Lithium
Section titled “Lithium”Some time ago one of the children in our practice, a child with a learning disorder developed a new and disturbing symptom- trichotillomania. Trichotillomania is the fancy term for hair-pulling; George had bald areas on his scalp from playing with bits of hair on his head.
What could we do?
Searching the National Library of Medicine,1 I found a report2 that lithium had been effective in eight of ten children with trichotillomania. We started George on a low dose of lithium.
Lithium, you ask? Isn't that for people with bi-polar (manic-depressive) disorder?
Lithium is an Essential Nutrient
Section titled “Lithium is an Essential Nutrient”Well, yes, dear Reader, but the beneficial effects of lithium on brain structure and individual mood are far too powerful to leave it in that pigeonhole. We, as individuals and as a society, need to recognize that lithium is an essential component of our diet and our physiology.3 Essential as in "required." In areas where lithium levels are low or absent in the drinking water, criminal behavior and drug abuse are higher than in areas with adequate lithium in the water.4 Lithium levels are lower in the hair of learning disabled students as well as violent criminals.5 When researchers gave low-dose supplements of lithium to those same groups, they discovered more stability of mood.6
So lithium has much more value to us as individuals and as a society than we're commonly aware of. But since we all know lithum as a treatment for bipolar disorder, let's start there.
Lithium and Bi-Polar Disorder
Section titled “Lithium and Bi-Polar Disorder”While doctors have written about bi-polar disorder since ancient times, only in 1949 was lithium first described as an effective mood-stabilizing agent for it, and only in 1970 was lithium approved by the FDA. I have many patients who happily take lithium to maintain a normal life despite bipolar disorder, and many who miss the "ups" when they take lithium and so avoid it and its alternative, valproic acid (Depakote).
In these recent exciting decades our new technologic tools have allowed us to see into the living brain. Scans show that some areas of the brain shrink by 40 percent in volume in people with untreated bipolar disorder. Treat those people with lithium, however, and you can prevent this shrinkage.
Lithium Increases Gray Matter in People with Bipolar Disorder
Section titled “Lithium Increases Gray Matter in People with Bipolar Disorder”Our brains contain neurons, which do the processing. Many of our neurons are in the outer layer, the cortex of the brain. When we look at the brain as a whole, this outer layer appears gray, hence the expression "gray matter." Deeper in the brain lies the white matter, composed mostly of axons, or connecting fibers. We do our computing in the gray matter and our data transmission in the white matter. One study of ten people with bipolar disorder measured gray-matter volume before treatment, then again after a month of lithium treatment. In eight of the ten patients, gray matter volume increased by about 3 percent, equivalent to about five teaspoons of functional brain. Further analysis showed that this was a true increase in neuronal tissue, not related to water retention or a lithium effect on the MRI image.7
Researchers found that the improvement in brain volume brought about by lithium occurred because lithium increased the production of proteins that protect brain cells from destruction.8
Lithium Protects the Brain from Dementia
Section titled “Lithium Protects the Brain from Dementia”So far, lithium is the only substance we know of that enhances the function of these neuroprotective proteins. Let's look at the one called bcl-2. Bcl-2 protects the brain in two distinct ways.
- Alzheimer's dementia involves the production in the brain of "gunk" called amyloid plaque and neurofibrillary tangles9. Bcl-2 and another neuroprotective protein act to reduce the formation of amyloid plaque and neurofibrillary tangles.
- We've written before (January 2007 newsletter) that the stress hormone, cortisol, can have a damaging effect on the brain when present in excessive amounts. Bcl-2 protects the brain from this damage, as well as from damage due to free radicals and radiation.
Researchers looked at 1400 people over the age of sixty and found that those who were given lithium for other reasons had significantly less cognitive loss than those who did not take lithium.10 While another study11 did not confirm this result, the great preponderance of the evidence indicates that lithium powerfully promotes brain health in many ways.12 Let's look at some of those ways.
Lithium and Depression
Section titled “Lithium and Depression”Not all depression will lift with an anti-depressant drug. In that case, psychiatrists will "augment" the anti-depressant drug with another drug. Lithium has been used for this purpose for over thirty years. This doesn't mean that we think that the depressed person has bipolar disorder. We just know, based on experience and research, that lithium can also help with depression.13
Lithium has a favorable effect on the serotonin system, the cortisol system, and, along with several anti-depressant drugs, it increases brain-derived neurotropic factor (BDNF).
BDNF is important because even ordinary depression results in shrinkage of the brain. The healthy brain produces BDNF which promotes growth and regeneration of brain cells. Stress, depression, and aging all decrease the production of BDNF.
Lithium and Stroke
Section titled “Lithium and Stroke”Lithium does not just promote growth of gray matter. It has been shown in animals to promote regeneration of the axon, the long fiber that carries a nerve signal from one place to another. In one experiment, researchers treated a group of rats with lithium for two weeks and compared them to group not so treated. In both groups, a major brain artery was blocked to cause a stroke. They measured the amount of brain tissue destruction in both groups, and discovered that the lithium treated group lost less than half as many brain cells as the untreated group. They walked better and suffered fewer coordination problems as a result.
Adverse Effects of Excessive Lithium
So, with all these benefits, why doesn't lithium enjoy a better reputation? The trouble is that lithium is best known as a treatment for bipolar disorder, and many people with that disorder require doses of lithium that are close to toxic levels. Such individuals need to be carefully monitored for toxic effects, which can include thyroid and kidney disorders, stomach upset, tremors, confusion, diarrhea, or lethargy14.
But lower doses, the doses normally found in our water and food, can cause no more trouble than the sodium, vitamin D, and vitamin A found in our food. (Each of which, by the way, is toxic in excess, just as lithium is.)
Lithium is a metal, as is iron. Except for hydrogen and helium, it has the simplest structure of all the elements. Our bodies have required it for millions of years, and our cells contain special structures to pump it through the membranes. The question is not "lithium, good or bad?" but "lithium, how much?"
There is no generally recognized RDA for lithium, but authorities believe it to be in the range of one milligram per day. This contrasts with the 80 to 160 milligrams of elemental lithium (up to 1800 milligrams of lithium carbonate15) for people with bipolar disorder. Many of the preventive effects for neurodegenerative disease occur at doses much lower than the dose used in bipolar disorder.
Summary
Section titled “Summary”Our daily lithium usually arrives in our grains and vegetables, the amount varying from place to place due to differing levels of groundwater lithium. While lithium has long been known as "the medicine for those crazy manic-depressive folks," it has important benefits for the brain in general. It is life-saving for many people with bipolar disorder and ordinary depression. Under a physician's supervision, it can also help with other neurologic and psychiatric conditions as well.
And George? Within a month, he stopped the hair-pulling. While he continued to be a challenge to his parents, their careful attention to his diet and to thoughtful limit-setting helped George to become a much happier and productive young man than most children faced with his initial challenges.
Endnotes:
1 http://gateway.nlm.nih.gov/gw/Cmd
2 Christenson GA,Popkin MK,Mackenzie TB,Realmuto GM. "Lithium treatment of chronic hair pulling." Journal of Clinical Psychiatry. 1991 Mar;52:116-20. (Issue number 3) Research reported by Department of Psychiatry, University of Minnesota Medical School, Minneapolis.. =6244= = Author's abstract: Ten patients with chronic hair pulling received trials of lithium carbonate of 2 to 14 months' duration. Eight patients demonstrated decreased hair pulling and mild to marked hair regrowth. Three responders experienced increased hair pulling subsequent to discontinuation of lithium treatment. Lithium's effect on hair pulling may be related to its observed benefits in treating aggressivity, impulsivity, and mood instability.
3 Schrauzer GN. "Lithium: occurrence, dietary intakes, nutritional essentiality." Journal of the American College of Nutrition. 2002 Feb;21:14-21. (Issue number 1) Research reported by Department of Chemistry and Biochemistry, University of California, San Diego, USA.. =21761= = Author's abstract: Lithium is found in variable amounts in foods; primary food sources are grains and vegetables; in some areas, the drinking water also provides significant amounts of the element. Human dietary lithium intakes depend on location and the type of foods consumed and vary over a wide range. Traces of lithium were detected in human organs and fetal tissues already in the late 19th century, leading to early suggestions as to possible specific functions in the organism. However, it took another century until evidence for the essentiality of lithium became available. In studies conducted from the 1970s to the 1990s, rats and goats maintained on low-lithium rations were shown to exhibit higher mortalities as well as reproductive and behavioral abnormalities. In humans defined lithium deficiency diseases have not been characterized, but low lithium intakes from water supplies were associated with increased rates of suicides, homicides and the arrest rates for drug use and other crimes. Lithium appears to play an especially important role during the early fetal development as evidenced by the high lithium contents of the embryo during the early gestational period. The biochemical mechanisms of action of lithium appear to be multifactorial and are intercorrelated with the functions of several enzymes, hormones and vitamins, as well as with growth and transforming factors. The available experimental evidence now appears to be sufficient to accept lithium as essential; a provisional RDA for a 70 kg adult of 1,000 microg/day is suggested.
4 Schrauzer GN,Shrestha KP. "Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions." Biol Trace Elem Res. 1990 May;25:105-13. (Issue number 2) Research reported by Department of Chemistry and Biochemistry, University of California at San Diego, Revelle College, La Jolla 92093.. =21762= = Author's abstract: Using data for 27 Texas counties from 1978-1987, it is shown that the incidence rates of suicide, homicide, and rape are significantly higher in counties whose drinking water supplies contain little or no lithium than in counties with water lithium levels ranging from 70-170 micrograms/L; the differences remain statistically significant (p less than 0.01) after corrections for population density. The corresponding associations with the incidence rates of robbery, burglary, and theft were statistically significant with p less than 0.05. These results suggest that lithium has moderating effects on suicidal and violent criminal behavior at levels that may be encountered in municipal water supplies. Comparisons of drinking water lithium levels, in the respective Texas counties, with the incidences of arrests for possession of opium, cocaine, and their derivatives (morphine, heroin, and codeine) from 1981-1986 also produced statistically significant inverse associations, whereas no significant or consistent associations were observed with the reported arrest rates for possession of marijuana, driving under the influence of alcohol, and drunkenness. These results suggest that lithium at low dosage levels has a generally beneficial effect on human behavior, which may be associated with the functions of lithium as a nutritionally-essential trace element. Subject to confirmation by controlled experiments with high-risk populations, increasing the human lithium intakes by supplementation, or the lithiation of drinking water is suggested as a possible means of crime, suicide, and drug-dependency reduction at the individual and community level.
5 Schrauzer GN,Shrestha KP,Flores-Arce MF. "Lithium in scalp hair of adults, students, and violent criminals. Effects of supplementation and evidence for interactions of lithium with vitamin B12 and with other trace elements." Biol Trace Elem Res. 1992 Aug;34:161-76. (Issue number 2) Research reported by Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093.. =21760= = Author's abstract: The lithium content of human hair shows an approximately linear response to extradietary lithium supplementation at dosage levels of up to 2000 micrograms/d. From the mean hair lithium concentration of 0.063 micrograms/g in 2648 predominantly American adults, and the reference hair lithium concentrations determined in the present study, the mean lithium intakes were calculated to be 730 micrograms/d. Hair lithium concentrations were extremely low in nearly 20% of the American samples, and in samples collected in Munich, Germany and Vienna, Austria. Hair lithium levels are low in certain pathological conditions, e.g., heart disease, in learning-disabled subjects, and in incarcerated violent criminals. The highest levels were observed in samples of a lithium-treated psychiatric patient. A statistically highly significant direct association was observed between the hair lithium and cobalt concentrations, which suggests a role of lithium in the transport and distribution of vitamin B12. Interactions of lithium with other trace elements are also discussed.
6 Schrauzer GN,de Vroey E. "Effects of nutritional lithium supplementation on mood. A placebo-controlled study with former drug users." Biol Trace Elem Res. 1994 Jan;40:89-101. (Issue number 1) Research reported by Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093-0314.. =21759= = Author's abstract: A total of 24 subjects, 16 males and 8 females, average age 29.4 +/- 6.5 y, were randomly divided into two groups. Group A received 400 micrograms/d of lithium orally, in tablets composed of a naturally lithium-rich brewer's yeast, for 4 wk. Group B was given normal, lithium-free brewer's yeast as a placebo. All the subjects of the study were former drug users (mostly heroin and crystal methamphetamine). Some of the subjects were violent offenders or had a history of domestic violence. The subjects completed weekly self-administered mood test questionnaires, which contained 29 items covering parameters measuring mental and physical activity, ability to think and work, mood, and emotionality. In the lithium group, the total mood test scores increased steadily and significantly during the period of supplementation. The 29 items were furthermore placed into three subcategories reflecting happiness, friendliness, and energy, as well as their negative counterparts. In Group A, the scores increased consistently for all subcategories until wk 4 and remained essentially the same in wk 5. In Group B, the combined mood test scores showed no consistent changes during the same period. The only positive change in some members of Group B occurred during wk 1 and was attributed to a placebo effect. In Group B, the placebo effect was noticeable for the subcategories of energy and friendliness; the happiness scores declined during the entire period of observation. Based on these results and the analysis of voluntary written comments of study participants, it is concluded that lithium at the dosages chosen had a mood-improving and-stabilizing effect.
7 Moore GJ,Bebchuk JM,Wilds IB,Chen G,Manji HK,Menji HK. "Lithium-induced increase in human brain grey matter." Lancet. 2000 Oct 7;356:1241-2. (Issue number 9237) = Author's abstract: Rodent studies have shown that lithium exerts neurotrophic or neuroprotective effects. We used three-dimensional magnetic resonance imaging and brain segmentation to study pharmacologically-induced increases in grey matter volume with chronic lithium use in patients with bipolar mood disorder. Grey-matter volume increased after 4 weeks of treatment. The increases in grey matter probably occurred because of neurotrophic effects.
8 One protein is called bcl-2, another is GSK-3ß
9 Manji HK,Moore GJ,Chen G. "Lithium at 50: have the neuroprotective effects of this unique cation been overlooked?" Biol Psychiatry. 1999 Oct 1;46:929-40. (Issue number 7) Research reported by Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.. =20362= = Author's abstract: Recent advances in cellular and molecular biology have resulted in the identification of two novel, hitherto completely unexpected targets of lithium's actions, discoveries that may have a major impact on the future use of this unique cation in biology and medicine. Chronic lithium treatment has been demonstrated to markedly increase the levels of the major neuroprotective protein, bcl-2 in rat frontal cortex, hippocampus, and striatum. Similar lithium-induced increases in bcl-2 are also observed in cells of human neuronal origin, and are observed in rat frontal cortex at lithium levels as low as approximately 0.3 mmol/L. Bcl-2 is widely regarded as a major neuroprotective protein, and genetic strategies that increase bcl-2 levels have demonstrated not only robust protection of neurons against diverse insults, but have also demonstrated an increase the regeneration of mammalian CNS axons. Lithium has also been demonstrated to inhibit glycogen synthase kinase 3 beta (GSK-3 beta), an enzyme known to regulate the levels of phosphorylated tau and beta-catenin (both of which may play a role in the neurodegeneration observed in Alzheimer's disease). Consistent with the increases in bcl-2 levels and inhibition of GSK-3 beta, lithium has been demonstrated to exert robust protective effects against diverse insults both in vitro and in vivo. These findings suggest that lithium may exert some of its long term beneficial effects in the treatment of mood disorders via underappreciated neuroprotective effects. To date, lithium remains the only medication demonstrated to markedly increase bcl-2 levels in several brain areas; in the absence of other adequate treatments, the potential efficacy of lithium in the long term treatment of certain neurodegenerative disorders may be warranted.
10 Lithium and dementia: a preliminary study. Terao T, Nakano H, Inoue Y, Okamoto T, Nakamura J, Iwata N. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Aug 30;30(6):1125-8. Epub 2006 Jun 6.
Department of Neuropsychiatry, Oita University Faculty of Medicine, Oita, Japan. terao@med.oita-u.ac.jp
Recent studies have shown that lithium may block the accumulation of amyloid-beta (Abeta) peptides and to inhibit the hyperphosphorylation of tau via the inhibition of GSK-3alpha in the brain of mice. The purpose of the present study is to examine whether lithium could potentially be effective for the prevention of Alzheimer's disease. We investigated the clinical records of 1,423 outpatients at a university psychiatric outpatient clinic and classified patients according to the following criteria: (a) absence of a diagnosis of dementia, (b) age 60 years or older, and (c) lithium had been prescribed and/or was currently prescribed. We compared these patients with randomly selected age and gender matched control group who had never been prescribed lithium. Despite no significant difference in MMSE scores between the lithium group, which consisted of patients receiving lithium treatment, and the control group, those who had previously received lithium and/or were currently prescribed lithium had significantly better MMSE scores than the control patients. The findings provide partial evidence to support the contention that lithium could offer hope as a preventive treatment for Alzheimer's disease. Further prospective studies with a large number of patients are warranted to investigate this potentially important effect.
11 Does lithium therapy protect against the onset of dementia? Abstract: Lithium compounds might theoretically play a role in preventing dementia by inhibiting formation both of beta amyloid and hyper phosphorylated tau protein. We carried out a case-control study to assess any possible clinical effects of lithium therapy on the diagnosis of dementia, using data from the General Practice Research Database, which collects routine data from primary care patients in the UK. Patients who received lithium had a higher risk of a diagnosis of dementia compared with those who did not (adjusted odds ratio 1.8, 95% CI 1.1-2.8). There was a trend toward increasing risk with increasing numbers of lithium prescriptions. This evidence does not support the use of lithium for preventing dementia.
Alzheimer Dis Assoc Disord 2005 Jan-Mar;19(1):20-2
12 Lithium: Potential Therapeutics Against Acute Brain Injuries and Chronic Neurodegenerative Diseases Akihiko Wada et all. J Pharmacol Sci 99, 307 – 321 (2005) Abstract. In addition to the well-documented mood-stabilizing effects of lithium in manicdepressive illness patients, recent in vitro and in vivo studies in rodents and humans have increasingly implicated that lithium can be used in the treatment of acute brain injuries (e.g., ischemia) and chronic neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, tauopathies, and Huntington's disease). Consistent with this novel view, substantial evidences suggest that depressive illness is not a mere neurochemical disease, but is linked to gray matter atrophy due to the reduced number/size of neurons and glia in brain. Importantly, neurogenesis, that is, birth /maturation of functional new neurons, continues to occur throughout the lifetime in human adult brains (e.g., hippocampus); the neurogenesis is impaired by multiple not-fully defined factors (e.g., aging, chronic stress-induced increase of glucocorticoids, and excitotoxicity), accounting for brain atrophy in patients with depressive illness and neurodegenerative diseases. Chronic treatment of lithium, in agreement with the delayed-onset of mood-stabilizing effects of lithium, up-regulates cell survival molecules (e.g., Bcl-2, cyclic AMP-responsive element binding protein, brain-derived neurotrophic factor, Grp78, Hsp70, and ß-catenin), while down-regulating pro-apoptotic activities (e.g., excitotoxicity, p53, Bax, caspase, cytochrome c release, ß-amyloid peptide production, and tau hyperphosphorylation), thus preventing or even reversing neuronal cell death and neurogenesis retardation.
13 Efficacy and mechanisms of action of lithium augmentation in refractory major depression. Bschor T, Bauer M. Curr Pharm Des. 2006;12(23):2985-92.
Lithium augmentation refers to the addition of lithium to an antidepressant in the acute treatment phase of patients with depressive episodes who have failed to respond satisfactorily to treatment with antidepressant monotherapy. This article reviews the clinical evidence and hypotheses on the mode of action of lithium augmentation. For this purpose, studies were identified by searching Medline and by scanning the references of published reviews and standard textbooks. With regard to efficacy, 28 prospective studies (with a total of 838 depressed patients) were identified. The majority of randomized controlled trials has demonstrated substantial efficacy of lithium augmentation. A recent meta-analysis including only double-blind, placebo-controlled trials (N = 9) provided firm evidence that lithium augmentation has a statistically significant effect on response rate compared to placebo, and showed that lithium augmentation should be administered for at least 2 weeks to allow assessment of the patient's response. A recent double-blind, placebo-controlled trial revealed that responders to lithium augmentation should be maintained on the lithium-antidepressant combination for a minimum of 12 months. From animal studies there is robust evidence that lithium augmentation increases serotonin (5-HT) neurotransmission, possibly through a synergistic action of lithium and the antidepressant on brain 5-HT pathways. Neuroendocrine studies in humans on the effects of lithium augmentation on the HPA system showed an unexpected and marked increase in the ACTH and cortisol response in the combined dexamethasone/CRH test. These results are in contrast to the established decline of HPA system activity during treatment with antidepressants. In conclusion, lithium is the foremost and most well-documented augmentation strategy in refractory depression. In international treatment guidelines and algorithms, lithium augmentation is considered a first-line treatment strategy for patients with a major depressive episode who do not adequately respond to standard antidepressant treatment.
14 http://en.wikipedia.org/wiki/Lithium_pharmacology#Lithium_toxicity_and_side_effects
15 Lithium is a metal. You could not absorb a tablet of pure lithium, any more than you could assimilate a tablet of pure iron. In both cases, the metal is combined with something else to form a compound that dissolves in water. (Chemists call such a compound a salt. What we call table salt is just one example of a chemical salt.) A 300 milligram tablet of lithium carbonate, a salt, contains about 40 milligrams of elemental lithium and 260 milligrams of carbonate.