Lithium: a Molecular Transducer of Mood-Stabilization in the Treatment of Bipolar Disorder
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INTRODUCTION Lithium: A Molecular Transducer of Mood-Stabilization in the Treatment of Bipolar Disorder Lithium is an element discovered over 175 years ago treatments (Goodwin and Jamison 1990; Schou 1991), (1817), and over the ensuing period of time, it has been the biochemical basis for lithium’s antimanic and utilized in various formulations as a remedy for a mul- mood-stabilizing actions remains to be fully elucidated titude of maladies afflicting the human body (Johnson (Lenox and Manji 1995; Manji et al. 1995). Elucidation of 1984); however, it was not until its serendipitous redis- the mechanism(s) by which lithium stabilizes an under- covery and the seminal work of Australian physician/ lying dysregulation of limbic and limbic-associated scientist, John Cade, 45 years ago, and subsequent clini- function also offers the potential to delineate the under- cal studies by Mogens Schou in the early 1950s, that lying etiology/pathophysiology of BD (Lenox et al. lithium was seen by modern psychiatry as an effective 1987; Manji et al. 1995). The recognition of the signifi- antimanic treatment and a prophylactic therapy for cant morbidity and mortality of the severe mood disor- manic-depressive illness (bipolar affective disorder, ders, as well as the growing appreciation that a signifi- BD) (Cade 1949; Schou 1979). The discovery of lithium’s cant percentage of patients respond poorly to existing efficacy as a mood-stabilizing agent revolutionized the treatments has made the task of discovering new thera- treatment of patients with BD—indeed, it is likely that peutic agents that work quickly, potently, specifically, the remarkable efficacy of lithium has, in fact, served to and with few side effects increasingly more important. spark a revolution that has, over time, reshaped not Indeed, in a recent article discussing the major impact only medical and scientific, but also popular concepts this monovalent cation has had on psychiatry, Schou of severe mental illnesses. After nearly three decades of (1997) expressed his disappointment that we have yet use in North America, lithium continues to be the main- to elucidate fully the mechanisms by which lithium ex- stay of treatment for this disorder, both for the acute erts its therapeutic effects. However, there has been tre- manic phase and as prophylaxis for recurrent manic mendous recent progress not only in the identification and depressive episodes (Goodwin and Jamison 1990; of signal transduction pathways as biochemical targets Lenox and Manji 1995). Adequate lithium treatment, par- of lithium’s actions, but also in characterizing dimen- ticularly in the context of a lithium clinic, is also reported sional features of BD that may confer differential treat- to reduce the excessive mortality observed in the illness ment responsiveness. This issue of Neuropsychopharma- (Baldessarini and Tondo 1997; Muller-Oerlinghausen et cology, for which Husseini K. Manji, M.D., and Robert al. 1992; Vestergaard and Aagaard 1991), and it has H. Lenox, M.D. serve as guest editors, pays tribute to been estimated that in most industrialized countries, the seminal the work of John Cade, which has had a 0.1% of the population is undergoing lithium treatment truly remarkable impact on the lives of millions (Schou 1991). The effect on the broader community is throughout the world. The following peer-reviewed pa- highlighted by one estimation that the use of lithium pers represent the thoughtful insights of some of the saved the United States $4 billion in the period 1969– leading preclinical and clinical researchers brought to- 1979 by reducing associated medical costs and restoring gether at the CINP meeting in Melbourne, Australia to productivity (Reifman and Wyatt 1980). However, de- provide a series of presentations focusing upon the cur- spite its role as one of psychiatry’s most important rent conceptualization about the neurobiology of BD NEUROPSYCHOPHARMACOLOGY 1998–VOL. 19, NO. 3 © 1998 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/98/$19.00 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(98)00021-9 162 H.K. Manji and R.H. Lenox NEUROPSYCHOPHARMACOLOGY 1998–VOL. 19, NO. 3 and the clinical and biochemical effects of mood-stabi- nia. These classifications will likely lead not only to im- lizing agents. proved research studies of more homogeneous popula- The clinical chapters are state-of-the-art discussions tions of BD patients, but may also serve to improve of key issues in the field. The first two papers provide overall individualized treatment delivery, in particular, apparently differing perspectives for a very fundamen- further defining the use of lithium and anticonvulsants tal research and treatment question—the specificity of in the treatment of BD. lithium’s effects in BD. The possibility that antiepileptic drugs might have Soares and Gershon present a compelling argument efficacy in bipolar disorder has encouraged early clini- that lithium shows a specificity for bipolar disorder— cal studies with several newer antiepileptic drugs—in an idea that was, in fact, proposed in Cade’s original his paper, Bowden presents data supporting the effec- 1949 work. They review the many controlled studies tiveness of valproate and lamotrigine. He reaffirms the that have been carried out, examining lithium for treat- data that the spectrum of efficacy of valproate may be ment of bipolar disorder and other psychiatric condi- somewhat broader than that of lithium, and further pre- tions. The authors conclude that the data analyzed give sents data from a study suggesting that pretreatment strong support for lithium being most effective for bi- plasma GABA is positively correlated with magnitude polar disorder, with minimal or no therapeutic effects of improvement in manic symptomatology with val- in other neuropsychiatric disorders. Such findings proate. Although the source and significance of plasma clearly have major implications for the field, because GABA remains to be fully elucidated, these findings de- they may lead to meaningful contributions to under- serve to be replicated in our efforts to search for a biolog- standing the pathophysiology of bipolar disorder and ical marker predictive of treatment response. In addition, help to develop newer treatments for this condition. Bowden comprehensively reviews the emergence of In his paper, Grof suggests that lithium treatment, valproate as a powerful lithium alternative, and/or ad- initially considered specific for bipolar disorder, has junct, and further reviews the preliminary, but intrigu- later been shown to provide additional benefits in affec- ing indications that lamotrigine may offer promise as tive and other disorders. He further states that a variety an even more effective treatment for the depressive of benefits should be taken into account when interpret- phases of bipolar illness. ing recently reported lower efficacy during lithium pro- Johnson, in his erudite paper, discusses an issue that phylaxis, as well as early relapses and loss of efficacy has sometimes led to rejection of lithium on safety after lithium discontinuation. He provides a compelling grounds—lithium’s potential adverse effects on renal argument that other factors, such as the accumulation function. He provides a fascinating historical overview of atypical, treatment-resistant patients in academic regarding lithium’s development in the treatment of centers and in particular the broadening of diagnoses of mania, outlining the way in which the report of the ef- affective disorders must be considered and that these fectiveness of lithium in the treatment of mania by John factors have complicated the interpretation of the recent Cade (1949) was followed by a number of studies con- reports. There seems to be little question, however, that firming his observations and developing guidelines for lithium continues to work well for patients with typical safe and effective use. He discusses the “safety alarms” bipolar disorders for whom it was originally proved ef- that were triggered by reports of kidney damage in the fective. The author has addressed an important issue re- late 1970s. Although at one time it was widely feared lating to evaluating the specificity of any treatment mo- that lithium treatment might lead to a decrease in the dality when clinical practice extends its use to other glomerular filtration rate, systematically collected data disorders for which there is variable therapeutic efficacy. indicate that even long-term treatment does not induce Dunner addresses an increasingly appreciated clini- renal insufficiency. In fact, it now seems clear that pro- cal question in the long-term study and treatment of gressive impairment of glomerular and tubular func- BD—the potential role of rapid cycling as a modifier of tion in patients during lithium maintenance is the ex- the course of the illness. Originally defined as four or ception rather than the rule and that it is related more to more affective episodes per year by Dunner and Fieve lithium intoxication, maintenance plasma lithium lev- in 1974, rapid-cycling BD has now become recognized els, concurrent medications, somatic illness, and age as having major implications for the choice of treat- than the duration of lithium treatment. Johnson con- ment. As such, there is a growing consensus that rapid cludes his paper by outlining practical guidelines for cycling be included as a course modifier to bipolar dis- lithium use and monitoring of renal function. orders in the DSM-IV. Dunner reviews the process for Post and associates present an integrated preclinical/ inclusion of rapid cycling as a course modifier to bipo- clinical overview for the neurobiology of BD and its lar disorders in DSM-IV; this process has involved de- treatment under different illness stages by combination fining bipolar II disorder, delineating the duration of treatments, in particular with anticonvulsants. This re- manic episode for bipolar I disorder, and clarification of search group has been instrumental in outlining molec- the diagnosis of cyclothymic disorder and mixed ma- ular mechanisms involved in the evolution of amygdala NEUROPSYCHOPHARMACOLOGY 1998–VOL.