Lithium pharmacology
Encyclopedia
Lithium
Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
, Li+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing
Mood stabilizer
A mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, typically bipolar disorder.-Uses:...
drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
, primarily in the treatment of bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, where they have a role in the treatment of depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
and particularly of mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
, 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. In depression alone (unipolar disorder) lithium can be used to augment other antidepressants. Lithium carbonate
Lithium carbonate
Lithium carbonate is a chemical compound of lithium, carbon, and oxygen with the formula Li2CO3. This colorless salt is widely used in the processing of metal oxides and has received attention for its use in psychiatry. It is found in nature as the rare mineral zabuyelite.-Properties:Like almost...
(Li2CO3), sold under several trade names, is the most commonly prescribed, while the citrate
Citrate
A citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...
salt lithium citrate
Lithium citrate
Lithium citrate is a chemical compound of lithium and citrate that is used as a mood stabilizer in psychiatric treatment of manic states and bipolar disorder. For the medical aspects of lithium citrate, see lithium pharmacology....
(Li3C6H5O7) is also used in conventional pharmacological treatments. The sulfate
Sulfate
In inorganic chemistry, a sulfate is a salt of sulfuric acid.-Chemical properties:...
salt lithium sulfate
Lithium sulfate
Lithium sulfate is a white inorganic salt with the formula Li2SO4. It is the lithium salt of sulfuric acid.-Properties:Lithium sulfate is soluble in water, though it does not follow the usual trend of solubility versus temperature — its solubility in water decreases with increasing temperature, as...
(Li2SO4) has been presented as an alternative. Lithium orotate
Lithium orotate
Lithium orotate, is a salt of orotic acid and lithium. It is available as the monohydrate, LiC5H3N2O4·H2O.Lithium orotate is generally marketed as a dietary supplement used in small doses to treat mental conditions including stress, bipolar disorder, alcoholism, ADHD, ADD, aggression, PTSD,...
(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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and interacts with a number of neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s and receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
, decreasing norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
release and increasing serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
synthesis.
Medical uses
Lithium treatment is used to treat maniaMania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
in bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
. 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
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
and mania in bipolar disorder. It is sometimes used for other psychiatric disorders such as cycloid psychosis and major depressive disorder. Lithium possesses a very important antisuicidal effect not shown in other stabilizing medications such as antiseizures drugs. Non-psychiatric applications are limited; however, its use is well established in the prophylaxis of some headaches related to cluster headache
Cluster headache
Cluster headache, nicknamed "suicide headache", is a neurological disease that involves, as its most prominent feature, an immense degree of pain in the head. Cluster headaches occur periodically: spontaneous remissions interrupt active periods of pain. The cause of the disease is currently unknown...
s (trigeminal autonomic cephalgias), particularly hypnic headache
Hypnic headache
Hypnic headaches are benign primary headaches that affect the elderly, with the average age of onset being 63 ± 11 years. They are moderate, throbbing, bilateral or unilateral headaches that wake the sufferer from sleep once or multiple times a night. They typically begin a few hours after sleep...
. An Italian pilot study in humans conducted in 2005–06 suggested that lithium may improve outcomes in the neurodegenerative disease amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
.
However, a randomised, double-blind, placebo-controlled trial comparing the safety and efficacy of lithium in combination with riluzole
Riluzole
Riluzole is a drug used to treat amyotrophic lateral sclerosis. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately 3–5 months....
for treatment of amyotrophic lateral sclerosis failed to demonstrate any benefit from a combination therapy over riluzole alone.
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.
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
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
levels in the body, lithium can cause dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
. 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.
High doses of haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
, fluphenazine
Fluphenazine
Fluphenazine is a typical antipsychotic drug used for the treatment of psychoses such as schizophrenia and acute manic phases of bipolar disorder. It belongs to the piperazine class of phenothiazines....
, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy
Toxic encephalopathy
* Baker, E. . Chronic toxic encephalopathy caused by occupational solvent exposure. Annals of Neurology. 63: 545-547- External links :*****...
has been reported.
Lithium salts have a narrow therapeutic/toxic ratio and should therefore not be prescribed unless facilities for monitoring plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
concentrations are available. Patients should be carefully selected. Doses are adjusted to achieve plasma concentrations of 0.4 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
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, dysarthria
Dysarthria
Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
, nystagmus, renal impairment
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
, confusion, and convulsion
Convulsion
A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body. Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure...
s. 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
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
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
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
(Depakote), if problems with the kidneys arise. An important potential consequence of long-term lithium usage is the development of renal diabetes insipidus
Diabetes insipidus
Diabetes insipidus is a condition characterized by excessive thirst and excretion of large amounts of severely diluted urine, with reduction of fluid intake having no effect on the concentration of the urine. There are several different types of DI, each with a different cause...
(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
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
, 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
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
and might be indicated in patients suffering from leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
.
A limited amount of evidence suggests that lithium may contribute to treatment of substance abuse for some dual-disorder patients.
Side effects
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. Cognitive depression in adults is disputed.Lithium is known to be responsible for significant amounts of weight gain. It increases the appetite and thirst ("polydypsia", potentially causing nephrogenic diabetes insipidus
Diabetes insipidus
Diabetes insipidus is a condition characterized by excessive thirst and excretion of large amounts of severely diluted urine, with reduction of fluid intake having no effect on the concentration of the urine. There are several different types of DI, each with a different cause...
), may cause more depression than before with suicidal thoughts and actions, and reduces the activity of thyroid hormone
Thyroid hormone
The thyroid hormones, thyroxine and triiodothyronine , are tyrosine-based hormones produced by the thyroid gland primarily responsible for regulation of metabolism. An important component in the synthesis of thyroid hormones is iodine. The major form of thyroid hormone in the blood is thyroxine ,...
(hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
). It is also believed to affect renal function.
Lithium is a well known cause of downbeat nystagmus. The nystagmus may be permanent or require several months of abstinence for improvement.
Lithium is also a teratogen causing birth defects in a small number of new born babies. If taken during a woman's pregnancy can cause her child to develop Ebstein's anomaly
Ebstein's anomaly
Ebstein 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 heart.-Presentation:...
, a heart defect.
Dehydration
Dehydration in patients taking Lithium salts can be very hazardous especially when combined with nephrogenic diabetes insipidusDiabetes insipidus
Diabetes insipidus is a condition characterized by excessive thirst and excretion of large amounts of severely diluted urine, with reduction of fluid intake having no effect on the concentration of the urine. There are several different types of DI, each with a different cause...
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.
Overdose
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, ataxiaAtaxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, confusion, lethargy, polyuria
Polyuria
Polyuria is a condition usually defined as excessive or abnormally large production or passage of urine . Frequent urination is sometimes included by definition, but is nonetheless usually an accompanying symptom...
, seizures and coma. Other toxic effects of lithium also include coarse tremor, muscle twitching, convulsion
Convulsion
A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body. Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure...
s and renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. Persons who survive a poisoning episode may develop persistent neurotoxicity.
Measurement in body fluids
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.Mechanism of action
Unlike other psychoactive drugs, Li+ typically produces no obvious psychotropic effects (such as euphoriaEuphoria (emotion)
Euphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of well-being, elation, happiness, ecstasy, excitement and joy...
) in normal individuals at therapeutic concentrations.
The precise mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
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
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
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
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s.
Recent research suggests three different mechanisms which may or may not act together to deliver the mood-stabilizing effect of this ion. The excitatory neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
glutamate could be involved in the effect of lithium as other mood stabilizers such as valproate and lamotrigine
Lamotrigine
Lamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...
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
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
.
An unrelated mechanism of action has been proposed in which lithium deactivates the GSK3β
GSK3B
Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene.- Function :Glycogen synthase kinase-3 is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms,...
enzyme. This enzyme normally phosphorylates
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
the Rev-Erbα
Rev-ErbA alpha
Rev-ErbA alpha also known as NR1D1 , is a protein that in humans is encoded by the NR1D1 gene.Rev-erbα is member of the Rev-ErbA family of nuclear receptors and is a transcriptional repressor...
transcription factor protein stabilizing it against degradation. Rev-Erbα in turn represses BMAL1
ARNTL
Aryl hydrocarbon receptor nuclear translocator-like, also known as ARNTL, Bmal1, or Mop3, is a gene which is associated with susceptibility to hypertension and type 2 diabetes.-Function:...
, 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 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
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(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. It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test, indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of learned helplessness
Learned helplessness
Learned helplessness, as a technical term in animal psychology and related human psychology, means a condition of a human person or an animal in which it has learned to behave helplessly, even when the opportunity is restored for it to help itself by avoiding an unpleasant or harmful circumstance...
.
Lithium
Lithium
Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
treatment has been found to inhibit the enzyme inositol monophosphatase
Inositol monophosphatase
Inositol monophosphatase , commonly referred to as IMPase, is an enzyme found in all cells and is thought to be key in bipolar disorder...
, leading to higher levels of inositol triphosphate. This effect was enhanced further with an inositol triphosphate reuptake inhibitor
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
. Inositol
Inositol
Inositol or cyclohexane-1,2,3,4,5,6-hexol is a chemical compound with formula 6126 or 6, a sixfold alcohol of cyclohexane. It exists in nine possible stereoisomers, of which the most prominent form, widely occurring in nature, is cis-1,2,3,5-trans-4,6-cyclohexanehexol, or myo-inositol...
disruptions have been linked to memory impairment and depression.
History
Lithium was first used in the nineteenth century as a treatment for goutGout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
after scientists discovered that, at least in the laboratory, lithium could dissolve uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
crystals isolated from the kidneys. The levels of lithium needed to dissolve urate in the body, however, were toxic. Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange
Carl Lange
Carl Georg Lange was a Danish physician and psychologist. He and William James independently developed the James-Lange theory of emotion, which posits that all emotions are developed from, and can be reduced to, physiological reactions to stimuli. Unlike James, Lange specifically stated that...
in Denmark
Denmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...
and William Alexander Hammond
William Alexander Hammond
William Alexander Hammond, M.D. was an American neurologist and the 11th Surgeon General of the U.S. Army...
in New York
New York
New York is a state in the Northeastern region of the United States. It is the nation's third most populous state. New York is bordered by New Jersey and Pennsylvania to the south, and by Connecticut, Massachusetts and Vermont to the east...
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
Susan Greenfield
Susan Adele Greenfield, Baroness Greenfield, CBE is a British scientist, writer, broadcaster, and member of the House of Lords. Greenfield, whose specialty is the physiology of the brain, has worked to research and bring attention to Parkinson's disease and Alzheimer's disease.Greenfield is...
due to the reluctance of the pharmaceutical industry to invest in a drug that could not be patented.
As accumulating knowledge indicated a role for excess sodium intake in hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
, lithium salts were prescribed to patients for use as a replacement for dietary table salt (sodium chloride
Sodium chloride
Sodium chloride, also known as salt, common salt, table salt or halite, is an inorganic compound with the formula NaCl. Sodium chloride is the salt most responsible for the salinity of the ocean and of the extracellular fluid of many multicellular organisms...
). This practise was discontinued in 1949 when reports of side effects and deaths were published, leading to a ban of lithium sales.
The use of lithium salts to treat mania was rediscovered by the Australian psychiatrist John Cade
John Cade
For the former Maryland State Senator, see John A. CadeFor the Louisiana Republican state chairman, see John H. Cade, Jr.Dr John Frederick Joseph Cade AO was an Australian psychiatrist credited with discovering the effects of lithium carbonate as a mood stabilizer in the treatment of bipolar...
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
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
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 tranquilizer
Tranquilizer
A tranquilizer, or tranquilliser , is a drug that induces tranquility in an individual.The term "tranquilizer" is imprecise, and is usually qualified, or replaced with more precise terms:...
s, 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.
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
Lithium chloride
Lithium chloride is a chemical compound with the formula LiCl. The salt is a typical ionic compound, although the small size of the Li+ ion gives rise to properties not seen for other alkali metal chlorides, such as extraordinary solubility in polar solvents and its hygroscopic...
as a substitute for table salt. Largely through the research and other efforts of Denmark's Mogens Schou
Mogens Schou
Mogens Schou was a Danish psychiatrist whose groundbreaking research into Lithium led to its utilization as a treatment for bipolar illness. His work ultimately benefited thousands of patients worldwide....
and Paul Baastrup in Europe, 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
in 1970. 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
Oita University
is a national university in Ōita, Ōita, Japan. The precursor of the school was founded in 1921 and was chartered as a university in 1949....
reported that low levels of naturally-occurring lithium in drinking water supplies reduced suicide rates. A previous report had found similar data in the American state of Texas
Texas
Texas is the second largest U.S. state by both area and population, and the largest state by area in the contiguous United States.The name, based on the Caddo word "Tejas" meaning "friends" or "allies", was applied by the Spanish to the Caddo themselves and to the region of their settlement in...
. In response, psychiatrist Peter Kramer
Peter D. Kramer
Peter D. Kramer, M.D., is an American psychiatrist, former Marshall Scholar and faculty member of Brown Medical School specializing in the area of depression. He considers depression to be a serious illness with tangible physiological effects such as disorganizing the brain and disrupting the...
raised the hypothetical possibility of adding lithium to drinking water.
Lithium has become a part of Western popular culture. Characters in Pi
Pi (film)
Pi, also titled ,WorldCat gives the title as [Pi] and provides a note which states, "Title is the mathematical symbol for Pi." . Amazon gives the title as Pi with no notation concerning the math symbol . is a 1998 American psychological thriller film written and directed by Darren Aronofsky...
, Premonition
Premonition (2007 film)
Premonition is a 2007 American drama film directed by Mennan Yapo and starring Sandra Bullock and Julian McMahon. Principal photography took place in Louisiana.-Plot:...
, Stardust Memories
Stardust Memories
Stardust Memories is a 1980 film written and directed by Woody Allen, who considers this to be one of his best films in addition to The Purple Rose of Cairo and Match Point. The film is shot in black-and-white, particularly reminiscent of Federico Fellini's 8½ , which it parodies...
, American Psycho
American Psycho (film)
American Psycho is a 2000 cult thriller film directed by Mary Harron based on Bret Easton Ellis's novel of the same name. Though predominantly a psycho thriller, the film also blends elements of horror, satire, and black comedy...
, and An Unmarried Woman
An Unmarried Woman
An Unmarried Woman is a 1978 American comedy-drama film that tells the story of the wealthy New York wife Erica Benton whose “perfect” life is shattered when her stockbroker husband Martin leaves her for a younger woman. The film documents Erica's attempts at being single again, where she suffers...
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
Koos Kombuis
Koos Kombuis is a South African musician, singer, songwriter and writer who became famous as part of a group of anti-establishment maverick Afrikaans musicians, who, under the collective name of Voëlvry , toured campuses...
, "Lithium
Lithium (Evanescence song)
Maxi 7" Vinyl Picture Disc-Chart performance:...
" by Evanescence
Evanescence
Evanescence is an American rock band founded in Little Rock, Arkansas in 1995 by singer/pianist Amy Lee and guitarist Ben Moody. After recording private albums, the band released their first full-length album, Fallen, on Wind-up Records in 2003. Fallen sold more than 17 million copies worldwide...
, "Lithium" by Nirvana
Nirvana (band)
Nirvana was an American rock band that was formed by singer/guitarist Kurt Cobain and bassist Krist Novoselic in Aberdeen, Washington in 1987...
, "Lithium and a Lover" by Sirenia
Sirenia (band)
Sirenia is a gothic metal band from Stavanger, Norway which incorporates a mixture of gothic metal and symphonic metal, as well as extreme metal and death metal elements...
, "Lithium Sunset", from the album Mercury Falling
Mercury Falling
Mercury Falling is the fifth studio album released by Sting. The album was marked by its tight studio production and use of brass reminiscent of recordings made at FAME Studios in the 1960s. This release was considered by many fans to signal the beginning of Sting's transition from heavier...
by Sting, "Tea and Thorazine" by Andrew Bird
Andrew Bird
Andrew Bird is an American musician, songwriter, and multi-instrumentalist.- Early life and the Bowl of Fire :...
, and "Lithium" by Thin White Rope
Thin White Rope
Thin White Rope was an American rock band fronted by Guy Kyser and related to the desert rock and paisley underground sub-genres. It was formed in Davis, California in 1984, and released five albums to critical acclaim....
.
Use in 7 Up
As with cocaine in Coca-Cola, lithium was widely marketed as one of a number of patent medicinePatent medicine
Patent medicine refers to medical compounds of questionable effectiveness sold under a variety of names and labels. The term "patent medicine" is somewhat of a misnomer because, in most cases, although many of the products were trademarked, they were never patented...
products popular in the late-19th and early-20th centuries, and was the medicinal ingredient of a refreshment beverage, 7 Up
7 Up
7 Up is a brand of a lemon-lime flavored non-caffeinated soft drink. The rights to the brand are held by Dr Pepper Snapple Group in the United States, and PepsiCo in the rest of the world, including Puerto Rico, where the concentrate is manufactured at the Pepsi facility in Cidra...
. Charles Leiper Grigg
Charles Leiper Grigg
Charles Leiper Grigg was the inventor of Bib-Label Lithiated Lemon-Lime soda, better known by its later name, 7 Up. He invented the drink in October 1929. Grigg became acquainted with the carbonated beverage business after moving to St. Louis, Missouri. Prior to inventing 7 Up, Grigg had created...
, who launched his St. Louis-based company The Howdy Corporation in 1920, invented a formula for a lemon-lime
Lemon-lime
Lemon-lime is a common carbonated soft drink flavor, consisting of lemon and lime flavoring. Sprite and 7 Up are the most popular examples.-Description:...
soft drink
Soft drink
A soft drink is a non-alcoholic beverage that typically contains water , a sweetener, and a flavoring agent...
in 1929. The product, originally named "Bib-Label Lithiated Lemon-Lime Soda", was launched two weeks before the Wall Street Crash of 1929. It contained the mood stabiliser lithium citrate
Lithium citrate
Lithium citrate is a chemical compound of lithium and citrate that is used as a mood stabilizer in psychiatric treatment of manic states and bipolar disorder. For the medical aspects of lithium citrate, see lithium pharmacology....
and was one of a number of patent medicine products popular in the late-19th and early-20th centuries. Its name was soon changed to 7 Up
7 Up
7 Up is a brand of a lemon-lime flavored non-caffeinated soft drink. The rights to the brand are held by Dr Pepper Snapple Group in the United States, and PepsiCo in the rest of the world, including Puerto Rico, where the concentrate is manufactured at the Pepsi facility in Cidra...
; all American beverage makers were forced to remove lithium in 1948.
External links
- Official FDA information published by Drugs.com
- "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)