DrugBank: Lithium (DB01356)

targets (5)

Identification

Name

Lithium

Accession Number

DB01356

Type

small molecule

Groups

approved

Description

Lithium was used during the 19th century to treat gout. Lithium salts such as lithium carbonate (Li2CO3), lithium citrate, and lithium orotate are mood stabilizers. They are used in the treatment of bipolar disorder, since unlike most other mood altering drugs, they counteract both mania and depression. Lithium can also be used to augment other antidepressant drugs. It is also sometimes prescribed as a preventive treatment for migraine disease and cluster headaches. The active principle in these salts is the lithium ion Li+, which having a smaller diameter, can easily displace K+ and Na+ and even Ca+2, in spite of its greater charge, occupying their sites in several critical neuronal enzymes and neurotransmitter receptors.

Structure

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

Not Available

Brand names

Eskalith
LithoTab

Brand name mixtures

Not Available

Categories

Not Available

CAS number

7439-93-2

Weight

Average: 6.941
Monoisotopic: 7.016004049

Chemical Formula

InChI Key

InChIKey=HBBGRARXTFLTSG-UHFFFAOYSA-N

InChI

InChI=1S/Li/q+1

Plain Text

IUPAC Name

lithium(1+) ion

SMILES

[Li+]

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Inorganic

Classes

Inorganic Ions and Gases

Substructures

Inorganic Ions and Gases

Pharmacology

Indication

Lithium is used as a mood stabilizer, and is used for treatment of depression and mania. It is often used in bipolar disorder treatment.

Pharmacodynamics

Although lithium has been used for over 50 years in treatment of bipolar disorder, the mechanism of action is still unknown. Lithium's therapeutic action may be due to a number of effects, ranging from inhibition of enzymes such as glycogen synthase kinase 3, inositol phosphatases, or modulation of glutamate receptors.

Mechanism of action

The precise mechanism of action 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. An increasing number of scientists have come to the conclusion that the excitatory neurotransmitter glutamate is the key factor in understanding how lithium works. Lithium has been shown to change the inward and outward currents of glutamate receptors (especially GluR3), without a shift in reversal potential. Lithium has been found to exert a dual effect on glutamate receptors, acting to keep the amount of glutamate active between cells at a stable, healthy level, neither too much nor too little. It is postulated that too much glutamate in the space between neurons causes mania, and too little, depression. Another mechanism by which lithium might help to regulate mood include the non-competitive inhibition of an enzyme called inositol monophosphatase. Alternately lithium's action may be enhanced through the deactivation of the GSK-3B enzyme. The regulation of GSK-3B by lithium may affect the circadian clock. GSK-3 is known for phosphorylating and thus inactivating glycogen synthase. GSK-3B has also been implicated in the control of cellular response to damaged DNA. GSK-3 normally phosphorylates beta catenin, which leads to beta catenin degratation. When GSK-3 is inhibited, beta catenin increases and transgenic mice with overexpression of beta catenin express similar behaviour to mice treated with lithium. These results suggest that increase of beta catenin may be a possible pathway for the therapeutic action of lithium.

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Route of elimination

Not Available

Half life

Not Available

Clearance

Not Available

Toxicity

Not Available

Affected organisms

Not Available

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Noven therapeutics llc
Jds pharmaceuticals llc

Packagers

Advanced Pharmaceutical Services Inc.
Amerisource Health Services Corp.
Anip Acquisition Co.
Apotex Inc.
Biotech Pharmaceuticals
Cardinal Health
Caremark LLC
Comprehensive Consultant Services Inc.
Coupler Enterprises Inc.
Dept Health Central Pharmacy
Direct Dispensing Inc.
Dispensing Solutions
Diversified Healthcare Services Inc.
Glenmark Generics Ltd.
Goldline Laboratories Inc.
Heartland Repack Services LLC
Hetero Drugs Ltd.
Hikma Pharmaceuticals
J T Baker
Kaiser Foundation Hospital
Lake Erie Medical and Surgical Supply
Liberty Pharmaceuticals
Major Pharmaceuticals
Mckesson Corp.
Murfreesboro Pharmaceutical Nursing Supply
Neuman Distributors Inc.
Noven Pharmaceuticals Inc.
Nucare Pharmaceuticals Inc.
Palmetto Pharmaceuticals Inc.
Pharmacy Service Center
Physicians Total Care Inc.
Prepackage Specialists
Prepak Systems Inc.
Rebel Distributors Corp.
Remedy Repack
Resource Optimization and Innovation LLC
Roxane Labs
Sandhills Packaging Inc.
Solvay Pharmaceuticals
Southwood Pharmaceuticals
Stat Rx Usa
Sun Pharmaceutical Industries Ltd.
Tya Pharmaceuticals
UDL Laboratories
Vangard Labs Inc.
West-Ward Pharmaceuticals

Dosage forms

Form	Route	Strength
Capsule	Oral
Liquid	Oral
Syrup	Oral
Tablet, extended release	Oral

Prices

Unit description	Cost	Unit
Eskalith cr 450 mg tablet	0.8 USD	tablet
Lithium Carbonate 450 mg Controlled Release Tabs	0.56 USD	tab
Lithium Carbonate 300 mg Controlled Release Tabs	0.5 USD	tab
Lithium Carbonate 600 mg capsule	0.44 USD	capsule
Lithium Carbonate 300 mg capsule	0.29 USD	capsule
Lithium Carbonate 300 mg tablet	0.29 USD	tablet
Lithate 20 mg capsule	0.28 USD	capsule
Lithium carb powder reagent	0.27 USD	g
Lithium carbonate 300 mg tab	0.22 USD	each
Lithium Carbonate 150 mg capsule	0.21 USD	capsule
Lithium Citrate 8meq/5ml Syrup	0.15 USD	ml
Lithium citrate 8 meq/5 ml sol	0.14 USD	ml
Pms-Lithium Carbonate 600 mg Capsule	0.14 USD	capsule
Carbolith 150 mg Capsule	0.13 USD	capsule
Lithate 5 mg capsule	0.12 USD	capsule
Lithane 150 mg Capsule	0.11 USD	capsule
Lithane 300 mg Capsule	0.11 USD	capsule
Carbolith 300 mg Capsule	0.1 USD	capsule
Apo-Lithium Carbonate 150 mg Capsule	0.06 USD	capsule
Apo-Lithium Carbonate 300 mg Capsule	0.06 USD	capsule
Pms-Lithium Carbonate 150 mg Capsule	0.06 USD	capsule
Pms-Lithium Carbonate 300 mg Capsule	0.06 USD	capsule

Patents

Not Available

Properties

State

solid

Melting point

0.512 g·cm −3

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
water solubility		ALOGPS
logP		ALOGPS
logP	0.00	ChemAxon Molconvert
logS		ALOGPS
pKa		ChemAxon Molconvert
hydrogen acceptor count	0	ChemAxon Molconvert
hydrogen donor count	0	ChemAxon Molconvert
polar surface area	0.00	ChemAxon Molconvert
rotatable bond count	0	ChemAxon Molconvert
refractivity	0.00	ChemAxon Molconvert
polarizability	1.78	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

Quiroz JA, Machado-Vieira R, Zarate CA Jr, Manji HK: Novel insights into lithium’s mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology. 2010;62(1):50-60. Epub 2010 May 7. Pubmed 20453535

External Links

Resource	Link
KEGG Compound	C15473
PubChem Compound	28486
PubChem Substance	46505392
ChemSpider	26502
ChEBI	30142
ChEMBL	30142
Therapeutic Targets Database	DNC000879
PharmGKB	PA450243
Drug Product Database	236683
RxList	http://www.rxlist.com/cgi/generic/lithium.htm
Drugs.com	http://www.drugs.com/lithium.html
Wikipedia	http://en.wikipedia.org/wiki/Lithium

ATC Codes

N05AN01
D11AX04

AHFS Codes

28:28.00
92:02.00*

PDB Entries

Not Available

FDA label

show (200 KB)

MSDS

show (72.1 KB)

Interactions

Drug Interactions

Not Available

Food Interactions

Avoid alcohol.
Avoid excessive quantities of coffee or tea (Caffeine).
Avoid iodine supplements.
Do not change your salt intake from day to day without telling your doctor.
Take with food to reduce irritation. Drink plenty of liquids.

Targets
1. Glycogen synthase kinase-3 beta Pharmacological action: unknown Actions: inhibitor Participates in the Wnt signaling pathway. Implicated in the hormonal control of several regulatory proteins including glycogen synthase, MYB and the transcription factor JUN. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA Organism class: human UniProt ID: P49841 Gene: GSK3B Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Borsotto M, Cavarec L, Bouillot M, Romey G, Macciardi F, Delaye A, Nasroune M, Bastucci M, Sambucy JL, Luan JJ, Charpagne A, Jouet V, Leger R, Lazdunski M, Cohen D, Chumakov I: PP2A-Bgamma subunit and KCNQ2 K+ channels in bipolar disorder. Pharmacogenomics J. 2007 Apr;7(2):123-32. Epub 2006 May 30. Pubmed Adli M, Hollinde DL, Stamm T, Wiethoff K, Tsahuridu M, Kirchheiner J, Heinz A, Bauer M: Response to Lithium Augmentation in Depression is Associated with the Glycogen Synthase Kinase 3-Beta -50T/C Single Nucleotide Polymorphism. Biol Psychiatry. 2007 Jul 10;. Pubmed O’Brien WT, Klein PS: Validating GSK3 as an in vivo target of lithium action. Biochem Soc Trans. 2009 Oct;37(Pt 5):1133-8. Pubmed 2. Inositol polyphosphate 1-phosphatase Pharmacological action: unknown Actions: inhibitor 1D-myo-inositol 1,4-bisphosphate + H(2)O = 1D- myo-inositol 4-phosphate + phosphate Organism class: human UniProt ID: P49441 Gene: INPP1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed Li Z, Stieglitz KA, Shrout AL, Wei Y, Weis RM, Stec B, Roberts MF: Mobile loop mutations in an archaeal inositol monophosphatase: modulating three-metal ion assisted catalysis and lithium inhibition. Protein Sci. 2010 Feb;19(2):309-18. Pubmed 3. Inositol monophosphatase Pharmacological action: unknown Actions: inhibitor Responsible for the provision of inositol required for synthesis of phosphatidylinositol and polyphosphoinositides and has been implicated as the pharmacological target for lithium action in brain Organism class: human UniProt ID: P29218 Gene: IMPA1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Sarkar S, Rubinsztein DC: Inositol and IP3 levels regulate autophagy: biology and therapeutic speculations. Autophagy. 2006 Apr-Jun;2(2):132-4. Epub 2006 Apr 6. Pubmed Trinquet E, Fink M, Bazin H, Grillet F, Maurin F, Bourrier E, Ansanay H, Leroy C, Michaud A, Durroux T, Maurel D, Malhaire F, Goudet C, Pin JP, Naval M, Hernout O, Chretien F, Chapleur Y, Mathis G: D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Anal Biochem. 2006 Nov 1;358(1):126-35. Epub 2006 Aug 30. Pubmed Ohnishi T, Ohba H, Seo KC, Im J, Sato Y, Iwayama Y, Furuichi T, Chung SK, Yoshikawa T: Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1. J Biol Chem. 2007 Jan 5;282(1):637-46. Epub 2006 Oct 26. Pubmed Tanizawa Y, Kuhara A, Inada H, Kodama E, Mizuno T, Mori I: Inositol monophosphatase regulates localization of synaptic components and behavior in the mature nervous system of C. elegans. Genes Dev. 2006 Dec 1;20(23):3296-310. Pubmed Ohnishi T, Yamada K, Ohba H, Iwayama Y, Toyota T, Hattori E, Inada T, Kunugi H, Tatsumi M, Ozaki N, Iwata N, Sakamoto K, Iijima Y, Iwata Y, Tsuchiya KJ, Sugihara G, Nanko S, Osumi N, Detera-Wadleigh SD, Kato T, Yoshikawa T: A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription. Neuropsychopharmacology. 2007 Aug;32(8):1727-37. Epub 2007 Jan 24. Pubmed 4. Inositol monophosphatase 2 Pharmacological action: unknown Actions: inhibitor Myo-inositol phosphate + H(2)O = myo-inositol + phosphate Organism class: human UniProt ID: O14732 Gene: IMPA2 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Cryns K, Shamir A, Shapiro J, Daneels G, Goris I, Van Craenendonck H, Straetemans R, Belmaker RH, Agam G, Moechars D, Steckler T: Lack of lithium-like behavioral and molecular effects in IMPA2 knockout mice. Neuropsychopharmacology. 2007 Apr;32(4):881-91. Epub 2006 Jul 12. Pubmed Ohnishi T, Ohba H, Seo KC, Im J, Sato Y, Iwayama Y, Furuichi T, Chung SK, Yoshikawa T: Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1. J Biol Chem. 2007 Jan 5;282(1):637-46. Epub 2006 Oct 26. Pubmed Ohnishi T, Yamada K, Ohba H, Iwayama Y, Toyota T, Hattori E, Inada T, Kunugi H, Tatsumi M, Ozaki N, Iwata N, Sakamoto K, Iijima Y, Iwata Y, Tsuchiya KJ, Sugihara G, Nanko S, Osumi N, Detera-Wadleigh SD, Kato T, Yoshikawa T: A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription. Neuropsychopharmacology. 2007 Aug;32(8):1727-37. Epub 2007 Jan 24. Pubmed 5. Glutamate receptor 3 Pharmacological action: unknown Actions: potentiator Receptor for glutamate. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of GLU are mediated by a variety of receptors that are named according to their selective agonists Organism class: human UniProt ID: P42263 Gene: GRIA3 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Karkanias NB, Papke RL: Lithium modulates desensitization of the glutamate receptor subtype gluR3 in Xenopus oocytes. Neurosci Lett. 1999 Dec 31;277(3):153-6. Pubmed

Targets

1. Glycogen synthase kinase-3 beta

Pharmacological action: unknown
Actions: inhibitor

Participates in the Wnt signaling pathway. Implicated in the hormonal control of several regulatory proteins including glycogen synthase, MYB and the transcription factor JUN. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA

Organism class: human
UniProt ID: P49841 Link_out

Gene: GSK3B Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Borsotto M, Cavarec L, Bouillot M, Romey G, Macciardi F, Delaye A, Nasroune M, Bastucci M, Sambucy JL, Luan JJ, Charpagne A, Jouet V, Leger R, Lazdunski M, Cohen D, Chumakov I: PP2A-Bgamma subunit and KCNQ2 K+ channels in bipolar disorder. Pharmacogenomics J. 2007 Apr;7(2):123-32. Epub 2006 May 30. Pubmed
Adli M, Hollinde DL, Stamm T, Wiethoff K, Tsahuridu M, Kirchheiner J, Heinz A, Bauer M: Response to Lithium Augmentation in Depression is Associated with the Glycogen Synthase Kinase 3-Beta -50T/C Single Nucleotide Polymorphism. Biol Psychiatry. 2007 Jul 10;. Pubmed
O’Brien WT, Klein PS: Validating GSK3 as an in vivo target of lithium action. Biochem Soc Trans. 2009 Oct;37(Pt 5):1133-8. Pubmed

2. Inositol polyphosphate 1-phosphatase

Pharmacological action: unknown
Actions: inhibitor

1D-myo-inositol 1,4-bisphosphate + H(2)O = 1D- myo-inositol 4-phosphate + phosphate

Organism class: human
UniProt ID: P49441 Link_out

Gene: INPP1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Li Z, Stieglitz KA, Shrout AL, Wei Y, Weis RM, Stec B, Roberts MF: Mobile loop mutations in an archaeal inositol monophosphatase: modulating three-metal ion assisted catalysis and lithium inhibition. Protein Sci. 2010 Feb;19(2):309-18. Pubmed

3. Inositol monophosphatase

Pharmacological action: unknown
Actions: inhibitor

Responsible for the provision of inositol required for synthesis of phosphatidylinositol and polyphosphoinositides and has been implicated as the pharmacological target for lithium action in brain

Organism class: human
UniProt ID: P29218 Link_out

Gene: IMPA1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Sarkar S, Rubinsztein DC: Inositol and IP3 levels regulate autophagy: biology and therapeutic speculations. Autophagy. 2006 Apr-Jun;2(2):132-4. Epub 2006 Apr 6. Pubmed
Trinquet E, Fink M, Bazin H, Grillet F, Maurin F, Bourrier E, Ansanay H, Leroy C, Michaud A, Durroux T, Maurel D, Malhaire F, Goudet C, Pin JP, Naval M, Hernout O, Chretien F, Chapleur Y, Mathis G: D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Anal Biochem. 2006 Nov 1;358(1):126-35. Epub 2006 Aug 30. Pubmed
Ohnishi T, Ohba H, Seo KC, Im J, Sato Y, Iwayama Y, Furuichi T, Chung SK, Yoshikawa T: Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1. J Biol Chem. 2007 Jan 5;282(1):637-46. Epub 2006 Oct 26. Pubmed
Tanizawa Y, Kuhara A, Inada H, Kodama E, Mizuno T, Mori I: Inositol monophosphatase regulates localization of synaptic components and behavior in the mature nervous system of C. elegans. Genes Dev. 2006 Dec 1;20(23):3296-310. Pubmed
Ohnishi T, Yamada K, Ohba H, Iwayama Y, Toyota T, Hattori E, Inada T, Kunugi H, Tatsumi M, Ozaki N, Iwata N, Sakamoto K, Iijima Y, Iwata Y, Tsuchiya KJ, Sugihara G, Nanko S, Osumi N, Detera-Wadleigh SD, Kato T, Yoshikawa T: A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription. Neuropsychopharmacology. 2007 Aug;32(8):1727-37. Epub 2007 Jan 24. Pubmed

4. Inositol monophosphatase 2

Pharmacological action: unknown
Actions: inhibitor

Myo-inositol phosphate + H(2)O = myo-inositol + phosphate

Organism class: human
UniProt ID: O14732 Link_out

Gene: IMPA2 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Cryns K, Shamir A, Shapiro J, Daneels G, Goris I, Van Craenendonck H, Straetemans R, Belmaker RH, Agam G, Moechars D, Steckler T: Lack of lithium-like behavioral and molecular effects in IMPA2 knockout mice. Neuropsychopharmacology. 2007 Apr;32(4):881-91. Epub 2006 Jul 12. Pubmed
Ohnishi T, Ohba H, Seo KC, Im J, Sato Y, Iwayama Y, Furuichi T, Chung SK, Yoshikawa T: Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1. J Biol Chem. 2007 Jan 5;282(1):637-46. Epub 2006 Oct 26. Pubmed
Ohnishi T, Yamada K, Ohba H, Iwayama Y, Toyota T, Hattori E, Inada T, Kunugi H, Tatsumi M, Ozaki N, Iwata N, Sakamoto K, Iijima Y, Iwata Y, Tsuchiya KJ, Sugihara G, Nanko S, Osumi N, Detera-Wadleigh SD, Kato T, Yoshikawa T: A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription. Neuropsychopharmacology. 2007 Aug;32(8):1727-37. Epub 2007 Jan 24. Pubmed

5. Glutamate receptor 3

Pharmacological action: unknown
Actions: potentiator

Receptor for glutamate. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of GLU are mediated by a variety of receptors that are named according to their selective agonists

Organism class: human
UniProt ID: P42263 Link_out

Gene: GRIA3 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Karkanias NB, Papke RL: Lithium modulates desensitization of the glutamate receptor subtype gluR3 in Xenopus oocytes. Neurosci Lett. 1999 Dec 31;277(3):153-6. Pubmed

Comments

Drug created on July 06, 2007 13:50 / Updated on January 13, 2011 13:19

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.