Lithium (medication)

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In 1970, lithium was approved by the United States Food and Drug Administration (FDA) for the treatment of bipolar disorder, which remains its primary use in the US.{{Cite book |vauthors=Fieve RR |url=https://books.google.com/books?id=-8BrAAAAMAAJ&q=The+Brain+,+Biochemistry+,+and+Behavior+.+Robert+L.+Habig |title=The Brain, Biochemistry, and Behavior: Proceedings of the Sixth Arnold O. Beckman Conference in Clinical Chemistry |date=1984 |publisher=American Association for Clinical Chemistry |isbn=978-0-915274-22-2 |veditors=Habig RL |pages=170 |chapter=Lithium: its clinical uses and biological mechanisms of action |access-date=27 May 2022 |archive-date=26 February 2024 |archive-url=https://web.archive.org/web/20240226075242/https://books.google.com/books?id=-8BrAAAAMAAJ&q=The+Brain+,+Biochemistry+,+and+Behavior+.+Robert+L.+Habig |url-status=live }} It is sometimes used when other treatments are not effective in a number of other conditions, including major depression,{{cite journal |vauthors=Bauer M, Adli M, Ricken R, Severus E, Pilhatsch M |date=April 2014 |title=Role of lithium augmentation in the management of major depressive disorder |journal=CNS Drugs |volume=28 |issue=4 |pages=331–342 |doi=10.1007/s40263-014-0152-8 |pmid=24590663 |s2cid=256840}} schizophrenia, disorders of impulse control, and some psychiatric disorders in children. Because the FDA has not approved lithium for the treatment of other disorders, such use is off-label.

Lithium is primarily used as a maintenance drug in the treatment of bipolar disorder to stabilize mood and prevent manic episodes, but it may also be helpful in the acute treatment of manic episodes.{{cite journal | vauthors = McKnight RF, de La Motte de Broöns de Vauvert SJ, Chesney E, Amit BH, Geddes J, Cipriani A | title = Lithium for acute mania | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 6 | pages = CD004048 | date = June 2019 | pmid = 31152444 | pmc = 6544558 | doi = 10.1002/14651858.CD004048.pub4 }} Although recommended by treatment guidelines for the treatment of depression in bipolar disorder, the evidence that lithium is superior to placebo for acute depression is low-quality;{{cite journal | vauthors = Rakofsky JJ, Lucido MJ, Dunlop BW | title = Lithium in the treatment of acute bipolar depression: A systematic review and meta-analysis | journal = Journal of Affective Disorders | volume = 308 | pages = 268–280 | date = July 2022 | pmid = 35429528 | doi = 10.1016/j.jad.2022.04.058 | s2cid = 248161621 }}{{cite journal | vauthors = Riedinger MA, van der Wee NJ, Giltay EJ, de Leeuw M | title = Lithium in bipolar depression: A review of the evidence | journal = Human Psychopharmacology | volume = 38 | issue = 5 | pages = e2881 | date = September 2023 | pmid = 37789577 | doi = 10.1002/hup.2881 | doi-access = free | hdl = 10067/2003410151162165141 | hdl-access = free }} atypical antipsychotics are considered more effective for treating acute depressive episodes.{{cite journal | vauthors = Cai L, Chen G, Yang H, Bai Y | title = Efficacy and safety profiles of mood stabilizers and antipsychotics for bipolar depression: a systematic review | journal = International Clinical Psychopharmacology | volume = 38 | issue = 4 | pages = 249–260 | date = July 2023 | pmid = 36947416 | doi = 10.1097/YIC.0000000000000449 | s2cid = 257665886 }} 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 (representing a low therapeutic index), 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}} Within the therapeutic range there is a dose-response relationship.{{cite journal | vauthors = Hsu CW, Tsai SY, Tseng PT, Liang CS, Vieta E, Carvalho AF, Stubbs B, Kao HY, Tu YK, Lin PY | title = Differences in the prophylactic effect of serum lithium levels on depression and mania in bipolar disorder: A dose-response meta-analysis | journal = European Neuropsychopharmacology | volume = 58 | pages = 20–29 | date = May 2022 | pmid = 35158229 | doi = 10.1016/j.euroneuro.2022.01.112 | s2cid = 246754349 }} A limited amount of evidence suggests lithium carbonate may contribute to the treatment of substance use disorders for some people with bipolar disorder.{{cite journal | vauthors = Rosenberg JM, Salzman C | title = Update: new uses for lithium and anticonvulsants | journal = CNS Spectrums | volume = 12 | issue = 11 | pages = 831–841 | date = November 2007 | pmid = 17984856 | doi = 10.1017/S1092852900015571 | s2cid = 26227696 }}{{cite journal | vauthors = Frye MA, Salloum IM | title = Bipolar disorder and comorbid alcoholism: prevalence rate and treatment considerations | journal = Bipolar Disorders | volume = 8 | issue = 6 | pages = 677–685 | date = December 2006 | pmid = 17156154 | doi = 10.1111/j.1399-5618.2006.00370.x }}{{cite journal | vauthors = Vornik LA, Brown ES | title = Management of comorbid bipolar disorder and substance abuse | journal = The Journal of Clinical Psychiatry | volume = 67 | issue = Suppl 7 | pages = 24–30 | year = 2006 | pmid = 16961421 }} Although it is believed that lithium prevents suicide in people with bipolar disorder, a 2022 systematic review found that "Evidence from randomised trials is inconclusive and does not support the idea that lithium prevents suicide or suicidal behaviour."{{cite journal | vauthors = Nabi Z, Stansfeld J, Plöderl M, Wood L, Moncrieff J | title = Effects of lithium on suicide and suicidal behaviour: a systematic review and meta-analysis of randomised trials | journal = Epidemiology and Psychiatric Sciences | volume = 31 | pages = e65 | date = September 2022 | pmid = 36111461 | doi = 10.1017/S204579602200049X | doi-access = free | pmc = 9533115 }}

Lithium is recommended for the treatment of schizophrenic disorders only after other antipsychotics have failed; 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.

Lithium is widely prescribed as an adjunct treatment for depression.

If therapy with antidepressants (such as selective serotonin reuptake inhibitors [SSRIs]) does not fully treat and discontinue{{cite journal | vauthors = Bauer M, Adli M, Ricken R, Severus E, Pilhatsch M | title = Role of lithium augmentation in the management of major depressive disorder | journal = CNS Drugs | volume = 28 | issue = 4 | pages = 331–342 | date = April 2014 | pmid = 24590663 | doi = 10.1007/s40263-014-0152-8 }} the symptoms of major depressive disorder (MDD) (also known as refractory depression or treatment resistant depression [TRD]){{cite journal | vauthors = Bauer M, Adli M, Baethge C, Berghöfer A, Sasse J, Heinz A, Bschor T | title = Lithium augmentation therapy in refractory depression: clinical evidence and neurobiological mechanisms | journal = Canadian Journal of Psychiatry | volume = 48 | issue = 7 | pages = 440–448 | date = August 2003 | pmid = 12971013 | doi = 10.1177/070674370304800703 }} then a second augmentation agent is sometimes added to the therapy.{{cite journal | vauthors = Ercis M, Ozerdem A, Singh B | title = When and How to Use Lithium Augmentation for Treating Major Depressive Disorder | journal = The Journal of Clinical Psychiatry | volume = 84 | issue = 2 | date = March 2023 | pmid = 36883886 | doi = 10.4088/jcp.23ac14813 }} Lithium is one of the few augmentation agents for antidepressants to demonstrate efficacy in treating MDD in multiple randomized controlled trials and it has been prescribed (off-label) for this purpose since the 1980s. A 2019 systematic review found some evidence of the clinical utility of adjunctive lithium, but the majority of supportive evidence is dated.{{cite journal | vauthors = Undurraga J, Sim K, Tondo L, Gorodischer A, Azua E, Tay KH, Tan D, Baldessarini RJ | title = Lithium treatment for unipolar major depressive disorder: Systematic review | journal = Journal of Psychopharmacology | volume = 33 | issue = 2 | pages = 167–176 | date = February 2019 | pmid = 30698058 | doi = 10.1177/0269881118822161 | url = http://journals.sagepub.com/doi/10.1177/0269881118822161 | access-date = 20 February 2024 | url-status = live | s2cid = 59411183 | archive-url = https://web.archive.org/web/20240220234924/https://journals.sagepub.com/doi/10.1177/0269881118822161 | archive-date = 20 February 2024 | url-access = subscription }}

While SSRIs have been mentioned above as a drug class in which lithium is used to augment, there are other classes in which lithium is added to increase effectiveness. Such classes are antipsychotics (used for bipolar disorder) as well as antiepileptic drugs (used for both psychiatric and epileptic cases). Lamotrigine and topiramate are two specific antiepileptic drugs in which lithium is used to augment.{{cite journal | vauthors = Finley PR | title = Drug Interactions with Lithium: An Update | journal = Clinical Pharmacokinetics | volume = 55 | issue = 8 | pages = 925–941 | date = August 2016 | pmid = 26936045 | doi = 10.1007/s40262-016-0370-y }}

There are a few old studies indicating efficacy of lithium for acute depression with lithium having the same efficacy as tricyclic antidepressants.{{cite book | vauthors = Bauer M, Grof P, Muller-Oerlinghausen B | title=Lithium in Neuropsychiatry: The Comprehensive Guide | publisher=Taylor & Francis | year=2006 | isbn=978-1-84184-515-9 | url=https://books.google.com/books?id=KXjrwAEACAAJ | access-date=17 July 2021 | page=}} A recent study concluded that lithium works best on chronic and recurrent depression when compared to modern antidepressant (i.e. citalopram) but not for patients with no history of depression.{{cite book | vauthors = Bauer M, Gitlin M | title=The Essential Guide to Lithium Treatment | chapter=Treatment of Depression with Lithium | publisher=Springer International Publishing | publication-place=Cham | year=2016 | isbn=978-3-319-31212-5 | doi=10.1007/978-3-319-31214-9_7 | pages=71–80}} A 2019 systemic review found no evidence to support the use of lithium for monotherapy.

Lithium is widely believed to prevent suicide and is often used in clinical practice towards that end. However, meta-analyses, faced with evidence base limitations, have yielded differing results, and it therefore remains unclear whether or not lithium is efficacious in the prevention of suicide.{{cite journal | vauthors = Nabi Z, Stansfeld J, Plöderl M, Wood L, Moncrieff J | title = Effects of lithium on suicide and suicidal behaviour: a systematic review and meta-analysis of randomised trials | journal = Epidemiology and Psychiatric Sciences | volume = 31 | pages = e65 | date = September 2022 | pmid = 36111461 | pmc = 9533115 | doi = 10.1017/S204579602200049X }}{{cite journal | vauthors = Del Matto L, Muscas M, Murru A, Verdolini N, Anmella G, Fico G, Corponi F, Carvalho AF, Samalin L, Carpiniello B, Fagiolini A, Vieta E, Pacchiarotti I | title = Lithium and suicide prevention in mood disorders and in the general population: A systematic review | journal = Neuroscience and Biobehavioral Reviews | volume = 116 | pages = 142–153 | date = September 2020 | pmid = 32561344 | doi = 10.1016/j.neubiorev.2020.06.017 | s2cid = 219942979 }}{{cite journal | vauthors = Börjesson J, Gøtzsche PC | title = Effect of lithium on suicide and mortality in mood disorders: a systematic review | journal = The International Journal of Risk & Safety in Medicine | volume = 30 | pages = 155–166 | date = September 2019 | issue = 3 | pmid = 31381531 | doi = 10.3233/JRS-190058 | s2cid = 199451710 }}{{cite journal | vauthors = Riblet NV, Shiner B, Young-Xu Y, Watts BV | title = Lithium in the prevention of suicide in adults: systematic review and meta-analysis of clinical trials | journal = BJPsych Open | volume = 8 | pages = e199 | date = November 2022 | issue = 6 | pmid = 36384820 | pmc = 9707499 | doi = 10.1192/bjo.2022.605 }}{{cite journal | vauthors = Cipriani A, Hawton K, Stockton S, Geddes JR | title = Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis | journal = BMJ | volume = 346 | pages = f3646 | date = June 2013 | pmid = 23814104 | doi = 10.1136/bmj.f3646 | doi-access = free }}{{cite journal | vauthors = Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J | title = Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review | journal = Bipolar Disorders | volume = 8 | pages = 625–639 | date = October 2006 | issue = 5p2 | pmid = 17042835 | doi = 10.1111/j.1399-5618.2006.00344.x | doi-access = free }} However, some evidence suggests it is effective in significantly reducing the risk of self-harm and unintentional injury for bipolar disorder in comparison to no treatment and to anti-psychotics or valporate.{{cite journal | vauthors = Hayes JF, Pitman A, Marston L, Walters K, Geddes JR, King M, Osborn DP | title = Self-harm, Unintentional Injury, and Suicide in Bipolar Disorder During Maintenance Mood Stabilizer Treatment: A UK Population-Based Electronic Health Records Study | journal = JAMA Psychiatry | volume = 73 | issue = 6 | pages = 630–637 | date = June 2016 | pmid = 27167638 | doi = 10.1001/jamapsychiatry.2016.0432 }}{{cite journal | vauthors = Fitzgerald C, Christensen RH, Simons J, Andersen PK, Benros ME, Nordentoft M, Erlangsen A, Hawton K | title = Effectiveness of medical treatment for bipolar disorder regarding suicide, self-harm and psychiatric hospital admission: between- and within-individual study on Danish national data | journal = The British Journal of Psychiatry | volume = 221 | issue = 5 | pages = 692–700 | date = April 2022 | pmid = 35450547 | doi = 10.1192/bjp.2022.54 }} According to meta-analyses, the increased presence of lithium in drinking water is correlated with lower overall suicide rates, especially among men. It is noted that further testing is needed to confirm this benefit.{{cite journal | vauthors = Barjasteh-Askari F, Davoudi M, Amini H, Ghorbani M, Yaseri M, Yunesian M, Mahvi AH, Lester D | title = Relationship between suicide mortality and lithium in drinking water: A systematic review and meta-analysis | journal = Journal of Affective Disorders | volume = 264 | pages = 234–241 | date = March 2020 | pmid = 32056756 | doi = 10.1016/j.jad.2019.12.027 }}{{cite journal | vauthors = Memon A, Rogers I, Fitzsimmons SM, Carter B, Strawbridge R, Hidalgo-Mazzei D, Young AH | title = Association between naturally occurring lithium in drinking water and suicide rates: systematic review and meta-analysis of ecological studies | journal = The British Journal of Psychiatry | volume = 217 | issue = 6 | pages = 667–678 | date = December 2020 | pmid = 32716281 | doi = 10.1192/bjp.2020.128 }}

Alzheimer's disease affects forty-five million people and is the fifth leading cause of death in the 65-plus population.{{cite journal | vauthors = Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM | title = Alzheimer's disease | journal = Lancet | volume = 397 | issue = 10284 | pages = 1577–1590 | date = April 2021 | pmid = 33667416 | doi = 10.1016/S0140-6736(20)32205-4 | pmc = 8354300 }}{{failed verification|date=June 2023}} There is no complete cure for the disease, currently. However, lithium is being evaluated for its effectiveness as a potential therapeutic measure. One of the leading causes of Alzheimer's is the hyperphosphorylation of the tau protein by the enzyme GSK-3, which leads to the overproduction of amyloid peptides that cause cell death. To combat this toxic amyloid aggregation, lithium upregulates the production of neuroprotectors and neurotrophic factors, as well as inhibiting the GSK-3 enzyme.{{cite journal | vauthors = Haussmann R, Noppes F, Brandt MD, Bauer M, Donix M | title = Lithium: A therapeutic option in Alzheimer's disease and its prodromal stages? | journal = Neuroscience Letters | volume = 760 | pages = 136044 | date = August 2021 | pmid = 34119602 | doi = 10.1016/j.neulet.2021.136044 | s2cid = 235385875 }} Lithium also stimulates neurogenesis within the hippocampus, making it thicker. Yet another cause of Alzheimer's disease is the dysregulation of calcium ions within the brain.{{cite journal |author5-link=De-Maw Chuang | vauthors = Wei HF, Anchipolovsky S, Vera R, Liang G, Chuang DM | title = Potential mechanisms underlying lithium treatment for Alzheimer's disease and COVID-19 | journal = European Review for Medical and Pharmacological Sciences | volume = 26 | issue = 6 | pages = 2201–2214 | date = March 2022 | pmid = 35363371 | pmc = 9173589 | doi = 10.26355/eurrev_202203_28369 }} Too much or too little calcium within the brain can lead to cell death. Lithium can restore intracellular calcium homeostasis by inhibiting the wrongful influx of calcium upstream. It also promotes the redirection of the influx of calcium ions into the lumen of the endoplasmic reticulum of the cells to reduce the oxidative stress within the mitochondria.

In 2009, a study was performed by Hampel and colleagues{{cite journal | vauthors = 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 | title = Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study | journal = The Journal of Clinical Psychiatry | volume = 70 | issue = 6 | pages = 922–931 | date = June 2009 | doi = 10.4088/JCP.08m04606 | pmid = 19573486 }} that asked patients with Alzheimer's to take a low dose of lithium daily for three months; it resulted in a significant slowing of cognitive decline, benefitting patients being in the prodromal stage the most. Upon a secondary analysis, the brains of the Alzheimer's patients were studied and shown to have an increase in BDNF markers, meaning they had actually shown cognitive improvement. Another study, a population study this time by Kessing et al.,{{cite journal | vauthors = Kessing LV, Gerds TA, Knudsen NN, Jørgensen LF, Kristiansen SM, Voutchkova D, Ernstsen V, Schullehner J, Hansen B, Andersen PK, Ersbøll AK | title = Association of Lithium in Drinking Water With the Incidence of Dementia | journal = JAMA Psychiatry | volume = 74 | issue = 10 | pages = 1005–1010 | date = October 2017 | pmid = 28832877 | doi = 10.1001/jamapsychiatry.2017.2362 | pmc = 5710473 }} showed a negative correlation between Alzheimer's disease deaths and the presence of lithium in drinking water. Areas with increased lithium in their drinking water showed less dementia overall in their population.

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 range of 0.5–1.3 mmol/L (0.5–1.3 mEq/L) 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.{{cite journal| vauthors = Amdisen A |title=Clinical and serum level monitoring in lithium therapy and lithium intoxication|journal= Journal of Analytical Toxicology |volume=2|issue=5|pages=193–202|year=1978|doi=10.1093/jat/2.5.193}}{{cite book | vauthors = Baselt R | title = Disposition of Toxic Drugs and Chemicals in Man | edition = 8th | publisher = Biomedical Publications | location = Foster City, CA | date = 2008 | pages = 851–854 | isbn = 978-0-9626523-7-0 }}

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 0.4{{efn|1=The 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 {{cite web | url = http://www.medicines.org.uk/emc/document.aspx?documentId=1239 | title = Camcolit 250 mg Lithium Carbonate | archive-url = https://web.archive.org/web/20160304000941/http://www.medicines.org.uk/emc/document.aspx?documentId=1239 | archive-date=4 March 2016 | date = 2 December 2010 | access-date = 5 May 2011 }} }}{{efn|1=One study ({{cite journal | vauthors = Solomon DA, Ristow WR, Keller MB, Kane JM, Gelenberg AJ, Rosenbaum JF, Warshaw MG | title = Serum lithium levels and psychosocial function in patients with bipolar I disorder | journal = The American Journal of Psychiatry | volume = 153 | issue = 10 | pages = 1301–1307 | date = October 1996 | pmid = 8831438 | doi = 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 fewer 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 ({{cite journal | vauthors = Perlis RH, Sachs GS, Lafer B, Otto MW, Faraone SV, Kane JM, Rosenbaum JF | title = Effect of abrupt change from standard to low serum levels of lithium: a reanalysis of double-blind lithium maintenance data | journal = The American Journal of Psychiatry | volume = 159 | issue = 7 | pages = 1155–1159 | date = July 2002 | pmid = 12091193 | doi = 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/L{{cite journal | vauthors = Grandjean EM, Aubry JM | title = Lithium: updated human knowledge using an evidence-based approach. Part II: Clinical pharmacology and therapeutic monitoring | journal = CNS Drugs | volume = 23 | issue = 4 | pages = 331–349 | year = 2009 | pmid = 19374461 | doi = 10.2165/00023210-200923040-00005 | publisher = Springer Science and Business Media LLC | s2cid = 38042857 }} on samples taken 12 hours after the preceding dose.

Given the rates of thyroid dysfunction, thyroid parameters should be checked before lithium is instituted and monitored after 3–6 months and then every 6–12 months.

Given the risks of kidney malfunction, serum creatinine, and eGFR should be checked before lithium is instituted and monitored after 3–6 months at regular intervals. Patients who have a rise in creatinine on three or more occasions, even if their eGFR is > 60 ml/min/

1.73m2 require further evaluation, including a urinalysis for haematuria, and proteinuria, a review of their medical history with attention paid to cardiovascular, urological, and medication history, and blood pressure control and management. Overt proteinuria should be further quantified with a urine protein-to-creatinine ratio.{{cite journal | vauthors = Davis J, Desmond M, Berk M | title = Lithium and nephrotoxicity: a literature review of approaches to clinical management and risk stratification | journal = BMC Nephrology | volume = 19 | issue = 1 | pages = 305 | date = November 2018 | pmid = 30390660 | pmc = 6215627 | doi = 10.1186/s12882-018-1101-4 | publisher = Springer Science and Business Media LLC | doi-access = free }}

For patients who have achieved long-term remission, it is recommended to discontinue lithium gradually and in a controlled fashion.{{cite journal | vauthors = Yazici O, Kora K, Polat A, Saylan M | title = Controlled lithium discontinuation in bipolar patients with good response to long-term lithium prophylaxis | journal = Journal of Affective Disorders | volume = 80 | issue = 2–3 | pages = 269–271 | date = June 2004 | pmid = 15207941 | doi = 10.1016/S0165-0327(03)00133-2 }}

In patients stopping the medication, discontinuation symptoms including irritability or restlessness, and somatic symptoms like vertigo, dizziness, or lightheadedness may occur. Symptoms occur within the first week and are generally mild and self-limiting within weeks.{{cite journal | vauthors = Gutwinski S, Fierley L, Schreiter S, Bermpohl F, Heinz A, Henssler J | title = [Lithium Withdrawal Symptoms – A Systematic Review] | language = de | journal = Psychiatrische Praxis | volume = 48 | issue = 7 | pages = 341–350 | date = October 2021 | pmid = 34015856 | doi = 10.1055/a-1481-1953 | publisher = Georg Thieme Verlag KG | s2cid = 243025798 }}

Studies testing prophylactic use of lithium in cluster headaches (when compared to verapamil), migraine attacks, and hypnic headache indicate good efficacy.

The adverse effects of lithium include:{{cite book |department=Truven Health Analytics, Inc. |title=DrugPoint® System (Internet) |location=Greenwood Village, CO |publisher=Thomsen Healthcare |year=2013}}{{cite book |title=Australian Medicines Handbook |year=2013 |publisher=Australian Medicines Handbook Pty. Ltd. |location=Adelaide |isbn=978-0-9805790-8-6}}{{cite book | author = Joint Formulary Committee |title=British National Formulary (BNF) 65 |year=2013 |publisher=Pharmaceutical Press |location=London, UK |isbn=978-0-85711-084-8 |pages=[https://archive.org/details/bnf65britishnati0000unse/page/240 240–242] |url=https://archive.org/details/bnf65britishnati0000unse/page/240 }}{{cite web |title=lithium (Rx) - Eskalith, Lithobid |url=http://reference.medscape.com/drug/eskalith-lithobid-lithium-342934 |work=Medscape |publisher=WebMD |access-date=7 October 2013 |url-status=live |archive-url=https://web.archive.org/web/20131204210443/http://reference.medscape.com/drug/eskalith-lithobid-lithium-342934 |archive-date=4 December 2013}}{{cite web |title=Lithobid (lithium carbonate) tablet, film coated, extended release |agency=Noven Therapeutics, LLC. |url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ea4ece7f-e81f-48de-b262-577db5b6fe6c#nlm42232-9 |via=DailyMed |publisher=National Library of Medicine |access-date=7 October 2013 |url-status=live |archive-url=https://web.archive.org/web/20131005083456/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ea4ece7f-e81f-48de-b262-577db5b6fe6c#nlm42232-9 |archive-date=5 October 2013}}{{cite web |title=Product Information Lithicarb (Lithium carbonate) |url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2012-PI-01382-3 |work=TGA eBusiness Services |publisher=Aspen Pharmacare Australia Pty Ltd |access-date=7 October 2013 |url-status=live |archive-url=https://web.archive.org/web/20170322203331/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2012-PI-01382-3 |archive-date=22 March 2017}}{{cite journal | vauthors = Aiff H, Attman PO, Aurell M, Bendz H, Ramsauer B, Schön S, Svedlund J | title = Effects of 10 to 30 years of lithium treatment on kidney function | journal = Journal of Psychopharmacology | volume = 29 | issue = 5 | pages = 608–614 | date = May 2015 | pmid = 25735990 | doi = 10.1177/0269881115573808 | s2cid = 9496408 }}

;Very Common (> 10% incidence) adverse effects

• Confusion
• Constipation (usually transient, but can persist in some)
• Decreased memory
• Diarrhea (usually transient, but can persist in some)
• Dry mouth
• EKG changes – usually benign changes in T waves
• Hand tremor (usually transient, but can persist in some) with an incidence of 27%. If severe, psychiatrist may lower lithium dosage, change lithium salt type or modify lithium preparation from long to short-acting (despite lacking evidence for these procedures) or use pharmacological help{{cite journal | vauthors = Baek JH, Kinrys G, Nierenberg AA | title = Lithium tremor revisited: pathophysiology and treatment | journal = Acta Psychiatrica Scandinavica | volume = 129 | issue = 1 | pages = 17–23 | date = January 2014 | pmid = 23834617 | doi = 10.1111/acps.12171 | publisher = Wiley | s2cid = 33784257 }}
• Headache
• Hyperreflexia — overresponsive reflexes
• Leukocytosis — elevated white blood cell count
• Muscle weakness (usually transient, but can persist in some)
• Myoclonus — muscle twitching
• Nausea (usually transient)
• Polydipsia — increased thirst
• Polyuria — increased urination
• Renal (kidney) toxicity which may lead to chronic kidney failure, although some cases may be misattributed{{cite journal | vauthors = Strawbridge R, Young AH | title = Lithium: how low can you go? | journal = International Journal of Bipolar Disorders | volume = 12 | issue = 1 | pages = 4 | date = January 2024 | pmid = 38289425 | pmc = 10828288 | doi = 10.1186/s40345-024-00325-y | quote = An in-depth recent study reported high interindividual variation but steeper declines in estimated glomerular filtration rate (eGFR) explained by lithium use but also found wrongful clinical attribution of some chronic kidney disease (CKD) cases to lithium (Fransson et al. 2022) which may have increased other records-based studies’ estimates (Strawbridge and Young 2022). [...] | doi-access = free }}
• Vomiting (usually transient, but can persist in some)
• Vertigo

;Common (1–10%) adverse effects

• Acne
• Extrapyramidal side effects — movement-related problems such as muscle rigidity, parkinsonism, dystonia, etc.
• Euthyroid goitre — i.e. the formation of a goitre despite normal thyroid functioning
• Hypothyroidism — a deficiency of thyroid hormone. Common among bipolar patients; lithium increases rates.
• Hair loss/hair thinning
• Weight gain{{cite journal | vauthors = Baptista T, Teneud L, Contreras Q, Alastre T, Burguera JL, de Burguera M, de Baptista E, Weiss S, Hernàndez L | title = Lithium and body weight gain | journal = Pharmacopsychiatry | volume = 28 | issue = 2 | pages = 35–44 | date = March 1995 | pmid = 7624385 | doi = 10.1055/s-2007-979586 }} — 5% incidence, tends to start fast and then plateau. Usually ends at 1–2 kg.

;Unknown incidence

• Sexual dysfunction
• Hypoglycemia{{cite journal | vauthors = Ben Salem C, Fathallah N, Hmouda H, Bouraoui K | title = Drug-induced hypoglycaemia: an update | journal = Drug Safety | volume = 34 | issue = 1 | pages = 21–45 | date = January 2011 | pmid = 20942513 | doi = 10.2165/11538290-000000000-00000 | publisher = Springer Science and Business Media LLC | s2cid = 33307427 }}
• Glycosuria

In addition to tremors, lithium treatment appears to be a risk factor for development of parkinsonism-like symptoms, although the causal mechanism remains unknown.{{cite book | vauthors = Silver M, Factor S | veditors = Friedman J |title=Medication-Induced Movement Disorders |publisher=Cambridge University Press |year=2015 |pages=131–140 |chapter=Chapter 12: VPA, lithium, amiodarone, and other non-DA |isbn=978-1-107-06600-7}}

In the average bipolar patient, chronic lithium use is not associated with cognitive decline.{{cite journal | vauthors = Burdick KE, Millett CE, Russo M, Alda M, Alliey-Rodriguez N, Anand A, Balaraman Y, Berrettini W, Bertram H, Calabrese JR, Calkin C, Conroy C, Coryell W, DeModena A, Feeder S, Fisher C, Frazier N, Frye M, Gao K, Garnham J, Gershon ES, Glazer K, Goes FS, Goto T, Harrington GJ, Jakobsen P, Kamali M, Kelly M, Leckband S, Løberg EM, Lohoff FW, Maihofer AX, McCarthy MJ, McInnis M, Morken G, Nievergelt CM, Nurnberger J, Oedegaard KJ, Ortiz A, Ritchey M, Ryan K, Schinagle M, Schwebel C, Shaw M, Shilling P, Slaney C, Stapp E, Tarwater B, Zandi P, Kelsoe JR | title = The association between lithium use and neurocognitive performance in patients with bipolar disorder | journal = Neuropsychopharmacology | volume = 45 | issue = 10 | pages = 1743–1749 | date = September 2020 | pmid = 32349118 | pmc = 7419515 | doi = 10.1038/s41386-020-0683-2 | hdl-access = free | hdl = 11250/2760690 }} Depending on dosage and duration of use, lithium can be either pro-convulsant, or as its historical use suggests, anti-convulsant.{{cite journal | vauthors = Bojja SL, Singh N, Kolathur KK, Rao CM | title = What is the Role of Lithium in Epilepsy? | journal = Current Neuropharmacology | volume = 20 | issue = 10 | pages = 1850–1864 | date = 2022 | pmid = 35410603 | pmc = 9886805 | doi = 10.2174/1570159X20666220411081728 }}

Most side effects of lithium are dose-dependent. The lowest effective dose is used to limit the risk of side effects.

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.{{cite journal |title=Safe and effective use of lithium |journal=Australian Prescriber |volume=36 |pages=18–21 |doi=10.18773/austprescr.2013.008 |year=2013 | vauthors = Malhi GS, Tanious M, Bargh D, Das P, Berk M |doi-access=free}}

Because lithium competes with 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.{{cite journal | vauthors = Wetzels JF, van Bergeijk JD, Hoitsma AJ, Huysmans FT, Koene RA | title = Triamterene increases lithium excretion in healthy subjects: evidence for lithium transport in the cortical collecting tubule | journal = Nephrology, Dialysis, Transplantation | volume = 4 | issue = 11 | pages = 939–942 | year = 1989 | pmid = 2516883 | doi = 10.1093/ndt/4.11.939 }} It increases the appetite and thirst ("polydypsia") and reduces the activity of thyroid hormone (hypothyroidism).

{{cite book | vauthors = Keshavan MS, Kennedy JS |title=Drug-induced dysfunction in psychiatry |publisher=Taylor & Francis |year=2001 |page=305 |url=https://books.google.com/books?id=pol0204fqjIC |isbn=978-0-89116-961-1}}

{{cite web |url=http://www.nrls.npsa.nhs.uk/resources/patient-safety-topics/medication-safety/?entryid45=65426 |title=Safer lithium therapy |archive-url=https://web.archive.org/web/20100130065528/http://www.nrls.npsa.nhs.uk/resources/patient-safety-topics/medication-safety/?entryid45=65426 |archive-date=30 January 2010 |publisher=NHS National Patient Safety Agency |date=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 cause renal dysfunction, although this does not appear to be common.

{{cite journal | vauthors = Bendz H, Schön S, Attman PO, Aurell M | title = Renal failure occurs in chronic lithium treatment but is uncommon | journal = Kidney International | volume = 77 | issue = 3 | pages = 219–224 | date = February 2010 | pmid = 19940841 | doi = 10.1038/ki.2009.433 | doi-access = free }}

Lambert et al. (2016), comparing the rate of hypothyroidism in patients with bipolar disorder treated with 9 different medications, found that lithium users do not have a particularly high rate of hypothyroidism (8.8%) among BD patients – only 1.39 times the rate in oxcarbazepine users (6.3%, the lowest group). Lithium and quetiapine are not statistically different in terms of hypothyroidism rates. However, lithium users are tested much more frequently for hypothyroidism than those using other drugs. The authors write that there may be an element of surveillance bias in understanding lithium's effects on the thyroid glands, as lithium users are tested 2.3–3.1 times as often. Furthermore, the authors argue that because hypothyroidism is common among BD patients regardless of lithium treatment, regular thyroid testing should be applied to all BD patients, not just those on lithium.{{cite journal | vauthors = Lambert CG, Mazurie AJ, Lauve NR, Hurwitz NG, Young SS, Obenchain RL, Hengartner NW, Perkins DJ, Tohen M, Kerner B | title = Hypothyroidism risk compared among nine common bipolar disorder therapies in a large US cohort | journal = Bipolar Disorders | volume = 18 | issue = 3 | pages = 247–260 | date = May 2016 | pmid = 27226264 | pmc = 5089566 | doi = 10.1111/bdi.12391 }}{{cite journal | vauthors = Kessing LV | title = Why is lithium [not] the drug of choice for bipolar disorder? a controversy between science and clinical practice | journal = International Journal of Bipolar Disorders | volume = 12 | issue = 1 | pages = 3 | date = January 2024 | pmid = 38228882 | pmc = 10792154 | doi = 10.1186/s40345-023-00322-7 | doi-access = free }}

Lithium is a teratogen, which can cause birth defects in a small number of newborns. Case reports and several retrospective studies have demonstrated possible increases in the rate of a congenital heart defects (CHDs) including Ebstein's anomaly if taken during the first trimester of pregnancy. The risk is dose-dependent: in the 2017 AMX registry study, the risk of "any malformations" is increased by {{val|11|152|47}}% in those taking no more than 600 mg of lithium carbonate daily, by {{val|60|220|93}}% in those taking 601–900 mg daily, and by {{val|222|380|75}}% in those taking more than 900 mg daily. The first two numbers do not indicate a statistically significant association.{{Cite web | work = MGH Center for Women's Mental Health |date=2021-03-04 |title=Essential Reads: Lithium and Pregnancy |url=https://womensmentalhealth.org/posts/lithium-and-pregnancy-still-a-viable-option/ |access-date=2024-12-05 |language=en-US}} In a 2018 meta-analysis, there was a statistically significant {{val|62|71|50}}% increase in congenital malformations in general, but not for cardiac malformations specifically ({{val|54|216|90}}% increase).{{cite journal | vauthors = Poels EM, Bijma HH, Galbally M, Bergink V | title = Lithium during pregnancy and after delivery: a review | journal = International Journal of Bipolar Disorders | volume = 6 | issue = 1 | pages = 26 | date = December 2018 | pmid = 30506447 | pmc = 6274637 | doi = 10.1186/s40345-018-0135-7 | doi-access = free }} Exposure during any part of the pregnancy is associated with a slight but statistically significant increase in the risks of preterm birth and of a larger-than-usual baby at birth.{{cite journal | vauthors = Callovini T, Montanari S, Bardi F, Barbonetti S, Rossi S, Caso R, Mandracchia G, Margoni S, Brugnami A, Paolini M, Manfredi G, Giudice LL, Segatori D, Zanzarri A, Onori L, Calderoni C, Benini E, Marano G, Massetti M, Fiaschè F, Di Segni F, Janiri D, Simonetti A, Moccia L, Grisoni F, Ruggiero S, Bartolucci G, Biscosi M, Ferrara OM, Bernardi E, Monacelli L, Giannico AM, De Berardis D, Battisti G, Ciliberto M, Brisi C, Lisci FM, D'Onofrio AM, Restaino A, Di Benedetto L, Anesini MB, Boggio G, Specogna E, Crupi A, De Chiara E, Caroppo E, Ieritano V, Monti L, Chieffo DP, Rinaldi L, Camardese G, Cuomo I, Brugnoli R, Kotzalidis GD, Sani G, Mazza M | title = Obstetric Outcomes in Women on Lithium: A Systematic Review and Meta-Analysis | journal = Journal of Clinical Medicine | volume = 13 | issue = 16 | date = August 2024 | page = 4872 | pmid = 39201016 | doi = 10.3390/jcm13164872 | doi-access = free | pmc = 11355283 }}

Lithium is effective for preventing relapse during and after pregnancy. As the risks of stopping Lithium can be significant, patients are sometimes recommended to stay on this medicine while pregnant. Careful weighing of the risks and benefits should be made in consultation with a psychiatric physician.{{Cite web |title=Lithium in pregnancy and breastfeeding |url=https://www.rcpsych.ac.uk/mental-health/treatments-and-wellbeing/lithium-in-pregnancy-and-breastfeeding |access-date=2024-12-05 |website=www.rcpsych.ac.uk |language=en}} The relatively low teratogenic risk of lithium allows such a choice.{{cite journal | vauthors = Singh S, Deep R | title = Pharmacological treatment of bipolar disorder in pregnancy: An update on safety considerations | journal = Indian Journal of Pharmacology | volume = 54 | issue = 6 | pages = 443–451 | date = November 2022 | pmid = 36722556 | pmc = 10043818 | doi = 10.4103/ijp.ijp_407_21 | doi-access = free }} The decision should be made before the start of pregnancy, as there is no reason for stopping lithium once the pregnancy has started.

For patients who are exposed to lithium, or plan to stay on the medication throughout their pregnancy, fetal echocardiography is routinely performed to monitor for cardiac anomalies.{{Cite journal | vauthors = Armstrong C |date=2008-09-15 |title=ACOG Guidelines on Psychiatric Medication Use During Pregnancy and Lactation |url=https://www.aafp.org/pubs/afp/issues/2008/0915/p772.html |journal=American Family Physician |language=en-US |volume=78 |issue=6 |pages=772–778}} Pregnancy is associated with a decrease in blood lithium levels (especially in the first and second trimesters), so more frequent monitoring with an increase in dose may be required to maintain control of symptoms. To prevent postpatrum psychosis, a higher blood lithium level may be desirable in the third trimester.

While lithium is typically the most effective treatment, possible alternatives to Lithium include Lamotrigine and Second generation Antipsychotics for the treatment of acute bipolar depression or for the management of bipolar patients with normal mood during pregnancy.

Initiating lithium immediately after delivery is also effective for preventing postpartum psychosis and postpartum bipolar relapse. This is an acceptable treatment option for women with a history of psychosis limited to the postpartum period. For women with diagnosed bipolar disorder, this provides less protection than maintaining lithium therapy during pregnancy.

While only small amounts of Lithium are transmitted to the infant in breastmilk, there is limited data on the safety of Breastfeeding while on Lithium. Medical evaluation and monitoring of infants consuming breastmilk during maternal prescription may be indicated.{{Cite web | vauthors = Nonacs R |date=2024-11-13 |title=Essential Reads: Lithium and Breastfeeding (2024) - MGH Center for Women's Mental Health |url=https://womensmentalhealth.org/posts/essential-read-lithium-and-breastfeeding/ |access-date=2024-12-05 |language=en-US}}{{Cite web |date=2023-08-14 |title=Pregnancy, breastfeeding and fertility while taking lithium |url=https://www.nhs.uk/medicines/lithium/pregnancy-breastfeeding-and-fertility-while-taking-lithium/#:~:text=Lithium%20and%20breastfeeding,you%20are%20planning%20to%20breastfeed. |access-date=2024-12-05 |website=nhs.uk |language=en}}

Lithium has been associated with several forms of kidney injury.{{cite journal | vauthors = Nielsen J, Kwon TH, Christensen BM, Frøkiaer J, Nielsen S | title = Dysregulation of renal aquaporins and epithelial sodium channel in lithium-induced nephrogenic diabetes insipidus | journal = Seminars in Nephrology | volume = 28 | issue = 3 | pages = 227–244 | date = May 2008 | pmid = 18519084 | doi = 10.1016/j.semnephrol.2008.03.002 }}{{cite journal | vauthors = Alexander MP, Farag YM, Mittal BV, Rennke HG, Singh AK | title = Lithium toxicity: a double-edged sword | journal = Kidney International | volume = 73 | issue = 2 | pages = 233–237 | date = January 2008 | pmid = 17943083 | doi = 10.1038/sj.ki.5002578 | doi-access = free }} It is estimated that impaired urinary concentrating ability is present in at least half 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 insipidus.{{cite journal | vauthors = Sands JM, Bichet DG | title = Nephrogenic diabetes insipidus | journal = Annals of Internal Medicine | volume = 144 | issue = 3 | pages = 186–194 | date = February 2006 | pmid = 16461963 | doi = 10.7326/0003-4819-144-3-200602070-00007 | s2cid = 6732380 }}{{cite journal | vauthors = Garofeanu CG, Weir M, Rosas-Arellano MP, Henson G, Garg AX, Clark WF | title = Causes of reversible nephrogenic diabetes insipidus: a systematic review | journal = American Journal of Kidney Diseases | volume = 45 | issue = 4 | pages = 626–637 | date = April 2005 | pmid = 15806465 | doi = 10.1053/j.ajkd.2005.01.008 }} In rare cases, some forms of lithium-caused kidney damage may be progressive and lead to end-stage kidney failure with a reported incidence of 0.2% to 0.7%.{{cite journal | vauthors = Presne C, Fakhouri F, Noël LH, Stengel B, Even C, Kreis H, Mignon F, Grünfeld JP | title = Lithium-induced nephropathy: Rate of progression and prognostic factors | journal = Kidney International | volume = 64 | issue = 2 | pages = 585–592 | date = August 2003 | pmid = 12846754 | doi = 10.1046/j.1523-1755.2003.00096.x | doi-access = free }}

Some reports of kidney damage may be wrongly attributed to lithium, increasing the apparent rate of this adverse effect. Nielsen et al. (2018), citing 6 large observational studies since 2010, argue that findings of decreased kidney function are partially inflated by surveillance bias. Furthermore, modern data does not show that lithium increases the risk of end-stage kidney disease. Davis et al. (2018), using literature from a wider timespan (1977–2018), also found that lithium's association with chronic kidney disease is unproven with various contradicting results. They also find contradicting results regarding end-stage kidney disease.{{cite journal | vauthors = Davis J, Desmond M, Berk M | title = Lithium and nephrotoxicity: Unravelling the complex pathophysiological threads of the lightest metal | journal = Nephrology | volume = 23 | issue = 10 | pages = 897–903 | date = October 2018 | pmid = 29607573 | doi = 10.1111/nep.13263 | publisher = Wiley | s2cid = 4552345 | doi-access = free | hdl = 11343/283773 | hdl-access = free }}

A 2015 nationwide study suggests that chronic kidney disease can be avoided by maintaining the serum lithium concentration at a level of 0.6–0.8 mmol/L and by monitoring serum creatinine every 3–6 months.

Lithium-associated hyperparathyroidism is the leading cause of hypercalcemia in lithium-treated patients. Lithium may lead to exacerbation of pre-existing primary hyperparathyroidism or cause an increased set-point of calcium for parathyroid hormone suppression, leading to parathyroid hyperplasia.

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.{{cite web|title=Lithium|url=http://www.webmd.com/vitamins-supplements/ingredientmono-1065-lithium.aspx?activeingredientid=1065&activeingredientname=lithium|website=WebMD|access-date=1 November 2014|url-status=live|archive-url=https://web.archive.org/web/20141102130014/http://www.webmd.com/vitamins-supplements/ingredientmono-1065-lithium.aspx?activeingredientid=1065&activeingredientname=lithium|archive-date=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.{{cite journal | vauthors = Finley PR, O'Brien JG, Coleman RW | title = Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction | journal = Journal of Clinical Psychopharmacology | volume = 16 | issue = 1 | pages = 68–71 | date = February 1996 | pmid = 8834421 | doi = 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.{{cite journal | vauthors = Oruch R, Elderbi MA, Khattab HA, Pryme IF, Lund A | title = Lithium: a review of pharmacology, clinical uses, and toxicity | journal = European Journal of Pharmacology | volume = 740 | issue = 740 | pages = 464–473 | date = October 2014 | pmid = 24991789 | doi = 10.1016/j.ejphar.2014.06.042 }} 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.

Some drugs 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.{{cite book| vauthors = Alldredge BK, Corelli RL, Ernst ME |title=Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs|date=1 February 2012|publisher=Lippincott Williams & Wilkins|location=Baltimore|isbn=978-1-60913-713-7|page=1991|edition=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.{{cite web| vauthors = Boyer EW |title=Serotonin syndrome|url=http://www.uptodate.com/contents/serotonin-syndrome|work=UpToDate|publisher=Wolters Kluwer|access-date=8 October 2013|url-status=live|archive-url=https://web.archive.org/web/20131216082302/http://www.uptodate.com/contents/serotonin-syndrome|archive-date=16 December 2013}} Lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other antidopaminergic medications.{{cite web| vauthors = Wijdicks EF |title=Neuroleptic malignant syndrome|url=http://www.uptodate.com/contents/neuroleptic-malignant-syndrome|work=UpToDate|publisher=Wolters Kluwer|access-date=8 October 2013|url-status=live|archive-url=https://web.archive.org/web/20131023145556/http://www.uptodate.com/contents/neuroleptic-malignant-syndrome|archive-date=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: ({{cite journal | vauthors = Sandyk R, Hurwitz MD | title = Toxic irreversible encephalopathy induced by lithium carbonate and haloperidol. A report of 2 cases | journal = South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde | volume = 64 | issue = 22 | pages = 875–876 | date = November 1983 | pmid = 6415823 }})({{cite journal | vauthors = Gille M, Ghariani S, Piéret F, Delbecq J, Depré A, Saussu F, de Barsy T | title = [Acute encephalomyopathy and persistent cerebellar syndrome after lithium salt and haloperidol poisoning] | journal = Revue Neurologique | volume = 153 | issue = 4 | pages = 268–270 | date = May 1997 | pmid = 9296146 }})

Indeed, these and other antipsychotics have been associated with an increased risk of lithium neurotoxicity, even with low therapeutic lithium doses.{{cite journal | vauthors = Emilien G, Maloteaux JM | title = Lithium neurotoxicity at low therapeutic doses Hypotheses for causes and mechanism of action following a retrospective analysis of published case reports | journal = Acta Neurologica Belgica | volume = 96 | issue = 4 | pages = 281–293 | date = December 1996 | pmid = 9008777 }}{{cite journal | vauthors = Netto I, Phutane VH | title = Reversible lithium neurotoxicity: review of the literature | journal = The Primary Care Companion for CNS Disorders | volume = 14 | issue = 1 | pages = PCC.11r01197 | date = 2012 | pmid = 22690368 | pmc = 3357580 | doi = 10.4088/PCC.11r01197 }}

A high incidence of seizures has been reported with serotonergic psychedelics like psilocybin and LSD in people taking lithium.{{cite journal | vauthors = Holze F, Liechti ME, Müller F | title = Pharmacological Properties of Psychedelics with a Special Focus on Potential Harms | journal = Current Topics in Behavioral Neurosciences | series = Curr Top Behav Neurosci | volume = | issue = | pages = | date = July 2024 | pmid = 39080236 | doi = 10.1007/7854_2024_510 | url = }}{{cite journal | vauthors = Fradet M, Kelly CM, Donnelly AJ, Suppes T | title = Psilocybin and hallucinogenic mushrooms | journal = CNS Spectr | volume = 29 | issue = 6 | pages = 611–632 | date = December 2024 | pmid = 39789676 | doi = 10.1017/S1092852924002487 | url = }}{{cite book | last=Thomas | first=Kelan | title=Toxicology and Pharmacological Interactions of Classic Psychedelics | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | date=2024 | doi=10.1007/7854_2024_508 | url=https://link.springer.com/10.1007/7854_2024_508 | access-date=14 May 2025 | page=}}{{cite journal | vauthors = Nayak SM, Gukasyan N, Barrett FS, Erowid E, Erowid F, Griffiths RR | title = Classic Psychedelic Coadministration with Lithium, but Not Lamotrigine, is Associated with Seizures: An Analysis of Online Psychedelic Experience Reports | journal = Pharmacopsychiatry | volume = 54 | issue = 5 | pages = 240–245 | date = September 2021 | pmid = 34348413 | doi = 10.1055/a-1524-2794 | doi-access = free }} In an analysis of online reports, 47% of 62{{nbsp}}accounts reported seizures when a psychedelic was taken while on lithium. Of these instances, 39% sought emergency medical treatment.

{{Main|Lithium toxicity}}

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 who 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.{{cite journal | vauthors = Gitlin M | title = Lithium side effects and toxicity: prevalence and management strategies | journal = International Journal of Bipolar Disorders | volume = 4 | issue = 1 | pages = 27 | date = December 2016 | pmid = 27900734 | pmc = 5164879 | doi = 10.1186/s40345-016-0068-y | doi-access = free }}

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.{{cite journal | vauthors = Netto I, Phutane VH | title = Reversible lithium neurotoxicity: review of the literature | journal = The Primary Care Companion for CNS Disorders | volume = 14 | issue = 1 | date = 2012 | pmid = 22690368 | pmc = 3357580 | doi = 10.4088/PCC.11r01197 }}

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.

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.{{cite book | isbn = 978-0-07-162442-8 | title = Goodman and Gilman's The Pharmacological Basis of Therapeutics | edition = 12th | vauthors = Brunton L, Chabner B, Knollman B | year = 2010 | publisher = McGraw-Hill Professional | location = New York | title-link = 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.{{cite journal | vauthors = Massot O, Rousselle JC, Fillion MP, Januel D, Plantefol M, Fillion G | title = 5-HT1B receptors: a novel target for lithium. Possible involvement in mood disorders | journal = Neuropsychopharmacology | volume = 21 | issue = 4 | pages = 530–541 | date = October 1999 | pmid = 10481837 | doi = 10.1016/S0893-133X(99)00042-1 | doi-access = free }} 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.{{cite journal | vauthors = Scheuch K, Höltje M, Budde H, Lautenschlager M, Heinz A, Ahnert-Hilger G, Priller J | title = Lithium modulates tryptophan hydroxylase 2 gene expression and serotonin release in primary cultures of serotonergic raphe neurons | journal = Brain Research | volume = 1307 | pages = 14–21 | date = January 2010 | pmid = 19840776 | doi = 10.1016/j.brainres.2009.10.027 | s2cid = 6045269 }}

Lithium has a plethora of proposed molecular targets:

• Lithium both directly and indirectly inhibits GSK3β (glycogen synthase kinase 3β) which results in the activation of mTOR. This leads to an increase in neuroprotective mechanisms by facilitating the Akt signaling pathway.{{Cite book|title=The Science and Practice of Lithium Therapy| vauthors = Malhi GS, Masson M, Bellivier F |date=2017|publisher=Springer International Publishing|isbn=978-3-319-45923-3|pages=62|oclc=979600268}} GSK-3β is a downstream target of monoamine systems. As such, it is directly implicated in cognition and mood regulation.{{cite journal | vauthors = Einat H, Manji HK | title = Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder | journal = Biological Psychiatry | volume = 59 | issue = 12 | pages = 1160–1171 | date = June 2006 | pmid = 16457783 | doi = 10.1016/j.biopsych.2005.11.004 | s2cid = 20669215 }} 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 neurotrophins. Inhibiton of GSK3β reverses this change.{{cite journal | vauthors = Gould TD, Picchini AM, Einat H, Manji HK | title = Targeting glycogen synthase kinase-3 in the CNS: implications for the development of new treatments for mood disorders | journal = Current Drug Targets | volume = 7 | issue = 11 | pages = 1399–1409 | date = November 2006 | pmid = 17100580 | doi = 10.2174/1389450110607011399 }}{{cite journal | vauthors = Böer U, Cierny I, Krause D, Heinrich A, Lin H, Mayr G, Hiemke C, Knepel W | title = Chronic lithium salt treatment reduces CRE/CREB-directed gene transcription and reverses its upregulation by chronic psychosocial stress in transgenic reporter gene mice | journal = Neuropsychopharmacology | volume = 33 | issue = 10 | pages = 2407–2415 | date = September 2008 | pmid = 18046304 | doi = 10.1038/sj.npp.1301640 | doi-access = free }}{{cite journal | vauthors = Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, Yücel M, Gama CS, Dodd S, Dean B, Magalhães PV, Amminger P, McGorry P, Malhi GS | title = Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors | journal = Neuroscience and Biobehavioral Reviews | volume = 35 | issue = 3 | pages = 804–817 | date = January 2011 | pmid = 20934453 | doi = 10.1016/j.neubiorev.2010.10.001 | s2cid = 11421586 }}
• In addition, several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium.{{cite journal | vauthors = York JD, Ponder JW, Majerus PW | title = Definition of a metal-dependent/Li(+)-inhibited phosphomonoesterase protein family based upon a conserved three-dimensional core structure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 11 | pages = 5149–5153 | date = May 1995 | pmid = 7761465 | pmc = 41866 | doi = 10.1073/pnas.92.11.5149 | doi-access = free | bibcode = 1995PNAS...92.5149Y }}{{cite journal | vauthors = Yenush L, Bellés JM, López-Coronado JM, Gil-Mascarell R, Serrano R, Rodríguez PL | title = A novel target of lithium therapy | journal = FEBS Letters | volume = 467 | issue = 2–3 | pages = 321–325 | date = February 2000 | pmid = 10675562 | doi = 10.1016/s0014-5793(00)01183-2 | s2cid = 43250471 | doi-access = free | bibcode = 2000FEBSL.467..321Y }} 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). 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-1.{{cite journal | vauthors = Toledano E, Ogryzko V, Danchin A, Ladant D, Mechold U | title = 3'-5' phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo | journal = The Biochemical Journal | volume = 443 | issue = 2 | pages = 485–490 | date = April 2012 | pmid = 22240080 | pmc = 3316155 | doi = 10.1042/BJ20111057 }}
• Another mechanism proposed in 2007 is that lithium may interact with nitric oxide (NO) signaling 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.{{cite journal | vauthors = Ghasemi M, Sadeghipour H, Mosleh A, Sadeghipour HR, Mani AR, Dehpour AR | title = Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test | journal = European Neuropsychopharmacology | volume = 18 | issue = 5 | pages = 323–332 | date = May 2008 | pmid = 17728109 | doi = 10.1016/j.euroneuro.2007.07.011 | s2cid = 44805917 }}{{cite journal | vauthors = Ghasemi M, Sadeghipour H, Poorheidari G, Dehpour AR | title = A role for nitrergic system in the antidepressant-like effects of chronic lithium treatment in the mouse forced swimming test | journal = Behavioural Brain Research | volume = 200 | issue = 1 | pages = 76–82 | date = June 2009 | pmid = 19166880 | doi = 10.1016/j.bbr.2008.12.032 | s2cid = 22656735 }}
• It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test,{{cite journal | vauthors = Ghasemi M, Raza M, Dehpour AR | title = NMDA receptor antagonists augment antidepressant-like effects of lithium in the mouse forced swimming test | journal = Journal of Psychopharmacology | volume = 24 | issue = 4 | pages = 585–594 | date = April 2010 | pmid = 19351802 | doi = 10.1177/0269881109104845 | s2cid = 41634565 }} 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.{{cite journal | vauthors = Malhi GS, Tanious M, Das P, Coulston CM, Berk M | title = Potential mechanisms of action of lithium in bipolar disorder. Current understanding | journal = CNS Drugs | volume = 27 | issue = 2 | pages = 135–153 | date = February 2013 | pmid = 23371914 | doi = 10.1007/s40263-013-0039-0 | hdl-access = free | s2cid = 26907074 | hdl = 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 unlikely.{{Cite book|title=Lithium and the Cell: Pharmacology and Biochemistry|vauthors=Birch NJ|url=https://books.google.com/books?id=HJtu3PqpAKgC&q=theoretic+%22lithium+receptor%22&pg=PA113|isbn=978-0-08-098429-2|date=2 December 2012|publisher=Academic Press|access-date=9 October 2020|archive-date=26 February 2024|archive-url=https://web.archive.org/web/20240226075322/https://books.google.com/books?id=HJtu3PqpAKgC&q=theoretic+%22lithium+receptor%22&pg=PA113#v=snippet&q=theoretic%20%22lithium%20receptor%22&f=false|url-status=live}}

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 complexes I and II of the mitochondrial electron transport chain.

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 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, leading to a homeostatic increase in glutamate re-uptake which reduces glutamatergic transmission.

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 cesium.

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.{{cite journal | vauthors = Brunello N, Tascedda F | title = Cellular mechanisms and second messengers: relevance to the psychopharmacology of bipolar disorders | journal = The International Journal of Neuropsychopharmacology | volume = 6 | issue = 2 | pages = 181–189 | date = June 2003 | pmid = 12890311 | doi = 10.1017/s1461145703003419 | doi-access = free | hdl = 11380/305821 | hdl-access = free }} 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.{{Cite book|title=The Science and Practice of Lithium Therapy| vauthors = Malhi GS, Masson M, Bellivier F |date=2017 |publisher=Springer International Publishing |isbn=978-3-319-45923-3 |pages=61 |oclc=979600268 }}

Lithium's therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms.{{cite journal | vauthors = Alda M | title = Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics | journal = Molecular Psychiatry | volume = 20 | issue = 6 | pages = 661–670 | date = June 2015 | pmid = 25687772 | pmc = 5125816 | doi = 10.1038/mp.2015.4 }} 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.

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.{{cite journal | vauthors = Einat H, Kofman O, Itkin O, Lewitan RJ, Belmaker RH | title = Augmentation of lithium's behavioral effect by inositol uptake inhibitors | journal = Journal of Neural Transmission | volume = 105 | issue = 1 | pages = 31–38 | year = 1998 | pmid = 9588758 | doi = 10.1007/s007020050035 | s2cid = 6707456 }} 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 are affected by lithium.{{cite journal | vauthors = Jope RS | title = Anti-bipolar therapy: mechanism of action of lithium | journal = Molecular Psychiatry | volume = 4 | issue = 2 | pages = 117–128 | date = March 1999 | pmid = 10208444 | doi = 10.1038/sj.mp.4000494 | doi-access = free }} myo-inositol is also regulated by the high affinity sodium mI transport system (SMIT). Lithium is hypothesized to inhibit mI entering the cells and mitigate the function of SMIT. Reductions of cellular levels of myo-inositol results in the inhibition of the phosphoinositide cycle.

Lithium's actions on Gsk3 result in activation of CREB, leading to higher expression of BDNF. (Valproate, another mood stabilizer, also increases the expression of BDNF.) As expected of increased BDNF expression, chronic lithium treatment leads to increased grey matter volume in brain areas implicated in emotional processing and cognitive control.{{cite journal | vauthors = Quiroz JA, Machado-Vieira R, Zarate CA, Manji HK | title = Novel insights into lithium's mechanism of action: neurotrophic and neuroprotective effects | journal = Neuropsychobiology | volume = 62 | issue = 1 | pages = 50–60 | date = 2010 | pmid = 20453535 | doi = 10.1159/000314310 | pmc = 2889681 }} Bipolar patients treated with lithium also have higher white matter integrity compared to those taking other drugs.{{cite journal | vauthors = Necus J, Sinha N, Smith FE, Thelwall PE, Flowers CJ, Taylor PN, Blamire AM, Cousins DA, Wang Y | title = White matter microstructural properties in bipolar disorder in relationship to the spatial distribution of lithium in the brain | journal = Journal of Affective Disorders | volume = 253 | pages = 224–231 | date = June 2019 | pmid = 31054448 | doi = 10.1016/j.jad.2019.04.075 | pmc = 6609924 }}

Lithium also increases the expression of mesencephalic astrocyte-derived neurotrophic factor (MANF), another neurotrophic factor, via the AP-1 transcription factor. MANF is able to regulate proteostasis by interacting with GRP78, a protein involved in the unfolded protein response.{{cite journal | vauthors = Abu-Hijleh FA, Prashar S, Joshi H, Sharma R, Frey BN, Mishra RK | title = Novel mechanism of action for the mood stabilizer lithium | journal = Bipolar Disorders | volume = 23 | issue = 1 | pages = 76–83 | date = February 2021 | pmid = 33037686 | doi = 10.1111/bdi.13019 | s2cid = 222257563 }}

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.{{cite journal | vauthors = Marmol F | title = Lithium: bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 32 | issue = 8 | pages = 1761–1771 | date = December 2008 | pmid = 18789369 | doi = 10.1016/j.pnpbp.2008.08.012 | s2cid = 25861243 }} Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange in Denmark and William Alexander Hammond in New York City 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, several lithium preparations were still produced for the control of renal calculi and uric acid diathesis.{{cite journal | vauthors = Shorter E | title = The history of lithium therapy | journal = Bipolar Disorders | volume = 11 | issue = Suppl 2 | pages = 4–9 | date = June 2009 | pmid = 19538681 | pmc = 3712976 | doi = 10.1111/j.1399-5618.2009.00706.x }} 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 the United States in February 1949, following the publication of reports detailing side effects and deaths.{{Cite web |title=Lithium: Discovered, Forgotten and Rediscovered |url=https://inhn.org/inhn-projects/archives/gershon-collection/lithium-discovered-forgotten-and-rediscovered |access-date=12 March 2023 |website=inhn.org |archive-date=12 March 2023 |archive-url=https://web.archive.org/web/20230312053117/https://inhn.org/inhn-projects/archives/gershon-collection/lithium-discovered-forgotten-and-rediscovered |url-status=live }}

Also in 1949, the Australian psychiatrist John Cade and Australian biochemist Shirley Andrews rediscovered the usefulness of lithium salts in treating mania while working at the Royal Park Psychiatric Hospital in Victoria.{{Cite web |title=Obituary – Shirley Aldythea Andrews – Obituaries Australia |url=https://oa.anu.edu.au/obituary/andrews-shirley-aldythea-14936 |access-date=26 October 2022 |website=oa.anu.edu.au |archive-date=26 October 2022 |archive-url=https://web.archive.org/web/20221026235753/https://oa.anu.edu.au/obituary/andrews-shirley-aldythea-14936 |url-status=live }} They were injecting rodents with urine extracts taken from manic 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), they needed soluble urate for a control. They used lithium urate, already known to be the most soluble urate compound, and observed that it caused the rodents to become tranquil. Cade and Andrews traced the effect to the lithium-ion itself, and after Cade ingested 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.{{cite journal | vauthors = Cade JF | title = Lithium salts in the treatment of psychotic excitement | journal = The Medical Journal of Australia | volume = 2 | issue = 10 | pages = 349–352 | date = September 1949 | pmid = 18142718 | pmc = 2560740 | doi = 10.1080/j.1440-1614.1999.06241.x | url = https://www.who.int/docstore/bulletin/pdf/2000/issue4/classics.pdf | url-status = live | archive-url = https://web.archive.org/web/20060525012749/http://www.who.int/docstore/bulletin/pdf/2000/issue4/classics.pdf | archive-date = 25 May 2006 }}

The rest of the world was slow to adopt this treatment, largely because of deaths that resulted from even relatively minor overdosing, including those reported from the 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. Following the recommendation of the APA Lithium Task Force (William Bunney, Irvin Cohen (Chair), Jonathan Cole, Ronald R. Fieve, Samuel Gershon, Robert Prien, and Joseph Tupin{{cite journal | vauthors = Fieve RR | title = Lithium therapy at the millennium: a revolutionary drug used for 50 years faces competing options and possible demise | journal = Bipolar Disorders | volume = 1 | issue = 2 | pages = 67–70 | date = December 1999 | pmid = 11252660 | doi = 10.1034/j.1399-5618.1999.010201.x }}), the application of lithium in manic illness was approved by the United States Food and Drug Administration in 1970,{{cite journal | vauthors = Mitchell PB, Hadzi-Pavlovic D | title = Lithium treatment for bipolar disorder | journal = Bulletin of the World Health Organization | volume = 78 | issue = 4 | pages = 515–517 | year = 2000 | pmid = 10885179 | pmc = 2560742 | url = https://www.who.int/docstore/bulletin/pdf/2000/issue4/classics.pdf | url-status = live | archive-url = https://web.archive.org/web/20060525012749/http://www.who.int/docstore/bulletin/pdf/2000/issue4/classics.pdf | archive-date = 25 May 2006 }} becoming the 50th nation to do so.

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,{{Cite news | vauthors = Agassi T |title = Sting is now older, wiser and duller |newspaper = The Jerusalem Post | date = 12 March 1996 | url = https://pqasb.pqarchiver.com/jpost/access/62551750.html?dids=62551750:62551750&FMT=ABS&FMTS=ABS:FT&date=Mar+12%2C+1996&author=TIRZAH+AGASSI&pub=Jerusalem+Post&desc=Sting+is+now+older%2C+wiser+and+duller |access-date = 25 June 2009 |url-status = dead |archive-url = https://web.archive.org/web/20120513213243/http://pqasb.pqarchiver.com/jpost/access/62551750.html?dids=62551750%3A62551750&FMT=ABS&FMTS=ABS%3AFT&date=Mar+12%2C+1996&author=TIRZAH+AGASSI&pub=Jerusalem+Post&desc=Sting+is+now+older%2C+wiser+and+duller |archive-date = 13 May 2012 }}

and "Lithium" by Thin White Rope.

As with cocaine in Coca-Cola, lithium was widely marketed as one of several patent medicine products popular in the late 19th and early 20th centuries and was claimed to be included in many drinks including lithia water and 7 Up.

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, at one point named "7Up Lithiated Lemon Soda", was launched two weeks before the Wall Street Crash of 1929."[https://web.archive.org/web/20080430022917/http://www.brandspeoplelove.com/csab/?TabId=148 7 UP: The Making of a Legend]". Cadbury Schweppes: America's Beverages. It claimed to contain the mood stabilizer lithium citrate, and was one of many patent medicine products popular in the late-19th and early-20th centuries.{{cite web |url=http://www.snopes.com/business/names/7up.asp |title=Urban Legends Reference Pages: 7Up |date=6 August 2004 |access-date=13 November 2007 |archive-date=6 May 2023 |archive-url=https://web.archive.org/web/20230506142602/https://www.snopes.com/fact-check/7up/ |url-status=live }} All references to lithium were removed in 1937 after it became clear that 7Up contains no lithium.{{Cite journal | vauthors = Lockhart B, Brown R |date=2024 |title=The Seven-Up Company and 7-Up Bottles The Real Story: A Look at the Myths, the Mystery, and the Magic |url=https://sha.org/bottle/pdffiles/7-UpStudy1.pdf |journal=Society for Historical Archaeology}} [https://sha.org/bottle/pdffiles/7-UpStudy2.pdf Chapter 1] [https://sha.org/bottle/pdffiles/7-UpStudy2.pdf Chapter 2]{{rp|§2}}

Many sources written by scientists (instead of historians) incorrectly report that 7 Up was forced to remove lithium in 1948, with an FDA action that supposedly banned lithium from beverages.{{Cite book | vauthors = Gielen M, Tiekink ER | title = Metallotherapeutic drugs and metal-based diagnostic agents: The use of metals in medicine | publisher = John Wiley and Sons | year = 2005 | page = 3 | isbn = 0-470-86403-6 }} Despite the supposed ban, in 1950, the Painesville Telegraph still carried an advertisement for a lithiated lemon beverage.{{cite news |title=ISALLY'S (ad) |author=anonymous |url=https://news.google.com/newspapers?id=t_FgAAAAIBAJ&pg=5399,1113713&dq=lithiated+lemon&hl=en |newspaper=Painesville Telegraph |date=13 July 1950 |access-date=8 September 2013 |archive-date=28 August 2021 |archive-url=https://web.archive.org/web/20210828145654/https://news.google.com/newspapers?id=t_FgAAAAIBAJ&pg=5399%2C1113713&dq=lithiated+lemon&hl=en |url-status=live }}

Lithium carbonate ({{chem|Li|2|CO|3}}) is the most commonly used form of lithium salts, a carbonic acid involving the lithium element and a carbonate ion. Other lithium salts are also used as medication, such as lithium citrate ({{chem|Li|3|C|6|H|5|O|7}}), lithium sulfate, lithium chloride, and lithium orotate.{{cite journal | vauthors = Wen J, Sawmiller D, Wheeldon B, Tan J | title = A Review for Lithium: Pharmacokinetics, Drug Design, and Toxicity | journal = CNS & Neurological Disorders Drug Targets | volume = 18 | issue = 10 | pages = 769–778 | date = 17 January 2020 | pmid = 31724518 | doi = 10.2174/1871527318666191114095249 | s2cid = 208019043 }}{{cite web |title=How and when to take lithium |url=https://www.nhs.uk/medicines/lithium/how-and-when-to-take-lithium/ |website=nhs.uk |access-date=6 December 2023 |date=14 August 2023 |archive-date=26 October 2023 |archive-url=https://web.archive.org/web/20231026075914/https://www.nhs.uk/medicines/lithium/how-and-when-to-take-lithium/ |url-status=live }} Nanoparticles and microemulsions have also been invented as drug delivery mechanisms. As of 2020, there is a lack of evidence that alternate formulations or salts of lithium would reduce the need for monitoring serum lithium levels or lower systemic toxicity.

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, 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.{{cite web|title=Lithium brands|url=https://www.drugs.com/international/lithium.html|publisher=Drugs.com|access-date=4 April 2017|url-status=live|archive-url=https://web.archive.org/web/20170405073627/https://www.drugs.com/international/lithium.html|archive-date=5 April 2017}}

Tentative evidence in Alzheimer's disease showed that lithium may slow progression.{{cite journal | vauthors = Forlenza OV, de Paula VJ, Machado-Vieira R, Diniz BS, Gattaz WF | title = Does lithium prevent Alzheimer's disease? | journal = Drugs & Aging | volume = 29 | issue = 5 | pages = 335–342 | date = May 2012 | pmid = 22500970 | doi = 10.2165/11599180-000000000-00000 | s2cid = 23864616 }}{{cite journal | vauthors = Wilson EN, Do Carmo S, Welikovitch LA, Hall H, Aguilar LF, Foret MK, Iulita MF, Jia DT, Marks AR, Allard S, Emmerson JT, Ducatenzeiler A, Cuello AC | title = NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats | journal = Journal of Alzheimer's Disease | volume = 73 | issue = 2 | pages = 723–739 | date = 2020 | pmid = 31868669 | doi = 10.3233/JAD-190862 | s2cid = 209448822 }} It has been studied for its potential use in the treatment of amyotrophic lateral sclerosis (ALS), but a study showed lithium had no effect on ALS outcomes.{{cite journal | vauthors = Ludolph AC, Brettschneider J, Weishaupt JH | title = Amyotrophic lateral sclerosis | journal = Current Opinion in Neurology | volume = 25 | issue = 5 | pages = 530–535 | date = October 2012 | pmid = 22918486 | doi = 10.1097/WCO.0b013e328356d328 }}

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• {{cite book | vauthors = Mota de Freitas D, Leverson BD, Goossens JL | chapter = Lithium in Medicine: Mechanisms of Action | title = Metal ions in Life Sciences | volume = 16 | pages = 557–584 | date = 2016 | pmid = 26860311 | doi = 10.1007/978-3-319-21756-7_15 | publisher = Springer | veditors = Sigel A, Sigel H, Sigel R | isbn = 978-3-319-21755-0 }}
• {{cite web | vauthors = Phelps J | date = 19 September 2014 | url = https://psycheducation.org/blog/lithium-basics/ | title = Lithium Basics | work = Psych | access-date = 11 February 2022 | archive-date = 11 February 2022 | archive-url = https://web.archive.org/web/20220211060657/https://psycheducation.org/blog/lithium-basics/ | url-status = live }}
• {{cite web | vauthors = Phillips ML | date = 16 February 2006 | title = Exposing lithium's circadian action | url = https://www.the-scientist.com/daily-news/exposing-lithiums-circadian-action-47818 | work = The Scientist | access-date = 17 August 2018 | archive-date = 8 August 2020 | archive-url = https://web.archive.org/web/20200808124701/https://www.the-scientist.com/daily-news/exposing-lithiums-circadian-action-47818 | url-status = live }}

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• {{cite web | title = Mood Stabilizers: An Updated List and Links | date = April 2004 | url = http://www.psycheducation.org/depression/meds/moodstabilizers.htm | archive-url = https://web.archive.org/web/20040811012851/http://www.psycheducation.org/depression/meds/moodstabilizers.htm | archive-date = 11 August 2004 | work = PsychEducation.org }}

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Category:Biology and pharmacology of chemical elements

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Category:Lithium

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Category:World Health Organization essential medicines

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