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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.[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), lithium 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.

Contents

History

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.[2] Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange in Denmark[3] and William Alexander Hammond in New York[4] used lithium to treat mania from the 1870s onwards. 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.[5]

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.[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 (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.[6]

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 Poul Baastrup in Europe,[2] 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.[7]

In 2009, Japanese researchers at Oita University reported that low levels of naturally-occurring lithium in drinking water supplies reduced suicide rates.[8] A previous report had found similar data in the American state of Texas.[9] In response, psychiatrist Peter Kramer raised the hypothetical possibility of adding lithium to drinking water.[10] Bioethicist Jacob Appel lent moral support to the possibility shortly thereafter, arguing that "One person's right to drink lithium-free water is no greater than another's right to drink lithium-enhanced water."[11]

Use in 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, 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.[12] 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. The beverage was marketed specifically as a hangover cure. Its name was soon changed to 7 Up. According to Gary Yu (UCSB) and researchers for the "Uncle John's Bathroom Reader", the name is derived from the atomic mass of lithium (approximately seven daltons). Lithium citrate was removed from 7 Up's formula in 1950.[13]

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 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.[14][15] 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.[16][17] 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 (15–20 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.

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.

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 1.2 mmol 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 1.5 mmol Li+/liter, 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 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+/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.

Lithium may be used as a treatment of seborrhoeic dermatitis.

Mechanism of action

Unlike other psychoactive drugs, Li+ typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations.[citation needed]

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+ 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.[18] 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.[19]

An unrelated proposed mechanism of action put forth at the University of Pennsylvania in 1996 posits that lithium ion deactivates the GSK-3B enzyme.[20] 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.[21] 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, 2009) have shown that the NO system could be involved in the antidepressant effect of lithium in the Porsolt forced swimming test in mice.[22][23] It was also reported that NMDA receptors blockage augments antidepressant-like effects of lithium in the mouse forced swimming test,[24] 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.[25] This effect was enhanced further with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression.

Harmful effects of lithium

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.[26]

Lithium is known to be responsible for significant amounts of weight gain.[27] It increases the appetite and thirst ("polydypsia", potentially causing nephrogenic diabetes insipidus), and reduces the activity of thyroid hormone (hypothyroidism).[28][29][30][31][32] It is also believed to affect renal function.[citation needed]

Lithium is a well known cause of downbeat nystagmus.[33] The nystagmus may be permanent or require several months of abstinence for improvement.[34]

Lithium is also a strong teratogen and if taken during a woman's pregnancy can cause her child to develop Ebstein's anomaly, a heart defect.

Cultural references to lithium-based medications

Several songs refer to the use of lithium as a mood stabilizer. "Lithium Sunset" from the album Mercury Falling by Sting, describes the antidepressant quality of sunsets, likening them to lithium.[35] "Lithium" by Nirvana, "Tea and Thorazine" by Andrew Bird, and "Lithium" by Evanescence are other examples. Sirius XM Satellite Radio in North America has a 1990s alternative rock station called Lithium.

Hundreds of soft drinks once 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 was called Lithia Coke and 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[36] 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 the popular HBO series The Sopranos, Tony Soprano receives Prozac and lithium as the medications from his physician, Jennifer Melfi, for anxiety attacks. Melfi discontinues the lithium after Tony's hallucinations about Isabella, 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.

In the Zach Braff film Garden State, the protagonist Andrew Largeman stops taking lithium and begins to experience life very differently.

In the Tom Kitt/Brian Yorkey musical next to normal, the protagonist Diana Goodman mentions having been treated with lithium at one time for her worsening bipolar disorder when she sings, "It was the year of too much lithium/ I hid out in the car..."

In an episode of The Critic, Jay Sherman tells a class of cab drivers that the only things that gets him through the day is lithium.

In the book Impulse, one of the main characters, Vanessa, takes lithium to help with her bipolar disorder.

In an episode of the UK television Sci-Fi series Red Dwarf, "Back To Reality", the mechanoid Kryten recommends use of lithium carbonate as a mood stabiliser.

References

  1. ^ Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J (October 2006). "Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review.". Bipolar disorders 8 (5 Pt 2): 625–39. doi:10.1111/j.1399-5618.2006.00344.x. PMID 17042835. 
  2. ^ a b c Marmol, F. (2008). "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. doi:10.1016/j.pnpbp.2008.08.012. PMID 18789369.  edit
  3. ^ http://www.clinchem.org/cgi/content/abstract/40/2/309
  4. ^ Lithium treatment for bipolar disorder. pdf
  5. ^ Greenfield, Susan: "Brain Power: Working out the Human Mind", page 91. Element Books Limited, 1999
  6. ^ Cade J. F. J. (1949). "Lithium salts in the treatment of psychotic excitement" (PDF). Medical Journal of Australia 2 (10): 349–52. PMID 18142718. http://www.who.int/docstore/bulletin/pdf/2000/issue4/classics.pdf. 
  7. ^ P. B. Mitchell, D. Hadzi-Pavlovic (2000). "Lithium treatment for bipolar disorder" (PDF). Bulletin of the World Health Organization 78 (4): 515–7. PMID 10885179. PMC 2560742. http://www.who.int/docstore/bulletin/pdf/2000/issue4/classics.pdf. 
  8. ^ Ohgami H. Terao T. et al, Lithium levels in drinking water and risk of suicide. British Journal of Psychiatry. 194(5):464-5; discussion 446, May 2009
  9. ^ Gonzalez R. Bernstein I., et al. An investigation of water lithium concentrations and rates of violent acts in 11 Texas counties: can an association be easily shown? Journal of Clinical Psychiatry. 69(2):325-6, 2008 Feb.
  10. ^ Listening to Lithium Sept 9. 2009
  11. ^ Beyond Fluoride: Pharmaceuticals, Drinking Water & the Public Health
  12. ^ "7 UP: The Making of a Legend". Cadbury Schweppes: America's Beverages.
  13. ^ 7 UP: The Making of a Legend". Cadbury Schweppes: America's Beverages
  14. ^ Mash, Eric J.; Russell A. Barkley (2006). Treatment of childhood disorders. Guilford Press. pp. 443. ISBN 1572309210. http://books.google.co.uk/books?id=KCZqs_NlfmQC. 
  15. ^ Schatzberg, Alan F.; Jonathan O. Cole, Charles DeBattista (2007). Manual of clinical psychopharmacology. American Psychiatric Publishing. pp. 267. ISBN 1585623172. http://books.google.co.uk/books?id=NvT0l6iL5IQC. 
  16. ^ "Lithium Slows ALS Progression In Study". Muscular Dystrophy Association. 2008-02-04. http://www.als-mda.org/research/news/080204Lithium_slows_ALS.html. Retrieved 2009-06-23. 
  17. ^ http://www.pnas.org/cgi/content/abstract/105/6/2052
  18. ^ Jope RS (March 1999). "Anti-bipolar therapy: mechanism of action of lithium". Mol. Psychiatry 4 (2): 117–28. doi:10.1038/sj.mp.4000494. PMID 10208444. 
  19. ^ Lenox RH, Wang L (February 2003). "Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks". Mol. Psychiatry 8 (2): 135–44. doi:10.1038/sj.mp.4001306. PMID 12610644. http://www.nature.com/mp/journal/v8/n2/abs/4001306a.html. 
  20. ^ Klein PS, Melton DA (August 1996). "A molecular mechanism for the effect of lithium on development". Proc. Natl. Acad. Sci. U.S.A. 93 (16): 8455–9. doi:10.1073/pnas.93.16.8455. PMID 8710892. PMC 38692. http://www.pnas.org/cgi/reprint/93/16/8455. 
  21. ^ Yin L, Wang J, Klein PS, Lazar MA (February 2006). "Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock". Science (journal) 311 (5763): 1002–5. doi:10.1126/science.1121613. PMID 16484495. http://www.sciencemag.org/cgi/content/full/311/5763/1002. 
  22. ^ Ghasemi M, Sadeghipour H, Mosleh A, Sadeghipour HR, Mani AR, Dehpour AR (May 2008). "Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test". Eur Neuropsychopharmacol 18 (5): 323–32. doi:10.1016/j.euroneuro.2007.07.011. PMID 17728109. 
  23. ^ Ghasemi M, Sadeghipour H, Poorheidari G, Dehpour AR (June 2009). "A role for nitrergic system in the antidepressant-like effects of chronic lithium treatment in the mouse forced swimming test". Behav Brain Res 200 (1): 76–82. doi:10.1016/j.bbr.2008.12.032. PMID 19166880. 
  24. ^ Ghasemi M, Raza M, Dehpour AR (2009) (2009). "NMDA receptor antagonists augment antidepressant-like effects of lithium in the mouse forced swimming test". J Psychopharmacol. doi:10.1177/0269881109104845. PMID 19351802. http://jop.sagepub.com/cgi/content/abstract. 
  25. ^ Einat H, Kofman O, Itkin O, Lewitan RJ, Belmaker RH (1998). "Augmentation of lithium's behavioral effect by inositol uptake inhibitors". J Neural Transm 105 (1): 31–8. doi:10.1007/s007020050035. PMID 9588758. http://link.springer.de/link/service/journals/00702/bibs/8105001/81050031.htm. 
  26. ^ Neurobehavioral Outcome following Lithium Exposure
  27. ^ Sperner-Unterweger, Barbara; W. Wolfgang Fleischhacker, Wolfgang P. Kaschka (2001). Psychoneuroimmunology. Karger Publishers. pp. 22. ISBN 380557262X. http://books.google.co.uk/books?id=Q0xJfkY5VRUC. 
  28. ^ Keshavan, Matcheri S.; John S. Kennedy (2001). Drug-induced dysfunction in psychiatry. Taylor & Francis. pp. 305. ISBN 089116961X. http://books.google.co.uk/books?id=pol0204fqjIC. 
  29. ^ Side Effects - Lithium / Various Brand Names - Bipolar Disorder Medications
  30. ^ Bipolar Medications and Weight Gain
  31. ^ Nutrition Articles - The Relationship between Weight Gain and Medications for Depression and Seizures
  32. ^ Found at NHS National Patient Safety Agency. Does not cite specific examples (http://www.nrls.npsa.nhs.uk/resources/patient-safety-topics/medication-safety/?entryid45=65426)
  33. ^ Lee, Michael S.; Lessell, Simmons (January 28, 2003). "Lithium-induced periodic alternating nystagmus". Neurology (journal) 60 (2): 344. PMID 12552061. http://www.neurology.org/cgi/content/citation/60/2/344. Retrieved 2009-12-20. 
  34. ^ Williams, Douglas P.; Jack Rogers and B. Todd Troost (September 1988). "Lithium-Induced Downbeat Nystagmus". Archives of Neurology 45 (9): 1022–1023. http://www.neurology.org/cgi/content/citation/60/2/344. Retrieved 2009-12-20. 
  35. ^ Agassi, Tirzah (1996-03-12). "Sting is now older, wiser and duller". The Jerusalem Post. http://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. Retrieved 2009-06-25. 
  36. ^ "Urban Legends Reference Pages: 7Up". http://www.snopes.com/business/names/7up.asp. Retrieved 2007-11-13. 

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