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Lithium is the most efficient long-term therapy for treatment and prevention of bipolar affective disorders,57,89,211 with a demonstrated antisuicidal effect and an ability to improve both the manic and depressive symptoms of the illness.15−17,51,59,86,87,145,192,212 Investigations on the use of lithium for compulsive gambling have also demonstrated beneficial results.99 In most industrialized nations, approximately one in 1000 persons is prescribed one or more of the various lithium formulations.8,187

The Swedish chemistry student Arfwedson discovered lithium in 1817.145 Lithium derives its name from the Greek word for stone, lithos, from which it was first isolated. Lithium has a long history of therapeutic use beginning in the mid 19th century, when lithium salts were used to treat individuals with gout. The therapy also improved symptoms of mania and depression.16,120,212 The soft drink 7-Up was originally formulated with lithium as its "active ingredient.5 During the 1930s and 1940s, lithium was used as a salt substitute ("Westsal") for patients with heart failure but was discontinued after several cases of acute lithium poisoning were described.61,68,92,188 The beneficial effects of lithium on bipolar disorder were "rediscovered" by Cade in 1949, when he noticed the calming effect of lithium carbonate on guinea pigs.48,49 The same year, however, the Food and Drug Administration (FDA) banned the use of lithium in response to reported poisonings.48,172,188 The FDA lifted the ban in 1970 and approved the use of lithium for the treatment of mania.

The simplicity of the lithium molecule belies the complexity of its mechanism of action. Although lithium has been used therapeutically for almost 50 years, the precise pharmacology of its therapeutic effects has not yet been fully elucidated.80 Part of the difficulty in defining the precise mechanism of lithium is the difficulty in defining the precise pathophysiology of bipolar disorder.192 Early efforts focused on dysfunctional neurotransmitter systems, particularly the role of biogenic amines. Lithium increases basal and stimulation-induced serotonin release and receptor sensitivity to serotonin.45,213 Lithium modulates the effect of norepinephrine through its interactions with the G-protein—mediated β-adrenergic receptor, stabilizing fluctuations in the intracellular pool of cyclic adenosine monophosphate (cAMP). It performs this function by inhibiting not only the inhibitory subunit Gi, which increases basal concentrations of cAMP but also the stimulatory subunit, Gs, preventing fluctuations from adrenergic stimulation.45

Clinically, the therapeutic effects of lithium and other mood-stabilizing pharmaceuticals become evident only after chronic administration, so their mechanism of action is likely not solely the result of acute biochemical interactions. Postulated mechanisms go beyond simple neurotransmitter function or dysfunction and focus on altered cellular signaling, neuronal plasticity, and neurogenesis. Rather than trying to identify any single neurotransmitter system as responsible for the complexity of depressive illness, efforts now are directed at elucidating the functional ...

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