Review article
Lithium: Bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium

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Abstract

Bipolar illness is a major psychiatric disorder that affects 1–3% of the worldwide population. Epidemiological studies have demonstrated that this illness is substantially heritable. However, the genetic characteristics remain unknown and a clear personality has not been identified for these patients. The clinical history of lithium began in mid-19th century when it was used to treat gout. In 1940, it was used as a substitute for sodium chloride in hypertensive patients. However, it was then banned, as it had major side effects. In 1949, Cade reported that lithium could be used as an effective treatment for bipolar disorder and subsequent studies confirmed this effect. Over the years, different authors have proposed many biochemical and biological effects of lithium in the brain. In this review, the main mechanisms of lithium action are summarised, including ion dysregulation; effects on neurotransmitter signalling; the interaction of lithium with the adenylyl cyclase system; inositol phosphate and protein kinase C signalling; and possible effects on arachidonic acid metabolism. However, none of the above mechanisms are definitive, and sometimes results have been contradictory. Recent advances in cellular and molecular biology have reported that lithium may represent an effective therapeutic strategy for treating neurodegenerative disorders like Alzheimer's disease, due to its effects on neuroprotective proteins like Bcl-2 and its actions on regulators of apoptosis and cellular resilience, such as GSK-3. However, results are contradictory and more specific studies into the use of lithium in therapeutic approaches for neurodegenerative diseases are required.

Introduction

Bipolar illness is a major psychiatric disorder that manifests itself commonly as episodes of mania and depression separated by periods of normal behaviour or euthymia. Falret categorised bipolar disorder as an illness in 1851. He described it as “folie circulaire” (circular madness), defined by manic and sad episodes separated by symptom-free intervals. In 1854, Baillarger used the term “folie à double forme” to describe cyclic (manic–melancholic) episodes. In both French diagnoses the prognosis was considered to be “desperate, terrible and incurable”. At the turn of the 19th century, Kraepelin's unifying approach to the classification of mood disorders resulted in bipolar disorders being grouped with manic-depressive insanity. This was a broad group that included single-episode and recurrent depression. As a consequence of the Kraepelin unification of affective disorders, research frequently failed to distinguish between depression, mania and bipolar disorder. However, other authors disagreed with the unified approach of Kraepelin. Instead, they maintained the distinction between mania, depression and bipolar disorder. The data on bipolar disorder collected in the 19th century and the first half of the 20th century before the introduction of modern antidepressants and mood stabilizers is of special value because it represents the natural history of the untreated disorder (Angst and Sellaro, 2000).

The current significance of bipolar disorders can be shown by some figures from the National Depressive and Manic-Depressive Association (National DMDA). This association focuses on the diagnosis and treatment of bipolar disorder. Nearly 5000 people call National DMDA's information line every month. In addition, its website receives a quarter of a million hits monthly (Lewis, 2000).

Bipolar disorder affects approximately 1–3% of the worldwide population. It is the sixth leading cause of disability in the U.S. At the present time, bipolar disorder affects 2.3 million American adults annually, costing the U.S. economy more than 44 billion dollars a year and less than 50% of people with bipolar disease are successfully treated (Lewis, 2000).

In studies carried out to date, no clear personality of patients with bipolar disorders has been identified. In some cases, bipolar patients seem more unstable and adventurous than other people. However, this is only one hypothesis of the specific personal characteristics. Evidence indicates that the first manic-depressive episode frequently occurs in a stressful period. However, other studies have demonstrated that there is no relation between the illness and the social and professional life of the person. Furthermore, it appears that sleep alterations can be induced by bipolar illness episodes (Frank et al., 2000, Hlastala et al., 2000).

Determining the age at onset of bipolar disorder is to a certain extent unreliable, as it is usually retrospective and dependent on recall (Angst, 1988). Different studies indicated a mean age of from 28 to 33 years (Angst and Sellaro, 2000). Other clinical studies show that bipolar symptoms frequently start in adolescence (Weissman et al., 1988) and that manic episodes usually manifest in the early 20s (Fogarty et al., 1994); affect women and men equally (in men, bipolar disorder frequently begins with a manic phase, while in women it usually starts with a depressive phase); and include all ethnic origin and social classes.

Section snippets

Genetic characteristics of bipolar disorder

Epidemiological studies have demonstrated that bipolar disorder is substantially heritable. Concordance of bipolar disorder for monozygotic twins is between 40 and 80% and from 10 to 20% for dizygotic twins. This difference suggests that the disorder has a genetic component (Plomin et al., 1997). Family studies using currently accepted diagnostic criteria have repeatedly demonstrated a 10- to 20-fold increase in the risk of bipolar illness among first-degree relatives of index cases, when

Brief history of lithium

Lithium was discovered by Arfwedson, a Swedish student of Chemistry in 1817. The new element was named lithium because it was discovered in a stone and the Greek word for stone is “lithos”.

Lithium is the lightest of the solid elements. It has an atomic weight of 6.94 D. The element has no known vital function in man or animals. However, it competes with different cations that are very abundant in the body, such as sodium, potassium, calcium and magnesium. The clinical history of lithium began

Therapeutic effects of lithium

Currently, lithium is the classic mood stabilizer and it was the first drug approved by the Food and Drug Administration (FDA) in 1974 for maintenance treatment of bipolar disorder (Pies, 2002). Curiously, in the 5th century AD, a Roman physician, Caelius Aurelianus, recommended the use of alkaline waters for some patients with mental disorders. These waters were probably rich in lithium salts (Kline, 1970).

In the last 50 years, the efficacy of lithium in the prophylaxis of bipolar depression

Main proposed mechanisms of lithium action for bipolar disorder

Studies over the years have proposed many biochemical and biological effects of lithium in the brain. Such research has paralleled advances in neuroscience and in experimental strategies developed during the last half-century. The interpretation of data has mainly been limited by experimental design and by the highly toxic concentrations used in the experiments.

Many theories on the mechanism of lithium action have been proposed; from alterations in ionic transport to modulation of genetic

Neuroprotective effects of lithium

In addition to the well-documented mood-stabilizing effects of lithium in manic-depressive illness patients, recent in vivo and in vitro studies have increasingly implicated that lithium as a neuroprotective agent efficacious in preventing apoptosis-dependent cellular death. Lithium neuroprotection is provided through multiple intersecting mechanisms and can be used in the treatment of acute brain injuries such as ischemia and chronic neurodegenerative diseases such as Alzheimer's disease,

Conclusion

Bipolar illness is a major psychiatric disorder commonly manifested as episodes of mania and depression separated by periods of normal behaviour or euthymia. It affects approximately 1–3% of the world's population but no clear pattern has been identified among patients. Lithium is one of the most widely used and best characterized prophylactic treatments for bipolar disorder, even though its mechanism of action remains unknown. Several pathways have been plausibly implicated in the effects of

References (193)

  • ChenR.W. et al.

    Long term lithium treatment suppresses p53and Bax expression but increases bcl-2 expression

    J Biol Chem

    (1999)
  • De SarnoP. et al.

    Regulation of Akt and glycogen synthase kinase-3beta phosphorilation by sodium valproate and lithium

    Neuropharmacology

    (2002)
  • DickD.M. et al.

    Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetic Iniciative

    Am J Hum Genet

    (2003)
  • DrevetsW.C. et al.

    PET imaging of serotonin 1A receptor binding in depression

    Biol Psychiatry

    (1999)
  • El-MallakhR.S.

    Ion homeostasis and the mechanism of action of lithium

    Clin Neurosci Res

    (2004)
  • El-MallakhR.S. et al.

    The Na,K–ATPase hypothesis for bipolar illness

    Biol Psychiatry

    (1995)
  • EscamillaM.A. et al.

    Assessing the feasibility of linkage disequilibrium methods for mapping complex traits: an initial screen for bipolar disorder loci on chromosome 18

    Am J Hum Genet

    (1999)
  • FeytC. et al.

    Lithium chloride increases the production of amyloid-β peptide independently from its inhibition of glycogen synthase kinase 3

    J Biol Chem

    (2005)
  • FrankE. et al.

    Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder

    Biol Psychiatry

    (2000)
  • HarwoodA.J.

    Signal transduction and Dictyostelium development

    Protist

    (2001)
  • HarwoodA.J. et al.

    Search for a common mechanism of mood stabilizers

    Biochem Pharmacol

    (2003)
  • HokinL.E. et al.

    A novel action of lithium: stimulation of glutamate release and inositol 1,4,5 triphosphate accumulation via activation of the N-methyl d-aspartate receptor in monkey and mouse cerebral cortical slices

    Adv Enzyme Regul

    (1996)
  • LewisL.

    A consumer perspective concerning the diagnosis and treatment of bipolar disorder

    Biol Psychiatry

    (2000)
  • AdamsJ.M. et al.

    The Bcl-2 protein family: arbiters of cell survival

    Science

    (1998)
  • AgamG. et al.

    Myo-inositol-1-phosphate (MIP) synthase: a possible new target for antibipolar drugs

    Bipolar Disord

    (2002)
  • AmandA. et al.

    Effect of catecholamine depletion on lithium-induced long-term remission of bipolar disorder

    Biol Psychiatry

    (1999)
  • AngstJ.

    Clinical course of affective disorders

  • AtackJ.R.

    Inositol monophosphatase inhibitors—lithium mimetics?

    Med Res Rev

    (1997)
  • BaastrupP.C. et al.

    Lithium as a prophylactic agent: its effect against recurrent depressions and manic-depressive psychosis

    Arch Gen Psychiatry

    (1967)
  • BadnerJ.A. et al.

    Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia

    Mol Psychiatry

    (2002)
  • BaldessariniR.J. et al.

    Effects of lithium treatment and its discontinuation on suicidal behavior in bipolar manic-depressive disorders

    J Clin Psychiatry

    (1999)
  • BaumannP. et al.

    A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical pharmacokinetic, and pharmacogenetic investigation

    J Clin Psychopharmacol

    (1996)
  • BeaulieuJ.M. et al.

    Lithium antagonizes dopamine-dependent behaviours mediated by an AKT/glycogen synthase kinase 3 signaling cascade

    Proc Natl Acad Sci USA

    (2004)
  • BeaulieuJ.M. et al.

    Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency

    Proc Natl Acad Sci USA

    (2008)
  • BelmakerR.H.

    Bipolar disorder

    N Engl J Med

    (2004)
  • BosettiF. et al.

    Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E2 concentration in rat brain

    Mol Psychiatry

    (2002)
  • BrunelloN.

    Mood stabilizers: protecting the mood…protecting the brain

    J Affect Disord

    (2004)
  • BuschA.L. et al.

    Lithium increases bcl-2 expression in chick cochlear nucleus and protects against deafferentation-induced cell death

    Neuroscience

    (2006)
  • CadeJ.F.J.

    Lithium salts in the treatment of psychotic excitement

    Med J Aust

    (1949)
  • Chalecka-FranaszekE. et al.

    Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons

    Proc Natl Acad Sci USA.

    (1999)
  • ChangM.C. et al.

    Lithium decreases turnover of arachidonate in several brain phospholipids

    Neurosci Lett

    (1997)
  • ChenD.F. et al.

    Bcl-2 promotes regeneration of severed axons in mammalian CNS

    Nature

    (1997)
  • ChenG. et al.

    Enhancement of hippocampal neurogenesis by lithium

    J Neurochem.

    (2000)
  • ChenuF. et al.

    Potentiation of antidepressant-like activity with lithium: mechanism involved

    Curr Drug Targets

    (2006)
  • ChuangD.M.

    The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials

    Ann NY Acad Sci

    (2005)
  • ChuangD.M. et al.

    Neuroprotective effects of lithium in cultured cells and animal models of diseases

    Bipolar Disord

    (2002)
  • CorcoranA.C. et al.

    Lithium poisoning from the use of salt substitutes

    JAMA

    (1949)
  • CraddockN. et al.

    Single major locus models for bipolar disorder are implausible

    Am J Med Genet

    (1997)
  • CuffiM.L. et al.

    Effect of α2-adrenoceptor blockade on lithium action in the rat brain

    Brain Res

    (2003)
  • De FerrariG.V. et al.

    Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils

    Mol Psychiatry

    (2003)
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