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Lithium is the third chemical element on the periodic table of the elements that is used, usually in its carbonate and citrate salts, to treat bipolar disorder (including preventing future mood episodes and treating them).[1] It is also used, as an adjunct (add-on treatment to improve response rates) to antidepressants in resistant cases of major depression and as an adjunct to antipsychotics in the treatment of chronic schizophrenia or bipolar-type schizoaffective disorder.[1] Likewise there are a few less studied uses of it, like in the treatment of cluster headaches.[1]

Explanatory notesEdit

AbbreviationsEdit

CR: Controlled release. These are formulations (usually tablets) that release the drug into the digestive tract more slowly than the immediate release formulations. 

IR:   Immediate release. These formulations release the drug into the digestive tract as rapidly as possible. 

Li:    Lithium.

Chemical termsEdit

Moles (mol for short), a quantity of a substance that represents a precise number of molecules or atoms (Avogadro's number, to be precise, at 602,214,130 followed by an additional 15 zeros), the molecular mass listed in drugboxes on this Wiki represents the gram weight of one mole of said drug. mmol is short for millimoles which is a thousandth of a mole. 

Another closely related unit molarity (M) is the concentration of a solution, in moles per litre of water or other fluid (like serum in blood). mM is 0.001M (that is, one thousandth of a mole). 

Medical usesEdit

Lithium is primarily used to prevent future mood episodes in people with bipolar disorder or schizoaffective disorder, although it can also be used to treat mania in bipolar patients, but due to its delayed onset of action (usually takes a week for any effect to be seen) when used for this purpose it is often combined with an antipsychotic (which act faster in mania).[1] Treatment-resistant cases of major depression (without mania) may also respond to adjunctive lithium (that is, when given lithium is given in conjunction with antidepressants), likewise chronic schizophrenics may also benefit from adjunctive lithium.[2]

It is one of only two psychiatric drugs that have been proven, in well-designed clinical trials, to prevent suicide, the other being clozapine.[3] Overall it seems to half suicide rates and not just in bipolar patients but also unipolar (that is, depression without manic episodes) patients.[3]

ContraindicationsEdit

The following contraindications (things that should prevent one from being given lithium) are taken from the Product Information sheet for Lithicarb:[4]

  • Kidney or heart disease
  • Significant hypothyroidism
  • Conditions that can cause low blood sodium, like Addison's disease (underactive adrenal glands), dehydration, severe disability and those on low-sodium diets.
  • Treatment with diuretics (drugs that increase urine production)
  • Previous hypersensitivity reactions to lithium or the inactive ingredients contained in the preparation of lithium used. For example, Lithicarb tablets contain lactose, hence would be inappropriate those with lactose intolerance or galactosaemia

Side effectsEdit

Its most dangerous side effects are acute interstitial nephritis (a kidney condition that can lead to irreversible damage to the kidney and even kidney failure requiring a transplant/dialysis), seizures, hallucinations and coma, all of which are rare.[2][4] The last three are usually the result of lithium toxicity (due to excess lithium in the brain).[4]

Its most common side effects include:

Compared to anticonvulsant mood stabilizers side effects tend to lead to more discontinuations with lithium, by about two-fold (that is twice as many people discontinue lithium due to side effects than the anticonvulsants lamotrigine and valproate).[5]

OverdoseEdit

Acute overdoseEdit

Acute overdoses, that is, when kids or the suicidal consume excessive amounts over the period of seconds, minutes or hours, are rarely fatal, unless another drug is involved in the overdose. This is because after an overdose event the high concentration of lithium in the stomach triggers vomiting within one hour of ingestion. Consequently only a relatively small amount manages to reach the bloodstream. Symptoms of overdose, besides vomiting an hour (or less) after ingestion, usually have a delay period before they appear and can include:

  • Abdominal pain
  • Weight loss
  • Nausea and vomiting
  • Diarrhoea (usually mild)
  • Giddiness
  • Incoordination
  • Tremor
  • Slurred speech
  • Twitching
  • Weakness
  • Depression

Chronic overdoses or lithium toxicityEdit

Chronic overdoses where the drug is taken at too high of doses (or when the levels in the blood are elevated by stress, inadequate water intake, low sodium diets, medications, pregnancy, etc.) for an extended period of time (like over weeks or months) are the most deadly, and are usually defined as when the levels in the blood exceed 1.5 mmol/L. The most common symptoms are digestive or neurological in nature. They include: nausea, vomiting, diarrhoea, muscle rigidity, tremor, muscle twitch, seizures, confusion, coma and death. Rarely heart-related complications have been reported that include: heart arrest, irregular heart rate and sudden death.

The potential for accidental chronic overdoses is such that blood monitoring after 5-7 days of treatment and then three monthly afterwards.[2]

InteractionsEdit

Lithium is notorious for its drug and herb interactions, any drug that has an effect on urine output or kidney function can affect the clearance of lithium by the kidneys, hence either reducing the levels of lithium to subtherapeutic doses or (and this is far more common) by increasing them to toxic levels. This includes:[1][4][6]

  • Diuretics (which increase urine output) such as thiazides (usually used to lower blood pressure, complications of heart failure and diabetes insipidus, a hormone condition), carbonic anhydrase inhibitors (including the anti-seizure drugs acetazolamide and topiramate), loop diuretics (also used to treat heart failure and its complications) and potassium-sparing diuretics.
  • Non-steroidal anti-inflammatory drugs (NSAIDs) including: aspirin, diclofenac (Voltaren), ibuprofen (Advil, Motrin and Nurofen), naproxen (Naprosyn), etc.
  • ACE inhibitors used to treat high blood pressure and other heart conditions
  • Sartans which are used to slow the progression of diabetes-induced kidney disease, heart failure and to treat high blood pressure.
  • Potassium citrate as it reduces the concentrations of lithium
  • Sodium bicarbonate as it can accelerate the clearance of lithium by the kidneys, hence reducing its levels in the body.
  • Theophylline (for emphysema, severe chronic asthma and chronic bronchitis), may reduce the levels in the blood.

along with any drug that elevates serotonin levels, due the risk of serotonin syndrome. Carbamazepine and typical antipsychotics can also trigger neurotoxicity (brain problems, similar to lithium toxicity) in those taking lithium.

Mechanism of actionEdit

Not well understood, likely involves numerous mechanisms, including: improving brain cell growth and survival, inhibition of several enzymes involve in brain activity (like glycogen synthase kinase 3 [GSK-3] and inositol monophosphatase), modulation of neurotransmitter release (including serotonin, noradrenaline and dopamine; they relay chemical messages between the electrically-excitable cells of the brain, spinal cord and nerves), etc.[7]

Lithium carbonateEdit

Lithium carbonate
Lithium carbonate
Synonyms CP-15467-61, Dilithium Carbonate, Lithium Carb., NSC-16895
Brand names Numerous, see brand name section
IUPAC name

IUPAC name
dilithium;carbonate
ChemSpider

10654

DrugBank

DB01356

PubChem

11125

PDB fields

N/A

Formula

CLi2O3

InChI
InChI
1S/CH2O3.2Li/c2-1(3)4;;/h(H2,2,3,4);;/q;2*+1/p-2
InChIKey
InChIKey
XGZVUEUWXADBQD-UHFFFAOYSA-L
SMILES
SMILES
[Li+].[Li+].C(=O)([O-])[O-]
(Jmol 3D structure)
Mol. mass

73.8909 g/mol

Lithium carbonate is, by far, the most commonly used salt of lithium used for the treatment of bipolar disorder. It is the only salt available in Australia, Canada and New Zealand, although other salts are available in the U.K. and the U.S.A. It is on the WHO-EM.[8]:32


Lithium citrateEdit

Lithium citrate
Lithium citrate
Synonyms None notable
Brand names See the brand name section.
IUPAC name

IUPAC name
trilithium;2-hydroxypropane-1,2,3-tricarboxylate
ChemSpider

12932

DrugBank

DB01356

PubChem

13520

PDB fields

N/A

Formula

C6H5O7

InChI
InChI
1S/C6H8O7.3Li/c7-3(8)1-6(13,5(11)12)2-4(9)10;;;/h13H,1-2H2,(H,7,8)(H,9,10)(H,11,12);;;/q;3*+1/p-3
InChIKey
InChIKey
WJSIUCDMWSDDCE-UHFFFAOYSA-K
SMILES
SMILES
[Li+].[Li+].[Li+].C(C(=O)[O-])C(CC(=O)[O-])(C(=O)[O-])O
(Jmol 3D structure)
Mol. mass

209.9227 g/mol

Lithium citrate is a lesser used salt of lithium, it has not been available in Australia, Canada, New Zealand or the U.S. for decades at least, although it is still used in the U.K.[1]


PropertiesEdit

Lithium has a half-life of 12-24 hours, it is not metabolized but is rather rather excreted unchanged in the urine.[7] About 95-99% of lithium consumed is excreted in the urine.[1]

HistoryEdit

Lithium has been used since the 19th century when it was used to treat gout, based on the observation that lithium urate[note 2] was significantly more water soluble than uric acid itself and as gout is due to the build-up of uric acid in the joints it was theorized it could be of use in this condition. It was soon noticed realized only exceptionally high doses (so high it would be toxic) of lithium could possibly dissolve enough uric acid for any appreciable amount to be excreted in the urine.[7]

PreludeEdit

Then in 1949 John Cade announced that lithium salts had mood stabilizing effects.[9] This discovery was rather accidental, although a scientific method was involved and it started a revolution in the field of psychiatry. It was the first mood stabilizer to be developed. He started a revolution in that up until his time there were no effective drug treatments for psychiatric disorders and as Cade once wrote in his diary,

I feel constantly that no one will ever leave here, except in a pine box

By 'here' Cade meant the psychiatric hospital he worked at. The only available treatments at the time were Freudian psychotherapy, ECT, fever therapy (where they purposely induce a fever for therapeutic purposes) and radical forms of brain surgery.

Cade's animal testingEdit

Cade theorized that bipolar patients excreted something toxic (namely uric acid) more than healthy individuals. He then tested this hypothesis by injecting guinea pigs with the urine of his bipolar patients and other psychiatric patients, the results seemed to support his hypothesis, as the bipolar patients' urine seemed far more toxic than those of his other psychiatric patients.[10] He realized that the uric acid found in urine along with urea and other compounds in the urine worked, in concert, with each other in order to magnify each other's toxicity.[10] So what he tried to do was he investigate this; to do this he had to find a way of dissolving high quantities of uric acid in water, which was impossible to do in its original form so he had to use a salt form.[10] So he selected the most water soluble urate salt — lithium, for this purpose.[10]

He discovered something amazing: for some reason the lithium ion in lithium urate seemed to protect the guinea pigs against the toxic effects of the uric acid and urea when both were injected at the doses that would normally result in the animal's deaths.[10] For some reason the guinea pigs injected with lithium urate, instead of dying, just became drowsy and relaxed.[10] He then began testing with lithium carbonate to see if it really was the lithium ion that produced these effects. He theorized that lithium salts might also act to relieve mania in bipolar patients.[10]

Cade's early human testsEdit

He, being a very honourable Christian gentleman, first tested the lithium on himself for a trial period of two weeks, to see if it was safe enough to give to his patients. Nowadays we would expect him to test it on numerous healthy volunteers (which are called phase I trials) before he would start giving it to those with a therapeutic need for the drug (that is, because they had the condition that was expected to be relieved by said drug) but due to limited resources (as he had to do all this research in his own time with any materials coming out of his own pocket) he only had himself and his psychiatric patients to test it on.[10] After he tolerated the lithium (although he did have some side effects like drowsiness, weakness and nausea/vomiting) he began to test it on some of his most desperate patients.

He was correct in his hypothesis that it would help his bipolar patients, and many patients that had been forcefully committed to a psychiatric institution at which he worked could once again function in society.[10] Namely they could hold down a job, they could look after themselves, and they were freed from the prisons that were their own minds. He published his findings in the Medical Journal of Australia in 1949.[10]

Unfortunately for Cade, the toxic effects (like life-threatening side effects) of lithium are not really noticed until one is treated with it long-term (usually past the 2 weeks he tested it on himself for), so a few of his patients died from lithium toxicity. Confounding this problem, during his time there were no blood tests available to detect the levels of lithium in his patient's blood, which nowadays is common practice whenever lithium is prescribed so as to prevent toxicity (as the dose can be lowered or increased according to serum levels of lithium).[10]

The United StatesEdit

Sadly, however, around the same time as Cade in the United States lithium chloride was sold as a low-sodium salt substitute as it tasted the same as table salt (sodium chloride).[10] This lead to a few deaths from lithium toxicity, and the United States' Food and Drug Administration (USFDA) responded by banning lithium.[10] Consequently it was not until 1970 that this ban was repealed after several well-designed clinical trials conclusively proved that lithium was both an effective treatment for bipolar disorder, but also a safe treatment for the disorder.[10] Many of these trials were run by Mogens Schou, a Danish psychiatrist.[10] It took so long for its U.S. approval, as lithium is a natural product and consequently, no one could patent it, hence there was no financial interest in developing it for the treatment of bipolar disorder. Lithium was only approved after overwhelming pressure from the public to perform these trials and then get the USFDA to approve it. This caused a drug company to fund these clinical trials as a philanthropic gesture

Presence in drinking waterEdit

Lithium naturally occurs in the drinking water of many areas of the world, at most the levels might reach 5.2 mg/L.[11] Compared to the standard dose for bipolar patients of 250-1000 mg/day.[11] Even at these low doses it has been found to prevent suicide, homicide (that is, people killing others), dementia and all-cause mortality.[11]

Brand namesEdit

Note:
* indicates products for which an CR formulation is available (along with immediate release).
‡ indicates products that are solely available as CR formulations.
¤ indicates products that are no longer marketed.

In brackets are where these brands are marketed (note: only countries that have English as a major official language are listed, except for India as the number of brands there is unbelievable), brands that are no longer marketed anywhere are usually not listed unless particularly notable.

Lithium carbonate: Camcolit* (HK¤, IE, SA, SG, UK), Carbolith (CA), Eskalith¤ (US), Licarb (HK), Liskonum‡ (UK), Lithane (CA, US¤), Lithicarb (AU, HK, NZ), Priadel‡ (AU¤, IE, NZ, SA¤, SG¤, UK) and Quilonum‡ (AU, SA).

Lithium citrate: Li-Liquid (UK) and Priadel 520mg/5ml liquid (UK).

Lithium hydroxide monohydrate: LITHIUM HYDROXIDE MONOHYDRATE solution (for oral use; US).[12]

Lithium sulfate: Lithiofor (HK).

External linksEdit

NotesEdit

  1. Usually does not cause any symptoms
  2. The uric acid salt of lithium

Reference listEdit

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Brayfield, A, ed. (18 December 2013). "Lithium Carbonate". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 7 September 2014. 
  2. 2.0 2.1 2.2 Rossi, S, ed. (July 2014). "Lithium". Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. Retrieved 8 September 2014. 
  3. 3.0 3.1 Cipriani, A; Hawton, K; Stockton, S; Geddes, JR (June 2013). "Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis.". BMJ 346: f3646. PMID 23814104. doi:10.1136/bmj.f3646. 
  4. 4.0 4.1 4.2 4.3 "PRODUCT INFORMATION LITHICARB Lithium carbonate" (PDF). TGA eBusiness Services. St Leonards, Australia: Aspen Pharmacare Australia Pty Ltd. 3 February 2012. Retrieved 8 September 2014. 
  5. Smith, LA; Cornelius, V; Warnock, A; Bell, A; Young, AH (June 2007). "Effectiveness of mood stabilizers and antipsychotics in the maintenance phase of bipolar disorder: a systematic review of randomized controlled trials.". Bipolar Disorders 9 (4): 394–412. PMID 17547586. doi:10.1111/j.1399-5618.2007.00490.x. 
  6. Rossi, S, ed. (July 2014). "Lithium - Drug Interactions". Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. Retrieved 8 September 2014. 
  7. 7.0 7.1 7.2 Oruch, R; Elderbi, MA; Khattab, HA; Pryme, IF; Lund, A (October 2014). "Lithium: A review of pharmacology, clinical uses, and toxicity.". European Journal of Pharmacology 740C: 464–473. PMID 24991789. doi:10.1016/j.ejphar.2014.06.042. 
  8. World Health Organization (October 2013). "WHO Model List of Essential Medicines 18th list" (PDF). World Health Organization. Geneva, Switzerland: World Health Organization. Retrieved 5 September 2014. 
  9. Cade, JF (September 1949). "Lithium salts in the treatment of psychotic excitement.". The Medical Journal of Australia 2 (10): 349–52. PMID 18142718. 
  10. 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 10.12 10.13 10.14 Mitchell, PB; Hadzi-Pavlovic, D (2000). "Lithium treatment for bipolar disorder." (PDF). Bulletin of the World Health Organization 78 (4): 515–7. PMC 2560742. PMID 10885179. 
  11. 11.0 11.1 11.2 Mauer, S; Vergne, D; Ghaemi, SN (September 2014). "Standard and trace-dose lithium: A systematic review of dementia prevention and other behavioral benefits.". The Australian and New Zealand Journal of Psychiatry 48 (9): 809–818. PMID 24919696. doi:10.1177/0004867414536932. 
  12. "LITHIUM HYDROXIDE MONOHYDRATE solution". DailyMed. Morton Grove Pharmaceuticals, Inc. June 2009. Retrieved 7 September 2014. 

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