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Lithium (medication)

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Lithium (medication)
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{{About|lithium as a medication|more general information on lithium as an element|Lithium}}{{Drugbox| drug_name = Lithium| IUPAC_name = Lithium(1+)| image = Lithium-carbonate2DCSD.svg| width = | alt = 2D chemical structure of lithium carbonate| caption = Lithium carbonate| tradename = Many
monograph|lithium-salts}}| MedlinePlus = a681039| pregnancy_AU = D| pregnancy_US = D| pregnancy_category= | legal_AU = S4| legal_CA = Rx-only| legal_UK = POM| legal_US = Rx-only| legal_status = | routes_of_administration = by mouth, parenteral| bioavailability = depends on formulation| protein_bound = None| metabolism = Renal| elimination_half-life = 24 h, 36 h (elderly)| excretion = >95% kidney| CAS_number = 7439-93-2| ATCvet = | ATC_prefix = N05| ATC_suffix = AN01| PubChem = 28486| DrugBank = DB01356| ChemSpiderID = 26502| ChEBI = 49713| UNII = 8H8Z5UER66Li|+}}| molecular_weight = 6.941 g/mol| smiles = [Li+]| StdInChI = 1S/Li/q+1| StdInChIKey = HBBGRARXTFLTSG-UHFFFAOYSA-Nlicence_EU=image2=Lithium-carbonate-xtal-1979-Mercury-3D-sf.png}}Lithium compounds, also known as lithium salts, are primarily used as a psychiatric medication. This includes the treatment of major depressive disorder that does not improve following the use of other antidepressants, and bipolar disorder.WEB, Lithium Salts,weblink The American Society of Health-System Pharmacists, Dec 1, 2015, live,weblink" title="web.archive.org/web/20151208101020weblink">weblink 2015-12-08, In these disorders, it reduces the risk of suicide.JOURNAL, Cipriani, A, Hawton, K, Stockton, S, Geddes, JR, Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis, BMJ (Clinical Research Ed.), 27 June 2013, 346, f3646, 23814104,weblink 10.1136/bmj.f3646, Lithium is taken by mouth.Common side effects include increased urination, shakiness of the hands, and increased thirst. Serious side effects include hypothyroidism, diabetes insipidus, and lithium toxicity. Blood level monitoring is recommended to decrease the risk of potential toxicity. If levels become too high, diarrhea, vomiting, poor coordination, sleepiness, and ringing in the ears may occur. If used during pregnancy, lithium can cause problems in the baby. It appears to be safe to use while breastfeeding.WEB, Lithium use while Breastfeeding,weblink LactMed, 1 December 2015, 2015-03-10, live,weblink" title="web.archive.org/web/20151208194527weblink">weblink 8 December 2015, Lithium salts are classified as mood stabilizers. How lithium works is not specifically known.In the nineteenth century, lithium was used in people who had gout, epilepsy, and cancer. Its use in the treatment of mental disorders began in 1948 by John Cade in Australia.BOOK, Sneader, Walter, Drug discovery : a history, 2005, Wiley, Chichester, 9780471899792, 63, Rev. and updated,weblink live,weblink 2017-09-08, It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.WEB, WHO Model List of Essential Medicines (19th List),weblink World Health Organization, 8 December 2016, April 2015, live,weblink" title="web.archive.org/web/20161213052708weblink">weblink 13 December 2016, It is available as a generic medication. The wholesale cost in the developing world in 2014 was between 0.12 and 0.20 USD per day.WEB, Lithium Carbonate,weblink International Drug Price Indicator Guide, 1 December 2015, In the United States at usual doses it costs about 0.90 to 1.20 USD per day. In 2016 it was the 222nd most prescribed medication in the United States with more than 2 million prescriptions.WEB, The Top 300 of 2019,weblink clincalc.com, 22 December 2018,

Medical uses

(File:Lithium300mg.jpg|thumb|A bottle of lithium capsules)Lithium is used primarily for bipolar disorder. It is sometimes used when other treatments are not effective in a number of other conditions, including major depression, schizophrenia, disorders of impulse control, and some psychiatric disorders in children. In mood disorders, of which bipolar disorder is one, it decreases the risk of suicide.JOURNAL, Cipriani, A., Hawton, K., Stockton, S., Geddes, JR., Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis, BMJ, 346, f3646, 2013, 10.1136/bmj.f3646, 23814104, This benefit is not seen with other medications.JOURNAL,weblink The Antisuicidal and Mortality-Reducing Effect of Lithium Prophylaxis: Consequences for Guidelines in Clinical Psychiatry, 12971012, 2003, Müller-Oerlinghausen, B, Berghöfer, A, Ahrens, B, 48, 7, 433–9, Canadian Journal of Psychiatry, live,weblink 2011-07-25, 10.1177/070674370304800702, JOURNAL, 10.1146/annurev.pharmtox.011008.145557, Lithium's Antisuicidal Efficacy: Elucidation of Neurobiological Targets Using Endophenotype Strategies, 2009, Kovacsics, Colleen E., Gottesman, Irving I., Gould, Todd D., Annual Review of Pharmacology and Toxicology, 49, 175–198, 18834309,

Bipolar disorder

Lithium carbonate treatment was previously considered to be unsuitable for children; however, more recent studies show its effectiveness for treatment of early-onset bipolar disorder in children as young as eight. The required dosage is slightly less than the toxic level, requiring close monitoring of blood levels of lithium carbonate during treatment.Semple, David "Oxford Hand Book of Psychiatry" Oxford Press. 2005.{{page needed|date=January 2012}} A limited amount of evidence suggests lithium carbonate may contribute to treatment of substance use disorders for some people with bipolar disorder.JOURNAL, 17984856, Rosenberg, J., Salzman, C., Update: New uses for lithium and anticonvulsants, CNS Spectrums, 12, 11, 831–841, 2007, 10.1017/S1092852900015571, JOURNAL, 10.1111/j.1399-5618.2006.00370.x, 17156154, Frye, M. A., Salloum, I. M., Bipolar disorder and comorbid alcoholism: Prevalence rate and treatment considerations, Bipolar Disorders, 8, 6, 677–685, 2006, JOURNAL, 16961421, Vornik, L., Brown, E., Management of comorbid bipolar disorder and substance abuse, The Journal of Clinical Psychiatry, 67 Suppl 7, 24–30, 2006,

Schizophrenic disorders

Lithium is recommended for the treatment of schizophrenic disorders only after other antipsychotics have failed and it has limited effectiveness when used alone. The results of different clinical studies of the efficacy of combining lithium with antipsychotic therapy for treating schizophrenic disorders have varied.

Major depressive disorder

If therapy with antidepressants does not fully treat the symptoms of major depressive disorder (MDD) then a second augmentation agent is sometimes added to the therapy. Despite not being approved by the FDA for use as an augmentation agent with any antidepressant for the treatment of MDD, lithium has nevertheless been prescribed for this purpose since the 1980s and is one of the few augmentation agents for antidepressants to demonstrate efficacy in treating MDD in multiple randomized controlled trials.JOURNAL, Bauer, M, Adli, M, Ricken, R, Severus, E, Pilhatsch, M, Role of lithium augmentation in the management of major depressive disorder, CNS Drugs, April 2014, 28, 4, 331–42, 10.1007/s40263-014-0152-8, 24590663,

Monitoring

Those who use lithium should receive regular serum level tests and should monitor thyroid and kidney function for abnormalities, as it interferes with the regulation of sodium and water levels in the body, and can cause dehydration. Dehydration, which is compounded by heat, can result in increasing lithium levels. The dehydration is due to lithium inhibition of the action of antidiuretic hormone, which normally enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine, leading to consequent loss of body water and thirst.Healy D. 2005. Psychiatric Drugs Explained. 4th ed. Churchhill Livingstone: London.{{page needed|date=January 2012}}Lithium concentrations in whole blood, plasma, serum or urine may be measured using instrumental techniques as a guide to therapy, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Serum lithium concentrations are usually in the 0.5–1.3 mmol/l range in well-controlled people, but may increase to 1.8–2.5 mmol/l in those who accumulate the drug over time and to 3–10 mmol/l in acute overdose.JOURNAL, Amdisen A., Clinical and serum level monitoring in lithium therapy and lithium intoxication, J. Anal. Toxicol., 2, 5, 193–202, 1978, 10.1093/jat/2.5.193, R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 851–854.Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring plasma concentrations are available. Doses are adjusted to achieve plasma concentrations of 0.4The UK Electronic Medical Compendium recommends 0.4–0.8 mmol/l plasma lithium level in adults for prophylaxis of recurrent affective bipolar manic-depressive illness Camcolit 250 mg Lithium Carbonate {{webarchive|url=https://web.archive.org/web/20160304000941weblink |date=2016-03-04 }} Revision 2 December 2010, Retrieved 5 May 2011One study (JOURNAL, Solomon, D., Ristow, W., Keller, M., Kane, J., Gelenberg, A., Rosenbaum, J., Warshaw, M., Serum lithium levels and psychosocial function in patients with bipolar I disorder, The American Journal of Psychiatry, 153, 10, 1301–1307, 1996, 8831438, 10.1176/ajp.153.10.1301, ) concluded a "low" dose of 0.4–0.6 mmol/L serum lithium treatment for patients with bipolar 1 disorder had less side effects, but a higher rate of relapse, than a "standard" dose of 0.8–1.0 mmol/l. However, a reanalysis of the same experimental data (JOURNAL, Perlis, R., Sachs, G., Lafer, B., Otto, M., Faraone, S., Kane, J., Rosenbaum, J., Effect of abrupt change from standard to low serum levels of lithium: A reanalysis of double-blind lithium maintenance data, The American Journal of Psychiatry, 159, 7, 1155–1159, 2002, 12091193, 10.1176/appi.ajp.159.7.1155, ) concluded the higher rate of relapse for the "low" dose was due to abrupt changes in the lithium serum levels{{synthesis inline|date=January 2012}} to 1.2 mmol {{chem|Li|+}}/l (lower end of the range for maintenance therapy and the elderly, higher end for children) on samples taken 12 hours after the preceding dose.

Adverse effects

Sources for the following lists.BOOK, Truven Health Analytics, Inc., DrugPoint® System (Internet), Greenwood Village, CO, Thomsen Healthcare, 2013, BOOK, Australian Medicines Handbook, 2013, Australian Medicines Handbook Pty. Ltd., Adelaide, 9780980579086, BOOK, Joint Formulary Committee, British National Formulary (BNF) 65, 2013, Pharmaceutical Press, London, UK, 9780857110848, 240–242, WEB, lithium (Rx) - Eskalith, Lithobid,weblink Medscape, WebMD, 7 October 2013, live,weblink" title="web.archive.org/web/20131204210443weblink">weblink 4 December 2013, WEB, Lithobid (lithium carbonate) tablet, film coated, extended release, Noven Theraputics, LLC.,weblink DailyMed, National Library of Medicine, 7 October 2013, live,weblink" title="web.archive.org/web/20131005083456weblink">weblink 5 October 2013, WEB, Product Information Lithicarb (Lithium carbonate),weblink TGA eBusiness Services, Aspen Pharmacare Australia Pty Ltd, 7 October 2013, live,weblink 22 March 2017, JOURNAL, Aiff, H., Attman, P.-O., Aurel, M., Bendz, H., Ramsauer, B., Schon, S., Svedlund, J., May 2015, Effects of 10 to 30 years of lithium treatment on kidney function, J Psychopharmacol, 29, 5, 608–614, 10.1177/0269881115573808, 25735990,
Very Common (> 10% incidence) adverse effects of lithium include:


Common (1–10%) adverse effects include:
Lithium is known to be responsible for 1–2 kg of weight gain. Weight gain may be a source of low self-esteem for the clinically depressed.BOOK, Sperner-Unterweger, Barbara, W. Wolfgang Fleischhacker, Wolfgang P. Kaschka, Psychoneuroimmunology, Karger Publishers, 2001, 22,weblink 978-3-8055-7262-0, In addition to tremors, lithium treatment appears to be a risk factor for development of parkinsonism symptoms, although the causal mechanism remains unknown.BOOK, Silver, M, Factor, S, Friedman, J, Medication-Induced Movement Disorders, Cambridge University Press, 2015, 131–140, Chapter 12: VPA, lithium, amiodarone, and other non-DA, 978-1-107-06600-7, Most side effects of lithium are dose-dependent. The lowest effective dose is used to limit the risk of side effects.

Hypothyroidism

The rate of hypothyroidism is around six times higher in people who take lithium. Low thyroid hormone levels in turn increase the likelihood of developing depression. People taking lithium thus should routinely be assessed for hypothyroidism and treated with synthetic thyroxine if necessary.WEB,weblink Safe and effective use of lithium,weblink" title="web.archive.org/web/20130725074215weblink">weblink 2013-07-25, dmy-all, Australian PrescriberBecause lithium competes with the receptors for the antidiuretic hormone in the kidney, it increases water output into the urine, a condition called nephrogenic diabetes insipidus. Clearance of lithium by the kidneys is usually successful with certain diuretic medications, including amiloride and triamterene.JOURNAL, 2516883, 1989, Wetzels, J.F., van Bergeijk, J.D., Hoitsma, A.J., Huysmans, F.T., Koene, R.A., Triamterene increases lithium excretion in healthy subjects: Evidence for lithium transport in the cortical collecting tubule, 4, 11, 939–942, Nephrology, Dialysis, Transplantation, 10.1093/ndt/4.11.939, It increases the appetite and thirst ("polydypsia") and reduces the activity of thyroid hormone (hypothyroidism).BOOK, Keshavan, Matcheri S., John S. Kennedy, Drug-induced dysfunction in psychiatry, Taylor & Francis, 2001, 305,weblink 978-0-89116-961-1, WEB,weblink Safer lithium therapy,weblink" title="web.archive.org/web/20100130065528weblink">weblink 2010-01-30, dmy-all, NHS National Patient Safety Agency, 1 December 2009, The latter can be corrected by treatment with thyroxine and does not require the lithium dose to be adjusted. Lithium is also believed to permanently affect renal function{{how|date=November 2016}}, although this does not appear to be common.JOURNAL, 10.1038/ki.2009.433, Bendz, Hans, Schön, Staffan, Attman, Per-Ola, Aurell, Mattias, 1 February 2010, Renal failure occurs in chronic lithium treatment but is uncommon, Kidney International, 77, 3, 19940841, 219–224,

Pregnancy and breast feeding

Lithium is a teratogen, causing birth defects in a small number of newborn babies.JOURNAL, Shepard, T.H., Brent, R.L., Friedman, J.M., Jones, K.L., Miller, R.K., Moore, C.A., Polifka, J.E., Update on new developments in the study of human teratogens, Teratology, 65, 4, 153–161, 2002, 10.1002/tera.10032, 11948561, Case reports and several retrospective studies have demonstrated possible increases in the rate of a congenital heart defect known as Ebstein's anomaly, if taken during a woman's pregnancy.JOURNAL, 18982835, 2008, Yacobi, S., Ornoy, A., Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review, 45, 2, 95–106, The Israel Journal of Psychiatry and Related Sciences, As a consequence, fetal echocardiography is routinely performed in pregnant women taking lithium to exclude the possibility of cardiac anomalies. Lamotrigine seems to be a possible alternative to lithium in pregnant women for the treatment of acute bipolar depression or for the management of bipolar patients with normal mood.JOURNAL, Epstein, R.A., Moore, K.M., Bobo, W.V., Treatment of bipolar disorders during pregnancy: Maternal and fetal safety and challenges, Drug, Healthcare and Patient Safety, 2015, 7, 7–29, 10.2147/DHPS.S50556, 25565896, 4284049, GabapentinJOURNAL, 12791334, 2003, Montouris, G., Gabapentin exposure in human pregnancy: Results from the Gabapentin Pregnancy Registry, 4, 3, 310–317, Epilepsy & Behavior, 10.1016/S1525-5050(03)00110-0, and clonazepamJOURNAL, 11340418, 2001, Weinstock, L., Cohen, L.S., Bailey, J.W., Blatman, R., Rosenbaum, J.F., Obstetrical and neonatal outcome following clonazepam use during pregnancy: A case series, 70, 3, 158–162, Psychotherapy and Psychosomatics, 10.1159/000056242, are also indicated as antipanic medications during the childbearing years and during pregnancy. Valproic acid and carbamazepine also tend to be associated with teratogenicity.While it appears to be safe to use while breastfeeding a number of guidelines list it as a contraindication including the British National Formulary.WEB,weblink Lithium carbonate, 2016-05-25, dead,weblink" title="web.archive.org/web/20161025022324weblink">weblink 2016-10-25, dmy-all,

Kidney damage

Lithium has been associated with several forms of kidney injury.JOURNAL, Nielsen, J., Kwon, T.H., Christensen, B.M., Frokiaer, J., Nielsen, S., May 2008, Dysregulation of renal aquaporins and epithelial sodium channel in lithium-induced nephrogenic diabetes insipidus, Semin. Nephrol., 28, 3, 227–244, 10.1016/j.semnephrol.2008.03.002, 18519084, JOURNAL, Alexander, M.P., Farag, Y.M., Mittal, B.V., Rennke, H.G., Singh, A.K., January 2008, Lithium toxicity: A double-edged sword, Kidney Int., 73, 2, 233–237, 10.1038/sj.ki.5002578, 17943083, It is estimated that impaired urinary concentrating ability is present in at least 50% of individuals on chronic lithium therapy, a condition called lithium-induced nephrogenic diabetes insipidus. Continued use of lithium can lead to more serious kidney damage in an aggravated form of diabetes insipidusJOURNAL, Sands, J.M., Bichet, D.G., February 2006, Nephrogenic diabetes insipidus,weblink Ann Intern Med, 144, 3, 186–194, 16461963, 10.7326/0003-4819-144-3-200602070-00007, Submitted manuscript, JOURNAL, Garofeanu, C.G., Weir, M., Rosas-Arellano, M.P., Garg, A.X., Clark, W.F., April 2005, Causes of reversible nephrogenic diabetes insipidus: A systematic review, Am J Kidney Dis, 45, 4, 626–637, 15806465, 10.1053/j.ajkd.2005.01.008, and chronic kidney failure. Chronic kidney disease is found in about one-third of people undergoing long-term lithium treatment, according to one study. Some forms of lithium-caused kidney damage may be progressive and lead to end-stage kidney failure.JOURNAL, Presne, C., Fakhouri, F., Noel, L.-H., Stengel, B., Even, C., Kreis, H., Mignon, F., Grunfeld, J.-P., August 2003, Lithium-induced nephropathy: Rate of progression and prognostic factors, Kidney Int., 64, 2, 585–592, 10.1046/j.1523-1755.2003.00096.x, 12846754,

Interactions

Lithium plasma concentrations are known to be increased with concurrent use of diuretics—especially loop diuretics (such as furosemide) and thiazides—and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Lithium concentrations can also be increased with concurrent use of ACE inhibitors such as captopril, enalapril, and lisinopril.WEB, Lithium,weblink WebMD, 1 November 2014, live,weblink" title="web.archive.org/web/20141102130014weblink">weblink 2 November 2014, Lithium is primarily cleared from the body through glomerular filtration, but some is then reabsorbed together with sodium through the proximal tubule. Its levels are therefore sensitive to water and electrolyte balance.JOURNAL, Finley, PR, Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction, J Clin Psychopharmacol, February 1996, 16, 1, 68–71, 8834421, 10.1097/00004714-199602000-00011, Diuretics act by lowering water and sodium levels; this causes more reabsorption of lithium in the proximal tubules so that the removal of lithium from the body is less, leading to increased blood levels of lithium.JOURNAL, Oruch, R, Lithium: a review of pharmacology, clinical uses, and toxicity, Eur J Pharmacol, October 5, 2014, 740, 464–73, 24991789, 10.1016/j.ejphar.2014.06.042, 740, ACE inhibitors have also been shown in a retrospective case-control study to increase lithium concentrations. This is likely due to constriction of the afferent arteriole of the glomerulus, resulting in decreased glomerular filtration rate and clearance. Another possible mechanism is that ACE inhibitors can lead to a decrease in sodium and water. This will increase lithium reabsorption and its concentrations in the body.There are also drugs that can increase the clearance of lithium from the body, which can result in decreased lithium levels in the blood. These drugs include theophylline, caffeine, and acetazolamide. Additionally, increasing dietary sodium intake may also reduce lithium levels by prompting the kidneys to excrete more lithium.BOOK, Brian K. Alldredge, Robin L. Corelli, Michael E. Ernst, Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs, 2012-02-01, Lippincott Williams & Wilkins, Baltimore, 978-1-60913-713-7, 1991, 10th, Lithium is known to be a potential precipitant of serotonin syndrome in people concurrently on serotonergic medications such as antidepressants, buspirone and certain opioids such as pethidine (meperidine), tramadol, oxycodone, fentanyl and others.WEB, Boyer, EW, Serotonin syndrome,weblink UpToDate, Wolters Kluwer, 8 October 2013, live,weblink" title="web.archive.org/web/20131216082302weblink">weblink 16 December 2013, Lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other antidopaminergic medications.WEB, Wijdicks, EFM, Neuroleptic malignant syndrome,weblink UpToDate, Wolters Kluwer, 8 October 2013, live,weblink" title="web.archive.org/web/20131023145556weblink">weblink 23 October 2013, High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported.Case reports: (JOURNAL, Sandyk, R., Hurwitz, M. D., Toxic irreversible encephalopathy induced by lithium carbonate and haloperidol. A report of 2 cases, South African Medical Journal, 64, 22, 875–876, 1983, 6415823, )(JOURNAL, Gille, M., Ghariani, S., Piéret, F., Delbecq, J., Depré, A., Saussu, F., De Barsy, T., Acute encephalomyopathy and persistent cerebellar syndrome after lithium salt and haloperidol poisoning, Revue Neurologique, 153, 4, 268–270, 1997, 9296146, )Indeed, these and other antipsychotics have been associated with increased risk of lithium neurotoxicity, even with low therapeutic lithium doses.JOURNAL, Emilien, G, Maloteaux, J, 1996, Lithium neurotoxicity at low therapeutic doses, Acta Neurol. Belg., 96, 4, 281–293, 9008777, JOURNAL, Netto, I, Phutane, V, 2012, Reversible lithium neurotoxicity: review of the literature, Prim Care Companion CNS Disord., 14, PCC.11r01197, 1, 10.4088/PCC.11r01197, 22690368, 3357580,

Overdose

Lithium toxicity, which is also called lithium overdose and lithium poisoning, is the condition of having too much lithium in the blood. This condition also happens in persons that are taking lithium in which the lithium levels are affected by drug interactions in the body.In acute toxicity, people have primarily gastrointestinal symptoms such as vomiting and diarrhea, which may result in volume depletion. During acute toxicity, lithium distributes later into the central nervous system resulting in mild neurological symptoms, such as dizziness.JOURNAL, Gitlin, Michael, 2016-12-17, Lithium side effects and toxicity: prevalence and management strategies, International Journal of Bipolar Disorders, 4, 1, 27, 10.1186/s40345-016-0068-y, 2194-7511, 5164879, 27900734, In chronic toxicity, people have primarily neurological symptoms which include nystagmus, tremor, hyperreflexia, ataxia, and change in mental status. During chronic toxicity, the gastrointestinal symptoms seen in acute toxicity are less prominent. The symptoms are often vague and nonspecific.JOURNAL, Netto, Ivan, Phutane, Vivek H., 2012, Reversible Lithium Neurotoxicity: Review of the Literature, The Primary Care Companion for CNS Disorders, 14, 1, 10.4088/PCC.11r01197, 2155-7772, 3357580, 22690368, If the lithium toxicity is mild or moderate, lithium dosage is reduced or stopped entirely. If the toxicity is severe, lithium may need to be removed from the body.

Mechanism of action

The specific biochemical mechanism of lithium action in stabilizing mood is unknown.Upon ingestion, lithium becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing norepinephrine release and increasing serotonin synthesis.BOOK, 978-0-07-162442-8, Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th, Brunton, L, Chabner, B, Knollman, B, 2010, McGraw-Hill Professional, New York, Goodman and Gilman's The Pharmacological Basis of Therapeutics, Unlike many other psychoactive drugs, {{chem|Li|+}} typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations.Lithium may also increase the release of serotonin by neurons in the brain.JOURNAL, Massot, O., Rousselle, J. C., Fillion, M. P., Januel, D., Plantefol, M., Fillion, G., 5-HT1B Receptors: A Novel Target for Lithium Possible Involvement in Mood Disorders, 10.1016/S0893-133X(99)00042-1, Neuropsychopharmacology, 21, 4, 530–541, 1999, 10481837, In vitro studies performed on serotonergic neurons from rat raphe nuclei have shown that when these neurons are treated with lithium, serotonin release is enhanced during a depolarization compared to no lithium treatment and the same depolarization.JOURNAL, Scheuch, K., Höltje, M., Budde, H., Lautenschlager, M., Heinz, A., Ahnert-Hilger, G., Priller, J., Lithium modulates tryptophan hydroxylase 2 gene expression and serotonin release in primary cultures of serotonergic raphe neurons, 10.1016/j.brainres.2009.10.027, Brain Research, 1307, 14–21, 2010, 19840776, Lithium both directly and indirectly inhibits GSK-3β which results in the activation of mTOR. This leads to an increase in neuroprotective mechanisms by facilitating the Akt signaling pathway.BOOK, The Science and Practice of Lithium Therapy, Frank., Malhi, Gin S. Masson, Marc. Bellivier, 2017, Springer International Publishing, 9783319459233, 62, 979600268, Importantly, GSK-3β is a downstream target of monoamine systems. As such, it is directly implicated in cognition and mood regulation.JOURNAL, Einat, Haim, Manji, Husseini K., June 2006, Cellular Plasticity Cascades: Genes-To-Behavior Pathways in Animal Models of Bipolar Disorder, Biological Psychiatry, 59, 12, 1160–1171, 10.1016/j.biopsych.2005.11.004, 16457783, 0006-3223, During mania, GSK-3β is activated via dopamine overactivity. GSK-3β inhibits the transcription factors β-catenin and cyclic AMP (cAMP) response element binding protein (CREB), by phosphorylation. This results in a decrease in the transcription of important genes encoding for neurotrophinsJOURNAL, Gould, Todd, Picchini, Alyssa, Einat, Haim, Manji, Husseini, 2006-11-01, Targeting Glycogen Synthase Kinase-3 in the CNS: Implications for the Development of New Treatments for Mood Disorders, Current Drug Targets, 7, 11, 1399–1409, 10.2174/1389450110607011399, 1389-4501, JOURNAL, Böer, Ulrike, Cierny, Irmgard, Krause, Doris, Heinrich, Annette, Lin, Hongyin, Mayr, Georg, Hiemke, Christoph, Knepel, Willhart, 2007-11-28, Chronic Lithium Salt Treatment Reduces CRE/CREB-Directed Gene Transcription and Reverses Its Upregulation by Chronic Psychosocial Stress in Transgenic Reporter Gene Mice, Neuropsychopharmacology, 33, 10, 2407–2415, 10.1038/sj.npp.1301640, 18046304, 0893-133X, JOURNAL, Berk, M., Kapczinski, F., Andreazza, A.C., Dean, O.M., Giorlando, F., Maes, M., Yücel, M., Gama, C.S., Dodd, S., January 2011, Pathways underlying neuroprogression in bipolar disorder: Focus on inflammation, oxidative stress and neurotrophic factors, Neuroscience & Biobehavioral Reviews, 35, 3, 804–817, 10.1016/j.neubiorev.2010.10.001, 20934453, 0149-7634, In addition, several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium.JOURNAL, York JD, etal, 1995, Definition of a metal-dependent/Li+-inhibited phosphomonoesterase protein family based upon a conserved three-dimensional core structure, Proc. Natl. Acad. Sci. U.S.A., 92, 11, 5149–5153, 10.1073/pnas.92.11.5149, 7761465, 41866, JOURNAL, Yenush, 2000, A novel target of lithium therapy, FEBS Lett, 467, 2–3, 321–325, 10.1016/s0014-5793(00)01183-2, 10675562, This hypothesis was supported by the low Ki of lithium for human pAp-phosphatase compatible within the range of therapeutic concentrations of lithium in the plasma of people (0.8–1 mM). Importantly, the Ki of human pAp-phosphatase is ten times lower than that of GSK3β (glycogen synthase kinase 3β). Inhibition of pAp-phosphatase by lithium leads to increased levels of pAp (3′-5′ phosphoadenosine phosphate), which was shown to inhibit PARP-1JOURNAL, Toledano E, etal, 2012, 3'-5' phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo, Biochem J, 443, 2, 485–90, 22240080, 10.1042/BJ20111057, 3316155, Another mechanism proposed in 2007 is that lithium may interact with nitric oxide (NO) signalling pathway in the central nervous system, which plays a crucial role in neural plasticity. The NO system could be involved in the antidepressant effect of lithium in the Porsolt forced swimming test in mice.JOURNAL, Ghasemi M, Sadeghipour H, Mosleh A, Sadeghipour HR, Mani AR, Dehpour AR, Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test, Eur Neuropsychopharmacol, 18, 5, 323–32, May 2008, 17728109, 10.1016/j.euroneuro.2007.07.011, JOURNAL, Ghasemi M, Sadeghipour H, Poorheidari G, Dehpour AR, A role for nitrergic system in the antidepressant-like effects of chronic lithium treatment in the mouse forced swimming test, Behav. Brain Res., 200, 1, 76–82, June 2009, 19166880, 10.1016/j.bbr.2008.12.032, It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test,JOURNAL, Ghasemi M, Raza M, Dehpour AR, NMDA receptor antagonists augment antidepressant-like effects of lithium in the mouse forced swimming test, J. Psychopharmacol. (Oxford), 24, 4, 585–94, April 2010, 19351802, 10.1177/0269881109104845, indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of learned helplessness.Lithium possesses neuroprotective properties by preventing apoptosis and increasing cell longevity.JOURNAL, Malhi GS, Potential mechanisms of action of lithium in bipolar disorder. Current understanding., CNS Drugs, 27, 2, 135–53, 2013, 23371914, 10.1007/s40263-013-0039-0, 11343/218106, Although the search for a novel lithium-specific receptor is ongoing, the high concentration of lithium compounds required to elicit a significant pharmacological effect leads mainstream researchers to believe that the existence of such a receptor is considered to be unlikely.BOOK, Lithium and the Cell: Pharmacology and Biochemistry, Nicholas J. Birch,weblink 9780080984292, 2012-12-02,

Oxidative metabolism

Evidence suggests that mitochondrial dysfunction is present in patients with bipolar disorder.Oxidative stress and reduced levels of anti-oxidants (such as glutathione) lead to cell death. Lithium may protect against oxidative stress by up-regulating complex I and II of the mitochondrial electron transport chain.

Dopamine and G-protein coupling

During mania, there is an increase in neurotransmission of dopamine that causes a secondary homeostatic down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression. Additionally, the post-synaptic actions of dopamine are mediated through G-protein coupled receptors. Once dopamine is coupled to the G-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmission. Studies found that in autopsies (which do not necessarily reflect living people), people with bipolar disorder had increased G-protein coupling compared to people without bipolar disorder. Lithium treatment alters the function of certain subunits of the dopamine associated G-protein, which may be part of its mechanism of action.

Glutamate and NMDA receptors

Glutamate levels are observed to be elevated during mania. Lithium is thought to provide long-term mood stabilization and have anti-manic properties by modulating glutamate levels. It is proposed that lithium competes with magnesium for binding to NMDA glutamate receptor, increasing the availability of glutamate in post-synaptic neurons. The NMDA receptor is also affected by other neurotransmitters such as serotonin and dopamine. Effects observed appear exclusive to lithium and have not been observed by other monovalent ions such as rubidium and caesium.

GABA receptors

GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission. It was found that patients with bipolar disorder had lower GABA levels, which results in excitotoxicity and can cause apoptosis (cell loss). Lithium has been shown to increase the level of GABA in plasma and cerebral spinal fluid.JOURNAL, Brunello, Nicoletta, Tascedda, Fabio, June 2003, Cellular mechanisms and second messengers: relevance to the psychopharmacology of bipolar disorders, The International Journal of Neuropsychopharmacology, 6, 2, 181–189, 10.1017/s1461145703003419, 12890311, 1461-1457, Lithium counteracts these degrading processes by decreasing pro-apoptotic proteins and stimulating release of neuroprotective proteins. Lithium's regulation of both excitatory dopaminergic and glutamatergic systems through GABA may play a role in its mood stabilizing effects.BOOK, The Science and Practice of Lithium Therapy, Frank., Malhi, Gin S. Masson, Marc. Bellivier, 2017, Springer International Publishing, 9783319459233, 61, 979600268,

Cyclic AMP secondary messengers

Lithium's therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms.JOURNAL, Malhi, Gin S., Tanious, Michelle, Das, Pritha, Coulston, Carissa M., Berk, Michael, February 2013, Potential Mechanisms of Action of Lithium in Bipolar Disorder, CNS Drugs, 27, 2, 135–153, 10.1007/s40263-013-0039-0, 23371914, 1172-7047, 11343/218106, JOURNAL, Alda, M, 2015-02-17, Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics, Molecular Psychiatry, 20, 6, 661–670, 10.1038/mp.2015.4, 25687772, 5125816, 1359-4184, The cyclic AMP secondary messenger system is shown to be modulated by lithium. Lithium was found to increase the basal levels of cyclic AMP but impair receptor coupled stimulation of cyclic AMP production. It is hypothesized that the dual effects of lithium are due to the inhibition of G-proteins that mediate cyclic AMP production. Over a long period of lithium treatment, cyclic AMP and adenylate cyclase levels are further changed by gene transcription factors.

Inositol depletion hypothesis

Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, involved in degrading inositol monophosphate to inositol required in PIP2 synthesis. This leads to lower levels of inositol triphosphate, created by decomposition of PIP2.JOURNAL, Einat H, Kofman O, Itkin O, Lewitan RJ, Belmaker RH, Augmentation of lithium's behavioral effect by inositol uptake inhibitors, J Neural Transm, 105, 1, 31–8, 1998, 9588758, 10.1007/s007020050035, This effect has been suggested to be further enhanced with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression. It is known with good certainty that signals from the receptors coupled to the phosphoinositide signal transduction is affected by lithium.JOURNAL, Jope RS, Anti-bipolar therapy: mechanism of action of lithium, Mol. Psychiatry, 4, 2, 117–128, 1999, 10208444, 10.1038/sj.mp.4000494, myo-inositol is also regulated by the high affinity sodium mI transport system (SMIT). Lithium is hypothesized to inhibit mI entering the cells and mitigating the function of SMIT. Reductions of cellular levels of myo-inositol results in the inhibition of the phosphoinositide cycle

History

Lithium was first used in the 19th century as a treatment for gout after scientists discovered that, at least in the laboratory, lithium could dissolve uric acid crystals isolated from the kidneys. The levels of lithium needed to dissolve urate in the body, however, were toxic.JOURNAL, Marmol, F., Lithium: Bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium, 10.1016/j.pnpbp.2008.08.012, Progress in Neuro-Psychopharmacology and Biological Psychiatry, 32, 8, 1761–1771, 2008, 18789369, Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange in DenmarkJOURNAL, 8313612, 1994, Lenox, RH, Watson, DG, Lithium and the brain: a psychopharmacological strategy to a molecular basis for manic depressive illness, 40, 2, 309–14, Clinical Chemistry, and William Alexander Hammond in New York CityJOURNAL,weblinkweblink dead, 2012-04-01, 10885179, 2000, Mitchell, PB, Hadzi-Pavlovic, D, Lithium treatment for bipolar disorder, 78, 4, 515–7, 2560742, Bulletin of the World Health Organization, used lithium to treat mania from the 1870s onwards. By the turn of the 20th century, as theory regarding mood disorders evolved and so-called "brain gout" disappeared as a medical entity, the use of lithium in psychiatry was largely abandoned; however, a number of lithium preparations were still produced for the control of renal calculi and uric acid diathesis.JOURNAL, Shorter E, 2009, The history of lithium therapy, Bipolar Disorders, 11, 4–9, 10.1111/j.1399-5618.2009.00706.x, 19538681, 3712976, As accumulating knowledge indicated a role for excess sodium intake in hypertension and heart disease, lithium salts were prescribed to patients for use as a replacement for dietary table salt (sodium chloride). This practice and the sale of lithium itself were both banned in 1949, following publication of reports detailing side effects and deaths.Also in 1949, the Australian psychiatrist John Cade rediscovered the usefulness of lithium salts in treating mania. Cade was injecting rodents with urine extracts taken from schizophrenic patients in an attempt to isolate a metabolic compound which might be causing mental symptoms. Since uric acid in gout was known to be psychoactive, (adenosine receptors on neurons are stimulated by it; caffeine blocks them), Cade needed soluble urate for a control. He used lithium urate, already known to be the most soluble urate compound, and observed that it caused the rodents to become tranquil. Cade traced the effect to the lithium ion itself, and after ingesting lithium himself to ensure its safety in humans, he proposed lithium salts as tranquilizers. He soon succeeded in controlling mania in chronically hospitalized patients with them. This was one of the first successful applications of a drug to treat mental illness, and it opened the door for the development of medicines for other mental problems in the next decades.JOURNAL, Lithium salts in the treatment of psychotic excitement, Cade J. F. J., Medical Journal of Australia, 1949, 2, 18142718, 10dfbnm, 349–52,weblink live,weblink" title="web.archive.org/web/20060525012749weblink">weblink 2006-05-25, The rest of the world was slow to adopt this treatment, largely because of deaths which resulted from even relatively minor overdosing, including those reported from use of lithium chloride as a substitute for table salt. Largely through the research and other efforts of Denmark's Mogens Schou and Paul Baastrup in Europe, and Samuel Gershon and Baron Shopsin in the U.S., this resistance was slowly overcome. The application of lithium in manic illness was approved by the United States Food and Drug Administration in 1970.JOURNAL, Lithium treatment for bipolar disorder, P. B. Mitchell, D. Hadzi-Pavlovic, Bulletin of the World Health Organization, 2000, 78, 4, 515–7, 10885179,weblink 2560742, Hadzi-Pavlovic, live,weblink" title="web.archive.org/web/20060525012749weblink">weblink 2006-05-25, In 1974, this application was extended to its use as a preventive agent for manic-depressive illness.Ronald R. Fieve, who had opened the first lithium clinic in North America in 1966, helped popularize the psychiatric use of lithium through his national TV appearances and his bestselling book, Moodswing. In addition, Fieve and David L. Dunner developed the concept of 'rapid cycling' Bipolar Disorder based on non-response to lithium.Lithium has now become a part of Western popular culture. Characters in Pi, Premonition, Stardust Memories, American Psycho, Garden State, and An Unmarried Woman all take lithium. It's the chief constituent of the calming drug in Ira Levin's dystopian This Perfect Day. Sirius XM Satellite Radio in North America has a 1990s alternative rock station called Lithium, and several songs refer to the use of lithium as a mood stabilizer. These include: "Equilibrium met Lithium" by South African artist Koos Kombuis, "Lithium" by Evanescence, "Lithium" by Nirvana, "Lithium and a Lover" by Sirenia, "Lithium Sunset", from the album Mercury Falling by Sting,NEWS, Agassi, Tirzah, Sting is now older, wiser and duller, The Jerusalem Post, 1996-03-12,weblink 2009-06-25, live,weblink" title="web.archive.org/web/20120513213243weblink">weblink 2012-05-13,
and "Lithium" by Thin White Rope.

7 Up

As with cocaine in Coca-Cola, lithium was widely marketed as one of a number of patent medicine products popular in the late-19th and early-20th centuries, and was the medicinal ingredient of a refreshment beverage. Charles Leiper Grigg, who launched his St. Louis-based company The Howdy Corporation, invented a formula for a lemon-lime soft drink in 1920. The product, originally named "Bib-Label Lithiated Lemon-Lime Soda", was launched two weeks before the Wall Street Crash of 1929."weblink" title="web.archive.org/web/20080430022917weblink">7 UP: The Making of a Legend". Cadbury Schweppes: America's Beverages. It contained the mood stabilizer lithium citrate, and was one of a number of patent medicine products popular in the late-19th and early-20th centuries.WEB,weblink Urban Legends Reference Pages: 7Up, 13 November 2007, Its name was soon changed to 7 Up. All American beverage makers were forced to remove lithium in 1948. Despite the 1948 ban, in 1950 the Painesville Telegraph still carried an advertisement for a lithiated lemon beverage.NEWS, ISALLY'S (ad), anonymous,weblink Painesville Telegraph, 13 July 1950, 8 September 2013,

Names

Lithium carbonate ({{chem|Li|2|CO|3}}), sold under several trade names, is the most commonly prescribed, while lithium citrate ({{chem|Li|3|C|6|H|5|O|7}}) is also used in conventional pharmacological treatments. Lithium orotate ({{chem|C|5|H|3|LiN|2|O|4}}), has been presented as an alternative.JOURNAL, Nieper HA, The clinical applications of lithium orotate. A two years study, Agressologie., 14, 6, 407–11, 1973, 4607169, Lithium bromide and lithium chloride have been used in the past as table salt; however, they fell out of use in the 1940s, when it was discovered they were toxic in those large doses. Many other lithium salts and compounds exist, such as lithium fluoride and lithium iodide, but they are presumed to be toxic as well and have never been evaluated for pharmacological effects.As of 2017 lithium was marketed under many brand names worldwide, including Cade, Calith, Camcolit, Carbolim, Carbolit, Carbolith, Carbolithium, Carbolitium, Carbonato de Litio, Carboron, Ceglution, Contemnol, D-Gluconsäure, Lithiumsalz, Efadermin (Lithium and Zinc Sulfate), Efalith (Lithium and Zinc Sulfate), Elcab, Eskalit, Eskalith, Frimania, Hypnorex, Kalitium, Karlit, Lalithium, Li-Liquid, Licarb, Licarbium, Lidin, Ligilin, Lilipin, Lilitin, Limas, Limed, Liskonum, Litarex, Lithane, Litheum, Lithicarb, Lithii carbonas, Lithii citras, Lithioderm, Lithiofor, Lithionit, Lithium, Lithium aceticum, Lithium asparagicum, Lithium Carbonate, Lithium Carbonicum, Lithium Citrate, Lithium DL-asparaginat-1-Wasser, Lithium gluconicum, Lithium-D-gluconat, Lithiumcarbonaat, Lithiumcarbonat, Lithiumcitrat, Lithiun, Lithobid, Lithocent, Lithotabs, Lithuril, Litiam, Liticarb, Litijum, Litio, Litiomal, Lito, Litocarb, Litocip, Maniprex, Milithin, Neurolepsin, Plenur, Priadel, Prianil, Prolix, Psicolit, Quilonium, Quilonorm, Quilonum, Téralithe, and Theralite.WEB, Lithium brands,weblink Drugs.com, 4 April 2017, live,weblink 5 April 2017,

Research

As of 2012 preclinical studies with lithium have shown that it might have neuroprotective effects. It has been studied in small clinical trials in Alzheimer's disease and ALS and has shown no effect on outcomes.JOURNAL, Forlenza, OV, de Paula, VJ, Machado-Vieira, R, Diniz, BS, Gattaz, WF, Does lithium prevent Alzheimer's disease?, Drugs & Aging, 1 May 2012, 29, 5, 335–42, 22500970, 10.2165/11599180-000000000-00000, JOURNAL, Ludolph, AC, Brettschneider, J, Weishaupt, JH, Amyotrophic lateral sclerosis., Current Opinion in Neurology, October 2012, 25, 5, 530–5, 22918486, 10.1097/WCO.0b013e328356d328,

See also

References

{{reflist}}

External links

Further reading

  • BOOK, Duarte, Mota de Freitas, Brian D., Leverson, Jesse L., Goossens, Springer, 2016, Metal Ions in Life Sciences, 16, The Alkali Metal Ions: Their Role in Life, Astrid, Sigel, Helmut, Sigel, Roland K.O., Sigel, Chapter 15. Lithium in Medicine: Mechanisms of Action, 557–584, 10.1007/978-4-319-21756-7_15, 2019-08-20,
{{Mood stabilizers}}{{Oxytocin and vasopressin receptor modulators}}{{Lithium compounds}}


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