medicine are common.  I think they form the basis for a number of commonly observed phenomenon.  Psychiatric practice is no exception.  The first thing that came to mind is the promise of the miracle drug that will take away all of your problems.  Many psychiatrists witness first hand patients who explicitly ask them for this kind of medication.  Many people become addicted to opioids because at the outset - it seems like these medications have the properties of an ideal medication.  There has been abundant criticism that new medications are oversold both by advertising and the way that advertising affects the pharmacology literature.  I am much less certain of that as there is more evidence accumulating that the pricing power of the companies themselves is the single largest factor driving much higher pharmaceutical prices and profits in the US.  There is the inescapable sense of hope being conveyed through both direct-to-consumer advertising and and the novelty of a new drug.  Although it has not been adequately tested, that new drug is a form of hope in a pill.  The interested people are all hoping for better therapeutic effects even in spite of the rapid delivery of a list of serious side effects "including death" at the very end of the commercial.

It also brought to mind some of the serious discussions that psychiatrists have with patients and how the biases might be a little different.  The most obvious one is lithium.  Lithium is one of the best medications in terms of therapeutic effects that psychiatrists prescribe.  The attitude of other physicians seems to be: "We will let them prescribe that medication almost exclusively" or "You psychiatrists sure do prescribe a lot of toxic medications."  Treating people with the most severe forms of mental illness almost exclusively for 30 years has caused me to witness many miracles of lithium therapy.  The commonest was the depressed bipolar patient not able to eat, barely taking in fluids, and certainly not able to function outside of a hospital setting.  After starting lithium, many of of these folks recover enough function within a week to be up in the daytime, eating and starting to care for themselves.  For me the miracle of lithium has been on the depressed side.  People who have failed antidepressants and whatever anticonvulsant is en vogue for bipolar disorder.

There is no other medication prescribed by psychiatrists that invokes fantasies and expectations more to patients than lithium.  Their expectations are generally very bad as in:  "That is some serious shit - dude..  Isn't that the medicine in that song......"  I have to remind people that the band was Nirvana and yes I am old enough to have watched them perform the song Lithium live on Saturday Night Live.  I have to explain calmly that it is a salt and that this makes it a unique kind of medicine with fairly unique precautions but that is can be safely taken.  I do point out that is if they end up taking it for decades or if they have repeated episodes of lithium toxicity - it can cause renal failure in some and the need for dialysis and renal transplantation.  I know this because of my experience with end stage renal disease that was attributed to lithium by my Renal Medicine consultants and the protracted course of dialysis, in some cases delirium, and ultimately renal transplantation.  I try to outline all of that, but it is hard to imagine how much information is getting through.  Like Dr. Fantrey's ICU experiences, nobody is more acutely aware of needing to provide hope than a psychiatrist talking directly to a depressed bipolar patient.  We are simultaneously assessing suicide risk - even in inpatient settings.  Acute care psychiatrists know that this is our job.  We have to keep this person alive so that they can recover.

I have to cautiously present the information on lithium as part of the informed consent discussion, but at some point I also started to include a line about lithium being a "potentially life-changing medication."  I explain that the person may experience mood stability like they have never had on the endless series of antidepressants, atypical antipsychotics, benzodiazepines, various anticonvulsants and the drift toward an inaccurate schizoaffective disorder diagnosis that they have been experiencing for years or decades.  I am always concerned about whether they hear the word potentially in my description.   I provide them with a detailed handout on lithium and encourage them to do whatever research they would like to do on the medication and I will answer any further questions.  Is this just another example of hope enacted in the countertransference, me trying to convey it to a desperate patient?  It is hard to imagine that patients who view lithium as a toxin at the outset could have unrealistic expectations about the drug.  Am I coloring their expectations by my description of the drug?  Would it be unfair to not include that information about potentially changing their life?

I think there are problems with all complex informed consent discussions.  These discussions can't be devoid of emotional content.  Like the surgical patients, some people will do better and some will do worse.  It is difficult to determine that ahead of time.  Every patient I see needs to benefit from my experience treating other patients.  And with lithium it is very good.  


George Dawson, MD, DFAPA


References:

Fantry A. Say What You Mean, Mean What You Say. JAMA. 2016;315(13):1337-1338. doi:10.1001/jama.2015.18910.