Lithium pharmacology

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Lithium in 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.^[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), the sulfate salt lithium sulfate (Li₂SO₄), aspartate and the orotate salt lithium orotate are alternatives.

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.

[edit] History

Solutions of lithium will dissolve uric acid crystals.^{[citation needed]} Against the background of nineteenth century theories linking excess uric acid to a range of disorders, including manic disorders, Carl Lange in Denmark and William Alexander Hammond in New York used lithium to treat mania from the 1870s onwards.^{[citation needed]}

However, by the turn of the century, the use of lithium in this way died out and was seemingly forgotten. This was also due to the reluctance of the pharmaceutical industry to invest in a drug that could not be patented.^[2]

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 (purinergic neurons are stimulated by it), 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.^[3]

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 deaths reported 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.^[4]

[edit] 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. It is sometimes used for other psychiatric disorders such as cycloid psychosis and unipolar depression. Non-psychiatric uses are limited however, its use in the prophylaxis of some headaches related to cluster headaches (trigeminal autonomic cephalgias:- particularly hypnic headache is well established. More recently, Lithium has shown promising results in a human trial in the neurodegenerative disease amyotrophic lateral sclerosis. It 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 (15-20mg per kg of body weight) is slightly less than the toxic level, requiring blood levels of lithium to be monitored closely during treatment. In order to prescribe the correct dosage, the patient's entire medical history, both physical and psychological, is sometimes taken into consideration. Blood tests are carried out every 3 months to ensure the level of lithium is appropriate and to prevent toxicity, along with kidney and thyroid tests.

Those who use lithium should receive regular (generally monthly once stable) blood tests and should monitor thyroid function annually and kidney function every three to six months 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.

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 0.6 to 1.2mmol Li+/litre (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 1.5mmol 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. The most common side effects end up being 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+/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. Doctors may change a bipolar patient's medication from lithium to another mood stabilizing drug, such as Depakote (divalproex sodium), 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.

[edit] Mechanism of action

Unlike other psychoactive drugs, Li⁺ 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. 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.

Recent research suggests three different mechanisms which may act together to deliver the mood-stabilizing effect of this ion ^[5]. 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.^{[citation needed]} The other mechanisms by which lithium might help to regulate mood include the alteration of gene expression^[6] and the non-competitive inhibition of an enzyme called inositol monophosphatase.

An unrelated proposed mechanism of action put forth at the University of Pennsylvania in 1996 posits that lithium ion deactivates the GSK-3B enzyme.^[7] The regulation of GSK-3B by lithium may affect the circadian clock -- and recent research (Feb 2006) seems to support this conclusion. When GSK-3B is activated, the protein Bmal1 is unable to reset 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.^[8] Lithium may thus restore normal brain function after it is disrupted in some people. The complete mechanism related to mood in this mechanism is not hypothesized.

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) have shown that the NO system could be involved in the antidepressant effect of lithium in the Porsolt forced swimming test in mice ^[9].

[edit] Harmful effects of lithium

Lithium is much less teratogenic than previously thought, though it does double the likelihood of Ebstein's anomaly (a cardiac defect), occurring at 0.1% when used during the first trimester of pregnancy.

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.^[10]

There have also been long term effects on the kidney, including diabetes insipidus with secondary distortion of bladder and urinary tract. Animal studies show long-term physical and behavioural effects extending beyond the first generation.^{[citation needed]}

Lithium is known to be responsible for (sometimes significant) weight gain, acne with scarring, thinning of hair, and pronounced tremor, usually in the hands but extending to lips and tongue when the person is stressed, or after prolonged use.^{[11][12][13] [14][15]}

[edit] Lithium and culture

As with many other psychoactive drugs (but relatively few therapeutic psychoactive drugs), songs have been written about its effects; "Lithium Sunset" by Sting, "Lithium" by Evanescence, and "Lithium" by Nirvana are some examples.

Hundreds of soft drinks included lithium salts or lithia water (naturally occurring mineral waters with higher lithium amounts). An early version of Coca Cola available in pharmacies' soda fountains called Lithia Coke was a mixture of Coca Cola syrup and lithia water. The soft drink 7 Up, originally named "Bib-Label Lithiated Lemon-Lime Soda", contained lithium citrate^[16] until it was reformulated in 1950. Additionally, Lithia light beer was brewed at the West Bend Lithia Company in Wisconsin. All of these were forced to remove lithium in 1948.

In popular HBO series The Sopranos Tony Soprano received Prozac and lithium as the medications from Dr. Melfi for anxiety attacks. Dr. Melfi later stopped the Lithium, because she thinks that Lithium caused Tony's hallucinations about Isabel, an exchange student from Italy who temporarily lived next door.

In the Darren Aronofsky film Pi, the protagonist Maximillian Cohen takes Lithium to relieve his mental illness.

[edit] References

• Hecht, Frederick; Shiel Jr, William: et al. Webster’s Medical Dictionary, IDG Books Worldwide inc: New York;2000: pg 225
• Nih.gov. http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202330.html (accessed June 8, 2006) US National Library of Medicine and National Institutes of Health.
• Yin I; Wang J; Klein PS; et al. Nuclear Receptor Rev-erba is a Critical Lithium-Sensitive Component of the Circadian Clock. Science (online) 2006, Vol.311no 5763. pp 1002-1005.
• Geddes, John: Burgess, Sally: et al. Long-term Lithium Therapy for Bi-polar Disorder: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Amer. Jour. Of Psych. 2004, 161:2, pp 217-222.
• Lynn, Edward J. M.D.; Satloff, Aaron M.D.; Tinling, David C., "abstract Mania and the Use of Lithium: A Three-Year Study", The American Journal of Psychiatry (March 1971)

[edit] Selected bibliography

• McIntyre RS, Mancini DA, Parikh S, Kennedy SH (2001). "Lithium revisited". Canadian journal of psychiatry. Revue canadienne de psychiatrie 46 (4): 322–7. PMID 11387787. 

• Bowden CL, Brugger AM, Swann AC, et al (1994). "Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group". JAMA 271 (12): 918–24. PMID 8120960. 

[edit] External links

• "Exposing lithium's circadian action"
• http://www.psycheducation.org/depression/meds/moodstabilizers.htm
• http://www.psycheducation.org/depression/meds/lithium.html
• SID 685039 — PubChem Substance Summary (Lithium Oxybutyrate)
• N05AN01