Progress in Neuro-Psychopharmacology and Biological Psychiatry
Review articleLithium: Bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium
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
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2019, Redox BiologyCitation Excerpt :As such, the GSK3β mediated Keap1-independent regulation of Nrf2 activity may be a actionable therapeutic target for hindering post-AKI CKD transition and for improving the long-term outcome of AKI. Among the many selective inhibitors of GSK3β, lithium is the first-generation inhibitor and has been safely used for over a half century as the FDA approved first line mood stabilizer for the treatment of bipolar affective disorders [44,46]. For basic science research, lithium has been commonly used as a standard blockade of GSK3β [71].