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This page is about lithium as a medication. For more general information on lithium as a chemical, see Lithium.
Lithium
Lithium citrate
Clinical data
Trade namesCamcolit (UK),
Eskalith (US),
Li-Liquid (UK),
Liskonum (UK),
Lithicarb (Australia),
Lithobid (US),
Priadel (UK),
Quilonum (Australia)
and others
AHFS/Drugs.comMonograph
MedlinePlusa681039
Pregnancy
category
  • AU: D
Routes of
administration		Oral, parenteral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilitydepends on formulation
Protein bindingNone
MetabolismRenal
Elimination half-life14-24 hours,
36 hours (elderly),
17.9 hours (children),
2.43 days (chronic treatment)[1]
Excretion>95% renal
Identifiers
  • Lithium(1+)
CAS Number
PubChem CID
DrugBank
Chemical and physical data
FormulaLi+
Molar mass6.941 g/mol
3D model (JSmol)
  • [Li+]
  • InChI=1S/Li/q+1
  • Key:HBBGRARXTFLTSG-UHFFFAOYSA-N

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.[2] In depression alone (unipolar disorder), lithium can be used to augment other antidepressants. Lithium carbonate (Li
2CO
3), sold under several trade names, is the most commonly prescribed, while lithium citrate (Li
3C
6H
5O
7) is also used in conventional pharmacological treatments. Lithium orotate (C
5H
3LiN
2O
4), has been presented as an alternative.[3] 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.[4] The specific biochemical mechanism of lithium action in mania is unknown.[5]

Medical uses

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Lithium is used primarily for bipolar disorder.[5] 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.[5] In mood disorders, of which bipolar is one, it decreases the risk of suicide.[6] This benefit is not seen with other medications.[7][8]

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.[9] High doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported.[10] A limited amount of evidence suggests lithium may contribute to treatment of substance abuse for some people with bipolar disorder.[11][12][13]

Lithium 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.[14]

Suicide

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High levels of naturally occurring lithium in drinking water have been associated with lower rates of suicide.[15][16][17]

Monitoring

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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.[18]

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.[19][20]

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[21][22] to 1.2 mmol Li+
/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

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Sources for the following lists.[1][23][24][25][26][27]

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
  • Weight gain
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 loss (gain more common with prolonged treatment)

Lithium is known to be responsible for 1–2 kg of weight gain.[28] Weight gain may be a source of low self-esteem for the clinically depressed.[29]

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

Hypothyroidism

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Most patients treated with lithium carbonate show elevated thyroid stimulating hormone levels in response to injections of thyrotropin-releasing hormone.[30] 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."[28]

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.[31] It increases the appetite and thirst ("polydypsia") and reduces the activity of thyroid hormone (hypothyroidism).[32][33][34][35] The latter can be corrected by treatment with thyroxine and does not require the lithium dose to be adjusted. Lithium is also believed to permanently affect renal function, although this does not appear to be common.[36]

Teratogenicity

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Lithium is also a teratogen, causing birth defects in a small number of newborn babies.[37] 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.[38] 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.[38] Gabapentin[39] and clonazepam[40] 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

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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. Dehydration can result in lithium retention, which can increase lithium levels.

Another danger is that rapid hydration with a large volume of plain water may very quickly produce hyponatremia with its danger of low sodium concentrations in plasma. Hyponatremia can cause lithium retention and thus increased lithium levels.

Interactions

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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.[1] Lithium concentrations can also be increased with concurrent use of ACE inhibitors such as captopril, enalapril, and lisinopril.[41]

Lithium is mainly removed from the body through glomerular function, but some is then reabsorbed together with sodium through the proximal tubule. Its levels are therefore sensitive to water and electrolyte balance.[42] Diuretics act by lowering water and sodium levels. This causes more reabsorption of lithium in the proximal tubules so that the removal of lithium from the body is less, leading to increased levels of lithium.[42][43] ACE inhibitors have also been shown in a retrospective case-control study to increase lithium concentrations. A possible mechanism is that ACE inhibitors can lead to a decrease in sodium and water. This will increase lithium reabsorption and its concentrations in the body.[42]

There are also drugs that can increase the clearance of lithium from the body, which can result in decreased lithium levels in the blood. These drugs include theophylline, caffeine, and acetazolamide. Additionally, increasing dietary sodium intake may also reduce lithium levels by prompting the kidneys to excrete more lithium.[44]

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.[1][45] Lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other antidopaminergic medications.[46]

Overdose

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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.[47] 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.[48]

Overdosage, usually with plasma concentrations over 1.5 mmol Li+
/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 Li+
/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[citation needed]. 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

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The specific biochemical mechanism of lithium action in stabilizing mood is unknown.[5]

Unlike many other psychoactive drugs, Li+
 typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations.[4]

Lithium may also increase the release of serotonin by neurons in the brain.[49] 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.[50]

Several authors proposed that pAp-phosphatase could be one of the therapeutic targets of lithium.[51][52] 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[53]

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.[54][55] It was also reported that NMDA receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test,[56] indicating the possible involvement of NMDA receptor/NO signaling in the action of lithium in this animal model of learned helplessness.

Lithium possesses neuroprotective properties by preventing apoptosis and increasing cell longevity.[57]

Oxidative metabolism

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Evidence suggests that mitochondrial dysfunction is present in patients with bipolar disorder.[57] Oxidative stress and reduced levels of anti-oxidants(such as glutathione) leads to cell death. Lithium can protect against oxidative stress because it up-regulates complex I and II of the mitochondrial electron transport chain.[57]

Dopamine and G-protein coupling

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During mania, there is an increase in neurotransmission of dopamine that causes a secondary homeostatic down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression.[57] Rats treated with lithium were found to have lower dopamine levels causing the brain to inhibit the re-uptake of dopamine.[57] The post-synaptic actions of dopamine are mediated through G-protein coupled receptors. Once dopamine is coupled to the G-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmissions. Studies found that in comparison, patients with bipolar disorder had increased G-protein coupling.[57] Lithium treatment alters the function certain subunits of the dopamine associated G-protein, which may contribute to bipolar disorder.[57]

Glutamate and NMDA receptors

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Glutamate is a reasonable target for mood stabilization because it is a stimulatory neurotransmitter that has found to be elevated during mania.[57] The NMDA glutamate receptor is structurally complex and is administered in several phychiatric disorders. Normally, Mg will bind to the NMDA receptor and inhibit activation, however when glutamate and glycine bind to the receptor simultaneously, Mg is displaced and the receptor is then activated. This activation increases the available glutamate for post synaptic neurons.[57] The role of Lithium in this process is to further compete with Mg at the NMDA glutamate binding site which stabilizes glutamate neurotransmission as the NMDA receptor is down-regulated which increases glutamate re-uptake which restores glutamate equilibrium.[57] This effect generally reduces glutamate-induced activation and therefore has neuroprotective potential. It has been noted that the NMDA receptor is affected by other neurotransmitters. Lithium administration enhances serotonergic neurotransmission by facilitating the post synaptic serotonin 5-HT1A receptor, which in turn activates the NMDA receptor.[57] This hypothesis is thought to be one of the pathways that Lithium provides long term mood stabilization and anti-manic properties. It has been found that these effects specific to lithium have not been observed in other monovalent ions such as Rb and Cs, and common anti-depressants. Lithium has been shown to reduce dopamine activity, dopamine normally increases NMDA receptor activity via dopamine DI receptors, this is also decreased by the actions of lithium on dopamine.[57]

GABA receptors

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GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission.[57] It was found that patients with bipolar disorder had lower GABA levels, which results in excitatory toxicity (increased excitatory neurotransmission) and can cause apoptosis(cell loss). To counter this, lithium reduces the levels of pro-apoptotic proteins by stimulating the release of neuroprotective proteins.[57] Also, lithium is known to increase levels of GABA, which causes a decrease in glutamate levels, down regulating the NMDA receptor.[57]

Cyclic AMP secondary messengers

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Cyclic AMP second messenger system is shown to be modulated by lithium. Lithium was found to increase the basal levels of cyclic AMP but impairs receptor coupled stimulation of cyclic AMP production.[57] It is hypothesized that the dual effects of lithium are due the inhibition of G-proteins that then mediate cyclic AMP production.[57] Receptor mediated production of cyclic AMP is controlled by a stimulatory G-protein, Gs and a counter balancing inhibitory G-protein Gi. Under basal conditions, cyclic AMP production is inhibited by G-protein influence through activation of protein kinase A (PKA). PKA regulates phosphorylation of ion channels cytoskeletal structures, and transcription factors. The cAMP response element binding element (CREB) protein can be activated from the mentioned. It affects the brain-derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (bcl-2) genes which may play a role neuroplasticity. The levels of BDNF are decreased in patients with bipolar disorder. After treatment with lithium, the BDNF and bcl-2 levels are shown to have increased.[57] Increased basal activity of cyclic AMP levels caused by lithium at concentrations of 2mm/L may occur due to lithium reducing activity of Gi by shifting equilibrium between a free active conformation and an inactive heterotrimeric conformation towards the active form. The action of lithium reduces the magnitude of fluctuations in cyclic AMP levels by increasing the lowest basal levels and decreasing maximal stimulated increases, thus stabilizing the activity of the signaling systems.[57] Over a long period of lithium treatment, cAMP and adenylate cyclase levels are further changed by gene transcription factors.[57]

Inositol depletion hypothesis

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Lithium treatment has been found to inhibit the enzyme inositol monophosphatase, leading to higher levels of inositol triphosphate.[58] This effect was enhanced further with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression. It is known with good certainty that signals from the receptors coupled to the phosphoinositide signal transduction is effected by lithium.[59] Phosphoinositides are important signaling molecules in receptor mediated signal transduction that play a role in central nervous system response. The mechanism starts by activation of a specific Phosphoinositide receptor that results in hydrolysis of phosphoinosital-4-5-biphophate (PIP2) into inositol triphosphate (IP3) and diglyceride through phospholipase C directed activity. PIP2 and diglyceride cause the activation of Protein Kinase C (PKC) and release of intracellular Calcium. IP3 is then phosphorylated by inositol 1-phosphatase (IPPase) and IMPase which results in the recovery of myo-inositol (mI) which is the main reactant in the Phosphoinositide cycle. It is hypothesized that lithium causes the reduction of IMPase and IPPase which lowers cellular levels of mI resulting in the inhibition of the Phosphoinositide cycle.[57]

myo-inositol is also regulated by the high affinity sodium mI transport system (SMIT), resulting in the extracellular mI entering the cell. Lithium is hypothesized to inhibit mI entering the cells and mitigating the function of SMIT.[57]

Animal studies provide uncertain data to support the two part hypothesis.[57] Myo-inisitol levels obtained from sampling the pre-frontal cortex were the same in patients showing signs of mania and patients treated with lithium. It has been reported that lithium treatment has been correlated with decreased mI levels in brains of children which demonstrated reduction in mania symptoms.[57] IMPase and IPPase concentrations are unaffected in normal mood patients when they are exposed to lithium showing that there is lack of evidence for the inositol depletion hypothesis. There is yet sufficient evidence of a direct correlation between lithium and homeostasis of inositiol.[57] Impacts of lithium on phosphoinositide concentrations are different depending on the brain region, cell cycle and endogenous inositol cycles in that region of the brain.[57] This effect was enhanced further with an inositol triphosphate reuptake inhibitor. Inositol disruptions have been linked to memory impairment and depression.[57]

Protein kinase activity

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Protein kinase C (PKC) is found through the brain and effects pre and post-synaptic neurotransmission.[57] PKC is activated by the neurotransmission of the phosopinositide cycle. PKC phosphorylates myristoylated alanine-rich C-kinase substrate(MARCKS), which plays a role in neuron excitability, modulation of gene expression and cell plasticity.[57] Animal studies show that there are increased PKC levels in the pre-frontal cortex of organisms exhibiting mania and bipolar disorder compared to control samples. Within two weeks of lithium treatment at therapeutic concentrations, PKC in platelets of humans with mania had been significantly reduced.[57] Lithium treatment was shown to decrease levels of MARCKS specifically within the hippocampus though the exact mechanism of PKC with regards to bipolar disorder is not known.[57]

GSK3-B

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Lithium was proposed to deactivate the GSK3β enzyme.[60] GSK3β 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.[61] 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. Lithium regulates cytoskeleton protein phosphorylation and function; as a result it affects the neuronal structure. Microtuble-associated proteins(MAPs) such as tau and MAP1B is phosphorylated by lithium, which stabilizes the neuronal cytoskeleton networks.[57]

Protein phosphorylation of cytoskeleton is inhibited by glycogen synthase kinase-3B101.[57] Desphosphorylation of tau at the glycogen synthase kinase-3 site caused by lithium enhances binding of tau to microtubules promoting microtubule assembly. In contrast, dephosphorylation MAP1B decreases ability to bind and stabilize microtubules. Opposing effects of dephosphorylation of tau and MAP-1B promoting microtubule disassembly and assembly respectively causes lithium inhibition of GSK-3.[57]

GSK-3 is an enzyme that is responsible for the regulation of glycogen synthesis. It is directly involved in gene transcription, synaptic plasticity, cell structure and cell resilience.[57] GSK-3 is also implicated to play a role on mood regulation. GSK-3 is shown to be activated in conditions of chronic stress or prolonged exposure to dopamine during periods of mania and is exhibited causation of hyperactivity in mice.[57] Lithium directly inhibits GSK-3 regulation of serine-9 phosphorylation. Inhibition of GSK-3 activates the Akt neurprotective pathway.[57] Inhibition of GSK-3 is not shown to produce anti-depressant effects with great reliability but many studies have shown anti-depressant like effects.[57] In rat models of depression, lithium has shown to increase synaptic plasticity and decrease GSK-3 expression though there are conflicting studies demonstrating that lithium has poor efficacy in the treatment of depressive phase of bipolar disorder.[57]

Intracellular calcium

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In 2014, it was proposed that lithium treatment works by affecting calcium signaling by antagonizing N-methyl-d-aspartate (NMDA) receptors and inhibiting inositol monophosphatase (IMP) to synergistically block the inflow of calcium into neurons from both external and internal calcium stores.[62]

Maintenance of calcium homeostasis is critical; dys-regulation of intracellular calcium is correlated with bipolar disorder.[57] Subjects with bipolar disorder exhibit elevation of intracellular calcium at both receptor-mediated and basal levels.[57] Calcium levels are a quantitative measurement of the state of the illness rather than a symptom of the bipolar disorder. Lithium has shown effects on intracellular calcium signalling.[57] Lithium blocks the uptake of calcium by cells in individuals with and without bipolar disorder. The reduction in calcium uptake by cells is due to the activation of NMDA receptors. Lithium also activates metabotropic glutamate receptors.[57]

Lithium decreases intracellular calcium stores and levels. Lithium functions by blocking excitotoxic processes, in part by calcium level modulation. Excitotoxic processes are hypothesized to be induced by kainate through the modulation of calcium entry inhibiting calpain proteases involved in apoptosis.[57]

History

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Lithium was first used in the 19th 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.[63] Because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, Carl Lange in Denmark[64] and William Alexander Hammond in New York[65] 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,[66] however a number of lithium preparations were yet produced for the control of renal calculi and ‘‘uric acid diathesis.’’.[67] 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 and the sale of lithium itself were both banned in 1949, following publication of reports detailing side effects and deaths.[63]

Also in 1949, the Australian psychiatrist John Cade rediscovered the usefulness of lithium salts in treating mania. 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 it caused the rodents to become tranquil. Cade traced the effect to the lithium ion itself, and so proposed lithium salts as tranquilizers. He 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.[68]

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,[63] 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.[69] 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,[70] and "Lithium" by Thin White Rope.

Use in 7 Up

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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.[71] 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.[72] Its name was soon changed to 7 Up. All American beverage makers were forced to remove lithium in 1948. Despite the 1948 ban, in 1950 the Painesville Telegraph still carried an advertisement for a lithiated lemon beverage.[73]

Research

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There is tentative evidence that lithium may prevent Alzheimer's disease and may change disease progress in those with early symptoms.[14] In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) it has failed to produce positive results.[74]

See also

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References

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  1. ^ a b c d Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 7 October 2013]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  2. ^ Baldessarini, Ross J; Tondo, Leonardo; Davis, Paula; Pompili, Maurizio; Goodwin, Frederick K; Hennen, John (2006). "Decreased risk of suicides and attempts during long-term lithium treatment: A meta-analytic review". Bipolar Disorders. 8 (5p2): 625–39. doi:10.1111/j.1399-5618.2006.00344.x. PMID 17042835.
  3. ^ Nieper HA (1973). "The clinical applications of lithium orotate. A two years study". Agressologie. 14 (6): 407–11. PMID 4607169.
  4. ^ a b Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.{{cite book}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "GG" was defined multiple times with different content (see the help page).
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Category:Lithium Category:Mood stabilizers Category:Biology and pharmacology of chemical elements Category:Drugs with unknown mechanisms of action

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