Lithium (medication)

Lithium compounds are used as a psychiatric medication. A number of salts of lithium are used as mood-stabilizing drugs, 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 in preventing depression, and reduces the risk of suicide in people with bipolar disorder. In depression alone (unipolar disorder), lithium can be used to augment other antidepressants. Lithium carbonate, sold under several trade names, is the most commonly prescribed, while lithium citrate is also used in conventional pharmacological treatments. Lithium orotate, has been presented as an alternative. Lithium bromide and lithium chloride have been used in the past, however they fell out of use in the 1940s when it was discovered they were toxic. Many other lithium salts and compounds exist, such as lithium fluoride and lithium iodide, but they are presumed to be toxic substances and have never been evaluated for pharmacological effects.

Upon ingestion, lithium becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing norepinephrine (noradrenaline) release and increasing serotonin synthesis. The specific biochemical mechanism of lithium action in mania is unknown.

Medical uses
Lithium is used primarily for bipolar disorder. It is sometimes used when other treatments are not effective in a number of other conditions including: major depression, schizophrenia, and some psychiatric disorders in children. In mood disorders, of which bipolar is one, it decreases the risk of suicide. This benefit is not seen with other medications.

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 is slightly less than the toxic level, requiring blood levels of lithium to be monitored closely during treatment. High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported. A limited amount of evidence suggests lithium may contribute to treatment of substance abuse for some people with dual-disorder.

Two forms of low dose lithium supplementation, lithium aspartate and lithium orotate, may protect the brain and encourage the growth of gray matter in the cerebral cortex and prevent and slow the progression of Alzheimer's disease, senile dementia and Parkinson's disease.

Suicide
Low levels of naturally occurring lithium in drinking water supplies may reduce suicide rates.

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 and water levels in the body, and can cause dehydration. Dehydration, which is compounded by heat, can result in increasing lithium levels. The dehydration is due to lithium inhibition of the action of antidiuretic hormone, which normally enables the kidney to reabsorb water from urine. This causes an inability to concentrate urine, leading to consequent loss of body water and thirst.

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 people, but may increase to 1.8–2.5 mmol/l in those who accumulate the drug over time and to 3–10 mmol/l in acute overdose.

Lithium salts have a narrow therapeutic/toxic ratio, so should not be prescribed unless facilities for monitoring plasma concentrations are available. People should be carefully selected. Doses are adjusted to achieve plasma concentrations of 0.4 to 1.2 mmol /l (lower end of the range for maintenance therapy and the elderly, higher end for children) on samples taken 12 hours after the preceding dose.

Side effects
Sources for the following lists.


 * Very Common (>10% incidence) adverse effects of lithium include:
 * Leukocytosis — elevated white blood cell count
 * Polyuria/polydypsia — increased thirst and urination
 * Dry mouth
 * Hand tremor (usually transient but it can persist in some people)
 * Headache
 * Decreased memory
 * Confusion
 * Muscle weakness (usually transient, but can persist in some)
 * ECG changes — usually benign changes in T waves.
 * Nausea (usually transient, but can persist in some)
 * Vomiting (usually transient, but can persist in some)
 * Diarrhea (usually transient, but can persist in some)
 * Constipation (usually transient, but can persist in some)
 * Muscle twitch
 * Hyperreflexia — overresponsive reflexes
 * Vertigo


 * Common (1-10%) adverse effects include:
 * Extrapyramidal side effects — movement-related problems such as muscle rigidity, parkinsonism, dystonia, etc.
 * Euthyroid goitre — i.e. the formation of a goitre despite normal thyroid functioning
 * Hypothyroidism — a deficiency of thyroid hormone.
 * Acne
 * Hair loss/hair thinning


 * Rare/Uncommon (<1%) adverse effects include:
 * Renal (kidney) toxicity which may lead to chronic kidney failure
 * Renal interstitial fibrosis
 * Seizure
 * Coma
 * Hallucinations
 * Erythema multiforme — a potentially fatal skin reaction
 * Brugada syndrome — a potentially fatal abnormality in the electrical activity of the heart.
 * Sinus node dysfunction
 * Transient reduction in peripheral circulation as a whole
 * Pseudotumor cerebri
 * Increased intracranial pressure and papilledema
 * Oedema
 * Myasthenia gravis — an autoimmune condition where the body's own defences attack the neuromuscular junction — the gap across which the nerves communicate with the muscles — leading to muscle weakness.
 * Hyperthyroidism — elevated blood concentrations of thyroid hormones.
 * Hypercalcaemia — elevated blood levels of calcium.
 * Hypermagnesaemia — elevated blood levels of magnesium.
 * Hyperparathyroidism — elevated blood levels of parathyroid hormone.


 * Unknown frequency adverse effects include:
 * Somnolence
 * Sexual dysfunction including impotence, vaginal dryness, erectile dysfunction, etc.
 * Flatulence
 * Indigestion
 * Gastritis
 * Abdominal pain
 * Glycosuria — glucose (blood sugar) in the urine
 * Decreased creatinine clearance — a sign of impaired kidney function
 * Albuminuria — protein in the urine another sign of impaired kidney function.
 * Oliguria — low urine output although excess urine output is more likely.
 * Changes in taste
 * Slurred speech
 * Hypotension — low blood pressure.
 * Bradycardia — low heart rate.
 * Nystagmus — involuntary eye movements that can interfere with vision.
 * Weight gain or loss (gain more common with prolonged treatment)

According to an Australian study, "The incidence of hypothyroidism is six-fold higher in people on lithium as compared to the general population. Hypothyroidism in turn increases the likelihood of developing clinical depression."

Lithium is known to be responsible for 1–2 kg of weight gain. Weight gain may be a source of low self-esteem for the clinically depressed. Because lithium competes with the receptors for the antidiuretic hormone in the kidney, it increases water output into the urine, a condition called nephrogenic diabetes insipidus. Clearance of lithium by the kidneys is usually successful with certain diuretic medications, including amiloride and triamterene. It increases the appetite and thirst ("polydypsia") and reduces the activity of thyroid hormone (hypothyroidism). The latter can be corrected by treatment with thyroxine. Lithium is also believed to permanently affect renal function, although this does not appear to be common.

Lithium is a well-known cause of downbeat nystagmus, which may be permanent or require several months of abstinence for improvement.

Most side effects of lithium are dose-dependent. The lowest effective dose is used to limit the risk of side effects.

Teratogenicity
Lithium is also a teratogen, causing birth defects in a small number of newborn babies. Case reports and several retrospective studies have demonstrated possible increases in the rate of a congenital heart defect known as Ebstein's anomaly, if taken during a woman's pregnancy. As a consequence, fetal echocardiography is routinely performed in pregnant women taking lithium to exclude the possibility of cardiac anomalies. Lamotrigine seems to be a possible alternative to lithium in pregnant women. Gabapentin and clonazepam are also indicated as antipanic medications during the childbearing years and during pregnancy. Valproic acid and carbamazepine also tend to be associated with teratogenicity.

Dehydration
Dehydration in people taking lithium salts can be very hazardous, especially when combined with lithium induced nephrogenic diabetes insipidus with polyuria. Such situations include preoperative fluid regimen or other fluid inaccessibility, warm weather conditions, sporting events, and hiking.

Another danger is that rapid hydration may very quickly produce hyponatremia with its danger of toxic sodium concentrations in plasma.

Interactions
Lithium concentrations are known to be increased with concurrent use of diuretics — especially loop diuretics (such as furosemide) and thiazides — and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin. Lithium is also known to be a potential precipitant of serotonin syndrome in people concurrently on serotonergic medications such as antidepressants, buspirone and certain opioids such as pethidine (meperidine), tramadol, oxycodone, fentanyl and others. Lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other antidopaminergic medications.

Overdose
Lithium toxicity may occur in persons taking excessive amounts either accidentally or intentionally on an acute basis or in people who accumulate high levels during ongoing chronic therapy. The manifestations include nausea, emesis, diarrhea, asthenia, ataxia, confusion, lethargy, polyuria, seizures and coma. Other toxic effects of lithium include coarse tremor, muscle twitching, convulsions and renal failure. People who survive a poisoning episode may develop persistent neurotoxicity. Several authors have described a "Syndrome of Irreversible Lithium-Effected Neurotoxicity" (SILENT), associated with episodes of acute lithium toxicity or long-term treatment within the appropriate dosage range. Symptoms are said to include cerebellar dysfunction.

Overdosage, usually with plasma concentrations over 1.5 mmol /l, may be fatal, and toxic effects include tremor, ataxia, dysarthria, nystagmus, renal impairment, confusion, and convulsions. If these potentially hazardous signs occur, treatment should be stopped, plasma lithium concentrations redetermined, and steps taken to reverse lithium toxicity.

Lithium toxicity is compounded by sodium depletion. Concurrent use of diuretics that inhibit the uptake of sodium by the distal tubule (e.g. thiazides) is hazardous and should be avoided because this can cause increased resorption of lithium in the proximal convoluted tubule, leading to elevated, potentially toxic levels. 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 /l are usually associated with serious toxicity requiring emergency treatment. When toxic concentrations are reached, there may be a delay of one or two 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 valproate(Depakote), if problems with the kidneys arise. An important potential consequence of long-term lithium use is the development of renal diabetes insipidus (inability to concentrate urine). Patients should therefore be maintained on lithium treatment after three to five 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.

Mechanism of action
The specific biochemical mechanism of lithium action in mania is unknown.

Unlike many other psychoactive drugs, typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations.

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 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. The other mechanisms by which lithium might help to regulate mood include the alteration of gene expression.

Lithium may also increase the release of serotonin by neurons in the brain. In vitro studies performed on serotonergic neurons from rat raphe nuclei have shown that when these neurons are treated with lithium, serotonin release is enhanced during a depolarization compared to no lithium treatment and the same depolarization.

An unrelated mechanism of action has been proposed in which lithium deactivates the GSK3β enzyme. This enzyme normally phosphorylates the Rev-Erbα transcription factor protein stabilizing it against degradation. Rev-Erbα in turn represses BMAL1, a component of the circadian clock. Hence, lithium by inhibiting GSK3β causes the degradation of Rev-Erbα and increases the expression of BMAL which damps 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.

Several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium. This hypothesis was supported by the low Ki of lithium for human pAp-phosphatase compatible within the range of therapeutic concentrations of lithium in the plasma of people (0.8–1 mM). Importantly, the Ki of human pAp-phosphatase is ten times lower than that of GSK3β (glycogen synthase kinase 3β). Inhibition of pAp-phosphatase by lithium leads to increased levels of pAp (3′-5′ phosphoadenosine phosphate), which was shown to inhibit PARP-1

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. 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.

Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, leading to higher levels of inositol triphosphate. This effect was enhanced further with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression.

History
Lithium was first used in the 19th century as a treatment for gout after scientists discovered, 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. Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange in Denmark and William Alexander Hammond in New York used lithium to treat mania from the 1870s onwards. By the turn of the 20th century, as theory regarding mood disorders evolved and so-called "brain gout" disappeared as a medical entity, the use of lithium in psychiatry was largely abandoned. Some suggest that the pharmaceutical industry was reluctant to invest in a drug that could not be patented however a number of lithium preparations were yet produced for the control of renal calculi and ‘‘uric acid diathesis.’’. 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 practice 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 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 it 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.

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 Paul Baastrup in Europe, and Samuel Gershon and Baron Shopsin in the U.S., this resistance was slowly overcome. The application of lithium in manic illness was approved by the United States Food and Drug Administration in 1970. In 1974, this application was extended to its use as a preventive agent for manic-depressive illness.

Ronald R. Fieve, who had opened the first lithium clinic in North America in 1966, helped popularize the psychiatric use of lithium through his national TV appearances and his bestselling book, Moodswing. In addition, Fieve and David L. Dunner developed the concept of 'rapid cycling' Bipolar Disorder based on non-response to lithium.

Lithium has now become a part of Western popular culture. Characters in Pi, Premonition, Stardust Memories,  American Psycho, Garden State, and An Unmarried Woman 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, "Lithium" by Evanescence, "Lithium" by Nirvana, "Lithium and a Lover" by Sirenia, "Lithium Sunset", from the album Mercury Falling by Sting, and "Lithium" by Thin White Rope.

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. Charles Leiper Grigg, who launched his St. Louis-based company The Howdy Corporation, invented a formula for a lemon-lime soft drink in 1920. 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 stabilizer lithium citrate, 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; all American beverage makers were forced to remove lithium in 1948. Despite the 1948 ban, the 13 July 1950 Painesville Telegraph has an advertisement for a lithiated lemon beverage on page 28.

Research
There is tentative evidence that lithium may prevent Alzheimer's disease and may change disease progress in those with early symptoms. In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) it has failed to produce positive results.