Lithium, Neuroprotective or Neurotoxic? Is Lithium Related to Happiness


Since its clinical use in the 19th century, lithium has fascinated and mystified the medical community. Lithium has been widely used as a therapeutic treatment for mood disorders due to its ability to prevent both manic and depressive episodes as well as suicide. Studies have shown that groups treated with lithium had significantly greater improvement in manic symptoms including irritability and aggression compared with the placebo groups [1,2]. A review in the New York Times titled "I Don't Believe in God, but I Believe in Lithium," tells the story of a woman who struggled with bipolar disorder for 20 years and how her lithium treatment alleviated her mania and allowed her to live a normal and happy life [3]. However, despite its long-standing use, lithium's mechanisms of action remain controversial.

Lithium is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Today, we think of lithium as the main component of batteries and cell phones as well as its use in many developing technologies. In our planet, lithium is found in granite rock, sea water, mineral springs, and soils. Lithium can be found in cereals, vegetables, plant-derived foods, and tap water in our daily diet. The main sources of lithium in diet are cereals, potatoes, tomatoes, and cabbage, with nuts being a particularly rich source of the element. [11,12]

Recent evidence has revealed lithium's wide range of effects on biological and disease-associated processes [4]. Of particular interest to clinicians and researchers has been its neuroprotective mechanisms in dementia, anti-aging properties and chronic stress. Non-human studies have indicated that these neuroprotective effects are partly due to lithium's modulation of oxidative stress, inflammation, and metabolic function. In a clinical trial of 45 older adults with Amnestic Mild Cognitive Impairment, the effects of long-term treatment of lithium on the progression from Amnestic Mild Cognitive Impairment to dementia were evaluated. Mild Cognitive Impairment is an early stage of memory loss in which a person may start to forget important information that was previously recalled easily. After one year of follow-up, patients receiving lithium presented stable cognitive performance, memory, and attention than placebo controls [5]. Another study by Coutts et al showed that in a cohort of bipolar disorder patients, lithium use is associated with longer telomere length associated with age-related diseases. Researchers in this study tested whether lithium affects the expression of genes responsible for telomere length maintenance. They found that genes responsible for normal telomere length regulation may play a role in mediating lithium's anti-aging mode of action [6]. Another study evaluated the effects of chronic stress and lithium treatments on oxidative stress parameters in different brain structures. Chronic stress is associated with high levels of reactive oxygen species. They induced animals to chronic stress, increasing the reactive oxygen species generation in an area of the brain essential for memory formation, the hippocampus, and the lithium-treated group decreased the reactive oxygen species generation in the hippocampus [7].


Due to the increasing evidence for lithium's mood-stabilizing and reasoning enhancing effects, pharmaceutical companies have begun touting lithium supplements, advertising its range of health benefits. But how safe is a daily intake of this small element?


Therapeutic doses for lithium change depending on a patient's age, weight, body fat composition, and renal function. As such, therapeutic doses for some people can be toxic for others [8,9]. For example, studies suggest that elderly individuals require much lower doses of lithium to achieve comparable effects as in younger adults [9]. Moreover, sufficient data shows that lithium toxicity occurs more often through repeated therapeutic administration, rather than an unintentional overdose [8]. Lithium toxicity can often go unnoticed, first presenting as gastrointestinal irregularity, muscle weakness, apathy, and sluggishness [8,10]. Severe toxicity can develop and lead to convulsions, seizures, and coma [8,10]. In addition to a patient's pre-existing conditions, drug interactions associated with lithium toxicity often involve prescriptions commonly prescribed to the elderly. Using diuretics (drugs that help the body get rid of sodium and water), angiotensin-converting enzyme (ACE) inhibitors, and anti-inflammatory drugs can all increase the likelihood of lithium toxicity [9].


Research has uncovered exciting and impressive neuroprotective, anti-aging, and metabolic benefits of lithium treatment. An optimal lithium intake may improve outcomes for those suffering from neurologic and psychiatric conditions. However, there is a lack of long-term and controlled clinical studies, particularly in general. All treatment considerations must balance the benefits with the potential risks and side effects. Thus, while the benefits reported are cause for excitement, more studies are needed to determine the optimal treatment for individuals [8,9]. Hence, don't rush off to buy Lithium supplements and start taking them. Without laboratory monitoring for lithium toxicity, people taking lithium supplements may be at risk of taking too much lithium. Clinicians should carefully assess lithium supplementation with continued monitoring of patient health and thorough education of patients and caregivers to prevent lithium toxicity and ensure the highest quality of patient care [8,9].


By Erin Scott, BS and Paula Vij, BS. Edited by Stephanie Palacio, PhD and Aldrin V. Gomes, PhD


References


1. Bowden CL, Grunze H, Mullen J, Brecher M, Paulsson B, Jones M, Vågerö M, Svensson K. (2005) A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry. 66(1):111-21.

2. Vieta E, Mullen J, Brecher M, Paulsson B, Jones M. (2005) Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomized, placebo-controlled studies. Curr Med Res Opin. 21(6):923-34

3. Lowe, J., (2015) 'I Don't Believe in God, but I Believe in Lithium' New York Times.

4. Jakobsson E, Argüello-Miranda O, Chiu SW, et al. (2017) Towards a Unified Understanding of Lithium Action in Basic Biology and its Significance for Applied Biology. J Membrane Biology 250 (6): 587-604.

5. Forlenza O. V.; Diniz B. S.; Radanovic M.; Santos F. S.; Talib L. L.; Gattaz W. F. (2011) Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomized controlled trial. Br J. Psychiatry 198(5), 351–356.


6. Coutts, F., Palmos, A.B., Duarte, R.R.R. et al. (2019) The polygenic nature of telomere length and the anti-ageing properties of lithium. Neuropsychopharmacol 44, 757–765.


7. de Vasconcellos, A.P.S., Nieto, F.B., Crema, L.M. et al. (2006) Chronic Lithium Treatment has Antioxidant Properties but does not Prevent Oxidative Damage Induced by Chronic Variate Stress. Neurochem Res 31, 1141–1151.


8. Konstantinos N. Fountoulakis, Eduard Vieta, Constantin Bouras, Grigorios Notaridis, Panteleimon Giannakopoulos, George Kaprinis, Hagop Akiskal, (2008) A systematic review of existing data on long-term lithium therapy: neuroprotective or neurotoxic? International Journal of Neuropsychopharmacology, 11, 2, 269–287,


9. Sproule, B.A., Hardy, B.G. & Shulman, K.I. (2000) Differential Pharmacokinetics of Lithium in Elderly Patients. Drugs & Aging 16, 165–177.


10. Hansen, H.S, Amdisen, A. (1978) Report of 23 cases and review of 100 cases from the literature. QJM: An International Journal of Medicine, 47, 2, 123–144.

11. Jathar, V S et al. (1980) "Manic depressive psychosis in India and the possible role of lithium as a natural prophylactic. II--Lithium content of diet and some biological fluids in Indian subjects." Journal of Postgraduate Medicine 26,1: 39-44.


12. Szklarska, D., & Rzymski, P. (2019). Is Lithium a Micronutrient? From Biological Activity and Epidemiological Observation to Food Fortification. Biological Trace Element Research, 189(1), 18–27.


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