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Lithium derives its name from lithos, the Greek word for stone, conferred to the element on its discovery in 1817 by the Swedish chemistry student Arfwedson. Lithium is a metal with no charge; lithium salts that are used therapeutically are monovalent cations. By the mid 19th century, lithium salts were used therapeutically for the treatment of gout, as well as mania and depression. The soft drink 7-Up originally contained lithium as its “active ingredient,” and during the 1930s and 1940s, it was used as a salt substitute (“Westal”) for patients with congestive heart failure until several cases of ­poisoning led to its discontinuation.7,17,61 In 1949, Cade “rediscovered” the calming effects of lithium by initially injecting a combination of lithium carbonate and urea (believed a source of mania) into normally “frenetic” guinea pigs and noting the resulting sedation. He subsequently tested it on 10 patients with mania.46,59 In 1954, Mogens Schou performed a randomized placebo controlled trial of lithium for mania, with promising results.59,204 However, for 20 years, until reapproved in 1974, lithium was banned by the US Food and Drug Administration in response to multiple reports of toxicity.7,59

Lithium is considered the most effective long-term therapy for treatment and prevention of relapse of bipolar affective disorders.58,80,86,97,207,212 It has a demonstrated antisuicidal effect57 and the ability to improve both the manic and the depressive symptoms, as well as augment the therapeutic efficacy of other approaches that have failed to achieve symptom remission.17,51,60,86,92,97,130,135,142,159 Lithium is also effective for compulsive gambling112,178 and has shown promise for use in neurodegenerative disorders such as Alzheimer disease, ischemic stroke, amyotrophic lateral sclerosis, Huntington disease, multiple sclerosis, and traumatic brain injury.53,139,152,172,202,240,241


Lithium is the chemically simplest xenobiotic in the modern pharmacopeia. It has a complex mechanism of action that eludes complete explication after more than 50 years of clinical use and study. The exploration of the mechanism of action of lithium is tied to the understanding of the physiology of mood disorders. In the classic model of psychopharmacology, xenobiotics exert their effects through interaction with monoamine neurotransmission, primarily dopamine, norepinephrine, and serotonin, in addition to their ­secondary signaling systems, primarily G protein–coupled receptors.28 Clinically, the therapeutic effects of lithium and similar mood-stabilizing pharmaceuticals become evident only after chronic administration, so their mechanism of action is unlikely solely the result of acute biochemical interactions.

One of the central processes involved in the pathogenesis of mood disorders and schizophrenia, as well as ...

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