Lithium salt

Lithium salts are chemical salts of lithium used primarily in the treatment of bipolar disorder as mood stabilizing drugs. They are also sometimes used to treat depression and mania. Lithium carbonate (Li2CO3), sold as Carbolith®, Cibalith-S®, Duralith®, Eskalith®, Lithane®, Lithizine®, Lithobid®, Lithonate® and Lithotabs®, is the most commonly prescribed, whilst the citrate salt lithium citrate (Li3C6H5O7), the sulfate salt lithium sulfate (Li2SO4), the oxybutyrate salt lithium oxybutyrate (C4H9LiO3), aspartateand the orotate salt lithium orotate are alternatives.

Lithium is widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing noradrenaline release and increasing serotonin synthesis.

History
The use of lithium salts to treat mania was first proposed by the Australian psychiatrist John Cade in 1949, after he discovered the effect of first lithium urate, and then other lithium salts, on animals. Cade soon succeeded in controlling mania in chronically hospitalized patients. This was the first successful application of a drug to treat mental illness, and opened the door for the development of medicines for other mental [[problems in the next decades.

The rest of the world was slow to adopt this revolutionary treatment, largely because of deaths which resulted from even relatively minor overdosing, and from use of lithium chloride as a substitute for table salt. Largely through the research and other efforts of Denmark's Mogens Schou in Europe, and Samuel Gershon in the U.S., this resistance was slowly overcome. The application of lithium for manic illness was approved by the United States Food and Drug Administration in 1970.

Treatment
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 week for lithium to have an effect. Lithium is also used as prophylaxis for depression and mania in bipolar disorder. Also, it is sometimes used for other disorders, like cycloid psychosis, unipolar depression, migraine and others. It is sometimes used as an "augmenting" agent, to increase the benefits of standard drugs used for unipolar depression. Lithium treatment is generally considered to be unsuitable for children.

Mechanism of Action
The precise mechanism of action of Li+ as a mood-stabilizing agent is currently unknown, but 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. Yet Li+ is similar enough to Na+ in that under experimental conditions, Li+ can replace Na+ for production of a single action potential in neurons.

Perhaps most the most interesting characteristic of Li+, is that it produces no obvious psychotropic effects (such as sedation, depression, euphoria) in normal individuals at therapeutic concentrations, differentiating it from the other psychoactive drugs.

Lithium toxicity and side effects
Those who use lithium should receive regular blood tests and should monitor the thyroid and kidney for toxic damage. 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.

High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported.

Lithium salts, with the possible exception of lithium orotate, 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 0.6 to 1.2mmol Li+/litre (lower end of the range for maintenance therapy and elderly patients) on samples taken 12 hours after the preceding dose. Overdosage, usually with plasma concentrations over 1.5mmol Li+/litre, may be fatal and toxic effects include tremor, ataxia, dysarthria, nystagmus, renal impairment, and convulsions. If these potentially hazardous signs occur, treatment should be stopped, plasma lithium concentrations redetermined, and steps taken to reverse lithium toxicity.

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+/litre 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. An important consequence is the development of 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 overdosing
Signs that lithium levels within the body are too high include: confusion, diarrhea, lethargy, severe tremors, and/or an upset stomach.

Lithium and culture
As with many other drugs, songs have been written about its effects, "Lithium Sunset" by Sting and "Lithium" by Nirvana among others.

The soft drink 7 Up, originally named "Bib-Label Lithiated Lemon-Lime Soda", contained lithium citrate until it was reformulated in 1950.

Hundreds of other soft drinks also included lithium salts or lithia waters as well as at least one brewery which produced Lithia beers (all of these were forced to remove lithium in 1948).

An early version of Coca Cola available in pharmacies' soda fountains called Lithia Coke was a mixture of Coca Cola syrup and litha water (lithia waters are naturally occurring mineral waters with higher lithium amounts).

The amount of lithium in any of the commercially available soft drinks was hundreds of times less than a minimum psychiatric dose but the ban didn't make any distinctions on that basis.

Selected Bibliography

 * McIntyre RS, Mancini DA, Parikh S, Kennedy SH. "Lithium revisited." Can J Psychiatry. 2001 May;46(4):322-7.
 * Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, and others. Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA 1994;271:918–24.