Lithium in pharmacology refers to use of the lithium ion, Li⁺, as a drug. Lithium (ˈlɪθiəm is a Chemical element with the symbol Li and Atomic number 3 An ion is an Atom or Molecule which has lost or gained one or more Valence electrons giving it a positive or negative electrical charge 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. Salt is a Dietary mineral composed primarily of Sodium chloride that is essential for Animal life but toxic to most land plants This article refers to the medication For other uses see Stabilizer. Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression Mania (from Greek μανία and that from μαίνομαι - mainomai, "to rage to be furious" is a severe medical condition 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. Lithium carbonate is a Chemical compound with the formula Li2CO3 A citrate can refer either to the Conjugate base of Citric acid, (C3H5O(COO33&minus or to the Esters of citric Lithium citrate (Li3C6H5O7 is a chemical compound of Lithium and Citrate that is used as a Mood stabilizer Lithium sulfate is a white inorganic salt used to treat Bipolar disorder (see Lithium pharmacology) Aspartic acid (abbreviated as Asp or D; Asx or B represent either aspartic acid or Asparagine) is an α- Amino acid Orotic acid is a Heterocyclic compound and an Acid; it is also known as pyrimidinecarboxylic acid. Lithium orotate, is a Lithium salt of Pyrimidinecarboxylic acid and Lithium.

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. In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. See Chemical synapse for an introduction to concepts and terminology used in this article In Biochemistry, a receptor is a Protein molecule embedded in either the Plasma membrane or Cytoplasm of a cell to which a mobile signaling Norepinephrine ( INN) (abbreviated norepi or NE) or noradrenaline ( BAN) (abbreviated NA or NAd) is a Serotonin (ˌsɛrəˈtoʊnən ( 5-hydroxytryptamine, or 5-HT) is a Monoamine Neurotransmitter synthesized in serotonergic Neurons

History

Solutions of lithium will dissolve uric acid crystals. Uric acid (or urate) is an Organic compound of Carbon, Nitrogen, Oxygen and Hydrogen with the formula C5H4N4O3 Kidney stones, also called renal calculi, are solid concretions (crystal aggregations of dissolved minerals in Urine; calculi typically form 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. Carl Georg Lange (1834 - 1900 was a Danish Physician and Psychologist. The Kingdom of Denmark ( ˈd̥ænmɑɡ̊ (archaic ˈd̥anmɑːɡ̊ commonly known as Denmark, is a country in the Scandinavian region of northern Europe William Alexander Hammond MD ( August 28 1828 &ndash January 5 1900) was an American neurologist and New York ( is a state in the Mid-Atlantic and Northeastern regions of the United States and is the nation's third most populous

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. For a topic outline on this subject see List of basic Australia topics. This article is about the Australian psychiatrist For the leader of the Kent Rebellion see Jack Cade. Year 1949 ( MCMXLIX) was a Common year starting on Saturday (link will display the full calendar of the Gregorian calendar. 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. A sedative, or more specifically a sedative-hypnotic, is a substance that depresses the Central nervous system (CNS resulting in calmness relaxation sleepiness 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. Lithium chloride is a Chemical compound with the formula Li[[Chlorine Cl]] Largely through the research and other efforts of Denmark's Mogens Schou in Europe, and Samuel Gershon in the U. Mogens Schou ( November 24, 1918 &ndash September 29, 2005) was a Danish psychiatrist whose groundbreaking research into Lithium 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]

Treatment

Lithium treatment is used to treat mania in bipolar disorder. Mania (from Greek μανία and that from μαίνομαι - mainomai, "to rage to be furious" is a severe medical condition Initially, lithium is often used in conjunction with antipsychotic drugs as it can take up to a week for lithium to have an effect. Antipsychotics are a group of Psychoactive drugs commonly but not exclusively used to treat Psychosis, which is typified by Schizophrenia. Lithium is also used as prophylaxis for depression and mania in bipolar disorder. Prophylaxis ( Greek "προφυλάσσω" to guard or prevent beforehand) is any medical or Public health procedure whose purpose In the fields of Psychology and Psychiatry, the terms depression or depressed refer to both expected and pathologically chronic or severe 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. Cluster headache is a neurological disease that involves as its most prominent feature an immense degree of pain More recently, Lithium has shown promising results in a human trial in the neurodegenerative disease amyotrophic lateral sclerosis. Neurodegenerative Disease ( Greek νέυρο- néuro-, "nerval" and Latin dēgenerāre, "to decline" or "to Amyotrophic Lateral Sclerosis ( ALS, sometimes called Maladie de Charcot, or in the United States Lou Gehrig's Disease) is a progressive 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. The kidneys are complicated organs that have numerous biological roles The thyroid is one of the largest Endocrine glands in the body

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. Haloperidol is a Typical antipsychotic. It is in the Butyrophenone class of Antipsychotic medications and has pharmacological effects similar Fluphenazine (marketed as Prolixin is a Typical antipsychotic drug Flupentixol ( INN) or flupenthixol (former BAN) marketed as Depixol and Fluanxol is a Typical antipsychotic Drug. Encephalopathy /ɛnˌsɛfəˈlɒpəθi/ literally means Disease of the Brain.

Lithium salts have a narrow therapeutic/toxic ratio and should therefore not be prescribed unless facilities for monitoring plasma concentrations are available. Blood plasma is the Liquid component of Blood, in which the Blood cells are suspended 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. Ataxia (from Greek α- as a negative prefix + -τάξις, meaning "lack of order" is a neurological sign and symptom consisting Dysarthria is a motor Speech disorder resulting from neurological injury, characterised by poor articulation (cf Nystagmus is a type of eye movement characterized by alternating slow phase movements in one direction and Saccade -like quick phases in the other direction 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. A diuretic is any Drug that elevates the rate of urination ( Diuresis) The distal convoluted tubule ( DCT) is a portion of Kidney Nephron between the Loop of Henle and the Collecting duct system. g. thiazides) is hazardous and should be avoided. Thiazide is a term used to describe a type of molecule and a class of Diuretic. 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. Histology (from the Greek = 'tissue' is the study of the microscopic anatomy of cells and tissues of Plants and 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. See also Valproic acid Valproate semisodium ( INN) or divalproex sodium ( USAN) consists of a compound of Sodium valproate and 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. Sustained-release ( SR) extended-release ( ER, XR, or XL) time-release or timed-release, controlled-release Preparations vary widely in bioavailability, and a change in the formulation used requires the same precautions as initiation of treatment. In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of 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.

Mechanism of action

Unlike other psychoactive drugs, Li⁺ produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations. A psychoactive drug or psychotropic substance is a Chemical substance that acts primarily upon the Central nervous system where it alters Brain Euphoria is a medically recognized emotional state related to Pleasure and Happiness.

The precise mechanism of action of Li⁺ as a mood-stabilizing agent is currently unknown. In Pharmacology, the term mechanism of action (MOA refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect It is possible that Li⁺ produces its effects by interacting with the transport of monovalent or divalent cations in neurons. An ion is an Atom or Molecule which has lost or gained one or more Valence electrons giving it a positive or negative electrical charge Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information 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. Membrane potential (or transmembrane potential) is the Voltage difference (or Electrical potential difference between the interior and exterior of a MembraneA biological membrane or biomembrane is an enclosing or separating Amphipathic layer that acts as a barrier within or around a cell. 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. In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information

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. See Chemical synapse for an introduction to concepts and terminology used in this article Glutamic acid (abbreviated as Glu or E) is one of the 20 Alpha Amino acids It is not among the human Essential amino acids Its Valproic acid ( VPA) is a Chemical compound that has found clinical use as an Anticonvulsant and mood-stabilizing drug, primarily in Lamotrigine (marketed as Lamictal (ləˈmɪktəl by GlaxoSmithKline, called Lamictin in South Africa, he למוג'ין ( Lamogine 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. Gene expression is the process by which inheritable information from a Gene, such as the DNA sequence, is made into a functional Gene product, such Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Inositol monophosphatase, commonly referred to as IMPase is an Enzyme found in all cells and is thought to be key in Bipolar disorder ( Manic depression

An unrelated proposed mechanism of action put forth at the University of Pennsylvania in 1996 posits that lithium ion deactivates the GSK-3B enzyme. Glycogen synthase kinase 3 ( GSK-3) is a Serine/threonine protein kinase, which means that it mediates the addition of phosphate molecules on certain serine and threonine ^[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].

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. Teratology stems from the Greek ( Genitive) meaning monster, or marvel and, meaning word, speech. Ebstein's anomaly is a Congenital heart defect in which the opening of the Tricuspid valve is displaced towards the apex of the Right ventricle of the 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. Diabetes insipidus ( DI) is a condition characterized by excretion of large amounts of severely diluted Urine, which cannot be reduced when fluid intake Animal studies show long-term physical and behavioural effects extending beyond the first generation.

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]}

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. A song is a Musical composition. Songs contain vocal parts that are performed 'sung' and generally feature Words ( Lyrics) commonly followed Gordon Matthew Thomas Sumner, CBE (born October 2, 1951) better known by his Stage name Sting, is a three time Academy Award " Lithium " is the second single from American Alternative metal band Evanescence 's second studio album The Open Door Evanescence is an American " Lithium " is a song by the American grunge band Nirvana, written by frontman Kurt Cobain. Nirvana was an American rock band that was formed by singer/guitarist Kurt Cobain and bassist Krist Novoselic in Aberdeen Washington.

Hundreds of soft drinks included lithium salts or lithia water (naturally occurring mineral waters with higher lithium amounts). Lithia water is Mineral water containing Lithium Salts Lithia water can occur naturally in spring form An early version of Coca Cola available in pharmacies' soda fountains called Lithia Coke was a mixture of Coca Cola syrup and lithia water. Coca-Cola is a carbonated Soft drink sold in stores restaurants and Vending machines in more than 200 countries The soft drink 7 Up, originally named "Bib-Label Lithiated Lemon-Lime Soda", contained lithium citrate^[16] until it was reformulated in 1950. 7 Up is a brand of a Lemon - lime flavored non-caffeinated Soft drink. 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. The Sopranos is an American Television drama series created by David Chase. Anthony John Soprano Sr, played by James Gandolfini, is a Fictional character on the HBO TV series The Sopranos. 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. Darren Aronofsky (born February 12, 1969 in Brooklyn, New York) is an American Film director, Screenwriter

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. John Geddes ( December 25, 1777 March 4, 1828) was an Antebellum Democratic-Republican Governor of South 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)

Selected bibliography

• McIntyre RS, Mancini DA, Parikh S, Kennedy SH (2001). The American Journal of Psychiatry (AJP is the official journal of the American Psychiatric Association (APA and the most widely read and cited Psychiatric "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.  

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