Lithium: Still a Cornerstone in the Long-Term Treatment in Bipolar Disorder?

<i>Background:</i> Scientific literature considers lithium a key treatment for the acute and long-term management of bipolar disorder (BD). Despite its worldwide clinical use, the effectiveness of lithium has been questioned. The aim of this work is to critically review the available data on randomized controlled trials (RCTs) concerning long-term lithium treatment. <i>Methods:</i> A systematic search for long-term treatment RCTs with at least 6 months of follow-up was performed. Six RCTs enrolling 1,561 bipolar I and II patients of adult and pediatric age, randomizing 534 to lithium, were identified. All studies are controlled trials sponsored by industry, investigating new treatments for BD, with lithium as an active comparator, and therefore not specifically designed to study lithium efficacy or safety. <i>Results:</i> Results from earliest studies suggest a high effectiveness of lithium against both mania and depression, while more recent studies highlight lithium as more effective than placebo in mania and hypomania, without significant evidence in depression. Lithium does not achieve significant differences in efficacy when compared with divalproex; it seems less effective than lamotrigine in preventing depression and less effective than olanzapine in manic and mixed episodes. <i>Conclusions:</i> Despite a number of methodological issues (enriched designs, unbalanced samples, potential inclusion of lithium nonresponders in some studies), lithium appears to have a clear antimanic prophylactic activity and some efficacy in the prevention of depression. Lithium should still have a major role in the long-term treatment of BD.