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BackgroundIn a previous meta-analysis of randomized controlled trials comparing lithium with placebo as a long-term treatment in bipolar disorders, we observed a clear preventative effect for manic episodes; however, the effect was equivocal for depressive episodes. Since then, the evidence base has grown further. In this update, we furthermore present the data on efficacy of lithium in comparison to alternative drug treatments. In addition, we analyze the data comparing lithium with placebo and other treatments regarding drop-outs due to reasons other than a mood episode and completion of study (no mood episode and no drop-out to reasons other than a mood episode).MethodsRandomized controlled trials (RCTs) were sought comparing lithium with placebo and lithium with an alternative treatment in bipolar disorders where the stated intent of treatment was prevention of mood episodes. To this purpose, the Cochrane Central Register of Controlled Trials (CENTRAL) was searched. Reference lists of relevant papers and major textbooks of mood disorders were examined. Authors, other experts in the field, and pharmaceutical companies were contacted for knowledge of suitable trials, published or unpublished.ResultsFor the comparison of lithium with placebo, seven trials (1,580 participants) were included. Lithium was more effective than placebo in preventing overall mood episodes (random effects RR 0.66, 95% CI 0.53 to 0.82), manic episodes (random effects RR 0.52, 95% CI 0.38 to 0.71), and, dependent on the type of analyses applied, depressive episodes (random effects RR 0.78, 95% CI 0.59 to 1.03; fixed effect RR 0.73, 95% CI 0.60 to 0.88). Lithium was inferior to placebo in leading to drop-outs for reasons other than a mood episode (random effects RR 1.33, 95% CI 1.07 to 1.65) but superior to placebo on study completion (random effects RR 1.69, 95% CI 1.12 to 2.55).For the comparison of lithium with anticonvulsants, seven trials were included (n = 1,305). In prevention of manic episodes, lithium showed superiority compared to anticonvulsants (random effects RR 0.66, 95% CI 0.44 to 1.00). However, there was no significant difference regarding prevention of overall mood episodes, depressive episodes, dropping-out to reasons other than a mood episode, or study completion.ConclusionsThe evidence base for lithium in the long-term treatment of bipolar disorders has strengthened. With no other drug available having such ample and consistent evidence for its efficacy lithium remains the most valuable treatment option in this indication.

Bipolar disorder (BD) is a major mood disorder that is characterized by manic and depressive symptoms which fluctuate in severity and over time. The affective burden of the illness is compounded by cognitive, psychosocial, and occupational dysfunction, along with increased rates of suicide, medical comorbidity, and premature mortality. [1][2][3][4][5][6][7] Current guidelines for the management of BD include treatments that are limited by suboptimal efficacy rates, medication intolerance, delayed onset of action, iatrogenic mood switches, and variable patient acceptability. There is a pressing public health need for measures to combat these shortcomings. The fields of chronobiology and chronotherapy offer alternative treatment strategies which may address these limitations. The primary aim of this project was to systematically review efficacy and tolerability evidence of the major chronotherapies for BD and propose practice recommendations based on this review. This commences with a brief introduction to chronobiology to provide a rudimentary overview of the basic science which underlies this field of treatment. | Introduction to the circadian systemThe basic science of chronobiology is the study of biological rhythms, biological timekeeping systems, and their effects on human health and disease. 8 The human time-keeping system is a strongly conserved, phylogenetically ancient, hierarchically organized, and open neurobiological network. It evolved to enable organisms to anticipate and coordinate their internal physiology