Lithium (medication)

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Lithium
2D chemical structure of lithium carbonate
Lithium carbonate, an example of a lithium salt
Clinical data
Trade namesMany[1]
AHFS/Drugs.comMonograph
MedlinePlusa681039
License data
Pregnancy
category
  • AU: D
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)[4]
Excretion>95% kidney
Identifiers
  • Lithium(1+)
JSmol)
  • [Li+]
  • InChI=1S/Li/q+1
  • Key:HBBGRARXTFLTSG-UHFFFAOYSA-N

Certain lithium compounds, also known as lithium salts, are used as psychiatric medication,[4] primarily for bipolar disorder and for major depressive disorder.[4] In lower doses, other salts such as lithium citrate are known as nutritional lithium and have occasionally been used to treat ADHD.[5] Lithium is taken orally (by mouth).[4]

Common side effects include

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.[6] The American Academy of Pediatrics lists lithium as contraindicated for pregnancy and lactation.[7] The United States Food and Drug Administration categorizes lithium as having positive evidence of risk for pregnancy and possible hazardous risk for lactation.[7][8]

Lithium salts are classified as mood stabilizers.[4] Lithium's mechanism of action is not known.[4]

In the nineteenth century, lithium was used in people who had

generic medication.[4] In 2020, it was the 197th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[13][14] It appears to be under-utilised in older people,[15]
though the reason for that is unclear.

Medical uses

mg capsules of lithium carbonate
.

In 1970, lithium was approved by the United States

major depression,[17] schizophrenia, disorders of impulse control, and some psychiatric disorders in children.[4] Because the FDA has not approved lithium for the treatment of other disorders, such use is off-label.[18][17]

Bipolar disorder

Lithium is primarily used as a maintenance drug in the treatment of bipolar disorder to stabilize mood and prevent

atypical antipsychotics are considered more effective for treating acute depressive episodes.[22] 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.[23] Within the therapeutic range there is a dose response relationship.[24] A limited amount of evidence suggests lithium carbonate may contribute to treatment of substance use disorders for some people with bipolar disorder.[25][26][27] 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."[28]

Schizophrenic disorders

Lithium is recommended for the treatment of schizophrenic disorders only after other antipsychotics have failed; it has limited effectiveness when used alone.[4] The results of different clinical studies of the efficacy of combining lithium with antipsychotic therapy for treating schizophrenic disorders have varied.[4]

Major depressive disorder

If major depressive disorder symptoms fail to respond to standard treatment (such as selective serotonin reuptake inhibitors [SSRIs]), a second agent is sometimes added. A recent systematic review found some evidence of the clinical utility of adjunctive lithium, but the majority of supportive evidence is dated. The same review found no evidence to support the use of lithium for monotherapy.[29]

Monotherapy

There are a few old studies indicating efficacy of lithium for acute depression with lithium having the same efficacy as tricyclic antidepressants.[30] 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.[31]

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.[32][33][34][35][36][37]

Alzheimer's disease

Alzheimer's disease affects forty-five million people and is the fifth leading cause of death in the 65 plus population.[38][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.[38] To combat this toxic amyloid aggregation, lithium upregulates the production of neuroprotectors and neurotrophic factors, as well as inhibiting the GSK-3 enzyme.[39] Lithium also stimulates neurogenesis within the hippocampus, making it thicker.[39] Yet another cause of Alzheimer's disease is the dysregulation of calcium ions within the brain.[40] Too much or too little calcium within the brain can lead to cell death.[40] Lithium is able to restore the intracellular calcium homeostasis through inhibiting the wrongful influx of calcium upstream.[40] 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.[40]

In 2009, a study was performed by Hampel and colleagues[41] 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.[39] 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.[39] Another study, a population study this time by Kessing et al.,[42] showed a negative correlation between Alzheimer's disease deaths and the presence of lithium in drinking water.[39] Areas with increased lithium in their drinking water showed less dementia overall in their population.[39]

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

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.[43]

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 

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.[44][45]

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[46][47] to 1.2 mmol Li+
/L [48] 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.[49]

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.[50]

Discontinuation

For patients who have achieved long term remission, it is recommended to discontinue lithium gradually and in a controlled fashion.[51][30]

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. [52]

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.[30]

Adverse effects

The adverse effects of lithium include:[53][54][55][56][57][58][59]

Very Common (> 10% incidence) adverse effects
  • Confusion
  • Constipation (usually transient, but can persist in some)
  • Decreased memory
  • Diarrhea (usually transient, but can persist in some)
  • Dry mouth
  • EKG changes — usually benign changes in T waves
  • Hand tremor (usually transient, but can persist in some) with an incidence of 27%. If severe, psychiatrist may lower lithium dosage, change lithium salt type or modify lithium preparation from long to short acting (despite lacking evidence for these procedures) or use pharmacological help[60]
  • 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)[49]
  • 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
Unknown incidence

Lithium carbonate can induce a 1–2 kg of weight gain.[62]

In addition to tremors, lithium treatment appears to be a risk factor for development of parkinsonism-like symptoms, although the causal mechanism remains unknown.[63]

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

Hypothyroidism

The rate of hypothyroidism is around six times higher in people who take lithium. Low thyroid hormone levels in turn increase the likelihood of developing depression. People taking lithium thus should routinely be assessed for hypothyroidism and treated with synthetic thyroxine if necessary.[62]

Because lithium competes with the

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.[67]

Pregnancy and breast feeding

Lithium is a

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[73] including the British National Formulary.[74]

Kidney damage

Lithium has been associated with several forms of kidney injury.

kidney damage in an aggravated form of diabetes insipidus.[77][78] Chronic kidney disease caused by lithium has not been proven with various contradicting results presented by a 2018 review.[79] 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%.[79][80]

Hyperparathyroidism

Lithium-associated

parathyroid hyperplasia
.

Interactions

Lithium

Lithium is primarily

proximal tubule. Its levels are therefore sensitive to water and electrolyte balance.[82] 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.[82][83] 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.[82]

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.[84]

Lithium is known to be a potential precipitant of

antidepressants, buspirone and certain opioids such as pethidine (meperidine), tramadol, oxycodone, fentanyl and others.[53][85] Lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other antidopaminergic medications.[86]

High doses of

flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported.[87]
Indeed, these and other
antipsychotics have been associated with increased risk of lithium neurotoxicity, even with low therapeutic lithium doses.[88][89]

Classical psychedelics such as psilocybin and LSD may cause seizures if taken while using lithium, although further research is needed.[90]

Overdose

Lithium toxicity, which is also called lithium overdose and lithium poisoning, is the condition of having too much lithium in the blood. This condition also happens in persons that are taking lithium in which the lithium levels are affected by drug interactions in the body.

In acute toxicity, people have primarily gastrointestinal symptoms such as vomiting and diarrhea, which may result in volume depletion. During acute toxicity, lithium distributes later into the central nervous system resulting in mild neurological symptoms, such as dizziness.[49]

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.[91]

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.[4]

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.[92]

Unlike many other

euphoria) in normal individuals at therapeutic concentrations.[92]
Lithium may also increase the release of serotonin by neurons in the brain.[93] 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.[94]

Lithium both directly and indirectly inhibits

PARP-1.[102]

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.[103][104] It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test,[105] 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.[106]

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.[107]

Oxidative metabolism

Evidence suggests that

mitochondrial dysfunction is present in patients with bipolar disorder.[106]

Dopamine and G-protein coupling

During mania, there is an increase in

autopsies (which do not necessarily reflect living people), people with bipolar disorder had increased G-protein coupling compared to people without bipolar disorder.[106] Lithium treatment alters the function of certain subunits of the dopamine associated G-protein, which may be part of its mechanism of action.[106]

Glutamate and NMDA receptors

neurons, leading to a homeostatic increase in glutamate re-uptake which reduces glutamatergic transmission.[106]
The NMDA receptor is also affected by other
monovalent ions such as rubidium and caesium.[106]

GABA receptors

proteins and stimulating release of neuroprotective proteins.[106] Lithium's regulation of both excitatory dopaminergic and glutamatergic systems through GABA may play a role in its mood stabilizing effects.[109]

Cyclic AMP secondary messengers

Lithium's therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms.

Inositol depletion hypothesis

Lithium treatment has been found to inhibit the enzyme

Neurotrophic Factors

Various neurotrophic factors such as BDNF and mesencephalic astrocyte-derived neurotrophic factor have been shown to be modulated by various mood stabilizers.[113]

History

Lithium was first used in the 19th century as a treatment for

William Alexander Hammond in New York City[11]
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.

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.[115]

Also in 1949, the

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.[117]

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,[114] 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[118]), the application of lithium in manic illness was approved by the United States Food and Drug Administration in 1970,[119] becoming the 50th nation to do so.[18] 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

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

7 Up

As with

Painesville Telegraph still carried an advertisement for a lithiated lemon beverage.[123]

Salts and product names

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.[124]

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

amyotrophic lateral sclerosis (ALS), but a study showed lithium had no effect on ALS outcomes.[128]

See also

References

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Further reading

External links