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Molecular and cellular mechanisms underlying mood stabilization in bipolar disorder: implications for the development of improved therapeutics

Molecular Psychiatry volume 7, pages S1–S7 (2002)Cite this article

The concept of psychoses has evolved significantly ever since Kraepelin created the concepts of manic-depressive insanity and dementia praecox. Kraepelin recognized the importance of studying the course of illness by differentiating the major psychoses into three types—dementia praecox, manic-depressive illness, and paranoia.1 He referred to dementia praecox as an illness with a deteriorating course, in contrast to manic-depressive illness, which was episodic with full recovery between episodes, and described to have a good prognosis.1 However, more recent studies have clearly shown that although bipolar disorder has been regarded as a remitting disorder with a generally favorable long-term outcome, this may only represent the situation for a minority of subjects afflicted with these devastating illnesses; thus, a number of studies and analyses have now shown that for a large percentage of patients, outcome is quite poor, with high rates of relapse, chronicity, lingering residual symptoms, subsyndromes, cognitive and functional impairment, and psychosocial disability.2,3,4,5,6,7 Furthermore, suicide is estimated to be the cause of death in up to 15% of individuals with mood disorders, and in addition to suicide, many other deleterious health-related effects are increasingly being recognized.8,9,10,11,12 Indeed, there is a growing appreciation that, far from being diseases with purely psychological manifestations, mood disorders are systemic diseases with deleterious effects on multiple organ systems.8,9,10,11 For example, mood disorders represent a major risk factor for both the development of cardiovascular disease, as well as for death after an index myocardial infarction.8 Furthermore, a recent study which controlled for physical illness, smoking and alcohol consumption found that the magnitude of the increased mortality risk conferred by the presence of high depressive symptoms was similar to that of stroke and congestive heart failure.9 The costs associated with disability and premature death represent an economic burden of tens of billions of dollars annually in the United States alone. It is thus not altogether surprising that the Global Burden of Disease Study has identified mood disorders among the leading causes of disability worldwide, and as illnesses which are likely to represent an increasingly greater health, societal, and economic problem in the coming years.13

The discovery of lithium's efficacy as an antimanic agent approximately 50 years ago revolutionized the treatment of patients with bipolar disorder—indeed, it is likely that the remarkable efficacy of lithium has served to spark a revolution that has, over time, reshaped not only medical and scientific, but also popular concepts of severe mental illnesses. Perhaps the single most important finding about the efficacy of lithium that has influenced American psychiatry is the fact that lithium, given over long periods of time, reduces the frequency and severity of subsequent affective episodes in bipolar disorder patients. This recurrent pattern has been eloquently argued to be core to the illness and hence should be in the forefront of our framing questions about etiology and treatment.14 Mean episode frequency is about four episodes in 10 years, an important estimate for the design of clinical trials. Furthermore, it has been the efforts to understand how a monovalent cation like lithium can exert such profound beneficial effects which has led investigators to examine the potential role of signal transduction pathways in bipolar disorder (see below). After nearly 50 years, 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.15 Adequate lithium treatment, particularly in the context of a lithium clinic, is also reported to reduce the excessive mortality observed in the illness.16,17,18 However, despite its role as one of psychiatry's most important treatments, the cellular mechanism(s) by which this unique monovalent cation exerts its therapeutic effects remain to be fully elucidated. Furthermore, increasing evidence suggests that a significant number of patients do not respond adequately to lithium therapy, with recent reviews noting failure rates of lithium to be 50% or higher.19,20 Several studies have suggested that particularly low rates of responsiveness to lithium occur in mixed or dysphoric mania, rapid cycling, and substance abuse comorbidity.14,21

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  1. Laboratory of Molecular Pathophysiology, NIMH, Bethesda, MD, USA

    H K Manji & C A Zarate

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Correspondence to H K Manji.

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Manji, H., Zarate, C. Molecular and cellular mechanisms underlying mood stabilization in bipolar disorder: implications for the development of improved therapeutics. Mol Psychiatry 7 (Suppl 1), S1–S7 (2002). https://doi.org/10.1038/sj.mp.4001068

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