Lithium is one of the most studied agents used to augment the pharmacologic effect of antidepressant drugs, particularly in refractory depression. We reviewed 22 case reports, 22 open trials, 5 open comparison studies, and 9 placebo-controlled studies of lithium augmentation and 6 studies in which antidepressants were added to, or coadministrated with, lithium. The efficacy of the augmentation therapeutic strategy is supported by these analyses, involving 969 patients. The optimal dose and the most effective blood levels of lithium are unclear, but a reasonable strategy would be to start with low doses (600-900 mg/day) and, if necessary, to increase the doses to obtain a level in accordance with the usual therapeutic range of blood levels (0.8-1.2 mEq/L). Some patients respond quickly, but others need a long and combined treatment; it is thus advantageous to prescribe lithium for at least 3 to 6 weeks. Despite the fact that the mechanism of action of lithium augmentation is still unknown, all refractory depressed patients can potentially be treated by lithium augmentation, particularly bipolar patients, to obtain full prophylactic effect as soon as possible.