Lithium pharmacology refers to use of the lithium ion, Li+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania, both acutely and in the long term. As a mood stabilizer, lithium is probably more effective in preventing mania than depression, and may reduce the risk of suicide in certain bipolar patients.[1] In depression alone (unipolar disorder) lithium can be used to augment other antidepressants. Lithium carbonate (Li2CO3), sold under several trade names, is the most commonly prescribed, while the citrate salt lithium citrate (Li3C6H5O7) is also used in conventional pharmacological treatments. The sulfate salt lithium sulfate (Li2SO4) has been presented as an alternative. Lithium orotate (orotic acid) is sometimes marketed as a "safe" natural alternative with fewer side-effects than conventional lithium, yet caution must be taken with all of the active lithium salts.
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.
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Lithium treatment is used to treat mania in bipolar disorder. Initially, lithium is often used in conjunction with antipsychotic drugs as it can take up to a month for lithium to have an effect. Lithium is also used as prophylaxis for depression and mania in bipolar disorder. It is sometimes used for other psychiatric disorders such as cycloid psychosis and major depressive disorder.[2][3] Lithium possesses a very important antisuicidal effect not shown in other stabilizing medications such as antiseizures drugs.[4][4][5] Non-psychiatric applications are limited; however, its use is well established in the prophylaxis of some headaches related to cluster headaches (trigeminal autonomic cephalgias), particularly hypnic headache. An Italian pilot study in humans conducted in 2005–06 suggested that lithium may improve outcomes in the neurodegenerative disease amyotrophic lateral sclerosis.[6][7] However, a randomised, double-blind, placebo-controlled trial comparing the safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis failed to demonstrate any benefit from a combination therapy over riluzole alone.[8]
Lithium is sometimes used as an augmenting agent to increase the benefits of standard drugs used for unipolar depression. Lithium 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 (15–20 mg per kg of body weight) is slightly less than the toxic level, requiring blood levels of lithium to be monitored closely during treatment. To prescribe the correct dosage, the patient's entire medical history, both physical and psychological, is sometimes taken into consideration. The starting dosage of lithium should be 400–600 mg given at night and increased weekly depending on serum monitoring.[9]
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, lithium can cause dehydration. Dehydration, which is compounded by heat, can result in increasing lithium levels. The reason why water is lost is because Lithium inhibits the action of antidiuretic hormone (ADH) which enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine leading to consequent loss of body water and thirst.[10]
High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported.
Lithium salts have a narrow therapeutic/toxic ratio and should therefore not be prescribed unless facilities for monitoring plasma concentrations are available. Patients should be carefully selected. Doses are adjusted to achieve plasma concentrations of 0.4[11][12] to 1.2 mmol Li+/L (lower end of the range for maintenance therapy and elderly patients, higher end for pediatric patients) on samples taken 12 hours after the preceding dose. Overdosage, usually with plasma concentrations over 1.5 mmol Li+/L, may be fatal, and toxic effects include tremor, ataxia, dysarthria, nystagmus, renal impairment, confusion, and convulsions. If these potentially hazardous signs occur, treatment should be stopped, plasma lithium concentrations redetermined, and steps taken to reverse lithium toxicity. The most common side effects are an overall dazed feeling and a fine hand tremor. These side effects are generally present during the length of the treatment, but can sometimes disappear in certain patients. Other common side effects, such as nausea and headache, can be generally remedied by a higher intake of water. Lithium unbalances electrolytes; to counteract this, increased water intake is suggested.
Lithium toxicity is compounded by sodium depletion. Concurrent use of diuretics that inhibit the uptake of sodium by the distal tubule (e.g. thiazides) is hazardous and should be avoided. In mild cases, withdrawal of lithium and administration of generous amounts of sodium and fluid will reverse the toxicity. Plasma concentrations in excess of 2.5 mmol Li+/L are usually associated with serious toxicity requiring emergency treatment. When toxic concentrations are reached, there may be a delay of 1 or 2 days before maximum toxicity occurs.
In long-term use, therapeutic concentrations of lithium have been thought to cause histological and functional changes in the kidney. The significance of such changes is not clear, but is of sufficient concern to discourage long-term use of lithium unless it is definitely indicated. Doctors may change a bipolar patient's medication from lithium to another mood stabilizing drug, such as valproate (Depakote), if problems with the kidneys arise. An important potential consequence of long-term lithium usage is the development of renal diabetes insipidus (inability to concentrate urine). Patients should therefore be maintained on lithium treatment after 3–5 years only if, on assessment, benefit persists. Conventional and sustained-release tablets are available. Preparations vary widely in bioavailability, and a change in the formulation used requires the same precautions as initiation of treatment. There are few reasons to prefer any one simple salt of lithium; the carbonate has been the more widely used, but the citrate is also available.
Lithium may be used as a treatment of seborrhoeic dermatitis (Lithium gluconate 8% gel). In addition, lithium has been shown to increase production of white blood cells in the bone marrow and might be indicated in patients suffering from leukopenia.[13]
A limited amount of evidence suggests that lithium may contribute to treatment of substance abuse for some dual-disorder patients.[14][15][16]
The average developmental score for the lithium-exposed group of children was 7–8 points lower than the control group (siblings), but well within the normal range of 100±15.[17] Cognitive depression in adults is disputed.
Lithium is known to be responsible for significant amounts of weight gain.[18] Because lithium competes with the receptors for the antidiuretic hormone in the kidney, it increases water output into the urine, a condition called nephrogenic diabetes insipidus. Clearance of lithium by the kidneys is usually successful with certain diuretic medications including amiloride and triamterene.[19] It increases the appetite and thirst ("polydypsia"), may cause more depression than before with suicidal thoughts and actions, and reduces the activity of thyroid hormone (hypothyroidism).[20][21][22][23][24] It is also believed to affect renal function.[25]
Lithium is a well known cause of downbeat nystagmus.[26] The nystagmus may be permanent or require several months of abstinence for improvement.[27]
Lithium is also a teratogen causing birth defects in a small number of new born babies.[28] Case reports and several retrospective studies have demonstrated possible increase in the rate of a congenital heart defect known as Ebstein's anomaly, if taken during a woman's pregnancy.[29] 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.[29] Gabapentin[30] and clonazepam[31] are also indicated as anti-panic medications during the childbearing years and during pregnancy. Valproic acid and carbamazepine also tend to be asociated with teratogenicity.
Dehydration in patients taking Lithium salts can be very hazardous especially when combined with nephrogenic diabetes insipidus and thus polyuria. Low sodium in water they drink may very quickly produce hyponatremia with its danger of toxic Lithium concentrations in plasma. Situation such as: preoperative fluid regimen (ECT) or otherwise fluid unaccessibility, warm water conditions, sporting events, hiking.
Lithium toxicity may occur in persons taking excessive amounts either accidentally or intentionally on an acute basis or in patients who accumulate high levels during ongoing chronic therapy. The manifestations include nausea, emesis, diarrhea, asthenia, ataxia, confusion, lethargy, polyuria, seizures and coma. Other toxic effects of lithium also include coarse tremor, muscle twitching, convulsions and renal failure.[32] Persons who survive a poisoning episode may develop persistent neurotoxicity.
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 patients, but may increase to 1.8–2.5 mmol/L in patients who accumulate the drug over time and to 3–10 mmol/L in victims of acute overdosage.[33][34]
Unlike other psychoactive drugs, Li+ typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations.
The precise mechanism of action of Li+ as a mood-stabilizing agent is currently unknown. It is possible that Li+ produces its effects by interacting with the transport of monovalent or divalent cations in neurons. However, because it is a poor substrate at the sodium pump, it cannot maintain a membrane potential and only sustains a small gradient across biological membranes. Li+ is similar enough to Na+ that under experimental conditions, Li+ can replace Na+ for production of a single action potential in neurons.
Recent research suggests three different mechanisms which may or may not act together to deliver the mood-stabilizing effect of this ion.[35] The excitatory neurotransmitter glutamate could be involved in the effect of lithium as other mood stabilizers such as valproate and lamotrigine exert influence over glutamate, suggesting a possible biological explanation for mania. The other mechanisms by which lithium might help to regulate mood include the alteration of gene expression.[36]
An unrelated mechanism of action has been proposed in which lithium deactivates the GSK3β enzyme.[37] This enzyme normally phosphorylates the Rev-Erbα transcription factor protein stabilizing it against degradation. Rev-Erbα in turn represses BMAL1, a component of the circadian clock. Hence lithium by inhibiting GSK3β causes the degradation of Rev-Erbα and increases the expression of BMAL which dampens the circadian clock[38] Through this mechanism, lithium is able to block the resetting of the "master clock" inside the brain; as a result, the body's natural cycle is disrupted. When the cycle is disrupted, the routine schedules of many functions (metabolism, sleep, body temperature) are disturbed. Lithium may thus restore normal brain function after it is disrupted in some people.
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 the neural plasticity. Ghasemi et al. (2008, 2009) have shown that the NO system could be involved in the antidepressant effect of lithium in the Porsolt forced swimming test in mice.[39][40] It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test,[41] indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of learned helplessness.
Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, leading to higher levels of inositol triphosphate.[42] This effect was enhanced further with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression.
Lithium was first used in the nineteenth 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.[43] Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange in Denmark[44] and William Alexander Hammond in New York[45] used lithium to treat mania from the 1870s onwards though there are reports of its use in the form of spring waters to treat mania in Roman and Greek times. By the turn of the century, this use of lithium was largely abandoned, according to Susan Greenfield due to the reluctance of the pharmaceutical industry to invest in a drug that could not be patented.[46]
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 practise was discontinued in 1949 when reports of side effects and deaths were published, leading to a ban of lithium sales.[43]
The use of lithium salts to treat mania was rediscovered by the Australian psychiatrist John Cade in 1949. Cade was injecting rodents with urine extracts taken from schizophrenic patients, in an attempt to isolate a metabolic compound which might be causing mental symptoms. Since uric acid in gout was known to be psychoactive (adenosine receptors on neurons are stimulated by it; caffeine blocks them), Cade needed soluble urate for a control. He used lithium urate, already known to be the most soluble urate compound, and observed that this caused the rodents to be tranquilized. Cade traced the effect to the lithium ion itself. Soon, Cade proposed lithium salts as tranquilizers, and 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.[47]
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,[43] and Samuel Gershon and Baron Shopsin in the U.S., this resistance was slowly overcome. The application of lithium for mania in manic illness was approved by the United States Food and Drug Administration in 1970.[48] In 1974 this application was extended to the use of lithium as a preventive agent for manic-depressive illness.
In 2009, Japanese researchers at Oita University reported that low levels of naturally-occurring lithium in drinking water supplies reduced suicide rates.[49] A previous report had found similar data in the American state of Texas.[50] In response, psychiatrist Peter Kramer raised the hypothetical possibility of adding lithium to drinking water.[51]
Lithium has become a part of Western popular culture. Characters in Pi, Premonition, Stardust Memories, American Psycho, and An Unmarried Woman all take lithium. 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: "Lithium Lips" by Mac Lethal, "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,[52] "Tea and Thorazine" by Andrew Bird, 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, 7 Up. Charles Leiper Grigg, who launched his St. Louis-based company The Howdy Corporation in 1920, invented a formula for a lemon-lime soft drink in 1929. The product, originally named "Bib-Label Lithiated Lemon-Lime Soda", was launched two weeks before the Wall Street Crash of 1929.[53] It contained the mood stabiliser lithium citrate and was one of a number of patent medicine products popular in the late-19th and early-20th centuries.[54] Its name was soon changed to 7 Up; all American beverage makers were forced to remove lithium in 1948.
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