|By mouth, parenteral|
|Drug class||Mood stabilizer|
|Bioavailability||depends on formulation|
|Elimination half-life||24 h, 36 h (elderly)|
|Chemical and physical data|
|Molar mass||6.941 g/mol|
|3D model (JSmol)|
Lithium compounds, also known as lithium salts, are primarily used as a psychiatric medication. They are primarily used to treat bipolar disorder and treat major depressive disorder that does not improve following the use of antidepressants. In these disorders, it reduces the risk of suicide. Lithium is taken orally.
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. 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. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2017, it was the 180th most commonly prescribed medication in the United States, with more than three million prescriptions.
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. This benefit is not seen with other medications.
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. 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. A limited amount of evidence suggests lithium carbonate may contribute to treatment of substance use disorders for some people with bipolar disorder.
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.
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.
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.
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.
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 to 1.2 mmol 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.
- Very Common (> 10% incidence) adverse effects of lithium include
- 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)
- Hyperreflexia — overresponsive reflexes.
- Leukocytosis — elevated white blood cell count
- Muscle weakness (usually transient, but can persist in some)
- Myoclonus — muscle twitching.
- Nausea (usually transient, but can persist in some)
- Polydipsia — increased thirst.
- Polyuria — increased urination.
- Renal (kidney) toxicity which may lead to chronic kidney failure
- Vomiting (usually transient, but can persist in some)
- Weight gain
- Common (1–10%) adverse effects include
- 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.
- Hair loss/hair thinning
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.
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. It increases the appetite and thirst ("polydypsia") and reduces the activity of thyroid hormone (hypothyroidism). 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?], although this does not appear to be common.
Pregnancy and breast feeding
Lithium is a teratogen, causing birth defects in a small number of newborn babies. 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. 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. Gabapentin and clonazepam are also indicated as antipanic medications during the childbearing years and during pregnancy. Valproic acid and carbamazepine also tend to be associated with teratogenicity.
Lithium has been associated with several forms of kidney injury. 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 insipidus 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.
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.
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. 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. 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.
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. Lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other antidopaminergic medications.
High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported. Indeed, these and other antipsychotics have been associated with increased risk of lithium neurotoxicity, even with low therapeutic lithium doses.
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.
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.
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.
Unlike many other psychoactive drugs, 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. 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.
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. Importantly, GSK-3β is a downstream target of monoamine systems. As such, it is directly implicated in cognition and mood regulation. 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 In addition, several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium. 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-1
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. It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test, indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of learned helplessness.
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.
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 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. 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.
Cyclic AMP secondary messengers
Lithium's therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms. 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. 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. 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
Various neurotrophic factors such as BDNF and mesencephalic astrocyte-derived neurotrophic factor have been shown to be modulated by various mood stabilizers.
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. 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, a number of lithium preparations were still produced for the control of renal calculi and uric acid diathesis. 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 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), 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.
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. 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, and "Lithium" by Thin White Rope.
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. 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. 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.
Salts and product names
Lithium carbonate (Li
3), sold under several trade names, is the most commonly prescribed, while lithium citrate (Li
7) is also used in conventional pharmacological treatments. Lithium orotate (C
4), has been presented as an alternative. 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 as toxic or more so than the chloride 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.
Tentative evidence in Alzheimer's disease showed that lithium may slow progression. 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.
- "Lithium brands". Drugs.com. Archived from the original on 5 April 2017. Retrieved 4 April 2017.
- "Lithium Salts". The American Society of Health-System Pharmacists. Archived from the original on 2015-12-08. Retrieved Dec 1, 2015.
- Cipriani, A; Hawton, K; Stockton, S; Geddes, JR (27 June 2013). "Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis". BMJ (Clinical Research Ed.). 346: f3646. doi:10.1136/bmj.f3646. PMID 23814104.
- "Lithium use while Breastfeeding". LactMed. 2015-03-10. Archived from the original on 8 December 2015. Retrieved 1 December 2015.
- Sneader, Walter (2005). Drug discovery : a history (Rev. and updated ed.). Chichester: Wiley. p. 63. ISBN 9780471899792. Archived from the original on 2017-09-08.
- World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
- "The Top 300 of 2020". ClinCalc. Retrieved 11 April 2020.
- "Lithium - Drug Usage Statistics". ClinCalc. Retrieved 11 April 2020.
- Cipriani, A.; Hawton, K.; Stockton, S.; Geddes, JR. (2013). "Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis". BMJ. 346: f3646. doi:10.1136/bmj.f3646. PMID 23814104.
- Müller-Oerlinghausen, B; Berghöfer, A; Ahrens, B (2003). "The Antisuicidal and Mortality-Reducing Effect of Lithium Prophylaxis: Consequences for Guidelines in Clinical Psychiatry". Canadian Journal of Psychiatry. 48 (7): 433–9. doi:10.1177/070674370304800702. PMID 12971012. Archived from the original on 2011-07-25.
- Kovacsics, Colleen E.; Gottesman, Irving I.; Gould, Todd D. (2009). "Lithium's Antisuicidal Efficacy: Elucidation of Neurobiological Targets Using Endophenotype Strategies". Annual Review of Pharmacology and Toxicology. 49: 175–198. doi:10.1146/annurev.pharmtox.011008.145557. PMID 18834309.
- McKnight, RF; de La Motte de Broöns de Vauvert, SJGN; Chesney, E; Amit, BH; Geddes, J; Cipriani, A (1 June 2019). "Lithium for acute mania". The Cochrane Database of Systematic Reviews. 6: CD004048. doi:10.1002/14651858.CD004048.pub4. PMC 6544558. PMID 31152444.
- Semple, David "Oxford Hand Book of Psychiatry" Oxford Press. 2005.[page needed]
- Rosenberg, J.; Salzman, C. (2007). "Update: New uses for lithium and anticonvulsants". CNS Spectrums. 12 (11): 831–841. doi:10.1017/S1092852900015571. PMID 17984856. S2CID 26227696.
- Frye, M. A.; Salloum, I. M. (2006). "Bipolar disorder and comorbid alcoholism: Prevalence rate and treatment considerations". Bipolar Disorders. 8 (6): 677–685. doi:10.1111/j.1399-5618.2006.00370.x. PMID 17156154.
- Vornik, L.; Brown, E. (2006). "Management of comorbid bipolar disorder and substance abuse". The Journal of Clinical Psychiatry. 67 Suppl 7: 24–30. PMID 16961421.
- Bauer, M; Adli, M; Ricken, R; Severus, E; Pilhatsch, M (April 2014). "Role of lithium augmentation in the management of major depressive disorder". CNS Drugs. 28 (4): 331–42. doi:10.1007/s40263-014-0152-8. PMID 24590663. S2CID 256840.
- Healy D. 2005. Psychiatric Drugs Explained. 4th ed. Churchhill Livingstone: London.[page needed]
- Amdisen A. (1978). "Clinical and serum level monitoring in lithium therapy and lithium intoxication". J. Anal. Toxicol. 2 (5): 193–202. doi: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.
- 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 Camcolit 250 mg Lithium Carbonate Archived 2016-03-04 at the Wayback Machine Revision 2 December 2010, Retrieved 5 May 2011
- One study (Solomon, D.; Ristow, W.; Keller, M.; Kane, J.; Gelenberg, A.; Rosenbaum, J.; Warshaw, M. (1996). "Serum lithium levels and psychosocial function in patients with bipolar I disorder". The American Journal of Psychiatry. 153 (10): 1301–1307. doi:10.1176/ajp.153.10.1301. PMID 8831438.) 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 (Perlis, R.; Sachs, G.; Lafer, B.; Otto, M.; Faraone, S.; Kane, J.; Rosenbaum, J. (2002). "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. doi:10.1176/appi.ajp.159.7.1155. PMID 12091193.) concluded the higher rate of relapse for the "low" dose was due to abrupt changes in the lithium serum levels[improper synthesis?]
- DrugPoint® System (Internet). Truven Health Analytics, Inc. Greenwood Village, CO: Thomsen Healthcare. 2013.
- Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty. Ltd. 2013. ISBN 9780980579086.
- Joint Formulary Committee (2013). British National Formulary (BNF) 65. London, UK: Pharmaceutical Press. pp. 240–242. ISBN 9780857110848.
- "lithium (Rx) - Eskalith, Lithobid". Medscape. WebMD. Archived from the original on 4 December 2013. Retrieved 7 October 2013.
- "Lithobid (lithium carbonate) tablet, film coated, extended release". National Library of Medicine. Noven Theraputics, LLC. Archived from the original on 5 October 2013. Retrieved 7 October 2013 – via DailyMed.
- "Product Information Lithicarb (Lithium carbonate)". TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. Archived from the original on 22 March 2017. Retrieved 7 October 2013.
- 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. doi:10.1177/0269881115573808. PMID 25735990. S2CID 9496408.
- Malhi, Gin S.; Tanious, Michelle; Bargh, Danielle; Das, Pritha; Berk, Michael (2013). "Safe and effective use of lithium". Australian Prescriber. 36: 18–21. doi:10.18773/austprescr.2013.008. Australian Prescriber
- Sperner-Unterweger, Barbara; W. Wolfgang Fleischhacker; Wolfgang P. Kaschka (2001). Psychoneuroimmunology. Karger Publishers. p. 22. ISBN 978-3-8055-7262-0.
- Silver, M; Factor, S (2015). "Chapter 12: VPA, lithium, amiodarone, and other non-DA". In Friedman, J (ed.). Medication-Induced Movement Disorders. Cambridge University Press. pp. 131–140. ISBN 978-1-107-06600-7.
- Wetzels, J.F.; van Bergeijk, J.D.; Hoitsma, A.J.; Huysmans, F.T.; Koene, R.A. (1989). "Triamterene increases lithium excretion in healthy subjects: Evidence for lithium transport in the cortical collecting tubule". Nephrology, Dialysis, Transplantation. 4 (11): 939–942. doi:10.1093/ndt/4.11.939. PMID 2516883.
- Keshavan, Matcheri S.; John S. Kennedy (2001). Drug-induced dysfunction in psychiatry. Taylor & Francis. p. 305. ISBN 978-0-89116-961-1.
- "Safer lithium therapy". NHS National Patient Safety Agency. 1 December 2009. Archived from the original on 30 January 2010.
- 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): 219–224. doi:10.1038/ki.2009.433. PMID 19940841.
- Shepard, T.H.; Brent, R.L.; Friedman, J.M.; Jones, K.L.; Miller, R.K.; Moore, C.A.; Polifka, J.E. (2002). "Update on new developments in the study of human teratogens". Teratology. 65 (4): 153–161. doi:10.1002/tera.10032. PMID 11948561.
- Yacobi, S.; Ornoy, A. (2008). "Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review". The Israel Journal of Psychiatry and Related Sciences. 45 (2): 95–106. PMID 18982835.
- Epstein, R.A.; Moore, K.M.; Bobo, W.V. (2015). "Treatment of bipolar disorders during pregnancy: Maternal and fetal safety and challenges". Drug, Healthcare and Patient Safety. 7: 7–29. doi:10.2147/DHPS.S50556. PMC 4284049. PMID 25565896.
- Montouris, G. (2003). "Gabapentin exposure in human pregnancy: Results from the Gabapentin Pregnancy Registry". Epilepsy & Behavior. 4 (3): 310–317. doi:10.1016/S1525-5050(03)00110-0. PMID 12791334. S2CID 902424.
- Weinstock, L.; Cohen, L.S.; Bailey, J.W.; Blatman, R.; Rosenbaum, J.F. (2001). "Obstetrical and neonatal outcome following clonazepam use during pregnancy: A case series". Psychotherapy and Psychosomatics. 70 (3): 158–162. doi:10.1159/000056242. PMID 11340418. S2CID 25166015.
- "Lithium carbonate". Archived from the original on 25 October 2016. Retrieved 25 May 2016.
- 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. doi:10.1016/j.semnephrol.2008.03.002. PMID 18519084.
- 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. doi:10.1038/sj.ki.5002578. PMID 17943083.
- Sands, J.M.; Bichet, D.G. (February 2006). "Nephrogenic diabetes insipidus". Ann Intern Med. 144 (3): 186–194. doi:10.7326/0003-4819-144-3-200602070-00007. PMID 16461963. S2CID 6732380.
- 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. doi:10.1053/j.ajkd.2005.01.008. PMID 15806465.
- 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. doi:10.1046/j.1523-1755.2003.00096.x. PMID 12846754.
- "Lithium". WebMD. Archived from the original on 2 November 2014. Retrieved 1 November 2014.
- Finley, PR (February 1996). "Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction". J Clin Psychopharmacol. 16 (1): 68–71. doi:10.1097/00004714-199602000-00011. PMID 8834421.
- Oruch, R (October 5, 2014). "Lithium: a review of pharmacology, clinical uses, and toxicity". Eur J Pharmacol. 740 (740): 464–73. doi:10.1016/j.ejphar.2014.06.042. PMID 24991789.
- Brian K. Alldredge; Robin L. Corelli; Michael E. Ernst (2012-02-01). Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs (10th ed.). Baltimore: Lippincott Williams & Wilkins. p. 1991. ISBN 978-1-60913-713-7.
- Boyer, EW. "Serotonin syndrome". UpToDate. Wolters Kluwer. Archived from the original on 16 December 2013. Retrieved 8 October 2013.
- Wijdicks, EFM. "Neuroleptic malignant syndrome". UpToDate. Wolters Kluwer. Archived from the original on 23 October 2013. Retrieved 8 October 2013.
- Case reports: (Sandyk, R.; Hurwitz, M. D. (1983). "Toxic irreversible encephalopathy induced by lithium carbonate and haloperidol. A report of 2 cases". South African Medical Journal. 64 (22): 875–876. PMID 6415823.)(Gille, M.; Ghariani, S.; Piéret, F.; Delbecq, J.; Depré, A.; Saussu, F.; De Barsy, T. (1997). "Acute encephalomyopathy and persistent cerebellar syndrome after lithium salt and haloperidol poisoning". Revue Neurologique. 153 (4): 268–270. PMID 9296146.)
- Emilien, G; Maloteaux, J (1996). "Lithium neurotoxicity at low therapeutic doses". Acta Neurol. Belg. 96 (4): 281–293. PMID 9008777.
- Netto, I; Phutane, V (2012). "Reversible lithium neurotoxicity: review of the literature". Prim Care Companion CNS Disord. 14 (1): PCC.11r01197. doi:10.4088/PCC.11r01197. PMC 3357580. PMID 22690368.
- Gitlin, Michael (2016-12-17). "Lithium side effects and toxicity: prevalence and management strategies". International Journal of Bipolar Disorders. 4 (1): 27. doi:10.1186/s40345-016-0068-y. ISSN 2194-7511. PMC 5164879. PMID 27900734.
- Netto, Ivan; Phutane, Vivek H. (2012). "Reversible Lithium Neurotoxicity: Review of the Literature". The Primary Care Companion for CNS Disorders. 14 (1). doi:10.4088/PCC.11r01197. ISSN 2155-7772. PMC 3357580. PMID 22690368.
- Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
- Massot, O.; Rousselle, J. C.; Fillion, M. P.; Januel, D.; Plantefol, M.; Fillion, G. (1999). "5-HT1B Receptors: A Novel Target for Lithium Possible Involvement in Mood Disorders". Neuropsychopharmacology. 21 (4): 530–541. doi:10.1016/S0893-133X(99)00042-1. PMID 10481837.
- Scheuch, K.; Höltje, M.; Budde, H.; Lautenschlager, M.; Heinz, A.; Ahnert-Hilger, G.; Priller, J. (2010). "Lithium modulates tryptophan hydroxylase 2 gene expression and serotonin release in primary cultures of serotonergic raphe neurons". Brain Research. 1307: 14–21. doi:10.1016/j.brainres.2009.10.027. PMID 19840776. S2CID 6045269.
- Frank., Malhi, Gin S. Masson, Marc. Bellivier (2017). The Science and Practice of Lithium Therapy. Springer International Publishing. p. 62. ISBN 9783319459233. OCLC 979600268.
- 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. doi:10.1016/j.biopsych.2005.11.004. ISSN 0006-3223. PMID 16457783. S2CID 20669215.
- 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. doi:10.2174/1389450110607011399. ISSN 1389-4501. PMID 17100580.
- 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. doi:10.1038/sj.npp.1301640. ISSN 0893-133X. PMID 18046304.
- 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. doi:10.1016/j.neubiorev.2010.10.001. ISSN 0149-7634. PMID 20934453. S2CID 11421586.
- York JD, et al. (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. Bibcode:1995PNAS...92.5149Y. doi:10.1073/pnas.92.11.5149. PMC 41866. PMID 7761465.
- Yenush (2000). "A novel target of lithium therapy". FEBS Lett. 467 (2–3): 321–325. doi:10.1016/s0014-5793(00)01183-2. PMID 10675562. S2CID 43250471.
- Toledano E, et al. (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. doi:10.1042/BJ20111057. PMC 3316155. PMID 22240080.
- Ghasemi M, Sadeghipour H, Mosleh A, Sadeghipour HR, Mani AR, Dehpour AR (May 2008). "Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test". Eur Neuropsychopharmacol. 18 (5): 323–32. doi:10.1016/j.euroneuro.2007.07.011. PMID 17728109. S2CID 44805917.
- Ghasemi M, Sadeghipour H, Poorheidari G, Dehpour AR (June 2009). "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. doi:10.1016/j.bbr.2008.12.032. PMID 19166880. S2CID 22656735.
- Ghasemi M, Raza M, Dehpour AR (April 2010). "NMDA receptor antagonists augment antidepressant-like effects of lithium in the mouse forced swimming test". J. Psychopharmacol. (Oxford). 24 (4): 585–94. doi:10.1177/0269881109104845. PMID 19351802. S2CID 41634565.
- Malhi GS (2013). "Potential mechanisms of action of lithium in bipolar disorder. Current understanding". CNS Drugs. 27 (2): 135–53. doi:10.1007/s40263-013-0039-0. hdl:11343/218106. PMID 23371914. S2CID 26907074.
- Nicholas J. Birch (2012-12-02). Lithium and the Cell: Pharmacology and Biochemistry. ISBN 9780080984292.
- 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. doi:10.1017/s1461145703003419. ISSN 1461-1457. PMID 12890311.
- Frank., Malhi, Gin S. Masson, Marc. Bellivier (2017). The Science and Practice of Lithium Therapy. Springer International Publishing. p. 61. ISBN 9783319459233. OCLC 979600268.
- 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. doi:10.1007/s40263-013-0039-0. hdl:11343/218106. ISSN 1172-7047. PMID 23371914. S2CID 26907074.
- Alda, M (2015-02-17). "Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics". Molecular Psychiatry. 20 (6): 661–670. doi:10.1038/mp.2015.4. ISSN 1359-4184. PMC 5125816. PMID 25687772.
- Einat H, Kofman O, Itkin O, Lewitan RJ, Belmaker RH (1998). "Augmentation of lithium's behavioral effect by inositol uptake inhibitors". J Neural Transm. 105 (1): 31–8. doi:10.1007/s007020050035. PMID 9588758. S2CID 6707456.
- Jope RS (1999). "Anti-bipolar therapy: mechanism of action of lithium". Mol. Psychiatry. 4 (2): 117–128. doi:10.1038/sj.mp.4000494. PMID 10208444.
- Abu‐Hijleh FA, Prashar S, Joshi H, Sharma R, Frey BN, Mishra RK. Novel Mechanism of Action for the Mood Stabilizer Lithium. Bipolar Disord. October 2020:bdi.13019. doi:10.1111/bdi.13019
- Marmol, F. (2008). "Lithium: Bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 32 (8): 1761–1771. doi:10.1016/j.pnpbp.2008.08.012. PMID 18789369. S2CID 25861243.
- Lenox, RH; Watson, DG (1994). "Lithium and the brain: a psychopharmacological strategy to a molecular basis for manic depressive illness". Clinical Chemistry. 40 (2): 309–14. doi:10.1093/clinchem/40.2.309. PMID 8313612.
- Mitchell, PB; Hadzi-Pavlovic, D (2000). "Lithium treatment for bipolar disorder" (PDF). Bulletin of the World Health Organization. 78 (4): 515–7. PMC 2560742. PMID 10885179. Archived from the original (PDF) on 2012-04-01.
- Shorter E (2009). "The history of lithium therapy". Bipolar Disorders. 11: 4–9. doi:10.1111/j.1399-5618.2009.00706.x. PMC 3712976. PMID 19538681.
- Cade J. F. J. (1949). "Lithium salts in the treatment of psychotic excitement" (PDF). Medical Journal of Australia. 2 (10dfbnm): 349–52. doi:10.1080/j.1440-1614.1999.06241.x. PMC 2560740. PMID 18142718. Archived (PDF) from the original on 2006-05-25.
- P. B. Mitchell, D. Hadzi-Pavlovic; Hadzi-Pavlovic (2000). "Lithium treatment for bipolar disorder" (PDF). Bulletin of the World Health Organization. 78 (4): 515–7. PMC 2560742. PMID 10885179. Archived (PDF) from the original on 2006-05-25.
- Agassi, Tirzah (1996-03-12). "Sting is now older, wiser and duller". The Jerusalem Post. Archived from the original on 2012-05-13. Retrieved 2009-06-25.
- "7 UP: The Making of a Legend". Cadbury Schweppes: America's Beverages.
- "Urban Legends Reference Pages: 7Up". Retrieved 13 November 2007.
- anonymous (13 July 1950). "ISALLY'S (ad)". Painesville Telegraph. Retrieved 8 September 2013.
- Nieper HA (1973). "The clinical applications of lithium orotate. A two years study". Agressologie. 14 (6): 407–11. PMID 4607169.
- Forlenza, OV; de Paula, VJ; Machado-Vieira, R; Diniz, BS; Gattaz, WF (1 May 2012). "Does lithium prevent Alzheimer's disease?". Drugs & Aging. 29 (5): 335–42. doi:10.2165/11599180-000000000-00000. PMID 22500970. S2CID 23864616.
- Wilson, Edward N. (2020). "NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats". J Alzheimers Dis. 73 (2): 723–739. doi:10.3233/JAD-190862. PMID 31868669.
- Ludolph, AC; Brettschneider, J; Weishaupt, JH (October 2012). "Amyotrophic lateral sclerosis". Current Opinion in Neurology. 25 (5): 530–5. doi:10.1097/WCO.0b013e328356d328. PMID 22918486.
- Mota de Freitas, Duarte; Leverson, Brian D.; Goossens, Jesse L. (2016). "Chapter 15. Lithium in Medicine: Mechanisms of Action". In Astrid, Sigel; Helmut, Sigel; Roland K.O., Sigel (eds.). The Alkali Metal Ions: Their Role in Life. Metal Ions in Life Sciences. 16. Springer. pp. 557–584. doi:10.1007/978-3-319-21756-7_15.
- "Lithium". Drug Information Portal. U.S. National Library of Medicine.
- "Exposing lithium's circadian action"
- "Lithium Basics"
- CID 11125 — PubChem Compound Summary (Lithium Carbonate)
- N05AN01 (WHO)