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The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis.
Bipolar Disord. 2009 Jun; 11 Suppl 2:92-109.BD

Abstract

Lithium has been and continues to be the mainstay of bipolar disorder (BD) pharmacotherapy for acute mood episodes, switch prevention, prophylactic treatment, and suicide prevention. Lithium is also the definitive proof-of-concept agent in BD, although it has recently been studied in other psychoses as well as diverse neurodegenerative disorders. Its neurotrophic effects can be viewed as a unifying model to explain several integrated aspects of the pathophysiology of mood disorders and putative therapeutics for those disorders. Enhancing neuroprotection (which directly involves neurotrophic effects) is a therapeutic strategy intended to slow or halt the progression of neuronal loss, thus producing long-term benefits by favorably influencing outcome and preventing either the onset of disease or clinical decline. The present article: (i) reviews what has been learned regarding lithium's neurotrophic effects since Cade's original studies with this compound; (ii) presents human data supporting the presence of cellular atrophy and death in BD as well as neurotrophic effects associated with lithium in human studies; (iii) describes key direct targets of lithium involved in these neurotrophic effects, including neurotrophins, glycogen synthase kinase 3 (GSK-3), and mitochondrial/endoplasmic reticulum key proteins; and (iv) discusses lithium's neurotrophic effects in models of apoptosis and excitotoxicity as well as its potential neurotrophic effects in models of neurological disorders. Taken together, the evidence reviewed here suggests that lithium's neurotrophic effects in BD are an example of an old molecule acting as a new proof-of-concept agent. Continued work to decipher lithium's molecular actions will likely lead to the development of not only improved therapeutics for BD, but to neurotrophic enhancers that could prove useful in the treatment of many other illnesses.

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Authors+Show Affiliations

Machado-Vieira R
Experimental Therapeutics, Mood and Anxiety Disorders Research Program, NIMH-NIH, Department of Health and Human Services, Bethesda, MD 20892, USA.
Manji HK
No affiliation info available
Zarate CA
No affiliation info available

MeSH

AnimalsAntidepressive AgentsApoptosisBipolar DisorderBrainGlycogen Synthase Kinase 3HumansLithium CompoundsNerve Growth FactorsNeuronsSuicide

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

19538689

Citation

Machado-Vieira, Rodrigo, et al. "The Role of Lithium in the Treatment of Bipolar Disorder: Convergent Evidence for Neurotrophic Effects as a Unifying Hypothesis." Bipolar Disorders, vol. 11 Suppl 2, 2009, pp. 92-109.
Machado-Vieira R, Manji HK, Zarate CA. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord. 2009;11 Suppl 2:92-109.
Machado-Vieira, R., Manji, H. K., & Zarate, C. A. (2009). The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disorders, 11 Suppl 2, 92-109. https://doi.org/10.1111/j.1399-5618.2009.00714.x
Machado-Vieira R, Manji HK, Zarate CA. The Role of Lithium in the Treatment of Bipolar Disorder: Convergent Evidence for Neurotrophic Effects as a Unifying Hypothesis. Bipolar Disord. 2009;11 Suppl 2:92-109. PubMed PMID: 19538689.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. AU - Machado-Vieira,Rodrigo, AU - Manji,Husseini K, AU - Zarate,Carlos A,Jr PY - 2009/6/23/entrez PY - 2009/6/23/pubmed PY - 2009/9/11/medline SP - 92 EP - 109 JF - Bipolar disorders JO - Bipolar Disord VL - 11 Suppl 2 N2 - Lithium has been and continues to be the mainstay of bipolar disorder (BD) pharmacotherapy for acute mood episodes, switch prevention, prophylactic treatment, and suicide prevention. Lithium is also the definitive proof-of-concept agent in BD, although it has recently been studied in other psychoses as well as diverse neurodegenerative disorders. Its neurotrophic effects can be viewed as a unifying model to explain several integrated aspects of the pathophysiology of mood disorders and putative therapeutics for those disorders. Enhancing neuroprotection (which directly involves neurotrophic effects) is a therapeutic strategy intended to slow or halt the progression of neuronal loss, thus producing long-term benefits by favorably influencing outcome and preventing either the onset of disease or clinical decline. The present article: (i) reviews what has been learned regarding lithium's neurotrophic effects since Cade's original studies with this compound; (ii) presents human data supporting the presence of cellular atrophy and death in BD as well as neurotrophic effects associated with lithium in human studies; (iii) describes key direct targets of lithium involved in these neurotrophic effects, including neurotrophins, glycogen synthase kinase 3 (GSK-3), and mitochondrial/endoplasmic reticulum key proteins; and (iv) discusses lithium's neurotrophic effects in models of apoptosis and excitotoxicity as well as its potential neurotrophic effects in models of neurological disorders. Taken together, the evidence reviewed here suggests that lithium's neurotrophic effects in BD are an example of an old molecule acting as a new proof-of-concept agent. Continued work to decipher lithium's molecular actions will likely lead to the development of not only improved therapeutics for BD, but to neurotrophic enhancers that could prove useful in the treatment of many other illnesses. SN - 1399-5618 UR - https://www.unboundmedicine.com/medline/citation/19538689/The_role_of_lithium_in_the_treatment_of_bipolar_disorder:_convergent_evidence_for_neurotrophic_effects_as_a_unifying_hypothesis_ L2 - https://doi.org/10.1111/j.1399-5618.2009.00714.x DB - PRIME DP - Unbound Medicine ER -