Chemistry:Lithium (medication)

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Short description: Mood-stabilizing psychiatric medication
Lithium carbonate
2D chemical structure of lithium carbonate
Lithium-carbonate-xtal-1979-Mercury-3D-sf.png
Lithium carbonate, an example of a lithium salt
Clinical data
Trade namesMany[1]
AHFS/Drugs.comMonograph
MedlinePlusa681039
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth, parenteral
Drug classMood stabilizer
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityDepends on formulation
Protein bindingNone
MetabolismKidney
Elimination half-life24 h, 36 h (elderly)[2]
Excretion>95% kidney
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
Chemical and physical data
FormulaLi+
Molar mass6.94 g·mol−1
3D model (JSmol)

Certain lithium compounds, also known as lithium salts, are used as psychiatric medication,[2] primarily for bipolar disorder and for major depressive disorder.[2] In lower doses, other salts such as lithium citrate are known as nutritional lithium and have occasionally been used to treat ADHD.[3] Lithium is taken orally.[2]

Common side effects include increased urination, shakiness of the hands, and increased thirst.[2] Serious side effects include hypothyroidism, diabetes insipidus, and lithium toxicity.[2] Blood level monitoring is recommended to decrease the risk of potential toxicity.[2] If levels become too high, diarrhea, vomiting, poor coordination, sleepiness, and ringing in the ears may occur.[2] Lithium is teratogenic at high doses, especially during the first trimester of pregnancy. The use of lithium while breastfeeding is controversial; however, many international health authorities advise against it, and the long-term outcomes of perinatal lithium exposure have not been studied.[4] The American Academy of Pediatrics lists lithium as contraindicated for pregnancy and lactation.[5] The United States Food and Drug Administration categorizes lithium as having positive evidence of risk for pregnancy and possible hazardous risk for lactation.[5][6]

Lithium salts are classified as mood stabilizers.[2] Lithium's mechanism of action is not known.[2]

In the nineteenth century, lithium was used in people who had gout, epilepsy, and cancer.[7] Its use in the treatment of mental disorders began with Carl Lange in Denmark [8] and William Alexander Hammond in New York City ,[9] who used lithium to treat mania from the 1870s onwards, based on now-discredited theories involving its effect on uric acid. Use of lithium for mental disorders was re-established (on a different theoretical basis) in 1948 by John Cade in Australia.[7] It is on the World Health Organization's List of Essential Medicines,[10] and is available as a generic medication.[2] In 2020, it was the 197th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[11][12] It appears to be under-utilised in older people,[13] though the reason for that is unclear.

Medical uses

A bottle of lithium medicine containing 300 mg capsules of lithium carbonate.

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 United States.[2][14] It is sometimes used when other treatments are not effective in a number of other conditions, including major depression,[15] schizophrenia, disorders of impulse control, and some psychiatric disorders in children.[2] Because the FDA has not approved lithium for the treatment of other disorders, such use is off-label.[16][15]

Bipolar disorder

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.[17] 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;[18][19] atypical antipsychotics are considered more effective for treating acute depressive episodes.[20] 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.[21] Within the therapeutic range there is a dose response relationship.[22] A limited amount of evidence suggests lithium carbonate may contribute to treatment of substance use disorders for some people with bipolar disorder.[23][24][25] 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."[26]

Schizophrenic disorders

Lithium is recommended for the treatment of schizophrenic disorders only after other antipsychotics have failed; it has limited effectiveness when used alone.[2] The results of different clinical studies of the efficacy of combining lithium with antipsychotic therapy for treating schizophrenic disorders have varied.[2]

Major depressive disorder

Lithium is widely prescribed as a treatment for depression.[16]

Augmentation

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. 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.[15]

Monotherapy

There are a few old studies indicating efficacy of lithium for acute depression with lithium having the same efficacy as tricyclic antidepressants.[27] 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.[28]

Prevention of suicide

Lithium is widely believed to prevent suicide, and 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.[29][30][31][32][33][34]

Alzheimer's disease

Alzheimer's disease affects forty-five million people and is the fifth leading cause of death in the 65 plus population.[35][failed verification] 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.[35] To combat this toxic amyloid aggregation, lithium upregulates the production of neuroprotectors and neurotrophic factors, as well as inhibiting the GSK-3 enzyme.[36] Lithium also stimulates neurogenesis within the hippocampus, making it thicker.[36] Yet another cause of Alzheimer's disease is the dysregulation of calcium ions within the brain.[37] Too much or too little calcium within the brain can lead to cell death.[37] Lithium is able to restore the intracellular calcium homeostasis through inhibiting the wrongful influx of calcium upstream.[37] It also promotes the redirection of the influx of the calcium ions into the lumen of the endoplasmic reticulum of the cells to reduce the oxidative stress within the mitochondria.[37]

In 2009, a study was performed by Hampel and colleagues[38] 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.[36] 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.[36] Another study, a population study this time by Kessing et al.,[39] showed a negative correlation between Alzheimer's disease deaths and the presence of lithium in drinking water.[36] Areas with increased lithium in their drinking water showed less dementia overall in their population.[36]

Monitoring

Those who use lithium should receive regular serum level tests and should monitor thyroid and kidney function for abnormalities, as it interferes with the regulation of sodium and water levels in the body, and can cause dehydration. Dehydration, which is compounded by heat, can result in increasing lithium levels. The dehydration is due to lithium inhibition of the action of antidiuretic hormone, which normally enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine, leading to consequent loss of body water and thirst.[40]

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.[41][42]

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[43][44] to 1.2 mmol Li+/L [45] 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.[46]

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 interval. 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, 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.[47]

Discontinuation

For patients who have achieved long term remission, it is recommended to discontinue lithium gradually and in a controlled fashion.[48][27]

Discontinuation symptoms may occur in patients stopping the medication including irritability, restlessness and somatic symptoms like vertigo, dizziness or lightheadedness. Symptoms occur within the first week and are generally mild and self-limiting within weeks. [49]

Cluster headaches, migraine and hypnic headache

Studies testing prophylactic use of lithium in cluster headaches (when compared to verapamil), migraine attacks and hypnic headache indicate good efficacy.[27]

Adverse effects

Sources for the following lists.[50][51][52][53][54][55][56]

Very Common (> 10% incidence) adverse effects of lithium include
  • 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[57]
  • 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)[46]
  • Polydipsia — increased thirst
  • Polyuria — increased urination
  • Renal (kidney) toxicity which may lead to chronic kidney failure
  • Vomiting (usually transient, but can persist in some)
  • Vertigo
  • Weight gain
Common (1–10%) adverse effects include
  • 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.
  • Hair loss/hair thinning
Unknown

Lithium carbonate can induce a 1–2 kg of weight gain.[59]

In addition to tremors, lithium treatment appears to be a risk factor for development of parkinsonism-like symptoms, although the causal mechanism remains unknown.[60]

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

In a systematic literature review, the authors found 250 reports containing 1100 individuals who developed lithium-related movement disorders. The abnormal movements encountered were parkinsonism, dyskinesia, myoclonus, dystonia, Creutzfeldt-Jakob-like syndrome, akathisia, restless legs syndrome symptoms, tics, cerebellar syndromes, and stuttering.[61]

Hypothyroidism

The rate of hypothyroidism is around six times higher in people who take lithium. Low thyroid hormone levels in turn increase the likelihood of developing depression. People taking lithium thus should routinely be assessed for hypothyroidism and treated with synthetic thyroxine if necessary.[59]

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.[62] It increases the appetite and thirst ("polydypsia") and reduces the activity of thyroid hormone (hypothyroidism).[63][64] 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, although this does not appear to be common.[65]

Pregnancy and breast feeding

Lithium is a teratogen, causing birth defects in a small number of newborn babies.[66] 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.[67] 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.[68] Gabapentin[69] and clonazepam[70] are also indicated as antipanic medications during the childbearing years and during pregnancy. Valproic acid and carbamazepine also tend to be associated with teratogenicity.

While it appears to be safe to use while breastfeeding a number of guidelines list it as a contraindication[71] including the British National Formulary.[72]

Kidney damage

Lithium has been associated with several forms of kidney injury.[73][74] 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.[74] Continued use of lithium can lead to more serious kidney damage in an aggravated form of diabetes insipidus.[75][76] Chronic kidney disease caused by lithium has not been proven with various contradicting results presented by a 2018 review.[77] 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%.[77][78]

Hyperparathyroidism

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.

Interactions

Lithium plasma concentrations are known to be increased with concurrent use of diuretics—especially loop diuretics (such as furosemide) and thiazides—and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen.[50] Lithium concentrations can also be increased with concurrent use of ACE inhibitors such as captopril, enalapril, and lisinopril.[79]

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.[80] 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.[80][81] 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.[80]

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.[82]

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.[50][83] Lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other antidopaminergic medications.[84]

High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported.[85] Indeed, these and other antipsychotics have been associated with increased risk of lithium neurotoxicity, even with low therapeutic lithium doses.[86][87]

Classical psychedelics such as psilocybin and LSD may cause seizures if taken while using lithium, although further research is needed.[88]

Overdose

Main page: Medicine: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 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.[46]

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.[89]

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.[2]

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.[90]

Unlike many other psychoactive drugs, Li+ typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations.[90] Lithium may also increase the release of serotonin by neurons in the brain.[91] 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.[92]

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.[93] GSK-3β is a downstream target of monoamine systems. As such, it is directly implicated in cognition and mood regulation.[94][93] During mania, GSK-3β is activated via dopamine overactivity.[93] 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.[95][96][97] In addition, several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium.[98][99] 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.[100]

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.[101][102] It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test,[103] 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.[104]

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.[105]

Oxidative metabolism

Evidence suggests that mitochondrial dysfunction is present in patients with bipolar disorder.[104] 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.[104]

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.[104] 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.[104] Lithium treatment alters the function of certain subunits of the dopamine associated G-protein, which may be part of its mechanism of action.[104]

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.[104] 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.[104] 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.[104]

GABA receptors

GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission.[104] 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.[106] Lithium counteracts these degrading processes by decreasing pro-apoptotic proteins and stimulating release of neuroprotective proteins.[104] Lithium's regulation of both excitatory dopaminergic and glutamatergic systems through GABA may play a role in its mood stabilizing effects.[107]

Cyclic AMP secondary messengers

Lithium's therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms.[108] 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.[104] It is hypothesized that the dual effects of lithium are due to the inhibition of G-proteins that mediate cyclic AMP production.[104] Over a long period of lithium treatment, cyclic AMP and adenylate cyclase levels are further changed by gene transcription factors.[104]

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.[109] 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.[110] 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.[104] Reductions of cellular levels of myo-inositol results in the inhibition of the phosphoinositide cycle.[104]

Neurotrophic Factors

Various neurotrophic factors such as BDNF and mesencephalic astrocyte-derived neurotrophic factor have been shown to be modulated by various mood stabilizers.[111]

History

Lithium was first used in the 19th century as a treatment for gout after scientists discovered that, at least in the laboratory, lithium could dissolve uric acid crystals isolated from the kidneys. The levels of lithium needed to dissolve urate in the body, however, were toxic.[112] Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange in Denmark [8] and William Alexander Hammond in New York City [9] 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.[16] 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 publication of reports detailing side effects and deaths.[113]

Also in 1949, the Australia n 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.[114] 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.[115]

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,[112] 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[116]), the application of lithium in manic illness was approved by the United States Food and Drug Administration in 1970,[117] becoming the 50th nation to do so.[16] In 1974, this application was extended to its use as a preventive agent for manic-depressive illness.

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,[118] and "Lithium" by Thin White Rope.

7 Up

As with cocaine in Coca-Cola, lithium was widely marketed as one of a number of patent medicine products popular in the late-19th and early-20th centuries, and was the medicinal ingredient of a refreshment beverage. Charles Leiper Grigg, who launched his St. Louis-based company The Howdy Corporation, invented a formula for a lemon-lime soft drink in 1920. The product, originally named "Bib-Label Lithiated Lemon-Lime Soda", was launched two weeks before the Wall Street Crash of 1929.[119] 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.[120] 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.[121]

Salts and product names

Lithium carbonate (Li2CO3) is the most commonly used form of lithium, although lithium citrate (Li3C6H5O7) and other salts, including lithium sulfate, lithium chloride, and lithium orotate are also used.[122][123] 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 to lower systemic toxicity.[122]

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.[1]

Research

Tentative evidence in Alzheimer's disease showed that lithium may slow progression.[124][125] 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.[126]

See also

References

  1. ↑ 1.0 1.1 "Lithium brands". Drugs.com. https://www.drugs.com/international/lithium.html. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 "Lithium Salts". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/lithium-salts.html. 
  3. ↑ Finally Focused: The Breakthrough Natural Treatment Plan for ADHD That Restores Attention, Minimizes Hyperactivity, and Helps Eliminate Drug Side Effects. Harmony Books. 9 May 2017. ISBN 9780451496591. https://books.google.com/books?id=T8aNEAAAQBAJ. 
  4. ↑ "Lithium during pregnancy and after delivery: a review". International Journal of Bipolar Disorders 6 (1): 26. December 2018. doi:10.1186/s40345-018-0135-7. PMID 30506447. 
  5. ↑ 5.0 5.1 "ACOG Guidelines on Psychiatric Medication Use During Pregnancy and Lactation". American Family Physician 78 (6): 772. 2008-09-15. ISSN 0002-838X. https://www.aafp.org/afp/2008/0915/p772.html. 
  6. ↑ "Lithium Carbonate Medication Guide". https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/017812s031,018421s031,018558s026lbl.pdf. 
  7. ↑ 7.0 7.1 Drug discovery : a history (Rev. and updated ed.). Chichester: Wiley. 2005. p. 63. ISBN 9780471899792. https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA63. 
  8. ↑ 8.0 8.1 "Lithium and the brain: a psychopharmacological strategy to a molecular basis for manic depressive illness". Clinical Chemistry 40 (2): 309–314. February 1994. doi:10.1093/clinchem/40.2.309. PMID 8313612. 
  9. ↑ 9.0 9.1 "Lithium treatment for bipolar disorder". Bulletin of the World Health Organization 78 (4): 515–517. 2000. PMID 10885179. PMC 2560742. https://www.who.int/entity/bulletin/archives/78(4)515.pdf. 
  10. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  11. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  12. ↑ "Lithium – Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Lithium. 
  13. ↑ "Lithium dispensed for adults aged ≥ 50 years between 2012 and 2021: Analyses of a 10% sample of the Australian Pharmaceutical Benefits Scheme" (in English). The American Journal of Geriatric Psychiatry 31 (9): 716–725. 2023-03-27. doi:10.1016/j.jagp.2023.03.012. ISSN 1064-7481. PMID 37080815. https://www.ajgponline.org/article/S1064-7481(23)00259-2/fulltext. 
  14. ↑ "Lithium: its clinical uses and biological mechanisms of action" (in en). The Brain, Biochemistry, and Behavior: Proceedings of the Sixth Arnold O. Beckman Conference in Clinical Chemistry. American Association for Clinical Chemistry. 1984. pp. 170. ISBN 978-0-915274-22-2. https://books.google.com/books?id=-8BrAAAAMAAJ&q=The+Brain+,+Biochemistry+,+and+Behavior+.+Robert+L.+Habig. 
  15. ↑ 15.0 15.1 15.2 "Role of lithium augmentation in the management of major depressive disorder". CNS Drugs 28 (4): 331–342. April 2014. doi:10.1007/s40263-014-0152-8. PMID 24590663. 
  16. ↑ 16.0 16.1 16.2 16.3 "The history of lithium therapy". Bipolar Disorders 11 (Suppl 2): 4–9. June 2009. doi:10.1111/j.1399-5618.2009.00706.x. PMID 19538681. 
  17. ↑ "Lithium for acute mania". The Cochrane Database of Systematic Reviews 2019 (6): CD004048. June 2019. doi:10.1002/14651858.CD004048.pub4. PMID 31152444. 
  18. ↑ "Lithium in the treatment of acute bipolar depression: A systematic review and meta-analysis". Journal of Affective Disorders 308: 268–280. July 2022. doi:10.1016/j.jad.2022.04.058. PMID 35429528. 
  19. ↑ "Lithium in bipolar depression: A review of the evidence". Human Psychopharmacology 38 (5): e2881. September 2023. doi:10.1002/hup.2881. PMID 37789577. 
  20. ↑ "Efficacy and safety profiles of mood stabilizers and antipsychotics for bipolar depression: a systematic review". International Clinical Psychopharmacology 38 (4): 249–260. July 2023. doi:10.1097/YIC.0000000000000449. PMID 36947416. 
  21. ↑ Semple, David "Oxford Hand Book of Psychiatry" Oxford Press. 2005.[page needed]
  22. ↑ "Differences in the prophylactic effect of serum lithium levels on depression and mania in bipolar disorder: A dose-response meta-analysis". European Neuropsychopharmacology 58: 20–29. May 2022. doi:10.1016/j.euroneuro.2022.01.112. PMID 35158229. 
  23. ↑ "Update: new uses for lithium and anticonvulsants". CNS Spectrums 12 (11): 831–841. November 2007. doi:10.1017/S1092852900015571. PMID 17984856. 
  24. ↑ "Bipolar disorder and comorbid alcoholism: prevalence rate and treatment considerations". Bipolar Disorders 8 (6): 677–685. December 2006. doi:10.1111/j.1399-5618.2006.00370.x. PMID 17156154. 
  25. ↑ "Management of comorbid bipolar disorder and substance abuse". The Journal of Clinical Psychiatry 67 (Suppl 7): 24–30. 2006. PMID 16961421. 
  26. ↑ "Effects of lithium on suicide and suicidal behaviour: a systematic review and meta-analysis of randomised trials". Epidemiology and Psychiatric Sciences 31: e65. September 2022. doi:10.1017/S204579602200049X. PMID 36111461. 
  27. ↑ 27.0 27.1 27.2 Lithium in Neuropsychiatry: The Comprehensive Guide. Taylor & Francis. 2006. ISBN 978-1-84184-515-9. https://books.google.com/books?id=KXjrwAEACAAJ. Retrieved 17 July 2021. 
  28. ↑ "Treatment of Depression with Lithium". The Essential Guide to Lithium Treatment. Cham: Springer International Publishing. 2016. pp. 71–80. doi:10.1007/978-3-319-31214-9_7. ISBN 978-3-319-31212-5. 
  29. ↑ "Effects of lithium on suicide and suicidal behaviour: a systematic review and meta-analysis of randomised trials". Epidemiology and Psychiatric Sciences 31: e65. September 2022. doi:10.1017/S204579602200049X. PMID 36111461. 
  30. ↑ "Lithium and suicide prevention in mood disorders and in the general population: A systematic review". Neuroscience and Biobehavioral Reviews 116: 142–153. September 2020. doi:10.1016/j.neubiorev.2020.06.017. PMID 32561344. 
  31. ↑ "Effect of lithium on suicide and mortality in mood disorders: a systematic review". The International Journal of Risk & Safety in Medicine 30 (3): 155–166. September 2019. doi:10.3233/JRS-190058. PMID 31381531. 
  32. ↑ "Lithium in the prevention of suicide in adults: systematic review and meta-analysis of clinical trials". BJPsych Open 8 (6): e199. November 2022. doi:10.1192/bjo.2022.605. PMID 36384820. 
  33. ↑ "Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis". BMJ 346: f3646. June 2013. doi:10.1136/bmj.f3646. PMID 23814104. 
  34. ↑ "Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review". Bipolar Disorders 8 (5p2): 625–639. October 2006. doi:10.1111/j.1399-5618.2006.00344.x. PMID 17042835. 
  35. ↑ 35.0 35.1 "Alzheimer's disease". Lancet 397 (10284): 1577–1590. April 2021. doi:10.1016/S0140-6736(20)32205-4. PMID 33667416. 
  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 "Lithium: A therapeutic option in Alzheimer's disease and its prodromal stages?". Neuroscience Letters 760: 136044. August 2021. doi:10.1016/j.neulet.2021.136044. PMID 34119602. 
  37. ↑ 37.0 37.1 37.2 37.3 "Potential mechanisms underlying lithium treatment for Alzheimer's disease and COVID-19". European Review for Medical and Pharmacological Sciences 26 (6): 2201–2214. March 2022. doi:10.26355/eurrev_202203_28369. PMID 35363371. 
  38. ↑ "Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study". The Journal of Clinical Psychiatry 70 (6): 922–931. June 2009. doi:10.4088/JCP.08m04606. PMID 19573486. 
  39. ↑ "Association of Lithium in Drinking Water With the Incidence of Dementia". JAMA Psychiatry 74 (10): 1005–1010. October 2017. doi:10.1001/jamapsychiatry.2017.2362. PMID 28832877. 
  40. ↑ Healy D. 2005. Psychiatric Drugs Explained. 4th ed. Churchhill Livingstone: London.[page needed]
  41. ↑ "Clinical and serum level monitoring in lithium therapy and lithium intoxication". Journal of Analytical Toxicology 2 (5): 193–202. 1978. doi:10.1093/jat/2.5.193. 
  42. ↑ Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. 2008. pp. 851–854. ISBN 978-0-9626523-7-0. 
  43. ↑ 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 Revision 2 December 2010, Retrieved 5 May 2011
  44. ↑ One study ("Serum lithium levels and psychosocial function in patients with bipolar I disorder". The American Journal of Psychiatry 153 (10): 1301–1307. October 1996. 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 ("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. July 2002. 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?]
  45. ↑ "Lithium: updated human knowledge using an evidence-based approach. Part II: Clinical pharmacology and therapeutic monitoring". CNS Drugs (Springer Science and Business Media LLC) 23 (4): 331–349. 2009. doi:10.2165/00023210-200923040-00005. PMID 19374461. 
  46. ↑ 46.0 46.1 46.2 46.3 "Lithium side effects and toxicity: prevalence and management strategies". International Journal of Bipolar Disorders 4 (1): 27. December 2016. doi:10.1186/s40345-016-0068-y. PMID 27900734. 
  47. ↑ "Lithium and nephrotoxicity: a literature review of approaches to clinical management and risk stratification". BMC Nephrology (Springer Science and Business Media LLC) 19 (1): 305. November 2018. doi:10.1186/s12882-018-1101-4. PMID 30390660. 
  48. ↑ "Controlled lithium discontinuation in bipolar patients with good response to long-term lithium prophylaxis". Journal of Affective Disorders 80 (2–3): 269–271. June 2004. doi:10.1016/S0165-0327(03)00133-2. PMID 15207941. 
  49. ↑ "[Lithium Withdrawal Symptoms – A Systematic Review]" (in de). Psychiatrische Praxis (Georg Thieme Verlag KG) 48 (7): 341–350. October 2021. doi:10.1055/a-1481-1953. PMID 34015856. 
  50. ↑ 50.0 50.1 50.2 DrugPoint® System (Internet). Greenwood Village, CO: Thomsen Healthcare. 2013. 
  51. ↑ Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty. Ltd.. 2013. ISBN 9780980579086. 
  52. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) 65. London, UK: Pharmaceutical Press. pp. 240–242. ISBN 9780857110848. https://archive.org/details/bnf65britishnati0000unse/page/240. 
  53. ↑ "lithium (Rx) - Eskalith, Lithobid". Medscape. WebMD. http://reference.medscape.com/drug/eskalith-lithobid-lithium-342934. 
  54. ↑ "Lithobid (lithium carbonate) tablet, film coated, extended release". National Library of Medicine. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ea4ece7f-e81f-48de-b262-577db5b6fe6c#nlm42232-9. 
  55. ↑ "Product Information Lithicarb (Lithium carbonate)". TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2012-PI-01382-3. 
  56. ↑ "Effects of 10 to 30 years of lithium treatment on kidney function". Journal of Psychopharmacology 29 (5): 608–614. May 2015. doi:10.1177/0269881115573808. PMID 25735990. 
  57. ↑ "Lithium tremor revisited: pathophysiology and treatment". Acta Psychiatrica Scandinavica (Wiley) 129 (1): 17–23. January 2014. doi:10.1111/acps.12171. PMID 23834617. 
  58. ↑ "Drug-induced hypoglycaemia: an update". Drug Safety (Springer Science and Business Media LLC) 34 (1): 21–45. January 2011. doi:10.2165/11538290-000000000-00000. PMID 20942513. 
  59. ↑ 59.0 59.1 "Safe and effective use of lithium". Australian Prescriber 36: 18–21. 2013. doi:10.18773/austprescr.2013.008. 
  60. ↑ "Chapter 12: VPA, lithium, amiodarone, and other non-DA". Medication-Induced Movement Disorders. Cambridge University Press. 2015. pp. 131–140. ISBN 978-1-107-06600-7. 
  61. ↑ "Lithium-associated movement disorder: A literature review". Brain Circulation 8 (2): 76–86. 2022. doi:10.4103/bc.bc_77_21. PMID 35909709. 
  62. ↑ "Triamterene increases lithium excretion in healthy subjects: evidence for lithium transport in the cortical collecting tubule". Nephrology, Dialysis, Transplantation 4 (11): 939–942. 1989. doi:10.1093/ndt/4.11.939. PMID 2516883. 
  63. ↑ Drug-induced dysfunction in psychiatry. Taylor & Francis. 2001. p. 305. ISBN 978-0-89116-961-1. https://books.google.com/books?id=pol0204fqjIC. 
  64. ↑ "Safer lithium therapy". NHS National Patient Safety Agency. 1 December 2009. http://www.nrls.npsa.nhs.uk/resources/patient-safety-topics/medication-safety/?entryid45=65426. 
  65. ↑ "Renal failure occurs in chronic lithium treatment but is uncommon". Kidney International 77 (3): 219–224. February 2010. doi:10.1038/ki.2009.433. PMID 19940841. 
  66. ↑ "Update on new developments in the study of human teratogens". Teratology 65 (4): 153–161. April 2002. doi:10.1002/tera.10032. PMID 11948561. 
  67. ↑ "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. 2008. PMID 18982835. 
  68. ↑ "Treatment of bipolar disorders during pregnancy: maternal and fetal safety and challenges". Drug, Healthcare and Patient Safety 7: 7–29. 2015. doi:10.2147/DHPS.S50556. PMID 25565896. 
  69. ↑ "Gabapentin exposure in human pregnancy: results from the Gabapentin Pregnancy Registry". Epilepsy & Behavior 4 (3): 310–317. June 2003. doi:10.1016/S1525-5050(03)00110-0. PMID 12791334. 
  70. ↑ "Obstetrical and neonatal outcome following clonazepam use during pregnancy: a case series". Psychotherapy and Psychosomatics 70 (3): 158–162. 2001. doi:10.1159/000056242. PMID 11340418. 
  71. ↑ "Lithium use while Breastfeeding". LactMed. 10 March 2015. https://www.drugs.com/breastfeeding/lithium.html. 
  72. ↑ "Lithium carbonate". https://www.evidence.nhs.uk/formulary/bnf/current/4-central-nervous-system/42-drugs-used-in-psychoses-and-related-disorders/423-drugs-used-for-mania-and-hypomania/lithium/lithium-carbonate. 
  73. ↑ "Dysregulation of renal aquaporins and epithelial sodium channel in lithium-induced nephrogenic diabetes insipidus". Seminars in Nephrology 28 (3): 227–244. May 2008. doi:10.1016/j.semnephrol.2008.03.002. PMID 18519084. 
  74. ↑ 74.0 74.1 "Lithium toxicity: a double-edged sword". Kidney International 73 (2): 233–237. January 2008. doi:10.1038/sj.ki.5002578. PMID 17943083. 
  75. ↑ "Nephrogenic diabetes insipidus". Annals of Internal Medicine 144 (3): 186–194. February 2006. doi:10.7326/0003-4819-144-3-200602070-00007. PMID 16461963. 
  76. ↑ "Causes of reversible nephrogenic diabetes insipidus: a systematic review". American Journal of Kidney Diseases 45 (4): 626–637. April 2005. doi:10.1053/j.ajkd.2005.01.008. PMID 15806465. 
  77. ↑ 77.0 77.1 "Lithium and nephrotoxicity: Unravelling the complex pathophysiological threads of the lightest metal". Nephrology (Wiley) 23 (10): 897–903. October 2018. doi:10.1111/nep.13263. PMID 29607573. 
  78. ↑ "Lithium-induced nephropathy: Rate of progression and prognostic factors". Kidney International 64 (2): 585–592. August 2003. doi:10.1046/j.1523-1755.2003.00096.x. PMID 12846754. 
  79. ↑ "Lithium". http://www.webmd.com/vitamins-supplements/ingredientmono-1065-lithium.aspx?activeingredientid=1065&activeingredientname=lithium. 
  80. ↑ 80.0 80.1 80.2 "Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction". Journal of Clinical Psychopharmacology 16 (1): 68–71. February 1996. doi:10.1097/00004714-199602000-00011. PMID 8834421. 
  81. ↑ "Lithium: a review of pharmacology, clinical uses, and toxicity". European Journal of Pharmacology 740 (740): 464–473. October 2014. doi:10.1016/j.ejphar.2014.06.042. PMID 24991789. 
  82. ↑ Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs (10th ed.). Baltimore: Lippincott Williams & Wilkins. 1 February 2012. p. 1991. ISBN 978-1-60913-713-7. 
  83. ↑ "Serotonin syndrome". UpToDate. Wolters Kluwer. http://www.uptodate.com/contents/serotonin-syndrome. 
  84. ↑ "Neuroleptic malignant syndrome". UpToDate. Wolters Kluwer. http://www.uptodate.com/contents/neuroleptic-malignant-syndrome. 
  85. ↑ Case reports: ("Toxic irreversible encephalopathy induced by lithium carbonate and haloperidol. A report of 2 cases". South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde 64 (22): 875–876. November 1983. PMID 6415823. )("[Acute encephalomyopathy and persistent cerebellar syndrome after lithium salt and haloperidol poisoning]". Revue Neurologique 153 (4): 268–270. May 1997. PMID 9296146. )
  86. ↑ "Lithium neurotoxicity at low therapeutic doses Hypotheses for causes and mechanism of action following a retrospective analysis of published case reports". Acta Neurologica Belgica 96 (4): 281–293. December 1996. PMID 9008777. 
  87. ↑ "Reversible lithium neurotoxicity: review of the literatur". The Primary Care Companion for CNS Disorders 14 (1): PCC.11r01197. 2012. doi:10.4088/PCC.11r01197. PMID 22690368. 
  88. ↑ "Classic Psychedelic Coadministration with Lithium, but Not Lamotrigine, is Associated with Seizures: An Analysis of Online Psychedelic Experience Reports". Pharmacopsychiatry 54 (5): 240–245. September 2021. doi:10.1055/a-1524-2794. PMID 34348413. 
  89. ↑ "Reversible lithium neurotoxicity: review of the literatur". The Primary Care Companion for CNS Disorders 14 (1). 2012. doi:10.4088/PCC.11r01197. PMID 22690368. 
  90. ↑ 90.0 90.1 Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. 2010. ISBN 978-0-07-162442-8. 
  91. ↑ "5-HT1B receptors: a novel target for lithium. Possible involvement in mood disorders". Neuropsychopharmacology 21 (4): 530–541. October 1999. doi:10.1016/S0893-133X(99)00042-1. PMID 10481837. 
  92. ↑ "Lithium modulates tryptophan hydroxylase 2 gene expression and serotonin release in primary cultures of serotonergic raphe neurons". Brain Research 1307: 14–21. January 2010. doi:10.1016/j.brainres.2009.10.027. PMID 19840776. 
  93. ↑ 93.0 93.1 93.2 The Science and Practice of Lithium Therapy. Springer International Publishing. 2017. pp. 62. ISBN 9783319459233. OCLC 979600268. 
  94. ↑ "Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder". Biological Psychiatry 59 (12): 1160–1171. June 2006. doi:10.1016/j.biopsych.2005.11.004. PMID 16457783. 
  95. ↑ "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. November 2006. doi:10.2174/1389450110607011399. PMID 17100580. 
  96. ↑ "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. September 2008. doi:10.1038/sj.npp.1301640. PMID 18046304. 
  97. ↑ "Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors". Neuroscience and Biobehavioral Reviews 35 (3): 804–817. January 2011. doi:10.1016/j.neubiorev.2010.10.001. PMID 20934453. 
  98. ↑ "Definition of a metal-dependent/Li(+)-inhibited phosphomonoesterase protein family based upon a conserved three-dimensional core structure". Proceedings of the National Academy of Sciences of the United States of America 92 (11): 5149–5153. May 1995. doi:10.1073/pnas.92.11.5149. PMID 7761465. Bibcode: 1995PNAS...92.5149Y. 
  99. ↑ "A novel target of lithium therapy". FEBS Letters 467 (2–3): 321–325. February 2000. doi:10.1016/s0014-5793(00)01183-2. PMID 10675562. 
  100. ↑ "3'-5' phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo". The Biochemical Journal 443 (2): 485–490. April 2012. doi:10.1042/BJ20111057. PMID 22240080. 
  101. ↑ "Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test". European Neuropsychopharmacology 18 (5): 323–332. May 2008. doi:10.1016/j.euroneuro.2007.07.011. PMID 17728109. 
  102. ↑ "A role for nitrergic system in the antidepressant-like effects of chronic lithium treatment in the mouse forced swimming test". Behavioural Brain Research 200 (1): 76–82. June 2009. doi:10.1016/j.bbr.2008.12.032. PMID 19166880. 
  103. ↑ "NMDA receptor antagonists augment antidepressant-like effects of lithium in the mouse forced swimming test". Journal of Psychopharmacology 24 (4): 585–594. April 2010. doi:10.1177/0269881109104845. PMID 19351802. 
  104. ↑ 104.00 104.01 104.02 104.03 104.04 104.05 104.06 104.07 104.08 104.09 104.10 104.11 104.12 104.13 104.14 104.15 "Potential mechanisms of action of lithium in bipolar disorder. Current understanding". CNS Drugs 27 (2): 135–153. February 2013. doi:10.1007/s40263-013-0039-0. PMID 23371914. 
  105. ↑ Lithium and the Cell: Pharmacology and Biochemistry. Academic Press. 2 December 2012. ISBN 9780080984292. https://books.google.com/books?id=HJtu3PqpAKgC&q=theoretic+%22lithium+receptor%22&pg=PA113. 
  106. ↑ "Cellular mechanisms and second messengers: relevance to the psychopharmacology of bipolar disorders". The International Journal of Neuropsychopharmacology 6 (2): 181–189. June 2003. doi:10.1017/s1461145703003419. PMID 12890311. 
  107. ↑ The Science and Practice of Lithium Therapy. Springer International Publishing. 2017. pp. 61. ISBN 9783319459233. OCLC 979600268. 
  108. ↑ "Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics". Molecular Psychiatry 20 (6): 661–670. June 2015. doi:10.1038/mp.2015.4. PMID 25687772. 
  109. ↑ "Augmentation of lithium's behavioral effect by inositol uptake inhibitors". Journal of Neural Transmission 105 (1): 31–38. 1998. doi:10.1007/s007020050035. PMID 9588758. 
  110. ↑ "Anti-bipolar therapy: mechanism of action of lithium". Molecular Psychiatry 4 (2): 117–128. March 1999. doi:10.1038/sj.mp.4000494. PMID 10208444. 
  111. ↑ "Novel mechanism of action for the mood stabilizer lithium". Bipolar Disorders 23 (1): 76–83. February 2021. doi:10.1111/bdi.13019. PMID 33037686. 
  112. ↑ 112.0 112.1 "Lithium: bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium". Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (8): 1761–1771. December 2008. doi:10.1016/j.pnpbp.2008.08.012. PMID 18789369. 
  113. ↑ "Lithium: Discovered, Forgotten and Rediscovered". https://inhn.org/inhn-projects/archives/gershon-collection/lithium-discovered-forgotten-and-rediscovered. 
  114. ↑ "Obituary – Shirley Aldythea Andrews – Obituaries Australia". https://oa.anu.edu.au/obituary/andrews-shirley-aldythea-14936. 
  115. ↑ "Lithium salts in the treatment of psychotic excitement". The Medical Journal of Australia 2 (10): 349–352. September 1949. doi:10.1080/j.1440-1614.1999.06241.x. PMID 18142718. PMC 2560740. https://www.who.int/docstore/bulletin/pdf/2000/issue4/classics.pdf. 
  116. ↑ "Lithium therapy at the millennium: a revolutionary drug used for 50 years faces competing options and possible demise". Bipolar Disorders 1 (2): 67–70. December 1999. doi:10.1034/j.1399-5618.1999.010201.x. PMID 11252660. 
  117. ↑ "Lithium treatment for bipolar disorder". Bulletin of the World Health Organization 78 (4): 515–517. 2000. PMID 10885179. PMC 2560742. https://www.who.int/docstore/bulletin/pdf/2000/issue4/classics.pdf. 
  118. ↑ "Sting is now older, wiser and duller". The Jerusalem Post. 12 March 1996. 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. 
  119. ↑ "7 UP: The Making of a Legend". Cadbury Schweppes: America's Beverages.
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  123. ↑ "How and when to take lithium" (in en). 14 August 2023. https://www.nhs.uk/medicines/lithium/how-and-when-to-take-lithium/. 
  124. ↑ "Does lithium prevent Alzheimer's disease?". Drugs & Aging 29 (5): 335–342. May 2012. doi:10.2165/11599180-000000000-00000. PMID 22500970. 
  125. ↑ "NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats". Journal of Alzheimer's Disease 73 (2): 723–739. 2020. doi:10.3233/JAD-190862. PMID 31868669. 
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Further reading

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