Lithium is an element discovered over 175 years ago (1817), and over the ensuing period of time, it has been utilized in various formulations as a remedy for a multitude of maladies afflicting the human body (Johnson 1984); however, it was not until its serendipitous rediscovery and the seminal work of Australian physician/scientist, John Cade, 45 years ago, and subsequent clinical studies by Mogens Schou in the early 1950s, that lithium was seen by modern psychiatry as an effective antimanic treatment and a prophylactic therapy for manic-depressive illness (bipolar affective disorder, BD) (Cade 1949; Schou 1979). The discovery of lithium's efficacy as a mood-stabilizing agent revolutionized the treatment of patients with BD—indeed, it is likely that the remarkable efficacy of lithium has, in fact, served to spark a revolution that has, over time, reshaped not only medical and scientific, but also popular concepts of severe mental illnesses. After nearly three decades of use in North America, lithium continues to be the mainstay of treatment for this disorder, both for the acute manic phase and as prophylaxis for recurrent manic and depressive episodes (Goodwin and Jamison 1990; Lenox and Manji 1995). Adequate lithium treatment, particularly in the context of a lithium clinic, is also reported to reduce the excessive mortality observed in the illness (Baldessarini and Tondo 1997; Muller-Oerlinghausen et al. 1992; Vestergaard and Aagaard 1991), and it has been estimated that in most industrialized countries, 0.1% of the population is undergoing lithium treatment (Schou 1991). The effect on the broader community is highlighted by one estimation that the use of lithium saved the United States $4 billion in the period 1969–1979 by reducing associated medical costs and restoring productivity (Reifman and Wyatt 1980). However, despite its role as one of psychiatry's most important treatments (Goodwin and Jamison 1990; Schou 1991), the biochemical basis for lithium's antimanic and mood-stabilizing actions remains to be fully elucidated (Lenox and Manji 1995; Manji et al. 1995). Elucidation of the mechanism(s) by which lithium stabilizes an underlying dysregulation of limbic and limbic-associated function also offers the potential to delineate the underlying etiology/pathophysiology of BD (Lenox et al. 1987; Manji et al. 1995). The recognition of the significant morbidity and mortality of the severe mood disorders, as well as the growing appreciation that a significant percentage of patients respond poorly to existing treatments has made the task of discovering new therapeutic agents that work quickly, potently, specifically, and with few side effects increasingly more important. Indeed, in a recent article discussing the major impact this monovalent cation has had on psychiatry, Schou (1997) expressed his disappointment that we have yet to elucidate fully the mechanisms by which lithium exerts its therapeutic effects. However, there has been tremendous recent progress not only in the identification of signal transduction pathways as biochemical targets of lithium's actions, but also in characterizing dimensional features of BD that may confer differential treatment responsiveness. This issue of Neuropsychopharmacology, for which Husseini K. Manji, M.D., and Robert H. Lenox, M.D. serve as guest editors, pays tribute to the seminal the work of John Cade, which has had a truly remarkable impact on the lives of millions throughout the world. The following peer-reviewed papers represent the thoughtful insights of some of the leading preclinical and clinical researchers brought together at the CINP meeting in Melbourne, Australia to provide a series of presentations focusing upon the current conceptualization about the neurobiology of BD and the clinical and biochemical effects of mood-stabilizing agents.

The clinical chapters are state-of-the-art discussions of key issues in the field. The first two papers provide apparently differing perspectives for a very fundamental research and treatment question—the specificity of lithium's effects in BD.

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